record_id,pubmedID,title,authors,abstract,year,label_included,label_abstract_screening
1,10071708,Comparative efficacy of olanzapine and haloperidol for patients with treatment-resistant schizophrenia.,A Breier; S H Hamilton,"There is relatively little information regarding the efficacy of newer atypical antipsychotic drugs for patients with schizophrenia who are treatment-resistant to neuroleptic agents. Several lines of evidence suggest that a clinical trial of olanzapine in this population is warranted. A subpopulation of patients (n = 526) meeting treatment-resistant criteria selected from a large, prospective, double-blind, 6-week study assessing the efficacy and safety of olanzapine and haloperidol were examined. Both last-observation-carried-forward (LOCF) and completers (observed cases) analyses were conducted. Olanzapine demonstrated significantly greater mean improvement from baseline in Positive and Negative Syndrome Scale (PANSS) negative symptoms, comorbid depressive symptoms assessed by the Montgomery-Asberg Depression Rating Scale, akathisia as measured by Barnes Akathisia Scale, and extrapyramidal symptoms as measured by Simpson-Angus Extrapyramidal Rating Scale with both LOCF and completers analyses. In addition, olanzapine was significantly superior to haloperidol for Brief Psychiatric Rating Scale total (p = .006), PANSS total (p = .005), and PANSS positive symptoms (p = .017) in completers of the 6-week study. Significantly greater response rates were observed in olanzapine-treated (47%) than haloperidol-treated (35%) patients in the LOCF analysis (p = .008), but significance was not reached in the completers analysis (p = .093). Mean doses (+/- SD) of olanzapine and haloperidol were 11.1 +/- 3.4 mg/day and 10.0 +/- 3.6 mg/day, respectively. Olanzapine was superior to haloperidol for key symptom domains and parkinsonian side effects. Implications of these data for the therapeutics of this severely ill subgroup are discussed.",1999.0,1,1
2,10071726,A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia.,D C Goff; D C Henderson; A E Evins; E Amico,"D-Cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor, has previously been shown to improve negative symptoms when added to conventional antipsychotics and, in one preliminary dose-finding study, worsened negative symptoms when added to clozapine. Seventeen schizophrenia outpatients treated with clozapine were assigned in random order to 6-week trials of D-cycloserine 50 mg/day and placebo in a crossover design separated by a 1 week placebo washout. Eleven patients competed the 13-week study. D-Cycloserine significantly worsened ratings of negative symptoms compared to placebo but did not significantly affect ratings of psychotic symptoms. The differing effects of D-cycloserine on negative symptoms when added to clozapine compared to conventional antipsychotics suggests that activation of the glycine recognition site may play a role in clozapine's efficacy for negative symptoms.",1999.0,0,0
3,10072410,Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson's disease.,Parkinson Study Group,"Drug-induced psychosis is a difficult problem to manage in patients with Parkinson's disease. Multiple open-label studies have reported that treatment with clozapine at low doses ameliorates psychosis without worsening parkinsonism. We conducted a randomized, double-blind, placebo-controlled trial of low doses of clozapine (6.25 to 50 mg per day) in 60 patients at six sites over a period of 14 months. The patients (mean age, 72 years) had idiopathic Parkinson's disease and drug-induced psychosis of at least four weeks' duration. All the patients continued to receive fixed doses of antiparkinsonian drugs during the four weeks of the trial. Blood counts were monitored weekly in all the patients. The mean dose of clozapine was 24.7 mg per day. The patients in the clozapine group had significantly more improvement than those in the placebo group in all three of the measures used to determine the severity of psychosis. The mean (+/-SE) scores on the Clinical Global Impression Scale improved by 1.6+/-0.3 points for the patients receiving clozapine, as compared with 0.5+/-0.2 point for those receiving placebo (P<0.001). The score on the Brief Psychiatric Rating Scale improved by 9.3+/-1.5 points for the patients receiving clozapine, as compared with 2.6+/-1.3 points for those receiving placebo (P=0.002). The score on the Scale for the Assessment of Positive Symptoms improved by 11.8+/-2.0 points for the patients receiving clozapine, as compared with 3.8+/-1.9 points for those receiving placebo (P=0.01). Seven patients treated with clozapine had an improvement of at least three on the seven-point Clinical Global Impression Scale, as compared with only one patient given placebo. Clozapine treatment improved tremor and had no deleterious effect on the severity of parkinsonism. In one patient, clozapine was discontinued because of leukopenia. Clozapine, at daily doses of 50 mg or less, is safe and significantly improves drug-induced psychosis without worsening parkinsonism.",1999.0,0,1
4,10072418,Managing psychosis in patients with Parkinson's disease.,J L Cummings,,1999.0,0,0
5,10072664,Comparison of risperidone and mosapramine addition to neuroleptic treatment in chronic schizophrenia.,N Takahashi; T Terao; T Oga; M Okada,"There is little information regarding the effects of risperidone addition to neuroleptic treatment in chronic schizophrenia. As a preliminary study, 10 neuroleptic-treated schizophrenic inpatients received risperidone (high 5HT2A/D2 ratio, i.e. the ratio between 5HT2A and D2 receptor occupancy) and mosapramine (low 5HT2A/D2 ratio) in a randomized, single-blind, crossover, add-on study consisting of 8 weeks of treatment each with risperidone and mosapramine. Although both additions resulted in significant, albeit modest, improvement, there was no significant difference in the scores on the Positive and Negative Syndrome Scale for Schizophrenia between risperidone and mosapramine addition. These results suggest that risperidone and mosapramine bring about comparable effects in add-on design. Thus, risperidone with a high 5HT2A/D2 ratio does not seem to be better than mosapramine with a low 5HT2A/D2 ratio when combined with conventional neuroleptics. Further studies including a large number of patients and a double-blind design are needed.",2000.0,0,1
6,10077298,Errorless learning and the cognitive rehabilitation of memory-impaired schizophrenic patients.,R E O'Carroll; H H Russell; S M Lawrie; E C Johnstone,"In recent years, evidence has accumulated that a significant proportion of schizophrenic patients have severe memory impairment, which cannot be attributed to the effects of medication, chronicity or institutionalization. Our group has demonstrated that memory impairment is associated with poor psychosocial outcome and treatment resistance. Work on the classical amnesic syndrome has suggested that memory training is facilitated by adopting an 'errorless learning' approach, where subjects do not experience failure during learning. This is based on the theory that the preserved implicit memory of amnesic patients results in implicitly remembered incorrect responses interfering with target items, in the absence of a functioning explicit memory system to allow differentiation. We compared three groups of subjects, memory-impaired schizophrenic patients, memory unimpaired schizophrenic patients and healthy controls. An errorless learning approach conferred a significant advantage on the memory-impaired schizophrenic group, bringing their performance up to the level of both control groups. In contrast, adopting a traditional trial and error, or errorful approach resulted in markedly impaired performance in the memory-impaired schizophrenic group only. We conclude that errorless learning approaches may be worthy of further evaluation in the cognitive rehabilitation of memory-impaired schizophrenic patients.",1999.0,0,0
7,10078501,Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder.,D Robinson; M G Woerner; J M Alvir; R Bilder; R Goldman; S Geisler; A Koreen; B Sheitman; M Chakos; D Mayerhoff; J A Lieberman,"We examined relapse after response to a first episode of schizophrenia or schizoaffective disorder. Patients with first-episode schizophrenia were assessed on measures of psychopathologic variables, cognition, social functioning, and biological variables and treated according to a standardized algorithm. The sample for the relapse analyses consisted of 104 patients who responded to treatment of their index episode and were at risk for relapse. Five years after initial recovery, the cumulative first relapse rate was 81.9% (95% confidence interval [CI], 70.6%-93.2%); the second relapse rate was 78.0% (95% CI, 46.5%-100.0%). By 4 years after recovery from a second relapse, the cumulative third relapse rate was 86.2% (95% CI, 61.5%-100.0%). Discontinuing antipsychotic drug therapy increased the risk of relapse by almost 5 times (hazard ratio for an initial relapse, 4.89 [99% CI, 2.49-9.60]; hazard ratio for a second relapse, 4.57 [99% CI, 1.49-14.02]). Subsequent analyses controlling for antipsychotic drug use showed that patients with poor premorbid adaptation to school and premorbid social withdrawal relapsed earlier. Sex, diagnosis, obstetric complications, duration of psychotic illness before treatment, baseline symptoms, neuroendocrine measures, methylphenidate hydrochloride challenge response, neuropsychologic and magnetic resonance imaging measures, time to response of the initial episode, adverse effects during treatment, and presence of residual symptoms after the initial episode were not significantly related to time to relapse. There is a high rate of relapse within 5 years of recovery from a first episode of schizophrenia and schizoaffective disorder. This risk is diminished by maintenance antipsychotic drug treatment.",1999.0,0,1
8,10084637,"Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized, double-blind trial. Risperidone Study Group.",I R Katz; D V Jeste; J E Mintzer; C Clyde; J Napolitano; M Brecher,"We report the findings from the first large, double-blind, placebo-controlled study conducted to evaluate the efficacy and safety of risperidone in the treatment of psychotic and behavioral symptoms in institutionalized elderly patients with dementia. 625 patients (67.8% women; mean age = 82.7 years) with DSM-IV diagnoses of Alzheimer's disease (73%), vascular dementia (15%), or mixed dementia (12%) and significant psychotic and behavioral symptoms were included. Each patient was randomly assigned to receive placebo or 0.5 mg/day, 1 mg/day, or 2 mg/day of risperidone for 12 weeks. The primary outcome measure was the Behavioral Pathology in Alzheimer's Disease rating scale (BEHAVE-AD). The study was completed by 70% of the patients. Baseline Functional Assessment Staging scores were 6 or 7 in more than 95% of the patients, indicating severe dementia. At endpoint, significantly greater reductions in BEHAVE-AD total scores and psychosis and aggressiveness subscale scores were seen in patients receiving 1 and 2 mg/day of risperidone than in placebo patients (p = .005 and p < .001, respectively). At week 12, 0.5 mg/day of risperidone was superior to placebo in reducing BEHAVE-AD aggression scores (p = .02). More adverse events were reported by patients receiving 2 mg/day of risperidone than 1 mg/day. The most common dose-related adverse events were extrapyramidal symptoms, somnolence, and mild peripheral edema. The frequency of extrapyramidal symptoms in patients receiving 1 mg/day of risperidone was not significantly greater than in placebo patients. Risperidone significantly improved symptoms of psychosis and aggressive behavior in patients with severe dementia. Results show that 1 mg/day of risperidone is an appropriate dose for most elderly patients with dementia.",1999.0,1,1
9,10094133,No evidence for association of serotonin-2A receptor variant (102T/C) with schizophrenia or clozapine response in a Chinese population.,C H Lin; S J Tsai; Y W Yu; H L Song; P C Tu; C B Sim; C P Hsu; K H Yang; C J Hong,"The serotonin hypothesis in schizophrenia had regained interest with the superior efficacy of clozapine in the refractory schizophrenic patients. Among the serotonin receptors, the serotonin 2A (5HT2A) receptor subtype is the most widely studied. Previous studies on the association between a silent mutation polymorphism of the 5HT2A gene (102T/C) and schizophrenia or clozapine response have yielded conflicting findings. Therefore, we investigated whether these genetic variants of the 5HT2A receptor are associated with schizophrenia or with response to clozapine treatment in a Chinese population. Ninety-seven schizophrenic patients and 101 control subjects were included in the study. The receptor variants were found at similar frequencies in schizophrenic patients and healthy control subjects. Also, we did not find the variants to influence the response to clozapine in schizophrenic patients. We suggest that the assessment method of clozapine response and the ethnicity may influence the result.",1999.0,0,0
10,10100910,A combined analysis of double-blind studies with risperidone vs. placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms.,P Lemmens; M Brecher; B Van Baelen,"Combined data from double-blind risperidone studies were used to analyse the severity of extrapyramidal symptoms (EPS) associated with treatment in patients with chronic schizophrenia. Factors associated with maximum EPS severity were increasing risperidone dose (< or = 8 mg/day was similar to placebo), lower baseline EPS scores, and longer duration of psychotic symptoms, particularly in older patients. EPS severity was significantly greater in patients receiving haloperidol or other antipsychotics than in those receiving risperidone (4 to 8 mg/day) or placebo. Antiparkinsonian medications were required by significantly fewer patients treated with risperidone (4 to 8 mg/day) than by patients treated with haloperidol or other antipsychotics. Combined efficacy data showed that 4 to 8 mg/day was also the most efficacious dose range; there was no increase in efficacy with doses over 4 mg/day. Based on these data and post-marketing experience, 4 mg/day is an appropriate initial target dose for most patients with schizophrenia. Higher doses may be appropriate for patients with chronic illness, and lower doses may be appropriate for patients with a first psychotic episode or for elderly patients.",1999.0,0,1
11,10155617,Measuring the costs of schizophrenia. Implications for the post-institutional era in the US.,K G Terkelsen; A Menikoff,"Schizophrenia is a stress-related biomedical condition of the brain, characterised by unusual internal experiences, severe and often persistent functional disability and socially inappropriate behaviour. It is estimated that schizophrenia affects approximately 1% of all adults worldwide. Young adults are especially vulnerable. It is an illness with profound economic impact on patients, their families and society at large. Before the 1950s, most patients with schizophrenia were admitted to hospital for long inpatient stays. Keeping the patient in an institutional setting was all that psychiatry could offer, because there was little active treatment available. After World War II, and especially following the introduction of chlorpromazine in 1954, treatment was offered increasingly in outpatient settings. At present, more than 90% of individuals with schizophrenia will receive most healthcare services in outpatient facilities, supplemented by brief hospital treatment. The trend toward community-based care continues into the 1990s, supported in part by recent pharmacotherapeutic developments that are making a new generation of drug treatment options available. Clozapine, the most widely used of these new drugs, has been the subject of several studies that compared its costs with those of conventional drug treatments. These early studies suggest that further reductions in the cost of hospital treatment are possible in the near future. At the same time, despite the increasing availability of effective treatment in outpatient settings, the shift of resources from institutional to community care will not occur as quickly as some might wish. Delays in the transformation of care systems are caused by political interest groups and the sheer inertia of the infrastructure left over from the era of institutional care. These factors must be taken into account in estimating the cost of schizophrenia care during the next decade. The aim of this review is to provide a clinical picture of schizophrenia, emphasising features that contribute most to the cost of illness. We define and quantify the direct and indirect costs of the illness, discuss the cost implications of new pharmacotherapeutic and psychosocial treatments, and critique strategies for measuring the economic efficacy of these new treatments. The difficulties in measuring the costs of schizophrenia that are related to the transition from institutional to community-based systems of care in the US are also reviewed.",1995.0,0,0
12,10172917,Measuring quality of life in patients with schizophrenia.,A G Awad; L N Voruganti; R J Heslegrave,"Schizophrenia is a chronic disabling illness that affects about 1% of the population. It is a heterogenous disorder with variable aetiological, prognostic and treatment response patterns. Its course is generally long term, with acute psychotic exacerbations that may require hospitalisation. The cornerstone of clinical management is the use of antipsychotic (neuroleptic) medications. Although these are effective, they can cause adverse effects that may impact negatively on the functional status of the individual. Early studies of quality of life in schizophrenia were mainly concerned with the development of techniques to identify patients' needs in the community. Difficulties encountered in these studies included: lack of agreement on definition of quality of life; lack of appropriate integrative conceptual models; concerns about reliability of patients' self-reports about their quality of life; and the lack of standardised quality-of-life measures appropriate for schizophrenia. A number of disease-specific or generic scales have subsequently been used for measurement of quality of life in schizophrenia. The list of disease-specific scales is extensive; unfortunately, many of them were used only in a single study or their psychometric properties were not specified. Generic scales can be applied across various types and severity of illness, as well as in different health interventions across demographic and cultural groups. Medication costs in schizophrenia represent only a small fraction of the total cost of the illness. However, pharmacoeconomic studies have attracted much interest as a result of the high cost of newly introduced medications and of concern about the limitations of antipsychotic medications, particularly their adverse effects, as exemplified by the reintroduction of clozapine for the treatment of refractory schizophrenia. Few studies have combined quality-of-life measures with cost analysis in schizophrenia; a number of these have methodological shortcomings. Many studies are retrospective in nature, and in most the number and length of hospitalisations has been used as the parameter for cost analysis, which can introduce bias depending on the varying approaches to hospitalisation. We conclude that the following factors are important in choosing or developing a quality-of-life measure for schizophrenia: quality of life is a multidimensional concept that has to be reflected in its measurement; the scale has to be appropriate for the purpose as well as the population studied; measurement has to include patients' self-reports about their quality of life; measures should include only items that are relevant and expected to change; single-item global measures are useful only when combined with multidimensional measures; in developing new scales, psychometric properties have to be established as well as being field-tested.",1996.0,0,1
13,10178498,Economic outcomes associated with the use of risperidone in a naturalistic group practice setting.,B S Nightengale; L Garrett; S Waugh; B J Lawrence; J Andrus,"The purpose of this cohort pilot study was to compare the resource utilization and economic outcomes associated with the use of risperidone versus haloperidol in a naturalistic setting. Patient charts from a large psychiatric group practice were reviewed, and hospital billing data were obtained. Patients meeting the inclusion criteria were placed into one of two cohorts depending on their medication history. Thirty patients treated with risperidone met the selection criteria, and a random quota sampling technique was used to allow for a matched control cohort of 30 patients treated with haloperidol. In the haloperidol and risperidone cohorts, 24 and 28 patients, respectively, were evaluated statistically. Mean utilization rates and costs per patient per month for each service were estimated by using regression analysis. Patients in the risperidone cohort had significantly fewer hospitalizations than did those in the haloperidol cohort (P = 0.004). Likewise, risperidone patients had significantly lower hospitalization costs than haloperidol patients (P = 0.005). Conversely, patients treated with risperidone visited the physician more frequently than did those treated with haloperidol (P = 0.0005). Estimated mean total monthly costs were $123.34 lower (95% confidence interval = $464, $217) per patient in the risperidone cohort than in the haloperidol cohort ($1,636.11 vs $1759.45; P = 0.4693). Significant reductions in hospital costs in the risperidone cohort offset higher medication and physician costs. Overall, total monthly costs were similar for the two cohorts.",1998.0,0,0
14,10192829,Ziprasidone 80 mg/day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group.,D G Daniel; D L Zimbroff; S G Potkin; K R Reeves; E P Harrigan; M Lakshminarayanan,"In this double-blind study, patients with an acute exacerbation of schizophrenia or schizoaffective disorder were randomized to receive either ziprasidone 80 mg/day (n = 106) or 160 mg/day (n = 104) or placebo (n = 92), for 6 weeks. Both doses of ziprasidone were statistically significantly more effective than placebo in improving the PANSS total, BPRS total, BPRS core items, CGI-S, and PANSS negative subscale scores (p < .05). Ziprasidone 160 mg/day significantly improved depressive symptoms in patients with clinically significant depression at baseline (MADRS > or = 14, over-all mean 23.5) (p < .05) as compared with placebo. The percentage of patients experiencing adverse events was similar in each treatment group, and resultant discontinuation was rare. The most frequent adverse events associated with ziprasidone were generally mild dyspepsia, nausea, dizziness, and transient somnolence. Ziprasidone was shown to have a very low liability for inducing movement disorders and weight gain. The results indicate that ziprasidone is effective and well tolerated in the treatment of the positive, negative, and depressive symptoms of an acute exacerbation of schizophrenia or schizoaffective disorder.",1999.0,1,1
15,10200742,Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Amisulpride Study Group.,J M Danion; W Rein; O Fleurot,"The goal of this placebo-controlled study was to evaluate the efficacy and safety of low doses of amisulpride, an atypical antipsychotic of the benzamide class with high affinity for D2 and D3 dopamine receptors, in the treatment of schizophrenic patients with predominantly primary negative symptoms. After completion of a 4-week washout period, schizophrenic patients with primary negative symptoms participated in a 12-week, multicenter double-blind trial of placebo (N = 83), amisulpride, 50 mg/day (N = 84), or amisulpride, 100 mg/day (N = 75). They were evaluated with the Scale for the Assessment of Negative Symptoms, the Scale for the Assessment of Positive Symptoms, the Brief Psychiatric Rating Scale, and the Montgomery-Asberg Depression Rating Scale. Both amisulpride treatment groups showed significantly greater improvement in negative symptoms than the placebo group. Positive symptom scores were low at baseline and changed minimally during the study, suggesting that the improvement in negative symptoms was independent of improvement in positive symptoms. The safety of amisulpride was comparable to that of placebo, and extrapyramidal symptoms were infrequent. Comparable efficacy and safety results were observed with either dose of amisulpride. These findings confirm and extend those of earlier placebo-controlled studies of low-dose amisulpride in the treatment of patients with predominantly negative symptoms of schizophrenia.",1999.0,0,0
16,10202629,"Sudden infant death syndrome, child sexual abuse, and child development.",S D Blatt; V Meguid; C C Church; A S Botash; F Jean-Louis; M P Siripornsawan; H L Weinberger,"Since the introduction of the Back to Sleep Campaigns, there has been a dramatic reduction in sudden infant death syndrome in this country. Steven Blatt and Victoria Meguid review the literature surrounding sleep position. Investigators have continued efforts to find other modifiable risk factors of sudden infant death syndrome. A prospective study of more than 33,000 neonates found a link between a prolonged QT electrocardiogram interval and sudden infant death syndrome. Also discussed are investigations seeking to explain the relationship between smoking and sudden infant death syndrome. Ann Botash, Florence Jean-Louis and Mongkae Ploy Siripornsawan review the latest thinking on genital warts and their relation to specific viral etiologies and child sexual abuse. Other symptoms and signs of sexual abuse are the focus of a number of articles that can help the practitioner care for these unfortunate children. Catherine Church reviews medication options for children diagnosed with pervasive developmental disorders or autism spectrum disorders. Finally, in this article, risperidone, fluoxetine and naltrexone are reviewed.",1999.0,0,0
17,10211146,Olanzapine versus haloperidol in the treatment of schizoaffective disorder. Acute and long-term therapy.,P V Tran; G D Tollefson; T M Sanger; Y Lu; P H Berg; C M Beasley,"The effectiveness of antipsychotic monotherapy in schizoaffective disorder is limited, and further constrained by safety concerns. We aimed to compare the efficacy, tolerability and safety profile of the new pharmaceutical, olanzapine, with haloperidol. Data were assessed from 300 DSM-III-R schizoaffective subjects from a larger double-blind prospective international study. Subjects were randomly allocated to six weeks of olanzapine (5-20 mg) or haloperidol (5-20 mg) treatment; responders were followed for up to one year of double-blind, long-term maintenance therapy. Olanzapine-treated patients achieved a statistically significant greater improvement than haloperidol treated patients on overall measures of efficacy, including clinical response. Significantly fewer olanzapine patients left the study early, and fewer adverse events were observed among those receiving olanzapine. During maintenance, olanzapine-treated patients continued to experience additional improvement, with fewer EPS but more weight gain than those on haloperidol. Olanzapine demonstrated substantial advantages over the conventional antipsychotic haloperidol in the management of schizoaffective disorder.",2001.0,1,1
18,10211147,Randomised double-blind comparison of the incidence of tardive dyskinesia in patients with schizophrenia during long-term treatment with olanzapine or haloperidol.,C M Beasley; M A Dellva; R N Tamura; H Morgenstern; W M Glazer; K Ferguson; G D Tollefson,"Tardive dyskinesia is important in the side-effect profile of antipsychotic medication. The development of tardive dyskinesia was evaluated in patients treated with double-blind, randomly assigned olanzapine or haloperidol for up to 2.6 years. Tardive dyskinesia was assessed by the Abnormal Involuntary Movement Scale (AIMS) and Research Diagnostic Criteria for Tardive Dyskinesia (RD-TD), it was defined as meeting RD-TD criteria at two consecutive assessments. The risk of tardive dyskinesia, the relative risk, incidence rate, and incidence rate ratio were estimated. The relative risk of tardive dyskinesia for the overall follow up period for haloperidol (n = 522) v. olanzapine (n = 1192) was 2.66 (95% CI = 1.50-4.70). Based on data following the initial six weeks of observation (during which patients underwent medication change and AIMS assessments as frequently as every three days), the one-year risk was 0.52% with olanzapine (n = 513) and 7.45% with haloperidol (n = 114). The relative risk throughout this follow-up period was 11.37 (95% CI = 2.21-58.60). Our results indicated a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol.",1999.0,0,1
19,10211930,Prolactin levels in premenopausal women treated with risperidone compared with those of women treated with typical neuroleptics.,G Caracci; R Ananthamoorthy,,1999.0,0,0
20,10220013,Schizophrenia and the serotonin-2A receptor promoter polymorphism.,K Ohara; M Nagai; K Tani; T Tsukamoto; K Ohara,"Serotonin-2A (5-HT2A) receptors have received much investigative attention in schizophrenia because (1) several studies have shown a decrease in the number of 5-HT2A receptors in the prefrontal cortex of postmortem brains of schizophrenic patients; (2) atypical antipsychotic drugs are antagonists for 5-HT2A receptors; and (3) a positive association between a T to C polymorphism at position 102 of the 5-HT2A receptor gene and schizophrenia has been reported. A G to A polymorphism at position -1438 of the 5-HT2A receptor gene was studied in 119 schizophrenic patients and 106 healthy control subjects, all of whom were Japanese. The genotype and allele frequencies did not differ between the patients and control subjects. Furthermore, the genotype frequency did not differ according to diagnostic subtype, family history, age at onset of illness, or daily dosage of antipsychotic medication. Our results suggest that the polymorphism does not contribute to the etiology or clinical characteristics of schizophrenia. However, the gene is greater than 20 kbp in length, and thus it is possible that other areas that affect expression of the gene may vary. We found that the -1438G/A variant was in linkage disequilibrium with the T102C polymorphism.",1999.0,0,0
21,10220130,Clinical trials of new antipsychotics: a critical appraisal.,C Barbui; S Garattini,In recent years the efficacy of new antipsychotics has been investigated through a number of randomized controlled trials. This paper considers some methodological flaws that affect these studies and proposes possible solutions. The final goal is the implementation of a new generation of trials with the aim of demonstrating superiority of effect of the new antipsychotic over the reference one.,1999.0,0,0
22,10221280,The distribution of body mass index among individuals with and without schizophrenia.,D B Allison; K R Fontaine; M Heo; J L Mentore; J C Cappelleri; L P Chandler; P J Weiden; L J Cheskin,"The objective of this study was to estimate and compare the distributions of body mass index (BMI: kg/m2) among individuals with and without schizophrenia, and, thereby, place the weight gain-inducing effects of antipsychotic drugs into context. Data sources were (1) the mental health supplement of the 1989 National Health Interview Survey (NHIS; N = 80,130 nonschizophrenic and 150 self-reported schizophrenic individuals), (2) baseline BMI data from a drug trial of the anti-psychotic ziprasidone supplied by Pfizer Inc (420 noninstitutionalized individuals with chronic psychotic disorders [DSM-IV schizophrenia or schizoaffective disorder]) and (3) data from the National Health and Nutrition Examination Survey III (NHANES III; N = 17,689 nonschizophrenic individuals) to act as a control group for the ziprasidone trial data. After age-adjusting BMI in each data set, the NHIS data revealed that men with schizophrenia have mean BMIs similar to those of men without schizophrenia (26.14 vs. 25.63, respectively). In contrast, women with schizophrenia in the NHIS data set had a significantly (p<.001) higher mean BMI than did women without schizophrenia (27.36 vs. 24.50, respectively). Moreover, each decile was higher for women with schizophrenia than for women without schizophrenia. Analysis of the ziprasidone and NHANES III data sets revealed that, on average, men with schizophrenia have mean BMIs comparable to those of men without schizophrenia (26.79 vs. 26.52, respectively). In these 2 data sets, women with schizophrenia also had a mean BMI similar to those of women without schizophrenia (27.29 vs. 27.39, respectively). Although there may be a small subpopulation of schizophrenic individuals who are underweight, individuals with schizophrenia were, on the whole, as obese as or more obese than individuals without schizophrenia, suggesting that weight gain induced by antipsychotic agents is an important concern for many individuals.",1999.0,0,0
23,10221361,"Psychotropic drugs in mothers' milk: a comprehensive review of assay methods, pharmacokinetics and of safety of breast-feeding.",K Yoshida; B Smith; R Kumar,"Many mentally ill women want to breast-feed their babies but, if they are taking psychotropic drugs, there is very little systematic data upon which to base decisions about whether or not it is safe to do so. We therefore attempt to provide a comprehensive and critical summary of existing case reports and of studies of breast-feeding in relation to commonly used psychotropic drugs. The literature review focuses on the following drugs: antidepressants: tricyclics and serotonin selective reuptake inhibitors (SSRIs); antipsychotic drugs: chlorpromazine, perphenazine, haloperidol and clozapine; mood stabilizers: lithium and carbamazepine; and benzodiazepines. The research literature consists mainly of single case reports and there have been very few attempts at controlled, longitudinal investigations. Findings are often difficult to compare because of differences in methods or because of lack of key information. Most data are available about the tricyclic antidepressants but even here we have found that the reports cover only a grand total of 66 mother-infant pairs. Dilemmas about whether or not to contraindicate breast-feeding arise most commonly in relation to postnatal depression. The findings to date suggest that provided that infants are healthy at the outset it is likely that the benefits of breast-feeding will outweigh potential hazards if their mothers are taking established tricyclic drugs at recommended dose levels. Much less is known about risks associated with SSRI antidepressants or about antipsychotic drugs such as phenothiazines and butyrophenones or mood stabilizers such as carbamazepine, all of which enter breast-milk. Safeguards are suggested for future single case studies, which, as they accumulate, will provide a platform for mounting controlled prospective studies properly to test for any acute toxic effects and for possible long-term adverse effects of such drugs on infants' development. Appendix 1 is a review of assay methods. Appendix 2 examines pharmacokinetic factors in newborn preterm and sick infants with special reference to contraindications to breast-feeding. Appendix 3 is a review of methods for assessing infant health and development.",1999.0,0,0
24,10227103,A comparison of the effect of clozapine with typical neuroleptics on cognitive function in neuroleptic-responsive schizophrenia.,M A Lee; K Jayathilake; H Y Meltzer,"Clozapine has been reported to improve selected aspects of cognitive function in neuroleptic-resistant schizophrenia. In this study, we report the first direct comparison of the effect of clozapine and typical neuroleptic drugs on cognitive function in neuroleptic-responsive schizophrenia. Sixty-four patients with recent onset, neuroleptic-responsive schizophrenia or schizoaffective disorder were randomly assigned to either clozapine (n = 35) or typical neuroleptics (n = 29) and followed for 12 months. They were administered a comprehensive cognitive test battery at baseline and at 6 weeks, 6 months and 12 months after initiating drug treatment. Treatment with clozapine improved psychomotor speed and attention [Digit Symbol Substitution Test (DSST)] and verbal fluency [Category Instance Generation and Controlled Word Association Test (CWAT)] at 6 weeks. The improvement in these measures was maintained throughout the 12-month period. Treatment with typical neuroleptics produced no sustained improvement in any cognitive measure, except for a tendency to improve delayed recall memory (Verbal List Learning Test). The improvement in the DSST and CWAT was significantly greater with clozapine treatment compared to that with typical neuroleptics. These improvements were not related to improvement in psychopathology. These results suggest that clozapine is superior to typical neuroleptics in improving specific types of cognitive function in recent onset, neuroleptic-responsive schizophrenia.",1999.0,1,1
25,10229062,Spontaneous slow and fast MEG activity in male schizophrenics treated with clozapine.,W Sperling; J Vieth; M Martus; J Demling; A Barocka,"The atypical neuroleptic clozapine induces specific electroencephalogram changes, which have not been investigated using the technique of magnetoencephalography (MEG). The present study investigated whether spontaneous magnetoencephalographic (MEG) activity in patients treated with clozapine differs from that in patients treated with haloperidol and untreated control subjects. A 2 x 37 channel biomagnetic system was used to record spontaneous magnetic activity for the frequency ranges (2-6 Hz), (7.5-12 Hz), (12.5-30 Hz) in schizophrenic patients and controls in two trials within 3 weeks. After data acquisition, the processed data were digitally filtered and the spatial distribution of dipoles was determined by a 3-D convolution with a Gaussian envelope. The dipole localisation was calculated by the dipole density plot and the principal component analysis. The target parameters were absolute dipole values and the dipole localisations. The relationship between absolute dipole values, dipole localisations and psychopathological findings (documented by the use of the PANSS, BPRS-scale) during a 3 week period with constant doses of clozapine and haloperidol was investigated using correlation analysis. Our results lend strong support to the assumption of a significant elevation of absolute dipole values [dipole density maximum (Dmax), dipole number (Dtotal), absolute and relative dipole density] in the fast frequency range (12.5-30 Hz) over the left hemisphere, especially in the temporoparietal region by clozapine. In this area, we found a dipole concentration effect only in patients treated with the atypical neuroleptic, whereas the dipole distribution in patients treated with haloperidol and healthy controls was concentrated in the central region. With regard to the absolute dipole values in the frequency ranges 2-6 Hz (delta, theta) and 7.5-12 Hz (alpha), we found no statistically significant differences between the groups investigated. In the slow frequency range (2-6 Hz) no difference was found between the clozapine and haloperidol group for the dipole localisation, which predominated in the temporoparietal region, in contrast to the central dipole distribution in control subjects. The results of an increase in beta activity under clozapine demonstrate a smaller reduction in activity in terms of unspecific sensory and motor paradigms in comparison with typical neuroleptics. The temporoparietal concentration of dipoles, in particular over the left half of the brain, might illustrate either their special role in the disease process, or the effects of the medication. The latter possibility was supported by the differing dipole distribution in the clozapine group with a left temporoparietal centre in both frequency ranges, and a deviating central dipole localisation in the fast activity range in the haloperidol group.",1999.0,0,0
26,10322240,Risperidone in the treatment of elderly patients with psychotic disorders.,S Madhusoodanan; M Brecher; R Brenner; J Kasckow; M Kunik; A E Negrón; N Pomara,"The authors evaluated the safety, tolerability, and efficacy of risperidone in 103 elderly patients (mean age, 71 years) with schizophrenia (75%) or schizoaffective disorder (25%). Using the Extrapyramidal Symptoms Rating Scale (ESRS), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression (CGI) scale, they conducted a prospective, open-label, 12-week trial in 14 psychiatric centers in the United States. Patients' symptoms were assessed at baseline and over a 12-week period. At endpoint, ESRS scores were significantly reduced, as were PANSS total and subscale scores. There were no clinically significant changes in electrocardiograms, laboratory test results, or vital signs. Risperidone was well tolerated and efficacious in elderly patients with schizophrenia or schizoaffective disorder.",2000.0,0,0
27,10327902,Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group.,M Tohen; T M Sanger; S L McElroy; G D Tollefson; K N Chengappa; D G Daniel; F Petty; F Centorrino; R Wang; S L Grundy; M G Greaney; T G Jacobs; S R David; V Toma,"The primary intent of this study was to compare the efficacy and safety of olanzapine and placebo in the treatment of acute mania. The design involved a random-assignment, double-blind, placebo-controlled parallel group study of 3 weeks' duration. After a 2- to 4-day screening period, qualified patients were assigned to either olanzapine (N = 70) or placebo (N = 69). Patients began double-blind therapy with either olanzapine, 10 mg, or placebo given once per day. After the first day of treatment, the daily dose could be adjusted upward or downward, as clinically indicated, by one capsule (olanzapine, 5 mg/day) within the allowed range of one to four capsules. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. Clinical response was defined a priori as a decrease of 50% or more from baseline in Young Mania Rating Scale total score. The olanzapine group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the placebo group. On the basis of the clinical response criteria, significantly more olanzapine-treated patients (48.6%) responded than those assigned to placebo (24.2%). Somnolence, dizziness, dry mouth, and weight gain occurred significantly more often with olanzapine. There were no statistically significant differences between the olanzapine-treated and placebo-treated patients with respect to measures of parkinsonism, akathisia, and dyskinesias. No discontinuations of treatment due to adverse events occurred in the olanzapine treatment group. The results from this study suggest that compared with placebo, olanzapine has superior efficacy for the symptoms of acute mania.",1999.0,1,1
28,10332914,Weight gain among patients on clozapine.,Y M Bai; C C Lin; J Y Chen; C Y Lin,,1999.0,0,1
29,10348471,Acute and chronic effects of clozapine in essential tremor.,R Ceravolo; S Salvetti; P Piccini; C Lucetti; G Gambaccini; U Bonuccelli,"Patients with essential tremor (ET) may not respond to commonly used drugs. Clozapine, an atypical neuroleptic drug, has been reported to improve postural Parkinson's disease tremor clinically resembling ET. The effects of a single dose of 12.5 mg clozapine and placebo were evaluated in a randomized, double-blind, crossover study in 15 drug-resistant patients with ET. Patient responders with more than 50% improvement after a single dose of clozapine subsequently received the drug (39+/-9 mg up to 50 mg) unblinded for a period of 15.8+/-7.7 months. Tremor was effectively reduced by a single dose of clozapine in 13 of 15 patients (p <0.01). Sedation was the only side effect reported during the clozapine test; however, the time course of sedation and of the antitremor effect were not coincident. A significant reduction of tremor was reported with chronic clozapine treatment (p <0.01) with no tolerance to drug antitremor effect, whereas sedation markedly decreased after 6-7 weeks of therapy. No clozapine-induced hematologic side effects were observed in our cohort of patients during long-term treatment. Our results suggest that in selected drug-resistant ET cases, clozapine should be considered before resorting to neurosurgical options.",1999.0,0,0
30,10349044,Does akathisia influence psychopathology in psychotic patients treated with clozapine?,C J Nair; R C Josiassen; G Abraham; J K Stanilla; J I Tracy; G M Simpson,"Akathisia has been reported to predict more severe symptoms and poorer treatment response to typical neuroleptics among patients with schizophrenia. Akathisia has also been associated with symptom exacerbation. This study addressed four questions: 1) Does akathisia predict greater severity in global psychopathology? 2) Is this effect global or specific? 3) Does clozapine treatment alter this relationship? 4) Does severity of psychopathology covary with the level of akathisia? Akathisia and clinical symptoms were examined in 33 ""treatment refractory"" schizophrenic patients treated with clozapine across 16 weeks. Weekly ratings were Barnes Akathisia Rating Scale, Abbreviated Dyskinesia Rating Scale, and Brief Psychiatric Rating Scale (BPRS). Patients were classified as ""with"" (n = 15) or ""without"" (n = 18) akathisia. Data analyses involved independent t-test comparisons of selected variables, between-group multivariate analyses of variance across time for BPRS Total scores and Guy's five factors, and partial correlations to assess covariation between BPRS scores and level of akathisia. Akathisia predicted more severe global psychopathology, specific to the Activation (AC) and Thought Disturbance (TH) factors. These relationships did not change with clozapine treatment even when akathisia declined. Interestingly, level of akathisia did not covary with severity of psychopathology. In this sample, akathisia predicted more severe psychopathology, specific to AC and TH BPRS factor scores. Clozapine treatment did not alter this relationship. Although the presence of akathisia predicted more severe symptoms, the level of akathisia did not covary across time with severity of psychopathology, suggesting an ""uncoupling"" of these symptom domains.",1999.0,0,0
31,10349067,Bipolar disorder in old age.,K I Shulman; N Herrmann,"To review the classification, clinical characteristics, and epidemiology of bipolar disorders in old age with a special focus on neurologic comorbidity, high mortality, and management. Most available data is gleaned from retrospective chart reviews and cohort studies. Treatment recommendations are based on evidence from younger populations and a few anecdotal case reports and series involving elderly people. While relatively rare in the community setting, mania in old age frequently leads to hospitalization. It is associated with late-onset neurologic disorders (especially cerebrovascular disease) involving the right hemisphere and orbitofrontal cortex. Prognosis is relatively poor; morbidity and mortality rates are high. Management of bipolarity includes cautious use of mood stabilizers, especially lithium and divalproex. Mania in old age should trigger a careful assessment of underlying neurologic disease, especially cerebrovascular disease. Close clinical follow up is essential.",1999.0,0,0
32,10350037,Schizophrenia and schizoaffective disorder treated with high doses of olanzapine.,A Fanous; J P Lindenmayer,,1999.0,0,1
33,10357026,Is bipolar disorder still underdiagnosed? Are antidepressants overutilized?,S N Ghaemi; G S Sachs; A M Chiou; A K Pandurangi; K Goodwin,"Previous studies have suggested that bipolar disorder may be underdiagnosed, and that antidepressants may be over-utilized in its treatment. Consecutively admitted patients (n =48) diagnosed with DSM-IV bipolar disorder, type I, (n = 44) or schizoaffective disorder, bipolar type, (n = 4) were interviewed systematically and their charts were reviewed to confirm diagnosis before admission. They were then treated according to systematic structured interview diagnoses. These data reflect the changes in diagnoses and treatment. 40% (19/48) were identified with previously undiagnosed bipolar disorder, all previously diagnosed with unipolar major depressive disorder. A period of 7.5+/-9.8 years elapsed in this group before bipolar diagnosis was made. Antidepressant use was high on admission (38%) and was reduced with acceptable treatment response rates. The adjunctive use of risperidone appeared to be a good treatment alternative. While diagnoses were made prospectively, treatment response was assessed retrospectively, and was based on non-randomized, naturalistic therapy. Systematic application of DSM-IV criteria identified previously undiagnosed bipolar disorder in 40% of a referred population of patients with mood disorders, all previously misdiagnosed as unipolar major depressive disorder. Antidepressants appeared overutilized and risperidone was an effective alternative adjunctive therapy agent.",1999.0,0,0
34,10359474,Cost-effectiveness of clozapine in patients with high and low levels of hospital use. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.,R Rosenheck; J Cramer; E Allan; J Erdos; L K Frisman; W Xu; J Thomas; W Henderson; D Charney,"This study examined the relationship between pretreatment hospital use and the cost-effectiveness of clozapine in the treatment of refractory schizophrenia. Data from a 15-site randomized clinical trial were used to compare clozapine with haloperidol in hospitalized Veterans Affairs patients with refractory schizophrenia (n = 423). Outcomes were compared among those with many days in the hospital use (hereafter, high hospital users) (n = 141; mean = 215 psychiatric hospital days in the year prior to study entry) and those with few days in the hospital use (hereafter, low hospital users) (n = 282; mean = 58 hospital days). Analyses were conducted with the full intention-to-treat sample (n = 423) and with crossovers excluded (n = 291). Clozapine treatment resulted in greater reduction in hospital use among high hospital users (35 days less than controls, P = .02) than among low users (21 days less than controls, P = .05). Patients taking clozapine also had lower health care costs; after including the costs of both medications and other health services, costs were $7134 less than for controls among high hospital users (P = .14) but only $759 less than for controls among low hospital users (P = .82). Clinical improvement in the domains of symptoms, quality of life, extrapyramidal symptoms, and a synthetic measure of multiple outcomes favored clozapine in both high and low hospital user groups. Substantial 1-year cost savings with clozapine are observed only among patients with very high hospital use prior to initiation of treatment while clinical benefits are more similar across groups. Cost-effectiveness evaluations, and particularly studies of expensive treatments, cannot be generalized across type of use groups.",1999.0,0,0
35,10360124,Rehospitalization rates of patients recently discharged on a regimen of risperidone or clozapine.,R R Conley; R C Love; D L Kelly; J J Bartko,"The purpose of this study was to examine rehospitalization rates of people receiving risperidone or clozapine who had been discharged from state psychiatric hospitals in Maryland. Rehospitalization status was monitored for all patients discharged from state psychiatric facilities on a regimen of either risperidone or clozapine between March 14, 1994, and Dec. 31, 1995. Patients were followed up with respect to readmission until Dec. 31, 1996. Time to readmission was measured by the product-limit (Kaplan-Meier) formula. Risk factors associated with rehospitalization were examined. One hundred sixty patients were discharged on risperidone, 75 having the diagnosis of schizophrenia. The patients with schizophrenia were more likely to be readmitted than the 85 patients with other mental disorders. Recidivism rates for schizophrenic patients discharged on risperidone versus those discharged on clozapine were not significantly different over the 24-month study period. However, no patient who received clozapine and remained discharged for more than 10 months (N = 49) was readmitted, while the readmission rate for risperidone-treated patients appeared to be steady up to 24 months. At 24 months 87% of the clozapine-treated patients and 66% of the risperidone-treated patients remained in the community. No clinical or demographic variables were found to predict rehospitalization. This study demonstrates that the rehospitalization rates of patients taking the second-generation antipsychotics risperidone and clozapine are lower than those in previously published reports of conventional antipsychotic treatment.",1999.0,1,1
36,10365650,Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders.,G Facciolà; A Avenoso; M G Scordo; A G Madia; A Ventimiglia; E Perucca; E Spina,"Two separate studies were carried out to assess the effect of valproic acid on the steady-state plasma concentrations of clozapine and its major metabolites norclozapine and clozapine N-oxide in psychotic patients. In the first study, concentrations of clozapine and metabolites were compared between patients treated with clozapine in combination with sodium valproate (n = 15) and control patients treated with clozapine alone (n = 22) and matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with valproate tended to have higher clozapine levels and lower norclozapine levels, but the differences did not reach statistical significance. In a subsequent study, plasma concentrations of clozapine and its metabolites were determined in 6 patients with schizophrenia stabilized on clozapine therapy (200-400 mg/d) before and after treatment with sodium valproate (900-1200 mg/d) for 4 weeks. Mean plasma concentrations of clozapine and its metabolites did not change significantly throughout the study, but there was a trend for clozapine levels to be higher and for norclozapine levels to be lower after valproate. Overall, these findings suggest that valproic acid may have an inhibiting effect on the CYP1A2- or CYP3A4-mediated conversion of clozapine to norclozapine. However, the interaction is unlikely to be clinically significant.",1999.0,0,1
37,10366172,Lower incidence of tardive dyskinesia with risperidone compared with haloperidol in older patients.,D V Jeste; J P Lacro; A Bailey; E Rockwell; M J Harris; M P Caligiuri,"To compare the 9-month cumulative incidence of tardive dyskinesia (TD) with risperidone to that with haloperidol in older patients. A prospective longitudinal study. An outpatient psychiatric clinic. Subjects were middle-aged and older (mean age 66 years) patients with schizophrenia, dementia, mood disorders, or other conditions with psychotic symptoms or severe behavioral disturbances. Sixty-one patients on risperidone were matched with 61 patients from a larger sample of haloperidol-treated patients in regard to age, diagnosis, and length of pre-enrollment neuroleptic intake to create clinically comparable groups. The median daily dose of each medication was 1.0 mg. Abnormal Involuntary Movement Scale, modified Simpson-Angus' scale for extrapyramidal symptoms, Brief Psychiatric Rating Scale, and Mini-Mental State Examination were administered at baseline, 1 month, and 3, 6, and 9 months. The diagnosis of TD was based on specific research criteria. The raters were blind to the patient's medication status. Life table analysis revealed that patients treated with haloperidol were significantly more likely to develop TD than patients treated with risperidone (P < .05, Peto-Prentice). The atypical antipsychotic risperidone is significantly less likely to result in TD than the conventional neuroleptic haloperidol in a high-risk group of older patients, at least over a 9-month period.",1999.0,0,1
38,10368852,Clinical outcome to clozapine treatment in chronic psychiatric inpatients.,C D Advokat; L J Bertman; J E Comaty,"1. A review of the medical records in a state psychiatric hospital was conducted to evaluate the clinical efficacy of the atypical antipsychotic, clozapine. 2. Using the Brief Psychiatric Rating Scale (BPRS), four groups of schizophrenic inpatients (n = 59) were operationally defined: Nonresponders (< 20% decrease from pre-drug baseline); Short-term Pharmacological Responders (20% decline, but not sustained); Long-term Pharmacological Responders (maintained a 20% decline) and Clinical Responders (maintained a 20% decline and achieved a BPRS < or = 36; the criterion of Kane et al. 1988). 3. There were 7 NRs, 13 STPRs, 21 LTPRs and 18 CRs 4. The STPR, LTPR and CR groups improved significantly within the first month of treatment and reached a 20% decrease in BPRS by 3 months. CRs required 5 months to attain a BPRS < or = 36. These criteria were reached at the same average doses (about 300-400 mg/day). 5. The proportion of CRs (30%) in this retrospective, naturalistic study, is remarkably close to the results of the definitive study by Kane et al. 1988. These results are also consistent with many of the controlled research studies of clozapine in hospitalized, treatment refractory psychiatric patients.",2001.0,0,0
39,10370450,Negative symptoms in schizophrenia: neurobiological models and treatment response.,D C Goff; A E Evins,"Evidence from lesioning studies and neuroimaging has linked negative symptoms to dysfunction of the prefrontal cortex, the limbic system, and the basal ganglia. Although such symptoms have been most strongly associated with dopaminergic hypoactivity in the prefrontal cortex, other neurotransmitters including norepinephrine, serotonin, and the excitatory amino acids may also play a role. In some patients moderate doses of conventional neuroleptics clearly improve negative symptoms; the response of such symptoms is relatively greater with clozapine and probably with certain serotonin-dopamine antagonists. Recent studies demonstrating improvement of negative symptoms when conventional neuroleptics are augmented with selective serotonin-reuptake inhibitors or with agents active at the glycine-modulatory site of the glutamatergic N-methyl-D-aspartate receptor complex suggest that further amelioration of primary negative symptoms may be possible through pharmacological strategies involving multiple neurotransmitter systems.",1999.0,0,0
40,10372607,The effects of clozapine on cognitive functioning in schizophrenia.,S R McGurk,"Cognitive function may be markedly impaired in patients with schizophrenia; however, it has only recently been recognized as an important factor in determining patient outcome. Research has shown that improvements in cognitive functioning occur independently of improvements in positive or negative clinical symptoms, and whereas typical antipsychotics may improve clinical symptoms, they have little or no efficacy in improving cognitive dysfunction. However, there is evidence that the atypical antipsychotic clozapine may improve this core deficit of schizophrenia. This review summarizes 12 published studies that assessed the effect of clozapine on cognitive functioning. As a group, these studies suggest that psychomotor speed, verbal fluency, and verbal learning and memory may be improved by treatment with clozapine. Such cognitive improvements with clozapine treatment may offer an advantage to patients with schizophrenia by enhancing the possibility of better vocational functioning and quality of life.",1999.0,0,0
41,10376128,Risperidone-induced increase of plasma norepinephrine is not correlated with symptom improvement in chronic schizophrenia.,R E See; A A Fido; M Maurice; M M Ibrahim; G M Salama,"Previous studies have shown an increase in plasma levels of norepinephrine (NE) after clozapine treatment of schizophrenia. This effect has been suggested to relate to improvement in symptoms. To test whether other novel antipsychotic drugs have such an effect, the present experiment examined schizophrenic symptoms and plasma levels of NE before and after 5 weeks of treatment with risperidone or haloperidol. Risperidone, but not haloperidol, significantly increased plasma NE; however, there was no correlation of this effect with clinical improvement on any symptom scale. This finding suggests that risperidone shares similar properties with clozapine in enhancing peripheral NE, but that these changes in plasma NE may not be a consistent indicator of atypical antipsychotic drug efficacy.",1999.0,0,0
42,10376627,Clozapine in drug-induced psychosis in Parkinson's disease. The French Clozapine Parkinson Study Group.,,,1999.0,0,1
43,10379638,Absence of interaction between erythromycin and a single dose of clozapine.,S Hägg; O Spigset; T Mjörndal; K Granberg; G Persbo-Lundqvist; R Dahlqvist,"To study the suggested pharmacokinetic interaction between erythromycin, a strong inhibitor of CYP3A4, and clozapine. Twelve healthy male volunteers received a single dose of 12.5 mg of clozapine alone or in combination with a daily dose of 1500 mg erythromycin in a randomised crossover study. Clozapine and its metabolites clozapine-N-oxide and desmethyl-clozapine were measured in serum samples which were collected during a 48 h period and in a sample of the urine secreted over the interval 0-12 h. There were no significant differences in mean area under the serum concentration time curves (1348 (633) nmol h x l(-1) in the control phase and 1180 (659) nmol h x l(-1) in the erythromycin phase), terminal halflives (19 (13) h and 15 (6) h, respectively), peak serum concentrations (92 (53) nmol x l(-1) and 77 (40) nmol x l(-1), respectively), time to peak serum concentrations (1.4 (0.7) h and 1.5 (1.0) h, respectively) or apparent oral clearances of clozapine (34 (15) l x h(-1) and 46 (37) l x h(-1), respectively). There were no significant differences in partial metabolic clearances to clozapine-N-oxide (5.1 (3.6) l x h(-1) and 7.8 (9.4) l x h(-1), respectively) or to desmethyl-clozapine (1.5 (1.3) l x h(-1) and 1.8 (1.7) l x h(-1), respectively) or in renal clearances of clozapine (0.8 (0.5) l x h(-1) and 1.0 (0.7) l x h(-1), respectively) between the two phases. These results demonstrate that erythromycin at a clinically relevant dosage does not inhibit the metabolism of clozapine. Hence, CYP3A4 seems to be of minor importance in the disposition of clozapine in humans at least when clozapine is taken at a low single dose.",1999.0,0,0
44,10394475,Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response.,R R Conley; C A Tamminga; D L Kelly; C M Richardson,"Treatment-resistance in schizophrenia remains a public health problem. Clozapine has been shown to be effective in about one third of this population, but carries with it medical risks and weekly blood draws. As olanzapine is a drug with a very similar biochemical profile to clozapine, it is important to evaluate whether non-response to olanzapine predicts clozapine non-response. Forty-four treatment-resistant patients received eight weeks of olanzapine, either in a double-blind trial or subsequent open treatment at a mean daily dose of 25 mg/day. Two of 44 patients (5%) responded to olanzapine treatment. Patients who did not respond could then receive clozapine. Twenty-seven subsequently received an 8-week open trial of clozapine. Patients who did and did not receive clozapine did not differ demographically or in psychopathology. Eleven of 27 (41%) met a priori response criteria during clozapine treatment (mean dose 693 mg/day) after failing to respond to olanzapine. This study demonstrates that failure to respond to olanzapine treatment does not predict failure to clozapine. Treatment-resistant patients who fail on olanzapine may benefit from a subsequent trial of clozapine.",1999.0,0,0
45,10394486,Olanzapine acute administration in schizophrenic patients increases delta sleep and sleep efficiency.,R J Salin-Pascual; M Herrera-Estrella; L Galicia-Polo; M R Laurrabaquio,"A delta sleep deficit has been observed in schizophrenic patients. Olanzapine is a novel atypical antipsychotic agent with affinity at dopaminergic, serotonergic, muscarinic, adrenergic and histaminergic binding sites. The present study was designed to analyze a sleep promoting effect reported for olanzapine. Twenty schizophrenic patients (DSM-IV) were studied, who were drug free and inpatients. Patients slept for 5 consecutive nights in the sleep unit as follows: one acclimatization night; two baseline nights (the first for sleep disorder screenings); and two olanzapine nights (10 mg olanzapine, one hour before sleep onset). Sleep continuity variables and total sleep time showed an overall improvement with olanzapine. Waking time was reduced since the first night of olanzapine administration. The main sleep architecture changes were: reduction in sleep stage 1, while sleep stage 2 and delta were significantly enhanced. Rapid eye movement density was also increased by the second olanzapine night. Total sleep improvement was due to the increase in sleep stages 2 and delta sleep. This may be related to serotonergic antagonistic properties of olanzapine. Olanzapine seems to have a sleep promoting effect in schizophrenic patients.",1999.0,0,0
46,10397376,Switching from therapy with typical antipsychotic agents to risperidone: long-term impact on patient outcome.,A K Malla; R M Norman; V Kotteda; S Zirul,"This paper reports the results of a retrospective, open-label study in 31 schizophrenic patients who had been switched from therapy with a typical antipsychotic agent to risperidone, a novel antipsychotic agent, in the course of their treatment in an outpatient/community program. The study was based on both a review of all 31 patients' charts and a structured interview of 26 of the patients. The change to risperidone had been made because of lack of efficacy or intolerance to typical antipsychotic agents after a mean of 3.5 years of therapy. Patients had been maintained on risperidone for a mean of 1.7 years at the time of the review. The impact of switching to risperidone was assessed by comparing clinical variables for the patients with their own historic control data. The current levels of symptoms, side effects, and social functioning were also assessed by means of the Interview for Retrospective Assessment of Onset of Schizophrenia and rating scales. Seventy-one percent and 81% of the patients exhibited a positive response, as measured by a 30% reduction in psychotic and disorganization syndromes, respectively. After the switch, significant declines were noted in service utilization; the level of psychotic, disorganization, and negative symptom dimensions; and the use of anticholinergic drugs (P < 0.01 for all). Assessments conducted at the time of the review revealed a low level of psychotic (mean, 3.5) and disorganization (mean, 3.0) symptoms, a moderate level of negative symptoms (mean, 19.5), and a low level of extrapyramidal symptoms (total mean parkinsonism score, 6.0). No significant changes were seen in the level of employment or in living conditions. Results of this study suggest that a switch to risperidone therapy because of the inefficacy of typical antipsychotic agents or patients' inability to tolerate them may lead to sustained and significant improvement in a substantial proportion of patients with schizophrenia.",1999.0,0,0
47,10401441,Evidence of clozapine's effectiveness in schizophrenia: a systematic review and meta-analysis of randomized trials.,K Wahlbeck; M Cheine; A Essali; C Adams,"The purpose of this study was to evaluate all available trial-based evidence on the effectiveness of clozapine in schizophrenia as compared with conventional neuroleptics. All randomized, controlled trials comparing clozapine with a conventional neuroleptic in which there was satisfactory concealment of patients' treatment allocation were located through electronic searches in all languages of several databases and through contacting authors of recent trials as well as the manufacturer of clozapine. At least two independent reviewers assessed trials for inclusion in the study and extracted data for meta-analysis. The review included 2,530 randomly assigned participants in 30 trials, most of them short-term. Clozapine-treated patients showed more clinical improvement and experienced significantly fewer relapses during treatment, although the risk of blood dyscrasias in long-term treatment may be as high as 7%. Scores on symptom rating scales showed greater improvement among clozapine-treated patients, who were also more satisfied with their treatment. However, there was no evidence that the superior clinical effect of clozapine is reflected in levels of functioning; on the other hand, global functional and pragmatic outcomes were frequently not reported. Clinical improvement was most pronounced in patients with treatment-resistant illness. This meta-analysis confirms that clozapine is more effective than conventional neuroleptics in reducing symptoms of patients with both treatment-resistant and nonresistant schizophrenia. Future trials should be long-term pragmatic community trials or should address the effectiveness of clozapine in special patient populations. An international standard set of outcomes, including pragmatic assessments of functioning, would greatly enhance the comparison and summation of trials and future assessments of effectiveness.",1999.0,0,1
48,10401484,Risperidone and clozapine for treatment-resistant schizophrenia.,H Y Meltzer,,1999.0,0,1
49,10401912,Novel antipsychotics: comparison of weight gain liabilities.,D A Wirshing; W C Wirshing; L Kysar; M A Berisford; D Goldstein; J Pashdag; J Mintz; S R Marder,"We performed a retrospective analysis of 122 clinical records of 92 male patients with DSM-III-R schizophrenia to examine the relative weight gain liabilities of clozapine, risperidone, olanzapine, and sertindole compared with haloperidol. We hypothesized that the unique pharmacodynamic profiles of these agents would contribute to different amounts and patterns of weight gain. Data were analyzed to determine differences in weight gain during treatment among patients receiving 5 different drug treatments (clozapine [N = 20], olanzapine [N = 13], risperidone [N = 38], haloperidol [N = 43], and sertindole [N = 8]). Measures of maximal weight gain, final weight, and duration to maximal weight gain were calculated. Repeated measures analyses of variance controlling for age, treatment duration, and initial weight revealed statistically significant differences between groups on all 3 measures. Clozapine and olanzapine had the greatest maximal weight gain liability (F = 4.13, df = 4,23; p = .01). Weight gain with clozapine, but not olanzapine or risperidone, appears to persist (as reflected by final weight) despite behavioral interventions (e.g., nutritional consultation, suggested exercise regimen; F = 5.69, df = 4,23; p = .003). Clozapine- and olanzapine-treated subjects appeared to gain weight over a prolonged period of time, whereas risperidone-and sertindole-treated subjects had a more limited period of weight gain (F = 2.95, df = 4,25; p = .04). Clozapine and olanzapine caused the most weight gain, risperidone was intermediate, and sertindole had less associated weight gain than haloperidol. The relative receptor affinities of the novel antipsychotics for histamine H1 appear to be the most robust correlate of these clinical findings.",1999.0,0,1
50,10401913,Clozapine and obsessions in patients with recent-onset schizophrenia and other psychotic disorders.,L de Haan; D H Linszen; R Gorsira,"The increase or emergence of obsessions was compared in young patients with recent-onset schizophrenia or other psychotic disorders taking clozapine and other antipsychotic drugs. We conducted a retrospective cohort study. Subjects were 121 consecutively admitted patients diagnosed with DSM-III-R schizophrenia, schizoaffective disorder, schizophreniform disorder, or psychotic disorder not otherwise specified. Obsessions were diagnosed according to DSM-IV criteria. More clozapine-treated subjects (20.6%) than subjects treated with other antipsychotic drugs (1.3%) experienced an emergence or increase of obsessions (p<.01). Use of clozapine is associated with the emergence or increase of obsessions in early-phase schizophrenia.",1999.0,0,0
51,10401914,Lithium augmentation fails to reduce symptoms in poorly responsive schizophrenic outpatients.,S C Schulz; P A Thompson; M Jacobs; P T Ninan; D Robinson; P J Weiden; K Yadalam; I D Glick; C L Odbert,"Nearly one third of patients suffering from schizophrenia do not fully respond to antipsychotic medication. Safe, effective, and cost-efficient methods to reduce symptoms are clearly needed; therefore, lithium as an adjunct to fluphenazine decanoate was tested in a placebo-controlled trial in outpatients who were part of the Treatment Strategies of Schizophrenia (TSS) study. Forty-one patients with DSM-III schizophrenia or schizoaffective disorder were assigned to either adjunctive lithium or placebo after at least 6 months of fluphenazine decanoate treatment to stabilize symptoms had failed. The trial was designed for 8 weeks of treatment, and patients assigned to placebo could afterward be administered lithium in an 8-week, open-label study. Assessment of the intent-to-treat analysis revealed no significant differences in demographic variables between the lithium and placebo groups. Although both groups showed significant (p = .00135) improvement as measured by total scores on the Brief Psychiatric Rating Scale (BPRS), there were no significant differences in response between the lithium and placebo groups. Patients originally treated with placebo added to neuroleptic did not have significantly greater improvement when receiving open-label adjunctive lithium. Although success with lithium augmentation therapy for persistent psychosis has been reported in the past, this study of well-characterized patients showed no benefit for this common strategy, thus indicating that care be used in utilizing lithium augmentation.",1999.0,0,0
52,10402608,Cognitive-behavioral therapy and clozapine for clients with treatment-refractory schizophrenia.,A Pinto; S La Pia; R Mennella; D Giorgio; L DeSimone,,1999.0,0,0
53,10404707,,,,,0,0
54,10404715,Olanzapine in the treatment of adolescent acute mania: a report of seven cases.,C A Soutullo; M T Sorter; K D Foster; S L McElroy; P E Keck,"Clozapine may be effective in adults and adolescents with treatment-resistant bipolar disorder. Olanzapine has a receptor affinity profile similar to that of clozapine. The responses of seven consecutive adolescents (ages 12-17) with DSM-IV bipolar disorder, manic episode, treated with olanzapine were evaluated. Response to olanzapine was rated as marked, moderate, minimal, none or worse. Five (71%) adolescents showed a marked or moderate response. The mean+/-SD olanzapine dose was 0.146+/-0.086 mg/kg/day (11+/-6 mg/day). Olanzapine may have antimanic effects in some adolescents with acute mania. Controlled studies of olanzapine in adolescent bipolar disorder appear to be warranted.",1999.0,0,0
55,10410494,"Comparison of the efficacy and acceptability of atypical antipsychotic drugs: a meta-analysis of randomized, placebo-controlled trials.",M Srisurapanont; N Maneeton,"Knowing the clinical differences of olanzapine, quetiapine, and risperidone would be of benefit for choosing an atypical antipsychotic drug. In order to compare their efficacy and acceptability, we conducted a meta-analysis of published, randomized, placebo-controlled trials by comparing the response and dropout rates of an atypical antipsychotic drug group and those of a placebo group. After a comprehensive search of study reports, the response and dropout rates of patients treated with an atypical antipsychotic drug and those treated with placebo were extracted on the intention-to-treat basis. The effect size with 95 per cent confidence interval (CI) of pooled data comparing the response and dropout rates of an atypical antipsychotic drug group and those of a placebo group were calculated by using the Peto method. The response-rate effect sizes (95% CIs) of olanzapine, quetiapine, and risperidone were 1.75 (1.06 to 2.89), 1.71 (1.20 to 2.42), and 3.28 (1.98 to 5.44), respectively. The dropout-rate effect sizes (95% CIs) of olanzapine, quetiapine, and risperidone were 0.55 (0.35 to 0.88), 0.65 (0.46 to 0.91), and 0.39 (0.24 to 0.62), respectively. In conclusion, olanzapine, quetiapine, and risperidone are more effective and more acceptable than placebo in treating schizophrenic patients. However, they are not different from each other in the respect of efficacy and acceptability. The cost of these agents should play an important role in choosing an atypical antipsychotic drug.",1999.0,0,0
56,10416727,The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis.,R S Keefe; S G Silva; D O Perkins; J A Lieberman,"Cognitive deficits are a fundamental feature of the psychopathology of schizophrenia. Yet the effect of treatment on this dimension of the illness has been unclear. Atypical antipsychotic medications have been reported to reduce the neurocognitive impairment associated with schizophrenia. However, studies of the pattern and degree of cognitive improvement with these compounds have been methodologically limited and have produced variable results, and few findings have been replicated. To clarify our understanding of the effects of atypical antipsychotic drugs on neurocognitive deficits in patients with schizophrenia, we have (1) reported on newly established standards for research design in studies of treatment effects on cognitive function in schizophrenia, (2) reviewed the literature on this topic and determined the extent to which 15 studies on the effect of atypical antipsychotics met these standards, (3) performed a meta-analysis of the 15 studies, which suggested general cognitive enhancement with atypical antipsychotics, and (4) described the pharmacological profile of these agents and considered the pharmacological basis for their effects on neurocognition. Finally, we suggest directions for the development of new therapeutic strategies.",1999.0,0,0
57,10416728,Risperidone versus haloperidol on secondary memory: can newer medications aid learning?,R S Kern; M F Green; B D Marshall; W C Wirshing; D Wirshing; S R McGurk; S R Marder; J Mintz,"The introduction of the new generation of antipsychotic medications for the treatment of schizophrenia has been accompanied by a growing interest in the neurocognitive effects of these drugs. The present study compared the effects of risperidone and haloperidol on secondary memory in a group of treatment-resistant schizophrenia patients. The study design included a baseline phase and two double-blind phases in which patients were randomly assigned to medication under two different dose conditions (fixed dose and flexible dose). Secondary memory was assessed at baseline, fixed-dose, and flexible-dose phases, using the California Verbal Learning Test (CVLT). Six measures were selected, which formed three factors (general verbal learning ability, retention, and learning strategy). Risperidone-treated patients showed greater improvement than haloperidol-treated patients in general verbal learning ability, a finding characterized by significant treatment effects on CVLT measures of learning acquisition, recall consistency, and recognition memory. After controlling for benztropine status, differences on the measures of learning acquisition and recall consistency remained significant, and differences in recognition memory weakened slightly (p = 0.07). No significant treatment effects were noted on retention or learning strategy. These findings suggest that risperidone may exert a facilitating effect on the acquisition of new verbal information, an effect that does not appear to be due to the activation of semantic encoding strategies.",2001.0,1,1
58,10416729,"The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia.",H Y Meltzer; S R McGurk,"Cognitive function is markedly impaired in most patients with schizophrenia. Antecedents of this impairment are evident in childhood. The cognitive disability is nearly fully developed at the first episode of psychosis in most patients. The contribution of cognitive impairment to outcome in schizophrenia, especially work function, has been established. Preliminary results indicate that cognitive function, along with disorganization symptoms, discriminate schizophrenia patients who are able to work full-time from those who are not. Typical neuroleptic drugs lack the ability to improve the various domains of cognitive function impaired in schizophrenia. Atypical antipsychotic drugs pharmacologically related to clozapine-quetiapine, olanzapine, risperidone, sertindole, and ziprasidone--share the ability to produce fewer extrapyramidal symptoms than typical neuroleptic drugs and more potent antagonism of serotonin2a relative to dopamine2 receptors. However, they have a number of different clinical effects. We have identified all the studies of clozapine, olanzapine, and risperidone that provide data on their effects on cognition in schizophrenia. Data for each drug are reviewed separately in order to identify differences among them in their effects on cognition. Twelve studies that report cognitive effects of clozapine are reviewed. These studies provide (1) strong evidence that clozapine improves attention and verbal fluency and (2) moderate evidence that clozapine improves some types of executive function. However, results of the effects of clozapine on working memory and secondary verbal and spatial memory were inconclusive. Risperidone has relatively consistent positive effects on working memory, executive functioning, and attention, whereas improvement in verbal learning and memory was inconsistent. Preliminary evidence presented here suggests that olanzapine improves verbal learning and memory, verbal fluency, and executive function, but not attention, working memory, or visual learning and memory. Thus, atypical antipsychotic drugs as a group appear to be superior to typical neuroleptics with regard to cognitive function. However, available data suggest that these drugs produce significant differences in specific cognitive functions. These differences may be valuable adjunctive guides for their use in clinical practice if cognitive improvements reach clinical significance. The effects of the atypical antipsychotic drugs on cholinergic and 5-HT2a-mediated neurotransmission as the possible basis for their ability to improve cognition are discussed. It is suggested that the development of drugs for schizophrenia should focus on improving the key cognitive deficits in schizophrenia: executive function, verbal fluency, working memory, verbal and visual learning and memory, and attention.",1999.0,0,1
59,10416732,The effects of neurocognitive remediation on executive processing in patients with schizophrenia.,T Wykes; C Reeder; J Corner; C Williams; B Everitt,"Approaches to cognitive remediation have differed across studies. Most of the larger studies have concentrated on group treatments designed without the benefit of recent laboratory-based studies. The current study describes a randomized trial of an intensive cognitive remediation program involving individual daily sessions of 1 hour for up to 3 months. It targets executive functioning deficits (cognitive flexibility, working memory, and planning) that are known to be problematic in people with schizophrenia. Procedural learning, as well as the principles of errorless learning, targeted reinforcement, and massed practice, was the basis of the intervention. The program was compared with an alternative therapy (intensive occupational therapy) to control for some of the effects of therapeutic contact. Some improvements in cognition followed both therapies. A differential effect in favor of cognitive remediation therapy was found for tests in the cognitive flexibility and the memory subgroups. There was a trend for those receiving atypical antipsychotic medication to benefit more from cognitive remediation for tests of cognitive flexibility. Although there were no consistent changes in symptoms or social functioning between groups, if improvement in cognitive flexibility tasks reached a threshold then there is some evidence that social functioning improved, even over the short duration of the trial. In addition, cognitive remediation differentially improved self-esteem. This study supports the view that cognitive remediation can reduce cognitive deficits and that this reduction may affect social outcome, at least in the short term.",1999.0,0,0
60,10416734,Glucose-induced increase in memory performance in patients with schizophrenia.,J W Newcomer; S Craft; R Fucetola; S O Moldin; G Selke; L Paras; R Miller,"Previous investigations have found that increasing circulating glucose availability can increase memory performance in rodents, healthy humans, and individuals with dementia of the Alzheimer's type. In this study, patients with schizophrenia, healthy control subjects, and controls with bipolar affective disorder were tested using double-blind treatment with either 50 g anhydrous dextrose plus 4 mg sodium saccharin (for ""taste"") or 23.7 mg saccharin alone, followed by cognitive testing on a complex battery. At this glucose dose, verbal memory performance on a paragraph recall task was increased during the glucose condition relative to the saccharin condition in the patients with schizophrenia; this effect was not detected in either the psychiatric or normal controls. The results provide preliminary support for the hypothesis that memory performance can be improved in patients with schizophrenia by increasing circulating glucose availability and suggest the importance of further evaluation of therapeutic manipulations of glucose availability.",1999.0,0,0
61,10416740,"Antipsychotics: Past and Future: National Institute of Mental Health Division of Services and Intervention Research Workshop, July 14, 1998.",K Dawkins; J A Lieberman; B D Lebowitz; J K Hsiao,"A workshop on ""Antipsychotics: Past and Future"" was convened by the National Institute of Mental Health (NIMH), Division of Services and Intervention Research (DSIR), on July 14, 1998, to review the results of recent antipsychotic drug research, discuss current standards of treatment, and identify areas needing further study. There has been a proliferation of new antipsychotic medications and a rapid increase in their clinical utilization. The new atypicals are beginning to supplant the older typical neuroleptic antipsychotics, and the scientific and ethical issues raised by this transition prompted the workshop. Given the apparent, albeit not fully defined, advantages of atypical drugs, particularly their safety profiles, the question is whether more comparisons with typical antipsychotics are warranted and whether clinical trial designs warrant (or would be justified in) the inclusion of typical drugs as standard active comparators. Workshop participants--including clinical researchers, patient advocates, bioethicists, and NIMH staff--discussed the conclusions drawn from current data, ethical issues for subjects in clinical trials, funding for ongoing studies using typical agents, and appropriate comparators for trials using atypical agents.",1999.0,0,0
62,10424639,"Reliability, validity, and application of the medical outcomes study 36-item short-form health survey (SF-36) in schizophrenic patients treated with olanzapine versus haloperidol.",S L Tunis; T W Croghan; D K Heilman; B M Johnstone; R L Obenchain,"Schizophrenia leads to impairments in mental, social, and physical functioning, which should be included in evaluations of treatment. This study was designed to determine the reliability and validity of the Medical Outcomes Study Short Form Health Survey (SF-36) for schizophrenic patients, to characterize perceived functioning and well being and to compare short-term change in SF-36 scores for patients treated with olanzapine or haloperidol. Data were obtained from a randomized, double-blind trial comparing these agents for safety, efficacy, and cost effectiveness. A 6-week acute treatment portion preceded a 46-week ""responder extension"" phase. A subsample (n = 1,155) completing a pre-treatment SF-36 provided data for this study. Psychometric analyses were conducted, and perceived level of functioning was compared with that for the US adult population. Change from baseline to 6 weeks was examined by treatment group. Clear evidence was obtained for the instrument's reliability and validity for these patients. There were marked deficits in General health, Vitality, Mental health, Social functioning, and in Role limitations resulting from both physical and emotional problems. Olanzapine-treated patients improved in 5 of 8 domains to a significantly greater degree than did haloperidol patients. The SF-36 can be a reliable and valid measure of perceived functioning and well being for schizophrenic patients. The perceptions of functioning can be valuable indices of disease burden and can help to demonstrate the effectiveness of newer antipsychotic medications such as olanzapine.",1999.0,0,1
63,10432467,Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia.,G W Dalack; L Becks; E Hill; O F Pomerleau; J H Meador-Woodruff,"The prevalence of smoking is markedly elevated in schizophrenia. Low smoking cessation rates and reports that some smokers with schizophrenia experience an acute increase in symptoms during attempts to quit smoking, suggest a self-medication model. Alternatively, smoking may modulate medication side effects. The effects of treated and untreated smoking abstinence on psychotic symptoms and medication side effects were examined in this study. Nineteen outpatients with schizophrenia or schizoaffective disorder participated in a randomized, double-blind, balanced crossover study: 1 day of ad libitum smoking followed by 3 days of acute smoking abstinence while wearing 22 mg/day active or placebo transdermal nicotine patches, with a return to 3 days of smoking between patch conditions. Daily symptom and side-effect ratings, nicotine and cotinine blood levels were collected. Twelve subjects completed the study. Neither positive symptoms nor mood symptoms changed. An increase in negative symptoms during the first abstinent day occurred in both placebo and active patch conditions, but was not sustained over subsequent abstinent days. Despite physiological signs of withdrawal, completers did not endorse increased nicotine withdrawal symptoms. Dropouts reported higher withdrawal symptoms, but also had no increase in psychiatric symptoms in either phase of the study. Of note, dyskinesias decreased during abstinence and placebo patch treatment, but increased during abstinence and the active patch conditions. Acute exacerbation of psychiatric symptoms is an unlikely explanation for any difficulty smokers with schizophrenia have in early abstinence.",1999.0,0,0
64,10432468,,,,,0,0
65,10435201,"The psychosis of schizophrenia: prevalence, response to atypical antipsychotics, and prediction of outcome.",A Breier; P H Berg,"Psychosis is a defining feature of schizophrenia consisting of formal thought disorder, delusions, and hallucinations. Although psychosis is present in the majority of patients with schizophrenia, the prevalence, responsiveness to atypical antipsychotic drug therapy, and prediction of outcome of individual psychotic symptoms in a population of well-diagnosed patients with schizophrenia have not been conclusively established. This paper examined the prevalence, responsiveness to the atypical antipsychotic olanzapine, and relationship to outcome of individual psychotic symptoms using data from a previously reported large multicenter, double-blind clinical trial of olanzapine (mean daily dose at endpoint = 13.6 +/- 6.9 mg/day). The most frequently reported psychotic symptoms at baseline were delusions (65%), conceptual disorganization (50%), and hallucinations (52%), and the majority of patients (68%) experienced from one to three symptoms. Additionally, with olanzapine treatment there were significant improvements (p < .001) in baseline to endpoint Positive and Negative Symptom Scale (PANSS) psychotic item scores, with the largest effect sizes observed for hallucinatory behavior, unusual thought content, suspiciousness/persecution, and delusions. During the acute phase of the trial, quality of life was correlated significantly with baseline conceptual disorganization (p = .038) and unusual thought content (p = .023), and time spent in the hospital was correlated with unusual thought content (p = .005). The implications of these for the clinical management of schizophrenia are discussed.",1999.0,0,1
66,10435503,An open trial of clozapine for dystonia.,B I Karp; S R Goldstein; R Chen; A Samii; W Bara-Jimenez; M Hallett,"Pharmacologic treatment of severe dystonia is often unsatisfactory. The atypical antipsychotic medication clozapine appears to improve tardive dystonia associated with conventional neuroleptic use. We studied the efficacy of clozapine for severe dystonia in five patients in an open trial. The patient cohort included four with generalized dystonia and one with Meige syndrome. All patients were evaluated at baseline and at least weekly while on medication with subjective assessment of response by the patient and physician rating using the Burke-Fahn-Marsden Evaluation Scale for Dystonia. All five subjects had significant improvement detected by the Burke-Fahn-Marsden Evaluation Scale as well as subjective improvement while on clozapine. Side effects, such as sedation and orthostatic hypotension, developed in all patients but was only treatment-limiting in one subject who developed persistent symptomatic orthostatic hypotension and tachycardia. Two of the four remaining patients continued clozapine after completion of the study; an additional patient was uncertain if the benefit outweighed the side effects. One patient discontinued treatment because of difficulty obtaining the FDA-required weekly white blood cell counts for patients on clozapine. We conclude that clozapine appears to be effective for generalized and refractory focal dystonia although its use may be limited by the side effects and need for hematologic monitoring.",1999.0,0,0
67,10435771,A comparison of olanzapine with haloperidol in cannabis-induced psychotic disorder: a double-blind randomized controlled trial.,M Berk; S Brook; A I Trandafir,"Little controlled data exist on the treatment of substance induced psychotic disorders. In this study, 30 patients meeting DSM-IV criteria for cannabis induced psychotic disorder were randomly allocated to receive either olanzapine or haloperidol in a 4-week double-blind clinical trial. There were no significant outcome differences between the two groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale (haloperidol 25.7; olanzapine 27.1; P = 0.70); Clinical Global Impression (CGI) severity scale (haloperidol 1.8, olanzapine 2.3; P = 0.21) or the CGI improvement scale (haloperidol 1.3, olanzapine 1.7; P = 0.16). The haloperidol group however, developed significantly more extrapyramidal side-effects as measured by the Simpson Angus Scale (haloperidol 11.4, olanzapine 2.5; P = 0.014). Significantly (P = 0.027) more biperidin was used for extrapyramidal side-effects in the haloperidol (7.143 mg) than in the olanzapine (0.357 mg) group. Olanzapine appears to be as effective as haloperidol in the treatment of cannabis induced psychotic disorder, but is associated with a lower rate of extrapyramidal side-effects.",1999.0,0,0
68,10440464,Use of atypical antipsychotic agents in bipolar and schizoaffective disorders: review of the empirical literature.,S N Ghaemi; F K Goodwin,"Atypical antipsychotic agents seem to be effective treatments for bipolar disorder, especially as adjunctive treatments. They may be a safer and more effective alternative to the common practice of maintenance adjunctive treatment with traditional antipsychotic agents in patients with bipolar disorder. However, currently available research studies are limited methodologically mainly to open-label, uncontrolled designs. Further research is required before the definitive efficacy of these agents in bipolar disorder is established. If randomized or double-blind data support the open-label data reviewed here, atypical antipsychotic agents may possess an important role in the adjunctive treatment of bipolar disorder.",1999.0,0,0
69,10448449,"Treatment of neuroleptic-induced akathisia with the 5-HT2 antagonist mianserin. Double-blind, placebo-controlled study.",M Poyurovsky; M Shardorodsky; C Fuchs; M Schneidman; A Weizman,"Serotonin (5-HT):dopamine imbalance may underlie neuroleptic-induced akathisia. To evaluate the efficacy of the 5-HT2 antagonist, mianserin in neuroleptic-induced akathisia. Thirty neuroleptic-treated patients with schizophrenia were randomly allocated in a double-blind design to receive either mianserin (15 mg/day) or placebo for five days. Patients were assessed at baseline and on Days 3 and 5 by the Barnes Akathisia Scale (BARS), as well as by other relevant clinical rating scales. Compared with the placebo group, the mianserin-treated patients showed a significant reduction in all four BARS subscales by Day 5, with mean reductions in the BARS global score of 9.9% and 52.2%, respectively (P = 0.006). Response to treatment (a reduction of at least two points on the BARS global subscale), was noted in six patients (40%) in the mianserin group and only one patient (9.1%) in the placebo group (P = 0.04, log odds ratio 2.23). Mianserin at a low dose may be a promising therapeutic option for patients with acute neuroleptic-induced akathisia.",1999.0,0,0
70,10450255,Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania.,T Suppes; A Webb; B Paul; T Carmody; H Kraemer; A J Rush,"Case series and follow-up studies suggest that clozapine may have mood-stabilizing properties in addition to antipsychotic action in patients with schizoaffective disorder, bipolar type, and bipolar I disorder, but the generalizability of these findings is limited. This article describes a randomized, open study of clozapine add-on therapy versus treatment as usual for patients with treatment-resistant illness and a history of mania. Thirty-eight patients meeting the DSM-IV criteria for schizoaffective or bipolar disorder that was deemed treatment-resistant were randomly assigned to clozapine add-on treatment (N = 19) or treatment as usual (no clozapine) (N = 19) and followed up for 1 year. Patients received monthly ratings on the Brief Psychiatric Rating Scale, Clinical Global Impression scale, Bech-Rafaelsen Mania Scale, Hamilton Depression Rating Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, Abnormal Involuntary Movement Scale, and a 40-item side effect checklist. Differences between treatment groups were assessed according to a pattern-mix random-regression model. An additional analysis compared group differences in rating scale scores against relative time in the study. Significant between-group differences were found in scores on all rating scales except the Hamilton depression scale. Total medication use over 1 year significantly decreased in the clozapine group. No significant differences between groups in somatic complaints were noted. The subjects with nonpsychotic bipolar I disorder who received clozapine showed a degree of improvement similar to that of the entire clozapine-treated group. Clozapine dose was significantly higher for the patients with schizoaffective illness than for those with bipolar disorder. The results of this study support clozapine's independent mood-stabilizing property. They demonstrate that clozapine use was associated with significant clinical improvement relative to treatment as usual.",1999.0,0,1
71,10453803,Clozapine reduces severe self-mutilation and aggression in psychotic patients with borderline personality disorder.,K N Chengappa; T Ebeling; J S Kang; J Levine; H Parepally,"Clozapine has been reported to be effective in diminishing violence toward others in psychotic patients. This article describes the impact of clozapine on severe self-mutilation among patients with the dual diagnoses of borderline personality disorder and persistent psychoses. Seven subjects known to the authors were selected for careful chart audits. These subjects had been admitted to 2 state psychiatric hospitals owing to severe self-mutilation and/or violence and subsequently treated with clozapine. A mirror-image design anchored to the start date of clozapine treatment and extending in either direction to a maximum of 1 year was used to extract data. Data extracted included incidents of self-mutilation (restraint), seclusion, the as and when needed (p.r.n.) use of medications, injuries to staff and peers, hospital privileges, and Global Assessment of Functioning (GAF) scores. The subjects were all white women with a mean age of 37 years. All subjects carried DSM-III-R or DSM-IV borderline personality disorder diagnoses and an Axis I disorder diagnosis. They had received trials of several psychotropic agents, often in combination and mostly without benefit. After clozapine treatment, there were statistically significant reductions in incidents of self-mutilation (restraint), seclusion, the use of p.r.n. antianxiety medications, and injuries to staff and peers. These subjects received higher levels of hospital privileges, and their GAF scores nearly doubled following clozapine treatment. Four subjects were subsequently discharged from hospital. These preliminary but nonetheless favorable results suggest that clozapine deserves careful consideration for a controlled study in patients with borderline personality disorder and psychoses, especially if the clinical issues include severe self-mutilation, aggression, and violence. Until such studies are done, the risk-to-benefit ratio of clozapine treatment needs to be carefully evaluated on an individualized basis in such subjects.",1999.0,0,1
72,10464776,[Early phase II study of quetiapine fumarate on schizophrenia].,M Murasaki; T Yamauchi; G Yagi; T Nakajima; Y Nakane; Y Kudo,"The efficacy and safety of quetiapine fumurate in the treatment of patients with schizophrenia were evaluated in an 8-week, multicenter, open-label study. The results of this study which included a total of 54 patients showed good efficacy and safety profile for quetiapine fumarate as seen by the improvement rate (moderate or above in the final global improvement rating) of 49.1% and safety rate (no problem in overall safety rating) of 66.0%. The mean BPRS total score decreased significantly from 55.5 +/- 10.9 points at baseline to 45.4 +/- 13.0 points at the completion of administration. The PANSS scores also showed significant improvement on all scales; the mean scores decreased from 20.7 +/- 6.3 points at baseline to 17.7 +/- 6.9 points at withdrawal or completion of administration on the positive scale, from 27.8 +/- 5.8 points to 24.0 +/- 7.3 points on the negative scale, and from 51.4 +/- 10.1 points to 44.7 +/- 12.4 points on the general psychopathology scale. Although the most frequent adverse reactions were somnolence (18.9%), insomnia (17.0%), nervousness (13.2%), dizziness (13.2%), malaise (13.2%), postural hypotension (11.3%), tachycardia (9.4%), and constipation (9.4%), the incidence of extrapyramidal symptoms was low (11.3%). From these results, quetiapine fumarate was suggested to be highly effective and safe for the treatment of schizophrenia.",1999.0,0,0
73,10468313,Safety of amisulpride (Solian): a review of 11 clinical studies.,C Coulouvrat; L Dondey-Nouvel,"We assessed the overall safety profile of amisulpride based on the results from 11 clinical studies performed in patients suffering from schizophrenia with predominance of positive or negative symptoms. A total of 1933 patients were randomly assigned to treatment with amisulpride (n = 1247) or haloperidol (n = 309), risperidone (n = 113), flupentixol (n = 62) and placebo (n = 202). Safety data collection was performed using open reporting, UKU scales or specific extrapyramidal side-effect scales; electrocardiogram recording and vital signs examination; laboratory data collection. Amisulpride demonstrated a satisfactory global safety profile in the range of doses usually prescribed. The number of patients having at least one extrapyramidal side-effect was higher in haloperidol patients compared with both amisulpride and risperidone patients (50% versus 30% in the two latter groups). For endocrine events, a similar rate was observed between amisulpride and risperidone groups (4% versus 6%, respectively) versus 1% in the haloperidol group. Electrocardiogram results were satisfactory, confirmed by the absence of cardiovascular events. The overall laboratory safety profile of amisulpride did not show clinically relevant abnormalities in liver function tests nor haematological abnormalities. Our extensive clinical data confirm the satisfactory safety profile of amisulpride which is superior to standard reference compounds.",1999.0,0,0
74,10474283,Olanzapine versus haloperidol in the treatment of schizophrenia and other psychotic disorders: quality of life and clinical outcomes of a randomized clinical trial.,D A Revicki; L A Genduso; S H Hamilton; D Ganoczy; C M Beasley,"Little information is available on the impact of the atypical antipsychotic olanzapine on quality of life (QOL). A 6-week, double-blind randomized multicenter trial, with a long-term extension, was conducted to evaluate the clinical efficacy and QOL of olanzapine and haloperidol in treating schizophrenia and other psychotic disorders. A total of 828 outpatients provided QOL data. Study patients were aged greater than 18 years with a DSM-III-R diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder and baseline BPRS (items scored on 0-6 scale) total scores, > or = 18 were randomized to 6 weeks of treatment with olanzapine 5 to 20 mg/day or haloperidol 5 to 20 mg/day. Patients entered a 46-week double-blind extension if they demonstrated minimal clinical response and were tolerant to study medication. The Quality of Life Scale (QLS) and SF-36 Health Survey were used to evaluate QOL. During the 6-week acute phase, olanzapine treatment significantly improved BPRS total (p = 0.004), PANSS total scores (p = 0.043), QLS total (p = 0.005), intrapsychic foundations (p < 0.001) and interpersonal relations scores (p = 0.036), and SF-36 mental component summary scores (p < 0.001) compared with haloperidol. During the extension phase, olanzapine treatment significantly improved PANSS negative scores (p = 0.035) and improved QLS total (p = 0.001), intrapsychic foundations (p < 0.001), and instrumental role category scores (p = 0.015) versus haloperidol treatment. Significantly more haloperidol patients discontinued treatment due to adverse events during the acute and extension phases (p = 0.041 and p = 0.014, respectively). Changes in QLS total and MCS scores were associated with changes in clinical symptoms, depression scores and extrapyramidal symptoms. Olanzapine was more effective than haloperidol in reducing severity of psychopathology and in improving QOL in patients with schizophrenia and other psychotic disorders. The QOL benefits of olanzapine, although modest, may be important for long-term treatment.",2001.0,1,1
75,10479950,New-onset diabetes mellitus and diabetic ketoacidosis associated with olanzapine treatment.,L E Goldstein; J Sporn; S Brown; H Kim; J Finkelstein; G K Gaffey; G Sachs; T A Stern,,1999.0,0,1
76,10482120,Experience with the atypical antipsychotics--risperidone and olanzapine in the elderly.,S Madhusoodanan; P Suresh; R Brenner; R Pillai,"There is paucity of published data regarding controlled trials with risperidone and olanzapine in elderly psychotic patients. Medical records of 151 hospitalized geropsychiatric patients (risperidone patients n = 114 and olanzapine patients n = 37) were analyzed for demographic data, target symptoms, doses, effects, side effects, comorbid medical conditions and concurrent medications. The mean age of the patients was 71 years. The male: female ratio was essentially the same for both groups. The mean daily dose was 3 mg for risperidone and 10 mg for olanzapine. 78% of the risperidone group and 75% of the olanzapine group appear to have responded to treatment. The discontinuation rates of medication was the same in both groups (22%). Adverse events were reported in 16-17% in both groups. It appears from this study that both risperidone and olanzapine are relatively safe and effective in geropsychiatric patients with comorbid medical illnesses. Controlled studies and head-to-head comparison studies are recommended.",1999.0,0,0
77,10482343,Effects of clozapine on awareness of illness and cognition in schizophrenia.,S Pallanti; L Quercioli; A Pazzagli,"Awareness of illness is a crucial factor in schizophrenia, both for clinical management and psychopathological modeling. To date, there has been relatively little investigation of the influence of treatment with conventional versus atypical neuroleptics in relation to awareness and cognitive functions. The effect of clozapine treatment, compared with conventional neuroleptics, was studied in 22 schizophrenic patients in a crossover study. The P300 component of the event-related potential and scores on the Scale for Unawareness of Mental Disorder (SUMD), the Extrapyramidal Side Effects Scale (EPS), and Andreasen's Scales for the Assessment of Positive (SAPS) and Negative Symptoms (SANS) were studied at time 1 (conventional neuroleptic treatment) and time 2 (after 6 months of treatment with clozapine, in patients who interrupted the previous conventional regimen). Significantly increased P300 amplitudes were associated with clozapine treatment, together with heightened insight and reduced involuntary movements. The results confirm the effectiveness of clozapine not only in enhancing neurocognitive function, but also in increasing awareness of illness in schizophrenic patients.",1999.0,0,1
78,10484947,Risperidone in treatment-refractory schizophrenia.,D A Wirshing; B D Marshall; M F Green; J Mintz; S R Marder; W C Wirshing,"The purpose of this study was to evaluate the clinical safety and efficacy of risperidone compared to haloperidol in patients with treatment-refractory schizophrenia. Sixty-seven medication-unresponsive subjects were randomly assigned to treatment with risperidone (N = 34) or haloperidol (N = 33). After a 3-7 day-placebo washout period, there was a 4-week, double-blind, fixed-dose comparison trial that was followed by a 4-week, flexible-dose phase. Measures of clinical change were quantified by standard psychopathologic and neuromotor instruments. Risperidone demonstrated clinical efficacy superior to that of haloperidol on the total Brief Psychiatric Rating Scale (BPRS) after the first 4 weeks of treatment. Risperidone did not show any advantage over haloperidol after an additional 4 weeks. Overall improvement on the BPRS at 4 weeks was significantly better for the risperidone group (24%) than for the haloperidol group (11%). Risperidone-treated subjects were significantly less likely than haloperidol-treated subjects to require concomitant anticholinergic medication after 4 weeks (20% versus 63%); they also had significantly les observable akathisia (24% versus 53%) and significantly less severe tardive dyskinesia. Baseline characteristics that correlated significantly with risperidone response were positive symptoms, conceptual disorganization, akathisia, and tardive dyskinesia. Risperidone was better tolerated and more effective in a subset of patients with treatment-refractory schizophrenia. Positive psychotic symptoms and extrapyramidal side effects at baseline appear to be powerful predictors of subsequent response to risperidone.",2001.0,0,1
79,10484954,Elevated frequency of diabetes mellitus in hospitalized manic-depressive patients.,F Cassidy; E Ahearn; B J Carroll,"Disturbance in glucose homeostasis in psychiatric populations has been suggested since the early part of this century. Increased comorbidity of diabetes mellitus in persons with major mood disorders has also been suggested. The goal of this study was to determine whether subjects diagnosed with bipolar disorder have an elevated rate of comorbid diabetes mellitus. Three hundred forty-five hospitalized patients, aged 20-74 years, who met the DSM-III-R criteria for bipolar disorder, manic or mixed subtype, were evaluated for a comorbid diagnosis of diabetes mellitus. The frequency of diabetes mellitus in the study group was determined and compared with the expected frequency, calculated as a weighted average based on sex and age from national norms. Variables characterizing the course and severity of the affective disorder in the group of diabetic bipolar subjects and a group of nondiabetic age-matched bipolar subjects were compared. The prevalence of diabetes mellitus among these bipolar patients was 9.9%, significantly greater than expected from national norms (3.4%). The patients with comorbid diabetes mellitus had significantly more lifetime psychiatric hospitalizations than the nondiabetic subjects, but age at first hospitalization and duration of psychiatric disorder were similar in the two groups. The frequency of diabetes mellitus in hospitalized patients diagnosed with bipolar disorder is higher than in the general population. Manic-depressive patients with diabetes mellitus have a more severe course of illness, as indicated by a greater number of psychiatric hospitalizations. Possible reasons for this increased comorbidity include a genetic relationship between the disorders, a causal relationship in which hypercortisolemia induces diabetes or diabetic vascular lesions contribute to mania, an overlapping functional disturbance affecting similar regions of the brain, or the effect of psychotropic medications.",1999.0,0,1
80,10485634,Olanzapine addition in obsessive-compulsive disorder refractory to selective serotonin reuptake inhibitors: an open-label case series.,E L Weiss; M N Potenza; C J McDougle; C N Epperson,"Despite the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of obsessive-compulsive disorder, a significant number of patients show no or only partial remission of symptoms. Some evidence exists to suggest that risperidone augmentation can be helpful in treating this refractory group. The efficacy of other atypical antipsychotic agents, such as olanzapine, in augmenting SSRIs in refractory obsessive-compulsive patients has yet to be systematically investigated. A series of 10 patients with DSM-IV obsessive-compulsive disorder showing significant residual symptoms following an adequate SSRI trial (12 weeks) were given open-label olanzapine augmentation for a minimum of an additional 8 weeks. Treatment response was assessed using the Yale-Brown Obsessive Compulsive Scale and the Clinical Global Impressions scale. Nine of the 10 patients in this series treated with olanzapine and an SSRI completed the 8-week augmentation trial. Of these, 4 demonstrated a complete remission or major improvement in obsessive-compulsive symptoms, 3 had partial remission, and 2 experienced no benefit. Nine patients experienced minimal adverse effects, primarily sedation, which did not interfere with continuing treatment. One patient discontinued olanzapine owing to excessive sedation. The results of this preliminary, open-label trial suggest that olanzapine may be effective in augmenting ongoing SSRI treatment for a portion of patients with obsessive-compulsive disorder refractory to SSRI treatment. Larger, placebo-controlled trials appear warranted to investigate the clinical efficacy and tolerability of olanzapine augmentation of SSRI treatment in SSRI-refractory obsessive-compulsive disorder.",1999.0,0,0
81,10495068,"Late-onset schizophrenia: epidemiology, diagnosis, management and outcomes.",P A Wynn Owen; D J Castle,"The onset of schizophrenia for the first time in late life has been considered rare, and the nosology of the late-onset functional psychoses remains contentious. However, it is clear that a significant proportion of individuals with a diagnosis of schizophrenia do have the first onset of the illness in late and very late life. The clinical presentation of such patients shows some differences from patients with early-onset disease, particularly in having a lower prevalence of premorbid dysfunction, negative symptoms and formal thought disorder. The longitudinal course is variable, possibly a reflection of aetiological heterogeneity. Atypical antipsychotic agents would appear to have significant benefits in the treatment of this group of patients, given the particular vulnerability of the elderly to extrapyramidal adverse effects, notably tardive dyskinesia.",1999.0,0,0
82,10495984,[Clinical efficacy of olanzapine].,K Yui,"The treatment of schizophrenic patients who fail adequate trials of typical neuroleptics is a major challenge. For these patients, the availability of atypical antipsychotics is a useful therapeutic advance. Olanzapine shows a superior and broader spectrum of efficacy in the treatment of schizophrenia, particularly its negative symptoms, with a substantially more favorable safety profile than conventional antipsychotic agents (e.g., haloperidol). However, little information on the clinical effects of olanzapine is available in Japan. This article provides information on the efficacy of olanzapine for various symptoms of schizophrenic patients and drug safety. Olanzapine is significantly superior to haloperidol in positive, negative, and depressive symptoms of patients, and for tardive dyskinesia and extrapyramidal symptoms. Significantly greater improvement in avolition-apathy is achieved with olanzapine as compared to risperidone. These advantages are related to high affinity at the 5-HT2 binding site, no association with an alteration in dopamine A9 firing rates, and lower D2 striatal receptor blockade of olanzapine. Treatment with 10 mg/day olanzapine is more appropriate for positive symptoms, and 12.5-17.5 mg/day olanzapine is more effective for negative symptoms. Patients will need help adapting to a new level of functioning after a successful switch to olanzapine, and overcoming the disappointment that eventually occurs when the limitations of olanzapine become apparent.",1999.0,0,0
83,10496251,"A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia.",P P De Deyn; K Rabheru; A Rasmussen; J P Bocksberger; P L Dautzenberg; S Eriksson; B A Lawlor,"To compare effects of risperidone with placebo (efficacy and tolerability) and haloperidol (tolerability) for treating demented patients with aggression and other behavioral symptoms. A 13-week double-blind study involving 344 patients with dementia randomly assigned to receive placebo or flexible doses (0.5 to 4 mg/d) of risperidone or haloperidol. Behavioral symptoms were assessed by the Behavior Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), the Cohen-Mansfield Agitation Inventory (CMAI), and the Clinical Global Impression (CGI) scale. Tolerability assessments included the Extrapyramidal Symptom Rating Scale, sedation levels, Functional Assessment Staging, Mini-Mental State Examination, and incidence of adverse events. The mean dose at endpoint was 1.1 mg/d of risperidone and 1.2 mg/d of haloperidol. Although not significant, a higher percentage of patients receiving risperidone than those receiving placebo showed clinical improvement (> or =30% reduction from baseline to endpoint in BEHAVE-AD total score) at endpoint and week 12. Reductions in the BEHAVE-AD total score were significantly greater with risperidone than with placebo at week 12. In a further analysis of aggression, the most dominant symptom in these patients, BEHAVE-AD and CMAI aggression cluster scores were significantly reduced compared with placebo at endpoint and week 12. CGI scores were also significantly reduced at endpoint and week 12. Severity of extrapyramidal symptoms with risperidone did not differ significantly from that of placebo and was less than that of haloperidol. A post hoc analysis showed significantly greater reductions in the BEHAVE-AD aggressiveness score with risperidone than haloperidol at week 12. Low-dose risperidone (mean 1.1 mg/d) was well tolerated and associated with reductions in the severity and frequency of behavioral symptoms, particularly aggression, in elderly patients with dementia.",1999.0,1,1
84,10500873,Olanzapine for patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study.,S M Dursun; D M Gardner; D C Bird; J Flinn,"This prospective, consecutive case-series outcome investigation evaluates the effectiveness of olanzapine in 16 patients with treatment-resistant schizophrenia. Treatment resistance was defined as nonresponsiveness to at least 3 antipsychotic drugs from at least 2 different chemical classes. A minimum baseline score on the Brief Psychiatric Rating Scale (BPRS) of 45 was required for enrolment. Outcome evaluation measures included the BPRS, Global Assessment Scale (GAS), and Abnormal Involuntary Movement Scale (AIMS). Subjects (n = 16) has a mean age of 40 years and mean duration of illness of 16 years. Olanzapine treatment was initiated at 5 mg daily and was increased based on clinical judgement up to a maximum of 40 mg daily. Significant decreases in mean BPRS (P < 0.001) and GAS (P < 0.01) scores were observed at weeks 4, 8, 12, and 16, compared with baseline. Eight of 16 patients responded to olanzapine, as defined by a 20% decrease in BPRS score by week 16. Dyskinetic movements significantly increased at week 4 (P < 0.01) but did not differ from baseline at weeks 8 and 16. These results suggest that olanzapine at moderate to high doses may offer an effective treatment for a significant proportion of patients with schizophrenia nonresponsive to multiple trials of conventional antipsychotics. A randomized controlled trial is encouraged to validate these findings, and comparative trials are required to determine when clinicians should consider this approach.",1999.0,0,1
85,10505485,Addition of low-dose fluvoxamine to low-dose clozapine monotherapy in schizophrenia: drug monitoring and tolerability data from a prospective clinical trial.,A Szegedi; I Anghelescu; J Wiesner; S Schlegel; H Weigmann; S Härtter; C Hiemke; H Wetzel,"Combining fluvoxamine and clozapine may be a strategy to improve therapeutic effects on negative symptoms in schizophrenic patients. Fluvoxamine, however, markedly inhibits the metabolism of clozapine, and hazardous side effects may result. This study prospectively investigated the safety and tolerability of an add-on therapy with fluvoxamine to a clozapine monotherapy in schizophrenic patients. Sixteen schizophrenic patients received 50 mg fluvoxamine as a comedication after having reached steady-state conditions under clozapine monotherapy. Patients were monitored for subjective adverse events, laboratory parameters, EEG and ECG recordings, orthostatic hypotension and their psychopathology. Concomitantly, serum concentrations of clozapine and metabolites were measured during monotherapy and after addition of fluvoxamine. In all patients, the serum concentrations of clozapine and metabolites were markedly increased (average: 2-3 fold, up to 5 fold for clozapine) after addition of fluvoxamine. Side effects remained almost unchanged in frequency and severity in spite of the pharmacokinetic interactions. ECG or laboratory parameters and orthostatic tests were similar under monotherapy and comedication. Minimal increases of EEG abnormalities were observed, but they were not associated with clinical impairment. Epileptic activities were always absent. The psychopathology improved which continued after start of the comedication. Though the addition of fluvoxamine to clozapine medication was well tolerated and critical side effects were absent, the combined treatment should be controlled by drug monitoring, as serum concentrations of clozapine increased to unpredictably high levels. Further studies have to find out if the combined treatment could be advantageous to clozapine monotherapy.",1999.0,0,0
86,10505585,"Controlled, double-blind investigation of the clozapine discontinuation symptoms with conversion to either olanzapine or placebo. The Collaborative Crossover Study Group.",G D Tollefson; M A Dellva; C A Mattler; J M Kane; D A Wirshing; B J Kinon,"The abrupt appearance of clozapine discontinuation symptoms represents a particularly unique situation that has not been characterized in a double-blind, placebo-controlled trial. A randomized, double-blind comparison of placebo (N = 53) and olanzapine 10 mg (N = 53) for 3 to 5 days following the abrupt discontinuation of clozapine (< 300 mg/day) was carried out. Subjects were assessed with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression Scale of Severity, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Mini-Mental State Evaluation. Subsequently both groups received open-label olanzapine (10-25 mg/day) for an additional 9 weeks. Statistically significantly more placebo-treated (24.5%) than olanzapine-treated (7.5%) patients experienced clozapine discontinuation symptoms (p = 0.017). Core symptoms included delusions, hallucinations, hostility, and paranoid reaction and translated into a significantly higher worsening from baseline on the PANSS total, PANSS General Psychopathology subscale, and MADRS among subjects randomly assigned to receive placebo. After open-label treatment with olanzapine for 9 weeks, both groups were clinically stable, suggesting that the discontinuation symptoms were transient. However, subjects who had been randomly assigned to the 3- to 5-day placebo discontinuation segment achieved somewhat less global clinical improvement. Although a pharmacologic interpretation is speculative, evidence of a clozapine discontinuation syndrome was apparent. In most cases, the direct substitution of a pharmacologically similar agent (olanzapine) prevented the syndrome. Clozapine discontinuation or noncompliance should be considered in the differential assessment of an acutely emergent psychosis. The possibility that subjects who experience a clozapine discontinuation syndrome may take longer or are less likely to clinically restabilize warrants further investigation.",1999.0,0,0
87,10511014,Psychopharmacology in autism.,L Y Tsai,"Autism is a neurobiological disorder. The core clinical features of autism include impairment in social interaction, impairments in verbal and nonverbal communication, and restricted, repetitive, and stereotyped patterns of behavior, interests, and activities. Autism often has coexisting neuropsychiatric disorders, including seizure disorders, attention deficit hyperactivity disorder, affective disorders, anxiety disorder, obsessive-compulsive disorder, and Tourette disorder. No etiology-based treatment modality has been developed to cure individuals with autism. However, comprehensive intervention, including parental counseling, behavior modification, special education in a highly structured environment, sensory integration training, speech therapy, social skill training, and medication, has demonstrated significant treatment effects in many individuals with autism. Findings from preliminary studies of major neurotransmitters and other neurochemical agents strongly suggest that neurochemical factors play a major role in autism. The findings also provide the rationale for psychopharmacotherapy in individuals with autism. This article reviews studies of neurochemical systems and related psychopharmacological research in autism and related neuropsychiatric disorders. Clinical indications for pharmacotherapy are described, and uses of various medications are suggested. This article also discusses new avenues of investigation that may lead to the development of more effective medication treatments in persons with autism.",1999.0,0,0
88,10511917,Olanzapine. Pharmacokinetic and pharmacodynamic profile.,J T Callaghan; R F Bergstrom; L R Ptak; C M Beasley,"Multicentre trials in patients with schizophrenia confirm that olanzapine is a novel antipsychotic agent with broad efficacy, eliciting a response in both the positive and negative symptoms of schizophrenia. Compared with traditional antipsychotic agents, olanzapine causes a lower incidence of extrapyramidal symptoms and minimal perturbation of prolactin levels. Generally, olanzapine is well tolerated. The pharmacokinetics of olanzapine are linear and dose-proportional within the approved dosage range. Its mean half-life in healthy individuals was 33 hours, ranging from 21 to 54 hours. The mean apparent plasma clearance was 26 L/h, ranging from 12 to 47 L/h. Smokers and men have a higher clearance of olanzapine than women and nonsmokers. After administering [14C]olanzapine, approximately 60% of the radioactivity was excreted in urine and 30% in faeces. Olanzapine is predominantly bound to albumin (90%) and alpha 1-acid glycoprotein (77%). Olanzapine is metabolised to its 10- and 4'-N-glucuronides, 4'-N-desmethylolanzapine [cytochrome P450 (CYP) 1A2] and olanzapine N-oxide (flavin mono-oxygenase 3). Metabolism to 2-hydroxymethylolanzapine via CYP2D6 is a minor pathway. The 10-N-glucuronide is the most abundant metabolite, but formation of 4'-N-desmethylolanzapine is correlated with the clearance of olanzapine. Olanzapine does not inhibit CYP isozymes. No clinically significant metabolic interactions were found between olanzapine and diazepam, alcohol (ethanol), imipramine, R/S-warfarin, aminophylline, biperiden, lithium or fluoxetine. Fluvoxamine, an inhibitor of CYP1A2, increases plasma concentrations of olanzapine; inducers of CYP1A2, including tobacco smoke and carbamazepine, decrease olanzapine concentrations. Orthostatic changes were observed when olanzapine and diazepam or alcohol were coadministered. Pharmacodynamic interactions occurred between olanzapine and alcohol, and olanzapine and imipramine, implying that patients should avoid operating hazardous equipment or driving an automobile while experiencing the short term effects of the combinations. Individual factors with the largest impact on olanzapine pharmacokinetics are gender and smoking status. The plasma clearance of olanzapine generally varies over a 4-fold range, but the variability in the clearance and concentration of olanzapine does not appear to be associated with the severity or duration of adverse effects or the degree of efficacy. Thus, dosage adjustments appear unnecessary for these individual factors. However, dosage modification should be considered for patients characterised by a combination of factors associated with decreased oxidative metabolism, for example, debilitated or elderly women who are nonsmokers.",1999.0,0,0
89,10516959,The brain metabolic patterns of clozapine- and fluphenazine-treated female patients with schizophrenia: evidence of a sex effect.,R M Cohen; T E Nordahl; W E Semple; D Pickar,"The regional cerebral glucose metabolic rates of clozapine-treated and fluphenazine-treated women with schizophrenia and normal controls were obtained by positron emission tomography (PET) using [18F]-2-fluoro-2-deoxy-D-glucose (FDG) as the tracer. The regional metabolic patterns were compared to each other and to the changes previously observed in men. In women, as in men, both clozapine- and fluphenazine-treatment were associated with lower metabolism in the superior prefrontal cortex and higher metabolism in the medial temporal lobe. In both men and women, clozapine treatment led to a greater lowering of inferior prefrontal cortex activity than fluphenazine, which was statistically significant in the larger male cohort. Fluphenazine led to higher metabolic rates in the lateral temporal lobe than clozapine did, but the differences between the two neuroleptics were not statistically significant in either group. The greatest differences in the female as compared to the male responses to fluphenazine and clozapine were in the cingulate and striatum. As compared to controls, the cingulate metabolic rates of women were reduced by 9.1% and 11.4% on clozapine and fluphenazine, respectively; whereas, men have a statistically nonsignificant reduction of 0.1% with clozapine and a 3.2% increase with fluphenazine. In men, fluphenazine was associated with a much greater elevation in basal ganglia metabolic rates than was clozapine, 23.5% as compared to 3.75%; whereas, in women, basal ganglia metabolic rates are nearly equally increased by fluphenazine (21.6%) and clozapine (15.1%).",1999.0,0,0
90,10529070,The comparative prophylactic efficacy of lithium and carbamazepine in patients with bipolar I disorder.,W Greil; N Kleindienst,"In a randomized prospective clinical trial with an observation period of 2.5 years, a subgroup analysis was carried out for the 114 patients with bipolar I disorder (DSM-IV) regarding the prophylactic efficacy of lithium and carbamazepine. Treatment outcome was evaluated taking rehospitalization, recurrence, subclinical recurrence, concomitant medication and severe adverse effects into consideration. Special interest was paid to the enzyme-inducing properties of carbamazepine, which might lessen the efficacy of psychotropic comedication. Lithium was superior to carbamazepine in bipolar I patients for various outcome criteria. Analyses in patients without psychotropic comedication indicate that the superiority of lithium is not the result of carbamazepine reducing plasma levels of concomitant drugs.",1999.0,0,0
91,10534086,Diagnosis and management of Alzheimer disease.,M P Daly,"Alzheimer disease afflicts millions of older Americans, with an estimated cost to society approaching $100 million annually. Family physicians will care for an increasing number of patients with Alzheimer disease as well as their caregivers and families. A comprehensive and systematic review of the literature published between 1985 and 1998 about diagnosing and treating Alzheimer disease was conducted, using ""dementia,"" ""Alzheimer's disease,"" and ""treatment"" as search strategy key words. Data and information that reported significant conclusions were critically reviewed. Potentially important new data about new agents that might be of benefit when caring for patients with Alzheimer disease are discussed. The primary goals when treating Alzheimer disease patients are enhancing autonomy and functional abilities and maintaining quality of life for patients and caregivers. In addition to diagnostic and pharmacologic treatment, primary care physicians will be called upon to provide nonpharmacologic support to assist with behavioral, social, and living environment problems faced by these patients and their families. The most common pharmacologic treatment is cholinesterase inhibition. Two cholinesterase inhibitors, tacrine and donepezil, are effective in treating cognitive and global function. Newer cholinesterase inhibitors should soon be available that might offer safety advantages as well as efficacy in treating behavioral and psychiatric symptoms related to Alzheimer disease. Other agents, including vitamin E, nonsteroidal anti-inflammatory drugs, estrogen, and Ginkgo biloba, are under investigation. Nonpharmacologic measures are important components in the management of Alzheimer disease. Support groups can help to diminish behavioral problems, maintain the patient's independence, and provide relief for caregivers and families.",1999.0,0,0
92,10537964,Clinical and economic outcomes of olanzapine compared with haloperidol for schizophrenia. Results from a randomised clinical trial.,S H Hamilton; D A Revicki; E T Edgell; L A Genduso; G Tollefson,"The purpose of this study was to compare, from the payor perspective, the clinical and economic outcomes of olanzapine to those of haloperidol for the treatment of schizophrenia. Clinical, quality-of-life and resource utilisation data were prospectively collected for US-residing patients with schizophrenia who were participating in a multicentre, randomised, double-blind clinical trial comparing olanzapine and haloperidol. Direct medical costs were estimated by assigning standardised prices (1995 values) to the resource utilisation data. 817 patients with schizophrenia who had a baseline Brief Psychiatric Rating Scale score (BPRS) > or = 18 (items scored 0 to 6) and/or were no longer tolerating current antipsychotic therapy. Olanzapine 5 to 20 mg/day (n = 551) or haloperidol 5 to 20 mg/day (n = 266) for 6 weeks. Patients showing a predefined level of clinical response entered a 46-week maintenance phase. After acute treatment, BPRS-based clinical improvements were seen in 38 and 27% of olanzapine and haloperidol patients, respectively (p = 0.002). Clinically important improvements on the Quality of Life Scale were achieved during acute treatment in 33% of olanzapine recipients and 25% of haloperidol recipients (p = 0.094). Olanzapine treatment in the acute phase led to significantly lower inpatient ($US5125 vs $US5795, p = 0.038) and outpatient ($US663 vs $US692, p = 0.001) costs, resulting in a significant overall reduction in mean total medical costs of $US388 (p = 0.033). This significant reduction in total costs was found despite olanzapine mean medication costs being significantly greater than haloperidol medication costs ($US326 vs $US15, p < 0.001). No significant differences in clinical improvement were observed in the maintenance phase. Maintenance phase olanzapine mean total medical costs were $US636 lower than haloperidol total costs (p = 0.128). Although olanzapine medication costs were significantly higher than haloperidol medication costs ($US3461 vs $US95, p < 0.001), this difference was offset by significantly lower inpatient ($US8322 vs $US10,662, p = 0.044) and outpatient ($US3810 vs $US5473, p = 0.038) costs. In this study, olanzapine treatment was more effective than haloperidol in producing clinical response in the acute phase. In addition, olanzapine treatment led to reductions in inpatient and outpatient costs that more than offset olanzapine's higher medication costs relative to haloperidol.",1999.0,0,0
93,10546082,[Economic comparison of olanzapine versus haloperidol in treatment of schizophrenia in France].,C Le Pen; H Lilliu; M P Allicar; V Olivier; K J Gregor,"The purpose of this study is to provide an economic comparison of olanzapine-treated and haloperidol-treated patients from the subset of French patients who participated in a large, international, randomised clinical trial in schizophrenia. Patients were evaluated from randomisation until discontinuation, drop out or completion of the 52-week study. The primary clinical measure was ""clinically important response"" (derived from BPRS total scores). The secondary measure was ""clinically important improvement"" (derived from CGI severity of illness scores). The primary economic measure was mean per diem, per patient total direct medical costs. A total of 275 French patients where included in the study. Demographics and other baseline differences between olanzapine- and haloperidol-treated patients were not statistically significant. Olanzapine-treated patients (205 +/- 142 days) experienced significantly (p < 0.001) longer evaluation periods than haloperidol-treated patients (132 +/- 129 days). Olanzapine-treated patients (54%) were significantly (p = 0.03) more likely to experience a clinically important response than haloperidol-treated patients (40%). Olanzapine-treated patients (69%) were significantly (p = 0.02) more likely to experience clinically important improvement than haloperidol-treated patients (54%). The mean per diem, per patient total direct medical cost was statistically lower (p = 0.033) for olanzapine-treated patients (FF619 +/- 509) compared to haloperidol-treated patients (FF756 +/- 478). Olanzapine treatment was associated with significantly better clinical outcomes and per diem total direct medical cost than haloperidol treatment. The findings indicate that olanzapine is dominant compared to haloperidol for the treatment of schizophrenia, in the context of analysed data. These findings produce increased relevance in France to the existing evidence supporting olanzapine's cost and effectiveness profiles.",1999.0,0,0
94,10549681,A comparative effectiveness study of risperidone and olanzapine in the treatment of schizophrenia.,B C Ho; D Miller; P Nopoulos; N C Andreasen,"Risperidone and olanzapine have each been demonstrated to be efficacious and safe in the treatment of patients with chronic schizophrenia. To evaluate their relative effectiveness, and to better understand the advantages and limitations of each neuroleptic during actual clinical use, we compared one directly against the other. Forty-two subjects with DSM-IV schizophrenia had received open-label treatment with either risperidone or olanzapine. Symptoms, global functioning, and extrapyramidal side effects before and after acute treatment were compared within and across groups. At 6-month follow-up, the relative effectiveness of these 2 atypical neuroleptics on symptoms and quality of life were further evaluated. Following an average of 4 weeks of acute treatment, both risperidone and olanzapine were effective in reducing negative, psychotic, and disorganized symptoms. Although both neuroleptics were associated with low occurrence of treatment-emergent parkinsonism, risperidone was more likely to induce akathisia. The measures for parkinsonism were no different across treatment groups, even after taking into account the higher rate of anticholinergic use in the risperidone group. Following 6 months of treatment with these 2 atypical neuroleptics, there was a significantly greater reduction in psychotic symptoms among risperidone-treated subjects. Otherwise, risperidone and olanzapine appear to be equally effective in reducing disorganized and negative symptoms and in improving the quality of life. Risperidone and olanzapine were equally effective as acute treatments. Risperidone was more effective for treatment of psychotic symptoms at 6 months, but otherwise the 2 medications were equally effective in the routine clinical care of patients with schizophrenia. If low (<6 mg/day) doses of risperidone are used, the 2 medications have comparable rates of parkinsonian side effects.",1999.0,0,1
95,10550857,Rapid-cycling bipolar disorder. An overview of research and clinical experience.,N Kilzieh; H S Akiskal,"Although many studies of RCBD have been reported over the last 2 decades, knowledge remains limited. Higher incidence in women is the sole clearly replicated finding in most studies. This finding might be mediated by cyclothymia, a temperament that is of higher prevalence in women and that might be considered as a normal variant of RC. Many questions remain unanswered. Review of putative risk factors, such as hypothyroidism and treatment with antidepressants, provides no conclusive answers. There is clinical evidence to implicate both factors. In principle, the thyroid connection can be approached rationally, yet there seems to be no relationship between thyroid status and response to thyroid augmentation. For this reason and given the potential risks of long-term thyroid use, this strategy should not be the first one to be tried in RC. Cumulatively, naturalistic studies over the past 30 years have strongly implicated antidepressants in switching and cycle acceleration, yet the double-blind, controlled, prospective studies that are needed to provide definitive answers are unlikely to be conducted for ethical reasons discussed in this article. Bipolar family history of RC probands appears indistinguishable from non-RC probands, indicating that most likely RCBD does not breed true. Although RC seems to be more lithium resistant with less likelihood of being symptom-free after 2 to 5 years of follow-up, many of these patients nonetheless have resolution of the RC course. There is no marked difference in suicide rates. An association of RC with bipolar type II, D-M-I pattern and those who switch into mania or hypomania on antidepressants is a provocative possibility: Antidepressants might introduce RC by first inducing a switch during a depressive episode, creating a D-M-I pattern, a pattern that is poorly responsive to lithium, which eventually degenerates into RC. Again, this sequence might be mediated by the high prevalence of cyclothymia in bipolar II patients. Thus, data from phenomenology, family history, and long-term outcome do not support RC as a separate entity. RC appears to be a temporary complicated phase in the illness, not a stable feature. This was noted by Kraepelin: I think I am convinced that that kind of classification must of necessity wreck on the irregularity of the disease. The kind and duration of the attacks and the intervals by no means remain the same in the individual case but may frequently change, so that the case must be reckoned always to new forms. Data by Gottschalk et al testify to the chaotic mood swings of contemporary bipolar disorder. Moreover RC is seen in other medical diseases, such as epilepsy, in which patients have phases of increase in frequency of episodes (seizures) that become refractory to treatment. Further longitudinal prospective studies are required to understand the complexity of this intriguing phenomenon and to provide better treatments. Algorithms deriving from tertiary research or university-based clinical experience may not generalize to RC or otherwise treatment-resistant bipolar patients seen in more routine practice. Illness severity in RCBD generally precludes double-blind controlled investigations. Meanwhile, clinicians may rely on discontinuing antidepressants, maintaining patients on combined mood stabilizers--of which valproate is probably the most useful--and making judicious use of atypical neuroleptics. Benzodiazepines and alcohol (which produce withdrawal), caffeine, stimulants, exposure to bright light, and sleep deprivation during excited phases should be avoided. Thyroid and nimodipine augmentation can be considered in those with the most malignant course. These are patients who need the maximal support that their psychiatrist can provide them. Office visits must be arranged as the last appointment of the day.",1999.0,0,0
96,10553730,Antipsychotic-induced weight gain: a comprehensive research synthesis.,D B Allison; J L Mentore; M Heo; L P Chandler; J C Cappelleri; M C Infante; P J Weiden,"The purpose of this study was to estimate and compare the effects of antipsychotics-both the newer ones and the conventional ones-on body weight. A comprehensive literature search identified 81 English- and non-English-language articles that included data on weight change in antipsychotic-treated patients. For each agent, a meta-analysis and random effects metaregression estimated the weight change after 10 weeks of treatment at a standard dose. A comprehensive narrative review was also conducted on all articles that did not yield quantitative information but did yield important qualitative information. Placebo was associated with a mean weight reduction of 0.74 kg. Among conventional agents, mean weight change ranged from a reduction of 0.39 kg with molindone to an increase of 3.19 kg with thioridazine. Among newer antipsychotic agents, mean increases were as follows: clozapine, 4.45 kg; olanzapine, 4.15 kg; sertindole, 2.92 kg; risperidone, 2.10 kg; and ziprasidone, 0.04 kg. Insufficient data were available to evaluate quetiapine at 10 weeks. Both conventional and newer antipsychotics are associated with weight gain. Among the newer agents, clozapine appears to have the greatest potential to induce weight gain, and ziprasidone the least. The differences among newer agents may affect compliance with medication and health risk.",1999.0,1,1
97,10553738,Double-blind study of clozapine dose response in chronic schizophrenia.,G M Simpson; R C Josiassen; J K Stanilla; J de Leon; C Nair; G Abraham; A Odom-White; R M Turner,"This study explored the relative efficacy of three different doses of clozapine. Fifty patients who met Kane et al.'s criteria for treatment-refractory schizophrenia or schizoaffective disorder were studied. All subjects were randomly assigned to 100, 300, or 600 mg/day of clozapine for 16 weeks of double-blind treatment. Forty-eight patients completed this first 16 weeks. Of the 50 patients, 36 went on to second and third 16-week trials of double-blind treatment at the remaining doses. Four subjects (8%) responded to the first 16-week condition, and one subject (2%) responded to the next 16-week crossover condition. A chi-square comparison of the response rates from the three dose groups failed to show a significant effect. An analysis of variance (ANOVA) comparison of Brief Psychiatric Rating Scale-Anchored (BPRS-A) total change scores from baseline to last observation carried forward showed a significant dose effect (600>300>100 mg/day) at 16 weeks of treatment. A crossover ANOVA of the BPRS-A total scores from the 48-week study also showed that the main effect for dose was highly significant; the 100-mg/day dose gave the higher (poorer) values, and the 300- and 600-mg/ day doses gave equal (better) values. Gender played a role in clinical response to treatment at 100 mg/day. Clozapine treatment at 100 mg/day was less effective than at 300 or 600 mg/day. At 100 mg/day, women responded better than did men. The 600 mg/day group had the best results, but an occasional patient required up to 900 mg/day. Overall response rates were lower than expected.",1999.0,0,0
98,10553752,D-serine added to clozapine for the treatment of schizophrenia.,G E Tsai; P Yang; L C Chung; I C Tsai; C W Tsai; J T Coyle,"D-Serine is a full agonist at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Previous administration of D-serine to schizophrenic patients taking nonclozapine antipsychotics improved positive, negative, and cognitive symptoms, whereas the partial agonist D-cycloserine improved negative symptoms of patients taking conventional antipsychotics but worsened symptoms in clozapine-treated patients. To study the difference between full and partial agonists at the NMDA receptor glycine site, the clinical effects of adding D-serine to clozapine were assessed. In a 6-week double-blind trial, 20 schizophrenic patients received placebo or D-serine (30 mg/kg per day) in addition to clozapine. Clinical efficacy, side effects, and serum levels of D-serine were determined every other week. The patients exhibited no improvement with D-serine, nor did their symptoms worsen, as previously reported with D-cycloserine. The results suggest either that clozapine may have an agonistic effect on the NMDA system or that clozapine-treated patients do not respond to D-serine.",1999.0,0,0
99,10557338,Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia.,G D Honey; E T Bullmore; W Soni; M Varatheesan; S C Williams; T Sharma,"Antipsychotic drug treatment of schizophrenia may be complicated by side effects of widespread dopaminergic antagonism, including exacerbation of negative and cognitive symptoms due to frontal cortical hypodopaminergia. Atypical antipsychotics have been shown to enhance frontal dopaminergic activity in animal models. We predicted that substitution of risperidone for typical antipsychotic drugs in the treatment of schizophrenia would be associated with enhanced functional activation of frontal cortex. We measured cerebral blood oxygenation changes during periodic performance of a verbal working memory task, using functional MRI, on two occasions (baseline and 6 weeks later) in two cohorts of schizophrenic patients. One cohort (n = 10) was treated with typical antipsychotic drugs throughout the study. Risperidone was substituted for typical antipsychotics after baseline assessment in the second cohort (n = 10). A matched group of healthy volunteers (n = 10) was also studied on a single occasion. A network comprising bilateral dorsolateral prefrontal and lateral premotor cortex, the supplementary motor area, and posterior parietal cortex was activated by working memory task performance in both the patients and comparison subjects. A two-way analysis of covariance was used to estimate the effect of substituting risperidone for typical antipsychotics on power of functional response in the patient group. Substitution of risperidone increased functional activation in right prefrontal cortex, supplementary motor area, and posterior parietal cortex at both voxel and regional levels of analysis. This study provides direct evidence for significantly enhanced frontal function in schizophrenic patients after substitution of risperidone for typical antipsychotic drugs, and it indicates the potential value of functional MRI as a tool for longitudinal assessment of psychopharmacological effects on cerebral physiology.",1999.0,0,0
100,10562961,[Atypical antipsychotic profiles of sigma receptor ligands].,S Okuyama,"This is a review on the recent results of research on sigma-receptor antagonists. NE-100, a selective sigma1-receptor antagonist, shows improvement of abnormal behaviors and cognitive dysfunction induced by phencyclidine (PCP). However, NE-100 does not inhibit dopamine agonist-induced behaviors nor induces catalepsy. The mode of action of NE-100 is estimated to be the indirect modulation of the NMDA/PCP-receptor ion channel complex and the modulation of dopamine release from the dopaminergic nerve terminals. The recently reported MS-355/MS-377, which is also a selective sigma1-receptor antagonist, has a similar pharmacological profiles as NE-100, but in addition, MS-355/MS-377 inhibits methamphetamine-induced formation of reversal tolerance and also inhibits apomorphine-induced climbing behavior like dopamine D2-receptor antagonists. The report on clinical trial targeting schizophrenia shows results on rimcazole, remoxipride, BMY 14802, panamesine (EMD 57445) and SL 82.0715. Rimcazole was effective in the open study, but the double blind trial was discontinued due to seizure induction. Remoxipride showed efficacy different from those of dopamine D2-receptor antagonists (less extrapyramidal adverse effects), but the trial was discontinued due to occurrence of aplastic anemia. Panamesine and SL 82.0714 showed favorable efficacy in the open studies, but BMY 14802 showed no efficacy in clinical trials.",1999.0,0,0
101,10565707,"Olanzapine in whole, not half, tablets for psychosis from Alzheimer's dementia.",S A Wolfgang,,1999.0,0,0
102,10565800,Olanzapine compared to lithium in mania: a double-blind randomized controlled trial.,M Berk; L Ichim; S Brook,"Neuroleptics are of established efficacy in mania. Controlled data on the use of olanzapine in mania is however, absent. In this study, 30 patients meeting DSM-IV criteria for mania were randomly allocated to receive either olanzapine or lithium in a 4 week double-blind randomized controlled design. There were no significant outcome differences between the two groups on any of the primary outcome measures, the Brief Psychiatric Rating Scale (lithium 28.2; olanzapine 28.0; P = 0.44); Clinical Global Impression (CGI) improvement scale (lithium 2.75, olanzapine 2.36; P = 0.163) or the Mania Scale (lithium 13.2, olanzapine 10.2; P = 0.315). Olanzapine was however, significantly superior to lithium on the CGI-severity scale at week 4 (lithium 2.83, olanzapine 2.29; P = 0.025). Olanzapine did not differ from lithium in terms of treatment emergent extrapyramidal side-effects as measured by the Simpson-Angus Scale. Olanzapine appears to be at least as effective as lithium in the treatment of mania.",1999.0,0,1
103,10565803,Lack of efficacy of the 5-HT3 receptor antagonist granisetron in the treatment of acute neuroleptic-induced akathisia.,M Poyurovsky; A Weizman,"The specific mechanism underlying the apparent involvement of the serotonergic (5-HT) system in the pathophysiology of extrapyramidal side-effects, particularly neuroleptic-induced akathisia (NIA), remains unknown. We hypothesized that the 5-HT3 receptor subtype may play a role in the light of the moderate-to-high affinity to this receptor of some of the atypical antipsychotic agents which have a low propensity to cause akathisia, as well as our earlier findings with the 5-HT2/5-HT3 antagonist mianserin. In an open-label pilot study, we administered the selective 5-HT3 antagonist granisetron (fixed dose, 2 mg/day) for 4 days to 10 neuroleptic-treated patients with acute NIA. Three patients discontinued granisetron because of a lack of response. The remainder showed no significant change in score on the Barnes Akathisia Scale during the trial. NIA symptoms remained unchanged or worsened in five patients (71.4%) and improved to a certain degree in only two. It seems that the 5-HT3 subtype of serotonergic receptor is not involved in the development of NIA, and 5-HT3 antagonists are ineffective in the serotonin-related pharmacotherapy of NIA.",1999.0,0,0
104,10584158,Retention rates in placebo- and nonplacebo-controlled clinical trials of schizophrenia.,A Labelle; L J Boulay; Y D Lapierre,"To determine if the inclusion of a placebo control in clinical trials of schizophrenia affects retention rates in the first 35 days of inclusion relative to trials that did not have a placebo control. This was a retrospective study of 8 double-blind clinical trials, 5 of which had a placebo control while 3 did not. Using survival analysis, retention rates between the placebo-controlled trials (PCTs) and the nonplacebo-controlled trials (NPCTs) were compared. Screening and percentage improvement on Brief Psychiatric Rating Scale and Positive and Negative Syndrome Scale scores were compared. Significantly more patients were retained in the 35-day period for NPCTs. Also, the PCT group had significantly more psychopathology at screening than did the NPCT group. Differences in retention rates between PCTs and NPCTs cannot be uniquely attributed to placebo itself.",1999.0,0,0
105,10584161,Hospital days in risperidone-treated patients.,R A Dickson; J T Dalby; D Addington; R Williams; G M McDougall,"To compare inpatient hospital days of a group of ""real world"" schizophrenia-spectrum patients for 3 years prior to and 3 years after risperidone initiation. This is a retrospective cohort study using a mirror-image design of hospital days in 120 patients over a 6-year period. Hospital admission and discharge information was obtained from chart review and database extraction at 3 outpatient treatment sites. The sample comprised all patients attending these clinics who were prescribed risperidone during the first year of the drug's release. Patients separated into 3 treatment groups: those who were prescribed risperidone for 3 uninterrupted years (N = 35), those who interrupted but resumed risperidone use and were prescribed the drug at 3 years (N = 8), and those who discontinued risperidone during the 3-year follow-up period (N = 77). The group continuing risperidone to 3 years demonstrated a significant decrease in hospital days after risperidone treatment, in contrast to the other 2 groups. The reduction in inpatient days for the total sample was not statistically significant. In this outpatient clinic sample, the 29% of patients who continued on risperidone showed a significant reduction in inpatient hospital days, from an average of 17.2 days per year in the 3 years before risperidone treatment to an average of 2.1 days per year for the 3 years of risperidone treatment.",1999.0,0,1
106,10584719,Myocarditis and cardiomyopathy associated with clozapine.,J G Kilian; K Kerr; C Lawrence; D S Celermajer,"Clozapine is effective for resistant schizophrenia. After two sudden deaths in physically well young men soon after starting clozapine, we investigated the cardiovascular complications for this drug. From January, 1993, to March, 1999, 8000 patients started clozapine treatment in Australia, and were registered with a mandatory monitoring service. We identified cases of myocarditis and cardiomyopathy from voluntary reports to the Australian Adverse Drug Reaction Committee and sought details of the relevant diagnostic studies, necropsies that had been done in suspicious cases, or both. 23 cases (20 men, three women, mean age 36 years [SD 9]) were identified: 15 of myocarditis and eight of cardiomyopathy associated with clozapine treatment. Six patients died. All cases of myocarditis (five deaths) occurred within 3 weeks of starting clozapine. Cardiomyopathy (one death) was diagnosed up to 36 months after clozapine was started. Necropsy results showed mainly eosinophilic infiltrates with myocytolysis, consistent with an acute drug reaction. Clozapine therapy may be associated with potentially fatal myocarditis and cardiomyopathy in physically healthy young adults with schizophrenia.",2000.0,0,1
107,10593449,Differential olanzapine plasma concentrations by sex in a fixed-dose study.,D L Kelly; R R Conley; C A Tamminga,"This study examined plasma concentrations of olanzapine by sex (20 males and seven females) in an 8-week fixed-dose study. Dosing was 12.5 mg/day for the first week, then 25 mg/day. Trough plasma concentrations were drawn at weeks 1, 3, 5 and 8. Women volunteers were found to have significantly higher plasma concentrations than men. This difference was first evident at study week 5. Women have higher plasma concentrations of olanzapine, possibly due to differences in metabolism of the CYP450 isoenzyme system.",2000.0,0,0
108,10593450,Measuring neuroleptic-induced akathisia by three-channel actometry.,K Tuisku; H Lauerma; M Holi; J Markkula; R Rimon,"Three-channel actometry was used to study neuroleptic-induced akathisia (NIA), a common and often serious disorder in association of traditional neuroleptic therapy. The aim was to explore the diagnostic possibilities of actometry in NIA and to examine in detail the motor phenomenology of the disorder in detail. The actometers were attached to the ankles and waists of ten patients, suffering from NIA, and to ten matched healthy controls. Five of the patients were changed to olanzapine treatment, and these patients were re-examined during the no-NIA condition. NIA was associated with manyfold movement activity during controlled rest (sitting) but not with increased daily overall motor activity. Movement frequencies in NIA seemed to be pathognomonic. Actometry is promising for investigation and clinical assessment of NIA. Olanzapine proved to be an adequate treatment choice for NIA patients.",2000.0,0,0
109,10606837,Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model.,H Takanaga; A Ohnishi; H Matsuo; H Murakami; H Sata; K Kuroda; A Urae; S Higuchi; Y Sawada,"Aims Ingestion of grapefruit juice (GFJ) alters the pharmacokinetics of various orally administered drugs. Quantitative evaluation of this GFJ-drug interaction is required for the proper clinical management of patients. Methods Using felodipine as a model drug, we constructed a pharmacokinetic model based on irreversible inhibition of intestinal cytochrome P450 3A4 (CYP3A4) by GFJ. We fitted previously published data [5, 6] for felodipine ER (extended release formulation) to the ratio of CLGI,int before and after grapefruit juice ingestion by nonlinear least-squares regression analysis to estimate the reaction rate constant between GFJ and CYP3A4 (K) and the elimination rate constant of CYP3A4 (k ). The model gave a turnover rate of CYP3A4 of 0.0849 h-1, corresponding to a half-life of 8.16 h, in agreement with reported values. The AUC-time profiles of felodipine ER in the case of different amounts and schedules of GFJ ingestion were simulated using the parameter values estimated from the model. The modelling leads to the important conclusion that GFJ-felodipine interaction increases with increasing frequency and amount of GFJ ingestion, and that an interval of 2-3 days between GFJ intake and felodipine administration is necessary if GFJ-felodipine interaction is to be avoided.",2000.0,0,0
110,10606838,Effect of caffeine on clozapine pharmacokinetics in healthy volunteers.,S Hägg; O Spigset; T Mjörndal; R Dahlqvist,"To assess the effects of caffeine on the pharmacokinetics of clozapine in healthy volunteers. This was an open label randomized crossover study in 12 nonsmoking healthy male volunteers. The subjects received a single oral dose of 12.5 mg clozapine in each phase with or without concomitant intake of caffeine (mean dose: 550 mg day-1, range: 400-1000 mg day-1 ). Serum concentrations of clozapine and its metabolites desmethyl-clozapine and clozapine-N-oxide were measured during a 48 h period in each phase. In addition, serum concentrations of caffeine and the metabolite paraxanthine were monitored. A 19% increase in mean clozapine AUC(0,infinity) (P=0.05) and a 14% decrease of mean oral clearance of clozapine were observed during concomitant intake of caffeine (P=0.05) compared with intake of only clozapine. Statistically significant decreases of mean ratios between AUC(0, 12h) for desmethyl-clozapine and AUC(0,12h) for clozapine (-18%), and between AUC(0,12h) for clozapine-N-oxide and AUC(0,12h) for clozapine (-23%) were observed during the caffeine phase (P=0.03 and 0.02, respectively). Oral clearance of clozapine and the ratio AUC(0, 12h) for desmethyl-clozapine/AUC(0,12h) for clozapine were correlated with the paraxanthine/caffeine ratio in serum after intake of caffeine (rs=0.62; P=0.03 and rs=0.77; P=0.003, respectively). These results suggest that caffeine in daily doses of 400-1000 mg inhibits the metabolism of clozapine to an extent that might be clinically significant in certain individuals.",2000.0,0,0
111,10610012,CYP2D6 mutations and therapeutic outcome in schizophrenic patients.,B A Hamelin; P G Dorson; D Pabis; D Still; R H Bouchard; E Pourcher; J Rail; J Turgeon; M L Crismon,"To investigate whether a relationship exists between the most common known cytochrome P450 (CYP) isozyme 2D6 mutations and schizophrenia. Because most antipsychotic and antidepressant agents interact with CYP2D6, we also investigated clinical outcomes in schizophrenic poor metabolizers (PMs) and extensive metabolizers (EMs). Prospective, observational study. Two psychiatric hospitals and a university-affiliated nonpsychiatric hospital. Thirty-nine consecutive schizophrenic patients (POP 1), 89 schizophrenics of French Canadian origin (POP 2), and 384 healthy French Canadians (POP 3). All study subjects were genotyped for CYP2D6 mutant alleles. POP 1 patients were evaluated before and after 21 or more days of treatment with antipsychotic drugs metabolized at least in part by CYP2D6. Whole blood was collected to determine CYP2D6 alleles *1, *3, *4, *5, *6, and *7 using standard restriction fragment length polymorphisms and polymerase chain reaction techniques. In comparison, CYP2D6 genotypes were determined in POP 2 and POP 3. Twenty-three (59.0%) of 39 patients in POP 1 were genotypically EM homozygotes, 15 (38.4%) were EM heterozygotes, and 1 (2.6%) was a PM. Similar genotype distributions were determined in POP 2 and in POP 3. Genotype distributions for all three populations were in Hardy-Weinberg equilibrium (p>0.05), and there was no significant difference among them (p=0.857). In POP 1, no differences were seen among genotypes in disease symptom severity, number and severity of adverse drug effects, or attitudes toward drug treatment at baseline and at the end of the study. In fact, all patients improved significantly during their hospital stay (all p<0.05), although independent of the CYP2D6 genotype. Common CYP2D6 mutant alleles were not associated with schizophrenia or with disease symptoms, antipsychotic-related adverse effects, or attitudes toward treatment.",1999.0,0,1
112,10610049,Brain event-related potentials (ERPs) in schizophrenia during a word recognition memory task.,J Kayser; G E Bruder; D Friedman; C E Tenke; X F Amador; S C Clark; D Malaspina; J M Gorman,"Impairments of recognition memory for words and attenuation of the ERP 'old-new' effect have been found in patients with left medial temporal lobe damage. If left temporal lobe dysfunction in schizophrenia involves medial structures (e.g. hippocampus), then schizophrenic patients might show similar abnormalities of verbal recognition memory. This study recorded ERPs from 30 electrode sites while subjects were engaged in a continuous word recognition memory task. Results are reported for 24 patients having a diagnosis of schizophrenia (n = 16) or schizoaffective disorder (n = 8) and 19 age-matched healthy controls. Both patients and controls showed the expected 'old-new' effect, with greater late positivity to correctly recognized old words at posterior sites, and there was also no significant difference between groups in P3 amplitude. However, accuracy of word recognition memory was poorer in patients than controls, and patients showed markedly smaller N2 amplitude. Reduced amplitudes of N2 and N2-P3 were associated with poorer performance, with highest correlations over the left inferior parietal (N2) and left medial parietal (N2-P3) region. Moreover, patients failed to show significantly greater left than right hemisphere amplitude of N2-P3 at posterior sites, which was seen for healthy controls. These findings suggest that impaired word recognition in schizophrenia may arise from a left lateralized deficit at an early stage of processing, beginning at 200-300 ms after word onset.",1999.0,0,0
113,10610054,Differential memory span--abnormal lateralization pattern in schizophrenic patients and their siblings?,P Franke; M Gänsicke; S Schmitz; P Falkai; W Maier,"The recurring digit span test is hypothesized to assess consolidation memory and hypothetically addresses neuropsychological left-temporohippocampal functioning, an area of the brain which is presumed to play a crucial role in schizophrenia. The present study applied the recurring digit span memory test and the recurring block span memory test (assumed to be an indicator of right-temporohippocampal functioning) to 106 acute schizophrenic patients (DSM-III-R), 49 siblings of these patients without DSM-III-R lifetime diagnoses as well as 53 non-related control subjects without DSM-III-R lifetime diagnoses. Results of our investigation indicate that schizophrenic patients differ from control subjects regarding recurring digit span in a reduced number of correct reproductions of recurring trials. Since performance of schizophrenic patients was only non-significantly different from control subjects regarding recurring block span memory, our findings point to a task-specific memory impairment in schizophrenia and argue against a generalized deficit in this disease. Furthermore, individuals at risk for schizophrenia also differed from control subjects concerning the recurring digit span memory test but not with regard to the recurring block span test. Therefore we conclude that the reduced cumulative learning curve of verbal material (reduced number of correct reproduction of recurring digit trials) in schizophrenic patients and their healthy siblings might represent a marker for the liability to schizophrenia and parallels neuroimaging findings concerning left-sided temporohippocampal abnormalities in this disease, which presumably play a key role in the etiology of schizophrenia.",1999.0,0,0
114,10622347,Amisulpride vs. risperidone in the treatment of acute exacerbations of schizophrenia. Amisulpride study group.,J Peuskens; P Bech; H J Möller; R Bale; O Fleurot; W Rein,"Amisulpride, a substituted benzamide with high selectivity for dopamine D3 and D2 receptors, was compared with the antipsychotic risperidone in patients with acute exacerbations of schizophrenia. The study was double-blind and involved 228 patients allocated, after a 3-6-day wash-out period, to amisulpride 800 mg (n = 115) or risperidone 8 mg (n = 113) for 8 weeks. Both treatments produced a marked improvement in schizophrenic symptomatology. Decreases in mean BPRS total score were 17.7 +/- 14.9 for amisulpride and 15.2 +/- 13.9 for risperidone, and all of the individual factors on the BPRS showed a numerically greater improvement in the amisulpride than in the risperidone patients. Both treatments were equally effective against positive symptoms on the PANSS positive syndrome subscale; however, there was a trend in favor of greater improvement in negative symptoms assessed on the PANSS negative subscale in patients receiving amisulpride with a decrease of 6.9 +/- 7.5 vs. 5.3 +/- 6.6 for risperidone (P = 0.09). Both drugs demonstrated good safety profiles, and scores on neurological scales (SAS, AIMS, and BAS) did not increase during treatment. A comparable proportion of patients received antiparkinsonian medication, 30 and 23% in the amisulpride and risperidone groups, respectively (P = 0.21). Patients receiving risperidone experienced an increase in body weight, which was significantly greater than for amisulpride (P = 0.026).",2000.0,1,1
115,10637399,Prevalence and correlates of parkinsonism in an institutionalized population of geriatric patients with chronic schizophrenia.,W Byne; C Stamu; L White; M Parrella; P D Harvey; K L Davis,"Geriatric patients with chronic schizophrenia are at increased risk for parkinsonism and cognitive impairment, but the relationship between the two has been insufficiently studied. (1) To determine the prevalence of parkinsonism in a cohort of institutionalized geriatric patients with chronic schizophrenia (N=79). (2) To examine the relationship of parkinsonism to potentially relevant variables including cognitive functioning, positive and negative symptoms, sex, age, age at first hospitalization, psychopharmacological regimen and tardive dyskinesia (TD). Tremor, rigidity and bradykinesia were rated on a five-point severity scale. Clinically significant parkinsonism was defined by the unambiguous presence of at least two of those signs. TD was assessed with the Modified Simpson Dyskinesia Scale. Schizophrenic symptoms were rated with the Positive and Negative Syndrome Scale, and cognitive functioning with the Mini-Mental State Examination and the Consortium to Establish a Registry for Alzheimer's Disease battery. The prevalence of parkinsonism was 19% and was significantly higher in women than in men. Age was a significant predictor of parkinsonism. Independent of age, bradykinesia was significantly correlated with MMSE, fluency and naming. Tremor, rigidity and medication status did not correlate with any cognitive variable assessed. Cognitive measures did not differ between subjects meeting and not meeting criteria for clinically significant parkinsonism. Rigidity and bradykinesia were significantly correlated with negative symptoms but no parkinsonism sign correlated with positive symptoms. Twelve subjects received ratings consistent with both TD and parkinsonism; however, no parkinsonian variable predicted the co-occurrence of TD. The present correlations suggest potential overlap among the neural substrates for bradykinesia, cognitive impairment and negative symptoms; however, further research is required to clarify that issue.",2000.0,0,0
116,10637400,Dementia in developing countries. A consensus statement from the 10/66 Dementia Research Group.,M Prince,"Less than one-tenth of all population-based research into dementia is directed towards the two-thirds or more of cases living in developing parts of the world. The 10/66 Dementia Research Group has been formed to redress this imbalance, encouraging active research collaboration between centres in different developing countries and between developed and developing countries. The 10/66 group consisted initially of researchers attending a symposium on dementia research in developing countries, held at the 1998 Alzheimer's Disease International conference. They noted a growing interest in this area, with many active researchers and others wishing to start new studies. There was felt to be an urgent need for more research: quantifying prevalence and incidence, exploring regional variations in international collaborations using harmonized methodologies, describing care arrangements for people with dementia, quantifying the impact on caregivers and evaluating the effectiveness of any newly implemented services. Methodological problems need to be addressed, particularly development of culture- and education-fair dementia diagnostic procedures. Good-quality research can generate awareness, pioneer service development and influence policy.",2000.0,0,1
117,10638400,Pharmacoepidemiology of psychotropic drugs in patients with severe mental disorders in Italy. Italian Collaborative Study Group on the Outcome of Severe Mental Disorders.,G Tognoni,"To describe the epidemiology of psychotropic drug use in a sample of Italian outpatient psychiatric services. Drug-utilisation survey conducted within the framework of a broader prospective follow-up study with 67 Italian outpatient psychiatric services. The data concern 2322 patients recruited over a 3-year period. Three-quarters of the cohort were prescribed antipsychotic drugs, one-half received benzodiazepines and nearly one-third received antidepressants. The trends in drug use from 1994 to 1997 show that for patients with schizophrenia there has been a decrease in the prescription of typical neuroleptics: the use of haloperidol passed from 56% to 42.4% and that of chlorpromazine dropped from 13.5% to 6.1%; during the same period, an increasing use of the atypical compound risperidone was observed. Among patients suffering from unipolar affective psychosis, the prescriptions of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) have not changed in time, while the proportion of patients receiving neuroleptic drugs has increased from 41% to 45.2%. In addition, the use of antiepileptic drugs and lithium increased, irrespective of diagnosis. Almost 40% of the patients on psychotropic drugs received three or more drugs. Finally, a positive association was found between the number of prescribed compounds and the daily dose administered. These data indicate that in the absence of a rational approach to drug use, a symptomatic approach is generally adopted, by which common sense, experience, information provided by non-independent agencies and other cultural parameters play an important role in the prescription strategy. Pharmacoepidemiology should more often consider the use of drugs as a dependent variable, to be investigated within the context of other clinical, cultural, social and setting-related parameters; this approach would enable a more comprehensive assessment of prescribing practices and strategies in routine clinical care.",2000.0,0,0
118,10638864,"The effects of typical antipsychotics, clozapine, and risperidone on neuropsychological test performance in schizophrenia.",K S Earnst; S F Taylor; I C Smet; R S Goldman; R Tandon; S Berent,,2000.0,0,0
119,10647097,Lack of drug interactions between mirtazapine and risperidone in psychiatric patients: a pilot study.,A J Loonen; C H Doorschot; M C Oostelbos; J M Sitsen,"An open-label, non-randomized, pilot study has been performed in inpatients in need of treatment with an antipsychotic (risperidone) and an antidepressant (mirtazapine) with the objective to preliminarily assess a possible pharmacokinetic interaction and the tolerability of this combination. A 1-4-week single drug treatment phase (risperidone 1-3 mg bid or mirtazapine 30 mg nocte) was followed by a 2-4-week combined drug treatment phase at unchanged doses. Twelve patients were enrolled, nine of whom were treated with risperidone in the single drug phase. Results of plasma level measurements are available for six patients and indicate that adding mirtazapine to risperidone does not alter steady-state plasma concentrations of risperidone and its 9-hydroxy metabolite. Data from one patient suggest that adding risperidone to mirtazapine does not result in clinically relevant changes in plasma concentrations of either compound. The combination was well tolerated and no major or relevant adverse events were observed. Adding risperidone to mirtazapine probably does not necessitate a change of the dosage of either drug, but more extensive investigations are needed.",2000.0,0,0
120,10650450,Effective neuroleptic medication removes prepulse inhibition deficits in schizophrenia patients.,A I Weike; U Bauer; A O Hamm,"The magnitude of the startle eyeblink response is reduced if the startle eliciting stimulus is shortly preceded by another stimulus. There is evidence that schizophrenia patients exhibit impairments in this so-called prepulse inhibition. Our study investigated whether prepulse inhibition is affected by neuroleptic drug treatment as is suggested by animal research. Prepulse inhibition was tested in five unmedicated and 20 medicated inpatients with schizophrenia, and 12 normal controls. The unmedicated schizophrenia patients showed a strong impairment of sensorimotor gating as indexed by the absence of prepulse inhibition. By contrast, the medicated patients showed a pronounced prepulse inhibition that did not differ from that of the normal controls. There was a substantial covariation between the rated severity of the positive syndrome and the amount of prepulse inhibition--i.e., the patients whose positive symptoms were rated as more severe showed less prepulse inhibition. These data suggest that the impaired sensorimotor gating of schizophrenia patients is not a stable vulnerability indicator, but may rather be related to the positive syndrome and may be improved by treatments with neuroleptic medication.",2000.0,0,0
121,10667619,Evidence-based psychopharmacology 2. Appraising a systematic review: is risperidone better than conventional antipsychotics in the treatment of schizophrenia?,J P Warner,"Systematic reviews are increasingly used to combine the results of several studies in order to define the treatment effect with a high degree of precision. However, reviews of this nature may lead to spurious results and should not be accepted uncritically. This article, the second in a series on evidence-based psychopharmacology, is intended to illustrate the process of critical appraisal of a systematic review. In this example, a systematic review of studies comparing risperidone with conventional antipsychotics is appraised. Interpretation of the results of the systematic review may be hampered by the way in which studies were selected.",2000.0,0,0
122,10667741,How long to wait for a response to clozapine: a comparison of time course of response to clozapine and conventional antipsychotic medication in refractory schizophrenia.,R Rosenheck; D Evans; L Herz; J Cramer; W Xu; J Thomas; W Henderson; D Charney,"This study compared the time course to clinical improvement with clozapine and with conventional antipsychotic medications. A double-blind trial compared clozapine and haloperidol in patients with schizophrenia who were refractory to conventional antipsychotic medication and were hospitalized for 30 to 364 days at 15 Veteran Affairs medical centers during the year before study entry. Patients in the original study were randomly assigned to haloperidol or clozapine and followed for 12 months, at maximum tolerable doses. Patients who completed a full year of treatment with clozapine (n = 122), or with either haloperidol or another conventional antipsychotic medication (n = 123) and who also completed the 9- or 12-month assessment were included. Response to treatment was defined as 20 percent improvement on standard scales of symptoms and quality of life at the latter of the 9- or 12-month interviews. More patients assigned to clozapine achieved 20 percent improvement in symptoms at each followup. Among patients who did not improve at 6 weeks, 3 months, or 6 months, there were no significant differences between clozapine and comparison patients in outcomes at 1 year. Among patients who did improve, maintenance of that improvement also did not differ between the groups at 1 year on symptom measures. Maintenance of improvement in quality of life at 1 year was significantly greater for clozapine patients who had improved at 6 months (p < 0.04). Significant differential symptom response to clozapine occurred exclusively during the first 6 weeks of treatment.",2000.0,0,0
123,10667742,Risperidone in the treatment of first-episode psychotic patients: a double-blind multicenter study. Risperidone Working Group.,R A Emsley,"An international, multicenter, double-blind study was conducted in 183 patients with a first psychotic episode (provisional schizophreniform disorder or schizophrenia; DSM-III-R) treated with flexible doses of risperidone or haloperidol for 6 weeks. At endpoint, 63 percent of risperidone-treated patients and 56 percent of haloperidol-treated patients were clinically improved (> or = 50% reduction in Positive and Negative Syndrome Scale total scores). Risperidone was better tolerated than haloperidol: the severity of extrapyramidal symptoms was significantly lower in the risperidone-treated patients; significantly fewer risperidone-treated patients required antiparkinsonian medication; and significantly fewer discontinued treatment because of adverse events. A post hoc analysis revealed that low doses of these antipsychotics were efficacious in some patients. Furthermore, the severity of extrapyramidal symptoms and the use of antiparkinsonian medications were significantly lower in patients receiving low doses (maximum, < or = 6 mg/day) than high doses (maximum, > 6 mg/day) of risperidone or haloperidol. These findings are consistent with the suggestion that patients with a first psychotic episode may require low doses of antipsychotic medications. Studies designed specifically to compare low and high doses of antipsychotics are warranted to help optimize treatment for these patients.",2000.0,1,1
124,10674777,Atypical antipsychotic agents: a critical review.,J A Worrel; P A Marken; S E Beckman; V L Ruehter,"The pharmacology, efficacy, and adverse effects of atypical antipsychotic agents when used to treat schizophrenia and other disorders are reviewed. Atypical antipsychotic agents were developed in response to problems with typical agents, including lack of efficacy in some patients, lack of improvement in negative symptoms, and troublesome adverse effects, especially extrapyramidal symptoms (EPSs) and tardive dyskinesia CTD). Atypical antipsychotics differ from typical psychotics in their ""limbic-specific"" dopamine type 2 (D2)-receptor binding and high ratio of serotonin type 2 (5-HT2)-receptor binding to D2 binding. In clinical trials in patients with non-treatment-resistant schizophrenia, risperidone and olanzapine were superior to placebo for positive and negative symptoms. Risperidone and olanzapine were superior to haloperidol on some measures. Quetiapine was better than placebo but was not better than typical antipsychotics. Head-to-head comparisons of atypical antipsychotics in non-treatment-resistant schizophrenia have been inconclusive. Clozapine remains the standard agent for treatment-resistant schizophrenia. Atypical agents are substantially more expensive than their typical antipsychotic counterparts. To fully determine the overall efficiency of these drugs, other potential benefits, such as improved quality of life, need to be factored in. Atypical antipsychotics are associated with a decreased capacity to cause EPSs, TD, neuroleptic malignant syndrome, and hyperprolactinemia. Clozapine carries a risk of agranulocytosis; the white blood cell count must be monitored. Atypical antipsychotics are increasingly being used for indications other than schizophrenia, such as the management of aggression, mania, and depression. Atypical antipsychotics are often considered first-line agents for treating schizophrenia and are promising treatment alternatives for other psychiatric and neurologic conditions.",2000.0,0,1
125,10682225,Combined electroconvulsive-clozapine therapy.,M Kupchik; B Spivak; R Mester; I Reznik; N Gonen; A Weizman; M Kotler,"We reviewed 36 reported psychiatric patients who were treated with a combination of electroconvulsive therapy (ECT) and clozapine. The indication of the ECT-clozapine treatment was resistance to classical antipsychotic agents, clozapine, or ECT alone. Sixty-seven percent of the patients benefited from the combined treatment. In most of the patients, the combined treatment was safe and well tolerated. Adverse reactions occurred in 16.6% of the patients and included prolonged ECT-induced seizures (one case), supraventricular (one case) and sinus tachycardia, and blood pressure elevation. It seems that combined ECT-clozapine treatment is effective and safe. This strategy may be a therapeutic option in treatment-resistant patients.",2000.0,0,0
126,10688158,Dopamine D2 receptor occupancy by olanzapine or risperidone in young patients with schizophrenia.,J Lavalaye; D H Linszen; J Booij; L Reneman; B P Gersons; E A van Royen,"A crucial characteristic of antipsychotic medication is the occupancy of the dopamine (DA) D2 receptor. We assessed striatal DA D2 receptor occupancy by olanzapine and risperidone in 36 young patients [31 males, 5 females; mean age 21.1 years (16-28)] with first episode schizophrenia, using [123I]iodobenzamide (IBZM) SPECT. The occupancy of DA D2 receptors was not significantly different between olanzapine and risperidone. However, in subgroups of most prescribed doses, DA D2 occupancy was higher in the risperidone 4-mg group (79%) compared to the olanzapine 15-mg group (62%). [123I]IBZM binding ratios decreased with olanzapine dose (r = -0.551; P < 0.01), indicating higher DA D2 receptor occupancy with higher olanzapine dose. Akathisia and positive symptoms were correlated with [123I]IBZM binding ratio (r = -0.442; P < 0.01; and r = -0.360; P < 0.05, respectively). Prolactin (PRL) levels were elevated in the risperidone, but not in the olanzapine group, at comparable D2 receptor occupancy levels. In the olanzapine group, PRL levels were correlated with [123I]IBZM binding ratio (r = -0.551; P < 0.01). In conclusion, both olanzapine and risperidone induce a high striatal D2 receptor occupancy, dependent on dose and group formation. The lower incidence of prolactin elevation with olanzapine, compared to risperidone, may not be attributed to a lower D2 receptor occupancy.",2000.0,0,1
127,10693159,Effects of atypical neuroleptics on sustained attention deficits in schizophrenia: a trial of risperidone versus haloperidol.,S K Liu; W J Chen; C J Chang; H N Lin,"To help determine whether sustained attention deficits as measured with the Continuous Performance Test (CPT) are stable vulnerability indicators of schizophrenia, we compared the CPT performance of schizophrenic patients before and after treatment with risperidone or haloperidol. In this double blind trial, 56 schizophrenic patients were randomly assigned to a 12-week regimen of either risperidone or haloperidol, after a 1-week washout period. The patients undertook two sessions of the CPT (undegraded and 25% degraded) twice, one at the end of the washout period and the other at the end of the study. Thirty-eight patients completed the study, 19 in each group. Both groups experienced significant improvements in clinical symptoms, and the risperidone group showed no change in the severity of extrapyramidal symptoms. Despite those improvements, the CPT performance indexes did not change significantly from the beginning to the end of the study. These findings indicate that sustained attention deficits might be stable vulnerability indicators of schizophrenia.",2000.0,1,1
128,10702809,Blood dyscrasias in clozapine-treated patients in Italy.,G Lambertenghi Deliliers,"Clozapine is a dibenzodiazepine derivative that is more effective than standard neuroleptic drugs in refractory schizophrenic patients, but its introduction in some countries was delayed by its propensity to cause blood dyscrasias. However, over the last ten years, different reports have clearly demonstrated that agranulocytosis and neutropenia can be easily prevented by means of strict hematologic surveillance. This article reviews the results of the first five years of the Italian Clozapine Monitoring System (ICLOS). The hematologic parameters of 2,404 patients registered between 1995 and 1999 were collected in a central database, before the patients began clozapine-treatment, weekly for the first 18 weeks, and then monthly throughout the duration of therapy. On the basis of conventional criteria, different risk levels have been identified with total leukocyte <3. 0x10(9)/L and/or an absolute neutrophil count <1.5x10(9)/L leading to immediate discontinuation of the drug. The analysis shows that 0.9% of the patients developed neutropenia and 0.7% agranulocytosis, mainly during the first 18 weeks of clozapine treatment. Drug discontinuation led to the normalization of hematologic parameters in all cases, and the use of growth factors reduced the risk of infectious complications. Transient leukocytosis and eosinophilia were also observed but these did not have any serious clinical effects. The ICLOS study confirms that regular hematologic monitoring is highly effective in minimizing the incidence of clozapine-associated blood dyscrasias. The lower than initially expected rates of agranulocytosis and associated deaths are encouraging in view of the benefits of this drug in treatment-resistant schizophrenia and other neurologic disorders.",2000.0,1,1
129,10704958,Olanzapine increases slow-wave sleep: evidence for blockade of central 5-HT(2C) receptors in vivo.,A L Sharpley; C M Vassallo; P J Cowen,"The study aimed to determine the effects of the atypical antipsychotic agent, olanzapine, on the polysomnogram in healthy subjects. We predicted that olanzapine, via serotonin(2C) (5-HT(2C)) receptor blockade, would increase slow-wave sleep (SWS). We studied the effects of single evening doses of olanzapine (5 mg and 10 mg orally) on the polysomnogram of 9 healthy male volunteers, using a placebo-controlled, double-blind, cross-over design. Compared to placebo, the 5-mg and 10-mg doses of olanzapine significantly increased SWS, sleep continuity measures, and subjective sleep quality. In addition, 10 mg of olanzapine suppressed rapid eye movement (REM) sleep and increased REM sleep latency. Olanzapine (5 mg and 10 mg) produced substantial (59.1% and 83.3%) and highly significant dose-related increases in SWS in humans probably via blockade of brain 5-HT(2C) receptors. 5-HT(2C) receptor antagonism may account for some of the therapeutic and adverse effects of olanzapine therapy.",2000.0,0,0
130,10706013,Extrapyramidal symptoms and oestrogen.,K N Thompson; J Kulkarni; A A Sergejew,"The present study aimed to investigate neuroleptic side-effect severity in women with psychosis, and to investigate their putative association with variations in sex steroids over the menstrual cycle. Based on the oestrogen hypothesis, which postulates a synergistic relationship between oestrogen and neuroleptics, it was hypothesized that oestrogen would exacerbate extrapyramidal symptoms. Twenty-five psychotic women were assessed using the ESRS and blood hormone analysis. Testing was conducted twice, 2 weeks apart, in a randomized cross-over design. Contrary to expectation the results indicated that high levels of oestrogen reduce hyperkinetic symptoms in women with psychosis, and this effect appears to be further potentiated when both oestrogen and progesterone are high. On the basis of these findings, and receptor studies in animals, it was concluded that oestrogen has different effects on dopamine dynamics in the mesolimbic and mesostriatal pathways.",2000.0,0,0
131,10706993,Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics.,M Maes; L Bocchio Chiavetto; S Bignotti; G Battisa Tura; R Pioli; F Boin; G Kenis; E Bosmans; R de Jongh; A Lin; G Racagni; C A Altamura,"There is now some evidence that schizophrenia may be accompanied by an activation of the inflammatory response system (IRS) and that typical antipsychotics may suppress some signs of IRS activation in that illness. This study was carried out to examine (i) the serum concentrations of interleukin-6 (IL-6), IL-6 receptor (IL-6R), IL-1R antagonist (IL-1RA) and Clara Cell protein (CC16), an endogenous anticytokine, in nonresponders to treatment with typical neuroleptics and (ii) the effects of atypical antipsychotics on the above IRS variables. The above parameters were determined in 17 patients with treatment-resistant schizophrenia (TRS) to treatment with neuroleptics and in seven normal volunteers and 14 schizophrenic patients who had a good response to treatment with antipsychotic agents. Patients with TRS had repeated measurements of the IRS variables before and 2 and 4 months after treatment with atypical antipsychotics. Serum IL-6 was significantly higher in schizophrenic patients, irrespective of their response to typical antipsychotics, than in normal controls. Serum IL-1RA was significantly higher in the TRS patients than in controls, whereas responders took up an intermediate position. The serum concentrations of CC16 were significantly lower after treatment with atypical antipsychotics during 4 months than before treatment. It is concluded that (i) schizophrenia and, in particular, TRS is characterized by an activation of the monocytic arm of cell-mediated immunity and (ii) atypical antipsychotics may decrease the anti-inflammatory capacity of the serum in TRS patients.",2000.0,0,0
132,10708264,,,,,0,0
133,10708839,Mexiletine in treatment-resistant bipolar disorder.,A Schaffer; A J Levitt; R T Joffe,"The purpose of this study was to evaluate the efficacy and safety of mexiletine, a medication with antiarrhythmic, anticonvulsant and analgesic properties, in treatment-resistant bipolar disorder patients. Twenty subjects with rapid-cycling bipolar disorder who had failed to respond or were intolerant to lithium, valproic acid and carbamazepine were entered into the 6-week, open label study. Subjects were followed on a weekly basis for dosing of mexiletine, blood levels, and completion of the Hamilton Depression Rating Scale (HAM-D) and the Manic State Rating Scale (MSRS). ""Burden of Mood Symptoms"" (BMS) was calculated by combining scores for the HAM-D and MSRS. Thirteen subjects (10 female, 3 male), mean age 41 years (S.D.=7.6), and mean duration of illness 20 years (S.D.=7.7) completed the study. The dose range of mexiletine was 200-1200 mg/day. Full response (>/=50% reduction in BMS) was seen in 46% of the subjects, and a partial response (25-49% reduction in BMS) in 15%. Of note, 5/5 subjects with a mixed or manic state demonstrated a full or partial response. This study has an open label design, and a small number of subjects. Mexiletine may be effective and safe in patients with highly treatment-resistant, chronic bipolar disorder. Randomized, controlled trials are required to confirm the current results.",2000.0,0,0
134,10711911,"Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia.",S E Purdon; B D Jones; E Stip; A Labelle; D Addington; S R David; A Breier; G D Tollefson,"The purpose of this investigation was to test the efficacy of novel antipsychotic medications in the treatment of cognitive impairment in early phase schizophrenia. Sixty-five patients in this multicenter double-blind study were randomly assigned to olanzapine (5-20 mg), risperidone (4-10 mg), or haloperidol (5-20 mg). Standard measures of clinical and motor syndromes were administered, as well as a comprehensive battery of tests to assess (1) motor skills, (2) attention span, (3) verbal fluency and reasoning, (4) nonverbal fluency and construction, (5) executive skills, and (6) immediate recall at baseline and after 6, 30, and 54 weeks of treatment. The general cognitive index derived from the 6 domain scores revealed a significantly greater benefit from treatment with olanzapine relative to haloperidol and olanzapine relative to risperidone, but no significant difference was shown between risperidone and haloperidol. The improvement related to olanzapine was apparent after 6 weeks and enhanced after 30 and 54 weeks of treatment. Exploratory within-group analyses of the 6 cognitive domains after a conservative Bonferroni adjustment revealed a significant improvement with olanzapine only on the immediate recall domain, and similar analyses of the 17 individual tests revealed a significant improvement with olanzapine only on the Hooper Visual Organization Test. These data suggest that olanzapine has some superior cognitive benefits relative to haloperidol and risperidone. A larger sample replication study is necessary to confirm and generalize the observations of this study and begin evaluation of the implications of this change to cerebral function and quality of life for people with schizophrenia.",2000.0,1,1
135,10722180,"A multicentre, double-blind, randomized comparison of quetiapine (ICI 204,636, 'Seroquel') and haloperidol in schizophrenia.",D L Copolov; C G Link; B Kowalcyk,"Quetiapine (ICI 204,636, 'Seroquel') is a new atypical antipsychotic agent with a similar binding profile to the original atypical antipsychotic, clozapine. Its clinical efficacy has already been demonstrated at multiple fixed doses (150-750 mg/day) and has been suggested to be comparable with haloperidol (12 mg/day). This international, 6-week, multicentre, double-blind, randomized, parallel-group trial compared quetiapine with haloperidol (455 mg and 8 mg mean total daily doses, respectively) in 448 hospitalized patients with acute exacerbation of chronic or subchronic schizophrenia (DSM-III-R), in order to establish their equivalence in terms of efficacy, and the nature of their tolerability profiles, especially in terms of extrapyramidal symptoms (EPS) and serum prolactin levels. Both quetiapine and haloperidol produced a clear reduction in the Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression (CGI) Severity of Illness and Global Improvement scores. At day 42, the PANSS total score was reduced by -18.7+/-1.63 in the quetiapine group, and -22.1+/-1.63 in the haloperidol group (P = 0.13, between-treatment). Quetiapine was better tolerated than haloperidol in terms of EPS as demonstrated by the significant differences in the Simpson Scale and Abnormal Involuntary Movement Scale scores (P < 0.05). Although patients in both groups had elevated serum prolactin concentrations at baseline, mean serum prolactin concentration decreased (by 16.5 microg/l) in quetiapine-treated patients, yet increased (by 5.9 microg/l) in patients treated with haloperidol. Quetiapine is an effective and well tolerated antipsychotic of comparable efficacy to haloperidol and lacks the latter compound's effect on prolactin and EPS.",2000.0,0,1
136,10737828,Management of negative symptoms among patients with schizophrenia attending multiple-family groups.,D G Dyck; R A Short; M S Hendryx; D Norell; M Myers; T Patterson; M G McDonell; W D Voss; W R McFarlane,"Outcomes for negative symptoms over a one-year period were examined in two groups of patients, one receiving psychoeducational multiple-family group treatment and one receiving standard care. A total of 63 outpatients, ages 18 to 45 years, with DSM-IV diagnoses of schizophrenic disorders were randomly assigned to standard care or multiple-family group psychoeducation treatment at a large mental health center in Spokane, Washington. Treatment assignment was stratified by whether patients were taking typical or atypical antipsychotic medications. Negative symptom status was monitored monthly for one year by raters blind to group assignment and measured as a composite of five symptoms using the Modified Scale for the Assessment of Negative Symptoms. When the analysis controlled for baseline negative symptoms, participants in the multiple-family group experienced significantly reduced negative symptoms compared with those receiving standard care. Taking atypical antipsychotic medication or having a diagnosis of substance abuse was not associated with the severity of negative symptoms. An additional analysis of the five individual negative symptoms indicated small but consistent group differences on all dimensions except inattention. Negative symptoms were significantly correlated with relapse to acute illness but not with outpatient or inpatient service use. The study demonstrated that a psychoeducational multiple-family group intervention was more effective than standard care in managing negative symptoms over a 12-month period. The results are particularly relevant because negative symptoms are associated with relapse, poor social and occupational functioning, cognitive impairment, and lower subjective quality of life.",2000.0,0,1
137,10739409,"Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia.",S Kapur; R Zipursky; C Jones; G Remington; S Houle,"Since all antipsychotics block dopamine D(2) receptors, the authors investigated how well D(2) receptor occupancy in vivo predicts clinical response, extrapyramidal side effects, and hyperprolactinemia. In a double-blind study, 22 patients with first-episode schizophrenia were randomly assigned to 1.0 or 2. 5 mg/day of haloperidol. After 2 weeks of treatment, D(2) receptor occupancy was determined with [(11)C]raclopride and positron emission tomography, and clinical response, extrapyramidal side effects, and prolactin levels were measured. Patients who showed adequate responses continued taking their initial doses, those who did not respond had their doses increased to 5.0 mg/day, and evaluations were repeated at 4 weeks for all patients. The patients showed a wide range of D(2) occupancy (38%-87%). The degree of receptor occupancy predicted clinical improvement, hyperprolactinemia, and extrapyramidal side effects. The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D(2) occupancy exceeded 65%, 72%, and 78%, respectively. The study confirms that D(2) occupancy is an important mediator of response and side effects in antipsychotic treatment. The data are consistent with a ""target and trigger"" hypothesis of antipsychotic action, i.e., that the D(2) receptor specificity of antipsychotics permits them to target discrete neurons and that their antagonist properties trigger within those neurons intracellular changes that ultimately beget antipsychotic response. While limited to haloperidol, the relationship between D(2) occupancy and side effects in this study helps explain many of the observed clinical differences between typical and atypical antipsychotics.",2000.0,0,0
138,10745060,Impaired prepulse inhibition of acoustic startle in schizophrenia.,A Parwani; E J Duncan; E Bartlett; S H Madonick; T R Efferen; R Rajan; M Sanfilipo; P B Chappell; S Chakravorty; S Gonzenbach; G N Ko; J P Rotrosen,"Schizophrenics show deficits in sensorimotor gating, as measured by prepulse inhibition of acoustic startle (PPI). The goal of this investigation is to further characterize PPI and habituation deficits in schizophrenia, and to examine whether differing subgroups of schizophrenics would show comparable PPI deficits. PPI was measured in 24 male schizophrenic subjects (9 acutely decompensated inpatients and 15 stable outpatients) and in 20 age-matched normal control subjects. Schizophrenic subjects were rated for positive and negative symptoms at the time of testing. Schizophrenic subjects showed deficits in prepulse inhibition and habituation as compared to normal subjects. Similar latency facilitation was produced by the prepulse in both groups. Acutely decompensated inpatients and stable outpatients did not differ in percent PPI. PPI did not correlate with severity of positive or negative symptoms. These results suggest that schizophrenic subjects have impaired central inhibitory mechanisms as measured by PPI, and support the hypothesis that periods of relative clinical remission are not accompanied by normalization of sensorimotor gating.",2000.0,0,0
139,10750263,"Eicosapentaenoic acid treatment in schizophrenia associated with symptom remission, normalisation of blood fatty acids, reduced neuronal membrane phospholipid turnover and structural brain changes.",B K Puri; A J Richardson; D F Horrobin; T Easton; N Saeed; A Oatridge; J V Hajnal; G M Bydder,"The administration of the omega-3 fatty acid eicosapentaenoic acid (EPA) to a drug-naive patient with schizophrenia, untreated with conventional antipsychotic medication, led to a dramatic and sustained clinical improvement in both positive and negative symptoms. This was accompanied by a correction in erythrocyte membranes of abnormalities in both n-3 and n-6 highly unsaturated fatty acids and with reduced neuronal membrane phospholipid turnover, as evidenced by serial 31-phosphorus cerebral magnetic resonance spectroscopy. Using recently developed techniques of image segmentation, subvoxel registration and quantitation, analysis of serial high-resolution 3D cerebral MRI scans showed that, in the year before EPA treatment, cerebral atrophy was taking place and that this atrophy was reversed by six months of EPA treatment. These results demonstrate that EPA can reverse both the phospholipid abnormalities previously described in schizophrenia and cerebral atrophy. They provide strong further evidence in support of the membrane phospholipid model of schizophrenia.",2000.0,0,0
140,10756621,"The newer, 'atypical' antipsychotic drugs--their development and current therapeutic use.",T Kendrick,"General practitioners (GPs) need to become more aware of a new generation of antipsychotic drugs that are 'atypical' in that, unlike traditional neuroleptics, they do not cause extrapyramidal side-effects; they may also be more effective against both the positive and negative symptoms of schizophrenia by their actions on various neurotransmitter pathways in the brain. This is a non-systematic review of the development of these new drugs and outlines how they are currently being used. It includes information found from an electronic search of the databases MEDLINE (from 1966 to June 1998) and EMBASE (from 1980 to January 1998) using the combined search terms 'antipsychotic agents', 'atypical', and 'schizophrenia'.",2000.0,0,0
141,10761820,Influence of methodology on outcomes of randomised clozapine trials.,K Wahlbeck; A Tuunainen; S Gilbody; C E Adams,"The aim of this study was to clarify the impact of various methodological quality factors on reported outcome of randomised clozapine trials. Trials comparing the atypical antipsychotic clozapine with other antipsychotic drugs were identified in extensive electronic searches. Two independent reviewers extracted data on methodology and primary outcomes, and assessed trial quality by use of three sets of criteria (Cochrane, Delphi, and Jadad). There was no association between trial quality, as measured by any of the criteria sets, and primary measures of outcome. Trials with the best score for randomisation and concealment according to the Delphi scale had a significantly lower relative risk for relapse in clozapine-treated groups, and studies with well reported random order generation according to Jadad criteria tended to have better odds ratios for clinical improvement on clozapine. These findings strengthen the evidence of true clozapine superiority in these aspects. No other quality items correlated to the primary outcomes. Inadequate randomisation techniques may be a source of bias in clozapine studies, but much more research is needed on the connections between trial quality and trial outcome.",2000.0,0,0
142,10766404,Neurotransmitter-related genes and antipsychotic response: pharmacogenetics meets psychiatric treatment.,M J Arranz; R W Kerwin,Pharmacogenetic research into neurotransmitter-related genes is helping to unravel genetic factors that determine antipsychotic response. Several genetic mutations in neurotransmitter receptors targeted by antipsychotic drugs have been found to be related to clinical response. Modern molecular genetic techniques will facilitate the identification of those mutations that determine treatment response. Future psychiatric prescription will include the genetic characterization of neurotransmitter receptors for the selection of the most beneficial drug according to the individual's pharmacogenetic profile.,2000.0,0,1
143,10770464,Subject selection for the placebo- and comparator-controlled trials of neuroleptics in schizophrenia.,P Mohr; P Czobor,"It has been suggested that inclusion of a placebo treatment arm in controlled clinical trials might bias the selection of study subjects. Presumably, patients in the placebo-controlled studies are more stable, but there are no data available to support such an assumption. The authors tested the hypothesis in a set of randomized trials of neuroleptics in treating schizophrenia by comparing placebo-controlled (PCTs) and comparator-controlled trials (CCTs) in terms of basic patient characteristics. The results, based on a total of 296 studies, showed that the patients in PCTs, compared with those in CCTs, were older (p < 0.002), had a longer duration of illness (p < 0.001), and a lower initial symptom severity (p < 0.02). No difference was found in the number of subjects per treatment arm or in the proportion of female subjects. However, investigation of studies which used same-gender study subjects revealed that female-only populations were more likely to be tested in PCTs (p < 0.03) than in CCTs. To investigate current trends in psychopharmacologic research, the authors tested separately a subset of trials of new atypical antipsychotics. The results indicated a significantly smaller number of females participating in the latest PCTs (p < 0.0003). Moreover, our findings suggest that the characteristics of patients in the current controlled trials are rather uniform; thus, the generalizability of new study findings for certain groups of patients with schizophrenia (e.g., with early or late onset or brief duration of illness) may be compromised.",2000.0,0,0
144,10773184,"Placebo effect in randomized, controlled studies of acute bipolar mania and depression.",P E Keck; J A Welge; S L McElroy; L M Arnold; S M Strakowski,"Randomized, double-blind, placebo-controlled, parallel group clinical trials have been the standard methodology for establishing the efficacy of new treatments for patients with bipolar disorder in manic, mixed, or depressive episodes. We examine the placebo response rate in acute treatment trials of acute mania (and mixed states) and bipolar depression. Also addressed are potential variables associated with placebo response, strategies to minimize placebo response, the optimum duration of placebo-controlled acute treatment trials, possible alternatives to the use of placebo, and the ramifications of these issues with regard to the design of studies in children, adolescents, and older adults with bipolar disorder.",2000.0,0,0
145,10783190,An assessment of clinical practice of clozapine therapy for veterans.,M Sajatovic; C R Bingham; D Garver; L F Ramirez; G Ripper; F Blow; L S Lehmann,"Clozapine therapy for 2,996 patients with treatment-refractory schizophrenia was examined over a five-year period in the Veterans Affairs health care system. Patients were assessed with the Brief Psychiatric Rating Scale (BPRS) and the Abnormal Involuntary Movement Scale (AIMS). BPRS scores, which were available for 522 patients, indicated a significant improvement, as did AIMS scores, which were available for 252 patients. Compared with individuals who showed a modest improvement, those with a more robust response to clozapine had higher initial BPRS scores and were three times more likely to have been suicidal in the month before starting clozapine therapy.",2000.0,1,1
146,10784481,,,,,0,0
147,10791380,Association of venous thromboembolism and clozapine.,S Hägg; O Spigset; T G Söderström,Data from the Swedish Adverse Reactions Advisory Committee suggest that use of clozapine is associated with venous thromboembolic complications. We summarise 12 cases of thromboembolism during clozapine treatment. In five cases the outcome was fatal.,2000.0,0,1
148,10800756,Switching outpatients between atypical antipsychotics.,A M Bogan; E Shellhorn; E S Brown; C McDanald; T Suppes,"1. Some reports have suggested an increase in symptoms when switching patients with psychosis from clozapine to other atypical antipsychotics. 2. No data are available on switching between atypical antipsychotics other than clozapine, though this is common in clinical practice. 3. Six patients with schizophrenia or schizoaffective disorder, bipolar type were switched to quetiapine after finishing a clinical trial of sertindole. 4. During the observation period of two to ten weeks no subjects worsened and one improved. Side effects were mild. 5. These preliminary data suggest that switching between some atypical agents may be well tolerated. Larger controlled trials are needed to confirm this observation.",2000.0,0,1
149,10814768,Psychosocial correlates of prepartum and postpartum depressed mood.,D Da Costa; J Larouche; M Dritsa; W Brender,"The aim of the present study was to delineate the influence of maternal stress, social support and coping styles on depressed mood during pregnancy and the early postpartum period. Beginning in the third month of pregnancy, data on numerous variables including daily stress (Hassles), state-anxiety (STAI-state), pregnancy-specific stress (PEQ) and depressed mood (DACL) were collected monthly. In each trimester social support (SSQ), coping strategies (CISS) and pregnancy progress were assessed. Approximately 4-5 weeks following delivery, information on labor, delivery and infant status was collected and the DACL and the Edinburgh Postnatal Depression Scale (EPDS) were administered. The final sample consisted of 80 women. Approximately 16% of the women in this sample experienced depressed mood in the postpartum and 25% of the sample reported depressed mood only during pregnancy. Women depressed only during pregnancy and those depressed in the postpartum reported more emotional coping and higher trait and state anxiety during gestation. More hassles during pregnancy was related to prepartum depressed mood, but not postpartum depressed mood. Consistent with the literature, the best predictor of postpartum depressed mood was depressed mood during pregnancy. The sample size was relatively small and we relied solely on self-reported depressive symptomology. The findings point to specific psychosocial variables which can be targeted early in pregnancy to reduce the rate of depressed mood in the prepartum and postpartum periods.",2000.0,0,0
150,10822097,Second-generation antipsychotics in the emergency care setting. A prospective naturalistic study.,M Raja; A Azzoni,"The objective of this subject was to examine the impact of the replacement of standard neuroleptics with atypical antipsychotic agents in an intensive psychiatric care unit. A mirror-image study was conducted. Cases admitted in the first semester of the year (when most of patients were treated with standard neuroleptics) were compared to cases admitted in the second semester of the year, when atypical antipsychotic agents were routinely utilized as first line treatment of patients with psychotic signs. Cases admitted in the first semester received a significantly higher daily dosage of antipsychotic drugs and more frequently received anticholinergics. In the second semester, a significantly higher number of patients received anticonvulsants, in particular valproate and gabapentin. There was no significant difference between the two groups of cases in the number of patients treated with antipsychotics, benzodiazepines, lithium, and carbamazepine and in the mean daily dose of benzodiazepines, lithium, carbamazepine, or valproate on the first day of hospitalization, the day of evaluation, and on discharge. On discharge, similar percentages of patients went home, were transferred to other Psychiatric Intensive Care Units (PICUs) or to private clinics, or left our PICU against medical advice. The length of hospitalization was similar in the two groups. There was no significant difference in the rate of aggressive or violent behavior registered in the two groups of cases. The risk of increasing violence rates, lengthening hospitalization, and facilitating patients' non-compliance should not be major concerns for physicians prescribing second-generation antipsychotics in the emergency care setting. Since these drugs have been shown to have at least similar efficacy (or greater efficacy in the case of clozapine) in the treatment of psychotic disorders as typical neuroleptics and to have a better side-effects profile, they should become first line treatment for patients with psychotic signs admitted to emergency care psychiatric facilities.",2000.0,0,0
151,10830153,Effectiveness of risperidone in simple schizophrenia: a single case report.,S Hirose,,2000.0,0,0
152,10831015,Longitudinal comparative study of risperidone and conventional neuroleptics for treating patients with schizophrenia. The Quebec Schizophrenia Study Group.,R H Bouchard; C Mérette; E Pourcher; M F Demers; J Villeneuve; M H Roy-Gagnon; Y Gauthier; D Cliche; A Labelle; M J Filteau; M A Roy; M Maziade,"This study compared the long-term (12 months) effectiveness of risperidone (RP) with that of conventional neuroleptics (CNs) in a population with chronic schizophrenia who had shown suboptimal response to CNs. A randomized, open, parallel, multicenter design was used. One hundred eighty-four subjects meeting DSM-IV criteria for schizophrenia were randomly assigned to receive either RP or a CN, and 165 of them completed the follow-up. Outcome measures were taken at 3, 6, and 12 months and included the Positive and Negative Syndrome Scale (PANSS) and the Extrapyramidal Symptom Rating Scale. Within this 12-month follow-up, RP was found to be superior to CNs in terms of both the average change in score from baseline on the PANSS (p = 0.006) and the proportion of good responders (as defined by a 20% decrease in total PANSS scores;p = 0.03). For positive symptoms, the effectiveness of the RP treatment tended to increase over time. At 12 months, the percentage of good responders in the RP group was twice as large as that in the CN group (30% vs. 15%;p = 0.03). The superiority of RP over CNs was constant over the three dose categories. In both the RP and the CN groups, the maximum decrease in psychopathology was achieved with the lowest dose range. A worsening of akathisia was less frequent in subjects receiving RP than in those receiving CNs (p = 0.02). In conclusion, this study showed that, compared with CNs, RP is beneficial in the treatment of patients with chronic schizophrenia and that some of these benefits may appear only after longer-term treatment.",2000.0,1,1
153,10831016,,,,,0,0
154,10831019,Sudden death in patients receiving clozapine treatment: a preliminary investigation.,I Modai; S Hirschmann; A Rava; R Kurs; P Barak; P Lichtenberg; M Ritsner,"The risk of sudden death during clozapine treatment is controversial. The authors present a review of sudden deaths that occurred at Sha'ar Menashe Mental Health Center between January 1991 and August 1997. The number of cases of deceased inpatients was retrieved from the hospital's computerized database and divided into three groups: sudden death, suicide, and disease-related death. Copies of mandatory reports of sudden death filed with the Ministry of Health were obtained, and the corresponding patient records were reviewed. The rates of sudden death, suicide, and disease-related deaths were calculated for clozapine-treated patients (CTPs) during and after treatment and for patients treated with other psychiatric agents (non-CTPs). Among 561 CTPs, there were 4 sudden deaths during treatment, 2 sudden deaths after treatment, 2 suicides during treatment, and 2 disease-related deaths during treatment. Among 4918 non-CTPs, there were 14 sudden deaths, 5 suicides, and 86 disease-related deaths, all of which occurred during treatment with other psychiatric agents. CTPs who experienced sudden death were 10.37 years younger and healthier than non-CTPs who experienced sudden death. The sudden death rate was 3.8 times higher for CTPs than for non-CTPs, whereas the rate of disease-related death was 5 times higher for non-CTPs than for CTPs. Contrary to expectations, the rate of suicide among patients currently receiving clozapine in this sample was 3.6 times higher than among non-CTPs. Because CTPs who experienced sudden death were also younger and healthier, it seems that treatment with clozapine may present a greater risk for sudden death than treatment with other psychiatric medications. The limited number of sudden death cases and deaths from other causes should be noted so that these findings are considered with caution.",2000.0,1,1
155,10831479,"Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study.",D C Henderson; E Cagliero; C Gray; R A Nasrallah; D L Hayden; D A Schoenfeld; D C Goff,"The goal of this 5-year naturalistic study of patients treated with clozapine was to examine the incidence of treatment-emergent diabetes mellitus in relation to other factors, including weight gain, lipid abnormalities, age, clozapine dose, and treatment with valproate. Data on age, gender, race, diagnosis, family history of diabetes, and age at clozapine initiation were collected from medical records of 82 outpatients with schizophrenia or schizoaffective disorder. Clozapine dose, data on use of valproate, and laboratory test results were recorded at 6-month intervals. The mean age at the time of clozapine initiation of the 82 patients was 36.4 years; 26.8% of the patients were women, and 91.5% were Caucasian. The mean baseline weight was 175.5 lb, and the mean body mass index was 26.9 kg/m(2). Thirty patients (36.6%) were diagnosed with diabetes during the 5-year follow-up. Weight gain, use of valproate, and total daily dose of clozapine were not significant risk factors for developing diabetes mellitus. Patients experienced significant weight gain that continued until approximately month 46 from initiation of clozapine. There was a nonsignificant increase in total serum cholesterol and a significant increase in serum triglycerides level. The results support the hypotheses that patients treated with clozapine experience significant weight gain and lipid abnormalities and appear to be at increased risk for developing diabetes.",2000.0,1,1
156,10836281,Long-term safety and efficacy of amisulpride in subchronic or chronic schizophrenia. Amisulpride Study Group.,L Colonna; P Saleem; L Dondey-Nouvel; W Rein,"Amisulpride is an atypical antipsychotic with selective affinity for dopamine D2/3 receptors. In this long-term, open, randomised, multicentre trial, patients with chronic or subchronic schizophrenia received amisulpride (n =370) or haloperidol (n = 118) for 12 months. Dosage regimens were flexible (amisulpride 200-800 mg/day, haloperidol 5-20 mg/day). Improvement in mean Brief Psychiatric Rating Scale total score was significantly greater for amisulpride than haloperidol (17.0 versus 12.8, P = 0.01). Positive symptoms (Positive and Negative Syndrome Scale [PANSS] positive) improved in a similar way in each group but amisulpride caused a significantly better improvement in negative symptoms (PANSS negative) (7.1 versus 3.7, P < 0.0001). Improvements in Global Assessment of Functioning (GAF) and Quality of Life Scale (QLS) scores were also significantly greater in the amisulpride group (GAF -20.1 versus -13.6, P = 0.001; QLS -0.64 versus -0.30, P = 0.02). Adverse events were mainly psychiatric in nature, and occurred with similar frequency in each group (amisulpride 254/370, 69%; haloperidol 82/118, 70%). Extrapyramidal symptoms were more frequent for haloperidol (48/118, 41% versus 96/370, 26% for amisulpride), leading to a greater requirement for antiparkinsonian medication (haloperidol 66/118, 56% versus amisulpride 118/370, 32%). Haloperidol significantly aggravated parkinsonism, akathisia and involuntary movement compared to amisulpride. The overall incidence of endocrine events was comparable between groups (4% for amisulpride, 3% for haloperidol). Maintenance of efficacy was comparable in both treatment groups; 59% of amisulpride patients and 55% of haloperidol patients improved after 1 month of therapy remained improved throughout the study period. Amisulpride is effective following flexible long-term administration and significantly improves social functioning and quality of life.",2000.0,0,0
157,10838063,Reduced phosphodiesters and high-energy phosphates in the frontal lobe of schizophrenic patients: a (31)P chemical shift spectroscopic-imaging study.,H R Volz; S Riehemann; I Maurer; S Smesny; M Sommer; R Rzanny; W Holstein; J Czekalla; H Sauer,"(31)Phosphorous magnetic resonance spectroscopy has been widely used to evaluate schizophrenic patients in comparison to control subjects, because it allows the investigation of both phospholipid and energy metabolism in vivo; however, the results achieved so far are inconsistent. Chemical shift imaging (CSI) has the advantage that instead of only one or a few preselected voxels the tissue of a whole brain slice can be examined. The aim of the present investigation was to determine whether the results of previous studies of our group, showing that phosphodiesters (PDE) are decreased in the frontal lobe of schizophrenic patients as compared to control subjects, might be confirmed in an independent unmedicated patient sample using the CSI technique. A carefully selected new cohort including 11 neuroleptic-free schizophrenic patients and 11 age- and gender-matched healthy control subjects was recruited. CSI was applied and an innovative analysis method for CSI data based on a general linear model was used. PDE, phosphocreatine, and adenosine triphosphate (ATP) were found to be significantly decreased in the frontal lobe of patients with schizophrenia. Because PDE was decreased in schizophrenic patients, the membrane phospholipid hypothesis of schizophrenia could not be corroborated. Further results indicate decreased ATP production in the frontal lobe of patients with schizophrenia.",2000.0,0,0
158,10839333,A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy.,S Kapur; R Zipursky; C Jones; C S Shammi; G Remington; P Seeman,"Quetiapine is a new atypical antipsychotic medication. As such, relatively little has been published regarding its in vivo effects at the dopamine type 2 (D2) and serotonin type 2a (5-HT2a) receptor systems. The following study was undertaken to explore these effects across the clinical dose range and relate this information to its clinical profile. Twelve patients with schizophrenia were randomly assigned to doses of 150 to 600 mg/d (n=3, at 150, 300, 450, and 600 mg/d) of quetiapine. After 3 weeks of treatment, D2 and 5-HT2a occupancy were measured using positron emission tomography (PET) imaging, 12 to 14 hours after the last dose. Clinical efficacy and adverse effect ratings were obtained at baseline, at the time of PET scanning, and at 12 weeks. Two additional patients were included to examine the effects of the drug 2 to 3 hours after last dose. Quetiapine was an effective antipsychotic and improved the extrapyramidal symptoms and prolactin level elevation noted at baseline. It achieved these results with minimal (0%-27%) D2 occupancy 12 hours after the last dose. Study of the additional subjects revealed that quetiapine does give rise to transiently high (58%-64%) D2 occupancy 2 to 3 hours after a single dose that then decreases to minimal levels in 12 hours. Quetiapine shows a transiently high D2 occupancy, which decreases to very low levels by the end of the dosing interval. Quetiapine's low D2 occupancy can explain its freedom from extrapyramidal symptoms and prolactin level elevation. The data suggest that transient D2 occupancy may be sufficient for its antipsychotic effect. Future studies controlling for nonpharmacological effects as well as activities on other receptors will be necessary to confirm this suggestion.",2000.0,0,0
159,10846709,[New i.e. atypical neuroleptic agents for negative symptoms of schizophrenia: results and methodological problems of evaluation].,H J Möller,"The results of controlled studies of the efficacy of the new atypical neuroleptics in treating negative symptoms show that these antipsychotics have a more pronounced effect on negative symptoms in acute schizophrenic patients than the classical neuroleptics. Supplementary complex statistical analyses substantiate that the increased efficacy of the atypical neuroleptics in treating negative symptoms can only partially be explained by indirect effects of better extrapyramidal tolerability, better effects on productive psychotic symptoms, etc. Instead, it is due largely to the stronger direct effect of these atypical neuroleptics. Clinical studies to evaluate their efficacy in chronic schizophrenic patients with stable, predominantly negative symptoms are still mostly lacking. First results support the presumption that atypical neuroleptics have a direct effect. Parallel to the evaluation of the new atypical neuroleptics, important progress has been made in the methodology of clinical studies in this area.",2000.0,0,0
160,10847306,"Clozapine for treatment-refractory schizophrenia, schizoaffective disorder, and psychotic bipolar disorder: a 24-month naturalistic study.",A Ciapparelli; L Dell'Osso; S Pini; M C Chiavacci; M Fenzi; G B Cassano,"The aim of this study was to evaluate the 24-month response to clozapine in patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder. Ninety-one psychotic patients with a principal DSM-III-R diagnosis of schizophrenia (N = 31), schizoaffective disorder (N = 26), or bipolar disorder with psychotic features (N = 34) were treated naturalistically with clozapine at flexible dosages over a 24-month period. Improvement was assessed by the 18-item Brief Psychiatric Rating Scale and the Clinical Global Impressions-Severity of Illness scale. All patients showed significant improvement 24 months from intake (p < .001). Such an improvement was significantly greater among patients with schizoaffective disorder or bipolar disorder than in patients with schizophrenia (p < .05). The presence of suicidal ideation at intake predicted greater improvement at endpoint. Clozapine appears to be effective and relatively well tolerated in acute and long-term treatment of patients with psychotic bipolar disorder or schizoaffective disorder who have not responded to conventional pharmacotherapies.",2000.0,0,1
161,10847307,The safety of olanzapine compared with other antipsychotic drugs: results of an observational prospective study in patients with schizophrenia (EFESO Study). Pharmacoepidemiologic Study of Olanzapine in Schizophrenia.,J C Gómez; J A Sacristán; J Hernández; A Breier; P Ruiz Carrasco; C Antón Saiz; E Fontova Carbonell,"Results of controlled clinical trials should be confirmed through safety and effectiveness studies in nonselected patient cohorts treated according to routine clinical practice. Outpatients with schizophrenia (ICD-10 criteria) entered this prospective, naturalistic study when they received a new prescription for an antipsychotic drug. Treatment assignment was based on purely clinical criteria, as the study did not include any experimental intervention. Safety was evaluated through the collection of spontaneous adverse events and a specific questionnaire for extrapyramidal symptoms. Global clinical status was measured through the Clinical Global Impressions-Severity (CGI-S) and the Global Assessment of Functioning (GAF) scales. From the 2967 patients included, 2128 patients were treated with olanzapine as monotherapy or combined with other drugs (olanzapine group), and 821 were treated with other antipsychotic drugs as monotherapy or combined with other drugs (control group). There were no statistical differences between treatment groups at baseline regarding age, gender, disease duration, or severity of symptoms. Olanzapine was well tolerated and effective in this study. Overall incidence of adverse events was significantly lower in the olanzapine group compared with the control group (p < .001). Somnolence and weight gain were significantly more frequent in the olanzapine group, and akathisia, dystonia, extrapyramidal syndrome, hypertonia, hypokinesia, and tremor were significantly higher in the control group. Clinical improvement at endpoint, measured through the mean change in the CGI-S and the GAF, was significantly higher in the olanzapine group compared with the control group (p = .004). These results show that olanzapine is safe and effective in nonselected schizophrenic outpatients and are consistent with the efficacy and safety profile that olanzapine has shown in previous controlled clinical trials.",2000.0,1,1
162,10847315,Medication continuation and compliance: a comparison of patients treated with clozapine and haloperidol.,R Rosenheck; S Chang; Y Choe; J Cramer; W Xu; J Thomas; W Henderson; D Charney,"This study compares medication continuation and regimen compliance with the atypical antipsychotic medication clozapine versus the conventional antipsychotic haloperidol. Data from a 15-site double-blind, randomized clinical trial (N = 423) were used to compare patients with DSM-III-R schizophrenia assigned to clozapine or haloperidol in terms of duration of participation while taking the randomly assigned study drug (continuation) and the proportion of prescribed pills that were taken (compliance). Multiple regression analysis was used to determine the relationship of baseline characteristics and measures of clinical change to continuation for the entire sample and for patients assigned to each medication. Patients assigned to clozapine continued taking the study drug for a mean of 35.5 weeks as compared with only 27.2 among patients assigned to haloperidol (F = 4.45, df = 1,422; p = .0001). No differences were found between the groups in the proportion of prescribed pills that were returned at any timepoint. Among patients assigned to haloperidol, poorer continuation was associated with being older and greater continuation with receiving public support. Among patients on clozapine treatment, continuation was poorer among African American patients and greater among patients who showed reduced clinical symptoms and akathisia. Continuation with clozapine was greater even after adjusting for these factors. Continuation with medication is greater with clozapine than haloperidol and is partly explained by greater symptom improvement and reduced side effects. No differences were found in regimen compliance.",2000.0,0,1
163,10855462,A comparison of the effects of clozapine and olanzapine on the EEG in patients with schizophrenia.,A Schuld; M Kühn; M Haack; T Kraus; D Hinze-Selch; C Lechner; T Pollmächer,"Clozapine is known to induce epileptic seizures and changes in EEG-patterns, including slowing and the appearance of epileptiform activity. Olanzapine, a new antipsychotic drug, shares many pharmacological and clinical properties with clozapine. However, in patients treated with olanzapine, no case of seizure induction has been reported so far, and the EEG has not been studied systematically. We examined the EEGs of patients with schizophrenia treated with either olanzapine (N = 9) or clozapine (N = 9) prior to medication and 3 to 7 weeks afterwards. Clozapine induced significant EEG slowing present in 78% of the patients, and definite epileptiform activity appeared in 33%. Olanzapine also induced significant EEG slowing, but less frequently (in 44% of the patients) and less pronounced than clozapine. Olanzapine had no significant effect an epileptiform activity, but in one patient, an isolated sharp/slow-wave complex was observed. These preliminary data suggest that olanzapine induces EEG slowing to a lower extent than clozapine. Olanzapine's possible effect an the seizure threshold deserves further attention.",2000.0,0,0
164,10858632,"Comparative evaluation of conventional and novel antipsychotic drugs with reference to their subjective tolerability, side-effect profile and impact on quality of life.",L Voruganti; L Cortese; L Oyewumi; Z Cernovsky; S Zirul; A Awad,"This study compared the effectiveness of conventional and novel antipsychotic drugs from a patient's perspective. Five comparable groups of schizophrenic patients (n=230) clinically stabilized on conventional antipsychotic drugs, risperidone, olanzepine, quetiapine or clozapine for a period of 6months or longer were cross-sectionally evaluated. Patients' clinical symptom profile, subjective responses and attitudes toward drugs, prevalence of dysphoria, akathisia, abnormal involuntary movements and Parkinsonian symptoms, and quality of life were ascertained using standardized rating scales. Between-group differences were examined with analysis of variance and chi-square tests. Patients receiving novel antipsychotic drugs experienced fewer side-effects, reported positive subjective responses and favourable attitudes toward their treatment, and revealed a lower prevalence of neuroleptic dysphoria. The differences were statistically significant (p<0.05) with the risperidone, olanzepine and quetiapine groups. Self-rated quality of life, measured with the sickness impact profile, was also significantly better among patients receiving novel antipsychotic drugs. These perceived benefits, however, were not reflected in the clinician rated (objective) measures of psychosocial functioning and quality of life. These findings substantiate the general notion that novel antipsychotic medications are uniformly better tolerated as indicated by the measures of subjective responses, side-effects and self rated quality of life.",2000.0,0,1
165,10861916,"A long-term, multicenter, open-label study of risperidone in elderly patients with psychosis. On behalf of the Risperidone Working Group.",M Davidson; P D Harvey; J Vervarcke; C A Gagiano; J D De Hooge; G Bray; M Dose; Y Barak; M Haushofer,"Studies have shown that risperidone is safe and efficacious in young and middle-aged adults with chronic schizophrenia, but considerably fewer data are available on the treatment of elderly patients with schizophrenia or other psychotic disorders, particularly long-term outcomes. A 12-month, open-label study was conducted to assess the effects of risperidone in elderly, chronically ill, psychotic patients. This study enrolled 180 elderly, chronically ill, psychotic patients (median age, 72 years [range 54-89]), 97 of whom completed the 12-month study. At endpoint, the mean dose of risperidone was 3.7 mg/day. Clinical improvement (> or =20% reduction in Positive and Negative Syndrome Score [PANSS] total score) was achieved by 54% of patients at endpoint. There were significant reductions in PANSS total, subscale (positive, negative, and general psychopathology), and cognition cluster scores at endpoint (p<0.001). Clinical Global Impressions severity of illness scores showed continued improvement through month 12 (p<0.001). In contrast, PANSS data from a historical comparable control group of patients receiving conventional antipsychotic agents showed no symptom improvement over a 12-month treatment period. The severity of preexisting extrapyramidal symptoms (EPS) in patients treated with risperidone decreased significantly from baseline to endpoint (p<0.001), and the use of antiparkinsonian medication decreased from 41.1% of patients before the trial to 25.6% during the trial. There were no spontaneous reports of tardive dyskinesia (TD) and the incidence of assessed TD was 4.3% in contrast to the expected 26% reported in middle-aged and elderly patients receiving conventional antipsychotic agents for 1 year. Long-term treatment with risperidone was associated with continued symptom improvement, a decrease in the severity of preexising EPS, and a low incidence of TD in elderly psychotic patients.",2000.0,1,1
166,10862124,Simultaneous determination of risperidone and 9-hydroxyrisperidone in plasma by liquid chromatography/electrospray tandem mass spectrometry.,M Aravagiri; S R Marder,"A simple and highly sensitive liquid chromatographic/electrospray tandem mass spectrometric (LC/MS/MS) assay was developed for the simultaneous determination of risperidone (RSP) and its major circulating metabolite 9-hydroxyrisperidone (9-OH-RSP) in the plasma of humans and rats. A simple one-step solvent extraction with 15% methylene chloride in pentane was used to isolate the compounds from plasma. The compounds were eluted from a phenyl-hexyl column and detected with a Perkin-Elmer SCIEX API2000 triple-quadrupole mass spectrometer using positive ion atmospheric pressure electrospray ionization and multiple reaction monitoring. The assay was linear over the range 0.1-100 ng ml(-1) when 0.5 ml of plasma was used in the extraction. The overall intra- (within-day) and inter- (between days) assay variations were < 11%. The variations in the concentrations of two long-term quality control samples from pooled patient plasma samples analyzed over a period of 6 months were approximately 10%. The analysis time for each sample was 4 min and more than 100 samples could be analyzed in one day by running the system overnight. The assay is simple, highly sensitive, selective, precise and fast. This method is being used for the therapeutic drug monitoring of schizophrenic patients treated with RSP and to study the pharmacokinetics and tissue distribution of RSP and 9-OH-RSP in rats.",2000.0,0,0
167,10868465,Atypical antipsychotics and weight gain--a systematic review.,D M Taylor; R McAskill,"To review systematically data relating to weight changes with atypical antipsychotics. We conducted a Medline search on October 29 1999 and covered the period 1980-99. All recovered papers were examined for further relevant reports. In addition, we wrote to pharmaceutical manufacturers and 10 practising clinicians to ask them to provide other relevant reports known to them. Eighty reports mentioning change in body weight were retrieved. Data relating to weight changes were of variable quality. Weight changes were indicated by a variety of measures. The majority of reports related to short-term changes. All atypical drugs, with the exception of ziprasidone, have been associated with weight increases. Clozapine seems to have the highest risk of weight gain, followed by olanzapine and quetiapine. There is probably a lower risk with risperidone, sertindole and zotepine and a still lower risk with amisulpride. Ziprasidone appears not to be associated with weight gain. In the absence of more compelling data, these rankings must be considered approximate and preliminary. Longer, more robust trials are needed.",2000.0,1,1
168,10870870,"A comparison of the effects of quetiapine ('seroquel') and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment. PRIZE Study Group.",R A Emsley; J Raniwalla; P J Bailey; A M Jones,"Quetiapine ('Seroquel') is a well-tolerated, novel, atypical antipsychotic with consistent efficacy in the treatment of schizophrenia. To date, no clinical studies have evaluated the effect of quetiapine in patients who only partially respond to conventional antipsychotics, yet this type of patient is most frequently seen by psychiatrists. Therefore, this international, multicentre, double-blind study was conducted to compare the efficacy and tolerability of 8 weeks' treatment of quetiapine 600 mg/day with haloperidol 20 mg/day in 288 patients who had a history of partial response to conventional antipsychotics and displayed a partial or no response to 1 month of fluphenazine (20 mg/day) treatment. Patients on quetiapine tended to have greater improvement than those on haloperidol in the primary efficacy measure, mean Positive and Negative Symptom Scale (PANSS) score, after 4 weeks' treatment (-9.05, -5.82, respectively, P = 0.061) and at study end (-11.50, -8.87, respectively, P = 0.234). Similarly, there was a trend towards patients on quetiapine demonstrating greater improvements in the secondary efficacy measures (Clinical Global Impression, PANSS subscale and Brief Psychiatric Rating Scale scores) [week 4 (baseline) to week 12 (end)], but the difference between treatments did not reach significance. Significantly more patients on quetiapine than on haloperidol showed a clinical response-patient response rates, defined as > 20% reduction in PANSS total score between weeks 4 and 12, were 52.2% for quetiapine and 38.0% for haloperidol (P = 0.043). Patients receiving quetiapine required less anticholinergic medication (P < 0.011), had greater reduction in extrapyramidal symptoms (EPS) (P = 0.005) and fewer treatment-emergent EPS-related adverse events compared to those on haloperidol (P < 0.001). Serum prolactin concentrations were elevated at the end of fluphenazine treatment in 73% of patients. Between weeks 4 and 12, elevated serum prolactin concentrations significantly decreased in quetiapine-treated patients compared to those receiving haloperidol (P < 0.001). At the end of quetiapine treatment, 83% of patients had normal prolactin levels while only 21% of patients receiving haloperidol were within the normal range. These results suggest that quetiapine may make a valuable contribution to the management of patients with a history of partial response to conventional antipsychotics.",2001.0,1,1
169,10873925,Low incidence of persistent tardive dyskinesia in elderly patients with dementia treated with risperidone.,D V Jeste; A Okamoto; J Napolitano; J M Kane; R A Martinez,"The authors studied the incidence of tardive dyskinesia in elderly institutionalized patients with dementia being treated with risperidone. After participating in a 12-week multicenter double-blind study during which they received placebo or one of three doses of risperidone, 330 patients (mean age=82.5 years) with Alzheimer's, vascular, or mixed dementia were enrolled in a 1-year open-label study during which they received flexible doses of risperidone. Persistent emergent tardive dyskinesia was defined according to scores on the dyskinesia subscale of the Extrapyramidal Symptom Rating Scale. The mean modal risperidone dose was 0.96 mg/day (SD=0.53), and the median length of risperidone use was 273 days. The 1-year cumulative incidence of persistent emergent tardive dyskinesia among the 255 patients without dyskinesia at baseline was 2.6%. Patients with dyskinetic symptoms at baseline experienced significant reductions in the severity of dyskinesia. Patients who received 0.75-1.5 mg/day of risperidone showed a significant improvement in psychopathologic symptoms over the 1-year period. Although there was no control group, the observed incidence of persistent tardive dyskinesia with risperidone seemed to be much lower than that seen in elderly patients treated with conventional neuroleptics. The average optimal dose of risperidone in elderly dementia patients was found to be 0.75-1.5 mg/day.",2000.0,1,1
170,10885641,Clozapine augmentation: safety and efficacy.,S A Chong; G Remington,"While clozapine has been demonstrated to be efficacious in refractory schizophrenia and possibly schizoaffective as well as bipolar disorders, a substantial number of patients still remain unresponsive. One strategy in treating these refractory patients is to augment clozapine with other somatic treatments. This article reviews the efficacy and safety of the combination of clozapine with other somatic treatments. A total of 70 articles were obtained from a manual, as well as computerized (Medline), search of the English language literature from 1978 to March 1998. Few controlled studies exist; most were case reports/series. From these data, the greatest risk of adverse effects seems to be associated with clozapine combined with benzodiazepines, valproate, or lithium, but no currently evaluated combination is absolutely unsafe. In terms of efficacy, the data suggest a number of potential augmentation strategies, although controlled data are few. Combination therapies with clozapine are common in clinical practice, despite a lack of empirical data, and the benefits and risks of these combinations need to be systematically reviewed.",2001.0,0,1
171,10885642,The effects of clozapine on alcohol and drug use disorders among patients with schizophrenia.,R E Drake; H Xie; G J McHugo; A I Green,"Several case studies indicate that clozapine use is associated with reductions in the use of nicotine, alcohol, or illicit drugs. Although not designed to assess clozapine, this study explored a posteriori the effects of clozapine on alcohol and drug use disorders among schizophrenia patients. Among 151 patients with schizophrenia or schizoaffective disorder and co-occurring substance use disorder who were studied in a dual-disorder treatment program, 36 received clozapine during the study for standard clinical indications. All participants were assessed prospectively at baseline and every 6 months over 3 years for psychiatric symptoms and substance use. Alcohol-abusing patients taking clozapine experienced significant reductions in severity of alcohol abuse and days of alcohol use while on clozapine. For example, they averaged 54.1 drinking days during 6-month intervals while off clozapine and 12.5 drinking days while on clozapine. They also improved more than patients who did not receive clozapine. At the end of the study, 79.0 percent of the patients on clozapine were in remission from alcohol use disorder for 6 months or longer, while only 33.7 percent of those not taking clozapine were remitted. Findings related to other drugs in relation to clozapine were also positive but less clear because of the small number of patients with drug use disorders. This study was limited by the naturalistic design and the lack of prospective, standardized measures of clozapine use. The use of clozapine by patients with co-occurring substance disorders deserves further study in randomized clinical trials.",2001.0,0,1
172,10901343,Electrocardiographic abnormalities in patients treated with clozapine.,U G Kang; J S Kwon; Y M Ahn; S J Chung; J H Ha; Y J Koo; Y S Kim,"Cardiovascular side effects of clozapine are not uncommon, but few systematic studies of these effects have been performed. In this study, we reviewed data on the electrocardiographic (ECG) abnormalities in patients treated with clozapine. Sixty-one patients treated with clozapine were selected from the Seoul National University Hospital Treatment-Resistant Schizophrenia Clinic. A retrospective chart review was conducted to identify ECG abnormalities and cardiovascular side effects. The prevalence of ECG abnormalities in patients who had been using antipsychotics other than clozapine was 13.6% at baseline, which increased significantly to 31.1% after commencement of clozapine treatment. Among the 53 patients without baseline ECG abnormalities, 13 showed new-onset ECG abnormalities after using clozapine. Normal ECG under previous antipsychotic medication reduced the risk of new-onset ECG abnormalities, whereas increased age was found to increase the risk. The occurrence of orthostatic hypotension or tachycardia was not related to the development of ECG abnormalities. Most of the newly developed abnormalities had little clinical significance, and they tended to occur during the initial phase of treatment. In 10 patients, ECGs normalized despite the continued use of clozapine. Clozapine increased corrected QT interval (QTc) in a dose-dependent fashion; however, the clinical significance of this observation is uncertain. Pathologic prolongation of QTc was found to be rare. Although a substantial portion of patients treated with clozapine developed ECG abnormalities, most of the abnormalities were benign and did not hinder further treatment.",2000.0,0,1
173,10902094,The pharmacotherapy of target symptoms associated with autistic disorder and other pervasive developmental disorders.,D J Posey; C J McDougle,"Research into the pharmacotherapy of autistic disorder has steadily increased over the past two decades. Several psychoactive medications have shown efficacy for selected symptoms of autistic disorder and can be used to augment critical educational and behavioral interventions that are the mainstays of treatment. A comprehensive review of medication trials conducted in individuals with autistic disorder and other pervasive developmental disorders is presented. The typical antipsychotic haloperidol is the best-studied medication in autistic disorder but is associated with a high rate of dyskinesias. Investigations to date suggest that the atypical antipsychotics such as risperidone have efficacy for certain symptoms of autistic disorder and may be better tolerated than typical antipsychotics. Preliminary results from trials with serotonin-reuptake inhibitors are favorable, although efficacy has not been demonstrated in younger age groups. Recent controlled studies of nalfrexone suggest that the drug has minimal efficacy. In two small controlled investigations, clonidine was more effective than placebo for a variety of symptoms, including hyperactivity and irritability; in one of these studies, however, the majority of patients relapsed within several months. Psychostimulants reduced hyperactivity and irritability in one small double-blind crossover study in children with autistic disorder, although these agents are frequently reported to exacerbate irritability, insomnia, and aggression in clinical populations. Recent controlled trials of secretin have not shown efficacy compared to placebo. Several other medications, including buspirone, mood stabilizers, and beta-blockers, have produced symptom reduction in some open-label studies and may warrant controlled investigation.",2001.0,0,0
174,10903413,H(2) antagonist nizatidine may control olanzapine-associated weight gain in schizophrenic patients.,E Sacchetti; L Guarneri; D Bravi,"Olanzapine is temporally associated, in a number of patients with schizophrenia, with weight gain. H(2) antagonists, like nizatidine, have been shown to control appetite in overweight patients. A patient with olanzapine temporally associated weight gain was treated with nizatidine as ""add-on"" therapy. Nizatidine treatment was associated with good control and subsequent reduction of weight after 4 to 5 weeks of therapy in a patient with repetitive episodes of weight gain during olanzapine treatment. Olanzapine was otherwise well tolerated and effective in controlling psychopathology. H(2) antagonist treatment with olanzapine may be a valid medical strategy in preventing and/or reducing weight gain in patients with schizophrenia. Controlled studies are recommended to confirm this observation.",2000.0,0,0
175,10907666,Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [123I]epidepride single photon emission tomography (SPET) study.,V Bigliani; R S Mulligan; P D Acton; R I Ohlsen; V W Pike; P J Ell; S Gacinovic; R W Kerwin; L S Pilowsky,"Previous work suggests clozapine preferentially targets limbic cortical dopamine systems, which could help account for its lack of extrapyramidal side effects (EPS) and superior therapeutic efficacy. To test the hypothesis that olanzapine, a novel atypical antipsychotic drug, occupies temporal cortical D2/D3 receptors to a greater extent than striatal D2/D3 receptors in vivo. Nine schizophrenic patients taking either olanzapine [(n=5; mean (SD) age: 32.5 (6.5) years; daily dose: 18.3 (2.6) mg] or sertindole [(n=4; mean (SD) age: 30.3 (7.4) years; daily dose: 16 (5.6) mg] were studied with [123I]epidepride ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxybenz amide) and single photon emission tomography (SPET). An estimate of [123I]epidepride 'specific binding' to D2/D3 receptors was obtained in patients and age-matched healthy volunteers. A summary measure was generated representing striatal and temporal cortical relative %D2/D3 receptor occupancy by antipsychotic drugs. Occupancy data were compared with previously studied groups of patients receiving typical antipsychotic drugs (n=12) and clozapine (n=10). Mean striatal and temporal cortical %D2/D3 receptor occupancy in olanzapine-treated patients was 41.3% (SD 17.9) and 82.8% (SD 4.2), respectively. Unexpectedly low levels of striatal relative %D2/D3 receptor occupancy were seen in two patients with typical antipsychotic-drug-induced movement disorder prior to switching to olanzapine. In the temporal cortex, mean D2/D3 dopamine receptor occupancy levels above 80% were seen for all antipsychotic drugs studied. The atypical antipsychotic drugs olanzapine and sertindole, in common with clozapine, demonstrate higher occupancy of temporal cortical than striatal D2/D3 dopamine receptors in vivo at clinically useful doses. This could help mediate their atypical clinical profile of therapeutic efficacy with few extrapyramidal side effects. Limbic selective blockade of D2/D3 dopamine receptors could be a common action of atypical antipsychotic drugs.",2001.0,0,0
176,10917410,Risperidone for the treatment of stuttering.,G A Maguire; G D Riley; D L Franklin; L A Gottschalk,"A randomized, double-blind, placebo-controlled study was conducted to assess the efficacy of risperidone in the treatment of developmental stuttering in 16 adults. Eight subjects received placebo and eight received risperidone at 0.5 mg once daily at night, increased to a maximum of 2 mg/day. After 6 weeks of treatment, decreases in all measures of stuttering severity were greater in the risperidone group than in the placebo group; the between-treatment difference was significant (p < 0.05) on the most important measure, the percentage of syllables stuttered. In the risperidone group, reductions from baseline in scores for the percentage of syllables stuttered, time stuttering as a percentage of total time speaking, and overall stuttering severity were significant (p < 0.01); changes in scores on the fourth measure of stuttering, duration, were not significant. No significant decreases occurred in the placebo group. Among the eight patients in the risperidone group, five responded best to 0.5 mg/day, with stuttering recurring at higher doses. The remaining three patients responded better with increasing doses of risperidone. Risperidone was generally well tolerated. The results of this small study indicate that risperidone may be effective in the treatment of developmental stuttering. This finding needs to be confirmed in a larger trial.",2001.0,0,0
177,10920469,"A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder.",C J McDougle; C N Epperson; G H Pelton; S Wasylink; L H Price,"To date, only 1 controlled study has found a drug (haloperidol) to be efficacious in augmenting response in patients with obsessive-compulsive disorder (OCD) refractory to serotonin reuptake inhibitor (SRI) monotherapy; patients with comorbid chronic tic disorders showed a preferential response. This report describes the first controlled study of risperidone addition in patients with OCD refractory to treatment with SRI alone. Seventy adult patients with a primary DSM-IV diagnosis of OCD received 12 weeks of treatment with an SRI. Thirty-six patients were refractory to the SRI and were randomized in a double-blind manner to 6 weeks of risperidone (n = 20) or placebo (n = 16) addition. Behavioral ratings, including the Yale-Brown Obsessive Compulsive Scale, were obtained at baseline and throughout the trial. Placebo-treated patients subsequently received an identical open-label trial of risperidone addition. For study completers, 9 (50%) of 18 risperidone-treated patients were responders (mean daily dose, 2.2 +/-0.7 mg/d) compared with 0 of 15 in the placebo addition group (P<. 005). Seven (50%) of 14 patients who received open-label risperidone addition responded. Risperidone addition was superior to placebo in reducing OCD (P<.001), depressive (P<.001), and anxiety (P =.003) symptoms. There was no difference in response between OCD patients with and without comorbid diagnoses of chronic tic disorder or schizotypal personalty disorder. Other than mild, transient sedation, risperidone was well tolerated. These results suggest that OCD patients with and without comorbid chronic tic disorders or schizotypal personality disorder may respond to the addition of low-dose risperidone to ongoing SRI therapy.",2000.0,0,0
178,10929273,Olanzapine in severe Gilles de la Tourette syndrome: a 52-week double-blind cross-over study vs. low-dose pimozide.,M Onofrj; C Paci; G D'Andreamatteo; L Toma,"We selected four patients with severe Gilles de la Tourette syndrome, high frequency of tics (two to ten per minute), vocalizations, and lack of comorbidity. These patients (aged 19-40 years) underwent a 52-week double-blind cross-over study with olanzapine (5 and 10 mg daily) vs. low-dose pimozide (2 and 4 mg daily). The reduction in rating scale scores for the syndrome was highly significant with 10 mg olanzapine vs. basal and vs. 2 mg pimozide, and was significant for 5 mg olanzapine vs. 4 mg pimozide. Only moderate sedation was reported by one patient during olanzapine treatment while three complained of minor motor side effects and sedation during pimozide treatment. At the end of the study all patients opted for olanzapine treatment.",2001.0,0,0
179,10937608,Comparative efficacy of risperidone and clozapine in the treatment of patients with refractory schizophrenia or schizoaffective disorder: a retrospective analysis.,Z A Sharif; A Raza; S S Ratakonda,"Clozapine is effective in up to 60% of patients with refractory schizophrenia, whereas the efficacy of risperidone remains unknown. This retrospective study examined the relative efficacy of these drugs in chronically institutionalized patients refractory to conventional antipsychotic agents. A total of 24 patients who at different time periods had received adequate trials of both clozapine and risperidone and met our inclusion criteria for minimum dose and duration of each trial were included; for clozapine, a minimum dose of 300 mg/day had to be maintained for at least 12 weeks, and for risperidone, a minimum dose of 6 mg/day for at least 6 weeks. Information obtained from systematic retrospective chart review was blindly rated by 2 psychiatrists using the 7-point Clinical Global Impressions-Improvement (CGI-I) scale on overall clinical state and along specific symptom domains of positive symptoms, negative symptoms, and aggressive behavior. The mean +/- SD dose was 520+/-94 mg/day for clozapine and 7.5+/-2.2 mg/day for risperidone. Fourteen patients (58%) were classified as responders to clozapine, while 6 (25%) responded to risperidone (CGI-I score of 1 or 2); on specific symptom domains, response rates to clozapine were 38% (9/24) on positive symptoms, 29% (7/24) on negative symptoms, and 71% (12/17) on aggressive behavior. For risperidone, response rates were 17% (4/24) on positive symptoms, 8% (2/24) on negative symptoms, and 41% (7/17) on aggressive behavior. The results of this study support the utility of first giving a risperidone trial in a treatment algorithm for refractory patients because of its better risk/benefit profile compared with clozapine. Clozapine, however, remains our gold standard in the management of these patients.",2000.0,0,0
180,10949157,"Interrater reliability levels of multiple clinical examiners in the evaluation of a schizophrenic patient: quality of life, level of functioning, and neuropsychological symptomatology.",D V Cicchetti; R Rosenheck; D Showalter; D Charney; J Cramer,"Sir Ronald Fisher used a single-subject design to derive the concepts of appropriate research design, randomization, sensitivity, and tests of statistical significance. The seminal work of Broca demonstrated that valid and generalizable findings can and have emerged from studies of a single patient in neuropsychology. In order to assess the reliability and/or validity of any clinical phenomena that derive from single subject research, it becomes necessary to apply appropriate biostatistical methodology. The authors develop just such an approach and apply it successfully to the evaluation of the functioning, quality of life, and neuropsychological symptomatology of a single schizophrenic patient.",2000.0,0,0
181,10954060,"Efficacy, cardiac safety and tolerability of sertindole: a drug surveillance.",L Pezawas; S Quiner; D Moertl; J Tauscher; C Barnas; B Küfferle; R Wolf; S Kasper,"Sertindole is a novel atypical antipsychotic, which has shown efficacy in the treatment of positive and negative symptoms of schizophrenia in phase II and III studies. Furthermore, these studies have demonstrated tolerability and a favourable side-effect profile. In contrast to classical antipsychotics, sertindole was not associated with extrapyramidal symptoms (EPS). We report drug surveillance data in 34 comorbid and comedicated sertindole treated patients suffering from different psychotic disorders. The drug surveillance consisted of two distinct phases: inpatient treatment and outpatient follow-up. Clinical global impression (severity and improvement of illness), psychotic symptoms, side-effects, and blood parameters have been carefully documented. With special respect to cardiac safety electrocardiograms (ECGs) have been recorded twice (during sertindole treatment and during treatment with an antipsychotic different from sertindole). Recommended ECG-parameters for assessment of the proarrhythmic risk of a drug have been calculated (QTc-, QTc2-interval; QT-, QTc-dispersion). The majority of patients (n = 29) have been treated previously with several typical and/or atypical antipsychotics. We observed a clinical response to sertindole treatment in 29 patients (85%). Both positive and negative symptoms improved with sertindole and no severe side-effects have been documented. EPS occurred at placebo level. A mean QTc-interval prolongation of 19.7 ms (4.7%) has been detected. None of the patients developed clinical or electrocardiographic evidence of cardiac dysrhythmia during sertindole treatment, or other clinical evidence of cardiac abnormalities. In summary, sertindole did show efficacy for positive and negative symptoms together with a favourable side-effect profile. No evidence for an increased proarrhythmic risk has been found.",2001.0,0,0
182,10958148,Single-dose pharmacokinetics of quetiapine in subjects with renal or hepatic impairment.,P T Thyrum; Y W Wong; C Yeh,"1. The atypical antipsychotic quetiapine ('Seroquel') provides equivalent efficacy to the typical antipsychotics chlorpromazine and haloperidol in the short-term treatment of schizophrenia. Moreover, the incidence of extrapyramidal symptoms associated with quetiapine treatment is equivalent to that observed with placebo treatment, which may lead to increased patient compliance with quetiapine compared with typical antipsychotics. 2. This report presents the results from two small studies aimed at determining the pharmacokinetics of quetiapine in nonpsychotic subjects with renal or hepatic impairment. Equal numbers of impaired subjects and healthy control subjects were administered a single, 25 mg dose of quetiapine, and plasma concentrations were determined up to 48 hr after dosing. 3. No clinically significant differences were found when the pharmacokinetic parameters for subjects with renal or hepatic impairment were compared with those for healthy control subjects. The results indicate that dosage adjustment of quetiapine may be unnecessary in psychotic patients with decreased renal function. 4. In subjects with hepatic impairment related to alcoholic cirrhosis, the results suggest that no change is needed in the recommended quetiapine starting dose (25 mg). However, because of a noted inter-subject variability in the clearance of quetiapine in the cirrhotic group, it is recommended that dose escalation be performed with caution in patients with hepatic impairment. 5. The single dose of quetiapine 25 mg generally was well tolerated in nonpsychotic subjects in good health or with either renal or hepatic impairments. Quetiapine also had no effect on the endogenous creatinine clearance of renally impaired or healthy control subjects.",2001.0,0,0
183,10958256,Haematological safety of antipsychotic drugs.,D J King; E Wager,"Many clinicians have become concerned about the safety of new antipsychotics particularly in view of the association of agranulocytosis with clozapine and of aplastic anaemia with remoxipride. The Committee on Safety of Medicines and Medicines Control Agency 'yellow card' post-marketing surveillance data were analysed for reports of haemopoietic disorders with the 16 antipsychotics in common use. Corrections for relative risk were made in three separate ways: (i) control for degree of use, using Northern Ireland prescribing data for 1995; (ii) percentage of total reports from 1963 to 1996; and (iii) examination of the first 5 years' post-marketing data only. After clozapine and remoxipride the highest risks of haemopoietic reactions appeared to be associated with the aliphatic phenothiazine derivatives thioridazine and chlorpromazine. There is therefore no evidence of any increased risk with high-potency drugs such as haloperidol or pimozide or with the newer drugs such as sulpiride or risperidone. Continued vigilance, however, is necessary as more new atypicals become available and begin to be widely prescribed.",2000.0,1,1
184,10959316,,,,,0,0
185,10986547,"Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group.",M Tohen; T G Jacobs; S L Grundy; S L McElroy; M C Banov; P G Janicak; T Sanger; R Risser; F Zhang; V Toma; J Francis; G D Tollefson; A Breier,"We compared the efficacy and safety of olanzapine vs placebo for the treatment of acute bipolar mania. Four-week, randomized, double-blind, parallel study. A total of 115 patients with a DSM-IV diagnosis of bipolar disorder, manic or mixed, were randomized to olanzapine, 5 to 20 mg/d (n = 55), or placebo (n = 60). The primary efficacy measure was the Young-Mania Rating Scale (Y-MRS) total score. Response and euthymia were defined, a priori, as at least a 50% improvement from baseline to end point and as a score of no less than 12 at end point in the Y-MRS total score, respectively. Safety was assessed using adverse events, Extrapyramidal Symptom (EPS) rating scales, laboratory values, electrocardiograms, vital signs, and weight change. Olanzapine-treated patients demonstrated a statistically significant greater mean (+/- SD) improvement in Y-MRS total score than placebo-treated patients (-14.8 +/- 12.5 and -8.1 +/- 12.7, respectively; P<.001), which was evident at the first postbaseline observation 1 week after randomization and was maintained throughout the study (last observation carried forward). Olanzapine-treated patients demonstrated a higher rate of response (65% vs 43%, respectively; P =.02) and euthymia (61% vs 36%, respectively; P =. 01) than placebo-treated patients. There were no statistically significant differences in EPSs between groups. However, olanzapine-treated patients had a statistically significant greater mean (+/- SD) weight gain than placebo-treated patients (2.1 +/- 2.8 vs 0.45 +/- 2.3 kg, respectively) and also experienced more treatment-emergent somnolence (21 patients [38.2%] vs 5 [8.3% ], respectively). Olanzapine demonstrated greater efficacy than placebo in the treatment of acute bipolar mania and was generally well tolerated.",2000.0,1,1
186,10989263,Mazindol treatment of negative symptoms.,W T Carpenter; A Breier; R W Buchanan; B Kirkpatrick; P Shepard; E Weiner,"Hypodopaminergic and hyponoradrenergic pathophysiology may be a basis for primary and/or secondary negative symptoms in schizophrenia. The hypothesis that enhanced neurotransmission in these systems would be therapeutic for negative symptoms was tested by comparing mazindol and placebo in a double-blind, cross-over design trial. Outcome following mazindol supplementation was comparable to placebo supplementation (F(1,30) = 0.9; p = .57). Results for deficit and non-deficit schizophrenia subjects were similar, and were not affected by whether concurrent the antipsychotic drug treatment was clozapine, fluphenazine, or haloperidol. The efficacy hypothesis was not supported for either primary or secondary negative symptoms.",2001.0,0,0
187,10993126,Functional outcomes in schizophrenia: a comparison of olanzapine and haloperidol in a European sample.,S H Hamilton; E T Edgell; D A Revicki; A Breier,"The primary aim of this study was to compare functional outcomes between patients with schizophrenia treated with olanzapine or haloperidol in Europe. The sample consisted of European patients from a large, international, double-blind, randomized clinical trial. Patients were randomized to receive either olanzapine (n = 520) or haloperidol (n = 258) for a 6-week acute phase followed by a 46-week maintenance phase for responders. Olanzapine-treated patients experienced superior improvements compared to haloperidol-treated patients on all efficacy measures assessed in both phases. A greater percentage of olanzapine-treated patients had > or = 20% improvement in the Quality of Life Scale total score during both the acute (50.0% versus 31.0%, P = 0.071) and maintenance (69.5% versus 41.7%, P = 0.006) phases compared to haloperidol-treated patients. For patients who entered the maintenance phase as outpatients, olanzapine-treated patients were significantly less likely to require subsequent hospitalization compared to haloperidol-treated patients (P = 0.001). A significantly greater percentage of the olanzapine group compared to the haloperidol group worked part-time or full-time (15.1% versus 5.3%, P = 0.018), participated in useful work > or = 75% of the time (21.0% versus 10.5%, P = 0.038), and socialized more than once a month (53.8% versus 37.9%, P = 0.004) during the maintenance phase. The findings from this study suggest that olanzapine's clinical profile leads to reduced hospitalization and improvements in work and social functioning superior to that achieved with haloperidol treatment.",2001.0,1,1
188,10993404,Quality of life in schizophrenia: a comparison of instruments. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.,J A Cramer; R Rosenheck; W Xu; J Thomas; W Henderson; D S Charney,"Health-related quality of life in schizophrenia can be assessed by direct patient response or by a rating based on a structured interview. This study compares both types of instruments using a series of five standards: (1) sensitivity to change over time, (2) sensitivity to treatment effect, (3) correlation with symptom severity, (4) correlation with global clinical ratings, and (5) correlation with other measures of health-related quality of life. Four hundred and twenty-three inpatients with schizophrenia participating in a clinical trial comparing clozapine and haloperidol (VA Cooperative Study in Health Services #17) were evaluated using multiple measures of health-related quality of life (Lehman Quality of Life Interview; Heinrichs-Carpenter-Hanlon Quality of Life Scale; Strauss-Carpenter Level of Function scale, and clinical response.) The Quality of Life Interview showed less sensitivity to change and treatment effect, as well as lower correlations with all other measures than the Quality of Life Scale and the Level of Function scale. The latter scales showed high sensitivity to both change and treatment effect, and moderate-high correlations with other measures and with each other. The Quality of Life Scale and the Level of Function scale rater assessments appeared to be substantially more sensitive to subtle change and treatment effects than the patient-reported Quality of Life Interview for clinical trials. Health-related quality of life in schizophrenia is a more heterogeneous concept than previously appreciated.",2001.0,0,1
189,10993997,Olanzapine and clozapine: comparative effects on motor function in hallucinating PD patients.,C G Goetz; L M Blasucci; S Leurgans; E J Pappert,"To compare olanzapine and clozapine for safety and efficacy measures of psychosis and motor function in patients with PD and chronic hallucinations. Hallucinations occur in approximately one third of patients with PD treated chronically with dopaminergic drugs. Although clozapine is known to be an effective antipsychotic agent that does not significantly exacerbate parkinsonism, its use requires frequent blood count assessment. Olanzapine is another novel antipsychotic that is not associated with blood dyscrasia, and if equally effective could become the preferred drug for treating hallucinations in subjects with PD. A randomized, double-blind, parallel comparison of olanzapine and clozapine in patients with PD with chronic hallucinations was conducted. The primary outcome measure was the Scale for the Assessment of Positive Symptoms (SAPS) for psychotic symptoms. The Unified Parkinson's Disease Rating Scale (UPDRS) motor subscale was used as a secondary outcome measure and as a safety monitoring tool. After 15 patients had completed the study, safety stopping rules were invoked because of exacerbated parkinsonism in olanzapine-treated subjects. UPDRS motor impairment scores from baseline to study end significantly increased with olanzapine treatment, and change scores between the olanzapine and clozapine groups significantly differed. The primary clinical domains responsible for the motor decline were gait and bradykinesia. Even with a smaller patient number than originally anticipated, clozapine significantly improved hallucinations and overall behavioral assessment, whereas olanzapine had no effect. At the doses studied, olanzapine aggravates parkinsonism in comparison with clozapine and should not be regularly used in the management of hallucinations in patients with PD.",2001.0,0,1
190,10993998,Low-dose olanzapine for levodopa induced dyskinesias.,A J Manson; A Schrag; A J Lees,"To assess the usefulness of low-dose olanzapine (2.5 to 7. 5 mg/day) for Levodopa-induced-dyskinesias (LID) in patients with PD. Ten patients with PD and LID took part in this randomized, placebo-controlled, double blind, crossover trial. Patients received a 2-week course of olanzapine or placebo in each treatment phase with 1-week washout in between. Dyskinesias were assessed at baseline and after each treatment period with an acute dopaminergic challenge and unified PD rating scale (UPDRS) questionnaires. Patients also kept on/off and dyskinesia diaries for the last 3 days prior to each assessment. There was a 41% difference in dyskinesia reduction on olanzapine compared to placebo, as measured by objective dyskinesia rating scales (mean percentage reduction abnormal involuntary movement score: 30% versus -11.2%, p < 0.02). Similar differences were demonstrated by patient diaries (mean reduction: 46% versus -2%, p < 0.02) and UPDRS items 32 and 33. Compared with placebo, treatment with olanzapine resulted in significant increases in 'off' time as measured by patient diaries (30% versus 2%) and reported adverse events (1.7 versus 0.1) including increased parkinsonism (1.1 versus 0.1) and a nonsignificant reported increase in drowsiness. Low-dose olanzapine is effective in reducing dyskinesias in PD, but even at very low doses can result in unacceptable increases in parkinsonism and 'off' time.",2001.0,0,0
191,11001281,Intravenous biperiden in akathisia: an open pilot study.,S Hirose; C R Ashby,"Antipsychotic-induced akathisia can be distressing and unendurable for prolonged periods. It has been shown that intramuscular biperiden is a relatively rapid and effective treatment for akathisia. However, the intravenous administration of biperiden may provide a more rapid effect, although this remains to be definitively proven. The subjects obtained for this study met the diagnostic criteria for schizophrenia as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The therapeutic effect of i.v. and i.m. biperiden was studied in an open clinical trial in twenty-three (12 male and 11 female) patients who developed antipsychotic-induced acute akathisia as defined by the research criteria of the DSM-IV. Following the development of akathisia, 5 mg of biperiden was intravenously injected in seventeen patients and intramuscularly in six patients. The therapeutic effect of biperiden on akathisia was clinically assessed by using the rating scale of Barnes. Following i.v. administration on biperiden, the mean time to onset and maximum effect occurred 1.6 (SD = 1.9) and 9.2 minutes (SD = 6.0), respectively. Furthermore, at the time of maximal effect, akathisia was completely ameliorated in all patients. The side effects reported were mild and transient. Following i.m. administration, the mean time to onset and maximum effect were 30.5 (SD = 5.9) and 50 minutes (SD = 7.4), respectively. Thus, the time to maximal effect was significantly less (40 minutes) after i.v. compared to i.m. administration. These results suggest that i.v. administration of 5 mg of biperiden could be used to provide a rapid and effective treatment for patients with severe akathisia.",2001.0,0,0
192,11015815,"Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: a double-blind, randomized, placebo-controlled trial. The HGEU Study Group.",J S Street; W S Clark; K S Gannon; J L Cummings; F P Bymaster; R N Tamura; S J Mitan; D L Kadam; T M Sanger; P D Feldman; G D Tollefson; A Breier,"Patients with Alzheimer disease (AD) commonly exhibit psychosis and behavioral disturbances that impair patient functioning, create caregiver distress, and lead to institutionalization. This study was conducted to assess the efficacy and safety of olanzapine in treating psychosis and/or agitation/aggression in patients with AD. A multicenter, double-blind, placebo-controlled, 6-week study was conducted in 206 elderly US nursing home residents with AD who exhibited psychotic and/or behavioral symptoms. Patients were randomly assigned to placebo or a fixed dose of 5, 10, or 15 mg/d of olanzapine. The primary efficacy measure was the sum of the Agitation/Aggression, Hallucinations, and Delusions items (Core Total) of the Neuropsychiatric Inventory-Nursing Home version. Low-dose olanzapine (5 and 10 mg/d) produced significant improvement compared with placebo on the Core Total (-7.6 vs -3.7 [P<.001] and -6.1 vs -3. 7 [P =.006], respectively). Core Total improvement with olanzapine, 15 mg/d, was not significantly greater than placebo. The Occupational Disruptiveness score, reflecting the impact of patients' psychosis and behavioral disturbances on the caregiver, was significantly reduced in the 5-mg/d olanzapine group compared with placebo (-2.7 vs -1.5; P =.008). Somnolence was significantly more common among patients receiving olanzapine (25.0%-35.8%), and gait disturbance occurred in those receiving 5 or 15 mg/d (19.6% and 17.0%, respectively). No significant cognitive impairment, increase in extrapyramidal symptoms, or central anticholinergic effects were found at any olanzapine dose relative to placebo. Low-dose olanzapine (5 and 10 mg/d) was significantly superior to placebo and well tolerated in treating agitation/aggression and psychosis in this population of patients with AD.",2000.0,1,1
193,11015817,Cost-effectiveness of clozapine compared with conventional antipsychotic medication for patients in state hospitals.,S M Essock; L K Frisman; N H Covell; W A Hargreaves,"An open-label, randomized controlled trial compared clozapine with physicians'-choice medications among long-term state hospital inpatients in Connecticut. The goal was to examine clozapine's cost-effectiveness in routine practice for people experiencing lengthy hospitalizations. Long-stay patients with schizophrenia in a state hospital were randomly assigned to begin open-label clozapine (n = 138) or to continue receiving conventional antipsychotic medications (n = 89). We interviewed study participants every 4 months for 2 years to assess psychiatric symptoms and functional status, and we collected continuous measures of prescribed medications, service utilization, and other costs. We used both parametric and nonparametric techniques to examine changes in cost and parametric analyses to examine changes in effectiveness. We used bootstrap techniques to estimate incremental cost-effectiveness ratios and create cost-effectiveness acceptability curves. Both groups incurred similar costs during the 2-year study period, with a trend for clozapine to be less costly than usual care in the second study year. Clozapine was more effective than usual care on many but not all measures. With the use of effectiveness measures that favored clozapine (extrapyramidal side effects, disruptiveness), bootstrap techniques indicated that, even when a payer is unwilling to incur any additional cost for gains in effectiveness, the probability that clozapine is more cost-effective than usual care is at least 0.80. These findings were not as evident when outcomes where clozapine was not clearly superior (psychotic symptoms, weight gain) were examined. Clozapine demonstrated cost-effectiveness on some but not all measures of effectiveness when the alternative was a range of conventional antipsychotic medications.",2000.0,0,0
194,11018226,Pharmacologic agents for the treatment of acute bipolar mania.,S L McElroy; P E Keck,"The knowledge base regarding the medical treatment of acute bipolar mania is rapidly expanding. Information about agents with established antimanic properties is increasing, and more agents with putative antimanic properties are being identified. We first review the controlled studies supporting the efficacy of the established antimanic agents lithium, valproate, and carbamazepine and standard antipsychotics. We then review available research on two important classes of drugs that are emerging as potential treatments for acute mania: the novel antipsychotics, which include clozapine, olanzapine, quetiapine, risperidone, and ziprasidone, and the new antiepileptics, which include gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, and zonisamide. We conclude that although controlled data are accumulating to support the efficacy of several atypical antipsychotics in the treatment of acute bipolar mania, particularly olanzapine, ziprasidone, and risperidone, the novel antiepileptics need more extensive study before it can be concluded that any of them possess specific antimanic properties. We also conclude that as the medical options for acute bipolar mania expand, treatment guidelines must remain both evidence based and flexible, so that they represent cutting edge medical science yet can be tailored to the specific needs of individual patients.",2001.0,0,1
195,11018228,Bipolar disorder therapeutics: maintenance treatment.,G S Sachs; M E Thase,"Although most of the care received by bipolar patients occurs during the maintenance phase, relatively little empirical data is available to guide long-term treatment decisions. We review literature pertaining to key questions related to use of pharmacotherapy in the maintenance phase of bipolar disorder. The few double-blind trials with a reasonable sample size are restricted to bipolar I patients and address a modest range of questions mostly related to use of lithium. One rigorous multicenter trial found valproate to have prophylactic benefit. Other studies with valproate alone and in combination suggest efficacy equivalent to lithium and perhaps greater than carbamazepine. Data available for combination treatment are sparse but moderately encouraging. Maintenance treatment with standard antidepressant medications appears destabilizing for some bipolar patients, particularly following a mixed episode. Although some bipolar patients may benefit from combined treatment with a mood stabilizer and a standard antidepressant medication, current knowledge does not allow confident selection of the bipolar patients who might benefit. Clozapine and perhaps other atypical antipsychotics are promising options for maintenance treatment but have not been evaluated in double-blind trials. The numerous other agents used in maintenance treatment are primarily adjuncts to lithium, valproate, or carbamazepine, and information about them is largely anecdotal and uncontrolled. Study design for maintenance trials remains an imperfect art. Conclusions must be drawn cautiously, given the limited generalizability of study designs that accession samples enriched with presumed treatment responders, randomize patients after brief periods of partial remission, abruptly taper prior treatment, make no attempt to distinguish relapse from recurrence, use no formal outcome assessments, or report hospitalization as the only outcome criterion.",2001.0,0,0
196,11025914,Treatment refractory schizophrenia.,J P Lindenmayer,"Treatment resistance constitutes a significant dilemma in schizophrenia since it affects a substantial number of patients, their families and the health care professionals involved in their care. Nonresponsiveness needs to be approached as a multidimensional syndrome by specifying which symptoms in the spectrum of positive symptoms, negative symptoms, excitement/hostility, cognitive symptoms, and anxiety/depression are failing to respond to treatment. This review presents some of the clinical, demographic and biological correlates of nonresponse, in addition to compliance issues, psychosocial factors or side effects and as-yet-untreated comorbidities as a source for nonresponse. The effects of the atypicals clozapine, olanzapine, risperidone and quetiapine as compared to typicals are reviewed using available double-blind studies in this treatment refractory group of schizophrenia patients. The limited number of reports on the comparison of atypical compounds amongst each other are critically presented. Given that a subset of patients still do not respond to these agents, clinicians are using various augmentation strategies. We review studies with augmentation strategies which remain difficult to interpret given the open label and uncontrolled nature of most of these studies.",2001.0,0,0
197,11030488,Clinical and psychopharmacologic factors influencing family burden in refractory schizophrenia. The Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.,R Rosenheck; J Cramer; G Jurgis; D Perlick; W Xu; J Thomas; W Henderson; D Charney,"This study compares the effect of clozapine and haloperidol and identifies other factors related to family burden as experienced by relatives of patients with refractory schizophrenia (DSM-III-R). Of 423 patients participating in a multisite randomized clinical trial, 221 identified a family member who was actively involved in their care and who agreed to complete a standardized measure of family burden at 6 weeks and 3, 6, 9, and 12 months after randomization, simultaneous with comprehensive patient assessments. Patient factors most consistently correlated with greater family burden were symptom severity, days living in the community (i.e., not in the hospital), and frequency of family contact. Among family members, clozapine was associated with significantly (p = .048) greater reduction in feelings of dissatisfaction related to providing support to the patient, but not in objective measures of support, amount of worry the patient engendered, or days of missed employment or household activity. Although clozapine reduces symptoms, thus lowering family burden, it also increases days living in the community, which tends to increase family burden, perhaps canceling out the benefit to families of reduced symptoms. Clozapine has a small but significant effect on the experience of families of patients. This is the first study to demonstrate that effective pharmacotherapy may be of some benefit to families as well as to patients.",2001.0,0,0
198,11048902,The effectiveness of olanzapine in treatment-refractory schizophrenia when patients are nonresponsive to or unable to tolerate clozapine.,; J N Beuzen; M Avnon; R H Belmaker; A Elizur; M Mark; H Munitz; M Schneidman; D Shoshani; P Kratky; S L Grundy; G D Tollefson,"This multicenter, open-label study was designed to assess the efficacy and tolerability of olanzapine in patients with chronic schizophrenia who are resistant to therapy with classic neuroleptic agents and are either not responsive to or unable to tolerate clozapine. Patients received olanzapine orally once daily for 18 weeks at doses ranging from 5 to 25 mg. The primary efficacy measure was change in the total score on the Positive and Negative Syndrome Scale (PANSS) from baseline to end point. Secondary efficacy measures were the total score on the Brief Psychiatric Rating Scale (BPRS); the PANSS positive, negative, general psychopathology, and mood subscores; and the Clinical Global Impression improvement score. Also recorded were spontaneously reported adverse events; extrapyramidal symptoms (assessed by the Abnormal Involuntary Movement Scale, Simpson-Angus Scale, and Barnes Akathisia Scale); vital signs; and clinical laboratory test results. Forty-eight patients were treated with olanzapine; of these, 45 were assessable over the full 18-week study period. Total scores on the PANSS and BPRS were reduced from baseline by an average of 17.7 (14.2%) and 9.8 points (20.2%), respectively. Eighteen patients (40.0%) experienced a treatment response, defined as a reduction in PANSS total score of > or = 20%. A total of 25 patients (55.6%) achieved a similar reduction in BPRS total score. Significant reductions were seen in both the positive and negative symptom scores on the PANSS (P < 0.001). Olanzapine was well tolerated, with minimal treatment-emergent adverse events or clinically relevant changes in vital signs or clinical laboratory test results. No clinically significant blood dyscrasias were observed in olanzapine-treated patients, including those who had discontinued clozapine because of treatment-associated leukopenia or neutropenia. The results of this study suggest that olanzapine may be of benefit in patients who are refractory to or unable to tolerate clozapine.",2001.0,0,1
199,11048905,Long-Term use of quetiapine in elderly patients with psychotic disorders.,P N Tariot; C Salzman; P P Yeung; J Pultz; I W Rak,"Quetiapine is an atypical antipsychotic agent that does not appear to increase patient risk for treatment-emergent extrapyramidal symptoms (EPS) or anticholinergic symptoms. Previous studies of quetiapine use in elderly patients with schizophrenia and other psychoses examined short-term administration (< or = 12 weeks). Given the growing elderly population, the commensurate increase in elderly patients with psychoses, and the expected increase in disease treatment-years, the effect of long-term quetiapine administration in older patients is of considerable interest. This study assesses the long-term tolerability, safety, and clinical benefit of quetiapine in elderly patients with psychosis. Elderly patients (> or = 65 years of age) with psychotic disorders, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, participated in this 52-week, open-label, multicenter trial. Investigators increased (and later adjusted) daily doses of quetiapine on the basis of clinical response and tolerability, and assessed safety and efficacy. Efficacy assessments were made using the 18-item Brief Psychiatric Rating Scale (BPRS), Clinical Global Impressions (CGI), Simpson-Angus Scale, and the Abnormal Involuntary Movement Scale (AIMS). For patients who withdrew before week 52, analyses were performed using observed data and the last observation carried forward. One hundred eighty-four patients with psychotic disorders (98 women and 86 men) with a mean age of 76.1 years entered the trial. Seventy-two percent had psychotic disorders due to general medical conditions such as Alzheimer's disease, and 28% had other psychotic disorders, most commonly schizophrenia. Overall, 89 (48%) patients completed treatment through 52 weeks. Median total daily dose was 137.5 mg. Reasons, for withdrawal included lack of efficacy (19%), adverse events or intercurrent illness (15%), failure to return for follow-up (13%), protocol noncompliance (3%), and diminished need for treatment (2%). Somnolence (31%), dizziness (17%), and postural hypotension (15%) were common adverse events, but they rarely resulted in withdrawal from therapy. EPS-related adverse events occurred in 13% of patients. At end point (week 52), mean total score on the Simpson-Angus Scale had decreased from baseline by 1.8 points, whereas changes in AIMS scores were negligible. No clinically important effects were reported relative to mean changes in hematologic, thyroid function, or hepatic function variables. Quetiapine treatment appeared to have no associated cardiovascular adverse outcomes despite cardiovascular comorbidities and unrestricted use of concomitant cardiovascular medications. Significant decreases in BPRS total score (n = 170, P < 0.001) and CGI Severity of Illness item score (n = 177, P < 0.002) were seen at end point (observed data and last observation carried forward). Decreases of > or = 20% in mean BPRS total score were observed in 83 (49%) patients. These results provide preliminary information to clinicians regarding tolerability, safety, and clinical improvement with quetiapine in elderly patients with psychotic symptoms, and support controlled studies of quetiapine in this patient population.",2001.0,1,1
200,11048906,"The effects of olanzapine, risperidone, and haloperidol on plasma prolactin levels in patients with schizophrenia.",S R David; C C Taylor; B J Kinon; A Breier,"There is relatively little comparative information on elevations in plasma prolactin level (PRL) with conventional versus novel antipsychotic agents. This paper examines the comparative effects on PRL of olanzapine, risperidone, and haloperidol based on data from 3 multicenter, double-blind, randomized clinical trials. Magnitude of response, dose dependency, time course, effects of sex and age, and response to switching from haloperidol to olanzapine are assessed. The effects of olanzapine, risperidone, and haloperidol on PRL were assessed in patients with schizophrenia or related psychoses participating in 3 double-blind clinical trials: (1) a 6-week acute trial comparing olanzapine 5 to 20 mg/d (n = 1,336) and haloperidol 5 to 20 mg/d (n = 660), with a 1-year, open-label olanzapine extension for responders; (2) a 54-week study comparing olanzapine 5 to 20 mg/d (n = 21), risperidone 4 to 10 mg/d (n = 21), and haloperidol 5 to 20 mg/d (n = 23) in early illness; and (3) a 28-week study comparing olanzapine 10 to 20 mg/d (n = 172) and risperidone 4 to 12 mg/d (n = 167). PRL elevations were significantly greater with risperidone than with either olanzapine or haloperidol in study 2. and significantly greater than with olanzapine in study 3 (all, P < 0.001). PRL elevations were significantly greater with haloperidol than with olanzapine in study 1 (P < 0.001 ). A dose-response relationship was not consistently confirmed with any of the drug treatments. Risperidone-associated PRL elevations peaked relatively early in treatment. In haloperidol- and risperidone-treated patients, the mean change in PRL was greater in women than in men. PRL decreased significantly when treatment was switched from haloperidol to olanzapine. This side-by-side analysis of 3 independent studies suggests that with the 3 antipsychotic drugs studied, PRL is elevated moderately by olanzapine (mean change, 1-4 ng/mL), intermediately by haloperidol (mean change, approximately 17 ng/mL), and strongly by risperidone (mean change, 45-80 ng/mL). No consistent dose-response relationship was observed, and the time course and sex-dependency of the response differed between the 3 agents. Patients with haloperidol-induced hyperprolactinemia may benefit from a switch to olanzapine. Long-term studies examining the health consequences of chronic hyperprolactinemia during antipsychotic treatment are needed.",2001.0,0,0
201,11058482,Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia.,T P George; D M Ziedonis; A Feingold; W T Pepper; C A Satterburg; J Winkel; B J Rounsaville; T R Kosten,"Schizophrenic patients have high rates of cigarette smoking. The authors compared the outcomes of two group psychotherapy programs for smoking cessation in patients with schizophrenia or schizoaffective disorder who were also treated with the nicotine transdermal patch and with either atypical or typical antipsychotic medications. Forty-five subjects were randomly assigned to 1) the group therapy program of the American Lung Association (N=17) or 2) a specialized group therapy program for smokers with schizophrenia (N=28) that emphasized motivational enhancement, relapse prevention, social skills training, and psychoeducation. All subjects participated in 10 weeks of treatment with the nicotine transdermal patch (21 mg/day) and 10 weekly group therapy sessions and continued to receive their prestudy atypical (N=18) or typical (N=27) antipsychotic medications. Outcome variables included treatment retention, rate of smoking abstinence, and expired-breath carbon monoxide level. Smoking abstinence rates did not differ in the two group therapy programs. However, atypical antipsychotic agents, in combination with the nicotine transdermal patch, significantly enhanced the rate of smoking cessation (55.6% in the atypical agent group versus 22.2% in the typical group), which was reflected by a significant effect of atypical versus typical agents on carbon monoxide levels. Risperidone and olanzapine were associated with the highest quit rates. The results suggest that 1) smoking cessation rates with the nicotine transdermal patch are modest in schizophrenia, 2) specialized group therapy for schizophrenic patients is not significantly different from American Lung Association group therapy in its effect on smoking cessation, and 3) atypical agents may be superior to typical agents in combination with the nicotine transdermal patch for smoking cessation in schizophrenia.",2001.0,0,0
202,11059992,Immediate effects of risperidone on cortico-striato-thalamic loops and the hippocampus.,P F Liddle; C J Lane; E T Ngan,"Functional imaging studies indicate that delusions and hallucinations in schizophrenia are associated with overactivity of the left hippocampus and ventral striatum. Hippocampal neuronal firing modulates feedback to cortex via cortico-striato-thalamic loops. To test the hypothesis that recovery from psychosis is associated with decrease in activity in cortico-striato-thalamic circuits, and, furthermore, that reduction in hippocampal activity predicts the degree of alleviation of delusions and hallucinations. Positron emission tomography (PET) was used to measure the effects of the atypical antipsychotic, risperidone, on glucose metabolism in eight first-episode schizophrenia patients. A single dose of risperidone produced decreases in metabolism in ventral striatum, thalamus and frontal cortex. The magnitude of decreases in left hippocampus predicted subsequent reduction in delusions and hallucinations. After six weeks' treatment with risperidone, the decreases in frontal metabolism were more extensive. The mechanism of antipsychotic action of risperidone entails reduction of hippocampal activity together with reduced feedback via cortico-striato-thalamic loops.",2001.0,0,0
203,11061283,Neurologic side effects in neuroleptic-naïve patients treated with haloperidol or risperidone.,R C Meibach,,2001.0,0,1
204,11072939,Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study.,G L Zornberg; H Jick,"Antipsychotic drugs have been associated with an increased risk of adverse events such as venous thromboembolism. Our aim was to assess this risk in users of conventional antipsychotic drugs who had been diagnosed with first-time, idiopathic venous thromboembolism. From a baseline population of 29,952 recipients of conventional and atypical antipsychotic drugs aged younger than 60 years, we identified 42 individuals with idiopathic venous thromboembolism and 172 matched controls. We compared risk of current and recent use of antipsychotic drugs with non-use before the index date in cases and controls. Current exposure to conventional antipsychotic drugs was associated with a significantly increased risk of idiopathic venous thromboembolism compared with non-use (adjusted odds ratio 7.1 [95% CI 2.3-21.97]). Although we found no difference between phenothiazines, thioxanthenes, or other conventional antipsychotic drugs, low potency antipsychotic drugs drugs such as chlorpromazine and thioridazine were more strongly associated with venous thromboembolism (odds ratio 24.1 [3.3-172.7]) than were high potency antipsychotic drugs such as haloperidol (3.3 [0.8-13.2]). The risk for venous thrombosis was highest during the first few months of conventional antipsychotic drug use. Current exposure to conventional antipsychotic drugs significantly increases the risk of idiopathic venous thromboembolism in men and women younger than 60 years of age.",2001.0,0,0
205,11093063,Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study.,N Kleindienst; W Greil,"In a randomized clinical trial with an observation period of 2.5 years, the differential efficacy of lithium versus carbamazepine was compared in 171 bipolar patients (DSM-IV). In order to investigate the efficacy of the two drugs in clearly defined subsamples, a series of subgroup analyses was carried out. First, patients with a bipolar I disorder (n = 114) were analyzed separately. In these patients, lithium was superior to carbamazepine. In contrast, carbamazepine was at least equally as efficacious as lithium in the subsample of patients with bipolar II disorder or bipolar disorder not otherwise specified (n = 57). In a second analysis on differential efficacy, the whole sample was subdivided into a classical subgroup (bipolar I patients without mood-incongruent delusions and without comorbidity; n = 67) and a nonclassical subgroup including all other patients (n = 104). Classical bipolar patients had a significantly lower hospitalization rate under lithium than under carbamazepine prophylaxis (26 vs. 62%, p = 0.012). For the nonclassical group, a tendency in favor of carbamazepine was found. In a third step, we analyzed the impact of episode sequence on differential efficacy. In a global view, the episode sequence prior to the index episode was not correlated to differential efficacy. Our results might, however, indicate that patients with an episode sequence of mania-depression-free interval responded better to lithium. Besides differential efficacy, suicidal behavior and patients' satisfaction with treatment were investigated. Regarding suicidal behavior, a trend in favor of lithium was found. The data on patients' satisfaction were significantly in favor of carbamazepine. In conclusion, lithium appears to be superior to carbamazepine in classical bipolar cases and might have additional impact on proneness to suicide. The distinctly larger group of patients with nonclassical features might profit more from carbamazepine which seems to be well accepted by the patients. Hence, treatment alternatives to lithium are desirable for the majority of bipolar patients.",2001.0,0,0
206,11093363,An assessment of iloperidone for the treatment of schizophrenia.,K K Jain,"Iloperidone (Novartis' Zomariltrade mark) is an atypical antipsychotic agent for the treatment of schizophrenia. Current trends in the treatment of schizophrenia indicate that some atypical antipsychotics are being recommended as first-line therapy. Atypical antipsychotics, in addition to being dopamine (D) receptor antagonists, are all relatively potent serotonin (5-HT) receptor antagonists and are less likely than conventional dopamine antagonists to induce movement disorders. However, all of these agents differ in their receptor profiles and clinical profiles. Iloperidone, a benzisoxazole, is a mixed 5-HT(2A)/D(2)antagonist. Iloperidone was found to be more potent than its analogues when compared with haloperidol in antagonising climbing behaviour in mice. Iloperidone is extensively metabolised and the main circulating metabolite is reduced iloperidone. In patients treated with iloperidone, a low incidence of extrapyramidal symptoms and weight gain has been shown. Data from Phase II trials demonstrated efficacy in patients at doses of 8 mg/day and tolerability was good up to 32 mg/day. Phase III prospective, double-blind, randomised trials with iloperidone are in progress under the ZEUS (Zomariltrade mark Efficacy Utility and Safety) programme involving 3300 patients. Iloperidone, with a balance of activity at the dopaminergic and serotonergic receptors, has obvious advantages over clozapine and olanzapine, both of which have a similar receptor profile as they favour serotonergic over dopamine receptors. Iloperidone is likely to reach the market in 2001 and has favourable prospects in the atypical antipsychotic market for schizophrenia, which is expanding from US$ 1.5 billion in 2000 to US$ 3 billion in 2005.",2001.0,0,0
207,11096331,Association study of apolipoprotein E epsilon4 with clinical phenotype and clozapine response in schizophrenia.,C J Hong; Y W Yu; C H Lin; H L Song; H C Lai; K H Yang; S J Tsai,"Schizophrenic patients with the apolipoprotein E (APOE = gene; apoE = protein) epsilon4 allele exhibited lower psychosis scores than patients without the epsilon4 allele in previous reports. The present study tested the hypothesis that the APOE epsilon4 allele confers association with the clinical manifestations of schizophrenia or clozapine response. A total of 95 schizophrenic patients who were treatment resistant were included in the study. The results demonstrated that the presence of the APOE epsilon4 allele did not influence the response to clozapine in schizophrenic patients, neither was the baseline psychopathology related to the APOE epsilon4 allele. Given the multiple functions of the apoE protein in the brain, further study of the influence of APOE on CNS medication response is needed.",2001.0,0,0
208,11098812,Augmentation with sulpiride for a schizophrenic patient partially responsive to clozapine.,J H Stubbs; C M Haw; C J Staley; C Q Mountjoy,Schizophrenic patients who are only partially responsive to clozapine pose a therapeutic challenge. In these circumstances some clinicians would consider adding in a second antipsychotic. We present a case report and review evidence for the efficacy of such augmentation strategies. Single case report and literature review. The total number of patients in studies and case reports of combining clozapine with other antipsychotics is small. There has been only one randomized controlled trial. This found the addition of sulpiride to clozapine resulted in clinical improvement in some patients. Further randomized controlled studies of augmentation of clozapine therapy are needed to provide scientific justification for this clinical practice.,2001.0,0,0
209,11099266,Atypical antipsychotics.,S Kapur; G Remington,,2001.0,0,1
210,11099280,Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis.,J Geddes; N Freemantle; P Harrison; P Bebbington,"To develop an evidence base for recommendations on the use of atypical antipsychotics for patients with schizophrenia. Systematic overview and meta-regression analyses of randomised controlled trials, as a basis for formal development of guidelines. 12 649 patients in 52 randomised trials comparing atypical antipsychotics (amisulpride, clozapine, olanzapine, quetiapine, risperidone, and sertindole) with conventional antipsychotics (usually haloperidol or chlorpromazine) or alternative atypical antipsychotics. Overall symptom scores. Rate of drop out (as a proxy for tolerability) and of side effects, notably extrapyramidal side effects. For both symptom reduction and drop out, there was substantial heterogeneity between the results of trials, including those evaluating the same atypical antipsychotic and comparator drugs. Meta-regression suggested that dose of conventional antipsychotic explained the heterogeneity. When the dose was </=12 mg/day of haloperidol (or equivalent), atypical antipsychotics had no benefits in terms of efficacy or overall tolerability, but they still caused fewer extrapyramidal side effects. There is no clear evidence that atypical antipsychotics are more effective or are better tolerated than conventional antipsychotics. Conventional antipsychotics should usually be used in the initial treatment of an episode of schizophrenia unless the patient has previously not responded to these drugs or has unacceptable extrapyramidal side effects.",2001.0,1,1
211,11104186,Current issues in Tourette syndrome.,H S Singer,,2001.0,0,0
212,11104211,Risperidone in the treatment of dopamine-induced psychosis in Parkinson's disease: an open pilot trial.,E Mohr; T Mendis; K Hildebrand; P P De Deyn,"To evaluate the safety and efficacy of risperidone in patients with Parkinson's disease (PD) who are experiencing significant dopamine-induced psychosis. Seventeen patients (median age, 72 yrs) participated in this 12-week, open pilot study receiving 0.5 to 3 mg oral risperidone per day. Maintenance antiparkinsonian medication was continued throughout, although psychotropic medication was discontinued. EFFICACY RESULTS: Risperidone produced a substantial improvement in psychotic symptoms, shown on the mean total positive subscale score on the Positive and Negative Syndrome Scale (PANSS) by a 30% improvement (-3.1 decrease) after 1 week and a 66% improvement (-6.8 decrease) at end point. This improvement was most evident in the items delusions, hallucinatory behavior, and suspiciousness/persecution. Risperidone also achieved significant improvement from baseline in Clinical Global Impression (CGI)-severity and CGI-improvement (p < 0.001, Page test). Risperidone treatment did not adversely affect symptoms specific to Parkinson's disease, as assessed by the Unified Parkinson's Disease Rating Scale (UPDRS). SAFETY RESULTS: Sixteen patients reported at least one adverse event, but only two patients withdrew as a result of adverse events. No significant changes or clinically relevant abnormalities were observed in laboratory parameters or vital signs. Short-term use of risperidone (mean dosage, 1.1 mg per day) improves the psychopathology of patients with PD who have dopamine-induced psychosis without adversely affecting the symptoms of PD. Higher doses and long-term use were not addressed in this study and may be precluded by extrapyramidal side effects.",2001.0,0,0
213,11105736,Strategies for switching from conventional antipsychotic drugs or risperidone to olanzapine.,B J Kinon; B R Basson; J A Gilmore; S Malcolm; V L Stauffer,"This study compared the efficacy and safety of 4 therapeutically relevant strategies for switching clinically stable patients from a conventional antipsychotic drug or risperidone to olanzapine. Two hundred nine outpatients with a DSM-IV diagnosis of schizophrenia or schizo-affective disorder who were clinically stable while being treated with a conventional antipsychotic drug or risperidone were openly randomly assigned to either abrupt or gradual discontinuation of their prior antipsychotic drug. Patients were further randomly assigned in a double-blind fashion to immediate olanzapine initiation (olanzapine, 10 mg q.d. for 3 weeks) or stepwise initiation (a sequence of 1 week each on placebo; olanzapine, 5 mg q.d.; and olanzapine, 10 mg q.d.). The efficacy of these 4 switching paradigms was assessed using the Clinical Global Impressions (CGI)-Improvement scale, Patient's Global Impressions (PGI)-Improvement scale, and Positive and Negative Syndrome Scale (PANSS). Safety assessments included ratings for extrapyramidal symptoms, cognitive impairment, adverse events, laboratory parameters, weight change, and vital signs. The paradigm of gradual antipsychotic drug discontinuation combined with an initial full dose of olanzapine, 10 mg/day, had the most favorable efficacy and tolerability profile overall. By week 3, the majority of completing patients on all 4 switching paradigms were either improved or clinically unchanged (> 90%). No clinically significant differences between switching paradigms were seen in laboratory values or vital signs. In this study, switching clinically stable outpatients with a diagnosis of schizophrenia or schizoaffective disorder to olanzapine was most successful when a full therapeutic dose of olanzapine was immediately initiated while gradually discontinuing prior conventional antipsychotic drug or risperidone treatment. Overall, switching was achieved without increased vulnerability to relapse or to occurrence of clinically burdensome antipsychotic drug withdrawal symptoms in the majority of patients.",2001.0,0,0
214,11106137,Hematologic reference ranges in a population of patients with schizophrenia.,S N Voss; T Sanger; C Beasley,"The potential hematotoxic effects of antipsychotic drugs are well known and may limit the use of some effective therapies. Although some previous studies have suggested that patients with schizophrenia may have altered ""normal"" values, only limited data were available. It is now believed that biological values do not usually follow a normal distribution; therefore, reference ranges are frequently used when interpreting laboratory tests in clinical practice and in research. However, it may be important to use disease-specific hematologic reference ranges when evaluating laboratory test results for patients with schizophrenia. In this study, data taken from patients with schizophrenia prior to treatment in previous phase II and phase III pharmaceutical studies were analyzed to produce reference ranges for a variety of hematologic parameters. An increased variability was shown in the reference ranges for all white blood cell indices between patients with schizophrenia and the population without schizophrenia. Certain reference values also showed heterogeneity for gender, age, and racial descent. This study suggests that abnormal hematologic findings in patients with schizophrenia should be assessed in the context of a valid reference range. This information will be of value to psychiatrists, laboratory scientists, and other physicians who encounter hematologic problems in patients with schizophrenia, as well as in the assessment of the adverse effects of new therapeutic agents.",2001.0,0,0
215,11106875,The effect of clozapine on caudate nucleus volume in schizophrenic patients previously treated with typical antipsychotics.,F E Scheepers; C C de Wied; H E Hulshoff Pol; W van de Flier; J A van der Linden; R S Kahn,"Typical antipsychotics have been reported to enlarge the caudate nucleus in schizophrenic patients. The atypical antipsychotic, clozapine, is associated with a decrease in caudate size in patients previously treated with typical antipsychotics. The present study investigates whether a change in caudate volume after switching from treatment with typical antipsychotics to treatment with clozapine is related to improvement in symptoms or tardive dyskinesia (TD). Twenty-six schizophrenic patients participated in this open study. Caudate nucleus volume and TD were assessed before discontinuing typical antipsychotics and after 24 weeks of treatment with clozapine. After discontinuing typical antipsychotics, symptoms were assessed in a 3 days drug-free period and subsequently once a month. Treatment with clozapine resulted in a decrease in caudate volume, improvement in symptoms and amelioration of TD. However, no difference in caudate volume changes was found between responders and non-responders to clozapine and no correlations were found between caudate volume changes and reduction of TD. In conclusion, this study replicates earlier findings that clozapine decreases caudate volume in patients previously treated with typical antipsychotics and suggests that this effect is unrelated to treatment response or to amelioration of TD.",2001.0,0,0
216,11110010,Effects of risperidone on affective symptoms in patients with schizophrenia.,J Peuskens; B Van Baelen; C De Smedt; P Lemmens,"The effects of risperidone on affective symptoms were determined by an analysis of pooled data from six double-blind trials of risperidone versus haloperidol in 1254 patients with chronic schizophrenia. Symptoms indicating mania were assessed by the Positive and Negative Syndrome Scale (PANSS) excitement and grandiosity items and by the excited cluster (excitement, hostility, uncooperativeness, and poor impulse control); anxious / depressive symptoms were assessed by the PANSS anxious / depressive cluster (somatic concern, anxiety, guilt feelings, and depression). Mean change scores from baseline to endpoint were compared in patients receiving risperidone, haloperidol or placebo by analysis of variance with factors for trial and baseline score included in the model. In all patients, change scores on excitement and grandiosity items and excited and anxious / depressive clusters were significantly greater for risperidone than for haloperidol or placebo. Dropouts due to inefficacy were less frequent with risperidone (5 of 59; 8%) than with haloperidol (7 of 38; 18%) or placebo (8 of 10; 80%). In patients with anxious / depressive symptoms at baseline (anxiety / depression cluster score > or = the median), anxiety / depression scores decreased significantly more with risperidone than with haloperidol, and symptom reduction occurred faster with risperidone. These results are consistent with previous reports and suggest that risperidone is more efficacious than haloperidol for affective symptoms in patients with schizophrenia.",2001.0,0,1
217,11120419,Improvement in cognition associated with novel antipsychotic drugs: a direct drug effect or reduction of EPS?,M Weiser; M Shneider-Beeri; N Nakash; N Brill; O Bawnik; S Reiss; S Hocherman; M Davidson,"Administration of novel, versus classic, antipsychotic agents to patients suffering from psychosis is associated both with moderately better scores on cognitive tests, and with fewer extrapyramidal symptoms (EPS). Because improved motor functioning may enable better performance on some components of cognitive test batteries, and because the advantages of the novel antipsychotics on cognitive performance are not very large, it is sometimes difficult to discern if improvement in a given cognitive task is due to a direct effect of the novel antipsychotic drug, or is secondary to the novel drug's decreased propensity to induce EPS. In an attempt to distinguish between these two possibilities, the present study examined the ability of patients suffering from schizophrenia receiving classic, versus novel antipsychotics, to perform a computerized visuo-motor test (VMT). VMT assesses planning capabilities, attention and executive functions known to be impaired in schizophrenia, which are suggested to be affected by novel antipsychotics. Seventy-six patients suffering from schizophrenia or schizophreniform disorder, receiving haloperidol (23 patients, mean dose 10.01+/-6.1mg/day), olanzapine (26 patients, mean dose 10.56 +/- 4.9 mg/day) or risperidone (27 patients, mean dose 4.35 +/- 1.7 mg/day) were assessed for EPS using the parkinsonian subscale of the Extrapyramidal Symptom Rating Subscale (ESRS), and with the VMT. Cognitive functioning as measured by the VMT was better for patients receiving risperidone or olanzapine, compared with those receiving haloperidol (F=6.636, df=2,67, P=0. 002), while the patients receiving haloperidol or risperidone suffered from more severe EPS compared with the patients receiving olanzapine (F=3.996, df=2,71, P=0.023). Although the patients receiving risperidone suffered from EPS similar in severity to the EPS of the patients receiving haloperidol, their performance on a task involving visuo-motor and attentional skills was similar to that of the patients receiving olanzapine. This finding implies that there is a dissociation between the antipsychotic drug's ability to affect cognitive functioning, and EPS. This dissociation indirectly suggests that the advantages offered by novel antipsychotics on cognitive performance are a direct effect, rather than being entirely mediated by improved movement abilities.",2001.0,0,1
218,11120421,"Risperidone versus haloperidol in psychotic patients with disturbing neuroleptic-induced extrapyramidal symptoms: a double-blind, multi-center trial.",A H Heck; P M Haffmans; I W de Groot; E Hoencamp,"A randomized, double-blind, multi-center trial was started to compare the severity of extrapyramidal symptoms (EPS) during risperidone and haloperidol treatment in schizophrenic patients who had disturbing EPS during their previous neuroleptic treatment. Additional objectives of this trial were comparing the antipsychotic effectiveness of the two treatments and the use of antiparkinsonian medication. Effects of flexible doses of risperidone and haloperidol were compared in 77 psychotic patients (83% with chronic schizophrenia) with disturbing neuroleptic-induced EPS (risperidone 40 patients, haloperidol 37). The trial was completed by 47 patients: 25 in the risperidone group (12 women, 13 men), and 22 in the haloperidol group (10 women, 12 men). An adequate antipsychotic effect was obtained in most patients by both treatments. The primary aim of this trial was comparing parkinsonism measured with the extrapyramidal syndrome rating scale (ESRS) during treatment with risperidone and haloperidol. Two primary parameters were selected: the change from baseline to the worst score during treatment of ESRS II (parkinsonism) and ESRS VI (clinical global impression of severity of parkinsonism). The CGI of severity of parkinsonism was better with risperidone (P=0.025), while the parkinsonism total score tended to be better with risperidone (P<0. 10). Before the double-blind treatment, 34 (of the 77) had used antiparkinson medication (risperidone 18, haloperidol 16). During the double-blind treatment phase, 21 patients had used antiparkinson medication (risperidone 11, haloperidol 10). The larger reduction of parkinsonism in the risperidone group was not due to a difference in the use of anti-parkinsonian medication. In this group of schizophrenic patients with disturbing EPS during previous neuroleptic treatment, a stronger reduction of parkinsonism was observed with risperidone than with haloperidol.",2001.0,1,1
219,11120426,Practice-related improvement in information processing with novel antipsychotic treatment.,P D Harvey; P J Moriarty; M R Serper; E Schnur; D Lieber,"Attentional deficits are prominent in schizophrenia, and skill learning is impaired. Novel antipsychotic treatment has been reported to improve certain cognitive skills in schizophrenic patients, but no information is yet available about the effect of newer medications on skill learning. Clinically stable patients with schizophrenia (n=16) and chronically hospitalized inpatients (n=8) were recruited while receiving conventional antipsychotic treatment. Subjects were tested at baseline on a visual continuous performance test (CPT), performed alone and simultaneously with an auditory CPT. Normal controls (n=8) were also tested at baseline. The inpatients and half of the outpatients were switched to treatment with risperidone. All patients then performed the visual CPT on a daily basis and performed the dual tasks once per week, for 4weeks. Patients who remained on conventional medications did not improve in their performance despite the extensive practice on the test. Both chronic and stable patients receiving risperidone treatment manifested a statistically significant (P<0.05) improvement from baseline on both single and dual-task visual CPT. Stable outpatients performed significantly better at the end of the protocol than the normal controls performance at baseline (P<0.05). These results suggest that practice-related improvements in the performance of information processing tests are enhanced by novel antipsychotic medications. Although the specific biological mechanism of this effect is not yet known, the results may suggest that use of newer medications will enhance skill development and perhaps facilitate rehabilitation of patients with schizophrenia.",2001.0,0,0
220,11136647,A novel augmentation strategy for treating resistant major depression.,R C Shelton; G D Tollefson; M Tohen; S Stahl; K S Gannon; T G Jacobs; W R Buras; F P Bymaster; W Zhang; K A Spencer; P D Feldman; H Y Meltzer,"Treatment-resistant depression is a significant public health concern; drug switching or augmentation often produce limited results. The authors hypothesized that fluoxetine could be augmented with olanzapine to successfully treat resistant depression. An 8-week double-blind study was conducted with 28 patients who were diagnosed with recurrent, nonbipolar, treatment-resistant depression without psychotic features. Subjects were randomly assigned to one of three groups: olanzapine plus placebo, fluoxetine plus placebo, or olanzapine plus fluoxetine. Fluoxetine monotherapy produced minimal improvement on various scales that rate severity of depression. The benefits of olanzapine monotherapy were modest. Olanzapine plus fluoxetine produced significantly greater improvement than either monotherapy on one measure and significantly greater improvement than olanzapine monotherapy on the other measures after 1 week. There were no significant differences between treatment groups on extrapyramidal measures nor significant adverse drug interactions. Olanzapine plus fluoxetine demonstrated superior efficacy for treating resistant depression compared to either agent alone.",2001.0,0,0
221,11143833,Impact of risperidone on seclusion and restraint at a state psychiatric hospital.,K N Chengappa; J Levine; R Ulrich; H Parepally; J S Brar; R Atzert; R Brienzo; A Gopalani,"To evaluate the impact of risperidone on seclusion and restraint in patients at a state psychiatric facility, shortly after risperidone's release. Patients who were in the hospital for at least 3 months prior to receiving risperidone and subsequently received risperidone for at least 3 months formed the cohort. A mirror-image design was used with duration to a maximum of 1 year before and 1 year after initiation of risperidone. The hospital population that did not receive either risperidone or clozapine during the same time period was used for comparison of trends of seclusion and restraint. Seventy-four patients (most with schizophrenia) met the inclusion criteria of the risperidone group. There were statistically significant decreases in the number of seclusion hours (2.2 [SD 5.5] to 0.26 [SD 0.06]) and of events (0.23 [SD 0.59] to 0.05 [SD 0.14]) per person per month during risperidone treatment, compared with the prerisperidone treatment period (P = 0.01). The comparison group also evidenced decreases on these measures during the same time period, but the risperidone-treated cohort achieved a proportionally greater reduction. There were similar trends toward reduction in the restraint measures during risperidone treatment compared with prerisperidone, but these did not achieve statistical significance. The comparison group also showed slightly decreased use of restraints over the study period. Risperidone appears to have had a positive impact on seclusion in this state-hospital psychiatric population. These data support the positive impact of risperidone on violence found in other studies. Violence and aggression are major factors that affect morale among psychiatric patients and staff. So, any benefit in this regard as a result of antipsychotic drug treatment is salutary for patients, families, and health care providers.",2001.0,0,1
222,11147929,Clozapine-induced agranulocytosis and hereditary polymorphisms of clozapine metabolizing enzymes: no association with myeloperoxidase and cytochrome P4502D6.,M Dettling; C Sachse; B Müller-Oerlinghausen; I Roots; J Brockmöller; A Rolfs; I Cascorbi,"The pathomechanisms of most drug-induced agranulocytoses are unclear; however, there are some studies pointing to genetic determinants. Some drug-induced agranulocytoses such as clozapine-induced agranulocytosis (CA) may be regarded as an idiosyncratic drug reaction because of its preclinical and clinical characteristics. To study some aspects of the genetic background of CA further, polymorphisms of specific metabolizing enzyme systems of clozapine were examined. Thirty-one schizophrenic patients with CA and 77 schizophrenic comparison subjects without this adverse effect underwent genotyping of a recently discovered G(-463)A polymorphism of myeloperoxidase (MPO) gene and cytochrome P4502D6. Neither the MPO mutation nor specific genotypes of cytochrome P4502D6 were associated with CA. Both were equally distributed among CA patients and controls. Thus, our data suggest lack of evidence of an association of CA and genetically variable activity of these specific drug metabolizing enzymes; however, this may be due to statistical reasons only. Thus, further studies with greater CA samples are necessary to draw final conclusions about these genetically based hypotheses.",2001.0,0,0
223,11151749,Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia.,K Raaska; P J Neuvonen,"A possible pharmacokinetic interaction between a CYP1A2 inhibitor, ciprofloxacin, and clozapine was studied in schizophrenia patients with stable clozapine treatment. A randomised double-blind cross-over study design with two phases was used. Seven schizophrenic inpatients volunteered to receive, in addition to their previous drug regimen, either 250 mg ciprofloxacin or placebo twice daily (b.i.d.) for 7 days. The phases were separated by a 7-day wash-out period. Serum concentrations of clozapine and its main metabolite N-desmethylclozapine were measured during both phases before the first dose on day 1 and on days 3 and 8. Ciprofloxacin increased mean serum concentration of clozapine and N-desmethylclozapine by 29% (P < 0.01) and 31% (P < 0.05), respectively. There was a significant positive correlation (r = 0.90, P < 0.01) between the individual concentrations of serum ciprofloxacin and the increase in concentrations of clozapine plus N-desmethylclozapine. The increase in serum clozapine concentrations correlated significantly (r = 0.89, P < 0.01) with the ratios of N-desmethylclozapine to clozapine concentrations. Even a low dose of ciprofloxacin can moderately increase serum concentrations of clozapine and N-desmethylclozapine. A probable mechanism of interaction is an inhibition of CYP1A2 enzyme by ciprofloxacin. The possibility of clinically significant interaction should be considered, especially when higher doses of ciprofloxacin are used concomitantly with clozapine.",2001.0,0,0
224,11154017,Antipsychotic treatment of psychosis and agitation in the elderly.,D G Daniel,"Agitated, aggressive behavior and psychosis are common manifestations of Alzheimer's disease that frequently lead to institutionalization. The usefulness of conventional neuroleptic treatment in this population is limited by narrow therapeutic windows because of limited efficacy and high sensitivity to side effects. More recently, investigational clinical trials have suggested potential utility for atypical antipsychotics such as risperidone, olanzapine, and quetiapine in treatment of behaviorally disturbed individuals and for the psychotic manifestations of dementia.",2001.0,0,0
225,11156810,Clozapine-associated reduction in arrest rates of psychotic patients with criminal histories.,W Frankle; D Shera; H Berger-Hershkowitz; A Eden Evins; C Connolly; D Goff; D Henderson,"The authors examined the relationship between treatment with clozapine and rates of arrest of psychotic outpatients with criminal histories. Patients who had been given a DSM-IV psychotic diagnosis were selected from an urban outpatient clinic database. Background checks performed on 360 patients identified 165 (45.8%) with positive criminal histories in Massachusetts. The authors reviewed the charts of these patients to determine several variables, including whether and when they had received clozapine. A Poisson regression model was used to regress arrest rates against the variables of age, sex, onset of illness, birth cohort, and clozapine treatment. Risk ratios (i.e., percent change in arrest rates) were then calculated by computing the exponential of the Poisson regression coefficients. The 165 patients included in the analysis had a total of 1,126 arrests. The mean number of arrests was 6.8. Differences were found between the 65 patients who received clozapine and the 100 patients who did not in number of arrests, sex, and onset of illness. The regression revealed significantly higher arrest rate estimates associated with more recent birth cohort (4.8%) and with onset of illness (64.6%) and lower arrest rate estimates associated with higher levels of education (11.6%), receiving clozapine (32.6%), and receiving clozapine during specific periods of time (68.9%). Clozapine's effect on arrest rates in this group of patients is large enough to warrant further investigation. The data indicate that clozapine may reduce recidivism in subjects with criminal histories who are in need of antipsychotic medication.",2001.0,0,0
226,11163780,Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine.,G D Tollefson; M A Birkett; G M Kiesler; A J Wood; Lilly Resistant Schizophrenia Study Group,"The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptic drugs is a major challenge. Clozapine has been one treatment option; however, it is not universally effective and is limited in its use by safety concerns. With the introduction of newer agents, their performance relative to clozapine is of great clinical interest. The primary objective of this study was to evaluate the efficacy and safety of olanzapine versus clozapine among treatment resistant DSM-IV schizophrenic patients. The study was primarily designed to demonstrate the ""noninferiority"" of olanzapine compared to clozapine after 18 weeks of double-blind treatment. Conclusions were based on the one-sided lower 95% confidence limit about the treatment effect observed from the primary efficacy variable (Positive and Negative Syndrome Scale [PANSS] Total). Mean changes from baseline to end point in PANSS Total score, using a last observation carried forward technique, showed that both agents were comparably effective in neuroleptic resistant patients, i.e., demonstrated the ""noninferiority"" of olanzapine when compared to clozapine. Overall, significantly fewer olanzapine-treated patients (4%) discontinued for an adverse event than their clozapine-treated (14%) counterparts (p =.022). Among spontaneously reported adverse events, increased salivation, constipation, dizziness, and nausea were reported significantly more often among clozapine-treated patients, whereas only dry mouth was reported more often among olanzapine-treated patients. Olanzapine was demonstrated to be noninferior to clozapine and better tolerated among resistant schizophrenic patients clinically eligible for treatment with clozapine.",2001.0,1,1
227,11163781,Consistency of atypical antipsychotic superiority to placebo in recent clinical trials.,S W Woods; M Stolar; M J Sernyak; D S Charney,"The use of control placebos in clinical trials of new antipsychotic medications is increasingly under examination. The active controlled equivalence study could offer a potential alternative design. First, however, it must be clear that any proposed standard control agent has been consistently superior to placebo in previous studies. Through a Freedom of Information Act request, we identified nine placebo-controlled trials of risperidone, olanzapine, or quetiapine. Meta-analysis indicated that the pooled estimate of the true population effect size +/- SE was 0.46 +/- 0.06 for categorical response rates and >0.53 +/- 0.07 for the continuous Brief Psychiatric Rating Scale change score outcome measure. If the desired detectable effect size is set very conservatively at a 95% confidence lower bound for the estimate of true effect size, statistical power for random samples of 80 per group drawn from a population of subjects similar to that of the nine meta-analyzed studies is.67 for categorical response rates and >.82 for the continuous measure, based on one-sided alpha =.05. These data suggest substantial confidence that a therapeutic dose of an atypical antipsychotic will be statistically superior to placebo in an adequately sized randomized trial, when reporting a continuous measure as the principal outcome.",2001.0,0,0
228,11165312,Concurrent validity of negative symptom assessments in treatment refractory schizophrenia: relationship between interview-based ratings and inpatient ward observations.,E A Gilbert; R P Liberman; J Ventura; R Kern; M J Robertson; S Hwang; M F Green,"The concurrent validity of interview-based ratings of negative symptoms in 35 inpatients with chronic, treatment refractory schizophrenia was evaluated. Correlations were examined between interview-based ratings of negative symptoms, measured by the Brief Psychiatric Rating Scale and the Positive and Negative Syndrome Scale, and the naturalistic behavior of inpatients as assessed by the Time Sample Behavior Checklist. Higher levels of interview-based negative symptoms were related to reduced interpersonal activity on the inpatient ward, but not to entertainment, instrumental or self-maintenance activities. These findings offer partial support for the concurrent validity of office-based ratings of negative symptoms, and highlight the importance of longitudinal observations of patients for accurate identification of negative symptoms.",2001.0,0,0
229,11182531,Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder.,P Davanzo; M A Thomas; K Yue; T Oshiro; T Belin; M Strober; J McCracken,"This project was designed to compare differences in brain proton spectra between children and adolescents with bipolar disorder (BPD) and gender and age-matched normal controls, and to measure changes in myo-inositol levels following lithium therapy, utilizing in vivo proton magnetic resonance spectroscopy (1H MRS). A single voxel (2x2x2 cm3) was placed in brain anterior cingulate cortex for acquisition of the 1H spectra at baseline and after acute (7 days) lithium administration in 11 children (mean age 11.4 years) diagnosed with BPD, and in 11 normal controls. Acute lithium treatment was associated with a significant reduction in the myo-inositol/creatine ratio. This decrement was also significant in lithium-responders when analyzed separate from non-responders. Compared to normal controls, BPD subjects showed a trend towards a higher myo-inositol/creatine during the manic phase. These preliminary data provide evidence that a significant reduction in anterior cingulate myo-inositol magnetic resonance may occur after lithium treatment, especially among responders. Follow-up studies involving a larger sample may allow us to confirm whether changes in myo-inositol associated with acute lithium therapy persist in long-term clinical response of patients with and without lithium compliance.",2001.0,0,0
230,11190417,Antipsychotic-Induced movement disorders in the elderly: epidemiology and treatment recommendations.,M R Caligiuri; D V Jeste; J P Lacro,"We reviewed the epidemiological aspects of antipsychotic-induced movement disorders as they pertain to older patients. The incidence and prevalence of drug-induced parkinsonism and tardive dyskinesia (TD) are significantly greater in the older patient than in the younger patient whereas akathisia seems to occur evenly across the age spectrum and dystonia is uncommon among older patients. The literature on risk factors associated with treatment-emergent movement disorders is highly variable. Treatment practices vary across the age range and the interaction between age and antipsychotic dosage confounds our understanding of the relative importance of treatment-related risk factors. However, there is general agreement that pre-existing extrapyramidal signs (EPS) increase the vulnerability of the patient to developing significant drug-induced movement disorders. Elderly patients with dementia are at greater risk than patients without dementia for persistent drug-induced EPS. Management of drug-induced movement disorders in the older patient requires careful consideration of the contraindications imposed by such agents as anticholinergics and beta-blockers. At present, well-controlled double-blind studies of second-generation antipsychotics such as clozapine, risperidone. olanzapine or quetiapine for reducing the risk of treatment-emergent movement disorders in the elderly have not been published. However, open-label studies of atypical antipsychotics demonstrate a markedly lower incidence of both EPS and TD compared with conventional antipsychotic treatment in the elderly. There is emerging literature in support of atypical antipsychotics for the treatment of existing drug-induced movement disorders. More controversial is the use of adjunctive antioxidants in newly treated patients who are vulnerable to drug-induced movement disorders. While the evidence is mixed in support of antioxidants for the treatment of TD, the possibility remains that prophylactic use of antioxidants may help reduce the incidence of TD. The development of a drug-induced movement disorder often reduces the quality of life in an elderly patient. Effective pharmacological management requires cooperation from the patient and family, which can be fostered early in the patient's care through proper informed consent. The risks and benefits of antipsychotic treatment in the elderly patient need to be communicated to the patient and family. At the present time, there is no consistently effective treatment for patients with TD once it develops. Therefore, attention should focus on its prevention and close monitoring.",2001.0,0,1
231,11195255,Does risperidone have a place in the treatment of nonschizophrenic patients?,I Schweitzer,"There is a now a substantial body of evidence that suggests the new antipsychotic agent, risperidone, may be safe and effective for treating psychotic, affective or behavioural symptoms associated with various disorders other than schizophrenia, schizophreniform disorder or schizo-affective disorder. These conditions include bipolar disorder, obsessive-compulsive disorder, Tourette's syndrome, dementia, Lewy body disease, mental retardation, Parkinson's disease, idiopathic segmental dystonia and organic catatonia. Although much of the data is anecdotal or in the form of open studies, there is now emerging a small number of well controlled investigations supporting efficacy for mania, dementia, behavioural disturbance in mental retardation and conduct disorder. Conventional antipsychotics have long been used, either in a primary capacity or as an adjunct to treat these disorders; however, they have limited benefit, pose significant risks of extrapyramidal side-effects, and may cause the potentially life-threatening neuroleptic malignant syndrome. In contrast, risperidone at the recommended low doses may be efficacious and pose reduced risk of motor side-effects. This article reviews the evidence that risperidone may be an effective new treatment for disorders other than schizophrenia.",2001.0,0,0
232,11198061,Refractory schizophrenia and atypical antipsychotics.,D M Taylor; D Duncan-McConnell,"Treatment resistant or refractory schizophrenia is a difficult to define condition of largely unknown prevalence. For 10 years, clozapine has been the standard treatment in this condition and is recognized unequivocally as being effective. However, clozapine is sometimes poorly tolerated and has the potential for severe toxicity. Partly as a result of this, other atypicals have recently been evaluated as treatments for refractory schizophrenia. In order to evaluate the evidence base relating to the drug treatment of refractory schizophrenia, we developed a refractoriness rating based on previous work. Using this rating, we assessed all trials of atypicals in schizophrenia unresponsive to at least one drug. Overall, clozapine was consistently shown to be effective in refractory schizophrenia, even when stringently defined. Data relating to olanzapine and risperidone are equivocal at best, and there is some evidence to suggest that they are less effective than clozapine. There is essentially no cogent evidence to support the use of any other atypical in refractory schizophrenia. Clozapine remains the drug of choice in this condition.",2001.0,1,1
233,11199942,Olanzapine plasma concentrations and clinical response: acute phase results of the North American Olanzapine Trial.,P J Perry; B C Lund; T Sanger; C Beasley,"Olanzapine is an atypical antipsychotic that is effective in the treatment of schizophrenia. Olanzapine plasma concentrations > or = 9.3 ng/mL (24 hours postdose) have been identified as a predictor of clinical response in acutely ill patients with schizophrenia. The authors report a receiver operating characteristic (ROC) curve analysis of 12-hour olanzapine concentrations and treatment response from the North American Double-Blind Olanzapine Trial. After a 4- to 7-day placebo lead-in, patients meeting DSM-III-R criteria for schizophrenia were randomly assigned to receive olanzapine, haloperidol, or placebo. Patients who were randomly assigned to receive olanzapine were given daily doses ranging from 2.5 to 17.5 mg/day for up to 6 weeks. Blood samples for the determination of olanzapine plasma concentrations were obtained between 10 and 16 hours (11.7 +/- 1.7 hours) after the last dose was administered. Therapeutic response data and olanzapine concentrations used for analysis were obtained from the endpoint visit for each patient if the patient had been receiving a fixed olanzapine dose for at least the last 2 weeks of the study. Plasma concentrations from previous visits were used if endpoint concentrations were invalid. Response was defined as a > or = 20% reduction in Brief Psychiatric Rating Scale (BPRS) scores and a Clinical Global Impression (CGI) Severity scale score of < or = 3 or a final BPRS score of < or = 35. The final ROC analysis included data from 84 patients and suggested an olanzapine concentration > or = 23.2 ng/mL to be a predictor of therapeutic response. Fifty-two percent of patients with 12-hour olanzapine concentrations > or = 23.2 ng/mL responded, whereas only 25% of patients with concentrations < 23.2 ng/mL responded. Furthermore, an olanzapine concentration > or = 23.2 ng/mL was a predictor of response in the Scale for the Assessment of Negative Symptoms (> or = 20% decrease and endpoint CGI < or = 3). Olanzapine concentrations were found to be a function of olanzapine dose (in milligrams per day) and gender such that prospective olanzapine dosing is feasible. A 12-hour olanzapine plasma concentration of > 23.2 ng/mL was a predictor of therapeutic response in acutely ill patients with schizophrenia. Males required a higher olanzapine dose to reach this threshold concentration than their female counterparts.",2001.0,0,0
234,11199944,"Ziprasidone in the short-term treatment of patients with schizoaffective disorder: results from two double- blind, placebo-controlled, multicenter studies.",P E Keck; K R Reeves; E P Harrigan; Ziprasidone Study Group,"This study assessed the efficacy of ziprasidone for the treatment of schizoaffective disorder. Data were taken from subsets of patients with schizoaffective disorder, derived from two separate double-blind, placebo-controlled, parallel-group, multicenter studies. A total of 115 hospitalized patients with an acute episode of schizoaffective disorder were randomly assigned to receive either fixed oral doses of ziprasidone 40 mg/day (N = 16), 80 mg/day (N = 18), 120 mg/day (N = 22), 160 mg/day (N = 25), or placebo (N = 34) for 4 to 6 weeks. Mean baseline-to-endpoint changes in Brief Psychiatric Rating Scale (BPRS) total, BPRS Core, Clinical Global Impressions Severity scale (CGI-S), BPRS Depressive, BPRS Manic, and Montgomery-Asberg Depression Rating Scale total scores were compared between the placebo and ziprasidone groups. Neurological (Simpson-Angus, Barnes Akathisia, Abnormal Involuntary Movement Scale [AIMS]) and other side effects were also assessed. Significant dose-related improvements on all primary efficacy variables (BPRS total, BPRS Core, CGI-S) and for BPRS Manic items were observed with ziprasidone treatment in a combined analysis of data from both studies (p < or = 0.01). Ziprasidone 160 mg/day was significantly more effective than placebo in improving mean BPRS total, BPRS Core, BPRS Manic, and CGI-S scores (p < 0.05). At 120 mg/day, ziprasidone was significantly more effective than placebo in improving mean CGI-S scores (p < 0.05). The incidence of individual adverse events was generally low in all treatment groups and was not dose-related. In addition, no significant differences were observed between baseline-to-endpoint mean changes in Simpson-Angus and AIMS scores with placebo or ziprasidone 40 to 160 mg/day. These results suggest that ziprasidone may have efficacy in the treatment of affective as well as psychotic symptoms of schizoaffective disorder, with a low side-effect burden.",2001.0,0,0
235,11199953,"Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine.",M W Agelink; T Majewski; C Wurthmann; K Lukas; H Ullrich; T Linka; E Klieser,"As part of a prospective clinical study investigating the effects of atypical neuroleptics on autonomic neurocardiac function (ANF), serial standardized recordings of conventional electrocardiograms and computer-calculated measurements of 5-minute resting heart rate variability (HRV) were obtained from 51 medication-free inpatients with schizophrenia (DSM-III-R-diagnosed) before and after an average of 14.1 days of treatment with amisulpride 400 mg/day (N = 12), olanzapine 20 mg/day (N = 13), sertindole 12 mg/day (N = 13), or clozapine 100 mg/day (N = 13). Reference values for the HRV data were obtained from a large group of well-matched healthy controls (N = 70). The most important findings were the following: (1) clozapine, olanzapine, and sertindole all prolonged mean frequency-corrected QTc times, which, in the case of sertindole, proved to be significant (Wilcoxon test p <0.05); (2) sertindole and clozapine significantly increased the mean resting heart rate; and (3) only clozapine significantly reduced the parasympathetic resting tone. The results of the HRV studies are discussed considering the in vitro receptor profiles of the atypical neuroleptics under study. Potential implications for the cardiac safety and tolerance of these drugs are also discussed.",2001.0,0,0
236,11199955,The effects of concomitant phenytoin administration on the steady-state pharmacokinetics of quetiapine.,Y W Wong; C Yeh; P T Thyrum,"Quetiapine fumarate ('Seroquel') is a newly introduced atypical antipsychotic with demonstrated efficacy in the treatment of positive and negative symptoms of schizophrenia. It is extensively metabolized, predominantly by cytochrome P450 3A4. Therefore, concurrent administration of drugs that induce or inhibit this enzyme may affect quetiapine pharmacokinetics. This study demonstrated that the potent cytochrome P450 enzyme-inducer phenytoin did indeed have a marked effect on the metabolism of quetiapine, resulting in a 5-fold increase in clearance when administered concomitantly to patients with DSM-IV-diagnosed schizophrenia, schizoaffective disorder, or bipolar disorder. These results indicate that dosage adjustment of quetiapine may be necessary when the two drugs are given concurrently and that caution may be required when administering other drugs that inhibit or induce cytochromes, particularly P450 3A4.",2001.0,0,1
237,11200962,Acute tryptophan depletion in schizophrenia.,K L Golightly; J A Lloyd; J E Hobson; P Gallagher; G Mercer; A H Young,"Brain 5-hydroxytryptamine (5-HT) function is implicated in the pathophysiology of schizophrenia and the action of new generation antipsychotic drugs. By the method of acute tryptophan depletion (ATD) 5-HT can be selectively manipulated. The aim of this study was to examine the effects of ATD on symptoms, mood and cognition in schizophrenic patients. Twenty-eight schizophrenic patients participated in a within subject, double-blind, placebo-controlled counterbalanced cross-over study. Patients with a concurrent DSM-IV axis I diagnosis were excluded. Symptoms, mood and cognitive function were evaluated following ATD or ingestion of a control drink. The depleting drink significantly reduced plasma total and free tryptophan. Tryptophan/LNAA ratios did not alter with the administration of the control drink, but differed significantly with ATD; however there was no significant change in tyrosine/LNAA ratio. ATD led to impairment in executive function that was dependent upon the order of administration. Tests of sustained attention, speed of processing, and everyday memory were not affected. No effects were observed on subjective mood ratings, movement disorders or PANSS scores. Acute tryptophan depletion selectively alters cognition in schizophrenia, but has no effect on symptoms, mood ratings or movement disorders.",2001.0,0,0
238,11205425,Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia.,E Spina; A Avenoso; G Facciolà; M Salemi; M G Scordo; M Ancione; A G Madia; E Perucca,"Evaluation of relationships between serum antipsychotic drug concentrations and clinical response may provide valuable information for rational dosage adjustments. For risperidone, this relationship has been little investigated to date. To assess the relationship between plasma concentrations of risperidone and its active 9-hydroxy-metabolite (9-OH-risperidone) and clinical response in schizophrenic patients who experienced an acute exacerbation of the disorder. Forty-two patients (30 males, 12 females, age 24-60 years) were given risperidone at dosages ranging from 4 to 9 mg/day for 6 weeks. The design of the study was open and risperidone dosage could be adjusted individually according to clinical response. Steady-state plasma concentrations of risperidone and its 9-hydroxymetabolite were measured after 4 and 6 weeks using a specific HPLC assay. Psychopathological state was assessed at baseline and at weeks 2, 4, and 6 by means of the positive and negative syndrome scale (PANSS), and patients were considered responders if they showed a greater than 20% reduction in total PANSS score at final evaluation compared with baseline. Mean plasma concentrations of risperidone, 9-OH-risperidone, and active moiety (sum of risperidone and 9-OH-risperidone concentrations) did not differ between responders (n = 28) and non-responders (n = 14). No correlation between plasma levels and percent decrease in total PANSS score was found for risperidone (rs = -0.187, NS), 9-OH-risperidone (rs = 0.246, NS), and active moiety (rs = 0.249, NS). Active moiety concentrations in plasma were higher (P < 0.001) in patients developing clinically significant parkinsonian symptoms (n = 7) than in those with minimal (n = 7) or no drug-induced parkinsonism (n = 28). In chronic schizophrenic patients experiencing an acute exacerbation of the disorder, plasma levels of risperidone and its active metabolite correlate with the occurrence of parkinsonian side effects, whereas no significant correlation appears to exist with the degree of clinical improvement.",2001.0,0,0
239,11206599,Intramuscular ziprasidone compared with intramuscular haloperidol in the treatment of acute psychosis. Ziprasidone I.M. Study Group.,S Brook; J V Lucey; K P Gunn,"This 7-day, randomized, open-label, multicenter, international study compared the efficacy and tolerability of intramuscular (i.m.) ziprasidone with haloperidol i.m. and the transition from i.m. to oral treatment in hospitalized patients with acute psychotic agitation (related to DSM-III-R diagnoses). Patients received up to 3 days of flexible-dose ziprasidone i.m. (N = 90) or haloperidol i.m. (N = 42) followed by oral treatment to day 7. After an initial ziprasidone i.m. dose of 10 mg, subsequent i.m. doses of 5 to 20 mg could be given every 4 to 6 hours (maximum daily dose = 80 mg) if needed, followed by oral ziprasidone, 80-200 mg/day. Haloperidol i.m. doses of 2.5 to 10 mg were given on entry, followed by 2.5 to 10 mg i.m. every 4 to 6 hours (maximum daily dose = 40 mg) if needed, then by oral haloperidol, 10-80 mg/day. The mean reductions in Brief Psychiatric Rating Scale (BPRS) total, BPRS agitation items, and Clinical Global Impressions-Severity scale scores were statistically significantly greater (p < .05, p < .01, and p < .01, respectively) after ziprasidone i.m. treatment compared with haloperidol i.m. treatment. Further reductions in these scores also occurred in both groups following transition to oral treatment. Ziprasidone was associated with a lower incidence of movement disorders and a reduced requirement for anticholinergic medication during both i.m. and oral treatment compared with haloperidol. Movement disorder scale scores improved with ziprasidone i.m. and oral treatment, but deteriorated with haloperidol. Other adverse events were rare with both treatments. Ziprasidone i.m. was significantly more effective in reducing the symptoms of acute psychosis and was better tolerated than haloperidol i.m., particularly in movement disorders. The transition from ziprasidone i.m. to oral ziprasidone was effective and well tolerated.",2001.0,0,0
240,11215574,Clozapine for the treatment of drug-induced psychosis in Parkinson's disease: results of the 12 week open label extension in the PSYCLOPS trial.,S A Factor; J H Friedman; M C Lannon; D Oakes; K Bourgeois; Parkinson Study Group,"To report the results of the 12-week, prospective, open label extension of the 4-week, multicenter, placebo-controlled, double-blind PSYCLOPS (PSYchosis and CLOzapine in the treatment of Parkinsonism) trial. This extension examined the chronic safety and efficacy of clozapine in the treatment of drug-induced psychosis in Parkinson's disease (PD). Psychosis is a serious late complication of PD and may be a harbinger to increased mortality. Clozapine, the first atypical antipsychotic, was shown in several small open label studies to improve psychosis without worsening of motor symptoms. This was recently confirmed in the double-blind PSYCLOPS trial. The 53 patients who completed the double-blind portion of PSYCLOPS were evaluated on their original randomized treatment (clozapine or placebo), then had study medication stopped. All were started on clozapine. The patients from both treatment groups were evaluated every 4 weeks over a 12-week period using standardized measures for psychosis and PD. The mean dose of clozapine was 28.78 mg/day. Those originally treated with placebo improved significantly in Brief Psychiatric Rating Scale and clinical global scores for psychosis to the same degree as the group originally randomized to clozapine in the double-blind study. Both groups maintained their response to week 16 (end of the combined double-blind and open label portions). There was no worsening of motor features as measured by the Unified Parkinson's disease rating scale. Eighteen patients were either hospitalized or died during the trial. The most common reasons were pulmonary. Low-dose clozapine is effective in treating drug-induced psychosis without worsening motor features of PD, and the response is maintained for at least 4 months. Patients with psychosis and PD were previously described as a group with high risk for morbidity and mortality. The high risk continues despite antipsychotic therapy.",2001.0,0,1
241,11217867,Olanzapine: an updated review of its use in the management of schizophrenia.,N Bhana; R H Foster; R Olney; G L Plosker,"Olanzapine, a thienobenzodiazepine derivative, is a second generation (atypical) antipsychotic agent which has proven efficacy against the positive and negative symptoms of schizophrenia. Compared with conventional antipsychotics, it has greater affinity for serotonin 5-HT2A than for dopamine D2 receptors. In large, well controlled trials in patients with schizophrenia or related psychoses, olanzapine 5 to 20 mg/day was significantly superior to haloperidol 5 to 20 mg/day in overall improvements in psychopathology rating scales and in the treatment of depressive and negative symptoms, and was comparable in effects on positive psychotic symptoms. The 1-year risk of relapse (rehospitalisation) was significantly lower with olanzapine than with haloperidol treatment. In the first double-blind comparative study (28-week) of olanzapine and risperidone, olanzapine 10 to 20 mg/day proved to be significantly more effective than risperidone 4 to 12 mg/day in the treatment of negative and depressive symptoms but not on overall psychopathology symptoms. In contrast, preliminary results from an 8-week controlled study suggested risperidone 2 to 6 mg/day was superior to olanzapine 5 to 20 mg/day against positive and anxiety/depressive symptoms (p < 0.05), although consistent with the first study, both agents demonstrated similar efficacy on measures of overall psychopathology. Improvements in general cognitive function seen with olanzapine treatment in a 1-year controlled study of patients with early-phase schizophrenia, were significantly greater than changes seen with either risperidone or haloperidol. However, preliminary results from an 8-week trial showed comparable cognitive enhancing effects of olanzapine and risperidone treatment in patients with schizophrenia or schizoaffective disorder. Several studies indicate that olanzapine has benefits against symptoms of aggression and agitation, while other studies strongly support the effectiveness of olanzapine in the treatment of depressive symptomatology. Olanzapine is associated with significantly fewer extrapyramidal symptoms than haloperidol and risperidone. In addition, olanzapine is not associated with a risk of agranulocytosis as seen with clozapine or clinically significant hyperprolactinaemia as seen with risperidone or prolongation of the QT interval. The most common adverse effects reported with olanzapine are bodyweight gain, somnolence, dizziness, anticholinergic effects (constipation and dry mouth) and transient asymptomatic liver enzyme elevations. In comparison with haloperidol, the adverse events reported significantly more frequently with olanzapine in > or = 3.5% of patients were dry mouth, bodyweight gain and increased appetite and compared with risperidone, only bodyweight gain occurred significantly more frequently with olanzapine. The high acquisition cost of olanzapine is offset by reductions in other treatment costs (inpatient and/or outpatient services) of schizophrenia. Pharmacoeconomic analyses indicate that olanzapine does not significantly increase, and may even decrease, the overall direct treatment costs of schizophrenia, compared with haloperidol. Compared with risperidone, olanzapine has also been reported to decrease overall treatment costs, despite the several-fold higher daily acquisition cost of the drug. Olanzapine treatment improves quality of life in patients with schizophrenia and related psychoses to a greater extent than haloperidol, and to broadly the same extent as risperidone. Olanzapine demonstrated superior antipsychotic efficacy compared with haloperidol in the treatment of acute phase schizophrenia, and in the treatment of some patients with first-episode or treatment-resistant schizophrenia. The reduced risk of adverse events and therapeutic superiority compared with haloperidol and risperidone in the treatment of negative and depressive symptoms support the choice of olanzapine as a first-line option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.",2001.0,0,1
242,11219487,Bodyweight gain with atypical antipsychotics. A comparative review.,T Wetterling,"The atypical antipsychotics have been shown to have superior efficacy compared with typical antipsychotics such as haloperidol, particularly in the treatment of negative symptoms of schizophrenia. Furthermore, they induce less extrapyramidal effects. However, following clinical use, marked bodyweight gain has been frequently observed with some of the atypical antipsychotic drugs. In order to examine and compare the frequency, amount and conditions of bodyweight gain during treatment with atypical antipsychotics, studies concerning bodyweight gain with these agents were identified through a MEDLINE search from 1966 to March 2000. Although comparison is limited by the different designs and recruitment procedures of the reviewed studies, the available data support the notion that the frequency as well as the amount of bodyweight gain is high in patients treated with olanzapine (average bodyweight gain 2.3 kg/month), clozapine (1.7 kg/month), quetiapine (1.8 kg/month), and possibly also zotepine (2.3 kg/month). Moderate changes in bodyweight have been observed in the treatment with risperidone (average bodyweight gain 1.0 kg/month). Ziprasidone seems to induce only slight bodyweight changes (0.8 kg/month). Bodyweight gain most frequently occurs in the first 12 weeks of treatment. Patients who were underweight at the beginning of treatment are at highest risk of gaining bodyweight. The underlying pathomechanism still remains largely unclear. The relative receptor affinities of the atypical antipsychotics for histamine H1 receptors as well as the ratio of their affinity for serotonin 5-HT2 and dopamine D2 receptors appear to be the most robust correlate of bodyweight gain. Furthermore, the induction of leptin secretion may have an important impact on bodyweight gain in patients treated with atypical antipsychotics. Although many questions concerning the pathogenesis of bodyweight gain remain unresolved, this adverse effect has to be taken into consideration when prescribing the atypical antipsychotics, particularly in view its affect on compliance during long term treatment and the long term effects of obesity on mortality and morbidity.",2001.0,0,1
243,11227395,Olanzapine versus risperidone. A prospective comparison of clinical and economic outcomes in schizophrenia.,E T Edgell; S W Andersen; B M Johnstone; B Dulisse; D Revicki; A Breier,"To compare the clinical and economic outcomes associated with olanzapine and risperidone treatment for schizophrenia. An international, multicentre, double-blind, prospective study. To facilitate economic comparisons, our sample was restricted to patients enrolled in US sites. 150 patients with a Diagnostic and Statistical Manual of mental disorders, 4th edition (DSM-IV) diagnosis of schizophrenia, schizoaffective disorder or schizophreniform disorder were randomised to therapy with either olanzapine 10 to 20 mg/day (n = 75) or risperidone 4 to 12 mg/day (n = 75) for a maximum of 28 weeks. In addition to tolerability and efficacy assessments, use of health services was assessed at baseline and prospectively, at 8-week intervals and at study completion. Clinically important response, defined as a 40% improvement in the Positive and Negative Syndrome Scale total score, maintenance of response and rates of treatment-emergent extrapyramidal symptoms were compared between groups. Direct medical costs were estimated by assigning standardised prices to resource units. Median total, inpatient/outpatient service and medication acquisition costs were compared between treatment groups. The mean modal dosages for the olanzapine and risperidone treatment groups were 17.7 +/- 3.4 mg/day and 7.9 +/- 3.2 mg/day, respectively. Olanzapine-treated patients were more likely to maintain response compared with risperidone-treated patients (p = 0.048). In addition, a smaller proportion of olanzapine-treated patients required anticholinergic therapy compared with risperidone-treated patients (25.3 vs 45.3%; p = 0.016). Total per patient medical costs over the study interval were $US2843 (1997 values) [36%] lower in the olanzapine treatment group than in the risperidone treatment group (p = 0.342). Medication costs were significantly higher for olanzapine-treated patients ($US2513 vs $US1581; p < 0.001), but this difference was offset by a reduction of $US3774 (52%) in inpatient/outpatient service costs for olanzapine-treated patients in comparison with risperidone-treated patients ($US3516 vs $US7291, p = 0.083). Median cost findings were consistent with results observed using other robust measures of central tendency and provide conservative estimates of potential savings that may be obtained from olanzapine therapy. In this study, olanzapine-treated patients experienced clinical improvements that translated into savings in costs of care for both inpatient and outpatient services. These savings offset the difference in medication acquisition cost between olanzapine and risperidone.",2001.0,1,1
244,11236069,Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study.,N Caspi; I Modai; P Barak; A Waisbourd; H Zbarsky; S Hirschmann; M Ritsner,"Treatment of aggression in schizophrenic patients is a major challenge. We sought to examine the efficacy of augmentation of antipsychotic treatment with pindolol in the amelioration of aggression. Thirty male inpatients meeting DSM-IV criteria for schizophrenia, aged 20-65 years involved in four or more aggressive incidents in the two previous months, were enrolled in a double-blind crossover study. Aggression was evaluated per incident, with the Overt Aggression Scale (OAS). Positive and Negative Syndrome Scale (PANSS) was administered at baseline, crossover and at endpoint. Patients received either pindolol or placebo augmentation 5 mg x three times a day until crossover, then switched. No significant differences were found in the PANSS scores between the placebo and pindolol treatments. OAS scores were significantly reduced for number of aggressive incidents towards objects and other persons during pindolol treatment (0.59 versus 1.46, F = 6.09, P < 0.02; 1.96 versus 3.23, F = 4.17, P < 0.05, respectively). Similar results were obtained for severity of incidents (0.89 versus 3.58, F = 19.42, P < 0.0001; 2.89 versus 6.85, F = 10.11, P < 0.004, respectively). Pindolol, with its dual beta and 5-HT1A blocking effect ameliorated both number and severity of aggressive acts. Influence on severity may be associated with a 5-HT1A antagonistic effect.",2001.0,0,0
245,11241729,Tolerability and effectiveness of atypical antipsychotics in male geriatric inpatients.,S Verma; C A Orengo; M E Kunik; D Hale; V A Molinari,"The atypical antipsychotics are gradually becoming the mainstay of treatment for psychosis in the elderly. The present study examines the effectiveness and tolerability of risperidone and olanzapine treatment in 34 matched male patients admitted to a VA Medical Center geriatric inpatient unit. The Positive and Negative Syndrome Scale for Schizophrenia (PANSS), the Cohen-Mansfield Agitation Inventory (CMAI), the Rating Scale for Side-Effects, the Extra-Pyramidal Rating Scale, and the Mini-Mental State Examination were administered at admission and discharge. T-tests at admission and discharge across groups indicate that the patients as a whole were performing significantly better following their stay on the CMAI (t(30)=4.31, p=0.000), the GAF (t(31)=9.73, p=0.000), the PANSS total score (t(29)=3.82, p=0.001), and the positive symptom portion of the PANSS (t(28)=4.29, p=0.000). No significant differences were detected between the two groups with regard to length of hospitalization, or reduction in scores on the PANSS, or CMAI, however the daily cost of risperidone was 1/3 as much as olanzapine (p=0.00). The two treatments were comparable in the elderly men evaluated in this study.",2001.0,0,0
246,11246103,Adjunctive gabapentin in treatment-resistant depression: a retrospective chart review.,S Yasmin; L L Carpenter; Z Leon; J M Siniscalchi; L H Price,"Previous studies in predominantly bipolar patients have suggested that gabapentin may be useful in treating mood disorders. This report describes its efficacy and tolerability as an adjunctive agent in treatment-resistant depression. A chart review was conducted on 27 outpatients presenting with a depressive disorder in whom gabapentin was added to ongoing treatment with a conventional antidepressant to which patients had not responded after at least 6 weeks. The majority of patients had either prominent anxiety or a history of soft bipolar features, but patients with bipolar I disorder were excluded. Clinical state and adverse effects were assessed retrospectively at each visit. Mean gabapentin trial duration was 15.2+/-7.8 weeks, with a mean final dose of 904+/-445 mg/day (range, 300-1800 mg/day). Clinician-rated measures of clinical state improved significantly from baseline to endpoint. Overall, 37.0% (n=10) of patients were responders at endpoint; another 18.5% (n=5) manifested a transient response not sustained to endpoint. Gabapentin was well tolerated; the most common adverse effects were fatigue, sedation, dizziness, and gastrointestinal symptoms. Treatment was uncontrolled and efficacy assessments were retrospective. These findings suggest that gabapentin may be of adjunctive benefit in the management of treatment-resistant depression.",2001.0,0,0
247,11247108,Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia.,B J Kinon; B R Basson; J A Gilmore; G D Tollefson,"Weight change and the weight-related health factors of nonfasting serum glucose, serum cholesterol, and diastolic blood pressure levels were analyzed in patients with DSM-III-R schizophrenia and related disorders who received treatment with olanzapine for up to 3 years, and comparisons were made to patients treated with haloperidol. Baseline body mass index (BBMI; kg/m2) and dose (mg/day) were investigated as predictors of long-term weight change experienced during olanzapine treatment. This analysis retrospectively examined 573 patients receiving olanzapine and 103 patients receiving haloperidol for 39 weeks or more from a study of 1,996 patients randomly assigned 2:1 to either olanzapine, 5 to 20 mg/day, or haloperidol, 5 to 20 mg/day. After 6 weeks of acute therapy, patients continued for 1 year or more with either double-blind or open-label olanzapine therapy or double-blind haloperidol therapy. Mean weight gain for olanzapine-treated patients observed for a median of 2.54 years trended toward a plateau after the first 39 weeks of treatment with a last-observation-carried-forward mean weight change of 6.26 kg (13.8 lb) and a median of 5.90 kg (13.0 lb). This was significantly higher than that for haloperidol-treated patients, whose mean weight gain was 0.69 kg (1.5 lb) after 1.15 years (p < .001). Patients with higher BBMI (> 27.6) gained significantly less weight during treatment with olanzapine than their lighter counterparts (BBMI < 27.6) (p < .001). The effect of olanzapine dose on weight was not significant (p > or = . 183). Median serum glucose at endpoint was not significantly associated (p = .096) with weight change for olanzapine. Median serum cholesterol and diastolic blood pressure for olanzapine-treated patients at endpoint showed a relationship with weight change that was statistically (p < or = .001) but not clinically significant. The difference in incidence of elevated serum glucose, cholesterol, or diastolic blood pressure between olanzapine and haloperidol therapy groups was not different (p > .05). Mean weight gain during olanzapine treatment trended toward a plateau after the initial 39 weeks of treatment with no further significant gain out to 3 years. Higher BBMI was predictive of a lower long-term weight gain, while dose was not a significant predictor of greater longer term weight change. The relationship between weight change and glucose was not statistically significant. The association between weight change and changes in cholesterol as well as changes in diastolic blood pressure was statistically significant but not considered clinically relevant based on the ranges observed.",2001.0,1,1
248,11249546,The new atypical antipsychotics: a review of pharmacoeconomic studies.,D A Revicki,"The pharmacoeconomic evaluation of atypical antipsychotics for the treatment of schizophrenia involves documentation of clinical effectiveness, quality of life and medical cost outcomes. The findings of pharmacoeconomic studies assist psychiatrists and mental healthcare decision-makers in identifying therapies that provide the greatest benefit to patients at the most acceptable cost. The cost-effectiveness of the newer atypical antipsychotics has been examined using non-controlled cohort studies (either retrospective or prospective), modelling studies or randomised clinical trials. The evidence, from a variety of studies, indicates that clozapine is a cost-effective treatment for neuroleptic refractory schizophrenia. Risperidone and olanzapine may be cost neutral, or at best slightly cost saving, compared with conventional antipsychotics, although they do improve patient clinical effectiveness and quality of life outcomes. There is too little data on pharmacoeconomic outcomes for sertindole and quetiapine to make any conclusions about their cost-effectiveness in treating schizophrenia.",2001.0,0,0
249,11252622,The evaluation of multiple surrogate endpoints.,J Xu; S L Zeger,"Surrogate endpoints are desirable because they typically result in smaller, faster efficacy studies compared with the ones using the clinical endpoints. Research on surrogate endpoints has received substantial attention lately, but most investigations have focused on the validity of using a single biomarker as a surrogate. Our paper studies whether the use of multiple markers can improve inferences about a treatment's effects on a clinical endpoint. We propose a joint model for a time to clinical event and for repeated measures over time on multiple biomarkers that are potential surrogates. This model extends the formulation of Xu and Zeger (2001, in press) and Fawcett and Thomas (1996, Statistics in Medicine 15, 1663-1685). We propose two complementary measures of the relative benefit of multiple surrogates as opposed to a single one. Markov chain Monte Carlo is implemented to estimate model parameters. The methodology is illustrated with an analysis of data from a schizophrenia clinical trial.",2001.0,0,0
250,11252646,Response to placebo among bipolar I disorder patients experiencing their first manic episode.,K N Chengappa; M Tohen; J Levine; T Jacobs; M E Thase; T M Sanger; D J Kupfer,"The first episode of an illness may respond differently to any treatment compared to multiple episodes of the same illness. This study details the treatment response of six first-episode manic patients who participated in a previously reported study of 139 subjects comparing olanzapine to placebo in bipolar I mania (Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KNR, Daniel DG. Olanzapine versus placebo in the treatment of acute mania. Am J Psychiatry 1999; 156: 702-709). Six first-episode subjects participated in a 3-week double-blind, random assignment, parallel group, placebo-controlled study of olanzapine for bipolar mania. The Young Mania Rating Scale (Y-MRS), Clinical Global Impression, and Hamilton Depression ratings were administered weekly. Lorazepam as rescue medication was permitted for the first 10 days. Five subjects were randomized to placebo and one to olanzapine. Two subjects (40%) with psychotic mania (who also had their first-illness episode) were assigned to placebo and responded with greater than 50% reduction in the Y-MRS score and also remitted in 3 weeks. Another placebo-assigned subject had a 46% reduction in the Y-MRS scores, and two placebo-assigned subjects worsened. The olanzapine-assigned subject had a 44% reduction in the Y-MRS score. In contrast, 34 of 69 (48.6%) multiple-episode olanzapine subjects responded and 14 of 61 (23.0%) of placebo-treated subjects did. This preliminary data set suggest there may be differences in treatment response between first-illness episode versus multi-episode bipolar manic subjects. Larger numbers of subjects with these illness characteristics are needed to either confirm or refute this suggestion.",2001.0,1,1
251,11254019,Pharmacologic loading in the treatment of acute mania.,P E Keck; S L McElroy; J A Bennett,"The rapid and safe reduction of manic symptoms is an important initial goal of the pharmacologic treatment of acute mania. The pharmacokinetics and studies of pharmacologic loading of lithium, valproate, and carbamazepine were reviewed. In addition, the feasibility of administering other agents with potential efficacy in mania, e.g., atypical antipsychotics and new anticonvulsants, was discussed. Further double-blind, controlled studies with adequate sample sizes comparing loading strategies with more gradual titration schedules of candidate antimanic agents are needed.",2001.0,0,0
252,11266405,Neuroleptic treatment of late-life schizophrenia.,C Salzman; L Tune,"There is a paucity of studies on the use of neuroleptic medication for treatment of the core symptoms of schizophrenia in elderly patients. The studies that are available have significant methodologic problems, including the mixing of early- and late-onset patients, inadequate outcome criteria, and the lack of control groups. Studies of conventional neuroleptics suggest that older patients have a moderate therapeutic response but are likely to develop side effects. The few studies of atypical antipsychotics now available suggest efficacy for treatment of behavioral disturbance in the elderly and a more favorable side-effect profile. The usefulness of all neuroleptics for the treatment of the core symptoms of late-life schizophrenia may depend on the duration and severity of the symptoms, with a poor response associated with greater severity and duration. It appears that patients with later-onset symptoms may respond better to all neuroleptics.",2001.0,0,0
253,11278146,Antipsychotic prescription use and costs for persons with schizophrenia in the 1990s: current trends and five year time series forecasts.,B C Martin; L S Miller; J A Kotzan,"Real advances in schizophrenia pharmacotherapy have been made over this decade with the development of more efficacious treatment options with fewer side-effects. These advances have high per-unit direct costs that may have a profound effect on drug budgets of systems caring for persons with schizophrenia. The objective of this study was to describe the changes in utilization and cost for antipsychotic prescriptions by atypical, clozapine, decanoate products, and traditional neuroleptics in a large naturalistic setting, i.e. the Georgia Medicaid population. Secondly, this study forecasted the categorized antipsychotic prescription utilization through the year 2002. Administrative claims data spanning 1990-1997 for Medicaid eligible persons suffering from schizophrenia in the state of Georgia were supplemented with psychiatric institutional data obtained from the Georgia Department of Human Resources. A total of 16227 Medicaid-eligible recipients had a code indicative of schizophrenia (ICD-9-CM=295.(**)) and were at least 16 years of age at the time of their first diagnosis. The mean recipient prescription use and expenditures were tallied for each month of the study and stratified by prescription category (atypical, clozapine, decanoate, and traditional antipsychotic). ARIMA time series models were identified and estimated using these monthly PMPM utilization and expenditures estimates to forecast 5 years beyond the last month of the study. The total use of antipsychotics increased modestly throughout the study period, and the use of atypicals, clozapine, and decanoate products increased substantially, while a decrease was observed for traditional antipsychotics. In 1995 dollars, antipsychotic expenditures increased from a mean of approximately $10 PMPM in 1990 to $95 projected for the year 2002. This transition from traditional oral antipsychotics to atypicals and decanoate products has a profound effect on drug expenditures for systems paying for the care of persons with schizophrenia. Further studies to determine the value of the transitions of therapy described in this study need to be evaluated using a system-wide- or Medicaid perspective.",2001.0,0,0
254,11278151,Effects of olanzapine and other antipsychotics on cognitive function in chronic schizophrenia: a longitudinal study.,M J Cuesta; V Peralta; A Zarzuela,"This study aimed to determine the effect of olanzapine and other antipsychotic drugs on cognitive functions after 6months of treatment. Baseline, 3month and 6month psychopathological and cognitive evaluations were made. Thirty-eight partially responsive outpatients with DSM-IV chronic schizophrenia diagnosis were included in the study. On the indication of their attending psychiatrists, 21 patients initiated treatment with olanzapine, and 17 remained on their previous treatment with other antipsychotic drugs. Cognitive assessments were blind to medication and psychopathological status. The olanzapine group presented a significantly greater improvement in negative symptomatology and verbal memory than the comparison group in repeated-measures of MANOVAs between baseline, 3month and 6month assessments. These differences remained statistically significant after covarying out gender, treatment with other atypical antipsychotics, biperidene doses and changes in positive and negative symptoms. In order to match previous differences between groups, cognitive baseline scores for each test were introduced as covariates, resulting in a significant improvement for the olanzapine group in negative symptomatology and the interference task of the Stroop test.We then re-analyzed the data, dividing the comparison group into two groups: risperidone-treated patients (n=9) and patients receiving conventional antipsychotic drugs (n=8). Post-hoc analyses between groups were carried out with baseline cognitive assessment as covariate. The olanzapine group improved significantly more than the risperidone group in negative symptomatology and in the interference task of Stroop test. The improvement in the number of categories of the Wisconsin Card Sorting Test was higher in risperidone patients than in those receiving olanzapine or conventional antipsychotic treatment. Conventional antipsychotic drugs did not present a significant improvement over atypical antipsychotic drugs in any cognitive function. In summary, in patients suffering from chronic schizophrenia, atypical antipsychotic agents were associated with slight differential improvements over time in attentional, verbal memory and executive functions compared with conventional neuroleptic drugs. No differential improvements were found in social functioning, verbal fluency, non-verbal domains of memory or visuo-motor abilities.",2001.0,1,1
255,11278160,Estrogen - a potential treatment for schizophrenia.,J Kulkarni; A Riedel; A R de Castella; P B Fitzgerald; T J Rolfe; J Taffe; H Burger,"Estrogen has been shown in animal studies to modulate both the dopamine and serotonin neurotransmitter systems - the main neurotransmitters implicated in the pathogenesis of schizophrenia. A double blind, 28 day, placebo-controlled study was conducted with three groups of women of child-bearing age (N=12 in each group) who received standardized antipsychotic medication plus 50mcg transdermal estradiol or 100mcg transdermal estradiol or transdermal placebo. Analyses show that women receiving 100mcg of estradiol made greater improvements in the symptoms of schizophrenia than both the 50mcg estradiol and placebo groups. Women receiving 50mcg estradiol had more improvement in their symptoms compared with the placebo group. The 100mcg estradiol group had significantly lower mean lutenizing hormone (LH) and higher mean prolactin levels across the study period compared with both the 50mcg and placebo groups. The addition of 100mcg adjunctive transdermal estrogen significantly enhanced the treatment of acute, severe psychotic symptoms in women with schizophrenia. The differential response of adding 50mcg versus 100mcg estradiol on the types of symptom affected may be related to the estrogen effect on LH and prolactin. The positive impact of estrogen treatment on psychotic symptoms by a direct effect on dopamine and serotonin systems or via an indirect prolactin-mediated effect may be very useful in the overall treatment of women with schizophrenia.",2001.0,0,0
256,11282684,Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials.,M Chakos; J Lieberman; E Hoffman; D Bradford; B Sheitman,"The authors conducted a review and meta-analysis of studies that compared the efficacy and tolerability of typical and second-generation antipsychotics for patients with treatment-resistant schizophrenia. A systematic search revealed 12 controlled studies (involving 1,916 independent patients), which were included in the review. For the seven studies that compared clozapine to a typical antipsychotic, a meta-analysis was performed to examine clozapine's effects on overall psychopathology, response rate, extrapyramidal symptoms, and tardive dyskinesia. The meta-analysis confirmed that treatment-resistant schizophrenic patients have more favorable outcomes when treated with clozapine rather than a typical antipsychotic, as reflected by Brief Psychiatric Rating Scale total score, categorical response rate, Scale for the Assessment of Negative Symptoms score, Simpson-Angus Rating Scale score, and compliance rate. Clozapine also conferred benefits on the sickest treatment-resistant schizophrenic patients. Patients treated with olanzapine also had more favorable outcomes with regard to categorical response and compliance rates. In the aggregate, the results of a meta-analysis indicated that clozapine exhibits superiority over typical antipsychotics in terms of both efficacy (as measured by improvement in overall psychopathology) and safety (in terms of reduced extrapyramidal side effects). However, the magnitude of the clozapine treatment effect was not consistently robust. Efficacy data for other second-generation antipsychotics in the treatment of patients with refractory schizophrenia were inconclusive. There is, therefore, a growing need to consider new and different treatment strategies, whether they be adjunctive or monotherapeutic, for schizophrenia that continues to be resistant or only partially responsive to treatment.",2001.0,0,1
257,11282699,An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone.,D J Lang; L C Kopala; R A Vandorpe; Q Rui; G N Smith; V M Goghari; W G Honer,"The basal ganglia may contribute to extrapyramidal movement disorders, affective disturbances, and cognitive deficits in schizophrenia. Basal ganglia volumes are putatively affected by antipsychotic medications. The purpose of this study was to determine the long-term effects of risperidone treatment in a cohort of first-episode patients with schizophrenia. The subjects were 30 patients with first-episode schizophrenia, 12 patients chronically treated with typical antipsychotics, and 23 healthy comparison subjects. They were scanned by magnetic resonance imaging at baseline. The first-episode patients received 1 year of continuous risperidone treatment, after which they and the comparison subjects were rescanned. Caudate, putamen, and globus pallidus volumes were determined from coronal images. The baseline caudate, putamen, and globus pallidus volumes were significantly larger in the chronically treated patients than in the untreated first-episode subjects and comparison subjects. These volumes did not differ between the first-episode patients and healthy comparison subjects. Basal ganglia volumes were unchanged after 1 year of exposure to risperidone in the first-episode subjects. Extrapyramidal movement disorders were present in the majority of chronically treated patients and more than one-third of the never-medicated first-episode patients at baseline. This group of first-episode patients did not exhibit abnormalities of basal ganglia volumes, nor were basal ganglia volumes affected by exposure to risperidone. Movement disorders were observed in both first-episode and chronically treated patients, suggesting effects of both illness and medications.",2001.0,0,0
258,11287404,Short-term inpatient pharmacotherapy of schizophrenia.,D N Osser; R Sigadel,"There is much practice variation in the pharmacotherapy of schizophrenia on short-term acute inpatient units, where the length of stay may be 1 week or less. We surveyed relevant practice guidelines, review articles, and individual studies and developed summary statements regarding evidence-supported procedures for short-term inpatient stabilization. If the patient requires parenteral treatment, the combination of intramuscular haloperidol 2-5 mg and lorazepam has the earliest effect. For initial oral treatment, monotherapy with one of the new ""atypical"" antipsychotics is favored. Some evidence suggests that risperidone may have an earlier onset of action. Olanzapine seems to have a relatively more rapid effect when started at a daily dose of 15 mg, rather than 5 or 10 mg. The role of quetiapine is somewhat unclear. In the event of nonresponse to the initial antipsychotic after 3-7 days, alternatives may include increasing the dose, switching to a different antipsychotic, or adding a mood stabilizer.",2001.0,0,0
259,11291531,Neuropsychological change in patients with schizophrenia after treatment with quetiapine or haloperidol.,S E Purdon; A Malla; A Labelle; W Lit,"To assess the efficacy of quetiapine, a recently introduced second generation antipsychotic medication, in reducing cognitive impairment in patients with schizophrenia. Prospective, randomized, double-blind clinical trial. 25 patients who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, (DSM-IV) criteria for schizophrenia were recruited from 3 Canadian hospitals. After a 48-hour washout period, 25 patients with schizophrenia were randomly assigned to double-blind treatment with quetiapine or haloperidol for 6 months and evaluated with rating scales for psychotic symptoms, mood and extrapyramidal side effects, as well as standardized neuropsychological measures sensitive to 6 cognitive domains: fine motor skill, attention span, verbal reasoning and fluency, visuospatial construction and fluency, executive skills and visuomotor tracking, and immediate recall of verbal and nonverbal materials. The measures were repeated 8 weeks and 6 months after treatment was initiated. Quetiapine improved psychosis and mood without inducing extrapyramidal symptoms. Quetiapine also had beneficial effects on cognitive skills, particularly verbal reasoning and fluency skills and immediate recall, with additional improvements on executive skills and visuomotor tracking and on the average of the 6 cognitive domains with sustained treatment. Patients taking haloperidol showed improvements in general clinical status, but no specific improvements on the positive syndrome, the negative syndrome, depression ratings or cognitive skills. These preliminary results support the potential value of quetiapine for improving cognitive impairment in patients with schizophrenia and emphasize the importance of further research with this promising atypical antipsychotic.",2001.0,1,1
260,11292518,Subjective response to and tolerability of long-term supraphysiological doses of levothyroxine in refractory mood disorders.,M Bauer; S Priebe; A Berghöfer; T Bschor; U Kiesslinger; P C Whybrow,"Although supplementation with supraphysiological doses of levothyroxine (T4) has been an effective treatment for refractory affective disorders in open studies, questions remain as to the tolerability of this treatment. This is the first study to investigate subjective patient response and tolerability to long-term treatment with adjunctive T4. Of 24 patients with refractory affective disorders or schizoaffective disorder who were consecutively included into an open trial with supraphysiological T4, 16 were eligible for this study. Four measures were used to rate tolerability to T4 treatment. Subjective response was graded on a scale ranging from -33 (maximal negative response) to +33 (maximal positive response). Positive and negative effects were assessed on a structured questionnaire. Clinical tolerance was assessed with the clinician-rated Thyroid Symptom List and the self-rated Von Zerssen Complaint Lists. Outcome was assessed with the CGI for prophylactic ratings (CGI-BP). At the time of assessment, patients had been treated with supraphysiological T4 (mean dose 368 microg/d) for a mean of 54 months. The total subjective response score was +25.2. Positive subjective response and observer-rated treatment success were moderately correlated. Ratings on the Thyroid Symptom List indicated an overall favorable side effect profile. General physical and mental symptoms were only slightly higher than in the general population. This was an open, cross-sectional study that only included responders and partial responders to T4 treatment. Subjective response and side-effect tolerability of long-term supraphysiological doses of T4 is favorable in patients with refractory mood and schizoaffective disorders who respond to the intervention.",2001.0,0,0
261,11298253,Adjunctive gabapentin in patients with intellectual disability and bipolar spectrum disorders.,M G Carta; M C Hardoy; I Dessì; M J Hardoy; B Carpiniello,"The aim of the present study was to assess the efficacy of adjunctive gabapentin (GBP) in the treatment of patients with intellectual disability (ID) and bipolar spectrum disorders. Ten affected subjects with demonstrable increases in symptomatology during 'significant' life events which had interfered with or induced the interruption of their rehabilitation programmes were chosen for this study. The meaning of 'significant' was defined for each patient as a frequently repeated life event which had elicited a marked increase in symptoms on at least two occasions. Gabapentin (300-900 mg day-1) was added to the standard therapy. The subjects' psychopathological conditions during the significant life event were assessed by means of standardized tools both before and after adjunctive therapy with GBP. A positive response to therapy was observed, with subsequent improvement of psychopathological conditions, particularly for anxiety and depressive symptoms. The promising results obtained with GBP suggest the need for further trials. Adjunctive GBP may become an alternative treatment approach for patients with ID in whom traditional mood-stabilizing agents have frequent contraindications.",2001.0,0,0
262,11305699,Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation.,G W Currier; G M Simpson,"Although agitation associated with psychosis is a common presentation in the psychiatric emergency service, there is no consensus concerning the best treatment. Standard treatment often consists of intramuscular (i.m.) injection of high-potency neuroleptics, sometimes combined with benzodiazepines. The objective of this study was to determine the relative efficacy, safety, and tolerability of oral risperidone versus intramuscular haloperidol, both in combination with lorazepam, for the emergency treatment of psychotic agitation in patients who are able to accept oral medications. A convenience sample of psychotic patients admitted to a large psychiatric emergency service who required emergency medication for the control of agitation and/or violence was offered risperidone (2 mg liquid concentrate) and oral lorazepam (2 mg) as an alternative to standard care at the institution, haloperidol (5 mg i.m.) and lorazepam (2 mg i.m.). Subjects who refused the oral medications were given the intramuscular treatment as a component of routine care. Thirty patients were enrolled in each treatment group. Although men were significantly more likely to choose oral medication (chi2 = 5.165, p < .023), other demographic characteristics did not differ significantly between the 2 treatment groups. Both groups showed similar improvement in agitation as measured by 5 agitation subscales of the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) scale, and time to sedation. No patients receiving risperidone demonstrated any side effects or adverse events, while 1 patient receiving intramuscular treatment with haloperidol developed acute dystonia. One subject receiving risperidone required subsequent treatment with haloperidol for ongoing agitation. Oral treatment with risperidone and lorazepam appears to be a tolerable and comparable alternative to intramuscular haloperidol and lorazepam for short-term treatment of agitated psychosis in patients who accept oral medications.",2001.0,0,1
263,11305704,A comparison of long-term outcome in first-episode schizophrenia following treatment with risperidone or a typical antipsychotic.,A K Malla; R M Norman; D J Scholten; S Zirul; V Kotteda,"Most reports assessing the efficacy and tolerability of risperidone have involved patients previously treated with typical antipsychotics. Such patients are more likely to have a greater resistance or intolerance to treatment, thus restricting our interpretation of the impact a new treatment might have on the course of schizophrenia and possibly biasing the results. The present study examines the relative effectiveness of risperidone and typical antipsychotics in patients being treated for their first episode of schizophrenia. From a cohort of 126 patients, 2 groups of 19 first-episode DSM-III-R/DSM-IV schizophrenia patients matched for age, gender, length of illness, and length of treatment and treated with either a typical antipsychotic or risperidone for a minimum of 1 year were compared on a number of outcome dimensions during their course of treatment and at follow-up. Treatment allocation was not random, and patients were judged to be compliant with medication. Patients treated with typical antipsychotics were followed up for a statistically nonsignificantly longer time (mean = 2.7 vs. 1.9 years). Six patients (31.6%) from the typical antipsychotic group were admitted to the hospital within the first year following the index admission compared with 1 patient (5.3%) in the risperidone group (admitted at month 14). Patients in the risperidone group showed a statistically significantly lower length of first hospitalization (p < .01), utilization of inpatient beds during the course of treatment (p < .001), and use of anticholinergic medication (p < .05). There were no statistically significant differences in symptom levels, either during the course of treatment or at follow-up; in the use of antidepressant, antianxiety, or mood-stabilizing drugs; or in changes in living circumstances or employment. These findings confirm at least equal long-term efficacy of typical antipsychotics and risperidone, but a possible advantage for risperidone in decreased service utilization and decreased use of anticholinergic drugs.",2001.0,1,1
264,11305706,Analysis of the QTc interval during olanzapine treatment of patients with schizophrenia and related psychosis.,J Czekalla; C M Beasley; M A Dellva; P H Berg; S Grundy,"There may be a temporal association between some antipsychotics and prolongation of the heart-rate-corrected QT interval (QTc) representing a delay in ventricular repolarization. QTc prolongation significantly exceeding normal intra-individual and interindividual variation may increase the risk of ventricular tachydysrhythmias, especially torsade de pointes, and therefore, sudden cardiac death. Electrocardiogram recordings obtained as part of the safety assessment of olanzapine in 4 controlled, randomized clinical trials (N = 2,700) were analyzed. These analyses were conducted to characterize any change in QTc temporally associated with olanzapine, compared with placebo, haloperidol, and risperidone, in acutely psychotic patients (DSM-III-R and DSM-IV) and to characterize variability and temporal course of the QTc in this patient population. Changes from baseline to minimum and maximum QTc were tested for significance, and baseline to acute-phase endpoint change in mean QTc was tested for significance within treatments and for differences between olanzapine and comparators. The possibility of a linear relationship between dose of olanzapine and mean change in QTc, as well as incidence of treatment-emergent prolongation of QTc (change from < 430 msec at baseline to > or =430 msec at endpoint), was tested. The incidence of maximum QTc > or = 450 msec during treatment was approximately equal to the incidence of QTc > or =450 msec at baseline. Results of these analyses suggest that olanzapine, as therapeutically administered to patients with schizophrenia and related psychoses, does not contribute to QTc prolongation resulting in potentially fatal ventricular arrhythmias.",2001.0,0,0
265,11305843,Clinical effects of a randomized switch of patients from clozaril to generic clozapine.,J C Kluznik; N H Walbek; M G Farnsworth; K Melstrom,"Clozapine was discovered in 1959 but withheld from the United States market after several deaths due to agranulocytosis. The medication was approved in the United States in 1989 on a compassionate-use basis and was first marketed in 1990 as Clozaril. In 1999, following approval by the U.S. Food and Drug Administration, Zenith Goldline Pharmaceuticals (ZGP) introduced a generic form of clozapine. After 5 weeks of data collection (phase I), 24 patients were randomly assigned to group A and 21 patients to group B. Patients had DSM-IV diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder with psychosis, or atypical psychosis with mood disorder. In phase II, group A received a mean daily dose of 630 mg of generic clozapine, and group B continued to receive Clozaril at a mean daily dose of 610 mg, each for 8 weeks. In phase III, group A was reassigned to Clozaril, and group B was switched to generic clozapine, each for 8 weeks. At the end of phase III, group B resumed Clozaril. Efficacy was measured with the Clinical Global Impressions-Improvement (CGI-I) scale, the Brief Psychiatric Rating Scale (BPRS), and the Beck Depression Inventory (BDI). Five patients experienced relapse when they were switched from Clozaril to generic clozapine. Eleven patients worsened short of full relapse, 9 while receiving ZGP generic clozapine and 2 while receiving Clozaril. CGI-I scores and BPRS scores favored patients receiving Clozaril significantly. Only BDI scores favored patients receiving generic clozapine significantly. Until more studies have been performed, clinicians and administrators should carefully monitor stable Clozaril-treated patients who are being switched to generic clozapine.",2001.0,0,0
266,11313165,Effect of amantadine on weight gain during olanzapine treatment.,M Floris; J Lejeune; W Deberdt,"Patients treated with olanzapine may gain weight, especially in the first months of therapy. Amantadine (100-300 mg/day) was started in 12 patients having a mean weight gain of 7.3 kg during olanzapine treatment. The patients' weight stabilised and over 3-6 months they lost an average of 3.5 kg. No clinical deterioration occurred and no adverse effects were reported. These observations merit confirmation in randomised, controlled trials.",2001.0,0,0
267,11320158,A double-blind placebo-controlled case study of the use of donepezil to improve cognition in a schizoaffective disorder patient: functional MRI correlates.,S C Risch; S McGurk; M D Horner; Z Nahas; S D Owens; M Molloy; C Gilliard; S Christie; J S Markowitz; C L DeVane; J Mintzer; M S George,"Cognitive impairment in multiple domains is common in patients with schizophrenia and may be a powerful determinant of poor functional ability and quality of life. We report a double-blind, placebo-controlled, cross-over study of donepezil augmentation in a schizoaffective disorder patient stabilized on olanzapine pharmacotherapy. The patient showed significant improvements in several cognitive measures and increased activation of prefrontal cortex and basal ganglia on functional MRI during the donepezil augmentation. In addition, the donepezil augmentation resulted in a reduction of depressive symptoms and in significant improvements in functional abilities and quality of life. Further studies of donepezil augmentation of neuroleptics in schizophrenia are warranted.",2001.0,0,0
268,11324382,,,,,0,0
269,11329400,A randomized double-blind study of risperidone and olanzapine in the treatment of schizophrenia or schizoaffective disorder.,R R Conley; R Mahmoud,"The safety and efficacy of risperidone and olanzapine were compared in a double-blind trial that used doses widely accepted in clinical practice. Subjects (N=377) who met DSM-IV criteria for schizophrenia or schizoaffective disorder were randomly assigned to receive 2-6 mg/day of risperidone (mean modal dose=4.8 mg/day) or 5-20 mg/day of olanzapine (mean modal dose=12.4 mg/day) for 8 weeks. The two study groups were similar at baseline except that the olanzapine group was slightly younger than the risperidone group. Seventy-five percent of the participants completed the trial, with no between-treatment differences in the proportion of dropouts. Similar proportions of the risperidone and olanzapine groups reported extrapyramidal symptoms (24% and 20%, respectively). Severity of extrapyramidal symptoms was low in both groups, with no between-group differences. Total Positive and Negative Syndrome Scale scores and scores on the five Positive and Negative Syndrome Scale factors were improved in both groups at week 8 (subjects who completed the study) and endpoint (all subjects, including dropouts). There were overall between-treatment differences in efficacy. Comparison of individual factors found no significant differences at endpoint; at week 8, however, improvements on Positive and Negative Syndrome Scale factors for positive symptoms and anxiety/depression were greater with risperidone than olanzapine. An increase in body weight of > or =7% was seen in 27% of olanzapine participants and 12% of risperidone participants. Both treatments were well tolerated and efficacious. The frequency and severity of extrapyramidal symptoms were similar in the two treatment groups. Greater reductions in severity of positive and affective symptoms were seen with risperidone than with olanzapine treatment among study completers. There was no measure on which olanzapine was superior. Greater weight gain was associated with olanzapine than with risperidone treatment.",2001.0,1,1
270,11333516,"[Incidence of extrapyramidal symptoms during treatment with olanzapine, haloperidol and risperidone: results of an observational study].",J A Sacristán; J C Gómez; F Ferre; J Gascón; A Pérez Bravo; J M Olivares,"To analyze the incidence of extrapyramidal symptoms (EPS) and the concomitant use of anticholinergic drugs in outpatients diagnosed of schizophrenia treated with olanzapine (OLZ) in comparison with haloperidol (HAL) and risperidone (RIS) under routine clinical practice conditions. The analysis was carried out on the basis of the information obtained in the EFESO study, an observational, prospective study carried out in outpatients diagnosed of schizophrenia and treated with olanzapine compared to other antipsychotic agents used in the clinical practice. The incidence of EPS in the OLZ treated group compared to the haloperidol and risperidone treatment groups in which over 100 patients were included is analyzed in the present work. The study duration was 6 months and the data were collected by 293 psychiatrists from mental health care areas. The percentage of patients who presented at least one adverse event (AE) (p 3/4 0.001) was less in the OLZ groups (47.8%) compared to those of the HAL (79.8%) and RIS (57.2%) subgroups. A lower percentage of patients treated with OLZ (36.9%) presented EPS in comparison to the RIS (49.6%) and HAL (76%) subgroups (p 3/4 0.001). A lower rate of patients from the OLZ group (10.2%) received anticholinergic treatments compared to the RIS (19.9%) and HAL (44%) subgroups (p< 0.001 in both cases). OLZ-treated patients presented a lower incidence of EPS and required less anticholinergic treatment than the HAL and RIS treated patients. These results, obtained in naturalistic conditions, coincide with the conclusions reached in randomized clinical trials carried out prior to the marketing of OLZ.",2001.0,0,0
271,11336611,Special issues in the treatment of paediatric bipolar disorder.,K D Chang; T A Ketter,"Paediatric bipolar disorder (PBD) is an increasingly diagnosed disorder affecting an estimated 1% of children and adolescents. Pharmacological treatment studies in PBD have lagged far behind those in adults. Children are currently treated with pharmacological agents, most of which have proven efficacy in adults. However, PBD is distinct from adult forms of bipolar disorder (BD) and may present unique treatment challenges. PBD often presents with rapid cycling and mixed manic states and a high co-morbidity with behavioural and attention disorders. Early onset depression may also be an early sign of PBD. Due to developmental considerations, the diagnosis of BD may be difficult to make in children without semi-structured interviews. This report discusses the special issues that should be considered when treating PBD and reviews the current literature regarding pharmacotherapy of this population. Mood stabilisers have been studied mostly in an open, uncontrolled fashion but there is growing evidence that lithium, divalproex and carbamazepine are effective in treating PBD. More recent treatment options include atypical antipsychotics and newer anticonvulsants. Other novel agents are currently being investigated in adult BD and may prove applicable to the paediatric form. Finally, based on the available data, a treatment algorithm for PBD is proposed.",2002.0,0,0
272,11346063,Olanzapine-induced diabetes mellitus.,D G Bonanno; L Davydov; S R Botts,"To report two cases of new-onset diabetes mellitus resulting after the initiation of olanzapine treatment. A 31-year-old African American man and a 44-year-old white man, both with schizoaffective disorder, developed diabetes mellitus within weeks or months of olanzapine initiation. Our reports of new-onset diabetes due to olanzapine are consistent with those in the literature. Although the mechanism is not yet known, it has been hypothesized that perhaps damage to the pancreatic islet cells, weight gain, dysregulation of the sympathetic system, and insulin resistance are contributing factors. Diabetes mellitus secondary to olanzapine use seems to be a rare occurrence. However, certain risk factors such as obesity, family history, and concomitant medications may predispose an individual to development of diabetes mellitus while taking olanzapine. An increased awareness of this reaction is essential in the treatment of patients at risk. Periodic serum glucose monitoring in these individuals may be warranted.",2001.0,0,1
273,11349485,Alzheimer's disease and related disorders.,M A Raskind; E R Peskind,"The cholinesterase inhibitors provide the first clearly effective treatments for the cognitive deficits of AD and appear to have a beneficial effect on activities of daily living function and noncognitive behavior. There is increasing support for starting donepezil, rivastigmine, or galantamine early in the disease course and maintaining treatment at least during the early and middle stages of AD. Depressive signs and symptoms complicating AD are treated best with SSRIs. Placebo-controlled trials support the use of citalopram and sertraline in AD complicated by depression. The atypical antipsychotics are the first choice for managing psychosis and disruptive agitation in AD and particularly in the Lewy body variant of AD. Studies suggest that low-dose treatment with risperidone, 1 mg/d, or olanzapine, 5 mg/d, offers the optimal ratio of therapeutic to adverse effects.",2001.0,0,0
274,11353441,A family-based study of the Cys23Ser 5HT2C serotonin receptor polymorphism in schizophrenia.,I Murad; I Kremer; M Dobrusin; M Muhaheed; I Bannoura; D J Müller; T G Schulze; A Reshef; M Blanaru; S Gathas; V Tsenter; M Rietschel; R H Belmaker; W Maier; R P Ebstein,"The 5HT2C receptor has a high affinity for clozapine, a nontypical neuroleptic, and has therefore been postulated to play a role in mediating negative symptoms and neuroleptic response in schizophrenia. In the current study, the Cys23Ser 5HT2C serotonin receptor polymorphism was examined for linkage to schizophrenia by genotyping 207 nuclear families consisting of both parents and schizophrenic child and using the transmission disequilibrium test to examine possible preferential transmission of these alleles from 68 heterozygous mothers to their ill child. No evidence was obtained for preferential transmission of the Cys23Ser 5HT2C alleles in schizophrenia in either of the two main ethnic groups examined (German and Palestinian Arab) or in the combined cohort (TDT chi-square = 0.00, NS).",2002.0,0,0
275,11354590,Detecting improvement in quality of life and symptomatology in schizophrenia.,J Cramer; R Rosenheck; W Xu; W Henderson; J Thomas; D Charney; Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia,"Instrument-based scores are often used as outcome measures. However, little is known about what changes in scores mean in terms of a clinical assessment of improvement or deterioration. The purpose of this report was to determine how much change in standard instrument scores represents a clinically detectable improvement or deterioration. The Veterans Affairs (VA) Cooperative Study of Clozapine in Refractory Schizophrenia evaluated 423 patients on clozapine or haloperidol. Symptoms and quality of life scales were completed at baseline; 6 weeks; and 3, 6, and 12 months. Among patients judged as ""improved"" by clinicians, the average percentage changes were a 21 percent decrease in Positive and Negative Syndrome Scale (PANSS) scores and a 26 percent increase in Quality of Life Scale (QLS) scores across all followup periods. The change in mean seven-point item scores were -0.46 (PANSS) and 0.23 (QLS). A major gain in clinically assessed improvement to ""much better"" was associated with a 45 percent decline in PANSS scores and 50 percent increase in QLS scores (change in mean seven-point item scores -0.88 and 0.92, respectively). Thus, modest changes in psychometric scales assessing symptoms and quality of life reflect clinically detectable improvement.",2001.0,0,1
276,11356587,Weight gain over 4 months in schizophrenia patients: a comparison of olanzapine and risperidone.,R Ganguli; J S Brar; Z Ayrton,"Weight gain frequently accompanies treatment with antipsychotics. In order to determine whether newer antipsychotic agents differ from each other with respect to weight gain, we compared two cohorts of patients with DSM-IV schizophrenia who had newly started treatment with either risperidone or olanzapine. After obtaining informed consent, data regarding body weight and height were culled from existing medical records of 100 patients (50 patients in each treatment group). Baseline body weight, close to the time of starting the new medication, and body mass index [BMI = weight (kg)/height (m) squared] were compared to the body weight and BMI following 4 months of treatment. There was no significant change in mean body weight or BMI in the group treated with risperidone (baseline weight = 83.1 kg +/- 20.5, follow-up = 82.8 kg +/- 19.9; matched pair t = 0.66, P = n.s.; baseline BMI = 29.6 +/- 9.4, follow-up = 29.5 +/- 9.1; matched pair t = 0.79, P = n.s.). However, in the group treated with olanzapine, there was a significant increase in both mean body weight and BMI (baseline weight = 84.9 kg +/- 25.0, follow-up = 87.1 kg +/- 25.1; matched pair t = 4.62, P < 0.001; baseline BMI = 29.5 +/- 7.4, follow-up = 30.3 +/- 7.5; matched pair t = 4.43, P < 0.001). In this naturalistic study, treatment with olanzapine was associated with a mean weight gain of about 2 kg from baseline, in patients with schizophrenia, while treatment with risperidone was associated with no mean weight change.",2001.0,0,1
277,11358771,Antipsychotic drugs and heart muscle disorder in international pharmacovigilance: data mining study.,D M Coulter; A Bate; R H Meyboom; M Lindquist; I R Edwards,"To examine the relation between antipsychotic drugs and myocarditis and cardiomyopathy. Data mining using bayesian statistics implemented in a neural network architecture. International database on adverse drug reactions run by the World Health Organization programme for international drug monitoring. Reports mentioning antipsychotic drugs, cardiomyopathy, or myocarditis. A strong signal existed for an association between clozapine and cardiomyopathy and myocarditis. An association was also seen with other antipsychotics as a group. The association was based on sufficient cases with adequate documentation and apparent lack of confounding to constitute a signal. Associations between myocarditis or cardiomyopathy and lithium, chlorpromazine, fluphenazine, haloperidol, and risperidone need further investigation. Some antipsychotic drugs seem to be linked to cardiomyopathy and myocarditis. The study shows the potential of bayesian neural networks in analysing data on drug safety.",2001.0,1,1
278,11378313,Quantitative EEG in schizophrenia and in response to acute and chronic clozapine treatment.,V Knott; A Labelle; B Jones; C Mahoney,"Topographic quantitative electroencephalographic (EEG) power and frequency indices were collected in 17 treatment refractory, DSM-III diagnosed schizophrenic patients, before and after acute (single dose) and chronic (six weeks) clozapine treatment, as well as in 17 healthy volunteers. Prior to treatment, patients exhibited greater overall absolute theta power, slower mean alpha frequency and elevated absolute delta and total power in anterior regions. Acute dosing increased total spectrum power globally, slow wave power posteriorally, mean alpha frequency and beta power anteriorally and decreased alpha power posteriorally. Six weeks of clozapine treatment significantly reduced clinical ratings of positive and negative symptoms as well as symptoms of global psychopathology. Chronic treatment resulted in EEG slowing as shown by decreases in relative alpha power, mean beta/total spectrum frequency and by widespread increases in absolute total and delta/theta power. The preliminary findings suggest that brain electric profiling may be a promising tool for assessing and understanding the central impact of pharmacotherapeutic interventions in schizophrenia.",2001.0,0,0
279,11378316,Improvement of schizophrenic patients' subjective well-being under atypical antipsychotic drugs.,D Naber; S Moritz; M Lambert; F G Pajonk; R Holzbach; R Mass; B Andresen; F Rajonk,"Recent research indicates that subjective well-being is a major determinant of medication compliance in schizophrenia. However, it is yet unresolved whether atypical neuroleptics differ regarding subjective side-effects. A self-report instrument has been constructed to evaluate 'subjective well-being under neuroleptics' (SWN). The primary aims of the present study were to develop a short form of the SWN and to investigate the extent to which the atypical antipsychotic improves the patient's subjective well-being. The short form of the SWN was constructed following an item analysis based on data from 212 schizophrenic patients medicated with either typical or atypical antipsychotics. The short form of the SWN showed sufficient internal consistency and good construct validity. The SWN was only moderately correlated with positive and negative syndrome scale (PANSS) scores or changes in psychopathology (r=-0.20 to -0.37). SWN-ratings in patients receiving olanzapine were superior compared to those of patients medicated with either clozapine or risperidone on three of five domains of well-being. Clozapine reduced global psychiatric symptoms significantly more than risperidone. It is concluded that the assessment of subjective well-being under antipsychotic treatment provides an independent outcome measure which is relevant to compliance.",2001.0,0,0
280,11378317,Risperidone versus haloperidol in long-term hospitalized chronic patients in a double blind randomized trial: a post hoc analysis.,J Rabinowitz; M Davidson,"Patients who remain in hospital for an extended time pose a special therapeutic challenge. The goal of this study was to examine whether the acute response of long-term hospitalized schizophrenic patients differs between haloperidol and risperidone based on a post hoc, sub-analysis of data from a large double blind pivotal trial. Data on chronic schizophrenic patients who had been hospitalized for at least 60 days (median 351 days) prior to entering this 8-week randomized double blind controlled trial were examined. This included 75 patients treated with 4 mg of risperidone and 69 treated with 10mg of haloperidol. Changes in symptoms were assessed with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) and the Clinical Global Impression (CGI). Data were analyzed using analysis of variance. The analyses revealed that patients receiving risperidone improved significantly more than those treated with haloperidol. Results suggest that the most often prescribed dose of risperidone, 4 mg, might be more effective for long-stay chronic schizophrenic patients than haloperidol 10mg.",2001.0,0,0
281,11378320,Diagnosis and treatment of psychiatric disorders in children with a schizophrenic parent.,R G Ross; N Compagnon,"Many children of a schizophrenic parent may inherit a portion of the genetic risk factors for schizophrenia. The frequency of DSM-IV psychopathology in children of a schizophrenic parent and the frequency and type of mental health treatment accessed by these youths is not well understood. Twenty-eight adults with schizophrenia were identified and 43 of their 6--15 year old children recruited. Clinical diagnoses, based on a structured DSM-IV interview; severity of impairment, based on the Child Global Assessment Scale; and treatment histories were obtained. Seventy-four per cent of children-with-a-schizophrenic-parent met diagnostic criteria for a current Axis I psychiatric disorder. The most common diagnostic categories included attention deficit/hyperactivity disorder (40%), any anxiety disorder (23%), and any depressive disorder (12%). Psychosis was present in 9% of this childhood sample. Of those children with a psychiatric diagnosis, 47% demonstrated current moderate or severe impairment. Approximately half of the children had received mental health evaluations and 26% had experienced at least one psychiatric medication trial. Children-with-a-schizophrenic-parent have frequent, often impairing, psychiatric problems. Despite this high prevalence, mental health evaluation and treatment is of similar frequency and type to other at-risk populations. The effectiveness and appropriateness of standard treatments remain unstudied in children-with-a-schizophrenic-parent.",2001.0,0,0
282,11379836,"Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone.",B R Basson; B J Kinon; C C Taylor; K A Szymanski; J A Gilmore; G D Tollefson,"Clinical factors predicting weight change in patients with schizophrenia and related disorders during acute treatment with the antipsychotic drugs olanzapine, risperidone, and haloperidol were sought through retrospective analyses. Six-week body-weight data from 2 trials, study 1 comparing olanzapine and haloperidol (N = 1,369) and study 2 olanzapine and risperidone (N = 268), were analyzed. Effects of 8 clinically relevant covariates--therapy, clinical outcome (Brief Psychiatric Rating Scale), baseline body mass index (BBMI), increased appetite, age, gender, race, and dose--on weight were compared. In study 1, olanzapine (vs. haloperidol) therapy, better clinical outcome, lower BBMI, and nonwhite race significantly affected weight gain. Effects of increased appetite and male gender on weight gain were significant for olanzapine but not for haloperidol. In study 2, better clinical outcome, lower BBMI, and younger age significantly affected weight gain. Increased appetite was more frequent during olanzapine treatment than during haloperidol, but not significantly different from risperidone. Significant differences in effect on weight change were found between olanzapine and haloperidol but not between olanzapine and risperidone. No evidence was found that lower antipsychotic drug doses were associated with lower weight gain. This report identifies predictive factors of acute weight change in patients with schizophrenia. Similar factors across antipsychotic drugs in predicting greater weight gain included better clinical outcome, low BBMI, and nonwhite race. Factors differing between conventional (haloperidol) and atypical (olanzapine) agents included increased appetite and gender. Choice of atypical antipsychotic drug (olanzapine vs. risperidone) was of minor importance with regard to influence on acute weight gain.",2001.0,0,0
283,11379837,A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities.,J K Buitelaar; R J van der Gaag; P Cohen-Kettenis; C T Melman,"Risperidone is an atypical antipsychotic drug that blocks dopamine as well as serotonin receptor systems. The present study was designed to examine the efficacy and safety of risperidone in a 6-week double-blind, randomized, parallel-group design in the treatment of aggression in adolescents with a primary diagnosis of DSM-IV disruptive behavior disorders and with subaverage intelligence. We randomly assigned 38 adolescents (33 boys; 10 subjects with slightly subaverage IQ, 14 with borderline IQ, and 14 with mild mental retardation), who were hospitalized for treatment of psychiatric disorders associated with severe aggression, to receive risperidone or placebo. The main efficacy measures were the Clinical Global Impressions-Severity of Illness scale (CGI-S), the modified Overt Aggression Scale (OAS-M), and the Aberrant Behavior Checklist (ABC). Side effects were measured using the Extrapyramidal Symptom Rating Scale (ESRS). The mean daily dose of risperidone at the end of treatment was 2.9 mg (range, 1.5-4 mg). Risperidone, compared with placebo, was associated with significant improvements on the CGI-S (p < .001) and the at-school ABC overall and hyperactivity scales (p < .05). During a 2-week washout following the 6-week trial, a statistically significant worsening was found in the risperidone group on the CGI-S scale, the OAS-M. and the ABC. Extrapyramidal symptoms were absent or very mild during risperidone treatment. Transient tiredness was present in 11 (58%) of 19 drug-treated subjects. Other untoward effects included sialorrhea, nausea, and slight weight gain (mean = 3.5% of body weight in the risperidone group). No clinically relevant changes were found in laboratory parameters, electrocardiogram, heart rate, or blood pressure. These results suggest that risperidone may be effective for severe aggression in adolescents with disruptive behavior disorders and subaverage intelligence, and these results are consistent with reports suggesting its effectiveness for treating severe aggression in adolescents in general.",2001.0,0,1
284,11379842,Long-term olanzapine therapy in the treatment of bipolar I disorder: an open-label continuation phase study.,T M Sanger; S L Grundy; P J Gibson; M A Namjoshi; M G Greaney; M F Tohen,"Olanzapine has demonstrated efficacy in the treatment of acute mania in 2 double-blind, placebo-controlled trials. We describe the results of the open-label extension from one of these trials. In a 3-week, double-blind study of patients with DSM-IV bipolar I disorder, olanzapine was superior to placebo for the treatment of acute manic symptoms. Of the 139 patients who entered the double-blind phase of the 3-week study, 113 patients continued into the 49-week open-label extension. Efficacy measurements including the Young Mania Rating Scale (YMRS), the 21-item Hamilton Rating Scale for Depression (HAM-D-21), the Clinical Global Impressions scale-Bipolar Version, and the Positive and Negative Syndrome Scale and safety measurements including the Simpson-Angus scale, the Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale were completed throughout. The analysis considered all treatment results, starting with the first olanzapine dose. Adjunctive lithium and fluoxetine were allowed during the open-label extension. The mean length of olanzapine treatment was 6.6 months, with a mean modal dose of 13.9 mg/day. A significant mean improvement in the YMRS total score, baseline to endpoint (-18.01, p < .001), was observed. During treatment, 88.3% of patients experienced a remission of manic symptoms (YMRS total score < or =12), and only 25.5% subsequently relapsed (YMRS total score > or = 15). Significant improvement in HAM-D-21 scores was observed (p < .001). Forty-one percent of patients were maintained on olanzapine monotherapy. The most common treatment-emergent adverse events reported were somnolence (46.0%), depression (38.9%), and weight gain (36.3%). During up to 1 year of olanzapine therapy, either as monotherapy or in combination with lithium and/or fluoxetine, patients with bipolar disorder demonstrated significant improvement in mania and depression symptoms with a favorable safety profile. Further double-blind, controlled studies are needed to confirm these results.",2001.0,1,1
285,11379843,Optimal dosing with risperidone: updated recommendations.,R Williams,"Drug dosages utilized during controlled clinical trials are not always optimal for patients encountered in day-to-day practice. The original trials of risperidone, a novel antipsychotic, suggested that an initial target dose of 6 mg/day was appropriate, but these trials were necessarily conducted among patients who were chronically impaired, hospitalized, and often partly drug resistant. Relevant data relating to the dosage of risperidone identified through an online (MEDLINE) search using the keywords risperidone, schizophrenia, schizoaffective disorder dementia, bipolar disorder, and dose were supplemented by a review of international and U.S. Congress abstracts in which the dose of risperidone was specifically described. On the basis of naturalistic studies, clinical audit, phase 4 trials, positron emission tomography data, and 5 years of clinical experience, the currently recommended target dose of risperidone is 4 mg/day for most patients, with less-rapid titration than previously recommended. Moreover, a lower dose than this and slower titration may be appropriate for elderly patients, young patients, and first-episode patients.",2001.0,0,0
286,11382303,Rapid capillary electrophoretic method for the determination of clozapine and desmethylclozapine in human plasma.,M A Raggi; F Bugamelli; R Mandrioli; C Sabbioni; V Volterra; S Fanali,"A rapid and sensitive high-performance capillary electrophoretic method for the determination of clozapine and its main metabolite desmethylclozapine in human plasma was developed. The separation of the two analytes was carried out in an untreated fused-silica capillary [33 cm (8.5 cm effective length) x 50 microm I.D.] filled with a background electrolyte at pH 2.5 containing beta-cyclodextrin. Baseline separation of clozapine and desmethylclozapine was recorded in less than 3 min. An accurate sample pretreatment by means of solid-phase extraction and subsequent concentration allows for reliable quantitation of clozapine in the plasma of schizophrenic patients under treatment with the drug. The method showed good precision (mean RSD = 4.0%) as well as satisfactory extraction yields (approximately 88%) and a good sensitivity (limit of quantitation = 0.075 microg ml(-1), limit of detection = 0.025 microg ml(-1)).",2001.0,0,0
287,11386505,Hyperglycemia in patients with schizophrenia who are treated with olanzapine.,J P Lindenmayer; R C Smith; A Singh; B Parker; E Chou; A Kotsaftis,,2001.0,0,1
288,11401000,"Intramuscular (IM) ziprasidone 20 mg is effective in reducing acute agitation associated with psychosis: a double-blind, randomized trial.",D G Daniel; S G Potkin; K R Reeves; R H Swift; E P Harrigan,"Intramuscular (IM) conventional antipsychotics and/or benzodiazepines are effective in the short-term treatment of acutely agitated psychotic patients but may be associated with adverse effects. A short-acting IM formulation of the novel antipsychotic, ziprasidone, which may offer advantages over conventional agents, has been developed. To compare ziprasidone IM 2 mg (n=38) and 20 mg (n=41) in the acute control and short-term management of agitated psychotic patients. A prospective, randomized, double-blind, 24-h study assessed efficacy using the Behavioral Activity Rating Scale (BARS) and the PANSS. The BARS is a validated rating scale for the assessment of treatment response in acute agitation associated with psychosis. Following the initial dose, three more doses could be given 4 h apart if needed during the 24-h period. The mean BARS score had decreased 15 min after the first 20 mg IM dose and was statistically significantly lower than the 2 mg group at 30 min post-dose. The improvement with the 20 mg dose increased until 2 h, and was maintained until at least 4 h post-dose (P<0.001). Two hours after the first injection, almost all of the patients receiving ziprasidone 20 mg were BARS responders compared with just one-third of those receiving 2 mg ziprasidone (P<0.001). The calming effect of ziprasidone was also evident by the significant reduction in PANSS agitation items (P<0.05) and CGI-severity at 4 h (P=0.008). Both ziprasidone doses were very well tolerated. Ziprasidone IM 20 mg was not associated with EPS, dystonia, akathisia, respiratory depression or with excessive sedation. Ziprasidone IM 20 mg substantially and significantly reduced the symptoms of acute agitation in patients with psychotic disorders. Ziprasidone 20 mg IM was very well tolerated and produced no dystonia or akathisia.",2001.0,0,1
289,11403983,Effects of olanzapine and haloperidol on serum prolactin levels in male schizophrenic patients.,E Esel; M Basturk; A Saffet Gonul; M Kula; M Tayfun Turan; I Yabanoglu; S Sofuoglu,"It has been proposed that new atypical antipsychotics cause minimal prolactin (PRL) elevation compared to traditional antipsychotic agents because they spare dopamine blockade within the brain's tuberoinfundibular tract. The aim of this study was to compare the effects of olanzapine and haloperidol on PRL secretion in male schizophrenic patients. Twenty-nine male schizophrenic inpatients were included in the study. Fifteen of them were given olanzapine in a fixed dose of 10 mg/day PO and 14 of them were given haloperidol in a fixed dose of 10 mg/day PO for 6 weeks after a 2-week drug washout period. Fifteen age-matched healthy control subjects were used as control group. PRL levels were measured both before and after the 6-week treatment period in the patients. At the end of the 6th week, the PRL values observed with olanzapine treatment were significantly less than those observed with haloperidol, but not different from those of the controls. There was a significant positive correlation between the PRL values and the severity of extrapyramidal side effects in only the haloperidol group after the six week's treatment period. Our data indicate that short-term olanzapine treatment at doses of 10 mg/day PO causes minimal elevations in PRL secretion in male schizophrenic patients in contrast to haloperidol. This finding is consistent with the previous reports and may be attributed to olanzapine's differential effects on dopamine neurotransmission.",2001.0,0,0
290,11408792,"Consensus on the Practical Use of Amisulpride, an Atypical Antipsychotic, in the Treatment of Schizophrenia.",Y Lecrubier; M Azorin; T Bottai; J Dalery; G Garreau; T Lempérière; A Lisoprawski; F Petitjean; J M Vanelle,"Clinical expectations in schizophrenia treatment have greatly increased since the introduction of new atypical antipsychotics, but the choice of therapeutic strategy has become more complex and reference guidelines are scarce. This paper summarizes the consensus of a broad range of professionals after long-term commercialization in France of an atypical antipsychotic, amisulpride. Participants were from psychiatric hospitals, private clinics, out-patients settings and research; all were experienced with the drug. Discussions focused on the practical use of amisulpride, as, in addition to the double-blind trials information, it may be useful for psychiatrists of other countries to intuitively understand the therapeutic properties of amisulpride. The topics selected include acute psychotic episodes, short- and long-term follow-up, feasibility of treating the initial phase, the elderly and switching treatments. The French experience emphasizes the central role of amisulpride as a first-line treatment of schizophrenia.",2001.0,0,0
291,11411190,Treatment of suicidality in schizophrenia.,H Y Meltzer,"Between 4 and 13% of people with schizophrenia commit suicide and between 25 and 50% make a suicide attempt, a reflection of the devastating toll this syndrome takes on the quality of life, that is, the subjective and objective sense of well-being. Many risk factors for suicide in schizophrenia have been identified, the most important of which are previous suicide attempts, depression, hopelessness, substance abuse, and male gender. Insight into having a serious mental illness and less severe cognitive impairment are also associated with increased risk for suicide in schizophrenia, most likely when accompanied by feelings of hopelessness. Typical neuroleptic drugs have not been shown to reduce the risk of suicide. However, several types of evidence suggest that clozapine, an atypical antipsychotic drug, appreciably reduces the suicide attempt and completion rates in schizophrenia and schizoaffective disorder, perhaps by as much as 75-85%. Other atypical antipsychotic drugs may have a similar effect, but direct evidence is lacking. Improvement in positive and negative symptoms, reduced extrapyramidal side effects (EPS), a direct antidepressant action, improved cognitive function, and improved compliance may contribute to reduced suicidality. The International Suicide Prevention Trial (InterSePT) is a large prospective, randomized study intended to compare the effectiveness of clozapine with that of olanzapine in reducing suicide and suicide-related events in schizophrenic and schizoaffective patients. Some information about suicidality in the patient sample is reported here.",2001.0,0,0
292,11411815,Rapid onset of therapeutic effect of risperidone versus haloperidol in a double-blind randomized trial.,J Rabinowitz; T Hornik; M Davidson,"Speed of onset of therapeutic effect is an important dimension of drugs employed to treat psychosis and schizophrenia. Faster onset is desirable to reduce the anguish caused by delusions and hallucinations and to protect patients and others from the consequences of poor judgment associated with psychotic exacerbation. Although sufficient studies have demonstrated that novel antipsychotics have advantages over clinically employed doses of classic drugs in terms of tolerability and aspects of efficacy, less is known about differences in speed of onset of therapeutic effect. This report consists of a post hoc subanalysis of data from a large double-blind, randomized pivotal trial in which we compared onset of therapeutic effect between risperidone and haloperidol. During an 8-week period, 227 patients with DSM-III chronic schizophrenia received 4 mg/day of risperidone and 226 patients received 10 mg/day of haloperidol. Symptoms were assessed 6 times (days 0, 7, 14, 28, 42, and 56) using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia and the Clinical Global Impressions-Severity of Illness scale (CGI-S). Data were analyzed using analysis of variance for multiple dependent variables and repeated-measures multivariate analysis of variance. The analyses revealed that patients receiving risperidone improved more rapidly than those receiving haloperidol as measured by PANSS total and CGI-S scores. Differences were most pronounced during the first week of treatment. Results suggest that risperidone offers a more rapid response than haloperidol, particularly during the active phase of illness when time to response can be crucial.",2001.0,1,1
293,11411816,The apparent effects of ziprasidone on plasma lipids and glucose.,S J Kingsbury; M Fayek; D Trufasiu; J Zada; G M Simpson,"We examined the effects of ziprasidone on body mass index (BMI) and serum levels of glucose, cholesterol, and triglycerides. As part of a multicenter study examining different strategies for switching to ziprasidone from other antipsychotics, we evaluated weight and serum glucose, cholesterol, and triglyceride measurements at baseline and following 6 weeks on ziprasidone treatment in 37 patients at our site. Short-term treatment with ziprasidone appeared to lead to significant reduction in serum cholesterol (p < .001) and triglyceride levels (p = .018) independent of changes in BMI. Ziprasidone treatment appeared to have no significant effect on BMI or glucose level, perhaps due to the small number of subjects. Ziprasidone appears to independently lead to a lowering of serum lipid levels.",2001.0,0,0
294,11414563,Inference in randomized studies with informative censoring and discrete time-to-event endpoints.,D Scharfstein; J M Robins; W Eddings; A Rotnitzky,"In this article, we present a method for estimating and comparing the treatment-specific distributions of a discrete time-to-event variable from right-censored data. Our method allows for (1) adjustment for informative censoring due to measured prognostic factors for time to event and censoring and (2) quantification of the sensitivity of the inference to residual dependence between time to event and censoring due to unmeasured factors. We develop our approach in the context of a randomized trial for the treatment of chronic schizophrenia. We perform a simulation study to assess the practical performance of our methodology.",2002.0,0,0
295,11417603,Risperidone monotherapy in preschool children with pervasive developmental disorders.,G Masi; A Cosenza; M Mucci; G De Vito,"The aim of this preliminary study was to examine the short-term efficacy and safety of the atypical antipsychotic risperidone in preschool autistic children. The sample consisted of 10 subjects (7 males and 3 females) aged 3 9/12 to 6 6/12 years (mean age 4.7 years). A 16-week open-label trial with risperidone monotherapy was initiated at a starting dose of 0.25 mg daily and was increased to a maximum dose of 0.50 mg (0.027 mg/kg daily). Outcome measures were the Childhood Autism Rating Scale, the Children's Psychiatric Rating Scale, Clinical Global Impression (improvement score), and the Children's Global Assessment of Functioning. Two subjects did not complete the trial because of side effects (tachycardia and flushes, fever and hyporexia). After the 16-week treatment, data from the eight children who completed the trial indicated a modest improvement in the Childhood Autism Rating Scale total score, Children's Psychiatric Rating Scale total score, and Children's Global Assessment of Functioning. According to the Clinical Global Impression, the global improvement score for four subjects was much improved or very much improved; the score for the other four children was minimally improved. None of the children exhibited behavioral deterioration. The side effects in the eight children were not severe.",2002.0,0,0
296,11417619,Acute necrotizing encephalopathy presenting as a basal ganglia syndrome.,S Ravid; L Topper; L Eviatar,"Acute necrotizing encephalopathy is a relatively new disease. The characteristic clinical findings are of febrile illness followed by rapid deterioration in mental status and seizures. The hallmark of the disease is multifocal bilateral symmetric lesions affecting the thalamus, hypothalamus, brainstem tegmentum, cerebral white matter, and cerebellum. The etiology is unknown, but immune-mediated mechanism was suggested. We present a 12-year-old previously healthy girl who developed increased sleepiness progressing to stupor and coma. Magnetic resonance imaging (MRI) of the brain showed the characteristic findings previously described in acute necrotizing encephalopathy. Her mental status improved dramatically with steroid treatment, and the MRI findings resolved completely within 6 months. Following the acute illness, she developed a complex neuropsychiatric disorder consistent with basal ganglia syndrome.",2002.0,0,0
297,11424902,Neurotoxicity as a mechanism for neurodegenerative disorders: basic and clinical aspects.,W Danysz,"This three day meeting focused on chronic neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amylotrophic lateral sclerosis (ALS). It attracted 69 participants from 10 countries with dominance of Chile and USA. Neurodegeneration and its prevention increasingly gain in importance as the number of people affected increases year-by-year. The meeting addressed various basic aspects having pragmatic implications such as: oxidative stress, inflammatory reaction, glial activation, role of glutamatergic system and apoptosis using a plethora of in vitro and in vivo methods.",2001.0,0,0
298,11426515,A meta-analysis of the use of typical antipsychotic agents in bipolar disorder.,M Tohen; F Zhang; C C Taylor; P Burns; C Zarate; T Sanger; G Tollefson,"The potential benefits of typical antipsychotic agents in bipolar disorder are offset by serious treatment-associated side effects. Despite these concerns and the availability of mood stabilizing agents, the treatment of bipolar disorder with typical antipsychotic agents appears to be widespread. A Medline search identified 16 publications that outlined medication use among 2378 bipolar disorder patients. Meta-analysis was used to estimate a weighted average of the relative proportions of the treatment use, where the weights were the reciprocals of the estimated variances for each study. Overall, 84.7% of bipolar patients received typical antipsychotic agents, with a loading toward a greater in-patient (90.7%) relative to out-patient (65.3%) use. Monotherapy accounted for 53.8% of typical antipsychotic use, and typical antipsychotic/mood stabilizer combination therapy accounted for 47.4%. In four studies where length of treatment data were available, the median of minimum typical antipsychotic use was 2.5 months, with 96.0% of the patients receiving typical antipsychotic agents. The meta-analytic technique employed in this analysis is limited by the possible inclusion of studies with unreliable study designs or biased treatment practices, publication bias in which some studies may not have been reported, and possible lack of identification of all relevant studies. Typical antipsychotic agents are commonly used in the treatment of bipolar disorder, possibly due to dissatisfaction with mood stabilizer monotherapy especially in psychotic mania, the high prevalence of psychotic symptoms in acute mania, inappropriate continuation of typical antipsychotic agents after initial stabilization, and/or unavailability or unfamiliarity with new treatments. These findings also suggest that typical antipsychotics may have not only antipsychotic effects in mania but perhaps also antimanic properties.",2002.0,0,0
299,11428347,"Clinical and biochemical correlates of ""high-dose"" clozapine therapy for treatment-refractory schizophrenia.",P F Buckley; L Friedman; A C Krowinski; Y Eaton; M Tronetti; D D Miller,,2001.0,1,1
300,11431240,"Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia.",P Wright; M Birkett; S R David; K Meehan; I Ferchland; K J Alaka; J C Saunders; J Krueger; P Bradley; L San; M Bernardo; M Reinstein; A Breier,"The authors evaluated the comparative efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular placebo for the treatment of acute agitation in schizophrenia. Hospitalized patients with schizophrenia received one to three injections of intramuscular olanzapine, 10 mg, intramuscular haloperidol, 7.5 mg, or intramuscular placebo over a 24-hour period. Agitation was measured with the excited component of the Positive and Negative Syndrome Scale and two additional scales. According to scores on the excited component of the Positive and Negative Syndrome Scale, both intramuscular olanzapine and intramuscular haloperidol reduced agitation significantly more than intramuscular placebo 2 and 24 hours following the first injection. Intramuscular olanzapine reduced agitation significantly more than intramuscular haloperidol 15, 30, and 45 minutes following the first injection. No patients treated with intramuscular olanzapine experienced acute dystonia, compared with 7% of those who were treated with intramuscular haloperidol. No significant QT(c) interval changes were observed in any patients. Intramuscular olanzapine represents a rapid, effective, and safe treatment for acute agitation in schizophrenia.",2001.0,0,0
301,11432120,Treatment of Alzheimer's disease.,J L Cummings,"A growing consensus indicates that Alzheimer's disease (AD) results from an increase in the production or accumulation of beta-amyloid protein (A beta) leading to nerve cell death. Mechanisms by which A beta accumulation leads to neuronal death include oxidative damage and inflammation. This article discusses the management of AD patients with antioxidants, cholinesterase inhibitors, and psychotropic agents. Studies show that these agents can slow the progression of the disease, improve cognition, and reduce behavioral disturbances. A therapeutic alliance between physician and caregiver is an essential element in successfully managing the AD patient. The 3Rs--repeat, reassure, and redirect--can help caregivers reduce behavioral disturbances in patients with AD and limit the need for pharmacologic management.",2001.0,0,0
302,11432122,Long-term care in dementia: patients and caregivers.,D I Kaufer,"General principles of managing chronic, age-associated diseases apply as much to Alzheimer's disease (AD) and other late-life dementing disorders as they do to congestive heart failure or osteoarthritis. Beyond efforts to maintain residual tissue or organ function, important physician roles include promoting general well-being and helping patients and their caregivers adjust to disease-related limitations. Physicians provide essential information to patients and their families about the disease, its social and legal ramifications, and community resources to facilitate care. Therefore, physicians must be knowledgeable about broadly intersecting medical, legal, financial, and ethical issues surrounding the long-term management of AD and other dementias. The many challenges faced by patients with dementia and their caregivers over time underscore the need for an ongoing diagnostic and therapeutic alliance with primary care physicians. This article reviews salient aspects of long-term care for patients with AD and other dementias, highlighting the vital and varied roles of physicians in managing these chronic brain disorders.",2001.0,0,0
303,11432684,Dropout rates in randomised antipsychotic drug trials.,K Wahlbeck; A Tuunainen; A Ahokas; S Leucht,"It has been assumed that new atypical drugs improve treatment compliance due to fewer adverse effects. Data supporting this assumption are scarce. The aim of this study was to study attrition rates in randomised controlled trials of oral administration of conventional antipsychotic drugs, atypical antipsychotic drugs and placebo. The database of the Schizophrenia Module of the Cochrane Library was utilised for the present study. The data in the Cochrane Module are collected by identifying relevant randomised controlled trials from several electronic databases and other sources. Number of dropouts was defined as patients leaving the study preterm due to any reason. Data from 328 treatment groups, consisting of 18,585 randomised subjects from 163 drug trials, were entered in the analysis. One-third of the subjects had dropped out of the trials. The dropout rates significantly increased for each calendar year. Year of trial publication, type of drug and trial length remained statistically significant contributors to dropout rates. In a model incorporating year of publication and trial length, placebo groups and groups treated with conventional antipsychotics had significantly higher attrition rates than groups treated with atypical drugs. When clozapine-treated groups were excluded from the analysis, no statistically significant advantage for atypical drugs over conventional drugs remained. Trial data implicate that a better compliance can be achieved by favouring atypical drugs rather than conventional alternatives in the treatment of schizophrenia. However, this effect is found only when groups treated with the atypical antipsychotic clozapine are included in the analysis. Our study did not find evidence for a statistically significant superiority in acceptability of novel atypical drugs when compared to conventional antipsychotics.",2002.0,0,0
304,11435270,Effects of long-term treatment with antipsychotics on serum leptin levels.,A Herrán; M T García-Unzueta; J A Amado; M T de La Maza; C Alvarez; J L Vázquez-Barquero,"Abnormal regulation of the adipocyte-derived hormone leptin could play a role in body weight gain induced by antipsychotics. To study the effects of long-term antipsychotic treatment on leptin levels in patients with schizophrenia. Serum leptin levels were determined in 59 out-patients with chronic schizophrenia and in the same number of healthy subjects controlled by gender, age and body mass index. Leptin levels did not differ between patients and controls. Leptin levels in patients with schizophrenia correlated with weight gain, even after controlling for current weight, but did not show any association with clinical variables. Antipsychotic class tended to exert different effects over leptin levels (among atypicals, olanzapine induced a greater increase). Elevation of leptin levels induced by chronic antipsychotic treatment can be attributed to weight gain, but other mechanisms could be involved.",2001.0,0,0
305,11440294,Meta-analysis comparing newer antipsychotic drugs for the treatment of schizophrenia: evaluating the indirect approach.,L Sauriol; M Laporta; M D Edwardes; M Deslandes; N Ricard; S Suissa,"Meta-analysis is a useful method to assess the efficacy of newer antipsychotic drugs compared with older drugs or placebo. However, few trials directly compare novel drugs to each other. The purpose of this study was to evaluate the method of indirect meta-analysis by applying it to data on olanzapine versus haloperidol and risperidone versus haloperidol to enable a comparison between olanzapine and risperidone. Published randomized controlled trials (RCTs) of risperidone, olanzapine, and/or haloperidol were identified through literature searches (1983 to 1999) of the MEDLINE, Current Contents, and HealthSTAR databases and reviewed. Data for the Brief Psychiatric Rating Scale (BPRS) total score, the Positive and Negative Syndrome Scale (PANSS) negative subscale, the percentage of patients using anticholinergic drugs, and the percentage of patients dropping out due to lack of efficacy, side effects, or any cause were extracted and combined using the indirect method. These findings were compared with those from a direct comparative study of olanzapine and risperidone. The literature search yielded 8 RCTs comparing risperidone to haloperidol and 3 comparing olanzapine to haloperidol. Only 1 trial directly comparing olanzapine and risperidone was found. In this trial, the change in BPRS total and PANSS negative subscale scores tended to be higher with olanzapine by 1.80 and 1.10, respectively, but these differences were not statistically significant. Indirect meta-analysis yielded similar results. Changes in both BPRS total scores and PANSS negative subscale scores tended to be higher with olanzapine by 0.37 and 0.54, respectively, and again, the differences were not statistically significant. In the indirect meta-analysis, the rate of anticholinergic drug use was 19.5% greater among patients treated with risperidone than among patients treated with olanzapine (P < 0.05). In the direct comparative RCT, the rate was 13.1% higher among patients treated with risperidone (P < 0.05). The dropout rates were similar for patients treated with risperidone and those treated with olanzapine in both analyses. An indirect meta-analysis of studies comparing olanzapine with haloperidol and risperidone with haloperidol yielded conclusions similar to those found in a direct comparative RCT of olanzapine and risperidone.",2002.0,1,1
306,11444160,Safety and efficacy of risperidone in substance abusers with psychosis.,M J Albanese,,2002.0,0,1
307,11448085,"Comparative study of mortality rates and cardiac dysrhythmias in post-marketing surveillance studies of sertindole and two other atypical antipsychotic drugs, risperidone and olanzapine.",L V Wilton; E L Heeley; R M Pickering; S A Shakir,"Sertindole (Serdolect), an atypical antipsychotic, was voluntarily suspended in the European Union in 1998 following regulatory concerns over reports of serious cardiac dysrhythmias and sudden unexpected deaths. The reported causes of death, their frequency, prolongation of the rate corrected QT interval (QTc) and cardiac dysrhythmias in patients prescribed sertindole were compared with those for patients treated with two other atypical antipsychotics. All patients in England, prescribed atypical antipsychotics by general practitioners during each drug's immediate post-marketing period, were identified using an observational cohort technique, prescription-event monitoring. Mortality rates in the sertindole cohort were compared with those in a comparator cohort using standardized mortality ratios and incidence rate ratios. Cardiovascular events were reviewed and followed up to identify cases of prolongation of QTc interval. There was no statistically significant difference in mortality rates between sertindole and the comparator cohort, although confidence intervals (CI) were wide due to small numbers in the sertindole cohort. A much smaller number of patients were prescribed sertindole than the other antipsychotics. Six cases of prolongation of QTc interval were identified in 462 patients (1.3%, 95% CI 0.5-2.8) treated with sertindole and one with unspecified electrocardiogram changes in the comparator cohort of 16,542 patients. This study contributes to the understanding of the occurrence of prolongation of QTc interval during clinical use of sertindole, the incidence of which was similar to that in clinical trials. Although no statistically significant difference was shown in mortality rates between sertindole and comparator cohort, the sertindole cohort was too small to rule out an association between the use of this drug and cardiovascular deaths.",2002.0,0,1
308,11459331,Risperidone olanzapine drug outcomes studies in schizophrenia (RODOS): efficacy and tolerability results of an international naturalistic study.,S Kasper; D Rosillon; I Duchesne; RODOS Investigator Group,"The Risperidone Olanzapine Drug Outcomes studies in Schizophrenia (RODOS) programme was an international series of naturalistic studies designed to evaluate drug use patterns and outcomes. RODOS consisted of retrospective chart reviews performed in patients who had been admitted to hospital and treated in 61 centres in nine countries. The analysed population consisted of 1901 patients with diagnoses of schizophrenia or schizoaffective disorder. The mean (SD) daily doses of risperidone and olanzapine were 5.3 (2.6) mg/day and 14.5 (5.1) mg/day, respectively. Patients treated with risperidone stayed an average of 3.8 days less in hospital compared to those receiving olanzapine (time to discharge was 43.6 days versus 47.4 days, respectively; P = 0.004). Risperidone was rated as effective in significantly more patients than olanzapine (84% versus 79%; P = 0.01). The time to onset of efficacy was significantly shorter with risperidone than with olanzapine (P < 0.001). The numbers of adverse events in the two treatment groups were not significantly different (13% risperidone, 11% olanzapine; P = 0.1). Correcting for small but statistically significant baseline differences between the two treatment groups did not produce a substantive change in the magnitude or significance of any outcome parameter. In conclusion, the clinical outcomes reported by RODOS suggest that risperidone may be more effective as a first-line therapy drug for schizophrenia than olanzapine.",2002.0,0,0
309,11459333,Olanzapine in the treatment of post-traumatic stress disorder: a pilot study.,M I Butterfield; M E Becker; K M Connor; S Sutherland; L E Churchill; J R Davidson,"Because the atypical antipsychotic olanzapine may be efficacious in treating post-traumatic stress disorder (PTSD) symptoms, we conducted a 10-week, double-blind, placebo-controlled evaluation in which 15 patients were randomized 2:1 to either olanzapine or placebo. The initial dosage was 5 mg/day and was titrated to a maximum of 20 mg/day. Eleven patients completed the study. Patients in both groups showed improvement in PTSD symptoms, but no between-group differences in treatment response were observed and a high placebo response rate was found. Both treatments were tolerated well, although the olanzapine treatment group had more weight gain. Olanzapine fared no better than placebo in this preliminary study in the treatment of PTSD. The lack of difference between olanzapine and placebo may in part be due to olanzapine's not being effective in PTSD or, alternatively, a small sample size, a high placebo response in certain forms of PTSD and the chronicity of PTSD symptoms in some patients.",2002.0,0,0
310,11463136,Perospirone.,S V Onrust; K McClellan,"Perospirone is an atypical antipsychotic agent for the treatment of schizophrenia. Its primary mode of action is through antagonism of serotonin 5-HT2A and dopamine D2 receptors. An 8-week course of oral perospirone 8 to 48 mg/day displayed efficacy in up to 75% of patients with schizophrenia participating in phase II and phase III trials. The onset of action of the drug was about 2 weeks. Perospirone was effective against positive, negative and general symptoms in patients with schizophrenia, as assessed with standard rating scales (Brief Psychiatric Rating Scale, Positive and Negative Symptom Scale). Compared with haloperidol 2 to 12 mg/day, perospirone 8 to 48 mg/day was significantly more effective against negative symptoms and tended to be more effective against general symptoms and most positive symptoms in a trial in 145 patients with schizophrenia. Perospirone had efficacy similar to that of mosapramine 50 to 300 mg/day in a comparative phase III trial in 159 patients. Extrapyramidal symptoms (EPS) tended to occur less often and were generally milder with perospirone than with haloperidol or mosapramine.",2001.0,0,0
311,11465676,On defining 'mood stabilizer'.,S N Ghaemi,,2002.0,0,0
312,11474842,Non-linear dynamic analysis of clozapine-induced electroencephalographic changes in schizophrenic patients--a preliminary study.,U G Kang; K T Par; Y M Ahn; Y J Koo; S C Yoon; S H Yi; Y S Kim,"1. In order to find the electroencephalographic (EEG) parameters that reflect the effect of clozapine in schizophrenic patients, the authors applied various non-linear analyses on multi-channel EEG data drawn from patients before and after a therapeutic trial of clozapine. 2. The correlation dimension was difficult to extract from our limited time series EEG data and the authors did not find a meaningful association with clozapine use. The primary Lyapunov exponent could be reliably calculated but also did not reflect the effect of clozapine. 3. However, the mutual cross-prediction (MCP) algorithm showed potentially meaningful results. The driving system was shifted to the frontal channels after a 4-week trial with clozapine. Moreover, MCP might have a value as a predictor of treatment response. 4. Although preliminary in nature, the MCP might have greater power for interpreting complex changes from channel to channel in EEG induced by clozapine.",2002.0,0,0
313,11476119,"A double-blind, randomized, prospective evaluation of the efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder.",P G Janicak; P E Keck; J M Davis; J W Kasckow; K Tugrul; S M Dowd; J Strong; R P Sharma; S M Strakowski,"The relative efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder was studied. Sixty-two patients (29 depressed type; 33 bipolar type) entered a three-site, randomized, double-blind, 6-week trial of risperidone (up to 10 mg/day) or haloperidol (up to 20 mg/day). Trained raters assessed baseline, weekly, and end-of-study levels of psychopathology with the Positive and Negative Syndrome Scale (PANSS), the 24-item Hamilton Rating Scale for Depression (HAM-D-24) and the Clinician-Administered Rating Scale for Mania (CARS-M). The authors were unable to statistically distinguish between risperidone and haloperidol in the amelioration of psychotic and manic symptoms. In addition, there was no difference in worsening of mania between the two agents in either subgroup (i.e., depressed or bipolar subgroups). For the total PANSS, risperidone produced a mean decrease of 16 points from baseline compared with a 14-point decrease with haloperidol. For the total CARS-M scale, risperidone and haloperidol produced mean change scores of 5 and 8 points, respectively, and for the CARS-M Mania subscale, 3 and 7 points, respectively. Additionally, risperidone produced a mean decrease of 13 points from the baseline 24-item HAM-D, compared with an 8-point decrease with haloperidol. In those patients who had more severe depressive symptoms (i.e., HAM-D baseline score >20), risperidone produced at least a 50% mean improvement in 12 (75%) of 16 patients in comparison to 8 (38%) of 21 patients receiving haloperidol. Haloperidol produced significantly more extrapyramidal side effects and resulted in more dropouts caused by any side effect. There was no difference between risperidone and haloperidol in reducing both psychotic and manic symptoms in this group of patients with schizoaffective disorder. Risperidone did not demonstrate a propensity to precipitate mania and was better tolerated than haloperidol. In those subjects with higher baseline HAM-D scores (i.e., >20), risperidone produced a greater improvement in depressive symptoms than haloperidol.",2002.0,1,1
314,11476123,"A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania.",K Meehan; F Zhang; S David; M Tohen; P Janicak; J Small; M Koch; R Rizk; D Walker; P Tran; A Breier,"There are no rapid-acting intramuscular formulations of atypical antipsychotics available for quickly calming an agitated patient with bipolar disorder. In this study, 201 agitated patients with bipolar mania were randomly assigned to receive one to three injections of the atypical antipsychotic olanzapine (10 mg, first two injections; 5 mg, third injection), the benzodiazepine lorazepam (2 mg, first two injections; 1 mg, third injection), or placebo (placebo, first two injections; olanzapine, 10 mg, third injection) within a 24-hour period. Agitation was measured at baseline, every 30 minutes for the first 2 hours, and at 24 hours after the first injection using the Positive and Negative Syndrome Scale-Excited Component subscale and two additional agitation scales. At 2 hours after the first injection, patients treated with olanzapine showed a significantly greater reduction in scores on all agitation scales compared with patients treated with either placebo or lorazepam. At 24 hours after the first injection, olanzapine remained statistically superior to placebo in reducing agitation in patients with acute mania, whereas patients treated with lorazepam were not significantly different from those treated with placebo or olanzapine. Furthermore, no significant differences among the three treatment groups were observed in safety measures, including treatment-emergent extrapyramidal symptoms, the incidence of acute dystonia, or QTc interval changes. These findings suggest that intramuscular olanzapine is a safe and effective treatment for reducing acute agitation in patients with bipolar mania.",2002.0,0,0
315,11476125,An evaluation of risperidone drug interactions.,C L DeVane; C B Nemeroff,"Risperidone, an atypical antipsychotic drug, is widely used in the treatment of psychoses associated with schizophrenia, Alzheimer's disease, and other psychiatric disorders. Polypharmacology is a necessary condition for the optimal treatment of many patients with comorbid psychiatric and medical illness. One concern raised by the widespread use of multiple concurrent pharmacotherapies is the potential for drug-drug interactions to adversely affect patient outcome. Accordingly, the biomedical literature was reviewed for reports of drug interactions involving risperidone, and the clinical significance of each report was evaluated. Additionally, the potential for risperidone to participate in drug interactions was evaluated by considering the drug's pharmacokinetic properties. Controlled studies and case reports indicate that risperidone has a low potential for metabolic drug interactions. Drugs that inhibit cytochrome P450 (CYP) 2D6 or induce or inhibit CYP3A4 may alter risperidone plasma concentrations, but the clinical significance of such interactions seems to be minimal. Adherence to a few guidelines for the design of dosage regimens should limit the effect of drug-drug interactions on patient status and contribute to optimal pharmacotherapy with risperidone.",2002.0,0,0
316,11476131,"Olanzapine for schizophrenia refractory to typical and atypical antipsychotics: an open-label, prospective trial.",J P Lindenmayer; J Volavka; J Lieberman; B Sheitman; L Citrome; M Chakos; P Czobor; B Parker; A Iskander,"The role of olanzapine in treatment-resistant schizophrenia is still unresolved. This article presents an open-label, prospective, 14-week trial with olanzapine in patients with schizophrenia and schizoaffective disorder selected for unambiguous resistance to either clozapine or risperidone and to typical antipsychotics. Forty-three inpatients (mean age, 41.6 years; mean duration of illness, 21.7 years) were enrolled and treated after cross-titration from their previous antipsychotic treatment with olanzapine 10 to 40 mg daily without any concomitant antipsychotic medication. Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale, and the Extrapyramidal Symptom Rating Scale. The change with olanzapine treatment was associated with a PANSS total score improvement of 3.7 (SD = 15.6; not significant). There was a significant improvement for the PANSS cognitive and depression/anxiety factors, whereas the PANSS excitement factor worsened. The improvement rate was superior in patients receiving olanzapine doses higher than 20 mg. A total of 16.7% of patients reached response criteria set forth by a previous study. There was a significant decrease in extrapyramidal side effects (t = 2.04; p < 0.05) and statistically significant, yet modest, weight gain. These results indicate that olanzapine is only modestly effective in these severely treatment-resistant patients with schizophrenia. However, a trial with olanzapine can be recommended in these patients before moving to augmentation strategies, given the lack of proven alternatives and the observation that 16.7% of patients reached the response criteria.",2002.0,0,1
317,11479065,Psychosis treatment prior to psychosis onset: ethical issues.,T H McGlashan,"Clinical trials have begun of antipsychotic treatments in persons who are prodromally symptomatic and at high risk for schizophrenia but who have not yet become psychotic. The ethical issues connected with intervening prior to making a diagnosis of psychosis are detailed. Compelling but tentative evidence suggests that early treatment may improve course and prognosis, and this has initiated a paradigm shift in thinking about the risks and benefits of early intervention. The nature of this evidence, its implications, its shortcomings, and its effect upon the ethics of treating schizophrenia are elaborated and discussed. It is concluded that clinical psychiatry is currently in a state of ""equipoise"" or genuine uncertainty about the comparative merits of early treatment, a state which endorses early intervention research, including intervention in the prodromal phase.",2001.0,0,0
318,11481167,A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia.,J M Azorin; R Spiegel; G Remington; J M Vanelle; J J Péré; M Giguere; I Bourdeix,"This prospective, double-blind, multicenter, parallel-group study compared the efficacy and safety of therapeutic doses of clozapine and risperidone in patients with severe chronic schizophrenia and poor previous treatment response. Male or female patients aged 18-65 years who met DSM-IV criteria for schizophrenia and study requirements for poor previous treatment response (N=273) were randomly assigned to double-blind treatment with either clozapine or risperidone administered over 12 weeks in increasing increments. The primary efficacy measures were the magnitude of improvement in Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI) scores. Adverse events were recorded throughout the study. The magnitude of improvement in mean BPRS and CGI scores from baseline to end of the study was significantly greater in the clozapine group than in the risperidone group. Statistically significant differences in favor of clozapine were also seen for most of the secondary efficacy measures (Positive and Negative Syndrome Scale, Calgary Depression Scale, Psychotic Depression Scale, and Psychotic Anxiety Scale). The adverse event profile was similar for both treatment groups, with a lower risk of extrapyramidal symptoms in the clozapine group. Clozapine showed superior efficacy over risperidone in this patient population. Both treatments were equally well tolerated as demonstrated through their adverse event profiles, although as expected clozapine was associated with a lower risk of extrapyramidal symptoms than risperidone.",2001.0,1,1
319,11488360,Olanzapine therapy in treatment-resistant psychotic mood disorders: a long-term follow-up study.,R Narendran; C M Young; A M Valenti; C A Pristach; M T Pato; J J Grace,"Recent studies suggest a role for the atypical antipsychotic olanzapine in the acute treatment of psychotic mood disorders, but long-term data are unavailable. The purpose of this naturalistic study was to determine the long-term effectiveness and tolerability of olanzapine as add-on therapy in psychotic mood disorders. Hospital records were reviewed for 125 inpatients at the state psychiatric hospital in Buffalo, N.Y., who received at least 6 weeks of add-on olanzapine treatment for psychotic mood disorders (schizoaffective disorders [bipolar and depressive type], bipolar disorders [I, II, and NOS], and major depressive disorder). A group of schizophrenic patients served as a control group (N = 50). Baseline measures, including age, gender, number of hospitalizations in the 2 years prior to olanzapine treatment, concomitant medications, the Clinical Global Impressions scale (CGI), and the Global Assessment of Functioning-Equivalent (GAF-EQ) and Kennedy Axis V psychological impairment, violence, social skills, and activities of daily living subscale scores, were obtained. Follow-up information was obtained from the patients at least 6 months after initiation of olanzapine or by chart review and discussion with the treating psychiatrist. Patients with a diagnosis of psychotic mood disorders were compared with patients with the non-affective psychotic disorder (schizophrenia) on a variety of outcome measures. Follow-up information was available on 102 patients (82%). Mean follow-up was 15 months; 50 (49%) of the 102 patients remained on olanzapine treatment at follow-up (32 psychotic mood disorder, 18 schizophrenic). The primary reason for discontinuation in both groups was lack of response. Both the psychotic mood disorder and schizophrenic groups had comparable outcomes on the CGI and GAF-EQ. Improvement on the Kennedy Axis V psychological impairment and social skills subscales was seen only in the psychotic mood disorders group (p < .01); both groups showed significant (p < .02) improvement in the violence subscale. Sustained mood-stabilizing effect was evident in only 7/27 (26%) of the psychotic mood disorders patients continuing on add-on olanzapine treatment at follow-up. Lack of response was the primary reason for discontinuation of add-on olanzapine in both groups. Mood symptoms predicted a better response to add-on olanzapine in patients with psychotic mood disorders on selective outcome measures. However, only 26% of the patients with psychotic mood disorders sustained a clinically meaningful mood-stabilizing effect with add-on olanzapine treatment at follow-up.",2001.0,0,0
320,11488366,Adherence assessments and the use of depot antipsychotics in patients with schizophrenia.,M Valenstein; L A Copeland; R Owen; F C Blow; S Visnic,"Antipsychotic medications significantly ameliorate the symptoms of schizophrenia, but patients are often noncompliant with these medications. Research evidence supports the use of depot antipsychotics in noncompliant patients. Between January 9, 1991, and December 19, 1995, 1307 veterans with schizophrenia or schizoaffective disorder (ICD-9) were enrolled in a study of enhanced psychosocial programming at 14 Veterans Administration Medical Centers. All had a history of high inpatient use. At enrollment, clinicians listed patient medications, rated patient compliance, and completed a Brief Psychiatric Rating Scale (BPRS) and Global Assessment of Functioning (GAF). Patients reported medication side effects. We describe depot antipsychotic use among these patients and examine the relationship between depot use, assessed compliance, and patient characteristics. At enrollment, 18% of patients in this cohort were receiving depot antipsychotics; however, clinicians reported that 49% had been noncompliant with medication in the past year. Depot use varied significantly with treatment site; African Americans were more likely to receive depot antipsychotics and less likely to receive atypical antipsychotics than white patients. Patients on depot and oral agents had similar levels of psychiatric symptoms, but patients on depot antipsychotics were more likely to receive high doses and complain of side effects. Clinicians prescribed depot antipsychotics relatively infrequently, despite high rates of noncompliance and high levels of inpatient use. Variation in use with treatment site and ethnic group suggests barriers to implementing research-based recommendations for depot use in noncompliant patients. Quality improvement programs should consider facilitating the appropriate use of depots.",2001.0,0,0
321,11512044,In vivo 5-HT2A receptor blockade by quetiapine: an R91150 single photon emission tomography study.,H M Jones; M J Travis; R Mulligan; R A Bressan; D Visvikis; S Gacinovic; P J Ell; L S Pilowsky,"Atypical antipsychotic drugs are thought to show a high degree of 5-HT2A receptor blockade, which may prevent the emergence of extrapyramidal symptoms. 5-HT2A binding was estimated using 123I-5-I-R91150 and single photon emission tomography (SPET) in six schizophrenic subjects treated with quetiapine at a mean (+/-SD) daily dose of 350+/-123 mg for at least 5 weeks and a matched sample of six healthy volunteers. Clinical and side-effect ratings were performed at baseline and at the time of SPET scanning. The reference region approach was used to define a 5-HT2A binding index in the frontal and temporal cortex. Quetiapine treatment resulted in a significant decline in 5-HT2A receptor availability in the frontal cortex (mean 0.98+/-0.09) relative to healthy volunteers (mean 1.33+/-0.16). All patients showed improvements in clinical symptom or side-effect ratings. The mean frontal cortex:cerebellum ratio after quetiapine treatment was significantly negatively correlated with reduction in the Abnormal Involuntary Rating scale and Simpson-Angus scores (P<0.05 Bonferroni corrected), but not with the reduction in the scores from the scale for the assessment of positive symptoms, the scale for the assessment of negative symptoms, the Montgomery-Asberg depression rating scale or patient age. Quetiapine treatment results in significant in vivo blockade of cortical 5-HT2A, similar to other atypical antipsychotic drugs. This effect may contribute to its placebo level extrapyramidal side-effect profile.",2001.0,0,0
322,11522468,Guanfacine treatment of cognitive impairment in schizophrenia.,J I Friedman; D N Adler; H D Temporini; E Kemether; P D Harvey; L White; M Parrella; K L Davis,"Norepinephrine plays a significant role in the working memory functions of the prefrontal cortex by its actions at alpha-2a noradrenergic receptors. Guanfacine has demonstrated efficacy in reversing working memory deficits in non-human primate. In the present study the effect of guanfacine adjunctive treatment to neuroleptics on the cognitive performance of schizophrenic patients was investigated in a four week, placebo-controlled, double-blind, parallel design trial. The primary analyses revealed no significant differences between guanfacine and placebo treatment; however, exploratory non-parametric statistics revealed some significant and some trend differences between guanfacine and placebo on spatial working memory test performance and CPT reaction time in those subjects treated with atypical neuroleptics.",2001.0,0,0
323,11524897,[Evaluated treatment approaches in child and adolescent psychiatry II].,L Baving; M H Schmidt,"The principle of evidence-based medicine is to integrate data concerning the efficacy of interventions into clinical practice. This article assesses the level of evaluation of psychosocial, psychopharmacological and combined interventions for mental disorders in childhood and adolescence (schizophrenic disorders, affective disorders, phobias and anxiety disorders, obsessive-compulsive disorder, posttraumatic stress disorder, anorexia nervosa, and bulimia nervosa). Three different levels of evaluation were defined for both psychosocial and psychopharmacological interventions: A (> or = 2 randomized controlled studies), B (1 randomized controlled study), and C (open studies and case studies). The level of evaluation was judged on the basis of original papers found in a comprehensive literature search. The number of controlled studies examining these disorders in children and adolescents is small, especially with regard to pharmacotherapy. However, the efficacy of (cognitive) behavior therapy for depressive disorders, phobias and anxiety disorders, as well as posttraumatic stress disorder has been demonstrated. There is still a considerable need to evaluate pharmacological treatment approaches for schizophrenic and affective disorders. Looking at psychosocial interventions in schizophrenic disorders, obsessive-compulsive disorder and eating disorders, specific aspects of treatment for young patients should be examined. Overall, the psychotherapy approach evaluated best is (cognitive) behavioral therapy.",2002.0,0,0
324,11527002,Cost effectiveness of the newer atypical antipsychotics: a review of the pharmacoeconomic research evidence.,D A Revicki,"A comprehensive evaluation of atypical antipsychotics for the treatment of schizophrenia involves documentation of clinical effectiveness, quality of life and medical cost outcomes. The results of pharmacoeconomic studies assist psychiatrists, and other healthcare decision-makers, in identifying pharmacotherapies that provide the greatest benefit to patients at the most acceptable cost. The cost-effectiveness of the newer atypical antipsychotics has been examined using clinical decision-modeling studies and randomized clinical trials. The research evidence suggests that clozapine is a cost-effective treatment for neuroleptic refractory schizophrenia. Olanzapine and risperidone may be cost-neutral or, at best, slightly cost-saving compared with conventional antipsychotics, although they do improve clinical symptoms and quality of life outcomes. There is insufficient published data on pharmacoeconomic outcomes for sertindole, quetiapine and ziprasidone to make any conclusions about their cost-effectiveness in treating schizophrenia.",2002.0,0,0
325,11530275,Double-blind olanzapine vs. haloperidol D2 dopamine receptor blockade in schizophrenic patients: a baseline-endpoint.,M Bernardo; E Parellada; F Lomeña; A M Catafau; M Font; J C Gómez; C López-Carrero; F Gutiérrez; J Pavía; M Salamero,"The aim of this study was to compare in vivo striatal D2 dopamine receptor occupancy induced by olanzapine and haloperidol in schizophrenic patients using a baseline-endpoint [(123)I]IBZM single photon computed emission tomography (SPECT) design. The relationships of striatal D2 receptor occupancy with clinical efficacy and extrapyramidal symptoms (EPS) were also assessed. Twenty-seven inpatients with schizophrenia or schizophreniform disorder were included in a 4-week prospective, randomized, double-blind, parallel and comparative clinical trial. Thirteen patients were treated with haloperidol (10 mg/day) and 14 with olanzapine (10 mg/day). Ratings of clinical status and EPS were obtained weekly. The percentage of D2 receptor occupancy was estimated by using basal ganglia (striatum)/frontal cortex IBZM uptake ratios obtained from each patient before and after 4 weeks of maintained antipsychotic treatment. Olanzapine led to a mean striatal D2 receptor occupancy of 49% (range 28-69%), which was significantly lower than that induced by haloperidol (mean 64%, range 46-90%). The baseline-endpoint SPECT design used in this study revealed lower antipsychotic D2 occupancy percentage values than those reported in the literature, using other approaches. The degree of striatal D2 receptor occupancy correlated to the EPS, which predominantly appeared in patients on haloperidol. No relationship was found between the striatal D2 receptor occupancy and clinical improvement. Olanzapine induced a lower striatal D2 occupancy than haloperidol. This low striatal D2 occupancy, together with the lower incidence of EPS in olanzapine-treated patients, contributed to confirm the atypical behavior of this new antipsychotic drug. Nevertheless, conclusions based on SPECT-estimated percentages of antipsychotic D2 occupancy should be cautious, since the SPECT design could influence the results. In this regard, SPECT studies including baseline and endpoint examinations should be encouraged.",2002.0,0,0
326,11532380,"Neurotransmitters, temperament and social functioning.",A J Bond,"Dimensional models can be usefully employed to describe both normal and disordered personality. Studies in molecular genetics, receptor binding, peripheral monoamines and pharmacological challenges have investigated the neurochemical basis of personality. Substantial evidence now exists to support a psychobiological model but the specificity of Cloninger's theory has not always been confirmed. Clinical studies have shown both temperament and character dimensions to improve with pharmacological treatment especially in treatment responders. Some personality changes are found to be independent of clinical effects and even to occur in normal subjects. Models of personality can help in predicting treatment outcome but individual dimensions may not be useful. It is hypothesised that social adaptation is related to the character dimensions and different sources of evidence link these to serotonergic actions. However, recent clinical studies have shown a specific effect of noradrenaline on self-perception and social motivation. Drugs with specific actions on different neurotransmitters may exert a distinctive pattern of effects on personality and social behaviour.",2002.0,0,1
327,11532382,Abnormal thermoregulation in drug-free male schizophrenia patients.,R Shiloh; A Weizman; Y Epstein; S L Rosenberg; A Valevski; P Dorfman-Etrog; N Wiezer; N Katz; H Munitz; H Hermesh,Schizophrenia patients may develop various thermoregulatory disturbances. We hypothesized that a standardized exercise-heat tolerance test [two 50-min bouts of walking a motor-driven treadmill at 40 degrees C (relative humidity=40%)] would reveal abnormal thermoregulation in drug-free schizophrenia patients. Six drug-free schizophrenia outpatients and seven healthy comparison subjects participated in this study. The schizophrenia patients exhibited significantly higher baseline and exertion-related rectal temperature. The relevance of these findings to the pathophysiology of schizophrenia-related thermoregulatory disorders is as yet unclear.,2002.0,0,1
328,11532383,Effects of the atypical antipsychotic risperidone on hostility and aggression in schizophrenia: a meta-analysis of controlled trials.,A Aleman; R S Kahn,"Atypical antipsychotics have been hypothesized to be more effective than classical antipsychotics in the treatment of hostility and aggression, due to their characteristic pharmacological profile, involving serotonergic as well as dopaminergic systems. In the present quantitative review the published evidence regarding the effects of risperidone on hostility and aggression in schizophrenia is evaluated. Meta-analysis of seven controlled trials revealed significant differences between risperidone and classical antipsychotics and between risperidone and placebo, although the effect size was small. Additional analyses in which only methodological rigorous studies were included showed highly significant differences (risperidone versus classical antipsychotics) and the effect size approached the 'medium' range. We conclude that risperidone is superior to classical antipsychotics and placebo in the treatment of hostility and aggression in schizophrenia. Neuropharmacological mechanisms that might account for this effect are discussed, and directions for future research are outlined.",2002.0,0,1
329,11532730,Symptom reduction and suicide risk among patients treated with placebo in antipsychotic clinical trials: an analysis of the food and drug administration database.,A Khan; S R Khan; R M Leventhal; W A Brown,"The assumption that psychotic patients assigned to placebo in clinical trials of antipsychotics are exposed to substantial morbidity and mortality is not based on data about what actually happens to such patients. This study assesses symptoms and risks of suicide and suicide attempts in psychotic patients assigned to receive placebo in clinical trials. The authors used the Food and Drug Administration database to assess suicides, suicide attempts, and psychotic symptom reduction in clinical trials of three new antipsychotics. Among 10,118 participating patients, 26 committed suicide and 51 attempted suicide. Rates of suicide and attempted suicide did not differ significantly between the placebo-treated and the drug-treated groups. Annual rates of suicide and attempted suicide based on patient exposure years were 1.8% and 3.3%, respectively, with placebo; 0.9% and 5.7% with an established antipsychotic; and 0.7% and 5.0% with a new antipsychotic. Symptom reduction was 16.6% with new antipsychotics (N=1,203), 17.3% with established antipsychotics (N=261), and 1.1% with placebo (N=462). These data may help inform discussions about the use of placebo in antipsychotic clinical trials.",2001.0,1,1
330,11549212,Antipsychotic-induced extrapyramidal syndromes. Risperidone compared with low- and high-potency conventional antipsychotic drugs.,I Schillevoort; A de Boer; R M Herings; R A Roos; P A Jansen; H G Leufkens,"To compare the risk of extrapyramidal syndromes (EPS) between patients using risperidone and those using low-potency conventional antipsychotic drugs (APDs) in outpatient clinical practice, as measured by the use of anticholinergic medication. We tried to replicate results from previous clinical trials that compared risperidone with high-potency APDs. Data was obtained from the PHARMO database containing filled prescriptions of 450,000 community-dwelling people in The Netherlands from 1986 to 1998. From the patients aged 15-54 years who had been newly treated with APDs, we defined mutually exclusive cohorts according to the APD first prescribed to a patient. APD exposure was followed until the first prescription of anticholinergic medication and was censored when APD prescribing was interrupted or switched. We estimated relative risks between risperidone and commonly used low-potency and high-potency APDs using Cox proportional hazards models, adjusting for age, gender, dose and other potential confounders. In 4094 patients who had been newly prescribed antipsychotic drugs, the overall incidence rate of anticholinergic drug therapy was 556 per 1000 person-years, which was dose dependent. Prescribed doses of all antipsychotics were low. While, in accordance with previous trials, risperidone showed a lower risk of EPS than the high potency APDs such as haloperidol (RR 0.26; 95% CI 0.10-0.64), we did not observe a lower EPS rate than low-potency APDs (risperidone vs thioridazine RR 1.73, 95% CI 0.49-6.13; risperidone vs pipamperone RR 2.50, 95% CI 0.78-8.04). The reduced EPS rates observed when comparing risperidone with high-potency antipsychotics such as haloperidol may not apply to comparisons with low-potency drugs.",2002.0,0,1
331,11552769,Treatment of the symptoms of schizophrenia: a combined analysis of double-blind studies comparing risperidone with haloperidol and other antipsychotic agents.,I D Glick; P Lemmens; E Vester-Blokland,"Combined data on efficacy were available from 12 double-blind short-term (maximum 8 weeks) trials comparing risperidone and other antipsychotics in patients with chronic schizophrenia. Patients received risperidone (n = 1056) or other antipsychotics (n = 703). Haloperidol (n = 473) was the most frequently prescribed other antipsychotic. Efficacy assessments include the Positive and Negative Syndrome Scale (PANSS) total, subscale (positive symptoms, negative symptoms and general psychopathology), cluster (cognitive and affective symptoms) and item (anxiety and hostility) scores. At endpoint, the mean decrease from baseline in PANSS total scores was significantly greater for patients receiving risperidone (-20.9) than other antipsychotics (-16.2; P < 0.001), or the subset receiving haloperidol (-14.3; P < 0.001). Risperidone-treated patients showed a significantly greater decrease in the positive (P < 0.01), negative (P < 0.05) and general psychopathology (P < 0.001) scores than patients receiving other antipsychotics or haloperidol. Scores for cognition, affective symptoms, anxiety and hostility each improved significantly (P < 0.05) more for patients receiving risperidone than those receiving other antipsychotics or haloperidol. Efficacy data on patients with an acute exacerbation were available from seven trials (risperidone n = 372, other antipsychotics n = 285, including haloperidol n = 120). At endpoint, the mean decrease from baseline in PANSS total scores was significantly greater for patients receiving risperidone (-24.7) than other antipsychotics (-19.8, P < 0.01) including haloperidol (-19.8, P < 0.05). Risperidone-treated patients also showed a greater decrease in positive symptom scores (-7.8) than those receiving other antipsychotics (-6.3; P < 0.01) or haloperidol (-7.1). A > or = 20% reduction in PANSS total score with risperidone, haloperidol and other antipsychotics was achieved by 65.9%, 54.3% and 54.9%, respectively; a > or = 30% PANSS reduction by 54.0%, 46.6% and 46.5% of patients, respectively; and a > or = 40% reduction by 43.8%, 33.7% and 34.4% of patients, respectively. These findings are consistent with earlier findings that show risperidone is more efficacious than haloperidol for reducing the symptoms of schizophrenia.",2002.0,0,1
332,11552955,Medication prescribing patterns for patients with bipolar I disorder in hospital settings: adherence to published practice guidelines.,P Z Lim; S L Tunis; W S Edell; S E Jensik; M Tohen,"The purposes of this paper were to examine the medication prescribing patterns for bipolar I disorder in hospital settings and to compare them to recently published expert consensus guidelines for medication treatment of bipolar disorder. Data were obtained from the 1996-2000 CQI+SM Outcomes Measurement System, on patients age 18 or older admitted to psychiatric inpatient units from over 100 medical-surgical hospitals. A total of 1864 patients with a primary discharge diagnosis of bipolar I or II disorder were identified from a large cohort of hospitalized patients. Patient characteristics were assessed at hospital admission and medication usage, at discharge. The medication analysis focused on the 1471 individuals with bipolar I mania or bipolar I depression (with or without psychotic features), representing 54% and 25% of admitted bipolar patients, respectively. At admission, the typical bipolar patient (mean age 57) had experienced a relatively severe and chronic course of illness. The array of psychotropic agents used was broad, with no single prescribing pattern predominant. Only one in three bipolar I (manic or depressed) patients with psychotic features was discharged on medications recommended by expert guidelines as preferred or alternate recommended treatment. Absent psychotic features, this dropped to one in six patients. Surprising was the relatively high use of antidepressants for patients with mania, particularly those without psychotic symptoms. Results suggest that a substantial proportion of patients with bipolar I disorder are discharged from hospitals on medications not generally recommended by current practice guidelines.",2001.0,0,0
333,11561931,,,,,0,0
334,11575868,Risperidone in the treatment of psychotic depression.,C Miodownik; V Lerner,"Risperidone has been primarily marketed for the treatment of schizophrenia. There are reports about its potential role for the treatment of affective illness. We report here another case of a patient with psychotic depression who was treated successfully with risperidone as monotherapy. This case report suggests that risperidone can be an efficient treatment mode for psychotic depression; however, it needs more data based on controlled study.",2002.0,0,0
335,11576036,Clozapine and haloperidol in moderately refractory schizophrenia: a 6-month randomized and double-blind comparison.,J M Kane; S R Marder; N R Schooler; W C Wirshing; D Umbricht; R W Baker; D A Wirshing; A Safferman; R Ganguli; M McMeniman; M Borenstein,"Despite the demonstrated efficacy of clozapine in severely refractory schizophrenia, questions remain regarding its efficacy for primary negative symptoms, comparison with a moderate dose of a first-generation antipsychotic, and adverse effects during a longer-term trial. This study examined its efficacy in partially responsive, community-based patients, compared clozapine with moderate-dose haloperidol, and extended treatment to 6 months. Randomized, double-blind, 29-week trial comparing clozapine (n = 37) with haloperidol (n = 34). Subjects with schizophrenia who were being treated in community settings at 3 collaborating clinical facilities were enrolled. Subjects treated with haloperidol were significantly more likely to discontinue treatment for lack of efficacy (51%) than were those treated with clozapine (12%). A higher proportion of clozapine-treated subjects met an a priori criterion of improvement (57%) compared with haloperidol-treated subjects (25%). Significantly greater improvement was seen in symptoms of psychosis, hostile-suspiciousness, anxiety-depression, thought disturbance, and total score measured on the Brief Psychiatric Rating Scale. No differences were detected in negative symptoms using the Brief Psychiatric Rating Scale or the Schedule for Assessment of Negative Symptoms. Subjects treated with clozapine experienced more excess salivation, dizziness, and sweating and less dry mouth and decreased appetite than those treated with haloperidol. Compared with a first-generation antipsychotic given in a moderate dose, clozapine offers substantial clinical benefits to treatment-refractory subjects who can be treated in the community. Advantages are seen in a broad range of symptoms but do not extend to negative symptoms.",2001.0,1,1
336,11578678,Use of olanzapine in dysphoric mania.,A Gonzalez-Pinto; B Lalaguna; F Mosquera; J L Pérez de Heredia; M Gutierrez; J Ezcurra; I Gilaberte; M Tohen,"The simultaneous presentation of both manic and depressive symptoms has long been recognized. Nevertheless, a variable prevalence of dysphoric mania has been reported. The aim of this study was to estimate the prevalence of dysphoric mania among hospitalized patients and to assess the effectiveness of olanzapine in this type of patients. Eighty-six patients who met DSM-IV criteria for mania were evaluated at admission with a protocol that included McElroy's criteria for dysphoric mania [Am. J. Psychiatry 149 (1992) 1633]. Treatment was administered according to clinical need, using mood stabilizers combined with antipsychotics. Sequential assessments were conducted throughout the study. Forty-four patients (51.2%) fulfilled McElroy's criteria for dysphoric mania. Fourteen of these dysphoric patients were treated with olanzapine in combination with mood-stabilizers. All patients improved in manic symptoms but patients treated with olanzapine improved significantly more than those treated with other antipsychotics in depressive symptoms. The lack of randomization is a methodological limitation of this study, so these findings should be considered as preliminary. Dysphoric symptoms are common in this population of manic patients. Olanzapine in combination with mood-stabilizers may be effective in these patients. Additional controlled studies are needed to replicate these results.",2002.0,0,0
337,11579009,Association of olanzapine-induced weight gain with an increase in body fat.,U Eder; B Mangweth; C Ebenbichler; E Weiss; A Hofer; M Hummer; G Kemmler; M Lechleitner; W W Fleischhacker,"The goal of this study was to explore the pathophysiology of weight gain during treatment with olanzapine for schizophrenia. The authors used a prospective, controlled, open study comparing body weight, body mass index, and related biological measures in mentally and physically healthy volunteers and olanzapine-treated patients with schizophrenia. Weight, eating behavior, leptin serum levels, body mass index, and body composition were assessed over an 8-week observation period. A significant increase in body weight, leptin serum levels, and percentage of body fat was seen in patients treated with olanzapine, but the drug-free comparison group did not show any significant changes. The weight gain during antipsychotic treatment with olanzapine was mainly attributable to an increase in body fat; patients' lean body mass did not change. In addition to the original finding that an increase in body fat is mainly responsible for olanzapine-induced weight gain, these findings confirm results obtained in other studies showing increases in body weight and serum leptin levels during treatment with second-generation antipsychotics.",2001.0,0,0
338,11585006,Ziprasidone: a new atypical antipsychotic.,P E Keck; S L McElroy; L M Arnold,"This paper reviews the clinical pharmacology, efficacy and safety of the new atypical antipsychotic, ziprasidone. All published citations regarding ziprasidone were retrieved and reviewed using a MEDLINE search (completed for citations to early 2001). In addition, abstracts from recent scientific meetings presenting data not yet published were reviewed. Like other new antipsychotic medications, ziprasidone fits the profile of an atypical agent, exerting efficacy in positive and negative symptoms of psychosis, as well as affective symptoms, with a low risk of neurological and neuroendocrinological side effects. Unlike newer agents, it does not appear to be associated with weight gain in most patients.",2001.0,0,0
339,11588990,New antidepressive and antipsychotic drugs in juvenile neuronal ceroid lipofuscinoses--a pilot study.,M L Bäckman; L E Aberg; E T Aronen; P R Santavuori,"Patients with juvenile neuronal ceroid lipofuscinosis (JNCL) often have severe psychiatric symptoms. These are common in their mid-teens and include such symptoms as anxiety and affective and psychotic disorders. The older antidepressants and antipsychotics do not seem to be effective and often cause many adverse effects. Therefore, we wanted to try the new psychotropic drugs in Finnish patients with JNCL. We also wanted to determine the profile of these drugs in this patient group. Fourteen Finnish patients with JNCL receiving psychotropic drug treatment with citalopram, risperidone, olanzapine or quetiapine, were included. The mean age at initiation of the new psychotropic drugs was 13.8 years. Indications for treatment were psychotic symptoms, affective symptoms, anxiety and an inadequate response to other psychotropic drugs, or even adverse reactions. Information on psychiatric symptoms and current treatment was gathered from interviews and from the medical records. Indications and the clinical outcome of the treatment were determined by a consensus of the assessments by parents and physicians. The psychotropic drugs most commonly used in Finnish patients with JNCL are citalopram and risperidone. The clinical outcome was good or satisfactory in 70%. The adverse effects most commonly reported were fatigue, weight gain and aggravation of extrapyramidal symptoms. Little research has been done in this area and there are no good guidelines for treatment of psychiatric symptoms in patients with JNCL. Therefore, every patient should be treated with the safest and most commonly used drugs in the lowest possible doses.",2001.0,0,0
340,11590972,Use of the Medication Event Monitoring System to estimate medication compliance in patients with schizophrenia.,E Diaz; H B Levine; M C Sullivan; M J Sernyak; K A Hawkins; J A Cramer; S W Woods,"To determine the feasibility of using the Medication Event Monitoring System (MEMS) to estimate medication compliance in patients with schizophrenia or schizoaffective disorder. Fourteen of 35 consecutive patients admitted to a psychiatric inpatient hospital with schizophrenia or schizoaffective disorder who met eligibility requirements and gave informed consent. After random assignment to either risperidone or typical antipsychotic treatment, medication upon discharge from hospital was dispensed in a bottle with a MEMS cap which recorded the number of bottle openings and the date and time of each opening. The first 6 patients were asked to return monthly for data downloading. The next 8 were asked to return weekly during the first month and every 2 weeks thereafter; they were also paid $5 for returning each bottle. MEMS data collected over a 6-month period and hospital readmission data. Patient medication compliance data were collected from 10 (71%) of 14 patients during the first month, from 7 (58%) of 12 (2 patients dropped out) during the second and from 5 (45%) of 11 (a third patient dropped out) during months 3-6. Mean compliance rates were 63% for the first month and ranged from 56% to 45% over the next 5. First-month compliance rates were significantly lower for those who were subsequently readmitted to hospital (n = 7) than for those who were not (p < 0.01). Electronic monitoring devices can be used to estimate compliance with medication regimens in patients with severe schizophrenic disorders, but there are methodological improvements that can be made to increase data recovery and compliance, and these are discussed.",2002.0,0,0
341,11593070,Olanzapine as long-term adjunctive therapy in treatment-resistant bipolar disorder.,E Vieta; M Reinares; B Corbella; A Benabarre; I Gilaberte; F Colom; A Martínez-Arán; C Gastó; M Tohen,"The aim of this study was to estimate the long-term effectiveness of olanzapine as adjunctive therapy in patients with bipolar disorder who exhibited an inadequate response to mood stabilizers. Twenty-three Research Diagnostic Criteria (RDC) patients with bipolar I and II were assessed by means of the Schedule for Affective Disorders and Schizophrenia and entered if they gave their consent to participate. All of them had experienced frequent relapses, residual subsyndromal symptoms, and inadequate responses to other drugs, such as lithium, valproate, or carbamazepine. While maintaining other drugs, they all received open-label, increasing doses of olanzapine, until achieving clinical response. Other drugs were maintained. The patients were assessed several consecutive times from baseline to the endpoint with the Clinical Global Impressions (CGI) scale for use in bipolar illness. Records of recurrences, hospitalizations, and side effects were also collected. The last-observation-carried-forward analysis showed that there was a significant reduction of CGI scores after the introduction of olanzapine, either in manic symptoms (p = 0.0015), depressive symptoms (p = 0.0063), or global symptoms (p = 0.0003). The most frequent adverse events were somnolence (17%) and weight gain (13%). The mean dose of olanzapine at the end of the 43-week follow-up was 8.1 mg/day. Olanzapine may be a useful medication for the long-term adjunctive treatment of patients with bipolar disorder who exhibit a poor response to mood stabilizers, such as lithium, valproate, or carbamazepine. These results suggest mood-stablizing properties of olanzapine.",2002.0,1,1
342,11593072,Clozapine enhances neurocognition and clinical symptomatology more than standard neuroleptics.,S G Potkin; K Fleming; Y Jin; B Gulasekaram,"Neurocognition and clinical symptomatology were evaluated in 27 patients with schizophrenia during a double-blind, placebo-controlled, cross-over study involving clozapine, an atypical antipsychotic agent, and haloperidol, a conventional neuroleptic. Patients were assessed 5 to 6 weeks after initiation of each phase. Clinical symptomatology, based on Brief Psychiatric Rating Scale and Scale for the Assessment of Negative Symptoms ratings, markedly improved after treatment with both haloperidol and clozapine. The beneficial effects of clozapine were statistically significantly greater than the effects from the haloperidol treatment. Regarding neurocognition, both agents proved efficacious in improving performance on nearly all measures compared with placebo. In addition, as compared with haloperidol, clozapine significantly improved performance on Trails B, Verbal Fluency, and measures of delayed verbal memory, and it tended to increase performance on most measures. Additional analyses indicated that the improvement on neurocognitive measures was not because of symptom amelioration; rather, neurocognitive deficits seem to be an intrinsic enduring feature of schizophrenia. The superiority of clozapine over haloperidol may be related to clozapine's unique psychopharmacologic profile.",2002.0,0,1
343,11593073,A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia.,D C Goff; L Leahy; I Berman; T Posever; L Herz; A C Leon; S A Johnson; G Lynch,"CX516, a positive modulator of the glutamatergic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, improves performance in tasks requiring learning and memory in animals. CX516 was added to clozapine in 4-week, placebo-controlled, dose-finding (N = 6) and fixed-dose (N = 13) trials. CX516 was tolerated well and was associated with moderate to large, between-group effect sizes compared with placebo, representing improvement in measures of attention and memory. These preliminary results suggest that CX516 and other ""ampakines"" hold promise for the treatment of schizophrenia.",2002.0,0,0
344,11593079,"Cognitive improvements in psychotic subjects treated with ""Seroquel"" (quetiapine fumarate): an exploratory study.",K Fleming; P Thyrum; C Yeh; D L Vargo; S G Potkin,,2002.0,0,1
345,11605078,In vivo (123)I IBZM SPECT imaging of striatal dopamine 2 receptor occupancy in schizophrenic patients.,C Barnas; S Quiner; J Tauscher; E Hilger; M Willeit; B Küfferle; S Asenbaum; T Brücke; M L Rao; S Kasper,"Single photon emission computed tomography (SPECT) using (123)I iodobenzamide (IBZM) as tracer substance has been shown to be a useful tool to visualize dopamine 2 (D2) receptor occupancy. We investigated the striatal D2 receptor occupancy of zotepine which is referred to the class of atypical antipsychotic drugs. (123)I IBZM and SPECT were used to visualize striatal dopamine 2 (D2) receptor occupancy in zotepine-treated schizophrenic patients. Two groups of schizophrenic patients receiving either 150 mg/day zotepine (n=6) or 300 mg/day (n=6) underwent examination. For the quantification of striatal D2 receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to untreated healthy controls (n=8) reported earlier. Zotepine led to a mean overall striatal D2 receptor occupancy of 73%. Patients with 150 mg daily showed a significantly lower occupancy (65.8%, SD=6.2) than patients with 300 mg/day (77.8%, SD=10.7; P<0.05). No clinically relevant extrapyramidal side effects occurred during treatment with zotepine. There was no correlation between the degree of striatal D2 receptor occupancy and clinical improvement.",2002.0,0,0
346,11605095,,,,,0,0
347,11607044,Fluvoxamine as an adjunctive agent in schizophrenia.,H Silver,"Schizophrenia is a common mental disorder that has an early onset and rates high as a cause of medical disability. Antipsychotic agents are the mainstay of treatment but response is often inadequate. Negative symptoms (disturbances in volition, social interaction and affective functions) are particularly difficult to treat and form a major obstacle to rehabilitation. A promising approach to improve response of negative symptoms has been to add a selective serotonin reuptake inhibitor (SSRI) antidepressant to antipsychotic treatment. This review examines evidence pertaining to the efficacy, tolerability, and safety of the SSRI fluvoxamine, combined with antipsychotic agents, in the treatment of negative symptoms in schizophrenia. Important methodological issues, such as differentiating primary and secondary negative symptoms, are discussed. The balance of available evidence indicates that fluvoxamine can improve primary negative symptoms in chronic schizophrenia patients treated with typical antipsychotics and suggests that it may also do so in some patients treated with clozapine. This combination is generally safe and well tolerated although, as antipsychotic drug concentrations may be elevated, attention to dose and drug monitoring should be considered appropriately. Combination with clozapine may require particular caution because of potential toxicity if serum clozapine levels rise steeply. The fluvoxamine doses effective in augmentation are lower than those usually used to treat depression. Evidence regarding the use of fluvoxamine augmentation to treat phenomena, such as obsessions and aggression, which may be associated with schizophrenia, is also examined. An important goal of future studies will be to define which patient groups can benefit from combined treatment.",2002.0,0,0
348,11642649,A follow-up study of a population of schizophrenic patients treated with clozapine.,M Bourin; B Guitton; E Dailly; P Hery; P Jolliet,"1. Clozapine is a dibenzodiazepine neuroleptic which presents the advantage of not having undesirable neurological side-effects. Its efficacy for the treatment of the symptoms of schizophrenia is known, but the use of clozapine is limited to treatment-resistant schizophrenic patients as it induces agranulocytosis with a higher incidence than that of other neuroleptic drugs. 2. The present study was designed in order to evaluate the benefit/risk of chronic treatment. The analysis was performed using the files of schizophrenic patients. These patients were not stabilized by a classical neuroleptic treatment and/or presented individual secondary effects. 3. Clozapine induced neutropenia and 1 case of agranulocytosis in 3 females. Analysis of leukocyte expression highlighted some premonitory symptoms in patients who presented neutropenia. The observation of 2 to 3 early successive peaks in leukocyte expression (between the third and tenth week of treatment) could be predictive of neutropenia in the 3 to 4 months of treatment. 4. The patients who presented a lower leukocyte base-line following a peak had a higher risk, of developing neutropenia. This might explain some late accidents beyond the first six months of treatment. 5. The present study confirmed the advantages of clozapine treatment and demonstrated that the risk of neutropenia may be diminished by the detection of premonitory symptoms and the early monitoring of patients at risk i.e. female patients and subjects with a lower leukocyte base-line.",2002.0,0,1
349,11669086,The effects of olanzapine on neurocognitive functioning in medication-refractory schizophrenia.,R C Smith; M Infante; A Singh; A Khandat,"Neurocognitive deficits are an enduring characteristic of schizophrenia, and remain prominent in patients whose positive symptoms have decreased after treatment with typical neuroleptics. Recent research has reported that olanzapine improves cognitive functioning in relapsing schizophrenia followed in an outpatient setting. Whether olanzapine will have an effect on improving cognitive function in chronic schizophrenics who have been hospitalized for long periods of time, and have shown a poor response to other conventional and atypical neuroleptics, has not been established. This study investigated cognitive function in chronic medication refractory schizophrenics who were treated with olanzapine or haloperidol in a double-blind study for 8 wk, and followed in an open olanzapine study for several additional months. Patients were evaluated with psychopathology rating scales and a battery of neuropsychological tests at baseline, end of double-blind and end of open-label phases of the study. At the end of the double-blind phase there were no significant differences between olanzapine and haloperidol, except for a trend for improvement on the Wisconsin Card Sort Test on olanzapine, which was significant at traditional but not corrected significance levels. After an additional 3 months of treatment with olanzapine doses of 20-40 mg/d, our statistical analysis showed significant improvement on overall neuropsychological test performance and specific cognitive tasks assessing verbal memory. However, these open-label results are difficult to interpret definitively because of the lack of a comparison drug group and the olanzapine dose escalation over time. Neurocognitive changes were not correlated with changes in psychopathology as assessed by PANSS or SANS scores.",2002.0,0,0
350,11684748,"Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia.",L Citrome; J Volavka; P Czobor; B Sheitman; J P Lindenmayer; J McEvoy; T B Cooper; M Chakos; J A Lieberman,"This study compared the specific antiaggressive effects of clozapine with those of olanzapine, risperidone, and haloperidol. A total of 157 inpatients with schizophrenia or schizoaffective disorder and a history of suboptimal treatment response were randomly assigned to receive clozapine, olanzapine, risperidone, or haloperidol in a double-blind 14-week trial. The trial was divided into two periods: eight weeks during which the dosage was escalated and then fixed, and six weeks during which variable dosages were used. The hostility item of the Positive and Negative Syndrome Scale (PANSS) was the principal outcome measure. Covariates included the items that reflect positive symptoms of schizophrenia (delusions, suspiciousness or feelings of persecution, grandiosity, unusual thought content, conceptual disorganization, and hallucinations) and the sedation item of the Nurses Observation Scale for Inpatient Evaluation (NOSIE). Patients differed in their treatment response as measured by the hostility item of the PANSS. The scores of patients taking clozapine indicated significantly greater improvement than those of patients taking haloperidol or risperidone. The effect on hostility appeared to be independent of the antipsychotic effect of clozapine on other PANSS items that reflect delusional thinking, a formal thought disorder, or hallucinations and independent of sedation as measured by the NOSIE. Neither risperidone nor olanzapine showed superiority to haloperidol. Clozapine has a relative advantage over other antipsychotics as a specific antihostility agent.",2002.0,0,1
351,11691681,"Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death.",A H Glassman; J T Bigger,"The authors review the mechanisms and establish the risk of torsade de pointes and sudden death with antipsychotic drugs. They present a review of original concepts, the distinction between familial and drug-induced cases of torsade de pointes, and the recognition of the role of noncardiac drugs in torsade de pointes and sudden death. They review the evidence linking QTc interval prolongation, potassium channels, and torsade de pointes from both the long QT syndrome and drugs. They examine the risk for torsade de pointes from antipsychotic drugs and estimate the frequency of sudden death on the basis of epidemiological data in normal and schizophrenic populations. All drugs that cause torsade de pointes prolong the QTc interval and bind to the potassium rectifier channel, but the relationships are not precise. Prediction of torsade de pointes and sudden death can be improved by examining dose dependency, the percent of QTc intervals higher than 500 msec, and the risk of drug-drug interactions. Although sudden unexpected death occurs almost twice as often in populations treated with antipsychotics as in normal populations, there are still only 10-15 such events in 10,000 person-years of observation. Although pimozide, sertindole, droperidol, and haloperidol have been documented to cause torsade de pointes and sudden death, the most marked risk is with thioridazine. There is no association with olanzapine, quetiapine, or risperidone. Ziprasidone does prolong the QT interval, but there is no evidence to suggest that this leads to torsade de pointes or sudden death. Only widespread use will prove if ziprasidone is entirely safe. To date, all antipsychotic drugs have the potential for serious adverse events. Balancing these risks with the positive effects of treatment poses a challenge for psychiatry.",2002.0,0,1
352,11691689,Clinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia.,M Gitlin; K Nuechterlein; K L Subotnik; J Ventura; J Mintz; D L Fogelson; G Bartzokis; M Aravagiri,"The goal of this report was to examine the clinical course following neuroleptic discontinuation of patients with recent-onset schizophrenia who had been receiving maintenance antipsychotic treatment for at least 1 year. Fifty-three volunteer patients with recent-onset schizophrenia who had been clinically stabilized on a maintenance regimen of fluphenazine decanoate for a mean of 16.7 months had their antipsychotic medications withdrawn under clinical supervision. Participants initially entered a 24-week, double-blind crossover trial in which fluphenazine and placebo were administered for 12 weeks each. For those who did not experience symptom exacerbation or relapse during this period, fluphenazine was openly withdrawn; participants were then followed for up to 18 additional months. When a low threshold for defining symptom reemergence was used, 78% (N=39 of 50) of the patients experienced an exacerbation or relapse within 1 year; 96% (N=48 of 50) did so within 2 years. Mean time to exacerbation or relapse was 235 days. When hospitalization was used as a relapse criterion, only six of 45 of individuals (13%) experiencing an exacerbation or relapse who continued in treatment in the clinic were hospitalized, demonstrating the sensitivity of the psychotic exacerbation criterion. The vast majority of clinically stable individuals with recent-onset schizophrenia will experience an exacerbation or relapse after antipsychotic discontinuation, even after more than a year of maintenance medication. However, clinical monitoring and a low threshold for reinstating medications can prevent hospitalization for the majority of these patients.",2002.0,0,1
353,11691710,Risperidone for tardive dyskinesia.,J Y Chen; Y M Bai; L Y Pyng; C C Lin,,2002.0,0,1
354,11700151,Olanzapine: a review of its use in the treatment of bipolar I disorder.,N Bhana; C M Perry,"Olanzapine, a thienobenzodiazepine derivative, is a psychotropic agent that has shown efficacy in the treatment of patients with bipolar I disorder. Olanzapine has a multireceptorial binding profile including a greater affinity for serotonin 5-HT(2A) than for dopamine D(2) receptors. Olanzapine 5 to 20 mg/day demonstrated significantly greater antimanic efficacy than placebo in two double-blind, randomised 3- or 4-week trials of patients with bipolar I disorder of either manic or mixed episodes, with or without psychotic features. Additionally, in one of these trials, improvements in cognitive function and hostility were superior with olanzapine. In cohorts of severely depressed and rapid cycling patients, improvements in manic and depressive symptoms and in manic symptoms only, were superior with olanzapine compared with placebo. Significant improvements from baseline in symptoms of mania, depression, cognitive functioning and hostility were seen with olanzapine in a 49-week extension phase study. In double-blind trials, olanzapine 10 mg/day appeared to have similar antimanic efficacy to oral lithium 400mg twice daily in the treatment of patients with pure mania (4-week small study). In patients with acute manic or mixed episodes olanzapine 5 to 20 mg/day appeared to be more effective than oral valproate semisodium (divalproex sodium) 500 to 2500 mg/day (3-week study) and at least as effective as oral haloperidol 3 to 15 mg/day (12-week study). Preliminary results from a large 6-week placebo-controlled study suggest that olanzapine 5 to 20 mg/day in combination with mood stabilisers (lithium or valproate semisodium) provides effective augmentation of antimanic treatment of patients with bipolar I disorder, with benefits seen in the first week. Adverse events reported significantly more often with olanzapine than with placebo were somnolence, dry mouth, dizziness and bodyweight gain, and in comparison with valproate semisodium were somnolence, dry mouth, increased appetite and bodyweight gain. Olanzapine was generally well tolerated with no clinically relevant abnormalities in laboratory tests, vital signs or electrocardiogram results. Olanzapine demonstrated superior efficacy compared with placebo in the short-term treatment of patients with bipolar I disorder with manic or mixed episodes, with or without psychotic features, and was generally well tolerated. According to preliminary data the antimanic efficacy of olanzapine appears similar to that of haloperidol and better than that of valproate semisodium in patients with bipolar I disorder experiencing a manic or mixed episode; among nonpsychotic patients with manic or mixed episodes olanzapine appears to be superior to haloperidol. Available data support the choice of olanzapine as an option in the short-term management of mania in patients with bipolar I disorder with manic or mixed episodes, with or without psychotic features.",2002.0,0,1
355,11708938,Effects of risperidone on aberrant behavior of persons with developmental disabilities: I. A double-blind crossover study using multiple measures.,J R Zarcone; J A Hellings; K Crandall; R M Reese; J Marquis; K Fleming; R Shores; D Williams; S R Schroeder,"The efficacy of the atypical antipsychotic risperidone was evaluated in the treatment of aberrant behavior (e.g., aggression, self-injury) in 20 individuals with developmental disabilities. A double-blind, crossover design was used to compare risperidone with placebo in a 22-week trial with a 6-month follow-up phase. Based on a 50% reduction in mean Aberrant Behavior Checklist--Community total scores, 50% of the participants were identified as responders. Naturalistic observations of a subset of five individuals showed that for 4 out of 5 participants, risperidone was effective in reducing aberrant behavior. Side effects included weight gain (84% of participants) and sedation (40% of participants). The advantages of conducting a comprehensive analysis of the effects of medication on aberrant behavior are discussed.",2002.0,0,0
356,11712620,Risperidone versus haloperidol in the treatment of acute exacerbations of chronic inpatients with schizophrenia: a randomized double-blind study.,X Y Zhang; D F Zhou; L Y Cao; P Y Zhang; G Y Wu; Y C Shen,"The purpose of this study was to compare the efficacy and safety of risperidone and haloperidol in treatment-resistant chronic schizophrenic patients. Subjects (n = 78) who met DSM-III criteria for schizophrenia were randomly assigned to receive 6 mg/day of risperidone or 20 mg/day of haloperidol for 12 weeks. Clinical efficacy was determined using the Positive and Negative Syndrome Scale (PANSS), and side-effects with the Treatment Emergent Symptom Scale (TESS). Risperidone produced a mean 39.8 +/- 24.1% reduction in total PANSS score compared to a mean 28.3 + 19.4% reduction in the haloperidol group (P < 0.05). Analysis of changes for the three subscores of the PANSS revealed that the general psychopathology and negative subscores were significantly improved in the risperidone group compared to the haloperidol group. As for the side-effects, the risperidone group showed a significantly lower TESS total score, as well as nervous system symptoms subscore and cardiovascular symptoms subscore, compared to the haloperidol group. Risperidone appears to be a more effective and better tolerated antipsychotic drug in treatment-refractory Chinese schizophrenia than haloperidol.",2002.0,0,0
357,11720694,5-HT(1A) receptor dysfunction in female patients with schizophrenia.,M A Lee; H Y Meltzer,"Serotonin (5-HT)(1A) receptors are of interest in the pathophysiology of schizophrenia (SCH) and the mechanism of action of atypical antipsychotic drugs. To test the hypothesis that 5-HT(1A) receptor responsivity is significantly different in patients with SCH compared to normal control subjects, the neuroendocrine study was performed using ipsapirone (IPS), a 5-HT(1A) partial agonist, as a probe. Ipsapirone 0.5 mg/kg, p.o. or placebo were administered, in random order, to patients with SCH (n = 43; 32 male) and normal controls (n = 33; 21 male). Blood samples for plasma cortisol and body temperature were obtained from 30 min before to 180 min after administration of IPS or placebo. Female normal control subjects had markedly greater increases in plasma cortisol following IPS than did male control subjects. The placebo response-corrected plasma cortisol response to IPS was significantly blunted in female SCH compared to female normal control subjects (p =.0001). The IPS-stimulated plasma cortisol response in male SCH did not differ from that of male normal control subjects or female SCH. There were no significant differences in the IPS-induced hypothermia in men and women or between patients with SCH and normal control subjects. Behavioral responses to IPS, including nausea, dizziness, irritability, and feeling less well, did not differ between groups. These results suggest that the post-synaptic 5-HT(1A) receptor mediated endocrine response is diminished in female SCH compared to female normal control subjects, possibly secondary to an abnormality in intracellular signal transduction mechanism.",2002.0,0,0
358,11722307,Agranulocytosis and granulocytopenia associated with quetiapine.,H G Ruhé; H E Becker; P Jessurun; C H Marees; M Heeringa; H D Vermeulen,"Quetiapine is a recently introduced atypical antipsychotic. Although adverse effects are mainly mild, more serious infrequent adverse effects including leucopenia are mentioned. We describe three case-reports concerning haematological adverse effects of quetiapine. Quetiapine was associated with leucopenia in two patients and clinically apparent agranulocytosis in one patient. Although a definite association has not been proven, clinicians should be aware of the possibility of agranulocytosis while using quetiapine. Further post-marketing surveys are required.",2002.0,0,1
359,11724088,Euglycemic clamp study in clozapine-induced diabetic ketoacidosis.,A M Avram; V Patel; H C Taylor; J P Kirwan; S Kalhan,"To describe the fifth case of clozapine-induced diabetic ketoacidosis (DKA) with complete resolution of abnormal glucose metabolism after discontinuation of clozapine as assessed by oral glucose tolerance testing (OGTT) and the first to be serially studied with markers of pancreatic autoimmunity; to demonstrate insulin resistance using the euglycemic clamp study and reduced pancreatic insulin reserve using intravenous glucose tolerance testing (IVGTT) in clozapine-induced diabetes mellitus and DKA, when the OGTT was normal; and to systematically review the previously described cases of clozapine-induced diabetes mellitus and DKA. A 33-year-old white man without past or family history of diabetes mellitus presented with DKA after eight months of clozapine therapy (50 mg twice daily). After treatment of DKA and discontinuation of clozapine, glucose tolerance and concurrent serum insulin concentrations reverted to normal as measured by two OGTT performed 60 and 320 days after resolution of DKA. Antiislet-cell antibodies, antiglutamic acid decarboxylase antibodies, and human insulin antibody were negative on two separate occasions. Euglycemic clamp study demonstrated insulin resistance manifested by a glucose disposal rate of approximately 55% of mean normal values. IVGTT demonstrated a low rate of glucose disappearance (KG = 0.95) and diminished first-phase insulin response when OGTT was normal, indicating impairment in insulin sensitivity and reduction in beta cell function 323 days after discontinuance of clozapine. This adverse reaction is considered probable according to the Naranjo probability scale. The occurrence of cases of DKA and new or worsening diabetes mellitus in patients using clozapine suggests a causal relationship. We hypothesize that the mechanism by which clozapine may produce glucose intolerance may require a preexisting latent defect in insulin secretion and insulin action. With the administration of clozapine, some of these patients may develop worsening insulin resistance and may fail to mount an appropriate compensatory beta cell insulin secretion for the degree of insulin resistance. As a consequence, hyperglycemia develops and its persistence results in glucose toxicity, further suppressing beta cell insulin secretion. Such combined defects in insulin secretion and sensitivity are known to be synergistic, leading to the development of abnormal glucose tolerance, which can be clinically manifested as a spectrum ranging from impaired glucose tolerance through severe hyperglycemia to DKA. Patients being started on clozapine should be carefully followed for the development or worsening of diabetes mellitus, regardless of the dose of the drug.",2002.0,0,0
360,11728844,Latent inhibition deficits in high-schizotypal normals: symptom-specific or anxiety-related?,H Braunstein-Bercovitz; T Rammsayer; H Gibbons; R E Lubow,"Latent inhibition (LI) is the phenomenon in which subjects who have repeatedly experienced an irrelevant stimulus perform more poorly on a new learning task with that stimulus than with a novel stimulus, presumably because of a decline in stimulus-specific attention. The present article reviews the literature on LI deficits in high-schizotypal normal subjects and schizophrenic patients. Although LI-deficits have been thought to be specific to these groups, evidence is presented that the effects may be related to the anxiety components of high-schizotypality and related pathologies.",2002.0,0,0
361,11728846,,,,,0,0
362,11735643,Amisulpride: a review of its use in the management of schizophrenia.,M P Curran; C M Perry,"Amisulpride, a substituted benzamide derivative, is a second-generation (atypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D2/D3 autoreceptors. At higher doses, amisupride antagonises postsynaptic dopamine D2 and D3 receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission. In patients with acute exacerbations of schizophrenia, the recommended dosage of amisulpride is 400 to 800 mg/day, although dosages < or =1200 mg/day may be administered. In comparative trials, amisulpride administered within this range (400 to 1200 mg/day) was as effective as haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in patients with acute exacerbations of schizophrenia with predominantly positive symptoms. Amisulpride was more effective than haloperidol but equally effective as risperidone in controlling negative symptoms. Amisulpride 400 to 800 mg/day was more effective than haloperidol, risperidone and flupenthixol in controlling affective symptoms in these patients. In randomised, double-blind trials involving patients with predominantly negative symptoms of schizophrenia, amisulpride 50 to 300 mg/day was more effective than placebo. Amisulpride is effective as maintenance therapy in patients with chronic schizophrenia. Long-term treatment with amisulpride was associated with improvements in quality of life and social functioning. Amisulpride is generally well tolerated. In well-controlled trials, the neurological tolerability profile (including ratings on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior to that of the conventional antipsychotics (haloperidol or flupenthixol), but was similar to that of the atypical antipsychotic risperidone. At low dosages of amisulpride (< or =300 mg/day), the incidence of adverse events (including extrapyramidal symptoms) reported with amisulpride was similar to that with placebo. In comparative trials, amisulpride 400 to 1200 mg/day showed efficacy in reducing overall symptomatology and positive symptoms similar to that of conventional antipsychotics and newer atypical antipsychotics in patients with acute exacerbations of schizophrenia. Moreover, its effective alleviation of negative and affective symptoms, its lower association with extrapyramidal symptoms and loss of cognitive function than conventional antipsychotics and its long-term efficacy justifies consideration of the use of higher dosages of amisulpride in this group of patients. Consequently, the dosage of amisulpride that is recommended in patients with acute exacerbations of schizophrenia is 400 to 800 mg/day, although dosages < or =1200 mg/day may be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be considered for the management of patients with negative symptoms of schizophrenia. Amisulpride is a first-line treatment option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.",2002.0,0,0
363,11735845,Antipsychotics and the risk of sudden cardiac death.,W A Ray; S Meredith; P B Thapa; K G Meador; K Hall; K T Murray,"Case reports link antipsychotic drugs with sudden cardiac deaths, which is consistent with dose-related electrophysiologic effects. Because this association has not been confirmed in controlled studies, we conducted a retrospective cohort study in Tennessee Medicaid enrollees, which included many antipsychotic users; there were also computer files describing medication use and comorbidity. The study was conducted before the introduction of risperidone and, thus, did not include the newer atypical agents. The cohort included 481,744 persons with 1,282,996 person-years of follow-up. This included 26,749 person-years for current moderate-dose antipsychotic use (>100-mg thioridazine equivalents), 31,864 person-years for current low-dose antipsychotic use, 37,881 person-years for use in the past year only, and 1 186,501 person-years for no use. The cohort had 1487 confirmed sudden cardiac deaths; from these, we calculated multivariate rate ratios adjusted for potential confounding factors. When current moderate-dose antipsychotic use was compared with nonuse, the multivariate rate ratio was 2.39 (95% confidence interval, 1.77-3.22; P<.001). This was greater than that for current low-dose (rate ratio, 1.30; 95% confidence interval, 0.98-1.72; P=.003) and former (rate ratio, 1.20; 95% confidence interval, 0.91-1.58; P<.001) use. Among cohort members with severe cardiovascular disease, current moderate-dose users had a 3.53-fold (95% confidence interval, 1.66-7.51) increased rate relative to comparable nonusers ( P<.001), resulting in 367 additional deaths per 10,000 person-years of follow-up. Patients prescribed moderate doses of antipsychotics had large relative and absolute increases in the risk of sudden cardiac death. Although the study data cannot demonstrate causality, they suggest that the potential adverse cardiac effects of antipsychotics should be considered in clinical practice, particularly for patients with cardiovascular disease.",2002.0,0,0
364,11735847,"Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-based approach.",B C Lund; P J Perry; J M Brooks; S Arndt,"Numerous case reports have linked clozapine to the development of diabetes mellitus and hyperlipidemia in patients with schizophrenia. However, investigators have been unable to clearly demonstrate this association when compared with a control group receiving conventional antipsychotics. Medical and pharmacy claims from the Iowa Medicaid program were used to compare incidence rates for diabetes, hyperlipidemia, and hypertension in 552 patients receiving clozapine and 2461 patients receiving conventional antipsychotics (eg, haloperidol, chlorpromazine hydrochloride), with the use of a retrospective cohort design. Logistic regression was used to compare incidence rates adjusting for age, sex, and duration of available follow-up. No significant differences in overall incidence rates for diabetes, hyperlipidemia, or hypertension were observed in patients receiving clozapine vs conventional antipsychotics. However, among younger patients (aged 20-34 years), clozapine administration was associated with a significantly increased relative risk of diabetes (2.5 [95% confidence interval, 1.2-5.4]) and hyperlipidemia (2.4 [95% confidence interval, 1.1-5.2]), but not hypertension (0.9 [95% confidence interval, 0.4-2.0]). These data suggest that clozapine may not be an independent cause of diabetes or hyperlipidemia, but instead acts as an effect modifier in susceptible populations by increasing weight or affecting insulin secretion and resistance. This finding requires confirmation in other settings and patient populations and with the other atypical antipsychotics (risperidone, olanzapine, and quetiapine fumarate). The potential long-term medical and economic implications of the early induction of diabetes and hyperlipidemia in patients with schizophrenia warrant further study.",2002.0,1,1
365,11738531,Affective reactivity of language and right-ear advantage in schizophrenia.,Joseph P Rhinewine; Nancy M Docherty,"A subset of schizophrenic patients has demonstrated increased language dysfunction in affectively stressful, compared to non-stressful conditions. Affective reactivity of right-ear advantage has been demonstrated in studies of dichotic listening in schizophrenia. The present study assessed whether participants who showed affective reactivity of speech were also those who showed affective reactivity of right-ear advantage. Data from 18 schizophrenic outpatients were analyzed. Affective reactivity of language was associated with affective reactivity of right-ear advantage. Findings should be regarded as preliminary due to the small sample size; however, they may potentially contribute to construct the validity of affective reactivity as a process discriminator in schizophrenia.",2002.0,1,1
366,11738535,Arithmetic fact retrieval and working memory in schizophrenia.,M Kiefer; A Apel; M Weisbrod,"Despite its importance in every-day life and vocational rehabilitation, arithmetic ability has rarely been investigated in schizophrenic patients. Those few studies reporting arithmetic deficits in schizophrenia, however, administered complex calculation tasks which drew not only on arithmetic abilities, but also on working memory resources known to be impaired in schizophrenia. In the present study, arithmetic abilities and working memory functions were investigated in schizophrenic patients (n=24) and healthy control subjects (n=24). Arithmetic fact retrieval was assessed in single-digit multiplication and corresponding division problems using a result verification task which minimized working memory demands. Problem size and the disparity of the proposed result were manipulated. The storage component of working memory was tested with a digit span forward task and the executive control component with a digit span backward as well as with verbal fluency tasks. Schizophrenic patients performed worse than controls only in the executive tasks. Digit span forward was preserved. In the arithmetic tasks, groups did not differ from each other, and a similar pattern of task manipulations was obtained. Hence, despite the executive control deficit retrieval of arithmetic facts is preserved in schizophrenia. Moreover, the same underlying cognitive processes as in control subjects are involved.",2002.0,0,1
367,11738537,Does cognitive function improve with quetiapine in comparison to haloperidol?,Dawn I Velligan; John Newcomer; Joseph Pultz; John Csernansky; Anne L Hoff; Roderick Mahurin; Alexander L Miller,"Recent evidence suggests that schizophrenia patients taking atypical antipsychotic medications may perform better on some tests of cognitive function than those treated with older antipsychotics. The current study compared the effects of quetiapine and haloperidol on measures of executive function, memory and attention. Subjects were 58 stable outpatients with schizophrenia (DSM III-R) who received a battery of cognitive tests as part of a randomized, double-blind, multi-site clinical efficacy study conducted by AstraZeneca Pharmaceuticals. Cognitive assessments were conducted prior to randomization when patients were receiving < or =30 mg haloperidol or equivalent (mean: 9.2mg/day haloperidol equivalents), and again after 24 weeks of fixed-dose treatment with either quetiapine 600 or 300 mg/day or haloperidol 12 mg/day. Analyses of covariance with planned comparisons were used to compare scores on cognitive measures at the end of 24 weeks by treatment group with baseline cognitive function scores used as covariates. Patients receiving quetiapine 600 mg/day improved to a greater extent than patients receiving haloperidol on overall cognitive function (p<0.02). Specific differences were found for executive function (Verbal Fluency Test, p<0.04), attention (Stroop Color Word Test, p<.03) and verbal memory (Paragraph Recall Test, p<0.02). Treatment group differences were not solely due to benztropine use, medication side effects, or changes in symptomatology. Treatment with quetiapine at higher doses (600 mg/day) relative to haloperidol appears to have a positive impact on important domains of cognitive performance that have been found to predict role function and community outcomes in patients with schizophrenia.",2002.0,1,1
368,11739062,National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer disease trial methodology.,L S Schneider; P N Tariot; C G Lyketsos; K S Dagerman; K L Davis; S Davis; J K Hsiao; D V Jeste; I R Katz; J T Olin; B G Pollock; P V Rabins; R A Rosenheck; G W Small; B Lebowitz; J A Lieberman,"The authors describe the development of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) protocol for Alzheimer disease (AD), a trial developed in collaboration with the National Institute of Mental Health (NIMH), assessing the effectiveness of atypical antipsychotics for psychosis and agitation occurring in AD outpatients. They provide an overview of the methodology utilized in the trial as well as the clinical-outcomes and effectiveness measures that were implemented.",2002.0,0,0
369,11743592,Pharmacoeconomic evaluation of clozapine in treatment-resistant schizophrenia: a cost-utility analysis.,P I Oh; M Iskedjian; A Addis; K Lanctôt; T R Einarson,"The high costs and efficacy of clozapine warrant a systematic pharmacoeconomic evaluation to assess its relative cost-utility compared with that of older antipsychotic therapies. An economic analysis of clozapine consisted of a meta-analysis and a cost-utility analysis. Clozapine was compared with haloperidol and chlorpromazine. An incidence-based deterministic decision analysis was used to model the management of chronic schizophrenia over one year. Probabilities of clinical outcomes were obtained from a random effects, single arm meta-analysis. Utility weights were evaluated in a cohort of patients by using a standard gamble methodology. A government payer perspective was adopted for this analysis. Clozapine was the dominant therapy in this analysis because it was associated with the lowest overall expected cost and highest expected number of quality-adjusted life years (QALYs). Compared with chlorpromazine, clozapine might save $38,879/year while producing 0.04 more QALYs. This analysis was limited in that studies were of short duration, the sample size for health utility analysis was small and the analysis was based on a model. Clozapine appears to be a very cost effective therapy in patients with treatment-resistant schizophrenia compared with haloperidol and chlorpromazine.",2002.0,0,0
370,11747852,Clozapine-associated diabetes.,E Koller; B Schneider; K Bennett; G Dubitsky,"Clozapine is a potent antipsychotic agent that has been marketed since 1990. Several published reports of diabetes mellitus occurring with clozapine therapy have appeared during the past 5 years. Because the risk and characteristics of clozapine-associated diabetes mellitus remain unclear, we conducted a descriptive epidemiologic study of spontaneous adverse event reports of hyperglycemia occurring in clozapine-treated patients. The Food and Drug Administration MedWatch surveillance program was queried (January 1990 through February 2001), and the results were pooled with published cases. Parameters assessed included documentation of diabetes, clinical severity, new-onset diabetes versus exacerbation of preexisting disease, demographic characteristics of patients, time to onset of hyperglycemia, and effect of drug discontinuation and rechallenge. We identified 384 reports. Of these, new-onset diabetes was diagnosed definitively in 242 patients, and 54 patients had exacerbation of preexisting disease. The mean (+/- SD) age was 40 +/- 12 years (range, 13 to 77). The male:female ratio was 2:0. Most cases appeared within 6 months of initiating clozapine therapy. One patient developed diabetes following a single 500-mg dose. There were 80 cases of metabolic acidosis or ketosis. Twenty-five patients died during hyperglycemic episodes. Forty-six patients had improved glycemic control after discontinuation or dose reduction of the drug.A causal relationship between clozapine and diabetes is suggested by the number of reports, the temporal relation to clozapine initiation, the relatively young age of the affected patients, and the prompt reversibility on withdrawal of the drug in some patients. The severity of reported cases ranged from mild glucose intolerance to diabetic ketoacidosis or hyperosmolar coma.",2002.0,0,1
371,11748775,A double-blind randomised comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients.,W C Chan; L C Lam; C N Choy; V P Leung; S W Li; H F Chiu,"Behavioural and psychological symptoms (BPSD) are common during the course of dementia and present severe problems to patients and their caregivers. To assess the therapeutic efficacy and safety of haloperidol and risperidone in treating BPSD in Chinese dementia patients. A 12-week double-blind randomised comparison of haloperidol and risperidone treatments was conducted in 58 patients with DSM-IV diagnosis of dementia of Alzheimer's type or vascular dementia. They were randomly assigned to receive flexible doses (0.5 to 2 mg/day) of haloperidol or risperidone. Clinical response was evaluated using the Cohen-Mansfield Agitation Inventory (CMAI), the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), Simpson-Angus Scale, Functional Assessment Staging and Cantonese version of the Mini-Mental State Examination. The mean doses at the last week were 0.90 mg/day of haloperidol and 0.85 mg/day of risperidone. Both haloperidol and risperidone significantly reduced the severity of BPSD (scores on CMAI and BEHAVE-AD), with no significant between-group differences. Haloperidol-treated patients showed a worsening on Simpson-Angus scale while there was no significant change in this measure in risperidone-treated patients. Low-dose haloperidol and risperidone were well tolerated and associated with reductions in the severity and frequency of behavioural symptoms in subjects with dementia. Risperidone may have a more favourable risk-benefit profile in view of its lower propensity to induce extrapyramidal symptoms.",2002.0,1,1
372,11753745,[Clinical relevance and treatment possibilities of rapid cycling in patients with bipolar disorder].,B Amann; R Stampfer; F Schmidt; P Mikhaiel; B Hummel; A Sterr; M Schäfer; H Grunze,"In the actual version of the WHO diagnostic guidelines, the ICD-10, subtypes of bipolar disorder are not specified, in contrast to the American DSM-IV, where bipolar disorder has already been differentiated in bipolar I (severe manic and depressive episodes) and bipolar II disorder (depressive and hypomanic episodes). Furthermore, aspects of the longitudinal course of the illness, like rapid cycling (RC), are reflected as well. Rapid cycling is defined as four or more affective episodes within one year of the illness. It has been postulated that rapid cycling is related with a poor response to lithium, to the same extent as mixed episodes or an atypical onset (depressive episode first) of the disease. Here, the current status of alternative pharmacological and supportive therapy of rapid cycling is presented and discussed. Furthermore, the article also displays biological parameters associated with rapid cycling like higher prevalence in women, hypothyreoidism, subtype of bipolar disorder, COMT-allele, influence of sleep or risk of antidepressant induced cycling.",2002.0,0,0
373,11755456,A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms.,Malcolm Peet; David F Horrobin; E-E Multicentre Study Group,"The objective was to test effects of ethyl eicosapentaenoate (E-E) on persistent ongoing symptoms in patients receiving different types of anti-schizophrenic drugs, typical antipsychotics, new atypical antipsychotics, and clozapine. 115 patients with DSM-IV-defined schizophrenia were studied, 31 on clozapine, 48 on new atypical drugs and 36 on typical antipsychotics. Placebo or 1, 2 or 4 g/day of E-E was given for 12 weeks in addition to the background medication. The main assessment was change from baseline to 12 weeks on the PANSS and its sub-scales. There were no treatment-related side effects or adverse biochemical or haematological effects. Patients on 2 and 4 g/day E-E showed significant reductions in triglyceride levels which had been elevated by clozapine. In patients given 2 g/day E-E there were improvements on the PANSS and its sub-scales, but there was also a large placebo effect in patients on typical and new atypical antipsychotics and no difference between active treatment and placebo. In patients on clozapine, in contrast, there was little placebo response, but a clinically important and statistically significant effect of E-E on all rating scales. This effect was greatest at 2 g/day. There was a positive relationship between improvement on rating scales and rise in red blood cell arachidonic acid concentration.",2002.0,0,0
374,11763004,The effect of olanzapine treatment on m-chlorophenylpiperazine-induced hormone release in schizophrenia.,F E Scheepers; C C Gespen de Wied; R S Kahn,"In addition to dopamine, serotonin (5-hydroxytryptamine, 5-HT) has been reported to play an important role in schizophrenia. Besides blocking dopamine, atypical antipsychotics also block 5-HT receptors. The clinical efficacy of the atypical antipsychotic clozapine is associated with the 5-HT antagonistic action of the drug and a high serotonergic tone before treatment. The atypical antipsychotic olanzapine has a receptor-binding profile similar to that of clozapine. The present study investigated whether treatment with olanzapine blocks hormone release induced by the 5-HT2c agonist m-chlorophenylpiperazine (m-CPP) and, if so, whether this 5-HT antagonistic effect is related to treatment response. Eighteen male schizophrenic patients participated in this study. All patients were challenged with m-CPP (0.5 mg/kg orally) in a double-blind, randomized, placebo-controlled design after a drug-free period of at least 2 weeks. Adrenocorticotropic hormone (ACTH), cortisol, and prolactin plasma levels were measured every 30 minutes up to 210 minutes after challenge. Patients were treated for 6 weeks with 10 mg olanzapine daily in an open design, after which the challenge tests were repeated. Olanzapine significantly blocked m-CPP-induced ACTH, cortisol, and prolactin release, suggesting that it is a potent 5-HT2c antagonist in vivo. This 5-HT antagonistic effect of olanzapine was not significantly correlated with treatment response. Also, no significant correlation was found between m-CPP-induced hormone release before treatment and clinical response after treatment with olanzapine. These findings suggest that olanzapine is a potent 5-HT2c antagonist in vivo but that this is unrelated to its clinical efficacy in this nonrefractory sample of schizophrenic patients.",2002.0,0,0
375,11763010,"Therapeutic effect of pirenzepine for clozapine-induced hypersalivation: a randomized, double-blind, placebo-controlled, cross-over study.",Y M Bai; C C Lin; J Y Chen; W C Liu,"The objective of this study was to investigate the efficacy of pirenzepine in the treatment of clozapine-induced hypersalivation. Pirenzepine is reported to counteract hypersalivation by its selective antagonistic activity on the M4-muscarinic receptor, which is stimulated by clozapine. Twenty patients with clozapine-induced hypersalivation underwent a random-order, double-blind, placebo-controlled, cross-over trial which lasted 8 weeks each for the pirenzepine and placebo investigations, with a 4-week washout period in between. The severity of hypersalivation was assessed using an objective measure: saliva production monitored through the diameter of wetted surface on tissue paper placed over the patient's pillow. Our study showed that pirenzepine had no significant therapeutic effect on hypersalivation compared with placebo, suggesting that hypersalivation induced by clozapine might have a neurobiological basis other than the M4-muscarinic receptor.",2002.0,0,0
376,11768836,"A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the quetiapine experience with safety and tolerability (QUEST) study.",J Mullen; M D Jibson; D Sweitzer,"The few published direct comparative studies of the tolerability and efficacy of atypical antipsychotic agents were performed in relatively homogeneous populations that may not be typical of patients seen in clinical practice. The Quetiapine Experience with Safety and Tolerability (QUEST) study compared the relative safety, tolerability, and efficacy of quetiapine and risperidone in outpatients with a broad range of psychotic symptoms. This was a multicenter, 4-month, open-label, randomized clinical trial. Patients were randomized in a 3:1 ratio to receive quetiapine or risperidone. Doses were adjusted to maximize efficacy and to minimize adverse events. Extrapyramidal symptoms (EPS) were assessed with an EPS checklist; adverse events were recorded. Efficacy was assessed using the Clinical Global Impression (CGI) scale, Positive and Negative Symptom Scale (PANSS), and Hamilton Rating Scale for Depression (HAM-D). A total of 728 patients were randomized, 553 to quetiapine and 175 to risperidone. Mean prescribed doses over the study period were 253.9 mg/d quetiapine and 4.4 mg/d risperidone. At the end of 4 months, EPS declined in both treatment groups, but quetiapine-treated patients were significantly less likely to require dose adjustment or concurrent anti-EPS medication (P < 0.001). The most common adverse events in the quetiapine and risperidone groups were somnolence (31.3% and 15.4%, respectively), dry mouth (14.5% and 6.9%), and dizziness (12.7% and 6.9%). Overall, tolerance to side effects with the 2 drugs, measured by dropout rates, was comparable. At each visit, a higher percentage of quetiapine-treated patients showed improvement on the CGI scale, but there were no significant between-group differences on the PANSS. At end point, quetiapine-treated patients had significantly lower HAM-D scores (P = 0.028). The results of this study suggest that quetiapine is as effective as risperidone for the treatment of psychotic symptoms, is more effective for depressive symptoms, may have a more favorable EPS profile, and has comparable overall tolerability.",2002.0,1,1
377,11769820,The pharmacovigilance of olanzapine: results of a post-marketing surveillance study on 8858 patients in England.,P N Biswasl; L V Wilton; G L Pearcel; S Freemantle; S A Shakir,"Olanzapine is an 'atypical' antipsychotic indicated for the treatment of schizophrenia. We analysed adverse events (AEs) reported in primary practice in England. Dispensed prescriptions issued between December 1996 and May 1998 provided exposure data. Questionnaires sent to general practitioners provided outcomes. Frequently reported AEs were: drowsiness/sedation (n = 19), extrapyramidal disorder (n = 13) and unspecified side-effects (n = 33). Events with highest incidence density in first month and reason for stopping were: drowsiness/sedation [n = 153, incidence density (ID)1 18.9], weight gain (n = 117, ID1 8.9) and malaise/lassitude (n = 65, ID1 5.2). Extrapyramidal disorders were more common in elderly population (> 70 years, ID1 3.6, risk 26.0 per 1,000 patients) compared to < 70 years (ID1 1.1, risk 8.4 per 1,000 patients). Serious suspected adverse reactions were neuroleptic malignant syndrome (n = 1) and angioneurotic ooedema (n = 2). There were eight reports of diabetes mellitus assessed as possibly due to olanzapine. Diabetes mellitus was an unlabelled AE and possible signal generated by prescription-event monitoring.",2002.0,0,1
378,11772722,Fluoxetine and olanzapine for resistant depression.,Franco Benazzi,,2002.0,0,0
379,11773657,Pharmacologic treatment of hospitalized patients with schizoaffective disorder.,Julianne Flynn; Thomas A Grieger; David M Benedek,"This study examined changes in the pharmacologic treatment of 70 patients who were hospitalized with a diagnosis of schizoaffective disorder at some time during a six-year period. An increasing use of divalproex sodium and atypical antipsychotics instead of lithium and conventional antipsychotics was observed. The use of a combination of an antipsychotic and a thymoleptic medication was more common than monotherapy, and physicians tended to continue antidepressants if patients had a history of depression. Patients with a new diagnosis of schizoaffective disorder were stabilized less quickly than those with a previous diagnosis. The use of divalproex sodium and newer antipsychotics did not reduce the time to stabilization in routine clinical practice.",2002.0,0,0
380,11775043,"Olanzapine treatment of female borderline personality disorder patients: a double-blind, placebo-controlled pilot study.",M C Zanarini; F R Frankenburg,"The intent of this study was to compare the efficacy and safety of olanzapine versus placebo in the treatment of women meeting criteria for borderline personality disorder (BPD). We conducted a double-blind, placebo-controlled study of olanzapine in 28 female subjects meeting Revised Diagnostic Interview for Borderlines and DSM-IV criteria for BPD. The subjects were randomly assigned to olanzapine or placebo in a 2:1 manner. Treatment duration was 6 months. Primary outcome measures were self-reported changes on anxiety, depression, paranoia, anger/hostility, and interpersonal sensitivity scales of the Symptom Checklist-90. Nineteen subjects were randomly assigned to olanzapine; 9. to placebo. When random effects regression modeling of panel data was used, controlling for baseline level of severity, olanzapine was associated with a significantly (p < .05) greater rate of improvement over time than placebo in all of the symptom areas studied except depression. Weight gain was modest in the olanzapine-treated group but was significantly higher than in those treated with placebo (p < .02). In addition, no serious movement disorders were noted. Olanzapine appears to be a safe and effective agent in the treatment of women with criteria-defined BPD, significantly affecting all 4 core areas of borderline psychopathology (i.e., affect, cognition, impulsivity, and interpersonal relationships).",2002.0,0,0
381,11777497,Validation of the behavioural activity rating scale (BARS): a novel measure of activity in agitated patients.,R H Swift; E P Harrigan; J C Cappelleri; D Kramer; L P Chandler,"We report psychometric results of the Behavioural Activity Rating Scale (BARS) using data from three Phase III clinical trials of intramuscular ziprasidone in acutely agitated patients with psychosis (Studies 1 and 2) or in stable psychotic patients (Study 3). Convergent validity and divergent validity were assessed with baseline data from Studies 1 and 2 in subjects with acute agitation. To investigate convergent validity, we sought Pearson and Spearman correlation of BARS scores with scores on the Clinical Global Impression of Severity (CGI-S) Scale and a predefined cluster of agitation-related items from the Positive and Negative Syndrome Scale (PANSS). For divergent validity, we sought Pearson and Spearman correlation between BARS scores and a predefined cluster of PANSS items measuring negative symptoms. Discriminant validity was investigated with the help of subjects with moderate psychopathology (Study 3). Wilcoxon rank-sum and two-sample t tests determined whether mean (or median) BARS scores differed between subjects with acute agitation (Studies 1 and 2) and moderate psychopathology (Study 3). Responsiveness to treatment effect and rater reliability were also evaluated. In Study 2, Pearson correlation coefficients of BARS scores with PANSS agitation items and CGI-S were moderate (convergent validity) and statistically significant (P<0.005). The correlation between BARS scores and PANSS negative component scores was low (divergent validity). Treatment effect size was larger for BARS than for PANSS agitation items and CGI-S (responsive to treatment differences). Virtually perfect inter- and intra-rater reliability was achieved. Study 1 produced similar results. BARS showed psychometrically valid properties for measurement of behavioral activity in acutely agitated patients with psychosis.",2002.0,0,0
382,11777671,Olanzapine treatment for patients with schizophrenia and substance abuse.,K H Littrell; R G Petty; N M Hilligoss; C D Peabody; C G Johnson,"The objective of this study was to evaluate the efficacy and safety of olanzapine in patients with schizophrenia and comorbid substance abuse disorders. Thirty patients who met DSM-IV criteria for schizophrenia or schizoaffective disorder as well as criteria for substance abuse or substance dependence, were treated in a 12-month prospective, open-label trial of olanzapine. Patients were evaluated with multiple efficacy and safety measures at baseline and then monthly thereafter. Statistically significant improvement was noted in psychopathology, levels of hope, and safety measures. Seventy percent (n = 21) of the patients achieved early full substance abuse remission at the end of the study period, while 30% (n = 9) achieved early partial substance abuse remission. Our results indicate that olanzapine treatment improved psychopathology, increased hopefulness, and reduced antipsychotic-associated side effects. The benefits observed with olanzapine treatment may contribute to the patients' substance abuse remission.",2002.0,1,1
383,11777998,A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia.,John G Csernansky; Ramy Mahmoud; Ronald Brenner; Risperidone-USA-79 Study Group,"Prevention of relapse is a major goal of maintenance treatment in patients with psychotic disorders. We performed a long-term comparison of a newer, atypical antipsychotic drug, risperidone, and an older, conventional neuroleptic drug, haloperidol, in terms of the rate of relapse in patients with schizophrenia and schizoaffective disorder. In a double-blind, prospective study at 40 sites, we randomly assigned adult outpatients in stable condition with chronic schizophrenia or schizoaffective disorder to receive treatment with flexible doses of either risperidone or haloperidol for a minimum of one year. Of the 397 patients who underwent randomization, data from 2 were excluded because they did not receive study medication; data from all 30 patients from one site were excluded by the sponsor, the Janssen Research Foundation, because of concern about the integrity of the data. The median duration of treatment was 364 days in the risperidone group and 238 days in the haloperidol group (P=0.02). Of the 177 patients assigned to risperidone and the 188 assigned to haloperidol who remained in the analysis, 44.1 percent and 52.7 percent, respectively, discontinued treatment for reasons other than relapse. The Kaplan-Meier estimate of the risk of relapse at the end of the study was 34 percent for the risperidone group and 60 percent for the haloperidol group (P<0.001); the risk ratio for relapse with haloperidol, from the Cox model, was 1.93 (95 percent confidence interval, 1.33 to 2.80; P<0.001). Early discontinuation of treatment for any reason was more frequent among haloperidol-treated patients (risk ratio, 1.52; 95 percent confidence interval, 1.18 to 1.96). Patients in the risperidone group had greater reductions in the mean severity of both psychotic symptoms and extrapyramidal side effects than those in the haloperidol group. Adult outpatients with clinically stable schizophrenia or schizoaffective disorder have a lower risk of relapse if they are treated with risperidone than if they are treated with haloperidol.",2002.0,1,1
384,11779284,Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy.,Mauricio Tohen; K N Roy Chengappa; Trisha Suppes; Carlos A Zarate; Joseph R Calabrese; Charles L Bowden; Gary S Sachs; David J Kupfer; Robert W Baker; Richard C Risser; Elisabeth L Keeter; Peter D Feldman; Gary D Tollefson; Alan Breier,"A 6-week double-blind, randomized, placebo-controlled trial was conducted to determine the efficacy of combined therapy with olanzapine and either valproate or lithium compared with valproate or lithium alone in treating acute manic or mixed bipolar episodes. The primary objective was to evaluate the efficacy of olanzapine (5-20 mg/d) vs placebo when added to ongoing mood-stabilizer therapy as measured by reductions in Young Mania Rating Scale (YMRS) scores. Patients with bipolar disorder (n = 344), manic or mixed episode, who were inadequately responsive to more than 2 weeks of lithium or valproate therapy, were randomized to receive cotherapy (olanzapine + mood-stabilizer) or monotherapy (placebo + mood-stabilizer). Olanzapine cotherapy improved patients' YMRS total scores significantly more than monotherapy (-13.11 vs -9.10; P = .003). Clinical response rates (> or = 50% improvement on YMRS) were significantly higher with cotherapy (67.7% vs 44.7%; P< .001). Olanzapine cotherapy improved 21-item Hamilton Depression Rating Scale (HAMD-21) total scores significantly more than monotherapy (4.98 vs 0.89 points; P< .001). In patients with mixed-episodes with moderate to severe depressive symptoms (DSM-IV mixed episode; HAMD-21 score of > or = 20 at baseline), olanzapine cotherapy improved HAMD-21 scores by 10.31 points compared with 1.57 for monotherapy (P< .001). Extrapyramidal symptoms (Simpson-Angus Scale, Barnes Akathisia Scale, Abnormal Involuntary Movement Scale) were not significantly changed from baseline to end point in either treatment group. Treatment-emergent symptoms that were significantly higher for the olanzapine cotherapy group included somnolence, dry mouth, weight gain, increased appetite, tremor, and slurred speech. Compared with the use of valproate or lithium alone, the addition of olanzapine provided superior efficacy in the treatment of manic and mixed bipolar episodes.",2002.0,1,1
385,11780884,"A pilot double-blind, dose-comparison study of risperidone in drug-naive, first-episode schizophrenia.",H Y Lane; W H Chang; C C Chiu; M C Huang; S H Lee; J Y Chen,,2002.0,0,0
386,11782241,Donepezil in schizophrenia--is it helpful? An experimental design case study.,G W MacEwan; T S Ehmann; I Khanbhai; C Wrixon,"To assess the clinical and cognitive effects of adding donepezil, a reversible acetylcholinesterase inhibitor, to the risperidone treatment of a high functioning stable out-patient with schizophrenia. Case study using an experimental ABAB design. Assessments were completed objectively by standardized neuropsychological tests and clinical rating scales and subjectively with visual analogue scales. Strong improvements attributable to donepezil were found for verbal fluency and the patient's subjective response. No adverse changes were noted in psychiatric symptoms or side effects. Cholinergic enhancement as an adjunctive treatment in schizophrenia should be explored in larger controlled trials.",2002.0,0,0
387,11791952,An open trial of olanzapine in the treatment of patients with psychotic depression.,E B Nelson; E Rielage; J A Welge; P E Keck,"Compared to major depression without psychosis, psychotic depression often responds poorly to treatment with tricyclic antidepressants alone. Atypical antipsychotics, which appear to possess thymoleptic properties, may represent a new treatment alternative for patients with psychotic mood disorders. This open-label, pilot study evaluated the efficacy of olanzapine monotherapy in patients with psychotic depression. Seven inpatients who met DSM-IV criteria for a major depressive episode (unipolar) with psychotic features participated in a 10-week open-label trial of olanzapine 10-20 mg/day. The Hamilton Rating Scale for Depression (HRSD), the Scale for the Assessment of Positive Symptoms (SAPS), and the Clinical Global Impression Scale (CGI) were performed at each visit to evaluate clinical response. Four out of the 5 study completers responded during the trial. Overall, there was a statistically significant change between baseline and final visit on the SAPS, HRSD, and the CGI Scale (p < .001). The results of this pilot study suggest that olanzapine may be an effective treatment for some patients with unipolar psychotic depression. However, these observations require replication in randomized, controlled trials.",2002.0,0,0
388,11793611,"Risk of extrapyramidal syndromes with haloperidol, risperidone, or olanzapine.",I Schillevoort; A de Boer; R M Herings; R A Roos; P A Jansen; H G Leufkens,"To compare the risk of extrapyramidal syndrome (EPS) between risperidone, olanzapine, and haloperidol, taking into account patients' past antipsychotic drug use and past EPS. Data were obtained from the PHARMO-database, containing filled prescriptions of 450,000 community-dwelling people in the Netherlands from 1986 through 1999. We defined cohorts of first-time users of haloperidol, risperidone, or olanzapine aged 15 to 54 years. In the first 90 days of treatment, we assessed the occurrence of EPS, defined as first use of any antiparkinsonian agent. We estimated relative risks of EPS for risperidone and olanzapine versus haloperidol using a Cox proportional hazards model. Patients were subdivided according to prior use of antipsychotic and antiparkinsonian drugs. We identified 424 patients starting treatment with haloperidol, 243 with risperidone, and 181 with olanzapine. Prior use of antipsychotic plus antiparkinsonian medication was significantly more frequent among users of risperidone and olanzapine than in those using haloperidol (36.2%, 40.3%, and 4.5%, respectively; p < 0.001). Within most subgroups of comparable treatment history, patients using risperidone and olanzapine showed reduced risks of EPS compared with haloperidol, although some of these findings did not reach statistical significance (RR 0.03-0.22). However, this was not observed for patients using risperidone who had experienced EPS in the past (RR 1.30; 95% CI 0.24 to 7.18). In general, we observed reduced risks of EPS for risperidone and olanzapine compared with haloperidol within subgroups of patients with a similar treatment history. However, the added value of risperidone in patients who have experienced EPS in the past needs further study.",2002.0,0,1
389,11793612,Effects of risperidone on gonadal axis hormones in schizophrenia.,Y Kaneda,"To investigate the effects of risperidone on the hypothalamo-pituitary-gonadal (HPG) axis of chronic schizophrenic male inpatients medicated regularly. Subjects included six inpatients who were diagnosed according to the Diagnostic and Statistical Manual, Fourth Edition, criteria for schizophrenia, and were termed treatment-refractory. Each patient gave informed consent for the research involved in this study. The neuroendocrine studies were done before and during risperidone administration. Patients took a mean dose of risperidone 9.5 mg/d for a mean period of 64.2 days. Psychotic symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). Prolactin (PRL) increased significantly during risperidone administration. However, luteinizing hormone, follicle-stimulating hormone, and testosterone did not show significant difference between blood concentrations before and during risperidone administration. Scores of the BPRS total, thought disturbance factor, and tension decreased significantly during risperidone administration. Throughout the study, none of the patients experienced clinically significant problems associated with elevated PRL concentrations including gynecomastia and/or sexual dysfunction. Addition of risperidone produced significant improvement of psychotic symptoms in treatment-resistant schizophrenic patients, and an increase in basal blood PRL concentrations, but not in basal blood HPG axis hormone concentrations. This preliminary result warrants further double-blind evaluation with a larger sample.",2002.0,0,0
390,11794418,Comparison of risperidone with olanzapine in elderly patients with dementia and psychosis.,Vicki L Ellingrod; Susan K Schultz; Karen Ekstam-Smith; Eric Kutscher; Carolyn Turvey; Stephan Arndt,"To compare the effects of risperidone and olanzapine on cognition in elderly patients with dementia and psychosis, and to compare the side effects of these drugs. Single-blind, multicenter, observational study. Four rural nursing care facilities. Nineteen elderly patients with dementia and psychosis. Eleven patients were treated with risperidone, eight with olanzapine. Rating assessments were completed at baseline, 1 month, and 2 months. Simple paired and unpaired t tests determined between- and within-group differences. Social functioning, including activities of daily living, improved over baseline in both groups (p=0.03). Cognition declined significantly (p<0.05) in the risperidone group; comparatively more side effects occurred and blood pressure decreased (p<0.05) in the olanzapine group. When compared with each group cross-sectionally at baseline and end point, however, the two groups did not differ significantly. Improvements in social functioning in all 19 patients suggest that both risperidone and olanzapine may help improve functioning in elderly patients with dementia and psychosis. Cognitive and side effect profiles of these drugs may differ substantially. Further study is needed to determine patient subpopulations who may be able to tolerate one drug over another.",2002.0,1,1
391,11799340,"Risperidone in the treatment of tourette syndrome: a double-blind, placebo-controlled trial.",Yves Dion; Lawrence Annable; Paul Sandor; Guy Chouinard,"A double-blind, placebo-controlled trial was performed to determine the efficacy and tolerability of 8 weeks of treatment with risperidone in the management of 48 adolescent and adult patients with Tourette syndrome. Twenty-four patients were randomly assigned to treatment with risperidone in doses of 0.5 to 6.0 mg/day, and 24 were assigned to placebo. The dosage of medication was increased in fixed increments during the first week of double-blind treatment and thereafter in a flexible dose regimen according to clinical response. Risperidone, at a median dose of 2.5 mg/day (range, 1 to 6 mg/day), was found to be significantly ( p < 0.05) superior to placebo on the Global Severity Rating of the Tourette Syndrome Severity Scale. The proportion of patients who improved by at least one point on this seven-point scale was 60.8% in the risperidone group and 26.1% in the placebo group. Treatment with risperidone was accompanied by an improvement in global functioning in patients with average to above-average impairment at baseline as measured by the Global Assessment of Functioning scale. With respect to extrapyramidal symptom scores measured on the Extrapyramidal Symptom Rating Scale, hypokinesia and tremor increased in the risperidone group, but the effect on tremor was largely confined to subjects with higher baseline tremor scores. There were no significant differences in dystonic reactions, dyskinetic movements, subjective parkinsonism, or akathisia. Risperidone did not increase obsessive-compulsive symptoms. Fatigue and somnolence were the most common adverse events associated with risperidone.",2002.0,0,0
392,11800502,"Lorazepam, sedation, and conscious recollection: a dose-response study with healthy volunteers.",C Huron; A Giersch; J M Danion,"The role of sedation in the benzodiazepine-induced impairment of conscious recollection is still subject to debate. The aim of this study was to investigate further the role of sedation using the Remember-Know procedure and a physiological measure of sedation based on pupillography in addition to standard measures of sedation and attention (digit-symbol substitution task, symbol cancellation task, self-rated sedation). Twelve subjects were tested after the intake of placebo, lorazepam 0.026 mg/kg and lorazepam 0.038 mg/kg, administered in a randomized order, with a minimum interval of 8 days between each administration. On a recognition memory task, they were asked to give 'Remember', 'Know' or 'Guess' responses to items that were recognized on the basis of conscious recollection, familiarity, or guessing, respectively. Lorazepam selectively impaired recognition based on 'Remember' responses. This impairment was greater in the lorazepam 0.038 mg/kg than in the lorazepam 0.026 mg/kg groups. Measures of sedation were not correlated with the proportion of 'Remember' responses. These results suggest that sedation alone cannot account for the impairment of conscious recollection induced by lorazepam.",2002.0,0,0
393,11803729,Clinical advantages of amisulpride in the treatment of acute schizophrenia.,T Burns; R Bale,"Five studies have been conducted with the atypical anti-psychotic amisulpride (100-1200 mg/day) involving 1358 patients with acute exacerbations of schizophrenia; four studies were short-term (4-8 weeks), double-blind studies and one was a 12-month, open, randomized comparison. Amisulpride improved positive symptoms consistently, and changes were more pronounced than with haloperidol, flupenthixol and risperidone; amisulpride showed a more rapid onset of action compared to haloperidol, and improvement in negative symptoms was more effective than with any comparator. An optimum response was obtained with amisulpride doses 400-800 mg/day. The long-term study confirmed the usefulness of amisulpride for maintenance treatment in schizophrenia, with a clear advantage over haloperidol, leading to better functioning and quality of life. Amisulpride caused fewer neurological side-effects than conventional anti-psychotics and less weight gain than risperidone, both of which are crucial factors for long-term compliance.",2002.0,0,0
394,11806403,Social functioning and quality of life in the schizophrenic patient: advantages of amisulpride.,P Saleem; J P Olié; H Loo,"Schizophrenia is associated with significant social, psychological and occupational dysfunction. Not only is this distressing for the patients and their family and friends, but it also results in high indirect costs. Reintegration back into society, one of the most important aspects of quality life for schizophrenic patients and their physicians, must therefore take into account a patient's social functioning and employability, as well as improvement in symptoms. Although the typical antipsychotics are effective in managing the positive symptoms of schizophrenia, they may not alleviate other aspects of the disorder. They are also associated with extrapyramidal symptoms and other severe adverse events that have significant consequences for quality of life and compliance. The atypical antipsychotic, amisulpride, has an improved safety and tolerability profile and has been shown to be significantly more effective than placebo and haloperidol on a number of quality of life and social functioning scales, including the Global Assessment of Functioning, the Quality of Life Scale, the Functional Status Questionnaire and the Psychosocial Aptitude Rating Scale. In conclusion, amisulpride, in addition to its proven clinical efficacy, may help reintegration of the schizophrenic patient back into society.",2002.0,0,0
395,11806864,Adjunctive high-dose glycine in the treatment of schizophrenia.,D C Javitt; G Silipo; A Cienfuegos; A M Shelley; N Bark; M Park; J P Lindenmayer; R Suckow; S R Zukin,"Glycine is an agonist at brain N-methyl-D-aspartate receptors and crosses the blood-brain barrier following high-dose oral administration. In a previous study, significant improvements in negative and cognitive symptoms were observed in a group of 21 schizophrenic patients receiving high-dose glycine in addition to antipsychotic treatment. This study evaluated the degree to which symptom improvements might be related to alterations in antipsychotic drug levels in an additional group of 12 subjects. Glycine treatment was associated with an 8-fold increase in serum glycine levels, similar to that observed previously. A significant 34% reduction in negative symptoms was observed during glycine treatment. Serum antipsychotic levels were not significantly altered. Significant clinical effects were observed despite the fact that the majority of subjects were receiving atypical antipsychotics (clozapine or olanzapine). As in earlier studies, improvement persisted following glycine discontinuation.",2002.0,0,0
396,11814539,Melperone in the treatment of neuroleptic-resistant schizophrenia.,H Y Meltzer; T Sumiyoshi; K Jayathilake,"Melperone is an effective antipsychotic drug that has been reported to have atypical properties, i.e. low extrapyramidal side effect liability at clinically effective doses. It also does not increase serum prolactin levels. Its effectiveness for patients with neuroleptic (treatment)-resistant schizophrenia has not been evaluated. In this study, melperone was administered, in an open trial design of 6 weeks' duration, to 44 patients with chronic neuroleptic-resistant schizophrenia. The Global Assessment Scale (GAS), Brief Psychiatric Rating Scale (BPRS) and measures of extrapyramidal symptoms and other clinical variables were assessed at baseline and 6 weeks. Thirty-seven patients completed the 6-week trial. Melperone significantly improved overall psychiatric status as measured by GAS score for all evaluable subjects [last value carried forward (LVCF) and a completers analysis]. No significant effects on BPRS measures of psychopathology scores were found in the LVCF or completers analysis. Patients who showed > or = 20% decrease in the BPRS Total score (N=7) were more likely to have high baseline psychopathology, as measured by BPRS Total and Anxiety-Depression subscales, than those who showed > or = 20% increase in the BPRS Total score (N=8). Non-responders to melperone generally did not respond to subsequent treatment with clozapine, indicating that this group of patients was very treatment resistant. Melperone was not associated with worsening of extrapyramidal symptoms, elevation in plasma prolactin levels, or an increase in body mass index (BMI). The results suggest that a proportion of neuroleptic-resistant patients with schizophrenia respond to melperone, which requires further controlled study.",2002.0,0,0
397,11815682,Olanzapine for the treatment of psychosis in patients with Parkinson's disease and dementia.,L Marsh; C Lyketsos; S G Reich,"Psychotic symptoms are a common complication in Parkinson's disease with dementia. The authors conducted an open-label 6-week trial of olanzapine preceded by a placebo lead-in in five subjects with Parkinson's disease, mild to moderately severe dementia, and psychosis. Four of the subjects terminated the trial early because of worsening motor function, sedation, or paranoia. There was no improvement in psychotic symptoms, and functional abilities declined significantly. Olanzapine appears to be poorly tolerated in patients with Parkinson's disease, psychotic symptoms, and dementia.",2002.0,0,0
398,11816864,The effects of olanzapine on the 5 dimensions of schizophrenia derived by factor analysis: combined results of the North American and international trials.,J M Davis; N Chen,"The choice of drug to treat a patient with schizophrenia is one of the most critical clinical decisions. Controversy exists on the differential efficacy of olanzapine. Raw data from all 4 registrational double-blind, random-assignment studies of olanzapine compared with placebo or haloperidol were obtained from Eli Lilly and Company for this meta-analysis. Analysis of covariance of the intent-to-treat last-observation-carried-forward endpoint scores was used to assess efficacy on Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome Scale (PANSS) total scores and the 5 factors derived by factor analysis (negative symptoms, positive symptoms, disorganized thoughts, impulsivity/hostility, and anxiety/depression). Olanzapine produced a statistically significantly greater reduction in schizophrenic symptoms than haloperidol (p < .05) on total scores on the BPRS and PANSS on each of the 5 factors as well as on almost all items. Olanzapine induced a response at a rate equal to that induced by haloperidol in the first few weeks, but by the end of the study produced a greater percentage of responders. Compared with haloperidol, olanzapine produced a somewhat greater response on symptoms responsive to haloperidol, but a markedly better response on symptoms unresponsive to haloperidol. This difference favoring olanzapine occurred to an equal degree in all subgroups examined. The incidence of parkinsonism or akathisia following olanzapine treatment was extremely low and not statistically distinguishable from placebo. Olanzapine produced a greater improvement than haloperidol particularly by benefiting a much larger number of items or factors. Extrapyramidal side effects and akathisia during olanzapine treatment were statistically indistinguishable from effects seen with placebo.",2002.0,0,1
399,11816872,"Risperidone safety and efficacy in the treatment of bipolar and schizoaffective disorders: results from a 6-month, multicenter, open study.",E Vieta; J M Goikolea; B Corbella; A Benabarre; M Reinares; G Martínez; A Fernández; F Colom; A Martínez-Arán; C Torrent; Group for the Study of Risperidone in Affective Disorders (GSRAD),"The goal of this study was to assess the efficacy and safety of risperidone in bipolar and schizoaffective disorders. 541 patients entered this open, multicenter, 6-month study. Patients were entered provided that they fulfilled DSM-IV criteria for bipolar disorder or schizoaffective disorder, bipolar type, during a manic, hypomanic, mixed, or depressive episode. Risperidone was added to any previous mood-stabilizing medication that the patients were taking. Efficacy was assessed with the Young Mania Rating Scale (YMRS), the Hamilton Rating Scale for Depression (HAM-D), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impressions scale (CGI). Extrapyramidal symptoms (EPS) were assessed using the UKU Side Effect Rating Scale. 430 patients completed the study. Addition of risperidone produced highly significant improvements (p < .0001) on the YMRS and HAM-D at both 6 weeks and 6 months and on the CGI and the scales of the PANSS at both 4 weeks and 6 months. There was a significant reduction in UKU total and subscale scores at 6 months. The mean dose of risperidone was 3.9 mg/day. There was no single case of new-emergent tardive dyskinesia, and there was a very low incidence of exacerbation of mania within the first 6 weeks (2%). Adverse events were few and mostly mild. the most frequent being EPS and weight gain. This large study provides additional evidence that risperidone is effective and well tolerated when combined with mood stabilizers in the treatment of bipolar disorder and schizoaffective disorder, bipolar type. Previous concerns about exacerbation of manic symptoms were not confirmed.",2002.0,1,1
400,11816875,Olanzapine versus other antipsychotics in the treatment of schizophrenia.,P S Masand,,2002.0,0,1
401,11823256,,,,,0,0
402,11823257,"Amisulpride, an unusual ""atypical"" antipsychotic: a meta-analysis of randomized controlled trials.",Stefan Leucht; Gabi Pitschel-Walz; Rolf R Engel; Werner Kissling,"The ""atypical"" profile of the new antipsychotics clozapine, olanzapine, quetiapine, and risperidone has been linked to combined antagonism of serotonin 2 (5-HT(2)) and dopamine 2 (D(2)) receptors. Although amisulpride is a highly selective D(3)/D(2) receptor antagonist, it is assumed to have atypical properties as well. The purpose of this article was to compare the atypical profile of amisulpride with that of the 5-HT(2)/D(2) antagonists. Randomized controlled trials that compared amisulpride with conventional antipsychotics or placebo for patients with schizophrenia were identified and included in a meta-analysis. The mean effect sizes found for amisulpride were compared with those of an updated meta-analysis of the 5-HT(2)/D(2) antagonists. Eighteen randomized controlled trials of amisulpride (N=2,214) were found. In 11 studies of acutely ill patients it proved to be consistently more effective than conventional antipsychotics for global schizophrenic symptoms (measured with the Brief Psychiatric Rating Scale) and negative symptoms. Amisulpride is to date the only atypical antipsychotic for which several studies of patients suffering predominantly from negative symptoms have been published. In four such studies amisulpride was significantly more effective than placebo. Three small studies with conventional antipsychotics as comparators showed only a trend in favor of amisulpride in this regard. Amisulpride was associated with clearly lower use of antiparkinsonian medication and with fewer dropouts due to adverse events than conventional antipsychotics. These results cast some doubt on the notion that combined 5-HT(2)/D(2) antagonism is the reason that the newer antipsychotic medications are effective for negative symptoms and have fewer extrapyramidal side effects.",2002.0,0,0
403,11823268,"Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder.",Jan Volavka; Pal Czobor; Brian Sheitman; Jean-Pierre Lindenmayer; Leslie Citrome; Joseph P McEvoy; Thomas B Cooper; Miranda Chakos; Jeffrey A Lieberman,"The authors compared the efficacy and safety of three atypical antipsychotics (clozapine, olanzapine, and risperidone) with one another and with haloperidol in the treatment of patients with chronic schizophrenia or schizoaffective disorder. In a double-blind trial, 157 inpatients with a history of suboptimal treatment response were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol for 14 weeks (an 8-week escalation and fixed-dose period followed by a 6-week variable-dose period). Clozapine, risperidone, and olanzapine (but not haloperidol) resulted in statistically significant improvements in total score on the Positive and Negative Syndrome Scale. Improvements seen in total and negative symptom scores with clozapine and olanzapine were superior to haloperidol. The atypical drugs, particularly olanzapine and clozapine, were associated with weight gain. The effects of atypical antipsychotics in this population were statistically significant but clinically modest. The overall pattern of results suggests that clozapine and olanzapine have similar general antipsychotic efficacy and that risperidone may be somewhat less effective. Clozapine was the most effective treatment for negative symptoms. However, the differences among treatments were small.",2002.0,0,0
404,11823283,Clozapine for first-episode schizophrenia.,Theodore T Kolivakis; Howard C Margolese; Linda Beauclair; Guy Chouinard,,2002.0,0,1
405,11824486,Short report: comparison of patient satisfaction and burden of adverse effects with novel and conventional neuroleptics: a naturalistic study.,J Rabinowitz; E J Bromet; M Davidson,"Converging evidence indicates that, in controlled drug trials, individuals receiving novel antipsychotic medications have fewer adverse effects than those receiving conventional antipsychotic medications. This in turn may lead to greater patient treatment satisfaction. This study examines patient satisfaction and burden of adverse effects in a county-wide epidemiologic study of first admission psychotic persons with psychosis who were receiving novel antipsychotic drugs (n = 42). Comparisons were made within this group, and between 25 of these persons and 25 others with the same diagnosis and sex, from the same epidemiologic study, who were receiving a comparable regimen of conventional antipsychotic drugs. Patients receiving novel antipsychotics were significantly more satisfied and were significantly less burdened by adverse effects than those receiving conventional antipsychotics. Among the group receiving novel antipsychotics, dosage was not related to satisfaction or burden of adverse effects. For those treated with risperidone (n = 27), there was a difference, approaching statistical significance, for greater satisfaction and less adverse effect burden among those persons with dosages less than 5 mg daily as compared to higher dosages.",2002.0,0,1
406,11825144,Olanzapine in acute bipolar mania.,K Jagadheesan,,2002.0,0,1
407,11825300,Antipsychotic medication: effects on regulation of glucose and lipids.,M M Kato; P J Goodnick,"Since the introduction of chlorpromazine in the 1950s, antipsychotics have been used for the treatment of schizophrenia. The phenothiazines were followed by the butyrophenones, particularly haloperidol. With all the movement disorder side effects of these medications (extrapyramidal syndrome, akathisia, tardive dyskinesia), the pharmaceutical industry has gradually released atypical antipsychotics. This class includes clozapine (released in the USA in 1990), risperidone (1994), olanzapine (1996), quetiapine (1998) and ziprasidone (2001). However, the rate of diabetes mellitus in patients with schizophrenia appeared to increase with the availability of this class of medications. In reviewing rate and degree of changes in weight, glucose control and lipid levels induced by typical and atypical antipsychotics, it was found that in contrast to case reports, there is a dearth of retrospective, open and controlled studies. However, in studies as early as 1964, significant weight increases were found to be associated with use of chlorpromazine. While the phenothiazines may have some effect on patients with chemical diabetes, there is little evidence of the typical antipsychotics producing diabetes mellitus de novo, or worsening diabetes that is already been discovered. Ziprasidone appears to be the antipsychotic with the most beneficial combination of effects: no weight gain, no change in glucose utilisation and reductions in cholesterol and serum triglycerides (TGs).",2002.0,0,0
408,11829199,Effect of influenza vaccination on serum clozapine and its main metabolite concentrations in patients with schizophrenia.,K Raaska; V Raitasuo; P J Neuvonen,"To study the effect of influenza vaccine on serum clozapine, N-desmethylclozapine and clozapine-N-oxide steady-state concentrations in patients with schizophrenia. This was an open-label study in 14 schizophrenic inpatients (with 2 drop-outs) using clozapine. Serum trough concentrations of clozapine. N-desmethylclozapine and clozapine-N-oxide, as well as the concentration of c-reactive protein (CRP), were measured immediately before conventional trivalent influenza vaccination and 2, 4, 7 and 14 days after the vaccination. Influenza vaccination had no significant effect on serum concentrations of clozapine, N-desmethylclozapine or clozapine-N-oxide. No changes in the clinical effects of clozapine were observed after vaccination. Influenza vaccination did not increase CRP. However, two drop-out patients who developed upper respiratory and abdominal symptoms had increased and elevated serum concentrations of clozapine, compared with the baseline. Influenza vaccination using conventional trivalent influenza vaccine does not affect serum concentrations of clozapine or its main metabolites. However, an infection-related increase in CRP may be associated with increased serum concentration of clozapine.",2002.0,0,0
409,11834192,[Usefulness of olanzapine in the levodopa-induced psychosis in patients with Parkinson's disease].,J R Chacón; E Durán; J A Durán; M Alvarez,"To evaluate the antipsychotic efficacy of olanzapine (OLZ) in patients with Parkinson's disease (PD) and drug-induced psychosis (DIP) and its repercussion on the motor function. Ten patients (5 women and 5 men) diagnosed of PD and DIP, aged 67 years (range: 50-81), with PD duration of 11.1 years (range: 6-23), treated chronically with levodopa per day, received a dose of 2.5 or 5.0 mg OLZ daily. Data concerning improvement of psychosis and worsening of motor function was based on Positive And Negative Symptoms Scale (PANSS) and Unified Parkinsons Disease Rating Scale (UPDRS) motor. Psychotic symptoms were improved in all patients. In most of them the improvement was almost total. Seven patients increased levodopa dose on OLZ, but significant worsening of motor function was reported just in one patient. None of the patients had agranulocytosis in the blood monitoring. Two patients presented weight gain. Seven patients improved their cognitive status. We conclude that OLZ at the doses studied may have efficacy for DIP which appears in PD and does not induce worsening of motor function in most of the patients.",2002.0,0,0
410,11835433,Epidemiology of primary blepharospasm.,Giovanni Defazio; Paolo Livrea,"We review epidemiological data on primary blepharospasm (BSP). There is a large variation in the stated prevalence of BSP, with crude estimates ranging from 16 to 133 per million in different studies. A large proportion of this variability may be the result of differences in physician education on BSP. Age and female gender may increase the risk of developing BSP. The few case-control studies focusing on adult dystonias including BSP showed an increased risk in association with family history of dystonia and/or postural tremor, prior head and face trauma, and prior eye disease (e.g., blepharitis and keratoconjunctivitis), and a decreased risk associated with cigarette smoking. No association was found with age-related medical conditions such as hypertension and diabetes, family history of parkinsonism, and a history of anxiety or depression. Broocks et al. [Am J Psychiatry, 1998;155:555-557] found a significantly higher frequency of obsessive-compulsive symptoms in BSP than hemifacial spasm despite the clinical similarity. Among putative risk factors for BSP, age at onset, female gender, and prior head or face trauma may affect spread of dystonia to adjacent body regions. While limited, the body of epidemiological data support the idea that environmental and familial, possibly genetic, factors may both be important in the etiology of BSP.",2002.0,0,0
411,11838627,"Vitamin B6 as add-on treatment in chronic schizophrenic and schizoaffective patients: a double-blind, placebo-controlled study.",Vladimir Lerner; Chanoch Miodownik; Alexander Kaptsan; Hagit Cohen; Uri Loewenthal; Moshe Kotler,"Vitamin B6, or pyridoxine, plays an intrinsic role in the synthesis of certain neurotransmitters that take part in development of psychotic states. Several reports indicate that vitamin B6 may be a factor in a number of psychiatric disorders and related conditions, such as autism, Alzheimer's disease, hyperactivity, learning disability, anxiety disorder, and depression. Moreover, there are anecdotal reports of a reduction in psychotic symptoms after vitamin B6 supplementation of psychopharmacologic treatment of patients suffering from schizophrenia or organic mental disorder. The aim of this study was to examine whether vitamin B6 therapy influences psychotic symptoms in patients suffering from schizophrenia and schizoaffective disorder. The effects of the supplementation of vitamin B6 to antipsychotic treatment on positive and negative symptoms in 15 schizophrenic and schizoaffective patients (DSM-IV criteria) were examined in a double-blind, placebo-controlled, crossover study spanning 9 weeks. All patients had stable psychopathology for at least 1 month before entry into the study and were maintained on treatment with their prestudy psychoactive and antiparkinsonian medications throughout the study. All patients were assessed using the Positive and Negative Syndrome Scale (PANSS) for schizophrenia on a weekly basis. Patients randomly received placebo or vitamin B6, starting at 100 mg/day in the first week and increasing to 400 mg/day in the fourth week by 100-mg increments each week. PANSS scores revealed no differences between vitamin B6- and placebo-treated patients in amelioration of their mental state. Further studies with larger populations and shorter duration of illness are needed to clarify the question of the possible efficacy of vitamin B6 in treatment of psychotic symptoms in schizophrenia.",2002.0,0,0
412,11853116,Cytokine profiles in schizophrenic patients treated with risperidone: a 3-month follow-up study.,Carlo L Cazzullo; Emilio Sacchetti; Alessandro Galluzzo; Adelaide Panariello; Andrea Adorni; Marco Pegoraro; Simona Bosis; Fulvia Colombo; Daria Trabattoni; Arianna Zagliani; Mario Clerici,"An increasing body of evidence suggests a role for the immune system in the pathogenesis of schizophrenia. The information concerning the effects of antipsychotics on cytokine profiles are limited and often controversial in particular regarding novel antipsychotics. The authors first investigated the production of various cytokines [interleukin (IL)-2, IL-4, IL-10, interferon (INF)-gamma] in drug-free (n = 12) and drug-naive (n = 3) schizophrenic patients and in healthy controls (n = 33) and then the modifications of cytokines values during a 3-month period of treatment with risperidone. In the baseline condition, the production of IL-2 and INF-gamma was significantly higher (P = .023 and .026, respectively) in patients than in controls. In the same patients, the use of risperidone was associated with augmented IL-10 (a suppressor of Type I cytokines) and decreased INF-gamma production. This modification suggests that clinical improvement is associated with a reduction in the inflammatory-like situation present in not currently treated schizophrenic patients.",2002.0,0,0
413,11869760,"Olanzapine versus haloperidol in schizoaffective disorder, bipolar type.",M Tohen; F Zhang; P E Keck; P D Feldman; R C Risser; P V Tran; A Breier,"The present analysis was performed on data from a subsample of patients with schizoaffective disorder, bipolar type, who participated in a multicenter, double-blind study comparing olanzapine to haloperidol. Patients with schizoaffective disorder bipolar type, characterized as currently manic, mixed, depressed, or euthymic, were assessed weekly for 6 weeks during treatment with either olanzapine or haloperidol. Manic symptoms were measured using the sum of six items of the BPRS, and depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale. In addition, cognitive functioning was measured using the sum of seven items from the PANSS. Repeated measures analyses were performed using random coefficients regression of the serial measurement of manic, cognitive, and depressive symptoms. A significant treatment difference was detected overall, indicating that olanzapine was significantly more effective than haloperidol in reducing symptoms of depression and improving patients' cognitive symptoms. The superiority of olanzapine over haloperidol in the reduction of manic symptoms did not reach statistical significance (P=.052). The greatest improvement in both manic and cognitive symptoms was seen in the olanzapine-treated 'currently manic' subgroup, and least improvement in the haloperidol-treated 'euthymic' subgroup. Depressive symptoms were most improved in the olanzapine-treated 'depressed' subgroup, and least improved in the corresponding haloperidol subgroup. Overall, olanzapine was superior to haloperidol with respect to thymoleptic effects in patients with schizoaffective disorder, bipolar type.",2002.0,1,1
414,11870017,"Placebo-controlled trial of D-cycloserine added to conventional neuroleptics, olanzapine, or risperidone in schizophrenia.",Uriel Heresco-Levy; Marina Ermilov; Jonathan Shimoni; Baruch Shapira; Gail Silipo; Daniel C Javitt,"The authors investigated the clinical effects of D-cycloserine when added to treatment with conventional neuroleptics, olanzapine, or risperidone for treatment-resistant schizophrenia. Twenty-four patients participated in a double-blind, placebo-controlled, 6-week crossover trial with D-cycloserine, 50 mg/day, added to their fixed dose of antipsychotic medication. Clinical ratings were performed every 2 weeks. D-Cycloserine treatment was well tolerated and resulted in a significant reduction in negative symptoms (mean=15%). The degree of improvement did not differ between patients treated with conventional neuroleptics and those treated with olanzapine or risperidone. These data support the efficacy of the addition of 50 mg/day of D-cycloserine to treatment with conventional neuroleptics and suggest that therapeutic benefits may also be attained when D-cycloserine is added to olanzapine or risperidone.",2002.0,0,0
415,11874209,Obsessive-compulsive symptoms during treatment with olanzapine and risperidone: a prospective study of 113 patients with recent-onset schizophrenia or related disorders.,Lieuwe de Haan; Nico Beuk; Britt Hoogenboom; Peter Dingemans; Don Linszen,"To determine whether severity of obsessive-compulsive symptoms (OCS) differs during treatment with olanzapine or risperidone and to establish whether duration of antipsychotic treatment is related to severity of OCS. We conducted a prospective study of consecutively hospitalized young patients (mean age = 22.4 years) with DSM-IV schizophrenia or related disorders (N = 113) who were treated with olanzapine or risperidone. Olanzapine or risperidone was randomly prescribed for patients who were drug-naive or were treated with typical antipsychotics before admission (N = 36). Patients who had started olanzapine (N = 39) or risperidone treatment (N = 23) prior to admission continued with that medication if they showed initial clinical response. Patients who prior to admission started olanzapine (N = 6) or risperidone (N = 9) but showed no response or suffered from adverse effects switched at admission to risperidone or olanzapine, respectively. Medical records, parents, and patients revealed information on duration of treatment and compliance with olanzapine or risperidone prior to admission. The Yale-Brown Obsessive Compulsive Scale (YBOCS) was administered at admission and 6 weeks thereafter. At baseline and 6-week assessments, OCS were found in about 30% of 106 evaluable cases and 15% met DSM-IV criteria for obsessive-compulsive disorder. No differences in OCS were found in the patients randomly assigned to olanzapine or risperidone. The 35 subjects treated with olanzapine at both assessments had significantly (p = .01) more severe OCS at week 6 than the 20 subjects treated with risperidone at both assessments. Duration of treatment with olanzapine was significantly (p < .01) related to severity of OCS. There are no differences in the short-term propensity of olanzapine or risperidone to induce or exacerbate OCS. However, severity of OCS was associated with duration of treatment with olanzapine.",2002.0,0,0
416,11874227,What role do atypical antipsychotic drugs have in treatment-resistant depression?,Michael E Thase,"Despite significant advances in the treatment of depression, many patients fail to respond to treatment with adequate dose and duration. Multiple therapeutic approaches are available for the treatment of patients not responding to standard antidepressant medication. These include switching medication or combination and augmentation strategies. A substantial number of patients do not respond to multiple treatment trials. These patients suffer from treatment-resistant depression (TRD) and represent a challenge to the treating physician. There have been a growing number of reports on the use of atypical antipsychotics as augmenting agents in nonpsychotic TRD. Second-generation antipsychotics are less likely to provoke parkinsonian side effects. It has also been reported that these agents produce lower rates of tardive movement disorders than traditional neuroleptics. Furthermore, second-generation antipsychotics are serotonin-2A/2C antagonists, possibly allowing them to improve the efficacy and some aspects of the side effect profile of selective serotonin reuptake inhibitors (SSRIs). Weight gain and sedation are likely to be the most common adverse events of such combined therapy. In a recent controlled clinical trial, the atypical antipsychotic olanzapine was combined with fluoxetine therapy in an 8-week, double-blind clinical trial in patients with TRD. This combination drug therapy demonstrated clinical efficacy on several rating scales and showed rapid onset of action. Although more studies will be required to confirm and extend these findings, the results suggest that there may be a clinical benefit to combining atypical antipsychotics with SSRIs in nonpsychotic TRD.",2002.0,0,0
417,11875967,A retrospective economic evaluation of olanzapine versus risperidone in the treatment of schizophrenia.,Zhongyun Zhao,"This retrospective study evaluates drug treatment patterns and economic outcomes of olanzapine in comparison with risperidone in the treatment of schizophrenia in usual practice. Results showed that patients taking olanzapine versus risperidone stayed on therapy longer (P < .0001) and were prescribed anti-Parkinsonian medications less frequently (P < .005). Compared with risperidone, olanzapine treatment resulted in lower direct mental health care costs ($1,827 less, P < .03) and lower direct total health care costs ($1,834 less, P < .05). The results of this study suggest that the initial selection of an antipsychotic for the treatment of schizophrenia is important: Olanzapine offset its acquisition cost by reducing medical service costs and demonstrated better drug treatment patterns than risperidone.",2002.0,0,0
418,11878086,[Clinical impact of atypical antipsychotics: prospective 6-month study of inpatients treated with risperidone or olanzapine].,B Hamel; P Courtet; C Vergnes; J P Boulenger,"A survey of clinical and therapeutic evolution in patients treated with an atypical antipsychotic, risperidone or olanzapine, was carried out at La Colombière Psychiatric Hospital, Montpellier. This prospective observational study was conducted over 6 months. Forty-nine patients were included in the olanzapine treatment group and thirty-five in the risperidone treatment group. The Clinical Global Impression (CGI) scale was used for evaluation at day 0, 7, 30, 90 and 180 of treatment. The majority of patients were improved after 30 days of treatment, and clinical improvement was observed in about 60 per cent of patients among those treated at day 180. The main therapeutic benefit occurred in respect of positive psychotic symptoms. Patients were discharged after 30 days of treatment. The atypical antipsychotic was not used with an additional neuroleptic for all patients. Tolerance was good, particularly for olanzapine. On the other hand, according to our results, others studies have to be performed to confirm the impact of the treatment on weight gain, assessment of subjective elements such as sedation, and the direct effect of the atypical antipsychotics on primary negative symptoms.",2002.0,0,0
419,11879174,Acute tryptophan depletion in schizophrenic patients treated with clozapine.,Tony P George; Marc N Potenza; Kathleen Degen; Michael J Sernyak; Scott Woods; Christopher J McDougle,,2002.0,0,1
420,11880946,[Atypical neuroleptics in the treatment of aggression and hostility in schizophrenic patients].,P Briken; E Nika; M Krausz; D Naber,"The treatment of aggressive symptoms in schizophrenic patients is a relevant clinical problem. We systematically review the efficacy of the different atypical neuroleptics on acute or persistent aggressive symptoms also regarding methodological problems. Currently typical neuroleptics are still first choice in treating acute aggressive symptoms, while risperidone and olanzapine could be alternatives. In persistent aggression clozapin shows the best specific results. Typical depot neuroleptics should be considered in cases when medication compliance is a problem.",2002.0,0,0
421,11886692,,,,,0,0
422,11890187,Mianserin or placebo as adjuncts to typical antipsychotics in resistant schizophrenia.,R Shiloh; Z Zemishlany; D Aizenberg; A Valevski; L Bodinger; H Munitz; A Weizman,"The beneficial effect of atypical antipsychotic drugs (APDs) in treatment-resistant schizophrenia patients has been attributed, mostly, to their relatively high serotonergic (5-HT)2 to dopaminergic (D)2 receptor blockade ratio. We hypothesized that a combination of typical APDs (D2 antagonists) and mianserin, a potent 5-HT2 antagonist, might also exert superior efficacy in this population. Eighteen inpatients with treatment-resistant schizophrenia who had an acute psychotic exacerbation of the disorder received, in a double-blind design, 30 mg/day mianserin (n = 9) or placebo (n = 9) in conjunction with typical neuroleptics [haloperidol (n = 9) or perphenazine (n = 9)]. Clinical status was evaluated before, during, and at the end of 6 weeks of combined treatment with the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms and Hamilton Rating Scale for Depression. The typical APD/mianserin group exhibited significantly greater improvement in total BPRS scores (17.6% versus 5.5%; P= 0.03) and a trend towards greater improvement in SAPS scores (35.3% versus 13.0%; P = 0.07). Our study indicates that patients with chronic treatment-resistant schizophrenia who have an acute psychotic exacerbation ('acute-on-chronic') may benefit from the addition of a potent 5-HT2 blocker, such as mianserin, to typical antipsychotics. Our findings may further emphasize the contribution of enhanced 5-HT2 blockade to the 'atypicality' of the atypical APDs and to their greater efficacy in alleviating symptoms of chronic treatment-resistant schizophrenia.",2002.0,0,0
423,11890188,"Time to study discontinuation, relapse, and compliance with atypical or conventional antipsychotics in schizophrenia and related disorders.",I D Glick; P H Berg,"To more clearly clarify the efficacy of the atypical antipsychotics compared to conventional antipsychotics, we add data on the outcome of patients diagnosed with schizophrenia from two large, international clinical trials comparing olanzapine with haloperidol (n = 1996) and olanzapine with risperidone (n = 339). Both studies comprised double-blinded, placebo controlled, random assignment trials. Health outcomes reported include: (i) time to discontinuation in the trial; (ii) clinical relapse; and (iii) time to drug non-compliance. When outcome was measured as time to discontinuation due to adverse events or lack of efficacy, olanzapine showed superiority over haloperidol and no difference compared to risperidone. Of those patients who had an initial response, there was no significant difference between olanzapine and haloperidol when outcome was measured using either: (i) 52-week relapse rates or (ii) time to first non-compliance. Using the measures of study discontinuation, relapse and non-compliance, in one trial the atypical antipsychotic olanzapine was superior to haloperidol, while in a second trial there were no differences between olanzapine and risperidone.",2002.0,0,0
424,11904128,A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia.,Joseph I Friedman; David N Adler; Evelyn Howanitz; Philip D Harvey; Grant Brenner; Humberto Temporini; Leonard White; Michael Parrella; Kenneth L Davis,"Despite the beneficial effects of atypical antipsychotics on cognition, these improvements will not return most schizophrenic patients to normative standards of cognitive functioning. Therefore, other treatments need to be considered. Subtle changes in cholinergic function in schizophrenic patients provide the rationale to test the effectiveness of cholinesterase inhibitors in treating cognitive impairment in schizophrenia. Given this, a 12-week, double-blind, placebo-controlled trial of donepezil (5 mg and 10 mg) as adjunctive treatment to risperidone was conducted in a total of 36 schizophrenic patients. Neither the 5-mg nor 10-mg dose of donepezil produced significant improvements in any cognitive measure compared with placebo. It is possible that nicotinic receptor desensitization produced by chronic tobacco use in these patients rendered their nicotinic receptors refractory to the effects of increased agonist activity produced by donepezil. An alternative treatment is the allosterically potentiating ligands, which enhance the activity of (sensitize) nicotinic receptors in the presence of acetylcholine.",2002.0,0,0
425,11904131,Cerebellar blood volume in bipolar patients correlates with medication.,Russell T Loeber; Staci A Gruber; Bruce M Cohen; Perry F Renshaw; Andrea R Sherwood; Deborah A Yurgelun-Todd,"Cerebellar abnormalities, including decreased tissue volume, have been implicated in the pathophysiology of bipolar disorder. Relatively little research has focused on blood flow in the cerebellum of patients with bipolar disorder. Furthermore, the significance of metabolic changes in the brains of psychiatric patients may be confounded by the effects of various pharmacotherapies. Having previously found differences in cerebellar blood volume in patients with bipolar disorder compared to healthy control subjects, this study examined whether some variability in the patient population may be an effect of medication. In this study, we have examined the association between medication status and cerebellar blood volume. Thirteen healthy comparison subjects and 21 bipolar patients underwent dynamic susceptibility contrast magnetic resonance imaging. Nine cerebellar regions were identified, and the absolute cerebellar blood volume data from each was compared to medication status measures. Patients on conventional antipsychotics had the lowest mean absolute blood volume measures for all cerebellar regions, whereas those on atypical antipsychotics had the highest blood volume measures. Comparison subjects had cerebellar blood volume measures in the middle, with results closer to subjects in the atypical group. This evidence suggests that antipsychotic treatment may influence cerebellar blood volume. This effect will be important in considering imaging studies on medicated patients with bipolar disorder and may suggest novel pathways by which these medications affect their changes.",2002.0,0,0
426,11910256,"The safety and pharmacokinetics of quetiapine when coadministered with haloperidol, risperidone, or thioridazine.",Steven G Potkin; Per T Thyrum; Gustavo Alva; Rimal Bera; Chiao Yeh; Lisa A Arvanitis,"The effects of haloperidol, risperidone, and thioridazine on the pharmacokinetics and side-effect profile of quetiapine were investigated in 36 patients with schizophrenia, schizoaffective disorder, or bipolar disorder in a single-center, two-period, multiple-dose, open-label, randomized trial. Over a one-to two-week period, quetiapine doses were escalated to 300 mg twice daily (bid). Patients were then treated for at least 7 days at the target quetiapine dose and subsequently entered into the combination therapy period, receiving haloperidol (7.5 mg, bid), risperidone (3 mg, bid), or thioridazine (200 mg, bid) for 8.5 days (after 3 days of dose escalation). Key assessments included the pharmacokinetics of quetiapine at steady state (area under the curve within a dosing interval [AUCtSS], maximum [CmaxSS], and minimum [CminSS] observed plasma concentrations, and oral clearance [Cl/f]), as well as the UKU Side Effect Rating Scale scores and safety evaluations. Neither risperidone nor haloperidol had significant effects on quetiapine pharmacokinetics. However, thioridazine produced statistically significant changes, decreasing the least squares means values of the AUCtSS, CmaxSS, and CminSS by 40%, 47%, and 31%, respectively, and increasing Cl/f by 68%. Increases in the following adverse events were noted during coadministration: somnolence (risperidone), insomnia and dry mouth (all three coadministered therapies), and dizziness (thioridazine). UKU side effect items that became worse in >or= 25% of patients during each coadministration period included sedation and increased sleep duration. Results of laboratory tests, electrocardiograms, and vital sign measurements revealed few clinically important changes. Clinical stability can be maintained with good tolerability during the transition from quetiapine monotherapy to periods of coadministration with haloperidol, risperidone, or thioridazine. Coadministration of either haloperidol or risperidone did not have any important effects on the steady-state pharmacokinetics of quetiapine. Thioridazine significantly increased the oral clearance of quetiapine. Increased doses of quetiapine may be necessary to control psychotic symptoms when thioridazine is coadministered with quetiapine.",2002.0,0,0
427,11910263,Effect of fluoxetine and imipramine on the pharmacokinetics and tolerability of the antipsychotic quetiapine.,Steven G Potkin; Per T Thyrum; Gustavo Alva; Danilo Carreon; Chiao Yeh; Amir Kalali; Lisa A Arvanitis; Pharmacokinetic Study Group,"The effects of fluoxetine and imipramine on the pharmacokinetics and nonpsychiatric side effect profile of quetiapine fumarate were investigated in 26 patients with schizophrenia, schizoaffective disorder, or bipolar disorder in a multicenter, two-period, multiple-dose, open-label, randomized trial. Over a 1- to 2-week period, patients were titrated to a 300-mg twice-daily dose of quetiapine. Patients treated for at least 7 days at the target dose entered a combination therapy period, receiving fluoxetine (60 mg daily) or imipramine (75 mg twice daily) for 8 days. Key assessments included pharmacokinetic analysis of quetiapine, the Udvalg for kliniske undersøgelser (UKU) Side Effect Rating Scale, and safety evaluations (e.g., adverse events, electrocardiograms, laboratory tests, and vital signs). Fluoxetine increased the quetiapine area under the plasma concentration time curve during a 12-hour interval (+12%), maximum plasma concentration during the dosing interval (C(ss)(max); +26%), and minimum plasma concentration at the end of the dosing interval (+8%), although it decreased oral clearance (-11%). The change in C(ss)(max) was statistically although not clinically significant. Imipramine did not affect the pharmacokinetics of quetiapine. Overall, scores on the UKU Side Effect Rating Scale improved during combination therapy with either agent, and no statistically significant deterioration was observed for any item. For safety assessments, the only clinically remarkable event was an imipramine-associated complete left bundle branch block in one patient. No unexpected side effects were reported. In conclusion, combination therapy with quetiapine and fluoxetine or imipramine had a minimal effect on quetiapine pharmacokinetics and was well tolerated.",2002.0,0,0
428,11910268,The anxiolytic effect of the novel antipsychotic ziprasidone compared with diazepam in subjects anxious before dental surgery.,Keith D Wilner; Richard J Anziano; Arlene C Johnson; Jeffrey J Miceli; James R Fricke; Cynthia K Titus,"The novel atypical antipsychotic ziprasidone has a pharmacologic profile notable for potent agonism of serotonin (5-HT)1A receptors, antagonism at 5-HT1D receptors, and reuptake inhibition of norepinephrine. 5-HT1A receptor agonism, in particular, suggests anxiolytic activity, and ziprasidone has shown preliminary efficacy in treating the symptoms of anxiety associated with psychotic disorders. In this study, the anxiolytic efficacy of ziprasidone was evaluated in nonpsychotic subjects who were anxious before undergoing minor dental surgery. We compared a single oral dose of 20 mg ziprasidone (N = 30) with that of 10 mg diazepam (N = 30) and placebo (N = 30) in a randomized, parallel-group, double-blind study. The peak anxiolytic effect of ziprasidone compared with that of placebo was similar to that of diazepam but had a later onset. At 3 hours postdose, the anxiolytic effect of ziprasidone was significantly greater than that of placebo (p < 0.05) and somewhat greater than that of diazepam. Diazepam showed a significantly greater anxiolytic effect than placebo at 1 hour (p < 0.05) but not at 3 hours. The sedative effect of ziprasidone was never greater than that of placebo, whereas that of diazepam was significantly greater than that of placebo 1 to 1.5 hours postdose. Ziprasidone was generally well tolerated. Only one patient reported treatment-related adverse events (nausea and vomiting) and, unlike diazepam, ziprasidone did not cause reductions in blood pressure. Dystonia, extrapyramidal syndrome, akathisia, and postural hypotension were not seen with ziprasidone. Thus, ziprasidone may possess anxiolytic effects in addition to its antipsychotic properties.",2002.0,0,0
429,11912568,The evolving role of topiramate among other mood stabilizers in the management of bipolar disorder.,K N Chengappa; S Gershon; J Levine,"Topiramate, a structurally novel anticonvulsant, is being evaluated for other neurological conditions such as migraine, neuropathic pain, and essential tremor, and also for psychiatric conditions such as bipolar disorder, bulimia, post-traumatic stress disorder, and schizoaffective disorder, in addition to obesity. This article will focus on the use of topiramate for bipolar disorder. The pharmacological profile of topiramate is compared to other established and putative mood stabilizers, and a rationale for its use in bipolar disorder is presented. Data from open clinical trials of topiramate for depression, mania, and rapid-cycling bipolar disorder are summarized. Preliminary data from one pilot dose-finding, double-blind, random-assignment, placebo-controlled, 3-week parallel group study of two doses of topiramate for acute bipolar I mania is reported. Safety data regarding topiramate was reviewed. Finally, the potential place of this agent in bipolar illness is considered. The pharmacological advantages for topiramate are low protein binding, minimal hepatic metabolism and mainly unchanged renal excretion, a 24-h half-life, and minimal drug interactions. Open clinical studies suggest a 50-65% response for refractory bipolar mania, and a 40-56% response for refractory bipolar depression in mainly add-on treatment. Open clinical studies of topiramate for rapid-cycling subjects and those for comorbid bulimia, substance abuse, post-traumatic stress, migraine, and obesity report effectiveness. The primary efficacy endpoint data (change from baseline Y-MRS total scores) of the placebo-controlled, random assignment parallel group phase II dose-finding study were not statistically significant. However, once the antidepressant-associated manias (28 of the sample, of 97 subjects) were excluded from the controlled study, the post-hoc analyses indicated the higher dose (512 mg/day) topiramate treatment group showed a statistically significant reduction in endpoint Y-MRS change scores as compared to placebo (p < 0.03). Adverse effects of topiramate in bipolar subjects include attention, concentration and memory problems, fatigue, sedation, transient paraesthesias, nausea, and anorexia. Some subjects experience word-finding difficulty. Weight loss may be seen in several topiramate-treated subjects with bipolar disorder. Topiramate appears to show promise as an addition to the agents available to treat bipolar disorder. More definitive controlled data on the efficacy of topiramate in the acute and continuation phases as well as for the prophylaxis either as monotherapy or as combination treatment of bipolar disorder are ongoing, and the results are awaited.",2002.0,0,0
430,11921147,"Reducing the burden of caring for Alzheimer's disease through the amelioration of ""delusions of theft"" by drug therapy.",Kazue Shigenobu; Manabu Ikeda; Ryuji Fukuhara; Naruhiko Maki; Kazuhiko Hokoishi; Akihiko Nebu; Kenjiro Komori; Hirotaka Tanabe,"Delusions of theft (delusions involving the theft of possessions) are one of the most frequent neuropsychiatric manifestations of Alzheimer's disease (AD). The current study investigated the presence and extent of such delusions before and after drug treatment in a group of AD patients, and the consequent effects on the burden of care on caregivers. The study was an open-label cohort design. The delusions studied consisted only of those involving theft of possessions. Sixteen AD patients served as subjects in order to assess the efficacy of Risperidone administration, in the reduction or elimination of these delusions. The caregiver burden was evaluated using the Zarit Caregiver Burden Interview (ZBI) before the administration of Risperidone and 12 weeks after administration, for cases where delusions of theft were eliminated or reduced. The burden of care on caregivers was significantly reduced (p < 0.001) through the elimination or reduction of delusions of theft. Delusions of theft are considered to be a major factor in increasing the burden of care, and the treatment of these, through appropriate drug therapy, is therefore of great importance in the continuation of satisfactory care in the home.",2002.0,0,0
431,11925293,Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia.,Michael J Sernyak; Douglas L Leslie; Renato D Alarcon; Miklos F Losonczy; Robert Rosenheck,"The development of both type I and type II diabetes after initiation of some atypical neuroleptics has been reported, primarily in studies involving small series of patients. This study used administrative data from a large national sample of patients with a diagnosis of schizophrenia to compare the prevalence of diabetes mellitus in patients receiving prescriptions for atypical and typical neuroleptics. All outpatients with schizophrenia treated with typical and atypical neuroleptics over 4 months in 1999 in the Veterans Health Administration of the Department of Veterans Affairs (VA) were included in this study. Patients treated with atypical neuroleptics were those who received prescriptions for clozapine, olanzapine, risperidone, or quetiapine. Patients with a diagnosis of diabetes were also identified by using ICD-9 codes in VA administrative databases. The prevalence of diabetes mellitus across age groups and among patients receiving prescriptions for different atypical neuroleptics was examined with multiple logistic regression. A total of 38,632 patients were included in the study: 15,984 (41.4%) received typical neuroleptics and 22,648 (58.6%) received any atypical neuroleptic (1,207 [5.3%] received clozapine; 10,970 [48.4%], olanzapine; 955 [4.2%], quetiapine; and 9,903 [43.7%], risperidone; 387 patients received prescriptions for more than one atypical neuroleptic). When the effects of age were controlled, patients who received atypical neuroleptics were 9% more likely to have diabetes than those who received typical neuroleptics, and the prevalence of diabetes was significantly increased for patients who received clozapine, olanzapine, and quetiapine, but not risperidone. However, for patients less than 40 years old, all of the atypical neuroleptics were associated with a significantly increased prevalence of diabetes. In this large group of patients with schizophrenia, receipt of a prescription for atypical neuroleptics was significantly associated with diabetes mellitus.",2002.0,0,1
432,11925294,Racial disparities in antipsychotic prescription patterns for patients with schizophrenia.,Eri Kuno; Aileen B Rothbard,"This study aimed to examine the extent and type of variation in antipsychotic prescription patterns between African American and Caucasian patients with schizophrenia. Subjects were 2,515 adult Medicaid recipients treated for schizophrenia in 1995 with one of four types of antipsychotic medication (traditional antipsychotics, clozapine, risperidone, or depot antipsychotics). Prescription and mental health service use data were collected from Medicaid claims files for the 12 months following the first filled antipsychotic prescription. Patterns of antipsychotic prescription were compared for African American (N=1,538, 61%) and Caucasian (N=977, 39%) subjects. African American subjects were significantly younger and more likely to receive Supplemental Security Income than were the Caucasian subjects, who received mental health services more continuously. African American subjects were less likely than Caucasian subjects to receive clozapine (8% versus 15%, respectively) and risperidone (25% versus 31%) and more likely to receive depot antipsychotics (26% versus 14%). The likelihood of receiving clozapine or risperidone remained significantly different after demographic and service use characteristics were controlled. This study found ethnic disparities in antipsychotic prescription patterns among a large number of publicly insured clients treated for schizophrenia. Given the rapidly changing pharmacological treatment environment, these findings have significant implications for differential quality of care for African American patients. Future studies employing client and provider characteristics are urgently needed to test alternative explanations for ethnic disparities.",2002.0,0,1
433,11926934,Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia.,John W Newcomer; Dan W Haupt; Robert Fucetola; Angela K Melson; Julie A Schweiger; Benjamin P Cooper; Gregg Selke,"Hyperglycemia and type 2 diabetes mellitus are more common in schizophrenia than in the general population. Glucoregulatory abnormalities have also been associated with the use of antipsychotic medications themselves. While antipsychotics may increase adiposity, which can decrease insulin sensitivity, disease- and medication-related differences in glucose regulation might also occur independent of differences in adiposity. Modified oral glucose tolerance tests were performed in schizophrenic patients (n = 48) receiving clozapine, olanzapine, risperidone, or typical antipsychotics, and untreated healthy control subjects (n = 31), excluding subjects with diabetes and matching groups for adiposity and age. Plasma was sampled at 0 (fasting), 15, 45, and 75 minutes after glucose load. Significant time x treatment group interactions were detected for plasma glucose (F(12,222) = 4.89, P<.001) and insulin (F(12,171) = 2.10, P =.02) levels, with significant effects of treatment group on plasma glucose level at all time points. Olanzapine-treated patients had significant (1.0-1.5 SDs) glucose elevations at all time points, in comparison with patients receiving typical antipsychotics as well as untreated healthy control subjects. Clozapine-treated patients had significant (1.0-1.5 SDs) glucose elevations at fasting and 75 minutes after load, again in comparison with patients receiving typical antipsychotics and untreated control subjects. Risperidone-treated patients had elevations in fasting and postload glucose levels, but only in comparison with untreated healthy control subjects. No differences in mean plasma glucose level were detected when comparing risperidone-treated vs typical antipsychotic-treated patients and when comparing typical antipsychotic-treated patients vs untreated control subjects. Antipsychotic treatment of nondiabetic patients with schizophrenia can be associated with adverse effects on glucose regulation, which can vary in severity independent of adiposity and potentially increase long-term cardiovascular risk.",2002.0,0,1
434,11927174,"Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia.",Karena M Meehan; Huei Wang; Stacy R David; Jennifer R Nisivoccia; Barry Jones; Charles M Beasley; Peter D Feldman; Jacobo E Mintzer; Louise M Beckett; Alan Breier,"This double-blind study investigated the efficacy and safety of rapid-acting intramuscular olanzapine in treating agitation associated with Alzheimer's disease and/or vascular dementia. At 2 h, olanzapine (5.0 mg, 2.5 mg) and lorazepam (1.0 mg) showed significant improvement over placebo on the PANSS Excited Component (PANSS-EC) and Agitation-Calmness Evaluation Scale (ACES), and both 5.0 mg olanzapine and lorazepam showed superiority to placebo on the Cohen-Mansfield Agitation Inventory. At 24 h, both olanzapine groups maintained superiority over placebo on the PANSS-EC; lorazepam did not. Olanzapine (5.0 mg) and lorazepam improved ACES scores more than placebo. Simpson-Angus and Mini-Mental State Examination scores did not change significantly from baseline. Sedation (ACES > or =8), adverse events, and laboratory analytes were not significantly different from placebo for any treatment. No significant differences among treatment groups were seen in extrapyramidal symptoms or in corrected QT interval at either 2 h or 24 h, and no significant differences among treatment groups were seen in vital signs, including orthostasis. Intramuscular injection of olanzapine may therefore provide substantial benefit in rapidly treating inpatients with acute dementia-related agitation.",2002.0,0,0
435,11927178,Novel factor-based symptom scores in treatment resistant schizophrenia: implications for clinical trials.,Robert P McMahon; Deanna L Kelly; Julie Kreyenbuhl; Brian Kirkpatrick; Raymond C Love; Robert R Conley,"To study the factor structure of symptoms in patients with treatment resistant schizophrenia and whether it is altered by treatment, we analyzed ratings on the Brief Psychiatric Rating Scale (BPRS) from two independent groups of patients with treatment resistant schizophrenia. With confirmatory factor analysis of pre-clozapine BPRS scores in 1074 patients in an administrative data base, the Clozapine Authorization and Monitoring Program (CAMP), we assessed the fit of published factor models and developed a better-fitting model. Model fit was validated in an independent group of 197 research unit participants. Stability of model fit six months post-clozapine was assessed in 834 CAMP patients. A new 4-factor model (negative symptoms, reality distortion, disorganization, and anxiety/depression) had better fit in both data sets than two commonly used factor models, and also fit better post-clozapine. We recommend these four factor scores as clinical trial outcomes in patients with treatment resistant schizophrenia.",2002.0,0,0
436,11948436,[Augmentation of selective serotonin reuptake inhibitors (SSRI) with atypical antipsychotics in the treatment of depression].,E Weimer; D F Braus; I Cavus; J Thome,"The treatment of severe depression represents a difficult task in the daily psychiatric practice. In certain cases, augmentation therapies in order to improve the efficacy of SSRIs can be useful. Recently, it has become possible to use atypical antipsychotics for SSRI augmentation. This option adds to the existing strategies in the treatment of depression and primary systematic studies show encouraging results. In this review, the possibility of a SSRI augmentation by additionally administering risperidone or olanzapine is critically discussed.",2002.0,0,0
437,11949778,A systematic review of the use of atypical antipsychotics in autism.,L Barnard; A H Young; J Pearson; J Geddes; G O'Brien,"Conventional antipsychotic medication is commonly prescribed to patients with autistic spectrum disorder. However, a high incidence of severe adverse reactions highlights the need to find more favourable treatments. Atypical antipsychotics may combine efficacy in ameliorating some autistic symptoms with a lower incidence of some adverse reactions. This article reviews the use of atypical antipsychotics in autistic disorder, with particular focus on behaviour, cognition and physical well-being. Thirteen studies using risperidone, three using olanzapine, one using clozapine, one using amisulpride and one using quetiapine were identified. Few firm conclusions can be drawn due to the limitations of the studies; however, there is an indication that risperidone may be effective in reducing hyperactivity, aggression and repetitive behaviours, often without inducing severe adverse reactions. Olanzapine and clozapine may also be effective; however, there is little evidence for using amisulpride or quetiapine in this population. Randomized trials are required to clarify the effectiveness of these agents.",2002.0,0,1
438,11955973,Prepulse inhibition of the startle response in risperidone-treated patients: comparison with typical antipsychotics.,Veena Kumari; William Soni; Tonmoy Sharma,"Individuals with schizophrenia are known to show deficits in prepulse inhibition (PPI) of the startle response. PPI refers to a response suppression in reaction to a strong startling stimulus, if preceded briefly by a weak non-startling stimulus and represents a well-established animal model to investigate information processing deficits in schizophrenia. This study examined PPI of the startle acoustic response in schizophrenic patients given typical antipsychotics or a second generation atypical antipsychotic, risperidone, using a naturalistic between-subjects design. Two groups of male schizophrenic patients: (i) stable on a range of typical antipsychotics (n = 20), and (ii) stable on risperidone (n = 10) were tested for PPI (prepulse-to-pulse intervals: 30, 60, and 120 ms, prepulses 15 dB above the background) of the acoustic startle response, and compared with a group of healthy male subjects (n = 20). Patients on typical antipsychotics showed significantly less PPI with 30 and 60 ms prepulse trials than healthy subjects. Risperidone-treated patients did not differ from healthy subjects for PPI with any prepulse trials. Further longitudinal within-subject studies are now required to examine whether risperidone is superior to typical antipsychotics in improving information processing functions, as assessed by PPI of the acoustic startle response, in treatment-responsive male patients with schizophrenia.",2002.0,0,0
439,11958362,Use of olanzapine for elderly patients with psychotic disorders: a review.,S Madhusoodanan; S Sinha; R Brenner; S Gupta; O Bogunovic,"The number of elderly persons with psychosis will increase with the increasing geriatric population. Olanzapine is one of the newer atypical antipsychotics with efficacy for positive and negative symptoms and safer side effect profile compared to conventional antipsychotics. The manuscript describes the pharmacology, efficacy and tolerability studies, adverse effects and dosing considerations in the elderly. Further studies are needed to fully assess the efficacy and safety of olanzapine in the elderly. Current research supports a role for olanzapine in treating elderly patients with schizophrenia, schizoaffective disorder and behavioral and psychological symptoms of dementia.",2002.0,0,0
440,11973119,Antihormonal treatment of paraphilic patients in German forensic psychiatric clinics.,J-P Czerny; P Briken; W Berner,The aim of this study was to investigate which antihormonal treatment strategies are used in German forensic psychiatric institutions. Forensic clinics were asked about the number of treated patients. Four hundred seventy-four patients were committed for sex offences; 12% received either CPA (n = 29) or LHRH- agonists (n = 29). Differences in efficacy were small. Several side effects confirm the importance of a protocol for minimizing medical complications.,2002.0,0,1
441,11973120,Mirtazapine overdose with benign outcome.,M Raja; A Azzoni,,2002.0,0,1
442,11978164,Ziprasidone: the fifth atypical antipsychotic.,Charles F Caley; Chandra K Cooper,"To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of ziprasidone as a treatment for schizophrenia. Information was selected from a MEDLINE search (July 2000-October 2001) of English-language medical literature using ziprasidone as the search term. Manual searches of pertinent journal article references, request for medical information from Pfizer, and access of the Web site of the Food and Drug Administration were also performed. All available published information regarding the pertinent characteristics of ziprasidone were considered for selection. Pharmacology and pharmacokinetic studies were selected to provide a comprehensive description of these characteristics. Clinical investigations were evaluated for design, sample size, diagnosis, duration, and outcome. Data from all investigations were selected by 1 author and reviewed by both authors. Ziprasidone is a benzisothiazolyl piperazine-type atypical antipsychotic that shares the serotonin(2A)/dopamine(2) (5-HT(2A)/D(2)) profile of the available atypical antipsychotics. Ziprasidone has demonstrated in vitro activity as a 5-HT(1A) receptor agonist and as a very weak inhibitor of serotonin and norepinephrine reuptake. These data do not support ziprasidone as being a clinically meaningful inhibitor of serotonin/norepinephrine reuptake. Oral bioavailability of ziprasidone taken with food is approximately 60%, half-life is approximately 6-7 hours, and protein binding is extensive at >99%. Twelve metabolites have been identified, yet only 4 of these are considered to be primary metabolites. Metabolism of ziprasidone by aldehyde oxidase produces its only metabolite with potential pharmacologic activity; CYP3A4 also contributes to the metabolism of ziprasidone. Clinical studies support ziprasidone as efficacious for the treatment of patients with acute exacerbations of schizophrenia or schizoaffective disorder. Daily doses permitted in these clinical trials ranged from 40 to 160 mg, but only doses between 120 and 160 mg/d have been superior to placebo. Future research efforts should be directed toward refractory schizophrenia, cognitive impairment in schizophrenia, affective and anxiety symptoms associated with schizoaffective disorder, and bipolar disorder. Adverse effect characteristics of ziprasidone commonly include headache, nausea, and somnolence; infrequent effects include extrapyramidal symptoms and weight gain. Ziprasidone has been reported to cause an average QTc prolongation of approximately 20 msec; there have only been 2 patients (0.06%) reported by the manufacturer to have a measured QTc interval >500 msec. Ziprasidone is a safe and efficacious atypical antipsychotic for the acute management of schizophrenia. Efficacy data and most safety data for ziprasidone support its use as a first-line treatment for schizophrenia; however, its potential effects on ventricular repolarization relegate it to second-line status in patients with comorbid cardiovascular risks.",2002.0,0,0
443,11982448,"A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia.",Alan Breier; Karena Meehan; Martin Birkett; Stacy David; Iris Ferchland; Virginia Sutton; Cindy C Taylor; Rebecca Palmer; Martin Dossenbach; Geri Kiesler; Shlomo Brook; Padraig Wright,"An intramuscular (IM) formulation of olanzapine has been developed because there are no rapid-acting IM atypical antipsychotic drugs currently available in the United States for treating acute agitation in patients with schizophrenia. Recently hospitalized acutely agitated patients with schizophrenia (N = 270) were randomized to receive 1 to 3 IM injections of olanzapine (2.5, 5.0, 7.5, or 10.0 mg), haloperidol (7.5 mg), or placebo within 24 hours. A dose-response relationship for IM olanzapine in the reduction of agitation was assessed by measuring the reduction in Positive and Negative Syndrome Scale Excited Component (PANSS-EC) scores 2 hours after the first injection. Safety was assessed by recording adverse events and with extrapyramidal symptom scales and electrocardiograms at 24 hours after the first injection. Olanzapine exhibited a dose-response relationship for reduction in agitation (F(1,179)= 14.4; P<.001). Mean PANSS-EC reductions 2 hours after the first injection of olanzapine (2.5 mg = -5.5; 5.0 mg = -8.1; 7.5 mg = -8.7; 10.0 mg = -9.4) were superior to those with placebo (-2.9; P =.01 vs olanzapine at 2.5 mg; P<.001 for each other olanzapine dose) but not with haloperidol (-7.5). A dose of 5.0, 7.5, or 10.0 mg of olanzapine caused a greater reduction in agitation than placebo 30 minutes after the first injection. There were no differences between treatment groups for hypotension, the most frequently reported adverse event, or for clinically relevant changes in the QTc interval. There was a greater incidence of treatment-emergent parkinsonism during treatment with IM haloperidol (16.7%) than with 2.5 (P =.03), 5.0 (P =.03), or 7.5 mg (P =.01) of IM olanzapine (0%) or with placebo (0%) (P =.01). Intramuscular olanzapine at a dose of 2.5 to 10.0 mg per injection exhibits a dose-response relationship in the rapid treatment of acute agitation in patients with schizophrenia and demonstrates a favorable safety profile.",2002.0,0,0
444,11986138,Supplementing clinic-based skills training with manual-based community support sessions: effects on social adjustment of patients with schizophrenia.,Shirley M Glynn; Stephen R Marder; Robert P Liberman; Karen Blair; William C Wirshing; Donna A Wirshing; Doreen Ross; Jim Mintz,"Although skills training is a validated psychosocial treatment for schizophrenia, generalization of the skills to everyday life has not been optimal. This study evaluated a behaviorally oriented method of augmenting clinic-based skills training in the community with the aim of improving opportunities, encouragement, and reinforcement for outpatients to use their skills in their natural environment. Sixty-three individuals with schizophrenia were randomly assigned to 60 weeks of clinic-based skills training alone or of clinic-based skills training supplemented with manual-based generalization sessions in the community. Patients were also randomly assigned to receive either haloperidol or risperidone. Therapists' fidelity to the manuals was measured. Patients' acquisition of the skills from pre- to posttraining was evaluated. The primary outcome measures were the Social Adjustment Scale-II and the Quality of Life Scale. Seventy-one percent of the patients completed the trial. Only six participants experienced psychotic exacerbations during the trial. There was no evidence of a differential medication effect on social functioning. Social functioning improved modestly in both psychosocial conditions over time; participants who received augmented skills training in the community showed significantly greater and/or quicker improvements. Given judicious and effective antipsychotic medication that limited exacerbations to less than 10% during the trial, a wide range of outpatients with schizophrenia demonstrated substantial learning of illness management and social skills in the clinic. When clinic-based skills training was augmented by in vivo training and consultation, transfer of the skills to everyday life was enhanced. These benefits were established regardless of the medications prescribed.",2002.0,0,0
445,11994888,"A pilot, randomized, open-label trial assessing safety and pharmakokinetic parameters of co-administration of rivastigmine with risperidone in dementia patients with behavioral disturbances.",Mark Weiser; Heschi H Rotmensch; Amos D Korczyn; Richard Hartman; Ana Cicin-Sain; Ravi Anand; Rivastigmine-Risperidone Study Group,"The majority of patients with Alzheimer's disease (AD) or vascular dementia display, in addition to cognitive impairment, various degrees of behavioral disturbances. As the use of cholinesterase inhibitors for the treatment of cognitive impairment in dementia becomes widespread, many of these patients will be treated concomitantly with cholinesterase inhibitors and with anti-psychotic drugs to ameliorate behavioral disturbances. Despite the widespread use of this combination in clinical practice, the safety and tolerability of such combination therapy has not been evaluated in controlled clinical trials. This pilot study examined the effects of addition of risperidone 0.5-2 mg/day to patients on rivastigmine 3-12 mg/day, and vice versa. 65 patients suffering from AD, 10 from vascular dementia, and 15 from both were randomized to open label rivastigmine and risperidone, alone or in combination, for 20 weeks. Adverse events caused by co-administration were assessed. No clinically relevant adverse interactions were observed. These preliminary results indicate that rivastigmine and risperidone can be safely co-administered. Confirmation of these results in large clinical trials studies is warranted.",2002.0,0,1
446,12000209,Phenylpropanolamine appears not to promote weight loss in patients with schizophrenia who have gained weight during clozapine treatment.,Mary C Borovicka; Matthew A Fuller; P Eric Konicki; John C White; Vickie M Steele; George E Jaskiw,"Weight gain is a common side effect of clozapine treatment and may expose patients to obesity-associated health risks. We proposed that concomitant treatment with an appetite suppressant such as phenylpropanolamine (PPA) would lead to a decrease in appetite and therefore loss of weight. This was a 12-week, double-blind, randomized, placebo-controlled trial of PPA, 75 mg/day, in outpatients with treatment-refractory schizophrenia (DSM-IV) who were stable on clozapine treatment for at least 4 months and had gained > 10% of their baseline body weight since starting clozapine. Patients were evaluated for adverse effects and weighed weekly. A Positive and Negative Syndrome Scale (PANSS) assessment, a short dietary quiz, and blood indices were completed monthly. Sixteen patients were equally randomly assigned to receive PPA or placebo. The groups did not differ in mean age, baseline weight, dose of clozapine, baseline PANSS scores, or the percent of weight gained since the start of clozapine. There was no significant effect of treatment on weight (t = 0.219, df = 10, p = .831). There was no significant change in either the total PANSS scores (t = -0.755, df = 10, p = .468), the positive or negative symptom cluster scores, or any of the remaining variables. Phenylpropanolamine 75 mg/day was well tolerated but was not effective in reversing established weight gain associated with clozapine treatment in stable outpatients with schizophrenia.",2002.0,0,0
447,12006892,Clozapine use and risk of diabetes mellitus.,Philip S Wang; Robert J Glynn; David A Ganz; Sebastian Schneeweiss; Raisa Levin; Jerry Avorn,"Recent reports have raised the concern that clozapine increases the risk for diabetes mellitus. Accurate pharmacoepidemiologic data on whether such a hazard exists and its magnitude are needed to enable clinicians and patients to make proper treatment decisions about clozapine. The authors performed a case-control study involving 7,227 cases of newly treated diabetes and 6,780 controls, all with psychiatric disorders. Cases and controls were older than 20 years and enrolled in government-sponsored drug benefit programs in New Jersey. The authors measured the use of clozapine or other antipsychotic medications and additional covariates. They developed logistic regression models adjusted for demographic, clinical, and health care use characteristics to identify whether clozapine users were at increased risk to begin treatment for diabetes. Clozapine use was not significantly associated with developing diabetes (adjusted odds ratio [OR], 0.98; 95% confidence interval [CI], 0.74-1.31). There was no suggestion of relationships between larger dosages or longer durations of clozapine use and increasing risks of diabetes. On the other hand, nonclozapine antipsychotic medication use was associated with a modest but significantly increased risk of developing diabetes (adjusted OR, 1.13; 95% CI, 1.05-1.22). Among individual nonclozapine antipsychotics, significantly elevated risks were observed for two phenothiazine agents: chlorpromazine (adjusted OR, 1.31; 95% CI, 1.09-1.56) and perphenazine (adjusted OR, 1.34; 95% CI, 1.11- 1.62). In contrast to earlier reports, these results provide some reassurance that clozapine does not increase the risk of developing diabetes. Additional data from pharmacoepidemiologic studies and randomized controlled trials are needed to exclude the possibility of residual confounding and ensure the appropriate use of this agent.",2002.0,1,1
448,12006893,Antipsychotic-induced weight gain and therapeutic response: a differential association.,Pál Czobor; Jan Volavka; Brian Sheitman; Jean-Pierre Lindenmayer; Leslie Citrome; Joseph McEvoy; Thomas B Cooper; Miranda Chakos; Jeffrey A Lieberman,"This study investigated the association between antipsychotic-induced weight gain and therapeutic response to haloperidol and three commonly used atypical neuroleptic medications in schizophrenia and schizoaffective disorder. The subjects were 151 patients enrolled in a double-blind experiment with a duration of 14 weeks comparing the therapeutic efficacy of haloperidol (n = 36), clozapine (n = 38), olanzapine (n = 38), and risperidone (n = 39). Absolute and relative (%) gain in body weight and body mass index (BMI) was determined for the entire duration of the double-blind treatment period; therapeutic response was assessed by the total score and the individual subscales of the Positive and Negative Symptom Scale. Compared with the pretreatment baseline, results indicated that for olanzapine and clozapine, therapeutic response was closely related to an absolute and relative gain in weight and to a gain in BMI. No association between weight gain and therapeutic response was found for risperidone and haloperidol. These findings suggest that patients who are likely to have the maximal benefits of olanzapine or clozapine treatment for symptom alleviation are at the highest risk of a clinically significant increase in weight gain.",2002.0,0,0
449,12007591,Sex differences in clinical response to olanzapine compared with haloperidol.,Jill M Goldstein; Lee S Cohen; Nicholas J Horton; Hang Lee; Scott Andersen; Mauricio Tohen; Ann- Marie K Crawford; Gary Tollefson,"There is current disagreement over whether men and women respond differently to typical or atypical antipsychotic medications. This study reanalyzed a large international clinical trial of olanzapine (Olz) compared with haloperidol (Hal) to test for sex differences in treatment response, controlling for illness chronicity and menopausal status. We hypothesized that women would show a greater response to either medication than men, particularly among first admission, premenopausal women. DSM-III-R schizophrenia inpatients (700 women and 1295 men) were randomly assigned to a 6-week trial of Olz vs. Hal. Longitudinal random effect models were used to test for interactions of sex with medication, chronicity and menopausal status on treatment response. Findings showed that women on olanzapine had a greater drop in overall symptomatology by week 4 than any other group, and their level of symptomatology remained lower throughout the 6-week trial. The sex differences in treatment response in olanzapine compared with haloperidol were, in part, dependent on chronicity and, in women, menopausal status. That is, first episode women on haloperidol exhibited an increase in symptomatology over the 6-week trial compared to their male counterparts, while multiply hospitalized women had a better treatment response on haloperidol than their male counterparts. Women on olanzapine had a significantly better treatment response than men, regardless of chronicity. Finally, premenopausal women had a significantly better treatment response than postmenopausal women, regardless of treatment and chronicity.",2002.0,1,1
450,12019665,Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone.,Kwang-Soo Kim; Chi-Un Pae; Jeong-Ho Chae; Won-Myong Bahk; Tae-Youn Jun; Dai-Jin Kim; Ruth A Dickson,"This study was conducted to prospectively examine the effect of switching from risperidone to olanzapine on female schizophrenia patients who experienced menstrual disturbances, galactorrhea, and/or sexual dysfunction. Twenty female patients with DSM-IV schizophrenia who were taking risperidone and were suffering from menstrual disturbances, galactorrhea, and/or sexual dysfunction were enrolled. Patients were switched from risperidone to olanzapine over a 2-week period, then treated with olanzapine for 8 additional weeks. The serum prolactin concentrations were examined every 2 weeks. The Positive and Negative Syndrome Scale (PANSS), Abnormal Involuntary Movement Scale (AIMS), Simpson-Angus Scale for Extrapyramidal Symptoms (SAS), and questions from the Dickson-Glazer Sexual Functioning Scale were administered to evaluate efficacy, extrapyramidal side effects, and sexual and reproductive functioning at baseline and the endpoint of 10 weeks. Serum prolactin levels decreased significantly (p < .01) following the switch from risperidone to olanzapine. Scores of PANSS, AIMS, and SAS at the endpoint were also significantly decreased (p < .01) compared to those of baseline. Patients experienced improvements in menstrual functioning and perceptions of sexual side effects. Olanzapine reversed hyperprolactinemia in risperidone-treated female schizophrenic patients. This was associated with a decrease in amenorrhea, improved cycle regularity, and a decrease in sexual side effects that the women attributed to antipsychotic medication. This study suggests that switching to olanzapine is a safe and effective alternative method for patients with antipsychotic-induced hyperprolactinemia associated sexual and/or reproductive dysfunction. Long-term follow-up studies are warranted, with particular attention to the course of sexual and reproductive dysfunction.",2002.0,0,0
451,12019667,Clinical predictors of response to clozapine treatment in ambulatory patients with schizophrenia.,Daniel S Umbricht; William C Wirshing; Donna A Wirshing; Marjorie McMeniman; Nina R Schooler; Stephen R Marder; John M Kane,"Despite the advent of new atypical antipsychotics, clozapine remains an important option in the treatment of patients with poor response to conventional antipsychotics. Clinicians would be well served if clinical characteristics could be identified that predict a favorable response to clozapine. A few studies addressing this issue have reported inconsistent results. The association of clinical characteristics with a sustained response was investigated in 37 partially treatment-refractory outpatients with a DSM-III-R diagnosis of chronic schizophrenia who had been assigned to clozapine treatment in a double-blind, haloperidol-controlled, long-term (29-week) study of clozapine. Response was defined as a 20% decrease of the Brief Psychiatric Rating Scale (BPRS) psychosis factor score sustained over 2 consecutive ratings. Differences between responders and nonresponders with regard to selected baseline variables were analyzed with t tests and chi2 tests. In addition, Cox regression analyses were performed to identify variables that best predicted a response to clozapine treatment. Clozapine responders were rated as less severely ill, showed a lesser degree of negative symptoms, and demonstrated fewer extrapyramidal side effects at baseline as compared with nonresponders. In addition, higher BPRS total scores--after controlling for the effects of the other variables--were associated with a response. In a cohort of partially treatment-refractory outpatients, a favorable response to clozapine was associated with characteristics describing less severely ill patients. The history of patients did not affect their response to clozapine.",2002.0,0,0
452,12019668,"A retrospective comparison of weight, lipid, and glucose changes between risperidone- and olanzapine-treated inpatients: metabolic outcomes after 1 year.",Jonathan M Meyer,"Metabolic side effects have been increasingly noted during therapy with novel antipsychotics, but there is a dearth of comprehensive comparative data in this area. The goal of this retrospective study was to examine the changes in weight parameters, fasting glucose, and fasting lipids in long-term inpatients treated with either risperidone or olanzapine. A retrospective study was performed by reviewing charts of patients at Oregon State Hospital, Salem, who were treated during July and August 1999, comparing metabolic outcomes during the first year of therapy with either risperidone or olanzapine. Data were analyzed also by age, sex, and concurrent use of lithium or valproate. Included for analysis were patients at least 18 years old with baseline weights obtained within 3 weeks of drug initiation, and baseline fasting triglycerides, cholesterol, and glucose obtained within 3 months prior to drug initiation and at 1 year of treatment (+/- 4 weeks). The patients meeting these criteria in each drug cohort (risperidone, N = 47; olanzapine, N = 47) included 1 patient with diagnosed diabetes mellitus prior to onset of treatment. Among those patients under 60 years old, olanzapine patients (N = 37) experienced significantly greater increases at 1 year in all metabolic parameters than the risperidone group (N = 39), except for weight variables: triglycerides +104.8 mg/dL (olanzapine) versus +31.7 mg/dL (risperidone) (p = .037); cholesterol +30.7 mg/dL (olanzapine) versus +7.2 mg/dL (risperidone) (p = .004); glucose +10.8 mg/dL (olanzapine) versus +0.74 mg/dL (risperidone) (p = .030). Patients under 60 years of age with concurrent use of lithium or valproate were associated with greater weight gain in both drug groups, but this difference was statistically significant only for the olanzapine cohort. Neither weight change nor use of lithium or valproate was associated with increases in glucose or lipids among those under 60 years old for either drug. Olanzapine therapy is associated with significantly greater increases in fasting glucose and lipid levels for nongeriatric adult patients than risperidone, and the increases are not correlated with changes in weight parameters. Appropriate monitoring of fasting glucose and serum lipid levels should be considered during extended treatment with atypical antipsychotics.",2002.0,0,1
453,12027048,Effects of neuroleptic medications on speech disorganization in schizophrenia: biasing associative networks towards meaning.,T E Goldberg; M Dodge; M Aloia; M F Egan; D R Weinberger,"While some cognitive accounts of disorganized speech, or thought disorder, in schizophrenia have emphasized failures in working memory/discourse planning or selective attention, we have suggested that thought disorder resides in the semantic system. In this study we assessed the effect of neuroleptic medication on thought disorder and semantic processing. Seventeen patients with schizophrenia were assessed while receiving neuroleptic medications and in crossover fashion, placebo. A number of measures were obtained: clinically rated thought disorder (using the Thought, Language and Communication Scale); working memory letter number span); lexical integrity (naming and receptive vocabulary); and, semantic priming of intracategorical word pairs. Semantic priming measures improved with neuroleptic medication, as did clinically rated thought disorder. No other measure changed significantly. Priming selectively covaried with changes in thought disorder. Changes in spreading semantic activation, measured in a semantic priming paradigm and presumably brought about by neuroleptics' influence on dopaminergic neuromodulatory systems, might reflect changes in the biases of pre-existing associative networks that favour or increase the accessibility of representations related by shared features. This study also has implications for the architecture of normal language in that a dissociation between the lexical and semantic levels was observed, due to the selective compromise of tasks demanding semantic processing.",2002.0,0,1
454,12034344,Physical consequences of schizophrenia and its treatment: the metabolic syndrome.,Martina C M Ryan; Jogin H Thakore,"Schizophrenia is a life shortening illness. Unnatural causes and natural causes are put forward as reasons for this excess mortality. In terms of the latter, a host of different physical disorders occur with increased frequency in schizophrenia. When taken together, some of these illnesses such as type 2 diabetes mellitus and cardiovascular disorders constitute the Metabolic Syndrome; a characteristic phenotype of those with this syndrome is excessive visceral fat distribution. The exact reasons why this particular syndrome occurs in schizophrenia is as yet unclear though factors such as life style, poor diet and lack of exercise may contribute to it's development. Alternatively, overactivity of the hypothalamic-pituitary-adrenal axis leading to hypercortisolaemia can also result in excessive visceral fat accumulation. This minireview aims to explore the potential role of these issues and medication in terms of the increased morbidity and mortality observed in schizophrenia.",2002.0,0,1
455,12042191,Olanzapine versus divalproex in the treatment of acute mania.,Mauricio Tohen; Robert W Baker; Lori L Altshuler; Carlos A Zarate; Trisha Suppes; Terrence A Ketter; Denai R Milton; Richard Risser; Julie A Gilmore; Alan Breier; Gary A Tollefson,"The effects of olanzapine and divalproex for the treatment of mania were compared in a large randomized clinical trial. A 3-week, randomized, double-blind trial compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day in divided doses) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton Depression Rating Scale were used to quantify manic and depressive symptoms, respectively. Safety was assessed with several measures. The protocol defined baseline-to-endpoint improvement in the mean total score on the Young Mania Rating Scale as the primary outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex (N=123). A priori categorizations defined response and remission rates: 54.4% of olanzapine-treated patients responded (> or = 50% reduction in Young Mania Rating Scale score), compared to 42.3% of divalproex-treated patients; 47.2% of olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania Rating Scale < or = 12), compared to 34.1% of divalproex-treated patients. The decrease in Hamilton depression scale score was similar in the two treatment groups. Completion rates for the 3-week study were similar in both groups. The most common treatment-emergent adverse events (incidence >10%) occurring more frequently during treatment with olanzapine were dry mouth, increased appetite, and somnolence. For divalproex, nausea was more frequently observed. The average weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex treatment. The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission, compared with the divalproex treatment group. Significantly more weight gain and cases of dry mouth, increased appetite, and somnolence were reported with olanzapine, while more cases of nausea were reported with divalproex.",2002.0,1,1
456,12042192,"Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder.",Robert M Bilder; Robert S Goldman; Jan Volavka; Pal Czobor; Matthew Hoptman; Brian Sheitman; Jean-Pierre Lindenmayer; Leslie Citrome; Joseph McEvoy; Michal Kunz; Miranda Chakos; Thomas B Cooper; Terri L Horowitz; Jeffrey A Lieberman,"Newer antipsychotic drugs have shown promise in ameliorating neurocognitive deficits in patients with schizophrenia, but few studies have compared newer antipsychotic drugs with both clozapine and conventional agents, particularly in patients who have had suboptimal response to prior treatments. The authors examined the effects of clozapine, olanzapine, risperidone, and haloperidol on 16 measures of neurocognitive functioning in a double-blind, 14-week trial involving 101 patients. A global score was computed along with scores in four neurocognitive domains: memory, attention, motor function, and general executive and perceptual organization. Global neurocognitive function improved with olanzapine and risperidone treatment, and these improvements were superior to those seen with haloperidol. Patients treated with olanzapine exhibited improvement in the general and attention domains but not more than that observed with other treatments. Patients treated with risperidone exhibited improvement in memory that was superior to that of both clozapine and haloperidol. Clozapine yielded improvement in motor function but not more than in other groups. Average effect sizes for change were in the small to medium range. More than half of the patients treated with olanzapine and risperidone experienced ""clinically significant"" improvement (changes in score of at least one-half standard deviation relative to baseline). These findings did not appear to be mediated by changes in symptoms, side effects, or blood levels of medications. Patients with a history of suboptimal response to conventional treatments may show cognitive benefits from newer antipsychotic drugs, and there may be differences between atypical antipsychotic drugs in their patterns of cognitive effects.",2002.0,1,1
457,12042193,Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia.,Norbert Müller; Michael Riedel; Constanze Scheppach; Bernd Brandstätter; Safet Sokullu; Karin Krampe; Markus Ulmschneider; Rolf R Engel; Hans-Jürgen Möller; Markus J Schwarz,"Abnormalities in the immune system in schizophrenia have been described. However, important findings such as high levels of activating cytokines in the CSF and signs of CNS inflammation have been controversial. The authors conducted a trial of the new selective cyclooxygenase-2 inhibitor celecoxib, an immunomodulatory drug, in schizophrenic patients to evaluate its therapeutic effects. In a prospective, double-blind evaluation, 50 patients with an acute exacerbation of schizophrenia were randomly assigned to either risperidone plus celecoxib or risperidone plus placebo. After a washout period, 25 patients received 2-6 mg/day of risperidone plus placebo and 25 received risperidone plus 400 mg/day of celecoxib for 5 weeks. The treatment effect was calculated by analysis of covariance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or risperidone dose or plasma level. Over 5 weeks, both groups of patients showed significant improvement in scores on the Positive and Negative Syndrome Scale and on all subscales. However, the celecoxib group showed significantly greater improvement in the total score. Additional treatment with celecoxib has significant positive effects on the therapeutic action of risperidone with regard to total schizophrenia psychopathology. Moreover, the fact that treatment with an immunomodulatory drug showed beneficial effects on schizophrenia symptoms indicates that immune dysfunction in schizophrenia is not just an epiphenomenon but is related to the pathomechanism of the disorder. However, a nonimmunological therapeutic effect of celecoxib mediated by the N-methyl-D-aspartic acid receptor has to be taken into account.",2002.0,0,0
458,12042201,"Olanzapine-induced weight gain in patients with first-episode schizophrenia: a double-blind, placebo-controlled study of fluoxetine addition.",Michael Poyurovsky; Artashes Pashinian; Irit Gil-Ad; Rachel Maayan; Michael Schneidman; Camil Fuchs; Abraham Weizman,"Since olanzapine-induced weight gain may be attributable to the antagonistic activity of olanzapine at the serotonin-2C receptor, the authors hypothesized that it might be attenuated by addition of the selective serotonin reuptake inhibitor fluoxetine. First-episode hospitalized schizophrenia patients (N=30) were randomly assigned in an 8-week double-blind study of olanzapine, 10 mg/day, coadministered with either fluoxetine, 20 mg/day (N=15), or placebo (N=15). The group receiving olanzapine plus fluoxetine showed significantly less improvement in positive and disorganized symptom dimensions than the group receiving olanzapine plus placebo. The two groups demonstrated similar and substantial gradual weight gains. These results suggest that fluoxetine coadministration is clinically ineffective and cannot attenuate olanzapine-induced weight gain.",2002.0,0,0
459,12044209,Atypical antipsychotics and cognition in schizophrenia.,Tonmoy Sharma,,2002.0,0,0
460,12045315,Efficacy of olanzapine and risperidone for treatment-refractory schizophrenia among long-stay state hospital patients.,Hassan S Dinakar; Robert N Sobel; James H Bopp; Anita Daniels; Sondra Mauro,"The authors studied the efficacy of olanzapine and risperidone among patients with treatment-refractory schizophrenia who had been hospitalized for more than five years and who were not suitable candidates for a clozapine trial. The patients were systematically reassessed and were given olanzapine or risperidone as part of a ""second-chance program."" The patients in both groups showed significant improvement in scores on the 18-item Brief Psychiatric Rating Scale after three months. Forty-four percent of the patients in the olanzapine group and 43 percent of those in the risperidone group were discharged to supervised residences on the basis of their clinical improvement. There is value in reassessing long-stay patients who have treatment-refractory schizophrenia and giving them systematic trials with new medications that become available.",2002.0,0,0
461,12046640,Improving outcome in schizophrenia: the potential importance of EPS and neuroleptic dysphoria.,Jes Gerlach,"Despite half a century of antipsychotic drug treatment, the outcome of therapy in schizophrenia remains disappointing. Relapse, rehospitalization, limited fulfilment of social roles, and suicide remain frequent, and the economic costs are high. Current relapse rates may be two to three times higher than those that could be achieved with optimal use of therapy. Poor compliance with treatment is considered to be a significant preventable cause of poor outcome and is in turn likely to be influenced by the patient's experience of drug treatment. There is some evidence that extrapyramidal symptoms (EPS), particularly akathisia and neuroleptic dysphoria, are associated with poor compliance and poor treatment outcome. Atypical antipsychotics have a lower risk of EPS than do standard antipsychotics. Some (risperidone, olanzapine, and ziprasidone) show evidence of a dose-related increase in EPS, but clozapine and quetiapine have demonstrated a placebo-level incidence of EPS across the dose range. Quetiapine does not require the regular blood monitoring mandated for clozapine, and results from a patient survey indicate a high degree of patient satisfaction with treatment. While further research is needed, it is possible that wider use of medications with low EPS and high patient acceptability could promote better compliance and improve the outcome of schizophrenia treatment.",2002.0,0,0
462,12046641,Phenomenology of and risk factors for new-onset diabetes mellitus and diabetic ketoacidosis associated with atypical antipsychotics: an analysis of 45 published cases.,Hua Jin; Jonathan M Meyer; Dilip V Jeste,"Case reports and small retrospective studies suggest that atypical antipsychotic agents may be associated with new-onset Type II diabetes mellitus (DM) or diabetic ketoacidosis (DKA); however, these reports often provide limited or no information on demographic variables such as age, gender, ethnicity, relationship to weight gain, and time course. We analyzed 45 published cases of new-onset DM or DKA for which followed initiation of atypical antipsychotic treatment. Of the 45 patients, 20 had received clozapine, 19 olanzapine, 3 quetiapine, and 3 risperidone. Eighty-seven percent patients were male, and 47% African American. Forty-two percent of these patients presented as DKA, and 50% manifested no weight gain at time of presentation with DM or DKA, although 84% were overweight before antipsychotic therapy. Eighty-four percent presented within 6 months and 59% within 3 months of commencing atypical antipsychotics. The DKA cohort had significantly younger age, less overweight at baseline, and higher proportion of women than did those with DM alone, without significant differences in distribution of ethnicity, weight gain, family history of DM, or duration of exposure to atypical agents. Clinicians should be aware of the potential risks of new-onset DM and DKA in patients taking atypical antipsychotics, and utilize appropriate clinical and laboratory monitoring to prevent serious adverse events.",2002.0,0,1
463,12047021,Clinical profile of an atypical antipsychotic: risperidone.,John M Davis; Nancy Chen,"Stimulated by Dawkins and colleagues' (1999) and Remington and Kapur's (2000) calls to develop clinical profiles of the new atypical antipsychotic drugs and by Mattes's critiques (1997, 1998), we performed two sets of analyses for risperidone. First, we reanalyzed data from the North American risperidone trial: risperidone was superior to haloperidol to an equal degree in patients with and without the deficit syndrome, in patients with paranoid and nonparanoid schizophrenia, in treatment-resistant and treatment-responsive patients (patients hospitalized for longer and shorter periods), and in patients with or without weight gain. Moreover, risperidone was more effective than haloperidol on symptoms nonresponsive and responsive to haloperidol; its effects on negative symptoms were independent of its effects on extrapyramidal symptoms; and it was effective in treating depression in schizophrenia. Second, we performed a meta-analysis of 18 controlled risperidone trials: risperidone was consistently more effective than conventional antipsychotics in treating positive and negative symptoms.",2002.0,0,0
464,12047024,Recent trends in antipsychotic combination therapy of schizophrenia and schizoaffective disorder: implications for state mental health policy.,Robin E Clark; Stephen J Bartels; Thomas A Mellman; William J Peacock,"Little is known about antipsychotic combination therapy, although this practice is becoming increasingly common in the treatment of schizophrenia. Medicaid pharmaceutical claims for a cohort of 836 New Hampshire beneficiaries with schizophrenia or schizoaffective disorder were followed from 1995 through 1999. Use of traditional and atypical antipsychotic medications, antidepressants, anxiolytic hypnotics, and mood stabilizers was tracked monthly. The number of medications, frequency of coprescription, and Medicaid pharmaceutical costs are described. The proportion of individuals with schizophrenia and schizoaffective disorder treated with atypical antipsychotics grew from 43 percent in 1995 to 70 percent in 1999. At the same time, concurrent use of two or more antipsychotic medications quadrupled, increasing from 5.7 percent to 24.3 percent. Persons with schizophrenia were also prescribed more antidepressants (increased from 18.5% in 1995 to 35.6% in 1999), anxiolytics (increased from 19.9% to 33.5%), and mood stabilizers (increased from 17.7% to 30.0%). The increase in multiple agent therapy appears to be broad-based. Data are needed on the effectiveness and cost-effectiveness of these practices to inform clinical decision making and health policy.",2002.0,0,1
465,12062881,The neurocognitive effects of low-dose haloperidol: a two-year comparison with risperidone.,Michael F Green; Stephen R Marder; Shirley M Glynn; Susan R McGurk; William C Wirshing; Donna A Wirshing; Robert P Liberman; Jim Mintz,"Neurocognitive deficits are core features of schizophrenia that are linked to functional outcome for the disorder. Recent studies and reviews have concluded that newer antipsychotic medications are better for neurocognitive deficits than conventional antipsychotic medications; however, one difficulty in interpreting this literature is that the comparisons have mainly been with high doses of conventional medications. This study examined the neurocognitive effects of low-dose haloperidol compared with risperidone over a 2-year period. Sixty-two patients were randomly assigned to medication (starting at 6 mg of each medication) and administered neurocognitive batteries six times over the course of follow-up. At 6 months, the mean dose of haloperidol was 5.0 mg, and the mean dose of risperidone was 6.0 mg. Neurocognitive data were reduced into cluster scores and a global summary score. We found no significant overall differences in treatment effects on the cluster scores or the global score. The global score revealed a significant group by time interaction, reflecting the fact that the haloperidol group tended to improve initially and then stay stable, whereas the risperidone group improved more gradually over the follow-up period. This study did not provide support for neurocognitive advantages of a newer antipsychotic medication over a low-dose conventional medication. We speculate that conventional medications may have neurocognitive benefits at low doses that are neutralized or reversed at higher doses.",2002.0,1,1
466,12075948,Clinical and economic outcomes associated with olanzapine for the treatment of psychotic symptoms in a county mental health population.,Douglas Del Paggio; Patrick R Finley; Jeanette M Cavano,"The comparatively high acquisition costs of the newer antipsychotic medications have caused the mental health community to look closely at their potential benefits. The purpose of this study was to perform a naturalistic analysis of changes in mental health service utilization, economic costs, and clinical outcomes after the initiation of olanzapine therapy for psychotic symptoms in an indigent patient population from a large county-operated mental health care system. This was a prospective, uncontrolled investigation using a mirror-image cohort design. All captured costs from patients who began olanzapine therapy between November 1, 1996, and April 30, 1998, were analyzed in an intent-to-treat fashion to compare resource utilization in the 12 months immediately before and after the intervention. Clinical function was assessed at baseline and 6 months using the Positive and Negative Syndrome Scale (PANSS). In a subgroup analysis, the baseline characteristics of patients who completed 12 months of olanzapine treatment were compared with those of patients who (1) changed medication or (2) changed pay or source or were lost to follow-up. One hundred eighty-nine patients were started on olanzapine treatment during the 18-month study entry phase. Patients were primarily male (63.5%) and had a mean age of 35.9 years. Most (66.3%) had a formal diagnosis of thought disorder. Fifty-six patients received olanzapine for 12 consecutive months, and 22 were switched to other psychotropic medications. Of the remaining 111 patients, 70 changed payors (ie, qualified for Medicaid), and 41 were lost to follow-up. In the subgroup analysis, patients who completed 12 months of treatment (ie, responders) had significantly lower mean PANSS total scores at baseline compared with those who changed payors or were lost to follow-up (P = 0.047), and were significantly more likely to have a formal diagnosis of thought disorder (P = 0.039). Responders demonstrated a significant reduction in PANSS total and negative subscale scores at 6-month follow-up (both measures, P < 0.001). In the intent-to-treat analysis of resource utilization in all patients with complete data sets (n = 78), hospitalization costs and crisis costs decreased significantly during the 12-month follow-up period (P = 0.003 and P = 0.009, respectively), and both outpatient and medication costs increased significantly (P = 0.035 and P < 0.001, respectively). Overall, the change in total annual resource utilization during the 12 months after initiation of olanzapine was not statistically significant (mean decrease per patient, $1,991; 95% CI, -$5,258 to $1,122). Initiation of olanzapine therapy was associated with favorable clinical outcomes in this population, particularly in patients with a formal diagnosis of thought disorder. Overall, there was a cost shift away from hospital and crisis costs toward medication and outpatient services costs. The decline in total resource utilization was not statistically significant, although it may be of practical importance.",2002.0,0,0
467,12079730,A placebo controlled trial of bupropion for smoking cessation in schizophrenia.,Tony P George; Jennifer C Vessicchio; Angelo Termine; Thomas A Bregartner; Alan Feingold; Bruce J Rounsaville; Thomas R Kosten,"Schizophrenic patients have high rates of cigarette smoking compared with the general population. We compared sustained-release (SR) bupropion with placebo for smoking cessation in patients with schizophrenic disorders. We also examined how antipsychotic class predicts smoking cessation outcomes with bupropion. Thirty-two subjects meeting DSM-IV criteria for schizophrenia or schizoaffective disorder and nicotine dependence were randomized to bupropion SR (BUP, 300 mg/day) or placebo (PLA). Outcomes included treatment retention, smoking abstinence rates, expired breath carbon monoxide (CO) levels, psychotic symptoms, and medication side effects. Bupropion significantly increased trial endpoint 7-day point prevalence smoking abstinence rates compared with placebo [BUP, 8/16 (50.0%), PLA, 2/16 (12.5%); chi(2) = 5.24, df = 1, p <.05], and reduced CO levels during the trial [Medication x Time interaction; Z = 3.09, p <.01]. Positive schizophrenia symptoms were not altered by BUP, but negative symptoms were significantly reduced. Atypical antipsychotic drug treatment enhanced smoking cessation responses to BUP. Major side effects were dry mouth, gastrointestinal symptoms, headache, and insomnia. Our results suggest that 1) BUP enhances smoking abstinence rates compared with PLA in nicotine-dependent schizophrenic smokers; 2) BUP is well-tolerated and safe for use in these patients; and 3) atypical antipsychotics may enhance smoking cessation outcomes with BUP.",2002.0,0,0
468,12084413,Newer atypical antipsychotic medication in comparison to clozapine: a systematic review of randomized trials.,Arja Tuunainen; Kristian Wahlbeck; Simon Gilbody,"The aim of this study was to evaluate the effectiveness of newer atypical antipsychotic drugs in comparison to clozapine for schizophrenia. Publications in all languages were searched from all relevant databases and all randomized controlled trials comparing clozapine with newer atypical drugs were included. The review and meta-analysis includes eight studies, most of them short in duration. Newer atypical drugs were broadly similar to clozapine when improvement was measured using a psychosis symptom rating scale or a global index. There was a trend for clozapine to be more effective than the others for positive symptoms, and less effective for the negative symptoms. The adverse effect profile of clozapine and newer atypical drugs was dissimilar: while clozapine produced more fatigue, hypersalivation, and orthostatic dizziness, new atypical drugs, with the exception of olanzapine, produced more extrapyramidal symptoms. As these results were obtained from few studies and a relatively small amount of patients, the equal effectiveness and tolerability of new atypical drugs in comparison with clozapine is not yet demonstrated. More trials of sufficient power, with longer duration, and measuring clinically important outcomes are urgently needed.",2002.0,1,1
469,12084415,D-Cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia.,A Eden Evins; Ed Amico; Thomas A Posever; Rob Toker; Donald C Goff,"D-Cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor has previously been shown to improve negative symptoms when added to conventional antipsychotics and to worsen negative symptoms when added to clozapine. The purpose of this study was to examine the effects of D-cycloserine when added to risperidone on negative symptoms of schizophrenia. Ten patients with schizophrenia who were treated with risperidone completed consecutive two week trials of placebo and four doses of D-cycloserine. Clinical assessments were videotaped and were scored by a rater who was blind to temporal sequence. D-Cycloserine at a dose of 50mg/day was associated with significant reduction in negative symptoms (mean=10%). Ratings of depression, extrapyramidal side effects, and cognitive function were unchanged. Serum concentrations of glutamate and serine increased significantly on this dose of D-cycloserine. This preliminary study suggests that combination of D-cycloserine, 50mg/day, with risperidone may improve negative symptoms of schizophrenia over a narrow dose range. The degree of improvement appears to be intermediate between improvement of negative symptoms observed with combination of D-cycloserine with conventional antipsychotics and worsening of negative symptoms observed with combination of D-cycloserine with clozapine in previous trials of identical design.",2002.0,0,0
470,12088164,A 28-week comparison of ziprasidone and haloperidol in outpatients with stable schizophrenia.,Steven R Hirsch; Werner Kissling; Josef Bäuml; Aidan Power; Rory O'Connor,"Ziprasidone is a novel antipsychotic with a unique pharmacologic profile. This study compared ziprasidone with the conventional antipsychotic haloperidol in outpatients with stable schizophrenia. Three hundred one outpatients with stable chronic or subchronic schizophrenia (DSM-III-R) were randomized and participated in this double-blind, multicenter, parallel-group clinical study comparing flexible-dose oral ziprasidone, 80-160 mg/day (N = 148), with haloperidol, 5-15 mg/day (N = 153), over 28 weeks. Patients were assessed using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions-Severity of Illness scale, the Montgomery-Asberg Depression Rating Scale, the Simpson-Angus Scale, the Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale. Modal doses at endpoint were 80 mg/day for ziprasidone and 5 mg/day for haloperidol. Improvements in all mean efficacy variables with both ziprasidone and haloperidol were observed. Significantly more patients were categorized as negative symptom responders (> or = 20% reduction in PANSS negative subscale score) in the ziprasidone group (48%) compared with the haloperidol group (33%) (p < .05). Ziprasidone had clear advantages over haloperidol in all evaluations of movement disorders. Changes in body weight were negligible with both treatments. No pattern of laboratory or cardiovascular changes was observed. Ziprasidone and haloperidol were both effective in reducing overall psychopathology; ziprasidone demonstrated effective treatment of negative symptoms and was better tolerated than haloperidol. Ziprasidone appears to offer an effective alternative to haloperidol in the long-term treatment of stable outpatients with schizophrenia.",2002.0,1,1
471,12090443,"Prevalence of obesity, lipid and glucose abnormalities in outpatients prescribed clozapine.",P Leonard; A Halley; S Browne,"Individuals with schizophrenia have standardised mortality rates which are double that of the general population. In addition to suicide, high rates of cardiovascular and respiratory disease contribute to this raised mortality rate. Although clozapine has been reported to improve psychotic symptoms and decrease suicide rates, attention has recently focussed on its potential to increase cardiovascular risk factors including obesity, dyslipidemia and diabetes mellitus. This study aimed to ascertain the prevalence of these risk factors in a cohort of Irish outpatients treated with clozapine.",2002.0,0,1
472,12091192,"Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety.",Gary S Sachs; Fred Grossman; S Nassir Ghaemi; Akiko Okamoto; Charles L Bowden,"The study assessed the efficacy and safety of risperidone as an adjunctive agent to mood stabilizers in the treatment of acute mania. This 3-week randomized, double-blind, placebo-controlled study included 156 bipolar disorder patients with a current manic or mixed episode who received a mood stabilizer (lithium or divalproex) and placebo, risperidone, or haloperidol. The primary efficacy measure was the Young Mania Rating Scale. Other assessments used the Brief Psychiatric Rating Scale, the Clinical Global Impression scale, and safety measures. The trial was discontinued by 25 (49%) of the 51 placebo group patients, 18 (35%) of the 52 risperidone group patients, and 28 (53%) of the 53 haloperidol group patients. Mean modal doses were 3.8 mg/day (SD=1.8) of risperidone and 6.2 mg/day (SD=2.9) of haloperidol. Significantly greater reductions in Young Mania Rating Scale scores at endpoint and over time were seen in the risperidone group and in the haloperidol group, compared with the placebo group. Young Mania Rating Scale total scores improved with risperidone and with haloperidol both in patients with psychotic features and in those without psychotic features at baseline. Extrapyramidal Symptom Rating Scale total scores at endpoint were significantly higher in the haloperidol patients than in the placebo patients. Antiparkinsonian medications were received by 8%, 17%, and 38% of patients in the placebo, risperidone, and haloperidol groups, respectively. Risperidone plus a mood stabilizer was more efficacious than a mood stabilizer alone, and as efficacious as haloperidol plus a mood stabilizer, for the rapid control of manic symptoms and was well tolerated.",2002.0,0,1
473,12091788,,,,,0,0
474,12093603,Effects of risperidone on the peripheral noradrenegic system in patients with schizophrenia: a comparison with clozapine and placebo.,Igor Elman; David S Goldstein; Alan I Green; Graeme Eisenhofer; Carol J Folio; Courtney S Holmes; David Pickar; Alan Breier,"Risperidone is an atypical antipsychotic drug that increases plasma norepinephrine (NE) levels, but the mechanism behind this effect is unclear. We measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE (3H-NE) in risperidone-treated patients and compared their data with those from patients treated with clozapine or placebo. NE levels in risperidone patients were significantly higher than in placebo patients, but lower than in clozapine patients. Neither drug, however, had significant effect on plasma levels of the main neuronal metabolite of NE, dihydroxyphenylglycol (DHPG), suggesting that adrenoceptors blockade alone would not explain the NE findings. The rate of release of endogenous NE into the bloodstream (spillover) was elevated in both risperidone and clozapine patients in a manner that paralleled their NE levels; the NE clearance in both groups did not differ from placebo. Following 3H-NE infusion in risperidone-treated individuals, production of 3H-DHPG was normal, as it was in the clozapine group, suggesting that risperidone does not impede neuronal uptake or intraneuronal metabolism of NE by monoamine oxidase. Our data suggest that both risperidone and clozapine elevate plasma NE levels via enhanced neurotransmitter spillover, with risperidone producing a smaller effect.",2002.0,0,0
475,12095076,"The cost-effectiveness of clozapine: a controlled, population-based, mirror-image study.",K P Hayhurst; P Brown; S W Lewis,"A retrospective cohort study, with a mirror-image design, was used to measure inpatient service utilization in 63 consecutive patients started on clozapine from a geographical catchment area compared to a control group matched for previous inpatient service use. An intent-to-treat analysis, including those patients (n = 28) who discontinued clozapine during the study period, showed a significant reduction in number of admissions and total time spent in hospital in the 2 years following clozapine initiation compared to the previous 2 years and to the follow-up period in the control group. This translated into a reduction of 7,300 pounds in hospitalization costs per patient started on clozapine, over the 2-year period. In those patients who continued clozapine treatment for the whole of the 2-year period, there was a two-thirds reduction in number of admissions and total time spent in hospital compared to no change in the clozapine discontinuers. These findings suggest that clozapine is a clinically and cost-effective intervention for severe schizophrenia in routine clinical settings.",2002.0,0,0
476,12103458,"Economic, clinical, and quality-of-life outcomes associated with olanzapine treatment in mania. Results from a randomized controlled trial.",Madhav A Namjoshi; Gopalan Rajamannar; Thomas Jacobs; Todd M Sanger; Richard Risser; Mauricio F Tohen; Alan Breier; Paul E Keck,"The objectives of this study were to determine the economic, clinical, and quality-of-life outcomes associated with olanzapine treatment in patients diagnosed with mania. Patients with a diagnosis of bipolar I disorder with manic or mixed episodes were enrolled in a randomized controlled trial. The study design comprised a 3-week acute phase followed by a 49-week open label extension. In the open label extension, the use of lithium and fluoxetine was permitted for patients who experienced breakthrough symptoms. Clinical, economic, and quality-of-life outcomes of treatment were assessed. During the acute phase, olanzapine patients experienced a statistically significant greater mean improvement from baseline on the Y-MRS total score compared to the placebo patients. In the open label extension, patients experienced a statistically significant mean change of 11.8 units on the Y-MRS from the end of the acute phase. When compared to costs incurred in the previous 12 months of therapy, patients experienced savings of almost $900 per month during the 49 weeks of olanzapine therapy. These cost savings were largely driven by reductions in in-patient costs during the open label extension. Health-related quality of life improvements measured by the SF-36 were seen on several dimensions both in the 3-week acute phase as well as in the 49-week open label extension. From a clinical, economic, and quality-of-life outcomes standpoint, olanzapine had a significant impact in the treatment of mania, and could be considered a cost-effective treatment option for use in this population if these findings are extrapolated to non-clinical trial populations.",2003.0,1,1
477,12107615,Low striatal and extra-striatal D2 receptor occupancy during treatment with the atypical antipsychotic sertindole.,Svante Nyberg; Hans Olsson; Ulrika Nilsson; Eli Maehlum; Christer Halldin; Lars Farde,"Sertindole is a new atypical antipsychotic drug. Preclinical pharmacology suggests that sertindole has a preferential effect on the activity of limbic and cortical dopaminergic neurons. Clinical trials have shown antipsychotic efficacy and very few extrapyramidal symptoms (EPS) with sertindole at 20 mg/day. This positron emission tomography (PET) study aimed to measure D(2) receptor occupancy in striatal and extra-striatal regions induced by clinically representative doses of sertindole in patients with schizophrenia. Four stabilized schizophrenic out-patients received sertindole 20 mg/day for 6-8 weeks. PET was performed using [(11)C]raclopride to measure D(2) receptor occupancy in the striatum and [(11)C]FLB457 to measure occupancy in the neocortex and thalamus, i.e. regions with very low D(2) receptor density. Striatal D(2) receptor occupancy was 52-68%. Similar occupancies were found in the thalamus, and the temporal and frontal cortices. Sertindole appears efficacious at a low D(2) receptor occupancy, comparable to that produced by clozapine. This finding could explain the low risk of EPS. The functional limbic selectivity of sertindole was not reflected in regional differences in receptor occupancy.",2003.0,0,0
478,12107621,A transcranial magnetic stimulation study of the effects of olanzapine and risperidone on motor cortical excitability in patients with schizophrenia.,Paul B Fitzgerald; Timothy L Brown; Z Jeff Daskalakis; J Kulkarni,"There has been a progressive increase in interest in the functioning of the main inhibitory and excitatory neurotransmitters in the pathophysiology of schizophrenia. Limited information is available as to how these neurotransmitters are affected by commonly prescribed antipsychotic agents. We investigated whether the atypical antipsychotics olanzapine and risperidone differ in their effects on inhibitory and excitatory cortical markers measured with transcranial magnetic stimulation. Electromyographic recordings from the abductor pollicis brevis muscle were made during focal transcranial magnetic stimulation to the contralateral motor cortex and during bilateral cortical stimulation. Twenty patients on each drug and 22 controls were studied with measures of the resting motor threshold, motor evoked potential size, post-excitatory silent period duration, cortical inhibition and facilitation to paired-pulse transcranial magnetic stimulation and transcallosal inhibition. The patient groups differed from the controls in the silent period and transcallosal inhibition measures, both of which assess cortical inhibitory activity. The two medication groups differed in the magnitude of the resting motor threshold and several measures of transcallosal inhibition that reflect the spread of inhibitory activity between hemispheres. These findings suggest that olanzapine and risperidone differ subtly in their effects on cortical inhibitory mechanisms. Further evaluation is required to establish whether these differences may reflect or underlie differences seen between these medications in their clinical profiles, including their effects on cognitive symptoms of schizophrenia.",2003.0,0,0
479,12107851,Psychopharmacological treatment of aggression in schizophrenic patients.,T Brieden; M Ujeyl; D Naber,"Aggressive behavior is frequently observed in schizophrenic patients. More than 50 % of all psychiatric patients and 10 % of schizophrenic patients show aggressive symptoms varying from threatening behavior and agitation to assault. The pharmacological treatment of acute, persisting and repetitive aggression is a serious problem for other patients and staff members. Not only is violent behavior from mentally ill patients the most detrimental factor in their stigmatization, aggression is also a considerable direct source of danger for the patients themselves. Based on rather limited evidence, a wide variety of medications for the pharmacological treatment of aggression has been recommended: typical and atypical antipsychotics, benzodiazepines, mood stabilizers, beta-blockers and selective serotonin reuptake inhibitors (SSRIs). Most clinical information on treating aggression has been collected for atypical neuroleptics, particularly for clozapine. Several retrospective and open studies indicate its efficacy. Treatment duration of 6 months is recommended to induce a stable reduction of physical and verbal aggression. Severe side effects have very rarely been seen. At the moment, clozapine seems to be the first choice in aggression treatment. Within the last few years, about 10 articles were published showing that this is the most effective antiaggressive agent in the treatment of aggression and agitation in psychiatric patients, independent of psychiatric diagnosis. However, clozapine, like all the other substances used, does not have an established indication for the treatment of aggressive symptoms. Noncompliance with medication makes it difficult to choose the right preparation for the medication: tablets, liquids, intramuscular injections and readily soluble ""FDDFs"" are available. Ethical, juridical and methodological problems prevent controlled studies from establishing a reference in the treatment of aggression in mentally ill patients. This review summarizes the current discussion and publications on the pharmacological treatment of aggression in schizophrenic patients of the last 20 years. In addition, we will briefly present studies and case reports concerning the treatment of aggression in other psychiatric patients.",2002.0,0,0
480,12126218,Olanzapine-associated diabetes mellitus.,Elizabeth A Koller; P Murali Doraiswamy,"To explore the clinical characteristics of hyperglycemia in patients treated with olanzapine. Retrospective, epidemiologic survey of spontaneously reported adverse events related to olanzapine therapy Government-affiliated drug evaluation center. Two hundred thirty-seven patients with olanzapine-associated diabetes or hyperglycemia. One hundred ninety-six cases from January 1994-May 15, 2001, were identified with the United States Food and Drug Administration's MedWatch Drug Surveillance System, and 41 cases published through May 15, 2001, were identified with MEDLINE or through meeting abstracts. Of the 237 cases, 188 were new-onset diabetes, 44 were exacerbations of preexistent disease, and 5 could not be classified. Mean patient age for newly diagnosed cases was 40.7+/-12.9 years and male:female ratio was 1.8. Seventy-three percent of all cases of hyperglycemia appeared within 6 months of start of olanzapine therapy. Eighty patients had metabolic acidosis or ketosis, 41 had glucose levels of 1000 mg/dl or greater, and 15 patients died. When olanzapine was discontinued or the dosage decreased, 78% of patients had improved glycemic control. Hyperglycemia recurred in 8 of 10 cases with rechallenge. Number of reports, temporal relationship to start of olanzapine therapy, relatively young age, and improvement on drug withdrawal suggest that olanzapine may precipitate or unmask diabetes in susceptible patients.",2003.0,0,1
481,12126596,Suicidality in schizophrenia: a review of the evidence for risk factors and treatment options.,Herbert Y Meltzer,"Suicide is a major contributor to the morbidity and mortality of schizophrenia, accounting for approximately 10% of deaths in these patients. The known risk factors for suicide in schizophrenia include prior suicide attempts, substance abuse, male sex, onset during first decade of illness, social isolation, depression, and feelings of hopelessness. There is significant evidence suggesting that clozapine reduces the suicide rate in patients with schizophrenia and schizoaffective disorder. Possible factors that lead to a decrease in suicidality with clozapine include the following: a direct antidepressant action, improved cognitive function and insight, diminished negative symptoms, reduced substance abuse, and improved compliance. These effects may converge or lessen feelings of hopelessness and more of its converse optimism. The International Suicide Prevention Trial (InterSePT) is a large prospective, 2-year randomized trial of the comparative effects of clozapine and olanzapine involving 980 patients at high risk for suicide in 11 countries in 56 sites. The study included complete freedom to augment these treatments if needed, blinded ratings, a blinded Suicide Monitoring Board, and equivalent clinical contact. The results support the superiority of clozapine over olanzapine to reduce the risk of suicidality and suggest its use should be considered for all patients with schizophrenia with high risk for suicide.",2002.0,0,1
482,12126869,Amisulpride improves depressive symptoms in acute exacerbations of schizophrenia: comparison with haloperidol and risperidone.,J Peuskens; H J Möller; A Puech,"The Brief Psychiatric Rating Scale (BPRS) anxiety/depression subscore has been used to assess affective symptoms in three studies (n = 612) comparing amisulpride (400-800 mg/day, n = 339) with haloperidol (15-20 mg/day, n = 160) and risperidone (8 mg/day, n = 113) in the treatment of acute exacerbations of schizophrenia. At endpoint, the mean improvement in the anxiety/depression subscore showed a significant (P = 0.011) difference in favour of amisulpride (5.6+/-6.1) compared with haloperidol (4.4+/-5.5) and risperidone (3.7+/-4.7). Amisulpride provided a significantly greater improvement compared both to haloperidol and risperidone in more severely depressed patients (BPRS anxiety/depression subscore > or = 16 at baseline, P = 0.001). This significant advantage in favour of amisulpride is seen from the 2nd week of treatment.",2002.0,0,1
483,12131603,Clozapine-treated subjects with treatment-resistant schizophrenia: a systematic review of experimental and observational studies.,P Brambilla; F Barale; E Caverzasi; G Tognoni; C Barbui,"Randomized clinical trials have limitations because they focus on small samples of highly selected patients. Observational studies, which follow large cohorts of typical patients receiving pharmacological treatments, should overcome some of these trial limitations and provide information that cannot be generated with clinical trials. The present study aimed to compare experimental and observational studies of clozapine-treated subjects with treatment-resistant schizophrenia. A systematic review of experimental and observational studies evaluating clozapine-treated subjects in treatment-resistant schizophrenia was carried out. We identified 50 studies that met the inclusion criteria. Less than one-third of clinical trials enrolled more than 50 patients compared to 44% of prospective and nearly 90% of retrospective studies. In addition, 78% of prospective and 89% of retrospective observational studies lasted more than 12 weeks, while the majority of trials lasted less than 8 weeks. Most clinical trials defined treatment-resistant schizophrenia according to Kane's criteria, while the majority of observational studies adopted implicit criteria. In comparison with clinical trials, observational studies provided a higher weighted mean rate of clozapine-responders and a lower weighted mean rate of clozapine-dropouts. This literature survey suggests that the role of observational studies in the evaluation of medicines should be reconsidered. A new generation of observational studies should be developed to provide evidence on patient outcome in typical settings and under real-world circumstances, and on variables which may affect outcome.",2002.0,0,1
484,12132564,Economic evaluations of olanzapine and risperidone.,James W Shaw,,2003.0,0,0
485,12143912,Switching to olanzapine from previous antipsychotics: a regional collaborative multicenter trial assessing 2 switching techniques in Asia Pacific.,Chien-Te Lee; Bernardo Jorge L Conde; Mahmud Mazlan; Taweesin Visanuyothin; Adrian Wang; Michael M C Wong; Daniel J Walker; Suraja M Roychowdhury; Huei Wang; Pierre V Tran,"This open-label, multicenter, randomized study compared the efficacy and safety of switching moderately ill Asian patients with schizophrenia from their current regimen of antipsychotic medication to the atypical antipsychotic olanzapine using either a direct switch method or a start-taper switch method. Asian inpatients and outpatients with DSM-IV schizophrenia (N = 108) currently treated with predominantly typical antipsychotics were switched to olanzapine (initial dose of 10 mg/day) for 6 weeks. Patients were randomly assigned to 1 of 2 groups: the direct switch group (N = 54) received only olanzapine, while the start-taper switch group (N = 54) received olanzapine and their usual antipsychotic in decreasing doses for the first 2 weeks. A successful switch was defined as completing 6 weeks of therapy without worsening of symptoms (Clinical Global Impressions-Severity of Illness scale [CGI-S]) or extrapyramidal side effects (Simpson-Angus Scale). Overall efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), and safety was assessed by recording adverse events and measuring vital signs. Statistically significant (p < .001) improvements from baseline to endpoint occurred in both switch groups in the CGI-S score and the PANSS total score and subscores. However, no significant differences were observed between the switch groups for any efficacy measure. Both techniques had comparable rates of successful switching (direct switch, 74.1% vs. start-taper switch, 67.9%). The frequency of treatment-emergent adverse events was similar between switch groups with no clinically significant differences in any laboratory value or vital sign. Weight gain occurred in both switch groups (p < .001), but the groups were not statistically different from each other. Both switch groups showed statistically significant (p < .01) improvements from baseline to endpoint on the Simpson-Angus Scale and Barnes Akathisia Scale. Moderately ill Asian patients with schizophrenia may experience a decrease in symptom severity and improvement in extrapyramidal symptoms when switched from their current medication to olanzapine therapy.",2002.0,0,0
486,12143914,A naturalistic study of risperidone treatment outcome using prognosis-adjusted discharge rates in New York State inpatients.,Daniel C Javitt; Angel Cienfuegos; Mario Miniati; Gail Silipo; Jerome Levine; Baerbel H Allingham; James Robinson,"Information concerning the effectiveness of newer atypical antipsychotics is derived largely from controlled clinical trials of relatively short duration. Limited information is available concerning naturalistic outcome of patients selected for clinical treatment with atypical antipsychotics. This study evaluates 1-year discharge rates among all patients treated with risperidone within the New York State inpatient psychiatric hospital system during the calendar years 1994 and 1995 (""period of interest"") relative to patients treated with all other antipsychotic medications. Data from the Integrated Research Database at Nathan Kline Institute (Orangeburg, N.Y.) were used. This database maintains complete treatment records for all inpatients within the New York State psychiatric inpatient system along with demographic, diagnostic, admission, and discharge information. Patients were identified at admission or first change in antipsychotic during the period of interest, and 1-year outcome was determined. 2198 risperidone-treated patients were identified versus 3259 treated with other antipsychotics. Length of hospitalization prior to treatment initiation was the primary predictor of discharge rate for both risperidone and control groups. When adjustment was made for between-group difference in prognosis (dischargeability), patients treated with risperidone within 30 days of admission were less likely to be discharged than those treated with all other agents (including clozapine), whereas risperidone was more effective in patients who had been hospitalized for 90 days or more prior to switch from another antipsychotic to risperidone. When database information is utilized to evaluate treatment effectiveness, adjustment must be made for a priori differences in prognosis or dischargeability. With appropriate methodology, database studies may indicate which patient groups are most likely to benefit from newer atypical antipsychotic agents.",2002.0,0,0
487,12151468,Risperidone in children with autism and serious behavioral problems.,James T McCracken; James McGough; Bhavik Shah; Pegeen Cronin; Daniel Hong; Michael G Aman; L Eugene Arnold; Ronald Lindsay; Patricia Nash; Jill Hollway; Christopher J McDougle; David Posey; Naomi Swiezy; Arlene Kohn; Lawrence Scahill; Andres Martin; Kathleen Koenig; Fred Volkmar; Deirdre Carroll; Allison Lancor; Elaine Tierney; Jaswinder Ghuman; Nilda M Gonzalez; Marco Grados; Benedetto Vitiello; Louise Ritz; Mark Davies; James Robinson; Don McMahon; Research Units on Pediatric Psychopharmacology Autism Network,"Atypical antipsychotic agents, which block postsynaptic dopamine and serotonin receptors, have advantages over traditional antipsychotic medications in the treatment of adults with schizophrenia and may be beneficial in children with autistic disorder who have serious behavioral disturbances. However, data on the safety and efficacy of atypical antipsychotic agents in children are limited. We conducted a multisite, randomized, double-blind trial of risperidone as compared with placebo for the treatment of autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior in children 5 to 17 years old. The primary outcome measures were the score on the Irritability subscale of the Aberrant Behavior Checklist and the rating on the Clinical Global Impressions - Improvement (CGI-I) scale at eight weeks. A total of 101 children (82 boys and 19 girls; mean [+/-SD] age, 8.8+/-2.7 years) were randomly assigned to receive risperidone (49 children) or placebo (52). Treatment with risperidone for eight weeks (dose range, 0.5 to 3.5 mg per day) resulted in a 56.9 percent reduction in the Irritability score, as compared with a 14.1 percent decrease in the placebo group (P<0.001). The rate of a positive response, defined as at least a 25 percent decrease in the Irritability score and a rating of much improved or very much improved on the CGI-I scale, was 69 percent in the risperidone group (34 of 49 children had a positive response) and 12 percent in the placebo group (6 of 52, P<0.001). Risperidone therapy was associated with an average weight gain of 2.7+/-2.9 kg, as compared with 0.8+/-2.2 kg with placebo (P<0.001). Increased appetite, fatigue, drowsiness, dizziness, and drooling were more common in the risperidone group than in the placebo group (P<0.05 for each comparison). In two thirds of the children with a positive response to risperidone at eight weeks (23 of 34), the benefit was maintained at six months. Risperidone was effective and well tolerated for the treatment of tantrums, aggression, or self-injurious behavior in children with autistic disorder. The short period of this trial limits inferences about adverse effects such as tardive dyskinesia.",2002.0,1,1
488,12151907,Weight and blood pressure change during clozapine treatment.,Scott P Baymiller; Patricia Ball; Robert P McMahon; Robert W Buchanan,"We examined whether clozapine-related weight gain is associated with an increase in mean arterial blood pressure. Weight gain and mean arterial blood pressure changes were assessed in 61 outpatients with schizophrenia who were randomly assigned to either clozapine or haloperidol in a 10-week parallel group, double-blind study and in 55 patients who chose to continue to receive clozapine in a subsequent 1-year open-label prospective study. Clozapine treatment was associated with significant weight gain in the double blind and open-label trials. Haloperidol treatment was not associated with significant weight gain. Neither clozapine nor haloperidol treatment were associated with significant changes in mean arterial blood pressure. There were no significant correlations between weight gain and mean arterial blood pressure change with either medication. Although clozapine treatment is associated with weight gain, the correlation between this weight gain and increases in arterial blood pressure during the first year of treatment appears to be low.",2002.0,1,1
489,12153335,Spotlight on ziprasidone in schizophrenia and schizoaffective disorder.,Nishan S Gunasekara; Caroline M Spencer; Gillian M Keating,"Ziprasidone is a novel antipsychotic agent with a pharmacological profile distinct from that of other currently available novel or classical antipsychotics. In preclinical studies, ziprasidone was predicted to have efficacy against positive, negative and affective symptoms of schizophrenia with a favourable tolerability profile, including a low propensity to induce extrapyramidal adverse effects. The drug has been administered orally to >300 patients with an acute exacerbation of schizophrenia or schizoaffective disorder in published 4- to 6-week randomised, double-blind trials. When given twice daily at dosages of between 80 and 160 mg/day, ziprasidone produced significantly greater improvements in overall symptomatology than placebo. In the largest study, ziprasidone 80 or 160 mg/day was also significantly more effective than placebo in reducing negative symptoms and, at 160 mg/day, was significantly more effective than placebo in improving depressive symptoms in patients with associated clinically significant depression. Data from a 4-week trial indicate that ziprasidone 160 mg/day has similar efficacy to haloperidol 15 mg/day. Ziprasidone 40 to 160 mg/day was more effective than placebo with respect to prevention of impending relapse and improvement of negative symptoms in 294 stable patients with chronic schizophrenia who were treated for up to 1 year. In addition, significantly more ziprasidone than haloperidol recipients achieved a negative symptom response in a 28-week study involving 301 stable patients with chronic or subchronic schizophrenia. In general, oral ziprasidone is well tolerated with an overall incidence of adverse events similar to placebo. Importantly, the drug has a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. Ziprasidone is associated with slight prolongation of the QTc interval; the clinical significance of this is not yet clear. The drug does not appear to be associated with sustained elevation of plasma prolactin levels. Preliminary data indicate that long-term oral ziprasidone treatment is well tolerated. Ziprasidone is the only novel antipsychotic currently available in a rapid-acting intramuscular formulation. Short-term treatment with intramuscular ziprasidone was effective and well tolerated in patients with acute agitation associated with psychosis. In addition, intramuscular ziprasidone reduced agitation scores by a significantly greater extent than haloperidol in a study involving patients with acute agitation associated with psychosis. Ziprasidone is a promising new antipsychotic that has shown significant efficacy in the oral treatment of patients with schizophrenia or schizoaffective disorder. The drug is well tolerated with a low propensity to induce extrapyramidal effects and a negligible effect on bodyweight. In addition, intramuscular ziprasidone shows efficacy and good tolerability in the treatment of acute agitation associated with psychotic disorders.",2002.0,0,0
490,12153826,"Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence.",Michael G Aman; Goedele De Smedt; Albert Derivan; Ben Lyons; Robert L Findling; Risperidone Disruptive Behavior Study Group,"The short-term efficacy and safety of risperidone in the treatment of disruptive behaviors was examined in a well-characterized cohort of children with subaverage intelligence. In this 6-week, multicenter, double-blind, parallel-group study of 118 children (aged 5-12 years) with severely disruptive behaviors and subaverage intelligence (IQ between 36 and 84, inclusive), the subjects received 0.02-0.06 mg/kg per day of risperidone oral solution or placebo. The a priori primary efficacy measure was the change in score from baseline to endpoint on the conduct problem subscale of the Nisonger Child Behavior Rating Form. The risperidone group showed significantly greater improvement than did the placebo group on the conduct problem subscale of the Nisonger Child Behavior Rating Form from week 1 through endpoint (change in score of -15.2 and -6.2, respectively). Risperidone was also associated with significantly greater improvement than placebo on all other Nisonger Child Behavior Rating Form subscales at endpoint, as well as on the Aberrant Behavior Checklist subscales for irritability, lethargy/social withdrawal, and hyperactivity; the Behavior Problems Inventory aggressive/destructive behavior subscale; a visual analogue scale of the most troublesome symptom; and the Clinical Global Impression change score. The most common adverse effects reported during risperidone treatment were headache and somnolence. The extrapyramidal symptom profile of risperidone was comparable to that of placebo. Mean weight increases of 2.2 kg. and 0.9 kg occurred in the risperidone and placebo groups, respectively. Risperidone was effective and well tolerated for the treatment of severely disruptive behaviors in children with subaverage IQ.",2002.0,1,1
491,12153919,Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study.,Carol E Koro; Donald O Fedder; Gilbert J L'Italien; Sheila S Weiss; Laurence S Magder; Julie Kreyenbuhl; Dennis A Revicki; Robert W Buchanan,"To quantify the association between olanzapine and diabetes. Population based nested case-control study. United Kingdom based General Practice Research Database comprising 3.5 million patients followed between 1987 and 2000. 19 637 patients who had been diagnosed as having and treated for schizophrenia. 451 incident cases of diabetes were matched with 2696 controls. Diagnosis and treatment of diabetes. Patients taking olanzapine had a significantly increased risk of developing diabetes than non-users of antipsychotics (odds ratio 5.8, 95% confidence interval 2.0 to 16.7) and those taking conventional antipsychotics (4.2, 1.5 to 12.2). Patients taking risperidone had a non-significant increased risk of developing diabetes than non-users of antipsychotics (2.2, 0.9 to 5.2) and those taking conventional antipsychotics (1.6, 0.7 to 3.8). Olanzapine is associated with a clinically important and significant increased risk of diabetes.",2002.0,0,1
492,12177583,"A 1-year, double-blind, placebo-controlled trial of ziprasidone 40, 80 and 160 mg/day in chronic schizophrenia: the Ziprasidone Extended Use in Schizophrenia (ZEUS) study.",M Arato; R O'Connor; H Y Meltzer; ZEUS Study Group,"We evaluated relapse in patients with stable, chronic schizophrenia over a 1-year period; inpatients were randomized to ziprasidone 40 mg/day (n = 72), 80 mg/day (n = 68), 160 mg/day (n = 67) or placebo (n = 71). The probability of relapse (Kaplan-Meier) at 1 year was significantly lower in the ziprasidone 40, 80, and 160 mg/day groups (43%, 35% and 36%, respectively) compared to placebo (77%; P = 0.002, P < 0.001 and P < 0.001, respectively). In those patients who remained on treatment for at least 6 months, only 9% subsequently relapsed on ziprasidone compared to 42% on placebo (P = 0.001). All three doses of ziprasidone were significantly superior to placebo on Positive and Negative Syndrome Scale (PANSS) efficacy variables (all P < 0.05). Ziprasidone was associated with a significantly greater mean improvement in the PANSS negative symptom subscale compared to placebo (P < 0.05). Discontinuation due to adverse events was similar with ziprasidone and placebo. Ziprasidone treatment was indistinguishable from placebo in assessments of movement disorders and was not associated with weight gain or cardiovascular abnormalities. These results demonstrate that ziprasidone was effective in reducing the frequency of relapse and was associated with long-term improvement in negative symptoms. Ziprasidone was well tolerated in this population of patients with chronic, stable schizophrenia.",2002.0,0,1
493,12177585,"Olanzapine versus haloperidol in the treatment of acute mania: clinical outcomes, health-related quality of life and work status.",L Shi; M A Namjoshi; F Zhang; G Gandhi; E T Edgell; M Tohen; A Breier; J M Haro,"We aimed to compare clinical outcomes, health-related quality of life (HRQOL) and work status associated with olanzapine and haloperidol treatment in patients with bipolar disorder. This double-blind, randomized controlled trial, comparing flexible dosing of olanzapine (5-20 mg/day, n = 234) to haloperidol (3-15 mg/day, n = 219), consisted of a 6-week acute phase, followed by a 6-week continuation phase. Symptomatic remission rates were similar for olanzapine- and haloperidol-treated patients at weeks 6 and 12. At week 6, significant changes in five dimensions of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) [general health (P = 0.010), physical functioning (P < 0.001), role limitations due to physical problems (P < 0.001), social functioning (P < 0.05) and vitality (P < 0.01)] and the SF-36 physical components summary score were found in favour of olanzapine compared to haloperidol. At week 12, olanzapine treatment maintained the significantly favourable HRQOL changes. At the end of week 12, patients on olanzapine showed significantly greater improvement than haloperidol in work activities impairment and household activities impairment scores on the Streamlined Longitudinal Interview Clinical Evaluation from the Longitudinal Interval Follow-up Evaluation (SLICE/LIFE) activities impairment scores. Subgroup analyses revealed that olanzapine treatment significantly increased a proportion of employed patients and their weekly paid working hours. In conclusion, compared to haloperidol, olanzapine treatment was comparably effective in the remission of bipolar mania and significantly improved HRQOL and work status in patients with bipolar I disorder.",2002.0,1,1
494,12188102,Evidence from a population pharmacokinetics analysis for a major effect of CYP1A2 activity on inter- and intraindividual variations of clozapine clearance.,Eric Dailly; Saik Urien; Evelyne Chanut; Bertrand Claudel; Nathalie Guerra; Christine Femandez; Pascale Jolliet; Michel Bourin,"Interindividual variations of clozapine clearance could be related to individual CYP1A2 activity. A population approach was used to investigate clozapine pharmacokinetics of multiple doses of clozapine in patients. Clozapine plasma concentrations were obtained in 23 patients from therapeutic drug monitoring (83 samples). CYP1A2 activity was estimated by the norclozapine/clozapine plasma levels ratio and data were processed by a nonlinear mixed-effect modelling method. Different covariates (age, body weight, height, CYP1A2 activity, daily dose of clozapine) were tested but CYP1A2 activity was the single parameter that improved significantly the predictive model. The best fit was obtained by integration of a linear relationship between clozapine clearance and CYP1A2 activity. The findings suggest that (i) CYP1A2 activity is a major factor that determines clozapine clearance and (ii) the norclozapine/clozapine ratio could constitute a valuable measure of the CYP1A2 activity. This ratio can be simply determined in the context of therapeutic drug monitoring and could explain the inter- and intraindividual variation of clozapine plasma levels.",2003.0,0,0
495,12202454,Optimal dosing of atypical antipsychotics in adults: a review of the current evidence.,Leslie Citrome; Jan Volavka,"This review describes dosing strategies used to optimize the beneficial effects of atypical antipsychotic medications. Differences between manufacturers' recommended dosing and actual clinical practice are reconciled using evidence from pivotal double-blind randomized registration studies, other randomized clinical trials, case series, and case reports. With clozapine and perhaps olanzapine, plasma levels are correlated with therapeutic response; with risperidone, plasma levels are not correlated with therapeutic response but may be related to the occurrence of extrapyramidal symptoms. Information related to optimal dosing of quetiapine and ziprasidone is more limited. In clinical practice, the mean daily dose of risperidone has decreased, whereas that for olanzapine is increasing. The percentage of patients receiving quetiapine at doses above the manufacturer's recommended maximum is higher than would be expected, further illustrating that dosing ranges established during registration studies may not reflect the needs of day-to-day practice.",2002.0,0,1
496,12204313,"Risperidone in the treatment of mania: efficacy and safety results from a large, multicentre, open study in Spain.",Eduard Vieta; Marisa Herraiz; Gemma Parramon; J M Goikolea; Antonio Fernández; Antoni Benabarre,"A number of open studies and preliminary results of unpublished double-blind trials have suggested that the novel antipsychotic risperidone may be effective and well tolerated in the treatment of acute mania in bipolar disorder. A total of 174 patients entered this large, open, multicentre trial. Inclusion criteria were: current manic, hypomanic or mixed episode (DSM-IV), and a Young Mania Rating Scale (YMRS) score of >7. Assessments included the YMRS, Positive and Negative Syndrome Scale (PANSS), Hamilton Rating Scale for Depression (HAM-D), Clinical Global Impression (CGI), and Udvalg for Kliniske Undersøgelser (UKU) subscale for neurological side effects. There were significant reductions (P<0.0001) on the YMRS, PANSS and HAM-D scores and a significant improvement (P<0.0001) in CGI ratings at the endpoint. There were no statistically significant increments in the severity of extrapyramidal symptoms according to the UKU. Risperidone was generally well tolerated. The mean dose of risperidone at the endpoint was 4.9+/-2.9 mg/day. This open study provides further evidence that risperidone is safe and effective in combination with mood stabilisers in the manic phase of bipolar disorder. The open design and the use of concomitant medications make unclear to what extent the positive results were entirely related to risperidone.",2002.0,0,1
497,12223251,Switching from conventional to novel antipsychotic drugs: results of a prospective naturalistic study.,L Voruganti; L Cortese; L Owyeumi; V Kotteda; Z Cernovsky; S Zirul; A Awad,"We examined the long-term consequences of switching patients from conventional to novel antipsychotic drugs, from a patient's perspective. In a prospective, single-blinded, naturalistic study, a cohort of subjects (n=150) with schizophrenia or schizo-affective disorder (DSM-IV) were switched from conventional neuroleptic drugs to either risperidone (n=50), olanzepine (n=50) or quetiapine (n=50), and monitored for a period of 2 to 6 years. The ensuing natural history of transitions in treatments was charted, and the outcomes including symptoms, side effects, subjective tolerability of drugs and their impact on quality of life were documented with standardized rating scales. Majority (85%) of the subjects benefited from a switch to the novel antipsychotic drugs, though some preferred to return to their original neuroleptic (8%), and others eventually required clozapine (7%) therapy. Novel antipsychotic drugs were significantly tolerated better, and had a positive impact on treatment-adherence, psychosocial functioning and quality of life. Among the novel drugs, risperidone was significantly better in improving negative symptoms, while olanzepine was particularly well tolerated and effective against comorbid anxiety and depressive symptoms. Patients treated with quetiapine reported fewer side effects, and showed a significantly greater improvement in neurocognitive deficits. Novel antipsychotics emerged as the drug of choice in view of their overall effectiveness, though conventional neuroleptics and clozapine will continue to have a limited but distinct role in the management of schizophrenia. The challenge for clinicians lies in matching a patient's clinical and biochemical profile with that of a drug's pharmacological actions, in order to achieve optimum outcomes.",2002.0,0,1
498,12223253,Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series.,Stefano Marenco; Michael F Egan; Terry E Goldberg; Michael B Knable; Robert K McClure; Georg Winterer; Daniel R Weinberger,"We used L-(quinoxalin-6-ylcarbonyl)piperidine (CX516) (a modulator of the alpha-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA) receptor) as a sole agent in a double blind placebo-controlled design in a small series of patients with schizophrenia who were partially refractory to treatment with traditional neuroleptics. The study entailed weekly increments in doses of CX516, from 300 mg tid for week 1 up to 900 mg tid on week 4. Patients were followed with clinical ratings, neuropsychological testing, and were monitored for adverse events. Four patients received 2 to 4 weeks of CX516, two received placebo and two withdrew during the placebo phase. Adverse events associated with drug administration were transient and included leukopenia in one patient and elevation in liver enzymes in another. No clear improvement in psychosis or in cognition was observed over the course of the study. CX516 at the doses tested did not appear to yield dramatic effects as a sole agent, but inference from this study is limited.",2002.0,0,0
499,12223254,Extrapyramidal symptom profiles in Japanese patients with schizophrenia treated with olanzapine or haloperidol.,Toshiya Inada; Gohei Yagi; Sadanori Miura,"Previous clinical trials have clearly shown the superiority of olanzapine to haloperidol in the improvement of extrapyramidal symptoms (EPS) in schizophrenic patients. The primary purpose of this study was to compare EPS profiles in Japanese schizophrenic patients treated with an atypical antipsychotic, olanzapine, or a typical antipsychotic, haloperidol, as measured by the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). The DIEPSS, which consists of eight individual parameters and one global assessment (overall severity), was used to evaluate 182 patients enrolled in this 8-week study. The primary safety analysis was maximum change (that could be either a decrease or increase) from baseline in DIEPSS total score. Secondary analyses included change from baseline to maximum in DIEPSS total score, change from baseline to endpoint (LOCF) in DIEPSS total score, and the rank sum of the maximum change (that could be either a decrease or increase) from baseline in the DIEPSS individual items. Incidence of treatment-emergent EPS adverse events using the DIEPSS scale was also analyzed. The olanzapine group showed statistically significant superiority to the haloperidol group on the primary analysis (p<0.001). Secondary analyses also demonstrated olanzapine's superiority in DIEPSS total, parkinsonism, akathisia and overall severity scores (all p< or =0.014). Categorical analysis of treatment-emergent akathisia and parkinsonism syndromes at endpoint showed improvement in the olanzapine group but worsening in the haloperidol group. The results from this study suggest that olanzapine, as in Caucasian populations, is a safe treatment in Japanese patients chronically ill with schizophrenia.",2002.0,1,1
500,12223264,"Effect of zotepine, olanzapine and risperidone on hostility in schizophrenic patients.",Peer Briken; Evangelia Nika; Steffen Moritz; Christian Haasen; Christian Perro; Oktay Yagdiran; Dieter Naber; Michael Krausz,,2002.0,0,1
501,12225492,The Bech-Rafaelsen Melancholia Scale (MES) in clinical trials of therapies in depressive disorders: a 20-year review of its use as outcome measure.,P Bech,"To evaluate the psychometric properties of the Bech-Rafaelsen Melancholia Scale (MES) by reviewing clinical trials in which it has been used as outcome measure. The psychometric analysis included internal validity (total scores being a sufficient statistic), interobserver reliability, and external validity (responsiveness in short-term trials and relapse prevention in long-term trials). The results showed that the MES is a unidimensional scale, indicating that the total score is a sufficient statistic. The interobserver reliability of the MES has been found adequate both in unipolar and bipolar depression. External validity including both relapse, response and recurrence indicated that the MES has a high responsiveness and sensitivity. The MES has been found a valid and reliable scale for the measurement of changes in depressive states during short-term as well as long-term treatment.",2002.0,0,1
502,12225494,One-year outcome in first episode psychosis patients in the Swedish Parachute project.,J Cullberg; S Levander; R Holmqvist; M Mattsson; I-M Wieselgren,"Implementing a system designed to treat first episode psychotic (FEP) patients. Every FEP patient (n=253) from a catchment area of 1.5 million inhabitants were asked to participate in this 5-year project. One historical (n=71) and one prospective (n=64) FEP group were used for comparisons. A total of 175 patients (69%) were followed up through the first year of treatment. Global Assessment of Functioning (GAF) values were significantly higher than in the historical comparison group but similar to the prospective group. Psychiatric in-patient care was lower as was prescription of neuroleptic medication. Satisfaction with care was generally high in the Parachute group. Access to a small overnight crisis home was associated with higher GAF. It is possible to successfully treat FEP patients with fewer in-patient days and less neuroleptic medication than is usually recommended, when combined with intensive psychosocial treatment and support.",2002.0,0,0
503,12230716,Schizophrenia.,Stephen Lawrie; Andrew McIntosh,,2002.0,0,0
504,12242060,Olanzapine in the treatment of dopamimetic-induced psychosis in patients with Parkinson's disease.,Alan Breier; Virginia K Sutton; Peter D Feldman; Deborah L Kadam; Iris Ferchland; Padraig Wright; Joseph H Friedman,"Studies in elderly patients demonstrate antipsychotic efficacy and favorable safety profiles for olanzapine. We report results from two placebo-controlled, double-blind studies of olanzapine for treatment of dopamimetic drug-induced psychosis in patients with Parkinson's disease (PD). Patients were treated with olanzapine or placebo for 4 weeks while dopamimetic therapy was held constant. Olanzapine was initiated at 2.5 mg/day, with 2.5-mg/day increases allowed every 3 to 4 days up to the maximum dose of 15 mg/day. Olanzapine patients showed significant improvements from baseline on positive symptoms and most efficacy measures, but no significant treatment-group differences were observed. Olanzapine performed significantly worse than placebo in both studies on the Unified Parkinson's Disease Rating Scale (UPDRS) total, Motor, and Activities of Daily Living scales, but not the UPDRS Tremor item or Complications scores. Corrected QT interval, vital signs, and body weight were not significantly different from placebo. These findings did not demonstrate superior efficacy of olanzapine for treatment of dopamimetic-induced psychosis in PD. The initial dose-titration schedule and mild baseline levels of psychosis may account for these findings. Future studies involving gradual dose titration are needed to explore further olanzapine's optimum use for patients with PD with treatment-related psychosis.",2002.0,0,0
505,12243210,"A randomized, placebo-controlled trial of the discontinuation of long-term antipsychotics in dementia.",Robert van Reekum; Diana Clarke; David Conn; Nathan Herrmann; Goran Eryavec; Tammy Cohen; Laurie Ostrander,"The objectives of this randomized clinical trial were to investigate the impact of the discontinuation of long-term antipsychotics in residents with dementia in chronic care institutions and to identify clinical predictors of safe discontinuation. Subjects included 34 residents with dementia who were on antipsychotics for more than 6 months and whose behavior was currently stable. Subjects were randomized to either continue receiving their regular dosage of antipsychotics or to receive placebo for 6 months. Early withdrawal from the study was not statistically different between the groups (relative risk [RR] = 1.57, 95% confidence interval [CI] 0.76-3.26), and though not significantly different, subjects in the placebo group were more likely to be withdrawn from the study because of worsening behavior (RR = 1.25, 95% Cl 0.33-4.76). Three subjects in the placebo group were withdrawn from the study due to worsening of extrapyramidal symptoms. The active treatment group had more behavioral problems (e.g., physical aggression towards others, p < .05) compared to the placebo group. The placebo group developed more apathy, but balancing this outcome was a relative improvement in cognitive functioning. Baseline antipsychotic dose was predictive of behavioral worsening upon discontinuation of long-term antipsychotic drugs. The primary limitation of the study was the small sample size. In conclusion, a trial of discontinuation of antipsychotics should be considered in this population.",2003.0,0,0
506,12351588,Pharmacogenomics in schizophrenia: the quest for individualized therapy.,Vincenzo S Basile; Mario Masellis; Steven G Potkin; James L Kennedy,"There is strong evidence to suggest that genetic variation plays an important role in inter-individual differences in medication response and toxicity. The rapidly evolving disciplines of pharmacogenetics and pharmacogenomics seek to uncover this genetic variation in order to predict treatment outcomes. The goal is to be able to select the drugs with the greatest likelihood of benefit and the least likelihood of harm in individual patients, based on their genetic make-up-individualized therapy. Pharmacogenomic studies utilize genomic technologies to identify chromosomal areas of interest and novel putative drug targets, while pharmacogenetic strategies rely on studying sequence variations in candidate genes suspected of affecting drug response or toxicity. The candidate gene variants that affect function of the gene or its protein product have the highest priority for investigation. This review will provide demonstrative examples of functional candidate gene variants studied in a variety of antipsychotic response phenotypes in the treatment of schizophrenia. Serotonin and dopamine receptor gene variants in clozapine response will be examined, and in the process the need for sub-phenotypes will be pointed out. Our recent pharmacogenetic studies of the subphenotype of neurocognitive functioning following clozapine treatment and the dopamine D(1) receptor gene (DRD1) will be presented, highlighting our novel neuroimaging data via [(18)F]fluoro-2-deoxy-D-glucose (FDG) metabolism position emission tomography (PET) that demonstrates hypofunctioning of several brain regions in patients with specific dopamine D(1) genotype. Preliminary candidate gene studies investigating the side-effect of clozapine-induced weight gain are also presented. The antipsychotic adverse reaction of tardive dyskinesia and its association with the dopamine D(3) receptor will be critically examined, as well as the added influence of antipsychotic metabolism via the cytochrome P450 1A2 gene (CYP1A2 ). Results that delineate the putative gene-gene interaction between DRD3 and CYP1A2 are also presented. We have also utilized FDG-PET subphenotyping to demonstrate increased brain region activity in patients who have the dopamine D(3) genotype that confers increased risk for antipsychotic induced tardive dyskinesia. The merits and weaknesses of neuroimaging technologies as applied to pharmacogenetic analyses are discussed. To the extent that the above data become more widely verified and replicated, the field of psychiatry will move closer to clinically meaningful tests that will be useful in deciding the best drug for each individual patient.",2003.0,1,0
507,12352274,Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects.,Christoph Hiemke; Avi Peled; Mahmoud Jabarin; Jack Hadjez; Harald Weigmann; Sebastian Härtter; Ilan Modai; Michael Ritsner; Henry Silver,"Olanzapine is a substrate of the cytochrome P450 enzyme (CYP) 1A2. In this study, pharmacokinetic interactions and clinical effects of adding the CYP1A2 inhibitor fluvoxamine to steady-state olanzapine was examined in patients suffering from schizophrenia. Eight patients had been treated for at least 3 months with 10 to 20 mg/day olanzapine. Fluvoxamine (100 mg/day) was added (week 0) to the olanzapine treatment and continued for 8 weeks. Concentrations of olanzapine and its metabolite N-desmethylolanzapine and of fluvoxamine were analyzed at weeks 0, 1, 4, and 8. Addition of fluvoxamine resulted in a 12% to 112% ( < 0.01) increase of olanzapine from 31 +/- SD 15 ng/mL (week 0) to 56 +/- 31 ng/mL (week 8) in all patients. N-desmethylolanzapine concentrations were not significantly changed ( > 0.05). Fluvoxamine concentrations were 48 +/- 26 ng/mL on week 1 and 83 +/- 47 ng/mL on week 8. It is concluded that fluvoxamine affects olanzapine degradation and thus increases olanzapine concentrations. Although the combination was well tolerated in this sample and the negative symptom response appeared to be favorable in at least five patients, the combination therapy of olanzapine and fluvoxamine should be used cautiously and should be controlled by therapeutic drug monitoring to avoid olanzapine-induced side effects or intoxications.",2002.0,0,0
508,12352279,"Re: Clomipramine vs. Haloperidol in the treatment of autistic disorder: a double-blind, placebo, crossover study.",Robert King; Garry Fay; Heather Wheildon,,2002.0,0,0
509,12352282,Effects of olanzapine plasma concentrations on depressive symptoms in schizophrenia: a pilot study.,Hsien-Yuan Lane; Shi-Chin Guo; Tzung-Jeng Hwang; Ying-Sheue Chen; Joseph J Cheng; Ying-Chiao Lee; Chen-Jee Hong; Hai-Gwo Hwu; Wen-Ho Chang,,2002.0,0,0
510,12355680,Risperidone decreases craving and relapses in individuals with schizophrenia and cocaine dependence.,David A Smelson; Miklos F Losonczy; Craig W Davis; Maureen Kaune; John Williams; Douglas Ziedonis,"To examine the efficacy of atypical neuroleptics for decreasing craving and drug relapses during protracted withdrawal in individuals dually diagnosed with schizophrenia and cocaine dependence. We conducted a 6-week, open-label pilot study comparing risperidone with typical neuroleptics in a sample of withdrawn cocaine-dependent schizophrenia patients. Preliminary results suggest that individuals treated with risperidone had significantly less cue-elicited craving and substance abuse relapses at study completion. Further, they showed a trend toward a greater reduction in negative and global symptoms of schizophrenia. Atypical neuroleptics may help reduce craving and relapses in this population. Future research should include more rigorous double-blind placebo-controlled studies with this class of medications.",2002.0,0,0
511,12360554,Olanzapine treatment for dopaminergic-induced hallucinations.,William G Ondo; Joel K Levy; Kevin Dat Vuong; Christine Hunter; Joseph Jankovic,"Atypical antipsychotic medications with lower affinities for D2 receptors are considered useful alternatives to treat drug-induced hallucinations in Parkinson's disease (PD). We conducted a double-blind, placebo-controlled, unforced titration, parallel design study (2:1 drug to placebo randomization ratio) using olanzapine (2.5-10 mg/day to effect) in 30 PD patients with drug-induced hallucinations. We performed an extensive battery of neuropsychological tests, the Unified Parkinson's Disease Rating Scale (UPDRS), assessments of on and off time at baseline and at 9 weeks after starting the medication. Sixteen patients on olanzapine (mean dose, 4.6 mg/night) and 11 on placebo completed the study. Compared with placebo, performance on the UPDRS item 2 (thought disorder), and a structured interview for hallucinations, both tended to improve on drug but neither reached statistical significance. A neuropsychological test battery did not show any significant differences. Total on UPDRS motor scores (P < 0.05) and timed tapping (P < 0.01) worsened while on drug compared to placebo. Bradykinesia (P < 0.01) and gait (P < 0.001) items on the UPDRS largely accounted for this deterioration. After completion of the study, 8 of 16 patients randomly assigned to drug continued olanzapine at a mean dose of 2.4 mg/day. However, at the last recorded visit only 5 of 24 (20.8%) of all patients exposed to drug (including those originally randomly assigned to placebo) remained on olanzapine. In patients with PD, low-dose olanzapine did not significantly improve hallucinations but did worsen motor function.",2003.0,0,0
512,12363115,Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder.,John M Kane; William H Carson; Anutosh R Saha; Robert D McQuade; Gary G Ingenito; Dan L Zimbroff; Mirza W Ali,"Aripiprazole is an investigational agent for treating schizophrenia that has a novel pharmacologic profile. The present study investigated the efficacy, safety, and tolerability of aripiprazole and haloperidol compared with placebo. A 4-week, double-blind, randomized study, conducted at 36 U.S. centers between July 1997 and June 1998, compared aripiprazole (15 mg/day, 30 mg/day) to placebo, with haloperidol (10 mg/day) as an active control. Fixed doses of each agent were administered from day 1 throughout the study. A total of 414 patients with a primary DSM-IV diagnosis of schizophrenia or schizoaffective disorder were randomized. Efficacy measures included the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, PANSS-derived Brief Psychiatric Rating Scale (BPRS) core, Clinical Global Impressions (CGI)-Severity of Illness, and mean CGI-Improvement scores. Safety and tolerability evaluations included extrapyramidal symptoms (EPS), weight gain, serum prolactin level, and QTc interval. Both doses of aripiprazole and haloperidol, 10 mg, produced statistically significant (p < or = .05) improvements from baseline in PANSS total, PANSS positive, PANSS-derived BPRS core, and CGI-Severity scores and significantly lower CGI-Improvement scores at endpoint, compared with placebo. Aripiprazole, 15 mg, and haloperidol, 10 mg, significantly improved PANSS negative score compared with placebo. Both aripiprazole doses and haloperidol separated from placebo for PANSS total scores at week 2. Unlike haloperidol, aripiprazole was not associated with significant EPS or prolactin elevation at endpoint compared with placebo. There were no statistically significant differences in mean changes in body weight across the treatment groups versus placebo, and no patients receiving aripiprazole experienced clinically significant increases in QTc interval. Aripiprazole, effective against positive and negative symptoms, is a safe and well-tolerated potential treatment for schizophrenia and schizoaffective disorder.",2002.0,0,1
513,12365879,Randomized controlled trial of interventions designed to reduce the risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms.,Patrick D McGorry; Alison R Yung; Lisa J Phillips; Hok Pan Yuen; Shona Francey; Elizabeth M Cosgrave; Dominic Germano; Jenny Bravin; Tony McDonald; Alison Blair; Stephen Adlard; Henry Jackson,"Most disability produced by psychotic illnesses, especially schizophrenia, develops during the prepsychotic period, creating a case for intervention during this period. However, only recently has it been possible to engage people in treatment during this phase. A randomized controlled trial compared 2 interventions in 59 patients at incipient risk of progression to first-episode psychosis. We termed this group ultra-high risk to emphasize the enhanced risk vs conventional genetic high-risk studies. Needs-based intervention was compared with specific preventive intervention comprising low-dose risperidone therapy (mean dosage, 1.3 mg/d) and cognitive behavior therapy. Treatment was provided for 6 months, after which all patients were offered ongoing needs-based intervention. Assessments were performed at baseline, 6 months, and 12 months. By the end of treatment, 10 of 28 people who received needs-based intervention progressed to first-episode psychosis vs 3 of 31 from the specific preventive intervention group (P=.03). After 6-month follow-up, another 3 people in the specific preventive intervention group became psychotic, and with intention-to-treat analysis, the difference was no longer significant (P=.24). However, for risperidone therapy-adherent patients in the specific preventive intervention group, protection against progression extended for 6 months after cessation of risperidone use. More specific pharmacotherapy and psychotherapy reduces the risk of early transition to psychosis in young people at ultra-high risk, although their relative contributions could not be determined. This represents at least delay in onset (prevalence reduction), and possibly some reduction in incidence.",2002.0,0,0
514,12366464,Antipsychotic polypharmacy: evidence based or eminence based?,S M Stahl,,2003.0,0,0
515,12366465,Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations.,O Freudenreich; D C Goff,"To review the literature on efficacy and risks of combining antipsychotics (atypical with atypical or conventional) and suggest a rationale and strategies for future clinical trials. A computerized Medline search supplemented by an examination of cross-references and reviews was performed. Empirical evidence for the efficacy of combining antipsychotics is too limited to draw firm conclusions. The practice of augmenting clozapine with more 'tightly bound' D2 receptor antagonists as exemplified by risperidone augmentation of clozapine has some empirical and theoretical support. The risks of augmentation strategies have not been studied systematically. No study has examined the economic impact of combination treatment. Further trials of antipsychotic combination therapies are needed before this currently unsupported practice can be recommended. Rationales for combination treatment include a broadening of the range of receptor activity or an increase in D2 receptor occupancy with certain atypical agents. Trial methodology needs to take into account subject characteristics, duration of treatment, optimization of monotherapy comparators, and appropriate outcome measures.",2003.0,1,1
516,12366880,Maintenance therapy in schizophrenia: a critical comment.,Sandra S M Chan; Gabor S Ungvari,"The paper's aim was to evaluate a rationale for maintenance therapy in schizophrenia and to consider the feasibility of intermittent targeted therapy as an alternative treatment strategy. This was achieved by a selected review of the relevant English-language literature published since 1966 through a Medline search and cross-referencing. Current scientific evidence for continuous maintenance therapy in schizophrenia was found equivocal as the randomization in clinical trials lumped together heterogeneous groups of patients, thereby creating a wide gap between research and clinical practice. In addition, the majority of studies took a narrow view of the concept of relapse. For these reasons, targeted intermittent treatment was probably prematurely discarded altogether. The rationale for use and optimal duration of maintenance antipsychotic pharmacotherapy for schizophrenia has not been adequately validated. The construct validity of outcome indicators currently used in maintenance treatment studies in schizophrenia should be reconsidered. Intermittent targeted treatment may represent a viable option in some clinical situations and warrant further evaluation. With the widespread use of atypical antipsychotics, current long-term maintenance strategies may need a reappraisal.",2003.0,0,0
517,12371307,New drugs with novel therapeutic characteristics. Have they been subject to randomized controlled trials?,Joel Lexchin,"To determine how many randomized controlled trials on the safety or efficacy of new drugs are published when these drugs are first marketed in Canada, and to determine the quality of the information in those trials. A MEDLINE search was conducted on each drug identified as having novel therapeutic characteristics and first marketed between 1990 and 2000. Number of trials dealing with the safety or efficacy of each drug published at the time the drug was marketed. Number of patients taking the study drug, length of the trial, and type of control. The number of trials varied substantially. For some drugs, there were more than 20 studies; for others only a single study. Many trials were small and short-term, and used placebo controls. Too few trials or inadequate trials on the safety and efficacy of new drugs are published when these drugs are first marketed in Canada. The lack of published trials means that physicians do not know whether results are generalizable to their patients, how to position the drug in relation to other treatments, or whether the drugs have long-term safety and efficacy.",2002.0,0,0
518,12378746,Severe ventricular arrhythmia and sudden death on neuroleptics.,,"(1) Neuroleptics prolong the QT interval, with a risk of torsades de pointes, ventricular tachycardia, syncope and sudden death. This adverse reaction is dose-dependent. (2) Most published cases have involved phenothiazines, and especially thioridazine. Most other neuroleptics have also been involved, including recent drugs such as risperidone and olanzapine. 'Hidden neuroleptics' such as cisapride and injectable domperidone carry the same risk. (3) While this effect has been known for several decades, the degree of risk associated with the various neuroleptics is still poorly known, and few epidemiological data are available. (4) The cornerstones of prevention of cardiac arrhythmia in patients treated with neuroleptics are to weigh up carefully the indications, prescribe the lowest effective dose, and monitor the ECG. All patients should also be screened for precipitating factors, such as other risk factors for torsades de pointes and combination with other drugs that favour torsades de pointes or provoke pharmacokinetic interactions.",2002.0,0,0
519,12380638,"How much are atypical antipsychotic agents being used, and do they reach the populations who need them? A Canadian experience.",Carolyn S Dewa; Gary Remington; Nathan Herrmann; Joan Fearnley; Paula Goering,"The introduction of new antipsychotic agents in the past decade has helped alter the treatments available to 2 vulnerable populations-those with schizophrenia and related psychotic conditions and elderly individuals with dementia. After examining overall trends in antipsychotic use, this analysis reviews patterns of atypical antipsychotic use in the elderly and financially disadvantaged populations of Ontario. It identifies affected subpopulations and offers several interpretations of how observed patterns of use reflect outpatient prescribing practices. This study used drug claims data from the Ontario Drug Benefit (ODB) program for the years 1992 to 1998. The use of antipsychotic agents was followed for 2 years in a subpopulation of ODB participants identified as consistent users of these agents (ie, those with evidence of > 1-time use). During the study period, the total number of ODB claimants grew by 1%, the number of claimants using antipsychotic agents increased by approximately 25%, and the expenditure per claimant in this group increased by nearly 250%. Much of this growth in expenditures was associated with use of the newer atypical antipsychotic agents olanzapine, risperidone, and quetiapine. Compared with patients aged > or = 65 years, those aged < 65 years were more likely to receive an initial prescription for an atypical antipsychotic or be switched to an atypical antipsychotic. However, the proportion of patients aged > 85 years consistently using antipsychotic agents was greater than predicted based on the proportion of the ODB population they represent. These patients were more likely to use conventional antipsychotic agents exclusively. The introduction of the atypical antipsychotic agents was paralleled by a striking increase in ODB expenditures for antipsychotic drugs, although use of these agents was not consistent across age groups. There was more switching to atypical antipsychotics, as well as greater use in general, among younger compared with older patients, despite evidence that the atypical antipsychotics may be safer in the elderly than conventional antipsychotics. Guideline dissemination may be an important way of familiarizing clinicians with the atypical agents. Health care systems should be aware of the potential for a substantial increase in health care costs with more widespread adoption of these medications.",2003.0,0,0
520,12383035,Aripiprazole.,Jane K McGavin; Karen L Goa,"Aripiprazole is a quinolinone derivative and the first of a new class of atypical antipsychotics. The drug has partial agonist activity at dopamine D(2) and serotonin 5-HT(1A) receptors, and is also an antagonist at 5-HT(2A) receptors. In patients with acute relapse of schizophrenia or schizoaffective disorder, aripiprazole 15 to 30 mg/day was at least as effective as haloperidol 10 mg/day and had similar efficacy to risperidone 6 mg/day in well designed, 4-week, placebo-controlled trials. Negative symptoms improved earlier in the aripiprazole than the risperidone group. Efficacy of aripiprazole was observed at week 1 in several trials and was sustained throughout the study periods. Aripiprazole was superior to placebo in a 26-week trial in patients with stable, chronic schizophrenia. In a 52-week trial involving patients with acute relapsing disease, aripiprazole was similar to haloperidol as assessed by time to failure to maintain response and was superior in ameliorating negative and depressive symptoms. The incidence of extrapyramidal symptoms during aripiprazole therapy was similar to that with risperidone and placebo but lower than with haloperidol. Compared with placebo, the proportion of patients with increased plasma prolactin levels and QTc prolongation was similar in patients treated with aripiprazole 15 to 30 mg/day but was significantly increased with haloperidol and risperidone.",2003.0,0,0
521,12387698,Developments in the pharmacological treatment of schizophrenia.,Gina Kuperberg; Robert Kerwin; Robin Murray,"Schizophrenia is, at once, a biological disease, a neuropsychological disorder and a dysfunction of social interactions. This presents clinicians with a series of problems with regards to therapy. In the first section of this article, some of the clinical challenges that face those attempting to develop new drugs, are summarised. Several potential pharmacological therapeutic targets that have been, and are continuing to be used, in the development of new antipsychotic drugs, are then considered. This is followed by an outline of the pharmacological and clinical profiles of some of the newer generation antipsychotics, as well as investigational drugs in the pipeline for schizophrenia. Finally, the implications of the introduction of these new drugs for the management of schizophrenia, are discussed.",2003.0,0,0
522,12390050,Sleep disorders in Parkinson's disease: epidemiology and management.,Mark Stacy,"Sleep problems are an under-emphasised cause of disability in Parkinson's disease (PD) and may be seen independently of PD, associated with primary PD pathology, or as a result of antiparkinsonian medications. Common sleep disorders include excessive daytime sleepiness, rapid eye movement (REM) sleep behaviour disorder, night-time wakefulness and restless legs syndrome. A number of strategies may be used to improve sleep cycle disturbances, and often these interventions do not require pharmacological manipulation. Restoring traditional mealtimes and scheduling activities during predicted periods of sleepiness may help alleviate daytime somnolence; the use of controlled-release levodopa preparations or administration of a catechol-O-methyl transferase (COMT) inhibitor with levodopa at bedtime may reduce periods of night-time wakefulness. Administration of clonazepam at bedtime may assist with REM sleep behaviour disorder but, because this agent can result in daytime somnolence, experimentation with dosage times is recommended. Sleep attacks are described as a sudden, unavoidable transition from wakefulness to sleep and, although rare, have been described with pramipexole, ropinirole and other dopamine agonists. Although the condition has yet to be recognised by the International Association of Sleep Disorders, patients with PD who report rapid sleep onset should be evaluated for the possibility of sleep attacks. If sleep attacks are suspected, it is reasonable to strongly caution patients regarding potentially risk-associated activities such as driving, and to consider careful withdrawal of dopaminergic therapy.",2003.0,0,0
523,12398067,The role of magnetic resonance imaging in the assessment of patients with established multiple sclerosis.,M Filippi,,2002.0,0,0
524,12399139,Effects of antipsychotics on prepulse inhibition of the startle response in drug-naïve schizophrenic patients.,Torben Mackeprang; Klaus T Kristiansen; Birte Y Glenthoj,"Disturbances in sensorimotor gating measured by prepulse inhibition of the startle response (PPI) have frequently been reported in medicated and unmedicated schizophrenia spectrum patients and in their relatives, suggesting that the deficit represents a stable vulnerability marker for schizophrenia. Clinical data on the effects of antipsychotics on PPI disturbances are scarce, but from preclinical studies, antipsychotics have been shown to influence PPI. To differentiate pathogenetic mechanisms from drug related effects, longitudinal clinical studies on the effect of antipsychotic treatment on PPI in drug-naive first-episode schizophrenic patients are needed. First-episode schizophrenic patients never previously medicated with antipsychotics were examined at inclusion and after 3 months of treatment with the atypical antipsychotic compound, risperidone, or the typical drug, zuclopenthixol. Healthy controls were used as a comparison group. The results confirm deficits in PPI in drug-naive first-episode patients. No effect of antipsychotic treatment on PPI dysfunction was observed in any of the treatment groups. The data are the first to show the possible effect of treatment with antipsychotic drugs on PPI disturbances in a longitudinal study of drug-naive schizophrenic patients. The data do not support any influence of treatment with antipsychotic drugs on sensorimotor gating deficits. Instead, the results point to the impairment in PPI as a stable vulnerability indicator.",2003.0,0,0
525,12404659,Re: Chan et al. A double-blind randomised comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients. Int J Geriatr Psychiatry 16: 1156 - 1162.,D Onalaja; A K Jainer,,2003.0,0,1
526,12409165,Depressive symptoms at baseline predict fewer negative symptoms at follow-up in patients with first-episode schizophrenia.,Piet Oosthuizen; Robin A Emsley; Mimi C Roberts; Jadri Turner; Linda Keyter; Natasha Keyter; Martijn Torreman,"There is uncertainty regarding the prognostic value of depressive symptoms in schizophrenia, having previously been associated with both favourable and poor outcome. This study investigated the relationship between baseline depressive symptoms and treatment outcome at 6, 12 and 24 weeks in 80 subjects with first-episode schizophrenia or schizophreniform disorder in terms of PANSS total and subscale score changes. No significant association was found between baseline PANSS depression factor scores and PANSS total and subscore changes. However, a significant inverse correlation between baseline depression scores and negative scores at 6, 12 and 24 weeks was found (p=0.044, 0.023 and 0.012, respectively). Multiple regression analysis indicated that this finding could not be explained on the basis of age, gender or duration of untreated psychosis. These findings support previous work suggesting that high baseline depressive scores predict favourable outcome.",2003.0,0,0
527,12409172,Longitudinal follow-up of neurochemical changes during the first year of antipsychotic treatment in schizophrenia patients with minimal previous medication exposure.,Juan R Bustillo; John Lauriello; Laura M Rowland; Lisa M Thomson; Helen Petropoulos; Roger Hammond; Blaine Hart; William M Brooks,"Reduced frontal N-acetylaspartate (NAA) has been repeatedly found in chronic schizophrenia and suggests neuronal loss or dysfunction. However, the potential confounding effect of antipsychotic drugs on NAA has not been resolved. The few studies of antipsychotic-nai;ve patients are inconclusive. A recent report suggests that antipsychotic drugs may increase NAA in the dorsolateral prefrontal cortex (DLPFC). We studied 10 minimally treated (less than 3 weeks lifetime exposure) schizophrenia patients and 10 normal controls with single-voxel proton magnetic resonance spectroscopy (1H-MRS) of the left frontal and occipital lobes. Concentrations of NAA, Cho, and Cre were determined and corrected for the proportion of cerebrospinal fluid (CSF) in the voxel. Patients were treated in a randomized-controlled double-blind design with either haloperidol or quetiapine. 1H-MRS was repeated within a year. There were no differences in frontal or occipital NAA between patients and controls at baseline. However, frontal NAA was reduced in the schizophrenia group within the first year of treatment. Patients had a clear clinical response to treatment but changes in frontal NAA were not correlated with symptom improvement. The well-described reduced frontal NAA in schizophrenia may not be a trait of the illness but may represent medication effect or progression of the disease.",2003.0,0,0
528,12409175,"""Normalization"" of brain activation in schizophrenia. An fMRI study.",A Lund; R Kroken; T Thomsen; K Hugdahl; A I Smievoll; R Barndon; J Iversen; N I Landrø; K Sundet; B R Rund; L Ersland; A Lundervold; A Asbjørnsen,,2003.0,0,0
529,12410058,Olanzapine for Huntington's disease: an open label study.,Raphael M Bonelli; Franz A Mahnert; Gerald Niederwieser,"The aim of this prospective open label study was to assess the efficacy of olanzapine for motor symptoms in Huntington's disease (HD). Olanzapine was administrated to nine patients with genetically confirmed HD in increasing doses until satisfactory clinical effect or the appearance of side effects. The patients were evaluated at baseline and after 14 days of treatment using the motor scale of the Unified HD Rating Scale (UHDRS). The patients improved significantly in most subscores of the UHDRS, including fine motor tasks, although some patients needed a rather high dose (30 mg per day). No adverse effects were reported by the patents spontaneously or were observed directly by the investigator. High-dose olanzapine seems to be useful in choreatic HD patients. A double blind, placebo-controlled trial appears warranted to definitively establish the symptomatic value of olanzapine in HD.",2003.0,0,0
530,12411265,Mental disorder and perceived threat to the public: people who do not return to community living.,Liz Jamieson; Pamela J Taylor,"In the UK, people with mental disorder thought to pose a high risk of harm to others are usually put in a high-security (special) hospital. Little is known about what happens after that. To test a hypothesis that, under current services and laws (from the mid-1980s), no one leaving high-security hospitals remains indefinitely institutionalised. The special hospitals' case register was used for case ascertainment and admission data; post-discharge data were collected from multiple sources on patients discharged in 1984 (census date 31.12.1995). In this discharge cohort (n=223), 36 (17%) did not return to the community: 17 died in special hospital and 19 continuously lived in other institutions until death or the census date. Over two-thirds of these had mental illness, were older on admission and had lived longer in special hospital than their better-rehabilitated peers. Offending history was irrelevant to this. Most post-discharge institution time was in open psychiatric hospital, or back in special hospital, not in medium secure units or prison. The hypothesis was not sustained, but fewer people never reached the community than before the mid-1980s. Atypical antipsychotics might reduce this number. We found no justification for a new tier of long-term medium secure units.",2002.0,0,0
531,12413636,"The effect of melperone, an atypical antipsychotic drug, on cognitive function in schizophrenia.",Tomiki Sumiyoshi; Karu Jayathilake; Herbert Y Meltzer,"Melperone, a butyrophenone, has been shown to possess atypical antipsychotic properties, i.e. ability to produce an antipsychotic effect in man at doses that cause minimal extrapyramidal side effects. In addition, melperone shares the following with other atypical antipsychotic drugs: (1) effectiveness for ameliorating negative symptoms; (2) no prolactin elevation; and (3) effectiveness in the treatment of some patients with neuroleptic-resistant schizophrenia. Other atypical antipsychotic drugs have been reported to improve cognitive function. This study was performed to investigate the effect of melperone on cognitive function. Nineteen patients with schizophrenia or schizoaffective disorder, including 11 neuroleptic-resistant patients, were treated with melperone for 6 weeks. A comprehensive neurocognitive test battery and psychopathological ratings (Brief Psychiatric Rating Scale, BPRS) were administered at baseline and after 6 weeks of melperone treatment. Treatment with melperone was associated with improvement in executive function, as measured by the Wisconsin Card Sorting Test (WCST)-Categories and WCST-Percent Perseveration. On the other hand, visuospatial manipulation, as measured by the Wechsler Intelligent Scale for Children-Revised (WISC-R) Maze, worsened during melperone treatment. There were no significant changes in other domains of cognition, i.e. verbal learning and memory, verbal working memory, verbal fluency and sustained attention. Scores of WCST-Categories and Perseveration at 6 weeks were predicted from the relevant cognitive test scores at baseline and the change in BPRS Total and Positive scores. These results suggest the usefulness of melperone for facilitating work and social function in patients with schizophrenia. The differences in the cognition-enhancing abilities between melperone and clozapine are discussed.",2003.0,0,0
532,12413639,An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia.,Robert W Buchanan; Ann Summerfelt; Cenk Tek; James Gold,"A pilot study was conducted to examine if donepezil could enhance cognitive function in patients with schizophrenia. Fifteen subjects who were on stable olanzapine treatment were entered into a 6-week open-labeled trial of donepezil. Subjects received baseline and end-of-study P50 and neuropsychological assessments. Donepezil treatment resulted in significant improvement in manual dexterity. There were moderate improvements in verbal recall memory and visual memory and processing speed, with smaller changes in P50 and verbal recognition memory. There was no effect on an attention measure. There were no changes in either positive or negative symptoms. These results suggest that cholinergic tone modulation may enhance selective behavioral functions in patients with schizophrenia, but further study is required to delineate the full extent of the potential benefit of this approach.",2003.0,0,0
533,12413640,Amoxapine shows atypical antipsychotic effects in patients with schizophrenia: results from a prospective open-label study.,Rogelio Apiquian; Elena Ulloa; Ana Fresan; Cristina Loyzaga; Humberto Nicolini; Shitij Kapur,"Amoxapine is marketed as an antidepressant. However, its receptor occupancy, in vitro and in vivo, and its effects in pre-clinical models are very similar to atypical antipsychotics. To examine if this leads to an atypical antipsychotic effect in the clinical context, the authors examined the antipsychotic and side-effect profile of amoxapine in acutely psychotic patients with schizophrenia. Seventeen patients were enrolled and 15 completed a prospective open-label 6-week study of amoxapine starting with a fixed-starting dose (150 mg/h) with standardized titration up to 250 mg/h, if required. Positive, negative, affective symptoms and side-effects were monitored using standardized weekly assessments. Amoxapine (median final dose 210 mg/h) was well-tolerated and showed significant improvement in positive and negative symptoms (both p<0.001), with a trend towards improvement in mood symptoms and no treatment-emergent extrapyramidal side-effects, akathisia or weight gain. Prolactin elevation was observed. These clinical data lend support to the pre-clinical suggestions that amoxapine may be an atypical antipsychotic. Given its lack of weight gain and that it is considerably less expensive than current options, amoxapine could be a valuable alternative for some patients. These considerations strongly call for more systematic, double-blind studies of amoxapine as an atypical antipsychotic.",2003.0,0,0
534,12413642,Serum glucose and lipid changes during the course of clozapine treatment: the effect of concurrent beta-adrenergic antagonist treatment.,Scott P Baymiller; Patricia Ball; Robert P McMahon; Robert W Buchanan,"We examined the effects of long-term clozapine treatment, concurrent treatment with beta-adrenergic antagonists, and clozapine-induced weight gain on serum glucose and lipid measures. Fifty subjects met the DSM-III-R criteria for schizophrenia or schizoaffective disorder, participated in a 10-week, double-blind comparison of haloperidol and clozapine and a 1-year, open-label clozapine trial, and had available serum glucose and lipid levels. Weight and glucose, and lipid laboratory values were measured at the baseline and throughout the double-blind and year-long study. There were significant increases in serum triglyceride, total cholesterol, and glucose levels during the course of clozapine treatment. There were no significant changes in high-density lipoprotein (HDL) or low-density lipoprotein (LDL). Propranolol and atenolol had additive effects on changes in the total cholesterol and triglycerides, with propranolol having the most pronounced effects. Propranolol and atenolol had no significant effect on the serum glucose levels. There were significant correlations between the triglyceride and HDL level changes and clozapine-associated weight gain during the study. There were no significant correlations between the change in serum total cholesterol, LDL, or glucose and weight gain. Clozapine therapy has adverse effects on glucose and lipid homeostasis, with clozapine-induced changes in serum glucose likely due to the inherent pharmacological properties of clozapine. Concurrent beta-adrenergic receptor antagonist treatment may have an additive effect on serum lipids, and clozapine-associated weight gain also plays a modest role in triglyceride increases.",2003.0,0,0
535,12413648,A pilot cross-over design study on QTc interval prolongation associated with sulpiride and haloperidol.,Kuan Pin Su; Winston W Shen; Chiao Lin Chuang; Kun Po Chen; Chiao Chicy Chen,,2003.0,0,0
536,12414079,Computer-assisted cognitive rehabilitation reduces negative symptoms in the severely mentally ill.,Dona M Bellucci; Kathryn Glaberman; Nick Haslam,"Thirty-four-day treatment program clients diagnosed with schizophrenia or schizoaffective disorder were randomly assigned to a computer-assisted cognitive rehabilitation (CACR) group or a wait-list Control group. CACR clients received 16 CACR sessions over an 8-week period. Measures of cognitive functioning, negative symptoms and self-esteem were administered at the beginning and end of this period. CACR clients showed greater improvement in cognitive functioning (verbal memory and attention) and negative symptoms. Symptom reduction was not mediated by raised self-esteem. CACR's effects may go beyond cognitive remediation to include some of the most disabling and refractory clinical features of schizophrenia.",2003.0,0,0
537,12414081,Cross-national cognitive assessment in schizophrenia clinical trials: a feasibility study.,Philip D Harvey; Lidia Artiola i Fortuny; Estelle Vester-Blockland; Goedele De Smedt,"Clinical trials for the treatment of schizophrenia now often include cognitive assessments in addition to clinical ratings of symptoms. Recently, these trials have included cross-national assessments. It is not clear if translated psychological tests produce consistent results across different languages. This paper presents the results of a study of the comparability of the results of cognitive assessments in different English-speaking countries and a number of countries where tests were translated into other languages. Performance on tests of executive functioning, verbal and visuo-spatial learning and memory, language skills, psychomotor speed, and vigilance was compared across the first episode patients with schizophrenia (n = 301) assessed in six different languages (English, French, Finnish, German, Hebrew, and Afrikaans), including two different countries where patients were assessed in English and other languages: Canada (French) and South Africa (Afrikaans). The variance in performance across the sites tested in English was as large as the variance between English and non-English speakers when all tests were considered. Performance differences across English and other languages were found only for executive functions, vigilance, and psychomotor speed, with executive functioning differences nonsignificant when education was considered. No differences were found between English and non-English speakers in Canada. These results suggest that the translation of tests of memory and verbal skills can lead to consistent results across translated versions of the tests. Differences between countries were greater than differences between languages, suggesting the need to consider representativeness of patient samples in terms of local educational attainment. In general, these data support the validity of cross-national neuropsychological assessments.",2003.0,0,0
538,12416594,The effects of novel antipsychotics on glucose and lipid levels.,Donna A Wirshing; Jennifer A Boyd; Laura R Meng; Jacob S Ballon; Stephen R Marder; William C Wirshing,"The novel antipsychotics are extensively used based on their favorable extrapyramidal side effect profiles. However, accumulating evidence suggests that these agents, particularly clozapine and olanzapine, have serious side effects of their own, including weight gain and elevated glucose and triglyceride levels. The goal of this study is to compare the effects of novel antipsychotics clozapine, olanzapine, risperidone, and quetiapine and typical antipsychotics haloperidol and fluphenazine on glucose and lipid levels. The charts of 590 patients were retrospectively reviewed. Of those, 215 patients had adequate laboratory data for inclusion. Glucose and lipid level data from 2 1/2 years before and after initiation of the target antipsychotic were included. Covariates, including patients' age, the duration of antipsychotic treatment, other medications that may affect glucose or lipid levels, and the initial laboratory values, were controlled for in the analyses. Glucose levels were increased from baseline for patients treated with clozapine, olanzapine, and haloperidol. There were statistically and clinically significant differences among the medications' effects on lipid profiles (p < .05). Those receiving clozapine and olanzapine demonstrated statistically significant increases in triglyceride levels compared with the other groups. Over one third of patients treated with any of the novel antipsychotics had clinically meaningful triglyceride elevations. It has been shown that novel antipsychotics are associated with weight gain. This risk factor along with others, such as elevated glucose and triglyceride levels, compounds the risk for coronary artery disease. Routine monitoring of glucose and lipid levels during treatment with novel antipsychotics should be advocated.",2002.0,0,1
539,12416598,"Risperidone, 2 mg/day vs. 4 mg/day, in first-episode, acutely psychotic patients: treatment efficacy and effects on fine motor functioning.",Marco C G Merlo; Helene Hofer; Walter Gekle; Gregor Berger; Joseph Ventura; Ingrid Panhuber; Gabriela Latour; Stephen R Marder,"The aim of this study was to examine differences in the improvement of clinical psychopathology and in fine motor functions at 2 doses of risperidone in first-episode, acutely psychotic patients. In a double-blind, fixed-dose study, 49 acutely psychotic, neuroleptic-naive patients who were admitted for the first time and who met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder were randomly assigned to 2 or 4 mg/day of risperidone. Treatment efficacy was measured using the Brief Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, The Clinical Global Impressions scale, and the Social and Occupational Functioning Assessment Scale. Fine motor functions were assessed using a computerized device (the Vienna Test System) and were compared with those of a control group of 20 healthy subjects who were matched for age, gender, and educational level. Treatment with doses of 2 and 4 mg of risperidone daily significantly reduced positive (p < .0001) and negative (p < .01) symptoms at 8 weeks. Although there were no significant differences in motor movements as measured using the Barnes Akathisia Scale and the Simpson-Angus Scale, computerized fine motor assessment showed significantly less motor dysfunction in the 2-mg/day group at 8 weeks. No significant correlations to plasma concentration of active moiety were found for data on psychopathology and fine motor functions. The 2 doses of risperidone did not differ in terms of clinical improvement, but the 2-mg/day dose produced fewer fine motor dysfunctions. These results suggest that a dose as low as 2 mg/day of risperidone may be effective for patients with first-episode psychosis.",2002.0,0,0
540,12416602,"Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database.",Frank D Gianfrancesco; Amy L Grogg; Ramy A Mahmoud; Ruey-hua Wang; Henry A Nasrallah,"Case series suggest that some antipsychotics may induce or exacerbate type 2 diabetes. This study measured the association of antipsychotic treatments with diabetes at a population level. Claims data for psychosis patients (ICD-CM-9 290.xx-299.xx) within health plans encompassing 2.5 million individuals were analyzed. Patients reporting preexisting type 2 diabetes up to 8 months prior to observation were excluded. The frequency of newly reported type 2 diabetes in untreated patients and among patients treated with antipsychotics from 5 categories (risperidone, olanzapine, clozapine, and high-potency and low-potency conventionals) was compared. Logistic regression models compared the odds of diabetes based on exposure to each of the antipsychotic categories. Based on 12 months of exposure, the odds of type 2 diabetes for risperidone-treated patients (odds ratio = 0.88, 95% CI = 0.372 to 2.070) was not significantly different from that for untreated patients, whereas patients receiving other antipsychotics had a significantly greater risk of diabetes than untreated patients (p < .05): olanzapine, 3.10 (95% CI = 1.620 to 5.934); clozapine, 7.44 (95% CI = 0.603 to 34.751); high-potency conventionals, 2.13 (95% CI = 1.097 to 4.134); and low-potency conventionals, 3.46 (95% CI = 1.522 to 7.785). Older age and greater use of non-antipsychotic psychotropic medications also contributed to risk of type 2 diabetes. Olanzapine also showed significantly higher (p < .01) odds of diabetes associated with increasing dose. Consistent with previously published literature, these data suggest that olanzapine, clozapine, and some conventional antipsychotics appear to increase the risk of acquiring or exacerbating type 2 diabetes and that the effect may vary by drug. In contrast to these agents, risperidone was not associated with an increased risk of type 2 diabetes.",2002.0,1,1
541,12416603,Olanzapine in refractory schizophrenia after failure of typical or atypical antipsychotic treatment: an open-label switch study.,Jean-Pierre Lindenmayer; Pal Czobor; Jan Volavka; Jeffrey A Lieberman; Leslie Citrome; Brian Sheitman; Miranda Chakos; Joseph P McEvoy,"When patients with schizophrenia fail to respond to an atypical antipsychotic, they are sometimes switched to another atypical compound. However, the benefits of such a switch have not been adequately studied. We present an open-label prospective 14-week trial with olanzapine in patients with schizophrenia and schizoaffective disorder whose treatment resistance to clozapine, olanzapine, risperidone, and haloperidol had been determined prospectively. The subjects were 45 inpatients with DSM-IV schizophrenia or schizoaffective disorder who failed to respond to treatment during a 14-week double-blind trial comparing clozapine, olanzapine, risperidone, and haloperidol. The patients had been selected for participation in the double-blind trial on the basis of a history of suboptimal response to previous treatment. Inclusion criteria for the present study were (1) completion of at least 8 weeks of the 14-week double-blind trial, (2) treatment resistance to 1 of the 4 compounds tested as evidenced by a decrease in total PANSS score of less than 20%, and (3) total PANSS score > or = 60. Subjects were cross-titrated from the previous double-blind treatment to open-label olanzapine, 10 to 40 mg/day, and were treated for 14 weeks without concomitant psychotropic medication. Patients were evaluated weekly with the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions scale, and Extrapyramidal Symptom Rating Scale. Open-label olanzapine treatment yielded no significant change in PANSS total, positive subscale, or negative subscale scores. There was a significant improvement for the PANSS cognitive factor (mean +/- SD change = 0.92 +/- 2.27; F = 7.5, df = 1,44; p <.009) and a marginally significant worsening for the excitement factor (mean change = -1.36 +/- 4.64; F = 4.0, df = 1,44; p < .053). Nine percent of patients (N = 4) were classified as responders using the Kane et al. criteria. The worsening in the PANSS excitement factor was significantly associated with the length of illness (t = -2.10, df = 44, p < .04). There was a nonsignificant decrease in extrapyramidal side effects and a significant increase in weight (mean increase = 3.5 +/- 6.2 kg [7.8 +/- 13.8 lb]; F = 5.29, df = 1,42; p <.0005). Our results indicate that in patients with treatment-resistant schizophrenia, a switch to olanzapine after treatment failure with an atypical agent or haloperidol may not reduce psychopathology in general, but may improve symptoms related to cognitive function.",2002.0,0,0
542,12418935,An assessment of the independent effects of olanzapine and risperidone exposure on the risk of hyperlipidemia in schizophrenic patients.,Carol E Koro; Donald O Fedder; Gilbert J L'Italien; Sheila Weiss; Laurence S Magder; Julie Kreyenbuhl; Dennis Revicki; Robert W Buchanan,"The newer antipsychotic agents exhibit a superior safety profile compared with conventional antipsychotic agents in terms of extrapyramidal symptoms. Previous studies have suggested an association between olanzapine treatment and hyperlipidemia. We evaluated this association using a large health care database. The study was derived from the England and Wales-based General Practice Research Database, composed of 3.5 million subjects followed up between June 1, 1987, and September 24, 2000. A total of 18 309 individuals diagnosed as having schizophrenia were identified. A 6:1 matched nested case-control design was used. Conditional logistic regression was used to derive adjusted odds ratios (ORs), controlling for sex, age, and other medications and disease conditions influencing lipid levels. Antipsychotic drug exposure was defined as the receipt of at least 1 prescription for an antipsychotic medication within the 3 months before the date of diagnosis of hyperlipidemia. There were 1268 incident cases of hyperlipidemia in the cohort, matched to 7598 control subjects. Olanzapine use was associated with nearly a 5-fold increase in the odds of developing hyperlipidemia compared with no antipsychotic exposure (OR, 4.65; 95% confidence interval [CI], 2.44-8.85) (P<.001) and more than a 3-fold increase compared with those receiving conventional agents (OR, 3.36; 95% CI, 1.77-6.39) (P<.001). Risperidone was not associated with increased odds of hyperlipidemia compared with no antipsychotic exposure (OR, 1.12; 95% CI, 0.60-2.11) (P =.72) or conventional antipsychotic exposure (OR, 0.81; 95% CI, 0.44-1.52) (P =.52). We observed a strong association between olanzapine exposure and hyperlipidemia in schizophrenic patients. The possible metabolic consequences of olanzapine use should be given serious consideration by treating physicians.",2002.0,0,1
543,12424166,Cardiac arrest and ventricular arrhythmia in patients taking antipsychotic drugs: cohort study using administrative data.,Sean Hennessy; Warren B Bilker; Jill S Knauss; David J Margolis; Stephen E Kimmel; Robert F Reynolds; Dale B Glasser; Mary F Morrison; Brian L Strom,"To examine the rates of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia and in non-schizophrenic controls. Cohort study of outpatients using administrative data. 3 US Medicaid programmes. Patients with schizophrenia treated with clozapine, haloperidol, risperidone, or thioridazine; a control group of patients with glaucoma; and a control group of patients with psoriasis. Diagnosis of cardiac arrest or ventricular arrhythmia. Patients with treated schizophrenia had higher rates of cardiac arrest and ventricular arrhythmia than controls, with rate ratios ranging from 1.7 to 3.2. Overall, thioridazine was not associated with an increased risk compared with haloperidol (rate ratio 0.9, 95% confidence interval 0.7 to 1.2). However, thioridazine showed an increased risk of events at doses > or =600 mg (2.6, 1.0 to 6.6; P=0.049) and a linear dose-response relation (P=0.038). The increased risk of cardiac arrest and ventricular arrhythmia in patients with treated schizophrenia could be due to the disease or its treatment. Overall, the risk with thioridazine was no worse than that with haloperidol. Thioridazine may, however, have a higher risk at high doses, although this finding could be due to chance. To reduce cardiac risk, thioridazine should be prescribed at the lowest dose needed to obtain an optimal therapeutic effect.",2002.0,0,1
544,12424822,"Classical and atypical neuroleptics, and bone mineral density, in patients with schizophrenia.",Mustafa Bilici; Hasim Cakirbay; Mustafa Guler; Mehmet Tosun; Metin Ulgen; Uner Tan,"There are some reports that classical neuroleptics may lead to osteoporosis or reduced bone mineral density (BMD). However, there is no adequate information about the effects of atypical neuroleptics on BMD. The aim of this study was to measure BMD in schizophrenic patients taking classical and atypical neuroleptics, compared to healthy controls. Seventy-five patients with schizophrenia (40 taking classical neuroleptics [CN], 35 taking atypical neuroleptics [AN]) and 20 healthy controls (HC) were included in the study. Spine (L1-L4) BMD was measured by dual-energy X-ray absorptiometry. ANOVA showed that BMD was higher in HC than AN and CN. In addition, there was a negative correlation between the duration of neuroleptic treatment and BMD and the duration of the illness. These findings suggest that atypical neuroleptics may be safer than the classical neuroleptics in terms of reduced BMD.",2003.0,0,0
545,12427578,Evaluating the consistency of pharmacotherapy exposure by use of state-of-the-art techniques.,Robert R Bies; Marc R Gastonguay; Kim C Coley; Patricia D Kroboth; Bruce G Pollock,"The authors examine the usefulness of population pharmacokinetics coupled with electronic compliance monitoring in evaluating consistency of exposure to pharmacotherapy. Adherence to pharmacotherapy can have a significant impact on drug response, especially in the treatment of schizophrenia and depression. Previous studies evaluating antipsychotics identified schizophrenic individuals with poor pharmacotherapy adherence as having a higher risk of rehospitalization. Other investigators have shown a relationship between pattern of taking selective serotonin-reuptake inhibitors (SSRIs) and probability of a positive outcome. Therefore, it is important to measure adherence patterns in clinical trials evaluating these treatments and to incorporate this information into the research findings. Two multisite trials with atypical antipsychotics and antidepressants were simulated to evaluate, by use of population pharmacokinetic methods, the impact of electronic monitoring on measuring consistency of exposure to pharmacotherapy. One of the trials is ongoing and evaluates exposure to atypical antipsychotics, and the other is a proposed trial that examines exposure to an SSRI. Erratic exposure patterns were detected with population pharmacokinetic techniques in the absence of Electronic Medication Event Monitoring (MEMS) data. In our simulations, the use of electronic monitoring improved the identification of atypical exposure by population pharmacokinetics both for the atypical antipsychotics and SSRIs. Our simulations demonstrate the potential usefulness of the combination of population pharmacokinetics with electronic monitoring as a robust method for accurately and precisely capturing both magnitude and consistency of pharmacotherapy exposure.",2003.0,0,0
546,12435529,"Psychotropic and neurotropic agents in dermatology: unapproved uses, dosages, or indications.",John Y Koo; Theresa C Ng,,2003.0,0,0
547,12439835,Impact of risperidone versus haloperidol on activities of daily living in the treatment of refractory schizophrenia.,Robert Paul Liberman; Daniel Gutkind; Jim Mintz; Michael Green; B D Marshall; Mary Jane Robertson; Jeffery Hayden,"Risperidone has been shown to improve verbal working memory, executive functioning, attention, reaction time, and verbal learning, which, in turn, have been associated with improved functional outcomes. We tested whether risperidone was associated with greater improvements than haloperidol in activities of daily living (ADLs) among persons having treatment-refractory schizophrenia. In a double-blind, controlled trial of fixed and flexible doses of haloperidol and risperidone, changes in ADLs were operationally monitored on a behavior therapy unit of a state hospital. While no differential effects were noted between risperidone and haloperidol in ADLS, these self-care skills significantly improved as subjects spent longer times on the behavior therapy unit. Working memory and verbal learning did correlate with improvements in ADLs, independent of drug condition. The contingencies of reinforcement and specific training programs on the behavior therapy unit may have been prepotent for the learning of ADLs, obscuring any differential impact of risperidone. Moreover, ADLs may be governed more by ""procedural"" learning than by working memory or verbal learning, with the former not differentially influenced by typical verus atypical antipsychotics.",2003.0,0,1
548,12444812,Quetiapine: an effective antipsychotic in first-episode schizophrenia despite only transiently high dopamine-2 receptor blockade.,Sitra Tauscher-Wisniewski; Shitij Kapur; Johannes Tauscher; Corey Jones; Zafiris J Daskalakis; George Papatheodorou; Irvin Epstein; Bruce K Christensen; Robert B Zipursky,"It has been suggested that transiently high dopamine-2 (D(2)) receptor occupancy by antipsychotic medication may be sufficient for inducing an antipsychotic response. We treated patients experiencing their first episode of schizophrenia with a single daily dose of quetiapine to achieve a transient daily peak of D(2) receptor blockade, to determine if this would lead to an antipsychotic response. Fourteen patients with a DSM-IV diagnosis of schizophrenia or schizophreniform or schizoaffective disorder were treated with quetiapine titrated to a single daily dose (mean +/- SD dose at the time of the positron emission tomography [PET] scan = 427 +/- 69 mg) for 12 weeks. Peak D(2) occupancy approximately 2 hours postdose and trough D(2) occupancy approximately 20 hours postdose were determined using PET and [(11)C]raclopride. Clinical symptoms and side effects were measured at baseline and every 2 weeks during the treatment phase. Quetiapine administration led to a mean peak D(2) occupancy of 62% +/- 10% 2 hours postdose, which declined to 14% +/- 8% approximately 20 hours postdose. Ten (71%) of 14 patients responded to treatment with quetiapine, scoring ""much improved"" or greater on the Clinical Global Impressions-Improvement scale. Plasma drug levels and peak D(2) occupancy were highly correlated (r = 0.84; p =.003), as were prolactin and plasma drug levels when measured 2.5 hours after drug administration (r = 0.60; p <.05). Mean weight gain for the 10 subjects who completed the 12-week study was 4.2 +/- 4.6 kg (9.3 +/- 10.2 lb). No clinically relevant motor side effects occurred during the trial. Patients with a first episode of schizophrenia responded to treatment with a single daily dose of quetiapine despite only transiently high D(2) receptor occupancy. Our findings raise the question of whether continuously high D(2) blockade is necessary for obtaining an antipsychotic response. Future studies aimed at evaluating the relative merits of ""transiently high"" versus ""continuously high"" D(2) occupancy are warranted.",2002.0,0,0
549,12444819,,,,,0,0
550,12452546,Olanzapine vs. haloperidol in the treatment of elderly chronic schizophrenia patients.,Yoram Barak; Eyal Shamir; Hanna Zemishlani; Ilona Mirecki; Paz Toren; Ronit Weizman,"Most of the data supporting the use of atypical antipsychotics (AA) is based on studies in young adult patients. The present study is an open-label naturalistic follow-up study of olanzapine treatment vs. haloperidol for elderly chronic schizophrenia patients. MEHTOD: 20 patients (mean age 72.7+/-5.9 years, mean disease duration 33.1+/-12.0 years) who met the DSM-IV criteria for schizophrenia were randomly assigned to olanzapine (n=10) or haloperidol (n=10) treatment during acute exacerbation. Primary outcome measure was rating on the Clinical Global Impression (CGI) scale and the Positive and Negative Symptom Scale (PANSS). Between-group differences were computed using analysis of covariance. PANSS Total score decreased from 84 at baseline to 65 after treatment with olanzapine while decreased only from 79 to 74 with haloperidol treatment (F= 6.66, P=.02). PANSS Negative subscale decreased from 19 at baseline to 15 with olanzapine treatment while increased (deteriorated) from 18 to 20 with haloperidol treatment (F=23.37, P=.0003). CGI decreased from baseline with both olanzapine and haloperidol treatments (1.1 vs. 0.4) but the decrease in the olanzapine group was significantly greater (F=4.63, P=.05). Mean weight increased in both groups but without statistical difference between groups. In elderly chronic schizophrenia patients, olanzapine treatment is superior to haloperidol in reducing negative symptoms as well as less induction of extrapyramidal symptoms (EPS).",2003.0,0,1
551,12452735,Glucose intolerance with atypical antipsychotics.,Karin Hedenmalm; Staffan Hägg; Malin Ståhl; Orjan Mortimer; Olav Spigset,"Previous studies have suggested that the atypical antipsychotics clozapine and olanzapine may be associated with an increased risk of glucose intolerance and diabetes mellitus. Early studies have also suggested an association between use of conventional antipsychotics and the development of glucose intolerance. To examine quantitatively the association between glucose intolerance including diabetes mellitus and the use of the atypical antipsychotics clozapine, olanzapine or risperidone, and to identify possible risk factors for the development of glucose intolerance during treatment with these drugs. All reports suggestive of glucose intolerance for clozapine, olanzapine and risperidone were identified in the WHO database for adverse drug reactions. In the analyses of possible risk factors for glucose intolerance all other reports of adverse drug reactions for clozapine, olanzapine and risperidone were used as reference. Using the Bayesian Confidence Propagation Neural Network method, the strengths of the associations over time between glucose intolerance and the use of these drugs were analysed. For comparison, the strengths of the associations between glucose intolerance and the use of the conventional antipsychotics haloperidol and chlorpromazine were also analysed. Clozapine, olanzapine and risperidone were significantly associated with glucose intolerance. In contrast, chlorpromazine and haloperidol were not associated with glucose intolerance. For clozapine, olanzapine and risperidone grouped together, the following potential risk factors for glucose intolerance were identified: an underlying diabetic condition (odds ratio [OR] 10.22, 95% CI 8.20-12.73), an increase in weight (OR 2.36, 95% CI 1.76-3.17), male gender (OR 1.27, 95% CI 1.11-1.47), and concomitant use of valproic acid (OR 1.97, 95% CI 1.61-2.40), selective serotonin reuptake inhibitors (OR 1.63, 95% CI 1.33-1.99) or buspirone (OR 2.24, 95% CI 1.33-3.77). Treatment with clozapine, olanzapine or risperidone appears to be associated with an increased risk of glucose intolerance.",2003.0,0,1
552,12454554,Dose-related effects of amisulpride on five dimensions of psychopathology in patients with acute exacerbation of schizophrenia.,Matthias J Müller; Hermann Wetzel; Franz-Xaver Eich; Werner Rein; Alain Puech; Otto Benkert; Amisulpride Study Group,"The present analysis investigated symptom-specific dose-response relationships of the atypical antipsychotic amisulpride (AMI) in schizophrenic patients. The effects of different AMI doses on five different symptom dimensions of the Brief Psychiatric Rating Scale (BPRS) were analyzed. Results on global efficacy and safety parameters have been previously published. Four AMI doses (100 mg/day [AMI100], 400 mg/day [AMI400], 800 mg/day [AMI800], 1200 mg/day) were compared with 16 mg haloperidol (HAL16) in a multicenter, double-blind, randomized, parallel-group, 4-week trial. A total of 319 patients with acute exacerbation of schizophrenia (DSM-III-R) were included. AMI100 was compared with the other AMI doses, and HAL16 was compared with all AMI dosage groups. Response on BPRS factors defined as > or = 40% improvement and ORs were computed. An optimal AMI dose was calculated for each BPRS factor based on linear and quadratic regression. For all BPRS factors, inverted u-shaped dose-response curves emerged (r2 > 95%). The estimated AMI dose optimum for the BPRS factors activation/ agitation (760 mg), thought disturbances (716 mg), and hostility/suspiciousness (694 mg) was higher than that for anergia/negative symptoms (584 mg) and depression/anxiety (672 mg). Significant differences (p < 0.05) were found for AMI400/800 versus AMI100 (thought disturbances, hostility/ suspiciousness), for AMI400/800 versus HAL16 (depression/anxiety, thought disturbances, hostility/suspiciousness), and for AMI400 versus HAL16 (anergia/negative symptoms). ORs for response of the BPRS factors depression/anxiety, anergia/negative symptoms, and hostility/suspiciousness were highest under treatment with AMI400 compared to AMI100 and HAL16. For the BPRS factors thought disturbances and activation/agitation, the highest response chance emerged under AMI800 compared to AMI100 or HAL16. AMI seems to show the best clinical efficacy in acutely schizophrenic patients in a moderate dose (400-800 mg/day), with a somewhat lower dose optimum for negative than for positive symptoms. The present finding of distinct dose-response relationships of AMI regarding the BPRS dimensions is in accordance with studies on the mechanism of action of AMI and provides a useful rationale for the clinical treatment of schizophrenic patients with AMI.",2003.0,0,0
553,12457019,,,,,0,0
554,12462294,An economic assessment of quetiapine and haloperidol in patients with schizophrenia only partially responsive to conventional antipsychotics.,Dominic Tilden; Mike Aristides; David Meddis; Tom Burns,"Many patients with schizophrenia exhibit only a partial response to conventional antipsychotic agents, making them difficult to treat adequately. This analysis models the cost-effectiveness of quetiapine compared with haloperidol in partial responders with schizophrenia. Outcome data from the Partial Responders International schiZophrenia Evaluation (PRIZE) clinical trial comparing quetiapine and haloperidol in partial responders with schizophrenia as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition were combined with data from the literature to construct a Markov model. The model was used to calculate treatment outcomes and total direct treatment costs from the perspective of the United Kingdom National Health Service over 5 years. The PRIZE study showed that quetiapine treatment resulted in a higher response rate and better tolerability than haloperidol treatment. These benefits have the potential to improve compliance and reduce relapse rates. The model showed that the higher acquisition cost of quetiapine was offset by lower costs for other medications, hospitalization, and other medical services. The total treatment cost over 5 years was 38,106 pounds for quetiapine and 38,350 pounds for haloperidol, a cost saving of 244 pounds in favor of quetiapine. Quetiapine-treated patients also spent longer in response states and experienced fewer relapses. Sensitivity analysis showed these results to be robust across a range of conditions. Quetiapine has the potential to improve outcomes compared with haloperidol in partial responders with schizophrenia, at a slightly lower total cost. The higher acquisition cost of quetiapine was offset by savings in other medical costs. Quetiapine could significantly improve the management of this patient group, without increasing the economic burden on the health service.",2003.0,0,0
555,12463729,Pharmacokinetic and safety assessments of galantamine and risperidone after the two drugs are administered alone and together.,Fenglei Huang; Kenneth C Lasseter; Luc Janssens; Tom Verhaeghe; Henry Lau; Qinying Zhao,"To explore the steady-state pharmacokinetic profile after coadministration of galantamine and risperidone, an open-label, randomized, single-center, two-way crossover drug-drug interaction study was conducted in 16 healthy elderly subjects, ages 60 years and older. The results showed that risperidone, when administered with galantamine, did not change the bioavailability of galantamine at steady state. In addition, systemic exposure of risperidone active moiety (risperidone plus 9-hydroxyrisperidone), the most clinically relevant component of risperidone treatment, was not affected by galantamine coadministration, while systemic exposure was increased by approximately 10% for risperidone and decreased by about 10% for 9-hydroxyrisperidone (active metabolite of risperidone). Galantamine and risperidone were both safe and well tolerated administered either alone or together. Thus, no dose adjustment for either risperidone orgalantamine is necessary when these two drugs are administered together in the dose range evaluated.",2003.0,0,0
556,12464464,Amisulpride vs. risperidone in chronic schizophrenia: results of a 6-month double-blind study.,Daniel Sechter; Joseph Peuskens; Odile Fleurot; Werner Rein; Yves Lecrubier; Amisulpride Study Group,"This multicenter, double-blind, randomized study evaluated the efficacy, safety and functional effects of two atypical antipsychotics, amisulpride and risperidone, in patients with chronic schizophrenia (DSM IV) with a recent worsening of symptoms. It was planned as a non-inferiority trial. 309 patients received amisulpride (400-1,000 mg/day) or risperidone (4-10 mg/day) for six months. Amisulpride was demonstrated to be not inferior to risperidone with respect to the decrease in Positive and Negative Syndrome Scale (PANSS) total score from baseline (90% 2-sided confidence interval (-5.6; 4.0)). Symptomatic improvement measured with the Brief Psychiatry Rating Scale (BPRS), the PANSS positive subscale, and the Bech Rafaelsen Melancholia Scale was similar in both groups. Amisulpride was significantly (p <.05) superior to risperidone in terms of response (>/=50% improvement in PANSS and BPRS total scores or ""very much/much improved"" on the Clinical Global Impression Scale) and also demonstrated better functional effects and subjective response. Both treatments were well tolerated and had a similar low incidence of extrapyramidal symptoms; however, amisulpride was associated with less weight gain and endocrine/sexual symptoms.",2003.0,1,1
557,12465075,Sublingual atropine for sialorrhea secondary to parkinsonism: a pilot study.,H Christopher Hyson; Andrew M Johnson; Mandar S Jog,"Sialorrhea is a relatively common symptom in idiopathic Parkinson's disease and related conditions for which most of the accepted treatments are either highly invasive or may cause substantial systemic side effects. This study describes an open-label pilot study of sublingual atropine drops for the treatment of sialorrhea in 7 patients (6 with Parkinson's disease, 1 with progressive supranuclear palsy). Participants demonstrated statistically significant declines in saliva production, both objectively and subjectively. Self-reported drooling severity showed a significant decline between baseline and 180 minutes, t(6) = 3.240 P < 0.025 (eta(2) = 0.636), and between baseline and 1 week, t(6) = 4.583 P < 0.005 (eta(2) = 0.778). Objectively measured saliva production decreased significantly between baseline and the 1-week follow-up, t(6) = 2.711 P < 0.05 (eta(2) = 0.551). Delirium occurred in 1 patient (concurrent with a urinary tract infection), and 2 patients experienced worsening of hallucinations (active hallucinosis was concealed by both individuals to allow participation in the trial). The remaining trial participants did not experience any anticholinergic side effects. This trial shows that, in selected patient populations, sublingual atropine is a simple and inexpensive treatment for sialorrhea associated with parkinsonism.",2003.0,0,0
558,12465082,Metric characteristics of the drug-induced extrapyramidal symptoms scale (DIEPSS): a practical combined rating scale for drug-induced movement disorders.,Jong-Hoon Kim; Hee Yeon Jung; Ung Gu Kang; Seong Hoon Jeong; Yong Min Ahn; Hee-Jung Byun; Kyoo-Seob Ha; Yong Sik Kim,"The metric properties of the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) were examined in 182 subjects treated with antipsychotics. Inter-rater reliability, test-retest reliability, and concurrent validity with other rating scales for EPS were high. Four factors were identified and the optimal diagnostic cut-off scores were obtained. These results suggest that the DIEPSS is a reliable and valid multidimensional rating scale.",2003.0,0,0
559,12467947,Changes in cognitive functioning following comprehensive treatment for first episode patients with schizophrenia spectrum disorders.,Laurel A Townsend; Ross M G Norman; Ashok K Malla; Anita D Rychlo; Rashid R Ahmed,"The course of cognitive functioning over a 1-year period was examined among a community cohort of individuals presenting with first episode schizophrenia spectrum psychosis. Data were obtained for 83 outpatients at entry to an early intervention program and 12 months later on the National Adult Reading Test, Wechsler Adult Intelligence Scales-Third Edition, Wechsler Memory Scales-Third Edition, Paced Auditory Serial Addition Task, Wisconsin Card Sorting Test, Stroop Colour and Word Test, Trail Making Test, Continuous Performance Task and Thurstone Word Fluency Test. Paired sample t-tests indicated significant and positive changes in verbal and non-verbal intelligence, auditory and visual memory, working memory and some aspects of executive functioning. Processing speed also improved though remained an area of relative weakness for this sample. Findings indicated generally average performance at both assessment periods. Neither gender nor duration of untreated psychosis were related to the degree of change in cognitive functioning for this sample. The implications of these findings and the impact of early intervention with this population are discussed.",2003.0,0,0
560,12469002,,,,,0,0
561,12469005,Donepezil for the treatment of behavioral symptoms in patients with Alzheimer's disease.,Diana Paleacu; Doron Mazeh; Ilona Mirecki; Michael Even; Yoram Barak,"Behavioral and psychologic symptoms of dementia (BPSD) are common manifestations in mid- and late-stage Alzheimer's disease (AD). Traditional treatments for BPSD are neuroleptics and sedatives, which are not devoid of serious adverse effects. A number of studies show beneficial effects in the treatment of BPSD with acetylcholinesterase inhibitors (AChEI). The present study aimed to evaluate the effect of donepezil (using the generic drug Memorit) as monotherapy for AD patients suffering from BPSD. Twenty-eight consecutive patients followed at the Memory Outpatient Clinic and Psychogeriatric Department of the Abarbanel Mental Health Center were treated with donepezil for 6 months. Starting dose was 5 mg daily during the first 4 weeks and continuation with 10 mg daily thereafter. Treatment effects were evaluated using the Mini Mental State Examination (MMSE), the Neuro-Psychiatric Inventory (NPI), and the Clinical Global Impression of Change Scale (CGIC) caregiver version. Twenty-four of 28 patients completed the study. Of these, five patients needed additional rescue neuroleptic treatment due to incomplete response. The mean dose of donepezil was 9.10 mg/day (median 10 mg/day). The overall NPI improved significantly from 33.4 to 21.2 (p = 0.008). The mean CGIC at study's end was 3.0 (mild improvement). The cognitive scores did not change significantly. When compared to the patients who completed the study, patients who discontinued had higher mean scores on the irritability and agitation subscales of the NPI, they were older, and they had longer disease duration and lower MMSE mean scores. Three adverse events were recorded: one syncope causing a toe phalanx fracture and gastrointestinal complaints that resolved over time in two additional patients. Acetylcholinesterase inhibitors should be considered for the treatment of BPSD before neuroleptic treatment is instituted in AD patients with low levels of irritability and agitation.",2003.0,0,0
562,12472374,Aripiprazole: profile on efficacy and safety.,Paul J Goodnick; Jason M Jerry,"Aripiprazole (Abilitat, Bristol-Myers Squibb) is the most recent addition to the new class of atypical antipsychotic medications, following the release of clozapine, risperidone, olanzapine, quetiapine and ziprasidone. Aripiprazole exhibits typical antagonism at dopamine (D2) receptors in the mesolimbic pathway, as well as having unique partial agonist activity at D2 receptors in the mesocortical pathway. As exemplified by other atypical antipsychotics, it displays strong 5-HT(2a) receptor antagonism and is similar to ziprasidone in also having agonistic activity at the 5-HT(1a) receptor. Among the atypical antipsychotics, aripiprazole displays the lowest affinity for alpha(1)adrenergic (alpha(1)), histamine (H1) and muscarinic (M1) receptors. This combination of effects may be responsible for its efficacy in positive and negative symptoms of schizophrenia and in bipolar disorder. Similarly, this profile may be the reason for the low rates of reported side effects observed. This includes general adverse events, a low incidence of reported weight gain and a low liability for inducing movement disorders. Other early data suggest that aripiprazole may induce reductions in plasma prolactin, as well as in plasma glucose and lipid profiles. Finally, results also support the proposition that aripiprazole may lead to reductions in corrected QT interval and have minimal drug interactions.",2003.0,0,0
563,12476326,"The plasma levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs.",Y-K Kim; I-B Suh; H Kim; C-S Han; C-S Lim; S-H Choi; J Licinio,"Interleukin-12 (IL-12) plays a key role in promoting T helper 1 (Th1) responses and subsequent cell-mediated immunity. Given the role of cytokines in the pathogenesis of psychiatric disorders, the dysregulation of IL-12 in these illnesses would be expected. We measured the plasma levels of IL-12 in 102 psychiatric patients (43 schizophrenia, 34 major depression and 25 bipolar disorder) and 85 normal controls. In addition, IL-12 levels of the patients were measured after an 8-week treatment to assess whether the levels were affected by medication. The IL-12 levels of the patient group with major depression were significantly higher than that of the control group, whereas no differences were found among the other groups. IL-12 values of the three patient groups decreased significantly after 8 weeks of treatment. These findings support the hypothesis that activation of the inflammatory response system and in particular of Th-1-like cells, is involved in the pathophysiology of major depression and that repeated administration of antidepressive and antipsychotic drugs may suppress IL-12 plasma concentrations in psychiatric patients.",2003.0,0,0
564,12479661,Gabapentin augmentation therapy in bipolar depression.,Po W Wang; Claudia Santosa; Matthew Schumacher; Mirene E Winsberg; Connie Strong; Terence A Ketter,"Gabapentin (GBP) may be useful in bipolar disorders, including as adjunctive therapy for bipolar depression, although controlled studies suggest inefficacy as primary treatment for mania or treatment-resistant rapid cycling. We performed a 12-week trial of open GBP (mean dose 1725 mg/day) added to stable doses of mood stabilizers or atypical antipsychotics in 22 (10 women, mean age 38.4 years) depressed (28-item Hamilton Depression Rating Scale (HDRS) > 18] bipolar (10 bipolar I, 12 bipolar II) disorder outpatients. Mean illness duration was 18.6 years, current depressive episode duration was 18.0 weeks. Prospective 28-item HDRS, Young Mania Rating Scale (YMRS) and Clinical Global Impression-Severity (CGI-S) ratings were obtained. Overall, HDRS ratings decreased 53% from 32.5 +/- 7.7 at baseline to 16.5 +/- 12.8 at week 12 (p < 0.0001). Twelve of 22 (55%) patients had moderate to marked improvement (HDRS decrease = 50%) with HDRS decreasing 78% from 27.9 +/- 6.2 to 6.2 +/- 4.5 (p < 0.0001). Eight of 22 (36%) patients remitted (HDRS > or = 8). In non-responders, HDRS decreased from 38.0 +/- 5.4 to 28.9 +/- 6.7 (p = 0.005). Ten of 13 (77%) mild to moderately depressed (baseline HDRS > 18 and <35) patients responded, while only two of nine patients (22%) with severe depression (HDRS > or = 35) responded (p < 0.03). Both groups, however, had similar, statistically significant HDRS decreases. GBP was well tolerated. Open adjunctive GBP was effective and well tolerated in patients with mild to moderate bipolar depression. This open pilot study must be viewed with caution, and randomized controlled studies are warranted.",2003.0,0,0
565,12479666,Olanzapine in diverse syndromal and subsyndromal exacerbations of bipolar disorders.,Suttiporn Janenawasin; Po W Wang; Anna Lembke; Matthew Schumacher; Bibi Das; Claudia M Santosa; Jenny Mongkolcheep; Terence A Ketter,"To evaluate effects of olanzapine in diverse exacerbations of bipolar disorders. Twenty-five evaluable bipolar disorder [14 bipolar I (BPI), 10 bipolar II (BPII) and one bipolar disorder not otherwise specified (BP NOS)] outpatients received open olanzapine (15 adjunctive, 10 monotherapy). Thirteen had elevated (11 syndromal, two subsyndromal) and 12 depressed (four syndromal, eight subsyndromal) mood symptoms of at least mild severity, with Clinical Global Impression-Severity (CGI-S) scores of at least 3. Only one had psychotic symptoms. With open olanzapine (15 adjunctive, 10 monotherapy), overall symptom severity (CGI-S) as well as mood elevation (Young Mania Rating Scale), depression (Hamilton and Montgomery-Asberg Depression Rating Scales), and anxiety (Hamilton Anxiety Rating Scale), rapidly decreased (significantly by days 2-3). Patients with the greatest baseline severity (CGI-S) had the greatest improvement. Fifteen of 25 (60%) patients responded. Time to consistent response was bimodal, with five early (by 0.5 +/- 0.3 weeks) and 10 late (by 7.0 +/- 1.9 weeks) responders. Early compared with late responders had 51% lower final olanzapine doses. Olanzapine was generally well tolerated, with sedation and weight gain the most common adverse effects. Olanzapine was effective in diverse exacerbations of bipolar disorders. The bimodal distribution of time to response and different final doses are consistent with differential mechanisms mediating early compared with late responses. Controlled studies are warranted to further explore these preliminary observations.",2003.0,0,0
566,12479667,Quetiapine in the treatment of rapid cycling bipolar disorder.,Eduard Vieta; Gemma Parramon; Elena Padrell; Evaristo Nieto; Anabel Martinez-Arán; Barbara Corbella; Francesc Colom; Maria Reinares; Jose M Goikolea; Carla Torrent,"This prospective open-label study assessed the impact of add-on quetiapine in the treatment of rapid cycling bipolar patients. Fourteen rapid cycling bipolar patients were treated with quetiapine, which was added to their ongoing medication regimen for 112 +/- 33 days. At the beginning of the study, five were manic, three were in a mixed state, three were depressed, two hypomanic and one was euthymic. Patients were assessed prospectively with a modified version of the Clinical Global Impression Scale for Bipolars (CGI-BP), the Young Scale for mania (YMRS) and the Hamilton Scale for Depression (HDRS). A significant reduction of the following scale scores was observed: a 1.8 point reduction for the general CGI-BP (p = 0.013), a -1.3 point for the mania subscale (p = 0.016), a -1.01 point for the YMRS (p = 0.025). Improvement in depressive symptoms was not significant, neither in the CGI-BP (-1 point, p = 0.074) nor in the HDRS (-5.2 points, p = NS). The most common side-effect was sedation (n = 6, 43%). Doses of quetiapine were significantly reduced by the end of the study (443 +/- 235 mg/day versus 268 +/- 190 mg/day, p = 0.008) and they also differed according to the initial episode to be treated (720 +/- 84 mg/day for mania, and 183 +/- 29 mg/day for depression, p = 0.023). Quetiapine could possibly be an effective treatment for rapid cycling bipolar patients. Adequate doses for acute episodes could significantly differ according to the episode polarity and the length of treatment.",2003.0,0,0
567,12485538,Risperidone improves behavior in children with autism.,Christian Caicedo; Steven H Williams,,2003.0,0,1
568,12490768,Adjunctive risperidone treatment in post-traumatic stress disorder: a preliminary controlled trial of effects on comorbid psychotic symptoms.,M B Hamner; R A Faldowski; H G Ulmer; B C Frueh; M G Huber; G W Arana,"Positive and negative symptoms of psychosis may be common in patients with chronic post-traumatic stress disorder (PTSD), but few studies have investigated the use of antipsychotic agents in these patients. This preliminary study examined the potential efficacy of risperidone in treating psychotic symptoms associated with chronic PTSD. In a 5-week, prospective, randomized, double-blind, placebo-controlled trial, adjunctive risperidone treatment was assessed in 40 combat veterans with chronic PTSD and comorbid psychotic features. Most patients were receiving antidepressants and some other psychotics with doses of concurrent medications held constant for at least 1 month prior to and during the study. Thirty-seven patients completed at least 1 week of treatment with risperidone or placebo. The Positive and Negative Syndrome Scale (PANSS) and the Clinician Administered PTSD Scale (CAPS) were used to assess symptoms. The PANSS was the primary outcome measure. At treatment endpoint, risperidone-treated patients showed a significantly greater decrease from baseline, albeit modest, in psychotic symptoms (PANSS total scores) than placebo-treated patients (P < 0.05). CAPS ratings declined significantly in both groups but did not differ significantly between groups. However, CAPS re-experiencing subscale scores had greater improvement in the risperidone-treated patients at week 5 (P < 0.05, completer analysis) with a trend towards greater improvement versus placebo a endpoint (P < 0.1, LOCF). Risperidone was well tolerated with minimal extrapyramidal symptoms. These preliminary results support studying the potential efficacy of risperidone for treating global psychotic symptoms associated with chronic PTSD with a suggestion that core re-experiencing symptoms may also be responsive. Further research using randomized, controlled trial designs in larger patient groups are needed to define more adequately the role of risperidone and other atypical agents in PTSD.",2003.0,0,0
569,12490774,Extrapyramidal symptom profiles assessed with the Drug-Induced Extrapyramidal Symptom Scale: comparison with Western scales in the clinical double-blind studies of schizophrenic patients treated with either olanzapine or haloperidol.,Toshiya Inada; Charles M Beasley; Yoko Tanaka; Daniel J Walker,"The superiority of olanzapine to haloperidol with respect to a decreased incidence of treatment-emergent extrapyramidal syndromes (EPS) in patients with schizophrenia was demonstrated in studies conducted in both Japan and Western countries. EPS measurements used in Western countries included the Simpson-Angus, Barnes akathisia and the Abnormal Involuntary Movement Scale, while the Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) was used in Japan. The aim of this study was to clarify how the DIEPSS captures EPS profiles. The baseline prevalence and treatment-emergent incidence of EPS in Japanese schizophrenic patients treated with olanzapine or haloperidol were retrospectively compared as assessed by the DIEPSS to the prevalence and incidence of EPS in primarily Caucasian schizophrenic patients who were treated with olanzapine or haloperidol. Specifically, the prevalence and incidence of dyskinesia, akathisia and parkinsonism were compared between the Japanese trial and an international trial to examine if appropriate definitions using the DIEPSS can be derived assuming that a comparable prevalence and incidence of the syndromes would be observed when any differences in residual antipsychotic exposure at the initiation of study treatment were accounted for. For the incidence of all EPS syndromes, odds ratios were observed to be similar between the two studies, indicating that appropriate criteria for the clinical diagnosis of the EPS syndromes could be established based on the DIEPSS. This preliminary and retrospective work suggests that the DIEPSS can be used to operationally define the presence or absence, and make the clinical diagnosis, of specific EPS syndromes.",2003.0,0,1
570,12494247,Moderators of placebo response to antipsychotic treatment in patients with schizophrenia: a meta-regression.,Jeffrey A Welge; Paul E Keck,"Variation in placebo response within and among clinical trials involving patients with schizophrenia can substantially affect conclusions about the efficacy of new antipsychotic medications. Therefore, it is of great importance to identify factors that moderate response to placebo in such trials. The objective of this meta-regression analysis was to estimate the effect of potential moderators of placebo response in randomized, short-term clinical trials involving patients with schizophrenia, schizoaffective disorder or schizophreniform disorder. Mean placebo response and potential moderators were extracted from 35 placebo-controlled, randomized trials of antipsychotic medications in patients with schizophrenia. Placebo response was defined as the absolute change in the Brief Psychiatric Rating Scale total score. Fixed-effects meta-regression was used to investigate between-trial variation in placebo response. Trial duration accounted for a substantial proportion of the between-trial variation in response (27%), with greater improvement on placebo observed in shorter trials. Other variables showed insufficient variation across trials to permit any inferences regarding their relationships with placebo response. Placebo-controlled trials of short duration (<6-8 weeks) are vulnerable to substantial placebo response. Recruiting patients with more severe pathology to mitigate placebo response does not appear to offer benefits and may even be counterproductive. Meta-analyses based on individual patient data offer the potential for much more detailed and inferentially sound exploration of factors affecting placebo response and are highly recommended.",2003.0,0,0
571,12496955,Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia.,Daniel E Casey; David G Daniel; Adel A Wassef; Katherine A Tracy; Patricia Wozniak; Kenneth W Sommerville,"This double-blind, randomized, multicenter study investigated the use of divalproex with an antipsychotic agent in patients hospitalized for acute exacerbation of schizophrenia. Patients (n = 249) who met DSM-IV criteria for schizophrenia were randomly assigned to receive olanzapine monotherapy, risperidone monotherapy, divalproex plus olanzapine, or divalproex plus risperidone for 28 days. Divalproex was initiated at 15 mg/kg/day and titrated over 12 days to a maximum dosage of 30 mg/kg/day. Olanzapine and risperidone, were, respectively, initiated at 5 and 2 mg/day and were titrated over the first 6 days to respective target fixed daily dosages of 15 and 6 mg/day. Improvements from baseline were observed at all evaluation points throughout the 28-day treatment period in the two combination therapy and the two antipsychotic monotherapy groups, with statistically significant treatment differences favoring combination therapy as soon as day 3 for Positive and Negative Syndrome Scale (PANSS) total score, derived Brief Psychiatric Rating Scale (BPRSd) total score, as well as PANSS and BPRSd subscales. These findings were confirmed in post hoc repeated-measures analyses of variance in which treatment differences favoring combination therapy were observed for PANSS total (p = 0.020) and PANSS positive scale scores (p = 0.002). Both combination therapy and antipsychotic monotherapy were well tolerated. Treatment with divalproex in combination with an atypical antipsychotic agent resulted in earlier improvements in a range of psychotic symptoms among acutely hospitalized patients with schizophrenia. Further evaluation is warranted to confirm these findings.",2003.0,0,0
572,12503835,The potential cardiotoxicity of antipsychotic drugs as assessed by heart rate variability.,B Silke; C Campbell; D J King,"Most antipsychotic drugs have cardiac effects as a consequence of their pharmacological actions. Recently, thioridazine has been subjected to a restricted indications notice and sertindole had its license withdrawn because of concerns about their potential cardiotoxicity. In the development of new atypical agents, heart-rate corrected QT effects are evaluated but it is unclear how predictive these are of clinically significant cardiotoxicity or sudden death. Heart rate variability (HRV) is a potential index of cardiotoxicity which has been found to be decreased following antidepressants and clozapine. We studied acute HRV changes following antipsychotic agents. Sixteen healthy male volunteers received risperidone (4 mg), olanzapine (10 mg), thioridazine (50 mg) or placebo in a randomized cross-over design. Subjective effects and psychomotor function were assayed at 2 h and both linear (summary statistics) and non-linear (scatterplot) measures of HRV were evaluated by continuous electrocardiogram recording over 10 h. Differential effects of single doses of the three antipsychotic drugs on HRV were found, and these were independent of their sedative effects. Olanzapine increased, and thioridazine decreased HRV, while risperidone had no effect. HRV is sensitive to the acute effects of antipsychotics. It may prove to be a reliable index of their potential for cardiotoxicity. Further studies in both healthy volunteers and patients on antipsychotic medication will be valuable.",2003.0,0,0
573,12503837,Efficacy of olanzapine in social anxiety disorder: a pilot study.,Stewart D Barnett; Michelle L Kramer; Charles D Casat; Kathryn M Connor; Jonathan R T Davidson,"Based on evidence suggesting anxiolytic properties of the atypical antipsychotic olanzapine, this study was conducted to evaluate whether olanzapine may be efficacious in treating social anxiety disorder (SAD). This study was an 8-week, double-blind, placebo-controlled evaluation of olanzapine as monotherapy in which 12 patients with the DSM-IV diagnosis of SAD were randomized to either olanzapine (n = 7) or placebo (n = 5). An initial dose of 5 mg/day was titrated to a maximum of 20 mg/day. Baseline to endpoint scores from the Brief Social Phobia Scale (BSPS), Social Phobia Inventory (SPIN), Liebowitz Social Anxiety Scale and Sheehan Disability Scale, as well as Clinical Global Impression-Improvement ratings, were compared for olanzapine versus placebo. Seven subjects completed all 8 weeks of the study, four in the olanzapine group and three in the placebo group. In the intent-to-treat analysis, olanzapine yielded greater improvement than placebo on the primary measures: BSPS (p = 0.02) and SPIN (p = 0.01). Both treatments were well tolerated, although the olanzapine group had more drowsiness and dry mouth. Olanzapine and placebo were both associated with negligible weight gain. Olanzapine was superior to placebo on the primary outcome measures in this preliminary study of SAD. Additional studies of olanzapine as a treatment for SAD are warranted.",2003.0,0,0
574,12504069,Efficacy of newer generation antipsychotics in the treatment of schizophrenia.,R Tandon; M D Jibson,"The advent of the newer 'atypical' antipsychotic medications has revolutionized the pharmacologic treatment of schizophrenia and other psychotic disorders. In contrast to the older conventional antipsychotic agents, atypical medications have a broader spectrum of efficacy (greater efficacy in negative, cognitive, and mood symptoms) and a lower risk of extrapyramidal symptoms (EPS) and tardive dyskinesia. Due to concerns surrounding hematological safety and other adverse effects, clozapine is used principally in patients refractory to treatment with other antipsychotic agents. The other three universally available atypical agents (risperidone, olanzapine, and quetiapine) collectively constitute about 70% of all antipsychotic prescriptions in the USA. Despite the broad popularity of these medications and their rapid adoption in general clinical practice, there are limited data on how they compare to each other with regards to their overall efficacy and also as to their efficacy in specific symptom domains. To address this question, two separate analyses were undertaken. First, all published, short-term, randomized, controlled clinical trials of these agents in schizophrenia and schizoaffective disorder were reviewed and the extent of improvement across these agents was compared. While the amount of improvement with a particular agent across its different studies varied, the average improvement was similar for the agents for all efficacy parameters considered. Secondly, all randomized, controlled clinical trials directly comparing two or more of these agents in patients with schizophrenia or schizoaffective disorder were analyzed. Only three such trials (all industry sponsored) were identified; while there were differences in methodology and small differences in efficacy on a minority of measures on which comparisons were undertaken, the preponderance of data suggested no differences in efficacy. While data thus far do not support assertions of differential efficacy between risperidone, olanzapine, and quetiapine, there are clear differences in their side-effect profiles and these are briefly summarized.",2003.0,0,0
575,12505103,Quetiapine is not associated with increase in prolactin secretion in contrast to haloperidol.,Murad Atmaca; Murat Kuloglu; Ertan Tezcan; Halit Canatan; Omer Gecici,"Typical antipsychotic drugs frequently cause hyperprolactinemia and even galactorrhea. In addition, these side effects may result in noncompliance with antipsychotic treatment. Capacity to avoid hyperprolactinemia has been accepted as one atypical criterion. The aim of the present study was to compare effects of haloperidol, the most commonly used antipsychotic, and quetiapine, a novel antipsychotic agent used in Turkey, on serum prolactin (PRL) levels. The study consisted of 35 females diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, 4(th) ed. (DSM-IV). Thirty-five patients in a drug-free period for at least 2 weeks were included to randomized quetiapine (n = 18) and haloperidol (n = 17) treatment group. All patients were assessed by Brief psychiatric rating scale (BPRS), Positive and negative syndrome scale (PANSS), and Extrapyramidal symptoms rating scale (ESRS). PRL levels were measured both at the beginning and at the sixth week of the study. Both treatment groups exhibited significant improvements in clinical signs as evaluated by BPRS and PANSS. While there was no significant difference in PRL level between groups at the beginning of the study, control prolactin (PRL) levels were significantly lower in quetiapine compared to haloperidol group. While no quetiapine group patients exhibited galactorrhea, we observed that two patients from the haloperidol group had galactorrhea related to hyperprolactinemia. The present study revealed that quetiapine is not associated with increase in PRL secretion in contrast to the conventional antipsychotic haloperidol.",2003.0,1,1
576,12505105,A cost-effectiveness clinical decision analysis model for treatment of Schizophrenia.,Cynthia S Palmer; Elizabeth Brunner; Luis Guillermo Ruíz-Flores; Francisco Paez-Agraz; Dennis A Revicki,"Schizophrenia afflicts approximately 0.7% of Mexican citizens during their lifetime. This study explored whether the difference in clinical efficacy and safety between atypical antipsychotics and conventional neuroleptics results in decreases in use and cost of medical services in Mexico, offsetting the higher price of atypical antipsychotics. A U.S. decision analytic Markov model was adapted for use in Mexico to determine cost-effectiveness of treatments and outcomes that Mexican patients with schizophrenia may experience over a 5-year period when treated with olanzapine, haloperidol, or risperidone. Model parameter estimates were based on clinical trial data, published medical literature, and where needed, clinician judgment. Direct medical costs were incorporated into the model and outcomes were estimated using lack of relapse and clinical outcomes based on the Brief Psychiatric Rating Scale (BPRS) as effectiveness indicators. All costs are reported in Mexican pesos. Over a 5-year period, the cost of treating schizophrenia ranged from 196,620 pesos per patient initiating therapy with haloperidol to 226,670 pesos per patient beginning therapy with risperidone. Olanzapine was estimated to have slightly better non-relapse and BPRS-based effectiveness outcomes, but comparative total medical costs compared to risperidone. Patients receiving olanzapine experienced 13 and 2% fewer relapses compared with patients on haloperidol and risperidone, respectively. The 5-year incremental cost-effectiveness ratio of olanzapine compared with haloperidol was 52,740 pesos per improved patient, BPRS-based outcome and 212,540 pesos per avoided relapse. Sensitivity analyses indicated the model was sensitive only to changes in drug costs. Compared with haloperidol, olanzapine therapy results in improved symptoms, fewer relapses, and is cost-effective, even with conservative values for key model parameters. Olanzapine results in slightly improved patient outcomes and comparable costs compared with risperidone.",2003.0,0,0
577,12507740,Duration and stability of the rapid-cycling course: a long-term personal follow-up of 109 patients.,A Koukopoulos; G Sani; A E Koukopoulos; G P Minnai; P Girardi; L Pani; M J Albert; D Reginaldi,"Recognition by the DSM-IV of rapid cyclicity as a course specifier has raised the question of the stability and long-term outcome of rapid-cycling (RC) patients. Data on this topic is sparse and often inconsistent. To our knowledge, these are the first personally followed patients over the long term, dealing directly with the issue of the duration of the RC course. We examined the evolution of the course of 109 RC patients (68 women and 41 men) followed for a minimum of 2 years and up to 36 years, beginning with the index episode when the RC course was diagnosed by the authors (A.K., G.P.M., P.G., L.P., D.R.). Patients were included in the study if they met criteria for RC as defined by>or=4 affective episodes per year (Dunner and Fieve, 1974). The follow-up period varied from 2-5 years for 25 patients, 6-10 years for 24 patients, 11-15 years for 24 patients, 16-20 years for 19 patients, 21-25 years for 13 patients, 30-36 years for four patients. In 13 patients (12%), RC emerged spontaneously and in 96 patients (88%), it was associated with antidepressant and other treatments. In 19 women (28% of all women) RC course started in perimenopausal age (45-54 years). The mean duration of RC during the follow-up period was 7.86 years (range 1-32) and its total duration (including RC course prior to the follow-up period) was 11 years (range 1-40). The total duration of the affective disorder, from the first episode to the end of the follow-up, was 21.78 years (range 1-70). At the end of the follow-up, 36 patients (33%) had complete remission for at least the past year, 44 (40%) stayed rapid cycling with severe episodes (six of this group committed suicide), while 15 (14%) were rapid cycling but with attenuated episodes. The other 14 patients (13%) became long cyclers, eight with severe episodes and six with milder ones. The main distinguishing features between those who remitted from and those who persisted in the RC course were: (1). the initial cycle pattern: patients with Depression-Hypomania(mania)-Free interval cycles (53 patients) had a worse outcome: 26.4% remitted and 52.8% persisted in the RC course through to the end of the follow up period. The Mania/Hypomania-Depression-Free interval cycles (22 patients) had a significantly better outcome, with 50% remitted and 27.2% persisting RC; and (2). the occurrence of the switch process from depression to hypomania/mania and the occurrence of agitated depressions made the prognosis worse. Continuous treatment was more effective against mania/hypomania than against depression, yet in all persisting RC cases the mania/hypomania remitted only partially. These data derive from clinics known for their expertise in mood disorders, and they may have attracted and retained patients with a more severe course. Treatment was uncontrolled and consisted more of lithium than divalproex, lamotrigene and olanzapine, recently shown to be beneficial in subgroups of patients with rapid-cycling. Our findings suggest that rapid cyclicity, spontaneous or induced, once established, becomes for many years a stable rhythm in a substantial proportion of patients, linked to endogenous and environmental factors. The suggestion is made to consider as rapid-cyclers, at least for research purposes, those patients who have had a rapid cycling course for at least 2 years, borrowing the duration criterion currently employed for other chronic disorders such as Dysthymia and Cyclothymia. That our patients had poorer prognosis than some other cohorts in the literature is probably due to the shorter duration of ""rapid-cycling"" at entry in the latter cohorts. A true understanding of the nature of rapid-cycling will require a rigorous definition of not only duration, but also pole-switching and course patterns at entry into study.",2003.0,0,0
578,12507747,Placebo-controlled trials do not find association of olanzapine with exacerbation of bipolar mania.,Robert W Baker; Denái R Milton; Virginia L Stauffer; Alan Gelenberg; Mauricio Tohen,"Published case reports describe apparent induction or exacerbation of manic-like symptoms during treatment with the atypical antipsychotics olanzapine and risperidone. To date, such reports are from uncontrolled clinical experience and therefore cannot clarify whether the atypical antipsychotics caused such manic-like states or simply failed to prevent them. Presumably, bipolar patients would be at increased risk for this putative adverse event. Therefore, we evaluated the potential of olanzapine to exacerbate symptoms of mania compared to placebo during treatment of bipolar mania. Two inpatient, double-blind, randomized trials investigating the efficacy of olanzapine 5-20 mg daily versus placebo for the treatment of acute mania were combined. Two hundred and fifty-four subjects participated (placebo n=129; olanzapine n=125) in the two studies. Severity of mania was quantified with the 11-item Young-Mania Rating Scale (Y-MRS). In a post-hoc analysis, after double-blind therapy up to 3 weeks, categorical comparison of olanzapine and placebo groups was made for any worsening and worsening by 10 or 20% from baseline Y-MRS scores (LOCF). The percentage of subjects with exacerbation at endpoint were: any worsening, placebo 37.7%, olanzapine 21.8% (P=0.005); >or=10% worsening, placebo 24.6%, olanzapine 14.5% (P=0.039); >or=20% worsening, placebo 15.6%, olanzapine 8.1% (P=0.064). Mania rating scores worsened for some patients during olanzapine therapy. However, this was significantly less common with olanzapine than with placebo. These controlled data suggest that clinical case reports of occurrence of 'mania' during treatment with olanzapine, and possibly those with other atypical antipsychotics, reflect exacerbation in the natural history of bipolar illness, rather than an adverse pharmacological effect. Post-hoc analysis of pooled data from two different studies.",2003.0,0,0
579,12507748,Olanzapine in the acute treatment of bipolar I disorder with a history of rapid cycling.,Todd M Sanger; Mauricio Tohen; Eduard Vieta; David L Dunner; Charles L Bowden; Joseph R Calabrese; Peter D Feldman; Thomas G Jacobs; Alan Breier,"A substantial proportion of patients with bipolar disorder are characterized by a rapidly cycling course and are particularly resistant to conventional treatment. This secondary analysis, defined a priori, was conducted on a larger data set from patients with bipolar I disorder to determine the efficacy of a 3-week treatment with the atypical antipsychotic olanzapine (5-20 mg/day, n=19) versus placebo (n=26) in patients with >or=4 episodes in the preceding year. Significantly fewer placebo patients completed treatment (34.6 vs. 73.7%, P=0.016), and more than half discontinued due to lack of efficacy (53.8 vs. 21.1%, P=0.035). Olanzapine reduced Young Mania Rating Scale (YMRS) total scores significantly more than placebo (-13.9 vs. -4.1, P=0.011). Clinical responses, defined as >or=50% improvement in YMRS, were achieved in 58% of olanzapine patients, compared with 28% of placebo patients (P=0.066). Extrapyramidal symptoms were not significantly changed in either group. Somnolence was the most common adverse event in both groups (olanzapine: 52.6%, placebo: 23.1%; P=0.060). No event occurred significantly more frequently with olanzapine than with placebo. No patients discontinued due to an adverse event. The duration of this study was limited to 3 weeks, precluding conclusions about long-term efficacy of olanzapine. Moreover, a sizeable placebo effect was obtained, possibly masking optimal therapeutic effect. Despite these limitations, treatment differences in efficacy were highly significant. These results indicate that olanzapine was effective in reducing symptoms of mania and well tolerated in patients with bipolar I disorder with a rapid-cycling course.",2003.0,1,1
580,12507749,,,,,0,0
581,12508833,Neuroreceptor imaging in psychiatric disorders.,W Gordon Frankle; Marc Laruelle,"Molecular imaging, the study of receptors, transporters and enzymes, as well as other cellular processes, has grown in recent years to be one of the most active neuroimaging areas. The application of single photon emission tomography (SPECT) and positron emission tomography (PET) techniques to the study of psychiatric illness has lead to increased understanding of disease processes as well as validated, in vivo, theories of illness etiology. Within the field of psychiatry these techniques have been applied most widely to the study of schizophrenia. Studies within schizophrenia are largely limited to either the dopamine or serotonin system. This is due in large part to the availability of suitable radiotracers as well as the current theories on the etiology of the illness. Two basic study designs are used when studying schizophrenia using molecular imaging and make up the majority of studies reviewed in this manuscript. The first type, termed ""clinical studies,"" compares the findings from PET and SPECT studies in those with schizophrenia to normal controls in an attempt to understand the pathophysiology of the illness. The second study design, termed ""occupancy studies,"" uses these techniques to enhance the understanding of the mechanism of action of the medications used in treating this illness. This review will focus on the findings of molecular imaging studies in schizophrenia, focusing, for the most part, on the serotonin and dopamine systems. Emphasis will be placed on how these findings and techniques are currently being used to inform the development of novel treatments for schizophrenia.",2003.0,0,0
582,12511175,Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT).,Herbert Y Meltzer; Larry Alphs; Alan I Green; A Carlo Altamura; Ravi Anand; Alberto Bertoldi; Marc Bourgeois; Guy Chouinard; M Zahur Islam; John Kane; Ranga Krishnan; J P Lindenmayer; Steven Potkin; International Suicide Prevention Trial Study Group,"Approximately 50% of patients with schizophrenia or schizoaffective disorder attempt suicide, and approximately 10% die of suicide. Study results suggest that clozapine therapy significantly reduces suicidal behavior in these patients. A multicenter, randomized, international, 2-year study comparing the risk for suicidal behavior in patients treated with clozapine vs olanzapine was conducted in 980 patients with schizophrenia or schizoaffective disorder, 26.8% of whom were refractory to previous treatment, who were considered at high risk for suicide because of previous suicide attempts or current suicidal ideation. To equalize clinical contact across treatments, all patients were seen weekly for 6 months and then biweekly for 18 months. Subsequent to randomization, unmasked clinicians at each site could make any interventions necessary to prevent the occurrence of suicide attempts. Suicidal behavior was assessed at each visit. Primary end points included suicide attempts (including those that led to death), hospitalizations to prevent suicide, and a rating of ""much worsening of suicidality"" from baseline. Masked raters, including an independent suicide monitoring board, determined when end point criteria were achieved. Suicidal behavior was significantly less in patients treated with clozapine vs olanzapine (hazard ratio, 0.76; 95% confidence interval, 0.58-0.97; P =.03). Fewer clozapine-treated patients attempted suicide (34 vs 55; P =.03), required hospitalizations (82 vs 107; P =.05) or rescue interventions (118 vs 155; P =.01) to prevent suicide, or required concomitant treatment with antidepressants (221 vs 258; P =.01) or anxiolytics or soporifics (301 vs 331; P =.03). Overall, few of these high-risk patients died of suicide during the study (5 clozapine vs 3 olanzapine-treated patients; P =.73). Clozapine therapy demonstrated superiority to olanzapine therapy in preventing suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide. Use of clozapine in this population should lead to a significant reduction in suicidal behavior.",2003.0,1,1
583,12518273,Prescribing second-generation antipsychotics and the evolving standard of care in Italy.,C Barbui; A Danese; G Guaiana; L Mapelli; L Miele; E Monzani; M Percudani; Study Group,"The present study was carried out to investigate the routine use of second-generation antipsychotic drugs in the Italian psychiatric care system. Seven outpatient psychiatric services enrolled a consecutive case series of patients who were being treated, or had started treatment, with clozapine, olanzapine, risperidone, or quetiapine. Information on sociodemographic and clinical variables, current psychotropic drug use, side-effects and past use of typical drugs was collected. In addition, patient symptoms and functional status were evaluated by the Health of the Nation Outcome Scale. Patients receiving off-label prescribing of second-generation antipsychotics were identified. A total of 209 patients were collected. In comparison with patients receiving other second-generation antipsychotics, living in residential facilities, unemployment, long psychiatric histories, and problems with activities of daily living and living conditions were more common in clozapine-treated patients. Nearly 80 % of patients receiving clozapine had schizophrenia compared to less than 50 % of those receiving other second-generation antipsychotics. Overall, 109 patients (52 %) received off-label prescriptions of second-generation antipsychotic drugs. This survey indicates that clozapine was mostly reserved for severe cases and poor responders; the high rate of off-label prescriptions highlights the gap existing between recommendations derived from randomised clinical trials and the current use of drugs.",2003.0,0,0
584,12519101,Quetiapine in bipolar disorder and cocaine dependence.,E Sherwood Brown; Vicki A Nejtek; Dana C Perantie; Leonardo Bobadilla,"Bipolar disorder is associated with the highest rates of substance abuse of any psychiatric illness. Therefore, treatments that stabilize mood and decrease drug use or cravings are of great interest. Atypical antipsychotics are in widespread use in patients with bipolar disorder. However, minimal data are available on their use in bipolar patients with comorbid substance abuse. Open-label, add-on, quetiapine therapy was examined for 12 weeks in 17 outpatients with bipolar disorder and cocaine dependence. Subjects were evaluated with a structured clinical interview; Hamilton Depression Rating (HDRS), Young Mania Rating (YMRS), Brief Psychiatric Rating (BPRS) scales; and Cocaine Craving Questionnaire (CCQ). Urine samples and self-reported drug use were also obtained. Data were analyzed using a last observation carried forward method on all subjects given medication at baseline. Significant improvement from baseline to exit was observed in HDRS, YMRS, BPRS and CCQ scores (p < or = 0.05). Dollars spent on cocaine and days/week of cocaine use decreased non-significantly, and urine drug screens did not change significantly from baseline to exit. Quetiapine was well tolerated, with no subjects to our knowledge discontinuing because of side-effects. The use of quetiapine was associated with substantial improvement in psychiatric symptoms and cocaine cravings. The findings are promising and suggest larger controlled trials of quetiapine are needed in this population.",2003.0,0,0
585,12523873,The risk of diabetes during olanzapine use compared with risperidone use: a retrospective database analysis.,J Jaime Caro; Alexandra Ward; Carey Levinton; Kimberly Robinson,"The relative risk of diabetes among patients undergoing risperidone treatment was compared with that of patients receiving olanzapine. A cohort was formed of 33,946 patients with at least 1 prescription for either olanzapine (N = 19,153) or risperidone (N = 14,793) between January 1, 1997, and December 31, 1999, recorded in the Régie de l'Assurance Maladie du Québec database. Patients were excluded if clozapine was dispensed to them during the study period or if they were diagnosed with diabetes before beginning antipsychotic therapy. New diabetes diagnoses made after the first antipsychotic prescription during the period were tabulated until December 31, 1999; censoring occurred at this date or at the last service date, if there was no record of using services during the last 6 months of follow-up. Crude hazard ratio and proportional hazard analyses were carried out. 319 patients developed diabetes on olanzapine treatment, and 217 developed diabetes on risperidone treatment; a crude hazard ratio of 1.08 (95% CI = 0.89 to 1.31, p =.43) was determined. When age, gender, and haloperidol use were controlled for using proportional hazard analysis, there was a 20% increased risk of diabetes with olanzapine relative to risperidone (95% CI = 0% to 43%, p =.05). Proportional hazard analyses adjusted for duration of olanzapine exposure indicated that the first 3 months of olanzapine treatment was associated with an increased risk of diabetes of 90% (95% CI = 40% to 157%, p <.0001), after adjusting for age, gender, and haloperidol use. Compared with risperidone, olanzapine was associated with an increased risk of developing diabetes. More studies are required to further investigate this association.",2003.0,1,1
586,12523875,"A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder.",John M Zajecka; Richard Weisler; Gary Sachs; Alan C Swann; Patricia Wozniak; Kenneth W Sommerville,"This study compared the efficacy, safety, and tolerability of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder. This randomized, 12-week, double-blind, parallel-group, multicenter study included DSM-IV-defined bipolar disorder type I patients hospitalized for acute mania and randomly assigned to treatment with divalproex or olanzapine. After an inpatient period of up to 21 days, subjects were followed as outpatients. Dose adjustment was permitted during the inpatient period. Efficacy was assessed using change from baseline in Mania Rating Scale (MRS) score to day 21; other efficacy measures included the Brief Psychiatric Rating Scale, the Hamilton Rating Scale for Depression, and the Clinical Global Impressions-Part I, Severity of Illness scale. The primary safety endpoint was change from baseline in weight. Other safety and tolerability endpoints included spontaneous adverse event reporting and changes from baseline in laboratory measures and vital signs. 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomly assigned to treatment. No significant differences between groups were found for any efficacy variable for change from baseline to day 21. Mean MRS score changes from baseline to day 21 were -14.8 for divalproex and -17.2 for olanzapine (p =.210). A significantly (p <.05) greater proportion of olanzapine-treated subjects experienced somnolence, weight gain, edema, rhinitis, and speech disorder (slurred speech); no adverse events were significantly greater in the divalproex group. A number of laboratory measures also demonstrated significant treatment differences, but the clinical significance of many of these is uncertain. Mean body weight changes were significantly greater in the olanzapine group (+ 8.8 lb [+ 4.0 kg]) than the divalproex group (+ 5.5 lb [+ 2.5 kg], p <.050). One death occurred during the study (olanzapine group, diabetic ketoacidosis). No significant difference in efficacy was found between treatment groups. Divalproex was associated with a more favorable adverse event profile and significantly less weight gain than olanzapine.",2003.0,1,1
587,12523876,Efficacy of quetiapine and risperidone against depressive symptoms in outpatients with psychosis.,Martha Sajatovic; Jamie A Mullen; Dennis E Sweitzer,"The treatment of psychotic symptoms in patients with mood disorders is a complex challenge. Antipsychotic medications in these individuals may be associated with extrapyramidal symptoms (EPS), worsening of depression, and functional impairment. Atypical antipsychotics such as quetiapine and risperidone are associated with a decreased incidence of adverse events such as EPS. The objective of this study was to compare the efficacy and tolerability of quetiapine and risperidone for the treatment of depressive symptoms in outpatients with psychosis. In this 4-month, multicenter, open-label trial, patients were randomly assigned in a 3:1 ratio of quetiapine to risperidone, and both drugs were flexibly dosed. Eligible patients had psychoses and demonstrated 1 of several DSM-IV diagnoses, including schizoaffective disorder, bipolar I disorder, major depressive disorder, delusional disorder, Alzheimer's dementia, schizophreniform disorder, vascular dementia, and substance abuse dementia. Patients were classified as mood disordered if they had bipolar disorder, major depressive disorder, or schizoaffective disorder. Efficacy was assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impressions scale. The Hamilton Rating Scale for Depression (HAM-D) was used to assess the level of depressive symptoms. The primary tolerability assessment was presence or absence of substantial EPS, defined as EPS severe enough to require an alteration in treatment. A total of 554 patients were randomly assigned to quetiapine and 175 to risperidone. Mean doses at 16 weeks were 318 mg for quetiapine and 4.4 mg for risperidone. Although both agents produced improvements in mean HAM-D scores, quetiapine produced a greater improvement than risperidone in all patients (p =.0015). Within the mood-diagnosed population, incidences of both substantial EPS (p =.001) and at least moderate EPS (p =.0373) occurred significantly less frequently among patients taking quetiapine. For patients with non-mood diagnoses, incidences of substantial EPS were fewer for patients taking quetiapine than for those taking risperidone (p =.062); however, this was not statistically significant. These results suggest that quetiapine may be a useful agent in the management of depressive symptoms in patients with psychosis.",2003.0,1,1
588,12523877,An open study of olanzapine and fluoxetine for psychotic major depressive disorder: interim analyses.,John D Matthews; Kathryn A Bottonari; Laura M Polania; David Mischoulon; Christina M Dording; Robert Irvin; Maurizio Fava,"Although atypical antipsychotic agents are commonly used in the treatment of psychotic depression, there are no published prospective studies on their use in this condition. The aim of this study was to assess, by interim analyses, the efficacy of the atypical antipsychotic agent olanzapine in combination with the selective serotonin reuptake inhibitor antidepressant agent fluoxetine. We enrolled 27 patients (17 women [63.0%] and 10 men [37.0%]; mean +/- SD age: 41.2 +/- 14.7 years) with DSM-IV-defined major depressive disorder with psychotic features into an open trial of olanzapine, 5 to 20 mg/day, plus fluoxetine, 20 to 80 mg/day. Patients were assessed at each visit with the 17-item Hamilton Rating Scale for Depression and both the psychotic and mood modules of the Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition. We are reporting the results of the first 6 weeks of treatment. Twenty-two (81.5%) of the 27 enrolled patients completed the 6-week open trial, and 5 (18.5%) dropped out, with only 2 (7.4%) dropping out due to side effects. Of the 27 patients, 74.1% (N = 20) met criteria for melancholic features, 14.8% (N = 4) had delusions alone, 18.5% (N = 5) had hallucinations alone, and 66.7% (N = 18) reported both delusions and hallucinations. In addition, the overall rates of response for the intent-to-treat group were as follows: depression response rate, 66.7% (N = 18); psychosis response rate, 59.3% (N = 16); psychotic depression response rate, 55.6% (N = 15); and psychotic depression remission rate, 40.7% (N = 11). The combination of olanzapine and fluoxetine appears to be a promising, safe, and effective treatment for psychotic depression. Double-blind studies are needed to confirm this impression.",2003.0,0,0
589,12530340,Risperidone in the treatment of Hispanic inpatients with schizophrenia: a pilot study.,Edyta J Frackiewicz; John M Herrera; John J Sramek; Yasmine Collazo; William B Lawson,"A growing body of scientific evidence over the last two decades suggests that certain ethnic groups may require lower dosages of standard antipsychotics for the treatment of schizophrenia symptoms. Recent studies have implicated the role of genetic and environmental factors in the metabolism of these drugs as the basis for this differential response. In this pilot study, 10 Hispanic and 8 non-Hispanic patients with schizophrenia were enrolled in a double-blind, parallel-group, inpatient risperidone dosing (daily versus twice daily) trial with the novel antipsychotic risperidone. The result of repeated measures ANOVA reveals a significant interaction effect for race, indicative of a faster rate of symptom improvement (PANSS General) in Hispanic patients. The findings suggest that this novel agent may be preferable for certain ethnic groups. A trend toward more frequently occurring extrapyramidal symptoms among Hispanics was also found, which suggests that dosages lower than those typically recommended may be necessary in Hispanic schizophrenics.",2003.0,0,1
590,12530415,Olanzapine treatment for patients with schizophrenia and cocaine abuse.,John Tsuang; Stephen R Marder; Amanda Han; Winnie Hsieh,,2003.0,0,0
591,12532717,[Schizoaffective disorder: clinical symptoms and present-day approach to treatment].,Vita Danileviciūte,"During 20th century serious mental disorders were divided into two groups according symptomatology and course of disorder. Individuals with dominating disturbance of perception, thinking and cognition were basically diagnosed having schizophrenic. Individuals with mood disturbance were basically diagnosed having affective disorders. However, there were patients who did not fit neatly into either category. In 1933 Jocob Kasanin introduced the term ""schizoaffective psychosis"". Scientific discussions involved the possibility that schizoaffective disorder was conceptualized most accurately as following: a type of schizophrenia, a type of affective disorder, a unique disorder that was separate from both schizophrenia and bipolar disorder, an arbitrary categorization of clinical symptoms that marked a continuum between schizophrenia and affective illness, a heterogeneous collection of ""interforms"" between schizophrenia and affective disorders. However, diagnosis of schizoaffective disorder is included both in DSM-IV-TR and ICD-10. Schizoaffective disorder is listed in the category ""schizophrenia and other psychotic disorders"". The differential diagnosis includes basically either schizophrenia or affective disorder. The epidemiological status of schizoaffective disorder is somewhat uncertain compared with schizophrenia because of dilemmas related to diagnosis and classification of the disorder. Treatment of schizoaffective disorder comprises psychotropic medication, supportive psychotherapy, social care, rehabilitation. The most important groups of psychotropic medications are: antipsychotics, antidepressants and mood stabilizers. Atypical antipsychotics are the first-line medication for schizoaffective disorder due to their pharmacological properties. In the case of schizoaffective disorders combination of atypical antipsychotics with antidepressants seems to be useful. Novel antidepressants have priority for the combination mentioned above. Peculiarities of mechanism of action of antidepressant are important for combinations. Mood stabilizers seem to be useful for treatment of certain type of schizoaffective disorder as well.",2003.0,0,0
592,12543269,Cognition enhancing or neuroprotective compounds for the treatment of cognitive disorders: why? when? which?,Brian P Lockhart; Pierre J Lestage,"Neurodegenerative disorders such as Alzheimer's disease, Lewy-Body dementia, Parkinson's disease and cerebrovascular dementia result in an insidious cognitive and behavioural decline culminating in the development of severe dementia. Based on current population projections it has been estimated that by 2050 the number of individuals over 65 will increase to 1.1 billion worldwide and as a consequence, the number of cases of dementia to 37 million. Faced with such an enormous public health and socio-economic burden it is evident that the importance of therapeutic intervention aimed at either finding a cure or preventing disease progression cannot be overstated. The aim of the present paper is to present an overview, in the context of a brain aging continuum, at what stage cognition enhancing and/or neuroprotective intervention strategies aimed at stabilising and/or preventing neurodegenerative disease could demonstrate potential clinical benefit. In particular, the clinical identification of patients with mild cognitive impairment and age-associated memory impairment which may represent a 'transition' state between normal aging and dementia is discussed as a potential clinical population cohort targeted for early intervention in dementia. Considering the wide spectrum of cognitive and psychotic effects in dementia juxtaposed with the neuropathological evolution of the disease, it is clear that a variety of therapeutic intervention(s) will be required in order, to at the least, stabilise disease progression. Evidently, since Alzheimer's disease is by far the most prevalent form of dementia, and will undoubtedly serve as the benchmark for any future treatment of dementia, an update of current symptomatic and disease-modifying therapeutic approaches (cholinergic, glutamatergic, nootropics, beta-amyloid cascade inhibitors) will be reviewed.",2003.0,0,0
593,12544370,Quetiapine treatment in patients with posttraumatic stress disorder: an open trial of adjunctive therapy.,Mark B Hamner; Sarah E Deitsch; Peter S Brodrick; Helen G Ulmer; Jeffrey P Lorberbaum,"In this 6-week, open-label trial, combat veterans meeting DSM-IV criteria for posttraumatic stress disorder (PTSD) were treated with the atypical antipsychotic quetiapine. The starting dose was 25 mg at bedtime with subsequent titration based on tolerability and clinical response. Primary outcome was measured using the Clinician Administered PTSD Scale (CAPS). Secondary assessments of efficacy included the Positive and Negative Symptom Scale (PANSS), the Hamilton Rating Scale for Depression, and the Clinical Global Impression Scale. Safety and tolerability evaluations included neurologic ratings, vital signs, and assessment of treatment-emergent side effects. Eighteen of 20 patients enrolled in the study completed 6 weeks of open-label treatment. The dose range of quetiapine was 25 to 300 mg daily, with an average of 100+/-70 mg/d. There was significant improvement in CAPS scores, from 89.8+/-15.7 to 67.5+/-21.0 (t=4.863, df=18, <0.005), and composite PANSS ratings from baseline to endpoint. General psychopathology (PANSS) and depressive symptoms (HRSD) were also reduced at the 6-week end point. There were no serious adverse events and no clinically significant changes in vital signs or neurologic ratings. This preliminary open trial suggests that quetiapine is well tolerated and may have efficacy in reducing PTSD symptoms in patients who have not had an adequate response other medications. Studies utilizing a randomized, controlled trial design and larger sample sizes are needed to better define the potential role of quetiapine and other atypical antipsychotics in the treatment of PTSD.",2003.0,0,0
594,12544372,A prospective trial of bupropion SR augmentation of partial and non-responders to serotonergic antidepressants.,Charles DeBattista; H Brent Solvason; Jennifer Poirier; Ellen Kendrick; Alan F Schatzberg,"Many patients fail to achieve an adequate response to a given antidepressant trial. The best-studied augmentation agents, lithium and thyroid supplementation are less commonly used. Augmenting antidepressants with bupropion has become an increasingly common strategy in the treatment of resistant depression. Several case reports and 2 open label studies suggest efficacy of this strategy. The purpose of this study is to further examine the utility of bupropion sustained release (SR) augmentation in patients with inadequate response to selective serotonin reuptake inhibitors. Patients who met DSM-IV criteria for major depression and had failed to achieve adequate response to an SSRI were considered for this study. Eligible patients were required to have a score of 16 on the 24-item Hamilton Depression Rating Scale (HDRS). Patients were treated openly for 6 weeks with bupropion SR added to their existing antidepressant. The dose range of bupropion was 150 to 300 mg per day. At each visit, patients were assessed using the Beck Depression Inventory (BDI), the Hamilton Depression Ratings Scale (HDRS), and the Clinical Global Impression (CGI). Twenty-eight patients (12 men, 16 women) entered the study. Twenty-five patients completed the six-week trial. With respect to the clinical benefit of bupropion SR augmentation, 15 out of 28, or 54% of patients, were classified as responders, showing a decrease in their HDRS or BDI scores of 50% or more between baseline and Week 6. This prospective, open-label trial supports the use of bupropion SR in the augmentation of SSRIs and venlafaxine. Placebo controlled trials should be completed to further evaluate the efficacy of this strategy.",2003.0,0,0
595,12544379,Clozapine pharmacokinetics in children and adolescents with childhood-onset schizophrenia.,Jean A Frazier; Louise Glassner Cohen; Leslie Jacobsen; Dale Grothe; James Flood; Ross J Baldessarini; Stephen Piscitelli; Grace S Kim; Judith L Rapoport,"Clozapine (CLZ) dose-related adverse effects may be more common in children than adults, perhaps reflecting developmental pharmacokinetic (PK) differences. However, no pediatric CLZ PK data are available. Accordingly, we studied CLZ and its metabolites, norclozapine (NOR), and clozapine-N-oxide (NOX) in six youth, ages 9-16 years, with childhood onset schizophrenia (COS). At the time of the PK study, mean CLZ dose was 200 mg (3.4 mg/kg). Serum was collected during week 6 on CLZ before and 0.5-8 h after a morning dose. Serum concentrations were assayed by liquid chromatography/UV-detection. Mean concentration, area-under-the-curve (AUC), and clearance were calculated. CLZ clearance averaged 1.7 L/kg-h. NOR concentrations (410) exceeded CLZ (289) and NOX (63 ng/ml) and AUC(0-8h) of NOR (3,356) > CLZ (2,359) > NOX (559 ng/ml-h) [53, 38, and 9% of total analytes, respectively]. In adults, NOR serum concentrations on average are 10-25% < CLZ, differing significantly from our sample. Dose normalized concentrations of CLZ (mg/kg-d) did not vary with age and were similar to reported adult values. Clinical improvement seen in 5/6 patients correlated with serum CLZ concentrations. In addition, clinical response and total number of side effects correlated with NOR concentrations. NOR (a neuropharmacologically active metabolite) and free CLZ may contribute to the effectiveness and adverse effects in youth.",2003.0,0,0
596,12556915,D1 receptor alleles predict PET metabolic correlates of clinical response to clozapine.,S G Potkin; V S Basile; Y Jin; M Masellis; F Badri; D Keator; J C Wu; G Alva; D T Carreon; W E Bunney; J H Fallon; J L Kennedy,"A goal of pharmacogenetics is to clarify associations between allelic variation and risk factors in psychiatric illness. We report changes in regional brain metabolism based on dopamine alleles. Treatment-resistant schizophrenic subjects were positron emission tomography scanned with 18F-fluorodeoxyglucose after 5 weeks each of placebo and clozapine treatment. Significant regional brain metabolic effects were found for the D1 receptor genotypes (P < 0.05), adjusted for multiple comparisons. Metabolic decreases for the 2,2 genotype but not the 1,2 genotype were observed in all major sectors of the brain, with the exception of the ventral parts of the caudate and putamen. Frontal, temporal, parietal, and occipital neocortices showed decreased metabolism as did the cingulate juxta-allocortex and the parahippocampal allocortex. Decreases were also observed in the thalamus, amygdala, and cerebellum bilaterally. No significant metabolic differences by genotype were observed for D3, 5HT(2A), and 5HT(2C) polymorphisms. In terms of clinical response, the DRD1 2,2 genotype significantly improved with clozapine treatment, demonstrating a 30% decrease in the Brief Psychiatric Rating Scale positive symptoms in contrast to a 7% worsening for the 1,2 genotype (P < 0.05). In this preliminary study, brain metabolic and clinical response to clozapine are related to the D1 receptor genotype.",2003.0,0,0
597,12559661,Atypical antipsychotic drugs improve cognition in schizophrenia.,Herbert Y Meltzer; Tomiki Sumiyoshi,,2003.0,0,0
598,12562574,"Impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia.",Martina C M Ryan; Patrick Collins; Jogin H Thakore,"This study examined the prevalence of impaired fasting glucose tolerance in first-episode, drug-naive patients with schizophrenia. In this cross-sectional study, fasting plasma levels of glucose, insulin, lipids, and cortisol were measured in 15 male and 11 female hospitalized Caucasian patients with DSM-IV schizophrenia (mean age=33.6 years) and age- and sex-matched healthy comparison subjects. The patients and comparison subjects were also matched in terms of various life-style and anthropometric measures. More than 15% of the drug-naive, first-episode patients with schizophrenia had impaired fasting glucose tolerance, compared to none of the healthy volunteers. Compared with the healthy subjects, the patients with schizophrenia had significantly higher fasting plasma levels of glucose (mean=88.2 mg/dl, SD=5.4, for the healthy subjects versus mean=95.8 mg/dl, SD=16.9, for the patients), insulin (mean=7.7 micro u/ml, SD=3.7, versus mean=9.8 micro u/ml, SD=3.9), and cortisol (mean=303.2 nmol/liter, SD=10.5, versus mean=499.4 nmol/liter, SD=161.4) and were more insulin resistant, as measured with homeostasis model assessment (mean=1.7, SD=0.7, for the healthy subjects versus mean=2.3, SD=1.0, for the patients). First-episode, drug-naive patients with schizophrenia have impaired fasting glucose tolerance and are more insulin resistant and have higher levels of plasma glucose, insulin, and cortisol than healthy comparison subjects.",2003.0,0,1
599,12562575,Changes in glucose and cholesterol levels in patients with schizophrenia treated with typical or atypical antipsychotics.,Jean-Pierre Lindenmayer; Pal Czobor; Jan Volavka; Leslie Citrome; Brian Sheitman; Joseph P McEvoy; Thomas B Cooper; Miranda Chakos; Jeffrey A Lieberman,"The association of hyperglycemia and hypercholesterolemia with use of atypical antipsychotics has been documented in case reports and uncontrolled studies. The authors' goal was to assess the effects of clozapine, olanzapine, risperidone, and haloperidol on glucose and cholesterol levels in hospitalized patients with schizophrenia or schizoaffective disorder during a randomized double-blind 14-week trial. One hundred fifty-seven patients with schizophrenia or schizoaffective disorder who were inpatients at four hospitals were originally included in the study. The 14-week trial consisted of an 8-week fixed-dose period and a 6-week variable-dose period. Planned assessments included fasting glucose and cholesterol, which were collected at baseline and at the end of the 8-week period and the following 6-week period. One hundred eight of the 157 patients provided blood samples at baseline and at least at one point after random assignment to clozapine, olanzapine, risperidone, or haloperidol during the treatment trial. Seven of these patients had diabetes; their glucose levels were >125 mg/dl at baseline. Data from 101 patients were used for statistical analyses. During the initial 8-week period there was an overall significant increase in mean glucose levels. There were significant increases in glucose levels at the end of the 8-week fixed-dose period for patients given clozapine (N=27) and those given haloperidol (N=25). The olanzapine group showed a significant increase of glucose levels at the end of the 6-week variable-dose period (N=22). Fourteen of the 101 patients developed abnormal glucose levels (>125 mg/dl) during the trial (six with clozapine, four with olanzapine, three with risperidone, and one with haloperidol). Cholesterol levels were increased at the end of the 8-week fixed-dose period for the patients given clozapine (N=27) and those given olanzapine (N=26); cholesterol levels were also increased at the end of the 6-week variable-dose period for patients given olanzapine (N=22). In this prospective randomized trial, clozapine, olanzapine, and haloperidol were associated with an increase of plasma glucose level, and clozapine and olanzapine were associated with an increase in cholesterol levels. The mean changes in glucose and cholesterol levels remained within clinically normal ranges, but approximately 14% of the patients developed abnormally high glucose levels during the course of their participation in the study.",2003.0,0,0
600,12562576,,,,,0,0
601,12562577,"Subjective experience and D2 receptor occupancy in patients with recent-onset schizophrenia treated with low-dose olanzapine or haloperidol: a randomized, double-blind study.",Lieuwe de Haan; Marion van Bruggen; Jules Lavalaye; Jan Booij; Peter M A J Dingemans; Don Linszen,"The authors tested the hypothesis that a dopamine D(2) receptor occupancy level between 60% and 70% in patients with recent-onset schizophrenia would result in optimal subjective experience. In addition, they sought preliminary evidence on whether subjective experience is better with low-dose olanzapine than with low-dose haloperidol. Subjects (N=24) who met DSM-IV criteria for schizophrenia were randomly assigned to 6 weeks of double-blind treatment with either olanzapine, 7.5 mg/day, or haloperidol, 2.5 mg/day. Subjective experience, psychopathology, and extrapyramidal symptoms were assessed at baseline and at endpoint. After 6 weeks, D(2) receptor occupancy was assessed with [(123)I]iodobenzamide single photon emission computed tomography. The two study groups were similar at baseline. After 6 weeks, patients receiving olanzapine had a significantly lower mean dopamine D(2) receptor occupancy (51.0%, range=36%-67%) than those given haloperidol (65.5%, range=45%-75%). Receptor occupancy between 60% and 70% was associated with optimal subjective experience, and subjective experience improved significantly in the haloperidol group. A level of D(2) receptor occupancy between 60% and 70% is optimal for subjective experience of patients with recent-onset schizophrenia. Substantial interindividual variation in D(2) receptor occupancy was seen at fixed low-dose levels of olanzapine and haloperidol. Olanzapine, 7.5 mg/day, showed no superior subjective response over haloperidol, 2.5 mg/day. Olanzapine may need to be dosed higher than 7.5 mg/day for most patients with recent-onset schizophrenia, and haloperidol needs to be individually titrated in the very low dose range to reach optimal occupancy.",2003.0,1,1
602,12562742,"Mood stabilisers plus risperidone or placebo in the treatment of acute mania. International, double-blind, randomised controlled trial.",Laksami N Yatham; Fred Grossman; Ilse Augustyns; Eduard Vieta; Arun Ravindran,"Few double-blind trials have examined the efficacy of a combination of a mood stabiliser and an atypical antipsychotic in acute mania. To determine the efficacy of risperidone in combination with a mood stabiliser in acute mania. Patients taking a mood stabiliser were randomised to 3 weeks' treatment with risperidone (n=75) or placebo (n=76). Young Mania Rating Scale (YMRS) scores improved rapidly with significantly greater reductions at week 1 in the risperidone group compared with the placebo group. At end-point YMRS scores decreased by 14.5 and 10.3 points in the risperidone and placebo groups, respectively. Significant improvements v. placebo (P<0.05) were noted in the risperidone group on several other clinically meaningful measures. Additionally, a post hoc analysis excluding carbamazepine-treated patients (plasma concentrations of risperidone active moiety were 40% lower in this group) revealed significantly greater reductions (P=0.047) in YMRS scores in the risperidone group than in the placebo group. Incidence of adverse events was similar in both groups. Risperidone is superior to placebo when used in combination with lithium or divalproex in acute mania.",2003.0,1,1
603,12563038,Movement disorders in children.,Bradley L Schlaggar; Jonathan W Mink,,2003.0,0,0
604,12564104,[Therapeutic advances in 2002 (1)].,A J Scheen,"The most important drugs registered and/or launched in Belgium during the last year in the various disciplines of internal medicine will be briefly described. The main characteristics of each molecule and its modalities of appropriate use in clinical practice will be emphasized. For all these molecules, both the efficacy and tolerance have been proven in randomised clinical trials according to the rules of Evidence-Based Medicine.",2003.0,0,0
605,12567158,Clozapine in Parkinson's disease psychosis: 5-year follow-up review.,Colin Klein; Jacob Gordon; Lea Pollak; J Martin Rabey,"The objective of this study was to monitor the long-term effect of clozapine administered to Parkinson's disease (PD) patients with psychosis. Confusion, visual hallucinations, and psychosis are major dose-limiting factors for long-term dopaminergic management of PD. Classic neuroleptic agents exacerbate the motor symptoms of the disease. For this reason, the introduction of atypical antipsychotic drugs has been a major advancement for the management of psychosis in patients with PD. Of them, clozapine is one of the most effective. Thirty-two patients (mean age, 73 years; mean disease duration, 12.2 years) with PD and psychosis (DSM-IV), 14 of them with dementia (DSM-IV), were followed for 5 years with periodic clinical evaluation, Mini Mental State Examination (MMSE), and Parkinsonian Psychosis Rating Scale (PPRS) administered before and following the study (at least once in 6 months). Periodic blood count was performed for tracking neutropenia. Nineteen patients (8 with dementia) have continued to receive clozapine (mean daily dose, 50 mg). Thirteen patients stopped medication: 9 because symptoms improved and did not return after weaning off clozapine; 3 patients because of somnolence; and 1 because of personal reasons. The average duration of treatment in those in whom medication was stopped was 8.5 months (range, 1-24 months). No correlation was found between age, sex, duration, and severity of disease (Yahr scoring), the presence of dementia, and the response to clozapine. Also, the PPRS scoring did not influence clozapine response. No case of neutropenia was found. According to the experience accumulated and the results of the present study, the authors believe clozapine is the best therapeutic choice currently available for the management of psychosis in patients with PD.",2003.0,0,0
606,12571431,,,,,0,0
607,12580830,"The European Schizophrenia Outpatient Health Outcomes (SOHO) study: rationale, methods and recruitment.",J M Haro; E T Edgell; P B Jones; J Alonso; S Gavart; K J Gregor; P Wright; M Knapp; SOHO Study Group,"The objective of the European Schizophrenia Outpatient Health Outcomes (SOHO) study is to understand the comparative costs and outcomes of antipsychotic drug treatment, with specific focus on olanzapine. The study will also provide a large database for research into the treatment and outcome of schizophrenia. The role of observational studies in the assessment of the effectiveness of antipsychotic agents is reviewed, and the rationale, design and recruitment issues surrounding the SOHO study are presented. SOHO is a 3-year, prospective, observational study of the health outcomes associated with antipsychotic treatment in Europe. Over 10 000 patients have been recruited from 10 countries. Baseline evaluation included measures of clinical status, social functioning, quality of life, service use and pharmacological treatment. Patients will be followed for 3 years. The SOHO study will complement randomized controlled trial findings on the treatment of schizophrenia and will address relevant clinical and policy research questions.",2003.0,1,1
608,12585015,Early intervention in schizophrenia: a critique.,Richard Warner,"Two forms of early intervention in psychosis are currently being proposed--intervention before the onset of illness with at-risk individuals and intervention after the onset of psychosis. The risks and potential benefits associated with these two approaches were examined using published data and Bayes probability theorem. Claims for benefits from early intervention in established psychosis go back more than two hundred years to the nineteenth-century advocates for asylum construction. Theoretical support for early intervention in psychosis rests on data suggesting that a longer duration of untreated psychosis (DUP) is associated with poor outcome. The association of DUP with outcome, however, appears to be inseparable from the confounding influence of the good outcome expected in recent-onset psychosis. Although some researchers advocate treating people with premorbid features of psychosis or other high-risk indicators, adequate screening measures and effective interventions are not yet available. The most promising current screening measure, if applied to the general population, would be accurate only two percent of the time. The accuracy of these measures can be improved by screening only those patients who are referred to a clinic, but this strategy will result in many cases in the population-at-large being overlooked. The risks and potential benefits associated with the two early intervention approaches are very different. The provision of optimal treatment early in psychosis could produce benefits, but people with brief, good-prognosis psychotic episodes are likely to receive unnecessary treatment. Screening the general population or patients referred to a clinic will have little public health impact on the incidence of schizophrenia. There is likely to be considerable negative impact on those who are inaccurately labeled as being at imminent risk of psychosis and are treated accordingly.",2003.0,0,0
609,12585566,The effects of atypical antipsychotics on serum prolactin levels.,Mark Hamner,"Hyperprolactinemia may be a concern in the treatment of patients with schizophrenia. The side effects associated with high prolactin levels can have a negative impact on patient compliance with treatment. Atypical antipsychotics as a group cause less hyperprolactinemia than conventional antipsychotics, yet there is considerable variation among specific drugs. Risperidone at higher doses has been shown to produce increases in prolactin similar to conventional antipsychotics. At the other end of the spectrum, clozapine and quetiapine produce minimal sustained increases in prolactin that are no different from placebo. However, correlations between prolactin elevations and clinical symptoms have not been well-established. This paper reviews the published literature regarding prolactin levels in treated and untreated patients with schizophrenia and the relationship of prolactin and dopamine. It concludes with an overview of the effects of specific atypical antipsychotics on prolactin levels in patients with schizophrenia.",2003.0,0,0
610,12587943,Aripiprazole: a review of its pharmacology and clinical use.,D M Taylor,"Atypical antipsychotics generally have a lower propensity for extrapyramidal side-effects (EPSE), hyperprolactinaemia and tardive dyskinesia than that associated with typical antipsychotics but may still produce troublesome side-effects, such as weight gain, cardiac rhythm changes and impaired glucose tolerance. Aripiprazole is a new atypical antipsychotic with a unique receptor binding profile that combines partial agonist activity at D2 and 5HT1A receptors with potent antagonism at 5HT2A receptors. Clinical studies in acute schizophrenic relapse, chronic schizophrenia and acute mania show it is robustly more effective than placebo. Once-daily aripiprazole 15-30 mg is as effective as haloperidol 10 mg/day and risperidone 6 mg/day in short-term treatment of schizophrenia and more effective than haloperidol 7-10 mg/day in maintenance of response in chronic schizophrenia. Aripiprazole appears to be well tolerated, with most studies suggesting a frequency of adverse effects similar to placebo. Aripiprazole seems not to cause significant EPSE, hyperprolactinaemia, excessive weight gain or cardiac rhythm disturbance. Limited data suggest that aripiprazole is not associated with impaired glucose tolerance.",2003.0,0,0
611,12590372,[New treatment for bipolar disorder in children and adolescents: learning from adult studies].,C Soutullo Esperón; S Barroilhet; I Landecho Acha; F Ortuño Sánchez-Pedreño,"Up to 45% of bipolar patients fail to respond adequately to or do not tolerate treatment with standard antimanics (lithium, valproate, carbamazepine, or olanzapine). Several new potential normothymic and antimanic treatments are under study. However, there is less literature available on new treatments for bipolar disorder in children and adolescents, but many youths with manic symptoms are treated with mood stabilizers. Our goal was to review the current literature on alternatives to lithium, valproate and carbamazepine in the treatment of bipolar disorder in children, adolescents and adults, focusing on the potential uses of these drugs in youth. In a comprehensive computerized and manual literature search in Medline, we identified articles, abstracts and book chapters describing new treatments for bipolar disorder in children, adolescent, and adults. We also manually searched the abstracts in recent APA, AACAP and ECNP Annual Meetings. There are very few studies on the treatment of youths with bipolar disorder. The strongest evidence of antimanic action in this age group is on lithium, valproate, and recently on olanzapine, and adjunctive risperidone. Evidence on new antiepileptics and other novel treatments is very limited or none. More controlled studies on the treatment of children and adolescents with bipolarity are needed. Lithium, valproate, olanzapine and risperidone are probably the drugs with more evidence as antimanic efficacy in children and adolescents, but potential risks and benefits of treatment versus no treatment must be discussed with parents.",2003.0,0,0
612,12590630,Combination therapy: is clinical practice leading the way?,Ron Welch; Mark Snaterse,,2003.0,0,0
613,12591593,Penultimate observation carried forward (POCF): a new approach to analysis of long-term symptom change in chronic relapsing conditions.,Rory O'Connor; Nina R Schooler,,2003.0,0,0
614,12596031,[Psychotherapy of positive symptoms in the treatment of patients with schizophrenia psychosis].,G Wiedemann; S Klingberg,"While the treatment of positive symptoms of patients with schizophrenic psychosis appeared until recently to be solely pharmacotherapeutic, new research findings show the efficacy of cognitive-behavioural psychotherapy (CBT) on positive symptoms in chronic psychotic patients. In addition, the effectiveness even in acute and recent-onset psychosis could be shown in some studies. The effects of CBT and standard care in psychosis compared to standard care alone and to other psychosocial interventions plus standard care are reviewed. The results of several studies and one meta-analysis show that CBT in schizophrenia patients has a direct effect on psychotic symptoms such as hallucinations as well as on relapse prevention. In routine settings,however,CBT has until now only rarely been delivered to these patients. In so-called large pragmatic trials, which might be subsumed as phase IIIb studies, the effects are tested. The therapeutic approach with the components of CBT for psychosis are described: building a therapeutic relationship, cognitive-behavioural coping strategies, developing an understanding of the experience of psychosis,working on hallucinations and delusions, addressing negative self-evaluations, anxiety, and depression,managing risk of relapse and social disability. Further clinical implications are described (capability of learning the therapeutic strategies, deliverability in broader clinical settings, acceptability by patients, combination with atypical neuroleptic drugs,and treatment of choice in risk populations).",2003.0,0,0
615,12598823,Plasma levels of homovanillic acid and the response to risperidone in first episode untreated acute schizophrenia.,Reiji Yoshimura; Nobuhisa Ueda; Koji Shinkai; Jun Nakamura,"We have previously reported that risperidone might improve negative symptoms in schizophrenia by influencing noradrenergic neurons. In the present study, we focused on the clinical efficacy and mechanisms of risperidone towards positive symptoms in the acute phase of schizophrenia. Thirty-four patients meeting DSM-IV criteria for schizophrenia and treated with risperidone alone were evaluated regarding their clinical improvement using the Positive and Negative Syndrome Scale (PANSS) before and 2 weeks after risperidone administration, and blood samples were also drawn at the same times. Plasma concentrations of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol were analysed by high-performance liquid chromatography with electrochemical detection. Plasma HVA levels in the responders to the risperidone treatment (more than 50% improvement in scores of positive symptoms in PANSS) were higher than those of non-responders before risperidone administration. Furthermore, there was a negative trend between changes in plasma HVA levels and improvement of total scores for positive symptoms in PANSS. These results suggest that higher levels of plasma HVA before risperidone administration might be a predictor of a good response to risperidone treatment, and the influence of risperidone on dopaminergic activity might be associated with its efficacy in treating symptoms of schizophrenia in the acute phase.",2003.0,0,0
616,12600227,Intramuscular preparations of antipsychotics: uses and relevance in clinical practice.,A Cario Altamura; Francesca Sassella; Annalisa Santini; Clauno Montresor; Sara Fumagalli; Emanuela Mundo,"Intramuscular formulations of antipsychotics can be sub-divided into two groups on the basis of their pharmacokinetic features: short-acting preparations and long-acting or depot preparations. Short-acting intramuscular formulations are used to manage acute psychotic episodes. On the other hand, long-acting compounds, also called ""depot"", are administered as antipsychotic maintenance treatment to ensure compliance and to eliminate bioavailability problems related to absorption and first pass metabolism. Adverse effects of antipsychotics have been studied with particular respect to oral versus short- and long-acting intramuscular formulations of the different compounds. For short-term intramuscular preparations the main risk with classical compounds are hypotension and extrapyramidal side effects (EPS). Data on the incidence of EPS with depot formulations are controversial: some studies point out that the incidence of EPS is significantly higher in patients receiving depot preparations, whereas others show no difference between oral and depot antipsychotics. Studies on the strategies for switching patients from oral to depot treatment suggest that this procedure is reasonably well tolerated, so that in clinical practice depot antipsychotic therapy is usually begun while the oral treatment is still being administered, with gradual tapering of the oral dose. Efficacy, pharmacodynamics and clinical pharmacokinetics of haloperidol decanoate, fluphenazine enanthate and decanoate, clopenthixol decanoate, zuclopenthixol decanoate and acutard, flupenthixol decanoate, perphenazine enanthate, pipothiazine palmitate and undecylenate, and fluspirilene are reviewed. In addition, the intramuscular preparations of atypical antipsychotics and clinical uses are reviewed. Olanzapine and ziprasidone are available only as short-acting preparations, while risperidone is to date the only novel antipsychotic available as depot formulation. To date, acutely ill, agitated psychotic patients have been treated with high parenteral doses of typical antipsychotics, which often cause serious EPS, especially dystonic reactions. Intramuscular formulations of novel antipsychotics (olanzapine and ziprasidone), which appear to have a better tolerability profile than typical compounds, showed an equivalent efficacy to parenteral typical agents in the acute treatment of psychoses. However, parenteral or depot formulations of atypical antipsychotics are not yet widely available.",2003.0,0,0
617,12605094,Dopamine D3 receptor gene Ser9Gly variant and schizophrenia: association study and meta-analysis.,Erik G Jönsson; Lena Flyckt; Edgar Burgert; Marc-Antoine Crocq; Kaj Forslund; Marja Mattila-Evenden; Gunnar Rylander; Marie Asberg; Vishwajit L Nimgaonkar; Gunnar Edman; Lars Bjerkenstedt; Frits-Axel Wiesel; Göran C Sedvall,"To further evaluate the controversial putative association between a Ser9Gly variant in the first exon of the dopamine D3 receptor gene (DRD3) and schizophrenia. Swedish patients with schizophrenia ( n=156) and control subjects ( n=463) were assessed for the DRD3 Ser9Gly variant. Meta-analyses including previous and the present Swedish case-control results were performed. No significant difference between the Swedish patients and controls were found, but there was an association between DRD3 Ser9Gly Ser/Ser and homozygous genotypes and response to anti-psychotic drugs. This finding was supported by an incomplete meta-analysis. In a meta-analysis of all case-control studies comprising 8761 subjects the association between DRD3 Ser9Gly homozygosity and schizophrenia ( =4.96, degree of freedom=1, p <0.05, odds ratio=1.10, 95% confidence interval=1.01-1.20) persisted. However, the previously proposed association between the Ser/Ser genotype and schizophrenia was not significant (chi2 =2.71, degree of freedom=1, p>0.05, odds ratio=1.08, 95% confidence interval=0.99-1.17). Whereas the present Swedish case-control analysis did not yield any evidence for association with the diagnosis, the present meta-analysis suggests that the DRD3 gene confer susceptibility to schizophrenia. Reasons for the discrepancies between prior studies are discussed.",2003.0,0,0
618,12606844,Flupenthixol versus risperidone: subjective quality of life as an important factor for compliance in chronic schizophrenic patients.,I Hertling; M Philipp; A Dvorak; T Glaser; O Mast; M Beneke; K Ramskogler; G Saletu-Zyhlarz; H Walter; O M Lesch,"The primary aim of this paper was to compare the effects of flupenthixol and risperidone on subjective quality of life and attitude towards medication in chronic schizophrenic patients with mainly negative symptoms. In a spectrum ranging from its typical end ""haloperidol"" to its atypical end ""clozapine"", flupenthixol has typical and atypical characteristics. The effects of flupenthixol versus risperidone were investigated in a multicenter, double-blind trial, whereas subjective quality of life was assessed by means of the EuroQuol-Visual Analogue Scale and the patient satisfaction questionnaire. The attitude towards medication was assessed by means of the Drug Attitude Inventory-30 (DAI-30). Mean daily dose of study medication was 6.6 (SD 2.9) mg/day flupenthixol and 3.6 (SD 1.2) mg/day risperidone. Both groups showed a significant improvement regarding subjective quality of life and positive attitude towards medication. Especially the categories ""control of their thoughts"", concentration and ""feeling better in general"" ameliorated in both groups. In the flupenthixol group, the ""ability to cope with stress"", ""feel more relaxed"" and the ""ability to achieve something"" improved significantly more than in the risperidone group. (1) The spectrum of schizophrenia can be treated effectively with different neuroleptic treatments. (2) Flupenthixol especially improves the ability to cope with stress, the ability to achieve something and feeling more relaxed. (3) Subjective quality of life significantly increased with no difference between the groups.",2003.0,1,1
619,12607072,Atypical antipsychotics and mood stabilization in bipolar disorder.,Paolo Brambilla; Francesco Barale; Jair C Soares,"The available literature on the use of atypical antipsychotics for the treatment of bipolar disorder was reviewed. All uncontrolled and controlled reports were identified through a comprehensive Medline search. Based on the available evidence, olanzapine was found to be the most appropriate atypical antipsychotic agent utilized for the treatment of manic bipolar patients, although there is also preliminary data suggesting the efficacy of risperidone and clozapine. The preliminary data evaluating the efficacy of quetiapine and ziprasidone in bipolar disorder are still very limited. Double-blind controlled studies with atypical antipsychotics in the long-term treatment of bipolar disorder are still largely not available, but will be critical to determine the effectiveness of these agents in the maintenance treatment of bipolar disorder. There are recent uncontrolled suggestions that olanzapine may have beneficial effects in depressed bipolar patients, which deserve further investigation in controlled studies. In conclusion, atypical antipsychotics, due to lower potential for neurotoxicity and preliminary evidence suggesting better efficacy than typical antipsychotics, are increasingly having a more prominent role in the pharmacological management of bipolar patients. Nonetheless, until there is systematic data from long-term controlled follow-up studies on the comparative efficacy of these agents with mood stabilizers, atypical antipsychotics should be cautiously utilized, and preferably in combination with a mood stabilizer for the maintenance phase of treatment.",2003.0,0,1
620,12610718,Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study.,Daniel E Casey; William H Carson; Anutosh R Saha; Amy Liebeskind; Mirza W Ali; Darlene Jody; Gary G Ingenito; Aripiprazole Study Group,"Switching patients from one antipsychotic to another can lead to tolerability problems or transient symptom exacerbations. It is important to compare switching strategies to determine which methods produce the best possible patient outcomes. To investigate the efficacy, safety and tolerability of three dosing strategies for switching chronic, stable patients with schizophrenia from current oral antipsychotic monotherapy to once-daily oral aripiprazole monotherapy. Patients in this 8-week, open-label, outpatient study were randomized to: 1). immediate initiation of 30 mg/day aripiprazole with simultaneous immediate discontinuation of current antipsychotic; 2). immediate initiation of 30 mg/day aripiprazole while tapering off current antipsychotic over 2 weeks; or 3). up-titrating aripiprazole to 30 mg/day over 2 weeks, while simultaneously tapering off current antipsychotic. Efficacy assessments included PANSS, CGI-S, and CGI-I scores. Safety assessments included: adverse events (AEs) recording, evaluation of extrapyramidal symptoms (EPS), vital signs, ECG, and clinical laboratory tests. Efficacy with aripiprazole was maintained during the study with numerical improvements compared with baseline in all three groups. The overall incidence of AEs was broadly comparable across all groups, and AEs were generally mild to moderate in severity and time-limited. Discontinuations due to AEs were comparable across the groups. No deterioration in EPS occurred in any group. The reduction in body weight and plasma prolactin levels following switch to aripiprazole were comparable across the three groups. Any of the three strategies evaluated can be used safely for switching patients to aripiprazole from antipsychotic monotherapy. Furthermore, patients' symptoms may continue to improve after switching to aripiprazole.",2003.0,0,0
621,12611852,Comparative effectiveness of antipsychotic drugs.,,,2003.0,0,0
622,12616671,Pharmacokinetic and safety assessments of concurrent administration of risperidone and donepezil.,Qinying Zhao; Charles Xie; Luana Pesco-Koplowitz; Xinwei Jia; Jean-Loup Parier,"Treatment of Alzheimer's disease sometimes uses combinations of drugs because dementia is frequently associated with behavioral symptoms. Risperidone and donepezil are both metabolized through cytochrome P450 2D6 and 3A4, raising the possibility of drug interactions with combination therapy. The objective of this study was to determine whether significant drug interactions occur with concomitant administration of donepezil and risperidone. In an open-label, three-way crossover study, 24 healthy men were randomly assigned to receive 0.5 mg of risperidone twice daily, 5 mg of donepezil once daily, or both drugs for 14 consecutive days, followed by a 21-day washout period. The treatment ratios of AUC and associated 90% confidence intervals (CIs) for risperidone active moiety, defined as risperidone plus 9-hydroxyrisperidone (ratio = 110.2%; 90% CI = 103.7-117.2), and for donepezil (ratio = 97.1%; 90% CI = 90.0-103.6) were within the 80% to 125% of bioequivalence range. The treatment ratios of Cmax and associated 90% CIs for risperidone active moiety (ratio = 114.6%; 90% CI = 107.0-122.8) and for donepezil (ratio = 96.1%; 90% CI = 90.0-102.6) were also within the bioequivalence range. Therefore, no significant pharmacokinetic differences occurred in either risperidone active moiety or donepezil when given alone or in combination. Adverse events (predominantly headache, nervousness, and somnolence) were minor and comparable for all treatment groups. The results indicate that no clinically meaningful drug interactions occurred between risperidone 1 mg daily and donepezil 5 mg daily at steady state, and therefore no dosage adjustment is required when both drugs are combined with the dosage regimen studied. Additional investigations are warranted to determine the potential for interactions in elderly patients with dementia who may eliminate risperidone and donepezil more slowly and thus be more vulnerable to clinical drug interactions than the young healthy subjects examined in this study.",2003.0,0,0
623,12629505,Association between CYP2D6 genotype and tardive dyskinesia in Korean schizophrenics.,D Nikoloff; J C Shim; M Fairchild; N Patten; B A Fijal; W H Koch; A MacPherson; D Flockhart; Y R Yoon; J S Yoon; Y H Kim; J G Shin,"The CYP2D6 gene codes for human cytochrome P450 2D6 enzyme, which is responsible for the metabolism of many psychiatric drugs. In schizophrenic patients treated with neuroleptics, decreased or loss of function CYP2D6 alleles may contribute to the development of tardive dyskinesia (TD), a movement disorder that frequently occurs with chronic neuroleptic treatment. The goal of this study was to determine whether the occurrence of TD is associated with CYP2D6 genotype in a cohort of Korean schizophrenics by employing a CYP450 GeneChip((R)) oligonucleotide microarray and PCR assays to screen for 19 CYP2D6 alleles. Our results revealed that males with at least one decreased or loss of function allele have a moderately greater chance of developing TD than males with only wild-type alleles. Female schizophrenics did not have a significantly greater chance of developing TD. Our results demonstrate the utility of CYP2D6 microarrays to assess genotype status in this Korean cohort.",2003.0,0,0
624,12629532,Treatment of weight gain with fluoxetine in olanzapine-treated schizophrenic outpatients.,Juan R Bustillo; John Lauriello; Katherine Parker; Roger Hammond; Laura Rowland; Michael Bogenschutz; Samuel Keith,"Significant weight gain is a side effect associated with olanzapine treatment in some patients. We investigated the efficacy of high-dose fluoxetine as a weight-reducing agent for patients who develop early weight gain with olanzapine treatment. Patients that gained >/=3% of their baseline weight in the initial 8 weeks of olanzapine treatment (n=31) were randomized to double-blind treatment with placebo or fluoxetine (60 mg/day). Clinical, weight, and weight-related measures were assessed. Fluoxetine failed to demonstrate weight-reducing effects (fluoxetine group: baseline mean 80.5 kg, SD=19.1, last mean=83.5 kg, SD=19.8; placebo group: baseline mean=77.1 kg, SD=12.1, last mean=78.8 kg, SD=10.6; F=1.3; df=1, 18; p=0.3). There were no differential effects in psychopathology, extrapyramidal side effects or weight-related measures between the placebo and fluoxetine groups. Serotonin reuptake inhibitors are probably not a practical option to counteract weight gain induced by atypical antipsychotics. Atypical-induced weight gain may result from mechanisms other than 5HT reuptake blockade.",2003.0,0,0
625,12630982,Low blood selenium concentrations in schizophrenic patients on clozapine.,K S Vaddadi; E Soosai; G Vaddadi,"To compare plasma and red-cell selenium concentrations of schizophrenic patients treated with clozapine, with healthy controls and patients with mood disorders. Plasma and red-cell selenium concentrations were measured in random venous blood samples from four groups: mood disorder (n = 36), schizophrenics treated with clozapine (n = 54), schizophrenics not treated with clozapine (n = 41) and a healthy control group (n = 56). Assays were performed by an independent laboratory that was blinded to the patient groups and specializes in estimating trace metal concentrations. Selenium concentrations in plasma and red cells were found to be significantly lower in schizophrenic patients treated with clozapine as compared with all other groups. Selenium is an essential antioxidant. Its deficiency has been implicated in myocarditis and cardiomyopathy. Low selenium concentrations in clozapine-treated patients may be important in the pathogenesis of life threatening cardiac side-effects associated with clozapine. Further clinical studies are being conducted to explore this important clinical observation and its therapeutic implications.",2003.0,0,0
626,12633119,Switching from depot antipsychotic drugs to olanzapine in patients with chronic schizophrenia.,Linda S Godleski; L Jane Goldsmith; W Victor Vieweg; Nancy C Zettwoch; Dejzi M Stikovac; Susan J Lewis,"Patients with chronic schizophrenia (DSM-IV criteria) often receive depot antipsychotic medications to assure longer administration and better compliance with their treatment regimen. This study evaluated whether patients stabilized on depot antipsychotic medication could be successfully transitioned to oral olanzapine. In a 3-month open-label study, 26 clinically stable patients with schizophrenia taking depot antipsychotics for over 3 years were randomly assigned to continue on their current depot dose or to switch to oral olanzapine. Clinical ratings (Positive and Negative Syndrome Scale [PANSS], Global Assessment of Functioning [GAF] scale, and Clinical Global Impressions [CGI] scale) and side effect parameters (Abnormal Involuntary Movement Scale [AIMS], Barnes Akathisia Scale, AMDP-5 scale, vital signs, and weight) were obtained monthly. Oral olanzapine patients (N = 13) demonstrated significant clinical improvement over the depot control group (N = 13) from baseline to 3-month endpoint (PANSS total, p =.012; PANSS general, p =.068; PANSS negative, p =.098; CGI-Improvement, p =.007; CGI-Severity, p =.026; GAF, p =.015). Side effect rating scales showed no statistical differences between the 2 groups (AIMS, Barnes Akathisia Scale, AMDP-5, vital signs). The depot control group showed no statistical superiority in any measure except weight change (p =.0005). After 3 months, all olanzapine patients preferred olanzapine to their previous depot medications and chose to continue on olanzapine treatment. Clinicians may expect clinical improvement when switching chronically psychotic patients from traditional depot antipsychotic drugs to oral olanzapine. Switching may be completed within a 4-week period with relative compliance being maintained and patients preferring oral olanzapine to their previous depot medications.",2003.0,1,1
627,12633121,"A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation, and psychosis of dementia.",Henry Brodaty; David Ames; John Snowdon; Michael Woodward; Jeff Kirwan; Roger Clarnette; Emma Lee; Ben Lyons; Fred Grossman,"This randomized, double-blind, placebo-controlled trial examined the efficacy and safety of risperidone in the treatment of aggression, agitation, and psychosis in elderly nursing-home patients with dementia. Elderly patients with a DSM-IV diagnosis of dementia of the Alzheimer's type, vascular dementia, or a combination of the 2 (i.e., mixed dementia) and significant aggressive behaviors were randomized to receive, for a period of 12 weeks, a flexible dose of either placebo or risperidone solution up to a maximum of 2 mg/day. Outcome measures were the Cohen-Mansfield Agitation Inventory (CMAI), the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) rating scale, and the Clinical Global Impression of Severity (CGI-S) and of Change (CGI-C) scales. A total of 345 patients were randomized to treatment with risperidone or placebo, and 337 patients received at least one dose of study drug. The trial was completed by 67% of patients in the placebo group and 73% of patients in the risperidone group. The mean +/- SE dose of risperidone was 0.95 +/- 0.03 mg/day. The primary endpoint of the study, the difference from baseline to endpoint in CMAI total aggression score, showed a significant reduction in aggressive behavior for risperidone versus placebo (p <.001). A similar improvement was also seen for the CMAI total non-aggression subscale (p <.002) and for the BEHAVE-AD total (p <.001) and psychotic symptoms subscale (p =.004). At endpoint, the CGI-S and the CGI-C scores indicated a significantly greater improvement with risperidone compared with placebo (p <.001). Overall, 94% and 92% of the risperidone and placebo groups, respectively, reported at least 1 adverse event. Somnolence and urinary tract infection were more common with risperidone treatment, whereas agitation was more common with placebo. There was no significant difference in the number of patients who reported extrapyramidal symptoms between the risperidone (23%) and placebo (16%) groups. Treatment with low-dose (mean = 0.95 mg/day) risperidone resulted in significant improvement in aggression, agitation, and psychosis associated with dementia.",2003.0,1,1
628,12634513,Do atypical antipsychotics fail to exert cognitive sparing effects?,Charalabos Papageorgiou; Panayiotis Oulis; Christos Vasios; George K Matsopoulos; Nikolaos Uzunoglu; Andreas Rabavilas; George N Christodoulou,"The aim of the study was to investigate patterns of the P600 component of event-related potentials (ERPs) elicited during a working memory test in 16 male schizophrenic patients experiencing auditory hallucinations before and after treatment with clozapine and olanzapine, and 13 male normal subjects matched for age and educational level. Before treatment, patients showed significantly reduced P600 amplitudes on the right parietal region compared with controls, and when in remission also showed significantly reduced P600 amplitudes located on the right parietal and temporofrontal areas, compared both to themselves before treatment and to normal controls. The patient's memory performance before and after treatment remained significantly lower than that of healthy controls. These findings may indicate that auditory hallucinations in schizophrenia are associated with impaired synchronization of the processes related to target detection, as reflected by the P600. The present study also casts doubts regarding the cognitive sparing effect of atypical antipsychotics, despite the fact that they mediate symptom improvement.",2003.0,0,0
629,12634982,Short-acting parenteral antipsychotics drive choice for classical versus atypical agents.,Gerard W K Hugenholtz; Joost J Stolker; Eibert R Heerdink; Willem A Nolen; Hubert G M Leufkens,"The objective of this study was to investigate which antipsychotics (classical versus atypical) are prescribed in a psychiatric hospital and which determinants affect the choice for one of these two classes of antipsychotics in newly admitted patients. In a retrospective cohort design, 522 newly admitted patients were followed from the date of admission until discharge from the hospital. In the cohort of newly admitted patients treated with an oral antipsychotic, a nested case-control study was conducted considering recipients of an atypical agent as cases. Controls were all other cohort members. The association of patient characteristics and the choice between classical versus atypical antipsychotics was studied using logistic regression analysis. The same analysis was performed with adjustment for possible confounding factors (age group, gender, DSM-IV diagnoses, use of short-acting parenteral antipsychotic, global assessment of functioning score, involuntary admissions and involuntary measures). Patients treated with classical oral antipsychotics were more often previously treated with short-acting parenteral antipsychotics than patients treated with atypical antipsychotics (40.8% vs 15.2%; adjusted OR=0.20 95% CI=0.09-0.44). No statistically significant difference was found between patients with different severities of disease. Availability of injectable forms seems to drive the choice for oral antipsychotic agents. Future introductions of short-acting parenteral atypical antipsychotics may have a large impact on first-choice oral antipsychotic treatment.",2003.0,0,0
630,12640214,Acute dysphoric mania: treatment response to olanzapine versus placebo.,Robert W Baker; Mauricio Tohen; Jan Fawcett; Richard C Risser; Leslie M Schuh; Eileen Brown; Virginia L Stauffer; Lixin Shao; Gary D Tollefson,"A substantial number of patients with mania have significant concomitant depressive features, and they may respond differently to mood stabilizers than patients with pure mania. This post-hoc analysis explored the response characteristics of olanzapine versus placebo in bipolar I manic patients with dysphoric and nondysphoric mania (differentiated by baseline Hamilton Depression Rating Scale [HAM-D] score of >20). Two similar, double-blind, randomized trials comparing olanzapine, 5-20 mg, to placebo were pooled for these analyses (N = 246). Mean changes in Young-Mania Rating Scale (Y-MRS) and HAM-D scores during 3 weeks of treatment were examined. Twenty-eight percent of patients had dysphoric mania (olanzapine, n = 33; placebo, n = 35). Among these patients, olanzapine-treated patients had greater improvement within 1 week than did placebo-treated patients on both mania ratings (Y-MRS: -9.7 vs. -3.0 points; = 0.011) and depressive symptom ratings (HAM-D: -9.9 vs. -5.4 points; = 0.025). Among those manic subjects without prominent depressive symptoms (olanzapine, n = 91; placebo, n = 87), mean Y-MRS improvement from baseline to endpoint with olanzapine (-11.5 points) versus placebo (-6.13 points) was comparable to the improvement seen with olanzapine versus placebo in the dysphoric mania subgroup ( = 0.476, test of interaction). In acutely ill manic patients with significant depressive symptoms, olanzapine demonstrated a broad spectrum of efficacy, effectively treating both manic and depressive symptoms. The magnitude of the antimanic response appears similar, regardless of baseline depressive features. Additional experience with putative mood stabilizers and atypical agents in mixed mania should include an exploration of their efficacy in treating both manic and depressive mood symptoms.",2003.0,1,1
631,12640221,Low-dose risperidone as adjunctive therapy for irritable aggression in posttraumatic stress disorder.,Edward P Monnelly; Domenic A Ciraulo; Clifford Knapp; Terence Keane,"Increased aggressive behavior can occur in association with posttraumatic stress disorder (PTSD). This study tested the hypothesis that low-dose risperidone reduces aggression and other PTSD-related symptoms in combat veterans. Subjects were male combat veterans with PTSD who scored 20 or higher on cluster D (hyperarousal) of the Patient Checklist for PTSD-Military Version (PCL-M). Subjects were randomly assigned to either risperidone or placebo treatment groups. Drugs were administered over a 6-week treatment period in a double-blind manner. Subjects received either risperidone (0.5 mg/day; n = 7) or matched placebo (n = 8) tablets during the first 2 weeks of the treatment period. The dose of risperidone could then be increased up to 2.0 mg/day on the basis of response. Prerandomization psychotropic regimens were continued. Subjects were evaluated with the PCL-M and the Overt Aggression Scale-Modified for Outpatients (OAS-M). In comparison with placebo treatment, reductions in scores between baseline and the last week of treatment were significantly greater for OAS-M irritability and PCL-M cluster B (intrusive thoughts) subscales and on the PCL-M total scale. These results suggest that low-dose risperidone administration reduces irritability and intrusive thoughts in combat-related PTSD.",2003.0,0,0
632,12640328,[Criteria defining antimanic drugs (psychopharmacological specificity and/or nonspecificity?)].,J-M Azorin,"The question as to whether specific antimanic drugs differ in their action profile from nonspecific drugs is addressed in regard to symptomatic, nosographic, regulatory and physiopathological issues. Results from clinical studies have shown that mood stabilizers and typical neuroleptics differ as regards improvement of manic symptoms: the former appear to act more evenly on all symptoms of mania, showing a more total normalization of affect, ideation and behaviour whereas the latter tend to sedate patients or to cause a psychomotor retardation, leaving the core manic symptoms unaffected. This has been many times underlined, in particular for lithium, notwithstanding the fact that rating scales employed in clinical trials have often been charged to fall far short of being sensitive enough to pick up the qualitative changes in manic psychopathology. Antimanic drugs may also be more or less specific in their capacities to treat all facets of the manic episode (psychotic, depressive, irritable) whatever the bipolar subtype (bipolar I, II, rapid and non-rapid cycling, secondary bipolar disorder) or the disease stage (early and late episodes). In this respect divalproate seems to have a broader spectrum of efficacy than other available agents. Newer antipsychotics such as olanzapine are promising too. From a regulatory point of view, the current European requirements for a specific antimanic drug are more stringent than the US requirements of the Food and Drug Administration (FDA). Efficacy must be demonstrated in short-term studies showing an effect in acute mania; moreover it has to be shown that efficacy is to be maintained during the episode. So far, three armed randomized controlled trials are required, in which the test product is compared both with placebo and with a standard treatment. A possible design is a comparison of test product, placebo and active control for 3 weeks followed by a two-arm phase for the remaining 9 weeks, comparing only test product and active control. In addition, a specific antimanic has to demonstrate that it does not cause switching to depression. As regards physiopathology, integrative models of bipolar disorder, ie kindling and behavioural sensitization, offer an exciting perspective on the specificity issue; agents active in these models initialize a cascade of intracellular signaling that leads to changes in the expression of immediate early genes as well as late effector genes in corticolimbic structures: the former may contribute to acute symptomatology whereas the latter give rise to neuroanatomical reorganization which could underlie more stable changes in mood and cognition. Due to their action on intracellular messaging systems, dopamine D(1) receptors, serotonin 5HT(1a) or 5HT(2a) receptors, especially in orbitofrontal circuit, antimanic agents may exhibit a more specific activity than other drugs. This specificity could concern a whole spectrum of bipolarity which might be characterized by impulsivity.",2003.0,0,0
633,12640589,[Effects of quetiapine at low doses on psychosis motor disability and stress of the caregiver in patients with Parkinson's disease].,S Giménez-Roldán; E Navarro; D Mateo,"Quetiapine is a novel neuroleptic drug with pharmacological properties close to clozapine, the most effective drug in the management of psychotic symptoms in patients with Parkinson s disease (PD). Unlike clozapine, however, quetiapine does not induce agranulocytosis and therefore no haematologic controls are required. To assess tolerability and effectiveness of low dose quetiapine on psychotic symptoms, sleep disturbances and stress of the caregiver in PD patients with dopaminomimetic psychosis. We carried out a 16 week, prospective, open label study on the effects of quetiapine in 7 consecutive PD patients with psychosis. A ceiling dose was arbitrarily established at 25 mg/d. Antiparkinsonian medication remained unchanged throughout the study. Motor symptoms were assessed with UPDRS motor subscale portion, Schwab England scale, and Hoehn Yahr diseases staging. The effects on hallucinations and paranoia, sleep disorder, and stress in the caregiver were scored separately, aside from a global score on the Neuropsychiatric Inventory (NPI). Global impression of both, investigators and caregiver was obtained at study conclusion. A patient died from unrelated causes. Under a mean quetiapine dose of 24.9 mg/d (12.5 37.2) motor impairment during on periods remained unchanged, both according to patients and caregiver whereas mean UPDRS motor score remained unchanged (35.5 4.5 versus 32.8 5.2). Levodopa induced dyskinesias disappeared in the single patient with this complication. Improvement occurred in mean NPI global score, as well as subscores for hallucinations and paranoia, and caregiver stress. In over half the patients, effectiveness was scored as very good or good both by examiners and caregivers. A confusional episode occurred in one patient under 25 mg/d but readily resolved while maintaining the benefit following dose reduction to 12.5 mg. Quetiapine at low doses appears a useful alternative for psychotic symptoms, sleep disorders and stress of the caregiver in patients with PD",2003.0,0,0
634,12648731,The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. I. Study rationale and design.,T H McGlashan; R B Zipursky; D Perkins; J Addington; T J Miller; S W Woods; K A Hawkins; R Hoffman; S Lindborg; M Tohen; A Breier,"The first double-blind placebo-controlled clinical trial of an atypical neuroleptic medication is being conducted in symptomatic treatment-seeking patients meeting new diagnostic criteria for a putative prodromal syndrome. This identifies them as being at high risk for developing psychosis in the near future. The study aims include prevention of psychosis onset and disability, as well as palliation of ongoing symptomatology. This report presents the study rationale and design. Recent studies will be reviewed that have advanced our knowledge about the early course of schizophrenia and our ability to predict onset prospectively, advances that have rendered prodromal intervention research feasible and ethical. The study design has many novel features. It tests for prevention versus delay in psychosis onset, as well as for efficacy and safety in a newly defined clinical population. This has required the development of innovative clinical research assessment instruments and a new operational definition of psychosis onset. The integration of these novel elements into an otherwise typical clinical trial design is detailed. The companion report will address sample recruitment and the clinical phenomenology at baseline of this putative ""prodromal"" entity.",2003.0,0,1
635,12648732,"The PRIME North America randomized double-blind clinical trial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. II. Baseline characteristics of the ""prodromal"" sample.",T J Miller; R B Zipursky; D Perkins; J Addington; S W Woods; K A Hawkins; R Hoffman; A Preda; I Epstein; D Addington; S Lindborg; E Marquez; M Tohen; A Breier; T H McGlashan,"The first double-blind placebo-controlled clinical trial of an atypical neuroleptic medication is being conducted in symptomatic treatment-seeking patients meeting new diagnostic criteria for a putative prodromal syndrome. This identifies them as being at high risk for developing psychosis in the near future. The study aims include prevention of psychosis onset and disability, as well as palliation of ongoing symptomatology. The purpose of this report is to describe the study's ""prodromally symptomatic"" sample at baseline, i.e., at intake immediately prior to randomization and prior to receiving study medication. Sixty treatment-seeking patients meeting prodromal inclusion criteria were recruited across four sites: New Haven, CT (n=39), Toronto, Ontario (n=9), Calgary, Alberta (n=6), and Chapel Hill, NC (n=6). The sample was young (median age 16), largely male (65%), and came from families with high titers of serious mental illness (44%). Most patients (93%) met criteria for the Attenuated Positive Symptom (APS) prodromal syndrome and presented with significant but nonpsychotic suspiciousness, perceptual aberrations, unusual thought content, and conceptual disorganization. They presented with minimal to mild affective symptoms and substance use/abuse, but they were quite functionally compromised (mean Global Assessment of Functioning (GAF) score=42). The prodromal sample was compared with other clinical-trial samples of adolescent depression, adolescent mania, and first episode schizophrenia. Prodromal patients proved not to be depressed or manic. They were less severely ill than untreated first episode schizophrenia but more severely ill than treated first episode schizophrenia. While not psychotically disabled, these patients nevertheless present with a clinical syndrome. Subsequent reports will detail the effects of drug versus placebo on prodromal symptoms, neuropsychological profile, and the rate of conversion to psychosis.",2003.0,0,1
636,12648735,The factor structure for the Positive and Negative Syndrome Scale (PANSS) in recent-onset psychosis.,Robin Emsley; Jonathan Rabinowitz; Martijn Torreman; RIS-INT-35 Early Psychosis Global Working Group,"The Positive and Negative Syndrome Scale (PANSS) is a widely used instrument for measuring severe psychopathology in adult patients with schizophrenia. Data, primarily on chronic patients, have been used to define factors for the PANSS. The present study examines the PANSS factor structure in a large sample of subjects with recent-onset schizophrenia, schizophreniform disorder and schizoaffective disorder who had been exposed to very limited antipsychotic medication. Equamax factor analysis was conducted on PANSS baseline assessments from a multicenter, 11 country drug trial that enrolled 535 patients. The forced five-factor solution essentially corresponds to the factors most frequently described previously, namely negative, positive, disorganized (or cognitive), excited and anxiety/depression. In the exploratory analysis, a seven-factor solution was obtained, with depression and anxiety symptoms separating and a motor component emerging. The results of this study partially support the use of a five-factor model for the PANSS, but suggest that scales for catatonia, depressive and anxiety syndromes should be included in future studies.",2003.0,0,0
637,12650685,What are the effects of antipsychotics on sexual dysfunctions and endocrine functioning?,H Knegtering; A E G M van der Moolen; S Castelein; H Kluiter; R J van den Bosch,"The literature is reviewed and preliminary results of new studies are presented showing that treatment with classical antipsychotics, as well as risperidone, induces sexual dysfunctions in 30-60% of the patients. These antipsychotics also frequently induce amenorrhoea and galactorrhoea. Although comparative studies are rare, it is likely that prolactin-sparing antipsychotics, as recently shown in a randomized trial of olanzapine versus risperidone, induce less sexual side effects.From these studies, it becomes apparent that prolactin elevation induced by classical antipsychotics and risperidone is probably a factor in inducing sexual dysfunctions, amenorrhoea and galactorrhoea. The role of other factors inducing sexual dysfunctions like sedation, proportional, variant -blockade, testosterone, dopamine, and serotonin is discussed. Finally, it is concluded that sexual and hormonal effects of antipsychotics, although clearly important, are often neglected in research as in clinical practice. Lowering the dosage or switching to a prolactin-sparing antipsychotic often reduces sexual side effects, amenorrhoea, and galactorrhoea.",2003.0,0,0
638,12650950,Nizatidine for prevention of weight gain with olanzapine: a double-blind placebo-controlled trial.,Patrizia Cavazzoni; Yoko Tanaka; Suraja M Roychowdhury; Alan Breier; David B Allison,"Weight gain is associated with treatment with olanzapine and other psychotropic agents. Nizatidine, a histamine H-2 receptor antagonist, has been proposed to have weight-reducing effects. This double-blind trial evaluated the efficacy of nizatidine in limiting weight gain in patients with schizophrenia and related disorders who were treated with olanzapine for up to 16 weeks. After an initial screening period, 175 patients were randomized to receive olanzapine (5-20 mg) with either placebo or nizatidine (150 mg b.i.d. or 300 mg b.i.d.). Significantly less weight gain was observed on average at weeks 3 and 4 with olanzapine+nizatidine 300 mg b.i.d. (P<0.05) compared to olanzapine+placebo, but the difference was not statistically significant at 16 weeks. Nizatidine was well-tolerated and did not adversely affect clinical outcomes. Nizatidine 300 mg b.i.d. may have an early transient effect in limiting the weight gain, but this potential early effect appeared to be diminished or eliminated by 16 weeks.",2003.0,0,0
639,12650957,"Effect of the 5-HT2 antagonist mianserin on cognitive dysfunction in chronic schizophrenia patients: an add-on, double-blind placebo-controlled study.",Michael Poyurovsky; Danny Koren; Inna Gonopolsky; Michael Schneidman; Camil Fuchs; Abraham Weizman; Ronit Weizman,"Preponderance of serotonin 5-HT2A antagonism over dopamine D2 blockade exerted by atypical antipsychotics may contribute to their cognitive-enhancing effect. In a double-blind placebo-controlled study we examined the effect of add-on mianserin (15 mg/day), an agent with marked 5-HT2A antagonism, on cognitive functioning in 30 chronic hospitalized DSM-IV schizophrenia patients stabilized on typical antipsychotics. The Automated Neuropsychological Assessment Metrics (ANAM) battery was used to assess learning, memory and sustained attention; Wisconsin Card Sorting Test (WCST) to assess executive function at baseline and endpoint (4 weeks). Clinical assessment included appropriate rating scales. The mianserin group overperformed the placebo group on selective ANAM memory/learning tests, reflected in moderate-to-high effect size values. No between-group differences were revealed in WCST and clinical ratings. Improved performance on selective neurocognitive tests with addition of the 5-HT2A antagonist mianserin to typical antipsychotics indicates a possible role of the 5-HT system in cognitive-enhancing effects. The effect of flexible doses of mianserin on cognitive deficits in a broader schizophrenia population merits further investigation.",2003.0,0,0
640,12654411,A retrospective cohort study of diabetes mellitus and antipsychotic treatment in the United States.,John B Buse; Patrizia Cavazzoni; Kenneth Hornbuckle; David Hutchins; Alan Breier; Lois Jovanovic,"Treatment-emergent diabetes mellitus (DM) has been described for conventional and atypical antipsychotics. In our study, antipsychotic prescription claims from AdvancePCS's database were used to identify patients starting antipsychotic monotherapy. The relative risk of developing DM was determined using prescription claims for antidiabetic agents in the following cohorts: AdvancePCS general patient population, combined conventional antipsychotics, and combined atypical antipsychotics. Cox proportional hazards regression was used to adjust for differences in age, gender, and duration of antipsychotic exposure between cohorts in the estimation of risk of developing diabetes. Hazard ratios for developing DM in the combined conventional, combined atypical, and individual conventional and atypical antipsychotic treatment cohorts were greater than the AdvancePCS general patient population cohort. An increased risk of developing diabetes compared with the AdvancePCS general patient population was observed during treatment with conventional or atypical antipsychotics.",2003.0,0,0
641,12656931,,,,,0,0
642,12658913,Measurement of simple reaction time in antipsychotic treatment of patients with schizophrenia.,Blanka Kores Plesnicar; Bojan Zalar; Martina Tomori; Ivan Krajnc,"The role of simple reaction time in schizophrenia has been extensively reported to date in professional literature. However, most studies have examined basic reaction time under static conditions using a single measurement. The aim of the present study was to establish whether any changes occur in simple reaction time during treatment with risperidone or olanzapine in in-patients suffering a relapse of schizophrenia. Seventeen in-patients suffering acute relapse of schizophrenia (DSM IV criteria) and twenty matched, healthy controls participated in an eight-week, double-blind pilot study. The patients were treated with conventional antipsychotics for seven days after admission and were then randomised to the treatment arms with risperidone (4 mg/day) or with olanzapine (10 mg/day) at a fixed dosage in the first week and thereafter in flexible dosages for the remaining seven weeks. Since no differences were found between reaction times of patients treated with risperidone or olanzapine, the two treatment groups were merged in the statistical analysis before being compared with the normal controls. Psychopathological symptoms were assessed using the Positive and Negative Symptom Scale (PANSS) and extrapyramidal symptoms with the Simpson Angus Scale and Abnormal Involuntary Movement Scale. Reaction time was measured with the Alpha apparatus, connected to a personal computer. All assessments and measurements were conducted four times during the treatment phase of the study. The reaction time of patients was significantly longer than that of the healthy controls (t1 = 17.11; p1 < 0.05). After eight weeks of treatment the reaction time of patients significantly improved but did not reach that of the healthy controls (t4 = 28.18, p4 < 0.05). Furthermore, the improved reaction time in the patients did not correlate with improvement of psychopathological symptoms or with improved extrapyramidal symptoms. The results of the study suggest that simple reaction time can improve during treatment with atypical antipsychotics.",2003.0,0,0
643,12659615,Clinical trial response and dropout rates with olanzapine versus risperidone.,Benedetta Santarlasci; Andrea Messori,"In schizophrenia, comparing treatment dropouts between olanzapine and risperidone can be useful to better understand their relative effectiveness. To analyze the differences in the rates of dropout from clinical trials and response between these 2 antipsychotics. Literature search was based on MEDLINE (1966-May 2002). Analysis 1 included 4 randomized studies (838 patients), analysis 2 included 2 randomized studies (n = 716), and analysis 3 assessed 5 clinical studies for olanzapine (n = 928) and 3 for risperidone (n = 290). Odds ratios were estimated by the fixed-effect model. The risk of treatment discontinuation (analysis 1) was significantly greater for risperidone than for olanzapine (42% vs. 33%, respectively). The response rates were identical for the 2 drugs (analysis 2). A slightly better pattern of maintenance of response was found for olanzapine (analysis 3). The pattern of dropout and maintenance of remission seems to be better controlled for olanzapine than for risperidone.",2003.0,1,1
644,12663838,An economic review of compliance with medication therapy in the treatment of schizophrenia.,Patricia Thieda; Stephen Beard; Anke Richter; John Kane,"The authors examined published economic evaluations of schizophrenia and antipsychotic therapies to determine the role of compliance with medication therapy in the economic cost of schizophrenia. The authors reviewed studies published from 1995 to 2002 that evaluated compliance with treatment for schizophrenia. Literature searches were conducted for that period by using MEDLINE, EMBASE, and Current Contents. The primary search terms were ""schizophrenia,"" ""compliance,"" ""relapse,"" and ""economic costs."" A definitive relationship exists between compliance and the economic costs of schizophrenia. Lower rates of compliance lead to higher costs of treating schizophrenia. However, the full implications are difficult to surmise from the literature because of inadequacies in the reporting of compliance rates and outcomes of treatment over time. The authors suggest collection of data on longer-term clinical outcomes as a means to improve future economic evaluations of schizophrenia treatments.",2003.0,0,0
645,12665398,Clozapine: in prevention of suicide in patients with schizophrenia or schizoaffective disorder.,Antona Wagstaff; Caroline Perry,"The atypical antipsychotic agent clozapine is associated with a lower propensity for extrapyramidal symptoms than classical antipsychotic agents. The pharmacokinetics of clozapine are affected by wide interpatient variability and a potential for drug interactions. Some studies have shown a relationship between plasma concentrations, duration of treatment and antipsychotic clinical response. Clozapine (mean 274.2 mg/day; n = 490) had a greater preventive effect on suicidality among patients with schizophrenia or schizoaffective disorder at high risk for suicide than olanzapine (mean 16.6 mg/day; n = 490) in a randomised, rater-blinded, multicentre study (p < 0.05; a 22-24% improvement). Other prospective noncomparative trials of the effects of clozapine on suicidal ideation or attempts endorsed these results, while results from retrospective trials are equivocal. Clozapine is commonly associated with sedation, hypersalivation, tachycardia, dizziness, constipation and orthostatic hypotension. Agranulocytosis, diabetes mellitus and weight gain may also occur.",2003.0,0,0
646,12668364,"Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial.",Paul E Keck; Marcio Versiani; Steven Potkin; Scott A West; Earl Giller; Kathleen Ice; Ziprasidone in Mania Study Group,"The study evaluated the efficacy and tolerability of ziprasidone, compared with placebo, in the treatment of adult patients with acute bipolar mania. Patients with a primary DSM-IV diagnosis of bipolar I disorder and a current manic or mixed episode (confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition) (N=210) were randomly assigned in a 2:1 ratio to 3 weeks of double-blind treatment with ziprasidone (40-80 mg twice daily) or placebo. Efficacy was assessed with the Schedule for Affective Disorders and Schizophrenia, Change Version (which contains the Mania Rating Scale), Positive and Negative Syndrome Scale, Clinical Global Impression (CGI) severity scale, CGI improvement scale, and Global Assessment of Functioning Scale. Primary efficacy variables were differences from baseline to endpoint (last observation carried forward) in mean Mania Rating Scale and CGI severity scale scores between the ziprasidone and placebo groups. Safety evaluations included monitoring of adverse events, vital signs, electrocardiogram results, and clinical laboratory values and assessment of movement disorders and akathisia. Ziprasidone produced rapid, sustained improvements relative to baseline and placebo on all primary and most secondary efficacy measures at endpoint. Significant improvements were typically observed within 2 days after treatment commenced and were maintained throughout the 3 weeks. Ziprasidone was well tolerated and associated with a low rate of extrapyramidal symptoms; neither weight gain nor clinically significant changes in vital signs or other safety parameters were observed with ziprasidone. Ziprasidone monotherapy was significantly superior to placebo in reducing symptoms of acute mania in patients with bipolar I disorder. Onset of action was rapid, and tolerability of ziprasidone was generally comparable to that of placebo.",2003.0,0,1
647,12670060,Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease.,Serge Gauthier; Howard Feldman; Jane Hecker; Bruno Vellas; David Ames; Ponni Subbiah; Edward Whalen; Birol Emir; Donepezil MSAD Study Investigators Group,"This subanalysis of a large, double-blind, placebo-controlled trial examined the prevalence of behavioral symptoms in moderate to severe Alzheimer's disease (AD), and the effect of treatment with donepezil. Two hundred ninety patients with moderate to severe AD (standardized Mini-Mental State Examination scores 5-17) were randomized to receive 24 weeks of once-daily doses of donepezil 5 mg/day for 28 days, and 10 mg/day thereafter per the clinician's judgment (n = 144), or placebo (n = 146). The outcome measure of interest was the 12-item Neuropsychiatric Inventory (NPI). Baseline demographics were similar between the treatment groups. Least squares mean (+/- SE) baseline NPI 12-item total scores were 19.55 +/- 1.48 and 19.30 +/- 1.45, respectively. At baseline, the most common symptoms were apathy/indifference (67%), aberrant motor behavior (53%), depression/dysphoria (52%), anxiety (49%), and agitation/aggression (45%). NPI individual item change from baseline scores at Week 24 using a last observation carried forward (LOCF) analysis showed benefits with donepezil treatment compared with placebo for all items, with significant treatment differences for depression/dysphoria, anxiety, and apathy/indifference (p < .05). Symptoms present at baseline that improved significantly for donepezil- compared with placebo-treated patients at Week 24 LOCF included anxiety, apathy/indifference, and irritability/lability (p < .05). When patients who were not receiving psychoactive medications at baseline were analyzed separately, significant improvements in NPI (continued) 12-item total score were observed with donepezil compared with placebo at most visits and at Week 24 LOCF (p < .05). Behavioral symptoms of the magnitude observed in this moderate to severe AD population improved with donepezil.",2003.0,0,0
648,12671523,High-dose olanzapine for treatment-refractory schizophrenia.,Vladimir Lerner,"To date there is no common or adequate therapeutic strategy for treatment of refractory schizophrenic patients. Increasing antipsychotics' doses in treatment-resistant schizophrenic patients is the most common intervention used by clinicians. Olanzapine is an atypical antipsychotic, which in a number of double-blind, placebo-controlled studies has been found to be more effective than haloperidol for the treatment of positive and negative symptoms of schizophrenia. During the last few years there have been several reports of successful results in prescribing olanzapine at dosages of more than 25 mg/day for treatment-resistant schizophrenic and schizoaffective patients. This report presents the results from the treatment of three resistant schizophrenic patients treated successfully with high dosages of olanzapine (35, 40, and 60 mg/day). None of the patients had any side effects, including abnormal laboratory levels and weight gain. The results and literature data suggest that in clinical practice some schizophrenic patients resistant to conventional neuroleptic treatment and not responding to olanzapine at recommended dosages as high as 20 mg/day may respond to higher dosages such as 40 or 60 mg/day, and these dosages are well tolerated. Further prospective clinical studies are needed.",2003.0,0,0
649,12671528,Donepezil as add-on treatment of psychotic symptoms in patients with dementia of the Alzheimer's type.,Joseph Bergman; Izidor Brettholz; Michael Shneidman; Vladimir Lerner,"Traditionally, the neuropsychiatric symptoms of Alzheimer's disease (AD) have been managed with neuroleptics or benzodiazepines, which have serious side effects. Preliminary observations suggest the possible value of cholinesterase inhibitors in the amelioration of psychotic symptoms in patients with dementia of the Alzheimer's type, dementia with Lewy bodies, and in patients with Parkinson's disease. Twelve inpatients with AD with psychotic symptoms and lack of improvement of their delusions/hallucinations during perphenazine treatment (8 mg/day) for 3 weeks received random open-label donepezil 5 mg daily in addition to an ongoing treatment of 8 mg/day perphenazine or 16 mg/day perphenazine. Assessments conducted at baseline and after weeks 2 and 4 included the Mini-Mental State Examination, the Global Deterioration Scale, the Positive and Negative Symptoms Scale, and the Clinical Global Impressions scale. Frequency of extrapyramidal symptoms was measured according to the Abnormal Involuntary Movement Scale. The donepezil-perphenazine group exhibited substantially greater and clinical improvements in mental state. At the end of the trial (4 weeks), Positive and Negative Symptoms Scale scores revealed significant differences between both groups (p = 0.006). The Clinical Global Impressions scale and the Mini-Mental State Examination scores also showed significant differences between the donepezil-perphenazine group and the perphenazine group (p = 0.028 and p = 0.027 respectively). No significant differences were found in the Global Deterioration Scale scores. Abnormal Involuntary Movement Scale scores showed a significant deterioration in extrapyramidal symptoms in the perphenazine group compared with the donepezil-perphenazine group (p = 0.016). Donepezil augmentation of neuroleptics may be appropriate for those patients for whom neuroleptic monotherapy either does not lead to symptom remission or is associated with intolerable adverse effects. This was an open-label study and there is need for larger studies with double-blind control and a long-term study design to define the efficacy of donepezil for patients with AD and psychotic symptoms.",2003.0,0,0
650,12680744,"Effects of acute procyclidine administration on prepulse inhibition of the startle response in schizophrenia: a double-blind, placebo-controlled study.",Veena Kumari; Elizabeth Zachariah; Adrian Galea; Hugh C Jones; Mrigen Das; Ravi Mehrotra; David Taylor; Tonmoy Sharma,"Prepulse inhibition (PPI) of the startle response refers to a reduction in response to a strong stimulus (pulse) if this is preceded shortly by a weak non-startling stimulus (prepulse). Consistent with theories of deficiencies in early stages of information processing, PPI is found to be reduced in patients with schizophrenia. Atypical antipsychotics are found to be more effective than typical antipsychotics in improving PPI in this population. Anticholinergic drugs are often used to control extrapyramidal symptoms induced by antipsychotic medication, especially by typical antipsychotics, in schizophrenic patients and are known to disrupt cognitive functions in both normal and schizophrenic populations. The effect of anticholinergics on PPI in schizophrenia has not yet been examined. This study determined the effects of procyclidine, an anticholinergic drug, on PPI in patients with schizophrenia given risperidone or quetiapine and not on any anticholinergic drugs, employing a placebo-controlled, cross-over design. Under double-blind conditions, subjects were administered oral 15 mg procyclidine and placebo on separate occasions, 2 weeks apart, and tested for acoustic PPI (prepulse 8 dB and 15 dB above the background and delivered with 30-ms, 60-ms and 120-ms prepulse-to-pulse intervals). Procyclidine significantly impaired PPI compared to placebo (assessed as percentage reduction) with 60-ms prepulse-to-pulse trials and increased the latencies to response peak across all trials. The use of anticholinergics needs to be carefully controlled/examined in investigations of information processing deficits using a PPI model and reduced to the minimum level in clinical care of schizophrenia.",2003.0,0,0
651,12680889,Valproate overdose: a comparative cohort study of self poisonings.,Geoffrey K Isbister; Corrine R Balit; Ian M Whyte; Andrew Dawson,"Based on individual case reports of massive overdoses, valproate is often regarded as having significant toxicity. This study aimed to describe the epidemiology of valproate poisoning and the spectrum of its clinical effects. Consecutive valproate poisonings were identified and compared with other anticonvulsant overdoses and all other poisonings, from a prospective database of poisoning admissions presenting to a regional toxicology service. National prescription data for the same period were obtained. There were 79 patients with valproate poisoning from January 1991 to November 2001, 15 cases with valproate alone. Of the 15 cases, drowsiness occurred in two patients (both taking> 200 mg kg-1), vomiting occurred in four and tachycardia in five. In patients co-ingesting other medications, moderate to severe effects were consistent with the co-ingestants. There was one death not directly related to valproate. One patient had metabolic acidosis and thrombocytopaenia consistent with severe valproate toxicity. Comparison of valproate, carbamazepine, phenytoin and control groups showed that length of stay for both phenytoin and carbamazepine was significantly longer than for valproate (P < 0.0001), and there was a significantly increased risk of intensive care unit admission for carbamazepine vs valproate (OR 2.73; 95% CI 1.22, 6.28; P = 0.015). Although valproate prescriptions increased over the 10 years, there was relatively greater increase in the incidence of valproate poisoning. The odds of a valproate overdose in 1992 compared with carbamazepine were 0.29 (95% CI 0.07, 1.28; P = 0.141), but in 2001 were 2.73 (95% CI 1.38, 5.39; P = 0.004). Valproate causes mild toxicity in the majority of cases. Massive overdoses of greater than 400 mg kg-1 can cause severe toxicity, but these are uncommon. The older anticonvulsants phenytoin and carbamazepine remain a greater problem than valproate in overdose.",2003.0,0,0
652,12680896,Assessment of treatment response in mania: commentary and new findings.,Ross J Baldessarini,"Assessment of therapeutic interventions in bipolar disorder is complicated by rapid, complex clinical changes, high placebo-response rates, and varying times to specific levels of clinical recovery that may not be adequately reflected in averaged rating-scale scores particularly in acute mania, calling for improved methods to evaluate treatment responses. Chengappa et al. (1). propose operational criteria for specific outcomes based on rating-scale data from two placebo-controlled trials of olanzapine in mania. These trials and other recent research were considered in commenting on the design, conduct, analysis and interpretation of experimental therapeutic trials in mania and to optimize olanzapine versus placebo contrasts by systematically varying end-point criteria for mania (YMRS) and depression (HDRS) ratings. Olanzapine versus placebo responses were optimally separated at scores of 10 for final paired mania and depression ratings, or 5 for each rating scale considered separately. Use of empirically determined end-points derived from standard rating scales used in experimental therapeutics research in mood disorders can improve both outcome-assessment and separation of active treatment from placebo responses in acute mania.",2003.0,0,0
653,12680897,"Bipolar depression: criteria for treatment selection, definition of refractoriness, and treatment options.",Lakshmi N Yatham; Joseph R Calabrese; Vivek Kusumakar,"This paper reviews controlled studies of bipolar depression, outlines criteria for choosing treatment, defines refractoriness in bipolar depression, and provides options for treatment of refractory bipolar depression. Controlled studies that examined the efficacy of treatments for acute and long-term treatment of bipolar depression were located through electronic searches of several databases and by manual crosssearch of references and proceedings of international meetings. Lithium comes close to fulfilling the proposed criteria for first-line treatment for bipolar depression, and those not responding to lithium should be considered to have refractory bipolar depression. Options for such patients include addition of lamotrigine or a second mood stabilizer, or a newer-generation antidepressant such as a serotonin re-uptake inhibitor or bupropion, or the atypical antipsychotic olanzapine. Although there is a paucity of research in the treatment of refractory bipolar depression, available data could be used for providing rational treatment options for such patients. However, further studies are urgently needed to determine which options are most appropriate for which type of patients.",2003.0,0,0
654,12682319,A placebo-controlled trial of risperidone in Tourette syndrome.,L Scahill; J F Leckman; R T Schultz; L Katsovich; B S Peterson,"To evaluate the efficacy and safety of risperidone in children and adults with Tourette syndrome. This was an 8-week, randomized, double-blind, placebo-controlled trial. The primary outcome measure was the Total Tic score of the Yale Global Tic Severity Scale (YGTSS). Thirty-four medication-free subjects (26 children and 8 adults) ranging in age from 6 to 62 years (mean = 19.7 +/- 17.0 years) participated. YGTSS Total Tic scores were similar at baseline (26.0 +/- 5.1 for risperidone vs 27.4 +/- 8.5 for placebo). After 8 weeks of treatment (mean daily dose of 2.5 +/- 0.85), the 16 subjects on risperidone showed a 32% reduction in tic severity from baseline, compared to a 7% reduction for placebo patients (n = 18) (F[2,64] = 6.07; p = 0.004). The 12 children randomized to risperidone showed a 36% reduction in tic symptoms compared to an 11% decrease in the 14 children on placebo (F[2,48] = 6.38; p = 0.004). Two children on risperidone showed acute social phobia, which resolved with dose reduction in one subject but resulted in medication discontinuation in the other. A mean increase in body weight of 2.8 kg was observed in the risperidone group compared to no change in placebo (F[2,64] = 10.68; p = 0.0001). No extrapyramidal symptoms and no clinically significant alterations in cardiac conduction times or laboratory measures were observed. Risperidone appears to be safe and effective for short-term treatment of tics in children or adults with Tourette syndrome. Longer-term studies are needed to evaluate the durability of efficacy and safety over time.",2003.0,0,0
655,12682669,,,,,0,0
656,12683258,"Cognitive function in schizophrenia. Deficits, functional consequences, and future treatment.",Tonmoy Sharma; Lena Antonova,"This article has discussed the relationship between cognitive deficits and functional outcome in schizophrenia. This relationship was noted first by Kraepelin and Bleuler at the beginning of the twentieth century. With the introduction of conventional neuroleptics, the focus shifted toward the treatment of positive symptoms. In the past few decades, cognitive dysfunction has been recognized as a fundamental feature of schizophrenia and has been shown repeatedly to have a negative association with functional outcome [6]. Improvement in cognitive functioning became one of the most important clinical targets in the treatment of schizophrenia in the 1990s [82]. Main domains of cognition that are disrupted significantly in schizophrenia include attention, executive function, verbal and visuospatial working memory, and learning and memory. Although conventional antipsychotics are effective in treating positive symptoms, they lack the ability to improve cognitive impairment and produce poor functional outcome. Previous research has shown superior efficacy of atypical antipsychotics on cognitive impairments in schizophrenia compared with conventional antipsychotics. Because the heterogeneity of atypical antipsychotics in their pharmacologic properties, they have differential profiles of cognitive efficacy in patients with schizophrenia. Establishing the cognitive profile of each atypical antipsychotic is an important task. This knowledge can be used to address individual cognitive problems and needs. Because cognitive deficits have been shown to have associations with different aspects of clinical symptoms, limited learning in rehabilitation programs, and functional outcome in schizophrenia, targeting individual cognitive deficits would lead to greater treatment success in terms of clinical and functional outcome. Although atypical antipsychotics have some benefit on cognitive function, further efforts to improve cognitive function are required. Attempts at improving cognition in schizophrenia with specific cognitive enhancers pharmacologically and psychological therapies such as cognitive remediation might lead to better functional outcome in patients with schizophrenia.",2003.0,0,0
657,12683261,Is schizophrenia a metabolic brain disorder? Membrane phospholipid dysregulation and its therapeutic implications.,Sahebarao P Mahadik; Denise R Evans,"The dysregulation of membrane phospholipid metabolism exists throughout the body from the onset of psychosis in schizophrenic patients. This dysregulation is primarily due to altered contents of phospholipid bound EPUFAs, AA and DHA. These EPUFAs are highly enriched in the brain and are crucial for brain and behavioral development. A phospholipid metabolic defect may preexist the onset of psychosis, even through early embryonic stages. Because these membrane phospholipids play a crucial role in the membrane receptor-mediated signal transduction of several neuro-transmitters and growth factors, their altered metabolism may contribute to the reported abnormal information processing in schizophrenia. Severity of symptoms seems to correlate with the membrane AA and DHA status, which is influenced by patients' dietary intake and lifestyle. Such a metabolic defect can be prevented, however, and some membrane pathology can be corrected by dietary supplementation with a combination of AA and DHA and antioxidants such as vitamins E and C. In schizophrenia, it may be advisable to provide supplementation at the early stages of illness, when brain has a high degree of plasticity. Finally, at this time, supplementation has to be considered as an augmentation of conventional antipsychotic treatment.",2003.0,0,0
658,12683262,Schizophrenia in late life.,Larry E Tune; Carl Salzman,"Antipsychotics, whether conventional or atypical, are the primary class of medications for the treatment of late-life psychosis. Although the efficacy of neuroleptics in controlling agitation and psychosis associated with late-life dementia has been established, evidence for their efficacy in treating core symptoms of late-life schizophrenia other than behavioral dyscontrol is just emerging. More controlled clinical trials are needed. The available data suggest that atypical neuroleptics are therapeutically efficacious, with a more favorable side-effect profile than conventional neuroleptics. This literature further suggests the importance of low therapeutic doses and careful attention to the emergence of side effects. Future studies must distinguish between patients with true schizophrenic disorder and patients with psychosis secondary to dementia, affective illness, or organic impairment. Patients must be characterized further as having EOS versus LOS because these disorders may differ in symptom profile, course, and response to treatment. There is also a need in future studies to separate out the results of treatment of patients with EOS who have been severely ill for most of their lives from those whose course has been less devastating. Within these two groups, treatment response, effective dose ranges, and sensitivity to side effects can be scrutinized more carefully.",2003.0,0,0
659,12683264,The new and evolving pharmacotherapy of schizophrenia.,Robin Emsley; Piet Oosthuizen,"Based on the evidence presented here, the following tentative conclusions can be drawn. Atypical antipsychotics (except amisulpride) have shown superiority over placebo in acute schizophrenia. Compared with conventional antipsychotics, they are at least as effective. Generally, analyses employing conservative criteria (e.g., Cochrane reviews) report few efficacy differences between atypical and conventional agents. There are now many well-controlled studies indicating modest advantages for the atypical antipsychotics, however, particularly in specific symptom domains. For the treatment of negative symptoms, olanzapine and to a lesser extent amisulpride seem most promising. Risperidone, olanzapine, and quetiapine display advantages in improving cognitive and depressive symptoms. There are indications that the atypical antipsychotics are associated with decreased likelihood of rehospitalization and improved quality of life. In head-to-head comparisons of atypical antipsychotics, none have shown consistent efficacy advantages. In severely refractory samples, no atypical antipsychotics have consistently been shown to be as effective as clozapine or superior to conventional agents. There are indications, however, that risperidone, olanzapine, and quetiapine have advantages over conventional agents in less severely refractory patients. Few maintenance RCTs have been published, and efficacy advantages for atypical antipsychotics in prospective RCTs in first-episode schizophrenia have not been reported.",2003.0,0,0
660,12683265,Understanding the new and evolving profile of adverse drug effects in schizophrenia.,Donna A Wirshing; Joseph M Pierre; Stephen M Erhart; Jennifer A Boyd,"This article has reviewed the emerging side-effect profiles of second-generation antipsychotic medications. Although these medications have favorable extrapyramidal side-effect profiles, clinicians must be aware of their propensity to cause weight gain, glucose and lipid abnormalities, and cardiac and sexual side effects. If clinicians are proactive about warning patients about these side effects and appropriately monitoring them, further morbidity and mortality may be prevented in this patient population. Initial choices of medication should be made based on the relative side-effect profiles in light of a particular patient's medical status. In the future, new treatments may be developed, with even fewer side effects.",2003.0,0,1
661,12683268,Treatment of the psychotic patient who is violent.,Peter F Buckley; Stephen G Noffsinger; Douglas A Smith; Debra R Hrouda; James L Knoll,"Aggression among patients with serious mental illness occurs relatively infrequently, but it is a significant concern for patients, relatives, mental health professionals, and the public. Recognition of this risk and providing access and continuity of appropriate psychiatric care should be major clinical and administrative objectives in the management of violence in psychotic patients. To date, pharmacologic approaches have been unclear and inconsistent. At present, typical antipsychotics continue to have a primary role in acute management and in long-term management, in which noncompliance necessitates the use of long-acting depot neuroleptic preparations. Atypical antipsychotics in acute and long-acting intramuscular forms doubtless will influence and expand the choice for acute management of hostile psychotic patients and the long-term management of poorly compliant patients who are at risk to become violent on relapse. Persistent aggression should be managed by atypical antipsychotics with a preferential indication for clozapine, for which the most data on efficacy are available. The role of adjunctive medications is presently unclear. A major focus of care should be to refine legal processes and to conduct intervention studies aimed at enhancing treatment compliance. Violence risk reduction is not only crucial from a societal perspective, but also it is a humanitarian necessity to alleviate the burden and stigma for patients with serious mental illness.",2003.0,0,0
662,12684609,Amisulpride versus risperidone in the treatment of schizophrenic patients: a double-blind pilot study in Taiwan.,Tzung J Hwang; Shin-Min Lee; Hsiao-Ju Sun; Hsin-Nan Lin; Shih-Jen Tsai; Ying-Chiao Lee; Ying-Sheue Chen,"The atypical antipsychotics, amisulpride and risperidone, have different receptor affinity characteristics. Although the relative efficacy of both drugs compared to conventional antipsychotics is well established, it remains unclear how the efficacy of amisulpride compares with risperidone. There have been no controlled studies comparing amisulpride to risperidone in Asian patients. The purpose of this study was to compare the efficacy and safety of amisulpride with that of risperidone in Taiwanese schizophrenic patients. Patients with productive positive symptoms (n = 48) were enrolled into this double-blind, randomized pilot study for 6 weeks. Patients received either amisulpride (400-800 mg/day) or risperidone (4-8 mg/day). Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI), Social and Occupational Functioning Assessment Scale (SOFAS), and patients' subjective responses to treatment were assessed during the trial period. Adverse events were recorded at each follow-up visit. At the end of the trial, the mean dosage was 630 +/- 134 mg/day and 6.88 +/- 1.54 mg/day for amisulpride and risperidone, respectively. There was no significant difference in the reduction of the PANSS total score (amisulpride -24.1 versus risperidone -28.4, p = 0.999), the PANSS positive subscale score (amisulpride -6.8 versus risperidone -8.3, p = 0.467), the PANSS negative subscale score (amisulpride -5.6 versus risperidone -6.4, p = 0.999), or the CGI score between the two groups. The extrapyramidal symptom ratings, the improvement in the SOFAS (amisulpride 11.1 versus risperidone 10.0) and the subjective response (amisulpride 82% versus risperidone 83%) were comparable. No serious adverse events were recorded in either treatment group. There was a statistically significant body weight gain in the risperidone group. In contrast, there was a statistically, though not clinically, significant reduction of blood pressure and heart rate in the amisulpride group. This study suggests that amisulpride is as effective as risperidone in the treatment of patients with schizophrenia. Both drugs were well tolerated, but had different side effect profiles.",2003.0,0,0
663,12691772,Efficacy of electroconvulsive therapy in treatment-resistant schizophrenia: a prospective open trial.,Wai-Kwong Tang; Gabor S Ungvari,"There is a lack of controlled trials examining the effectiveness of electroconvulsive therapy (ECT) combined with olanzapine or risperidone in treatment-resistant schizophrenia (TRS). The authors conducted a prospective, open, controlled trial of ECT in TRS in a long-term psychiatric rehabilitation unit in Hong Kong. Thirty patients with TRS from an inpatient psychiatric rehabilitation unit participated in this study. All subjects were resistant to a host of antipsychotic medications given singly or in different combinations. In addition, they were also resistant to or they refused clozapine treatment. Fifteen patients completed a course of ECT consisting of 8-20 sessions. Fifteen patients who refused ECT formed the control Subjects were assessed at baseline, 1 week, 1 month, and 2 months after their last ECT. Assessment instruments included the Brief Psychiatric Rating Scale (BPRS), Hamilton Depression Rating Scale (HDRS), Scale for the Assessment of Negative Symptoms (SANS), Global Assessment Scale (GAS), Clinical Global Impression (CGI), CGI Severity of Illness [CGI(SOI)], CGI Global Improvement [CGI(GI)], Nurses' Observation Scale for Inpatient Evaluation (NOSIE-30), and occupational therapists' rating of the subjects' functioning with respect to work (OT-W), social (OT-S), and leisure (OT-L) activities. In comparison with the control group, the ECT group showed statistically significant improvement only in the GAS and CGI at each posttreatment evaluation. There was a trend for ECT to reduce positive and negative symptoms, although the rate of improvement did not reach statistically significant levels. ECT augmentation of risperidone and olanzapine is of marginal efficacy compared to reports of the greater augmentation of these antipsychotics with other agents.",2003.0,0,0
664,12691783,Safety and effectiveness of olanzapine versus conventional antipsychotics in the acute treatment of first-episode schizophrenic inpatients.,Julio Bobes; Juan Gibert; Antonio Ciudad; Enrique Alvarez; Fernando Cañas; José-Luis Carrasco; Josep Gascón; Juan-Carlos Gómez; Miguel Gutiérrez,"To assess the safety and effectiveness of olanzapine compared to typical antipsychotics in the treatment of first-episode schizophrenics in acute psychiatric inpatient wards. Data were collected from a prospective, comparative, nonrandomized, open, observational study of 904 inpatients with schizophrenia. One hundred and fifty-eight patients fulfilled the criteria for first-episode schizophrenia, defined as (1) the International Classification of Diseases: Mental and Behavioral Disorders, 10th ed. (ICD-10) diagnosis of schizophrenia, (2) antipsychotic nai;ve, and (3) a course of illness of less than 5 years. Eighty-nine (56.3%) of these patients were assigned to the olanzapine treatment group (OLZ) and 69 (43.7%) to the control group that received treatment with conventional antipsychotics (CON). Safety was evaluated in terms of the spontaneous adverse events reported and a specific questionnaire for extrapyramidal symptoms (EPS). Clinical status was measured by means of the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression of Severity (CGI-S). Clinical response was defined as the baseline-endpoint decrease in BPRS>40% plus an endpoint BPRS<18 or an endpoint CGI</=3. The rate of clinical response to treatment in the OLZ was 76.7%, compared to 54.4% in the CON (chi(2)=8.48; P=.003). Olanzapine was significantly more effective than conventional antipsychotics in lowering the total BPRS score (P=.0003), as well as each of the following BPRS subscales: positive symptoms (P=.0019), negative symptoms (P<.0001), depression (P=.018), and agitation (P=.007), even after mean scores were adjusted for their baseline value and disease duration. Olanzapine also proved to be significantly superior to conventional antipsychotics in lowering mean CGI scores (P=.013). The frequency with which new EPS appeared, or previously existing ones worsened, was significantly greater in the CON than in the OLZ (55.1% vs. 13.5%; P<.001). Anticholinergics were needed more frequently in the CON than in the OLZ (58.0% vs. 6.7%; P<.0001). The results of this observational, naturalistic study show that olanzapine is safe and effective in a nonselected sample of acute, first-episode schizophrenic inpatients.",2003.0,0,1
665,12691784,The influence of olanzapine on immune cells in patients with schizophrenia.,Mustafa Bilici; Yavuz Tekelioğlu; Saniye Efendioğlu; Ercüment Ovali; Metin Ulgen,"In vitro and preclinical studies show that biochemical and behavioral effects of olanzapine are quite similar to those of clozapine. In recent years, some cases of reported agranulocytosis due to olanzapine have been published. However, none of these studies compared the hematological and immune parameters before and after treatment. The present study is aimed at investigating the influence of olanzapine on the immune cell parameters by comparing these before and in the third month of olanzapine treatment in patients of schizophrenia. Twenty patients who were diagnosed as schizophrenic depending on the DSM-IV diagnostic criteria were included in the study. The immune parameters of patients were compared by measuring them before the treatment and 3 months after treatment. Immune parameters were analyzed by using flow-cytometry equipment labeled Coulter Epics Elite ESP. The positivity of cell-surface antibody was evaluated as percentage. The rates of CD8 in the third month of the treatment were considerably increased relative to pretreatment. Furthermore, rates of CD4/CD8 were significantly decreased in the third month of the treatment relative to before treatment. These findings suggest that immune impairment may occur during olanzapine treatment in patients with schizophrenia.",2003.0,0,0
666,12691793,Quetiapine treatment of psychotic symptoms and aggressive behavior in patients with dementia with Lewy bodies: a case series.,Hitoshi Takahashi; Keizo Yoshida; Takio Sugita; Hisashi Higuchi; Tetsuo Shimizu,"The authors describe here the clinical outcomes of quetiapine treatment in nine patients with dementia with Lewy bodies (DLB) who manifested psychotic symptoms and aggressive behavior. Patients who had a score of 3 or higher on any of the three items of the Neuropsychiatric Inventory (NPI), agitation/aggression, hallucinations, and delusions, were given quetiapine 25-75 mg/day. Each patient's clinical status was assessed at baseline and after 4 and 8 weeks of treatment by using the NPI, Mini-Mental State Examination (MMSE), and Simpson-Angus Scale (S-A). Five of nine patients had a positive response with a decline of more than 50% in the sum of scores for three items of the NPI. The other three patients withdrew from quetiapine treatment due to somnolence or orthostatic hypotension. The remaining patient exhibited no clinically significant change in the NPI score. The S-A scale was not affected by quetiapine treatment in any patient. These findings suggest that quetiapine may be effective in treating psychotic symptoms and disruptive behavior in some patients with DLB. Further placebo-controlled, randomized, double-blind trials with this drug are needed to confirm this observation.",2003.0,0,0
667,12695313,Suicide risk in placebo vs active treatment in placebo-controlled trials for schizophrenia.,Jitschak G Storosum; Barbara J van Zwieten; Tamar Wohlfarth; Lieuwe de Haan; Arif Khan; Wim van den Brink,"If there is an increased risk of suicide in the placebo arms of placebo-controlled studies in patients with schizophrenia, it would be a strong ethical argument against the conduct of placebo-controlled studies in this patient population. We tested whether the risk of suicide and attempted suicide in the placebo arms of placebo-controlled studies among patients with schizophrenia is higher than in the active treatment arms of such studies. All placebo-controlled double-blind studies that were part of a registration dossier for the indication schizophrenia, and that were submitted to the regulatory authority of the Netherlands from January 1, 1992, through December 31, 2002, were reviewed for suicide and attempted suicide. In 31 studies, 7152 patients were included: 1888 in placebo groups (398.2 person-years) and 5264 in active compound groups (981.3 person-years). One suicide occurred in the placebo groups (0.05%, or an incidence rate of 251 per 100,000 years of exposure) and 1 in the active compound groups (0.02%, or an incidence rate of 102 per 100,000 years of exposure). This difference was not statistically significant. Two attempted suicides occurred in the placebo groups (0.11%, or an incidence rate of 502 per 100,000 years of exposure) and 11 in the active compound groups (0.21%, or an incidence rate of 1121 per 100,000 years of exposure). This difference was also not statistically significant. Concern about increased risk of suicide or attempted suicide in the placebo group should not be an argument against the conduct of placebo-controlled trials in schizophrenia, provided that appropriate precautions are taken.",2003.0,0,0
668,12698209,Aripiprazole: efficacy and tolerability profile of a novel-acting atypical antipsychotic.,Peter F Buckley,"Aripiprazole, the latest atypical antipsychotic to come to clinical practice, has a proposed mechanism of action different to other agents, most notably in its partial agonist action at dopamine (D2) receptors and at serotonin (5HT1A) receptors. Placebo-controlled comparative trials of aripiprazole confirm efficacy for positive, negative and general psychopathology. Treatment-emergent adverse effects appear low. Aripiprazole is associated with low propensity for extrapyramidal side effects, an absence hyperprolactinemia and a low propensity for weight gain. Aripiprazole's clinical role will be determined by clinical experience, additional phase IV studies, and comparative information for this agent with respect to the efficacy and tolerability profiles of other atypical antipsychotic medications.",2003.0,0,0
669,12700715,Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine.,Jeffrey A Lieberman; Michael Phillips; Hongbin Gu; Scott Stroup; Peiyan Zhang; Lan Kong; Zhongfu Ji; Gary Koch; Robert M Hamer,"The purported advantages of second-generation or ""atypical"" antipsychotics relative to first-generation antipsychotics have not been examined in patients with a first episode of schizophrenia. This flexible-dose study examined efficacy and safety in a randomized, double-blind, 52-week trial, comparing chlorpromazine (CPZ) and clozapine (CLZ) in treatment naive patients experiencing their first episode of schizophrenia. In all, 160 inpatients with first-episode schizophrenia or schizophreniform disorder were randomized to CPZ or CLZ and followed them for 52 weeks or until dropout. The primary efficacy measure was time to first remission and proportion of time remaining in remission. The analysis was supplemented by comparisons on a profile of clinical symptoms and side effects. Of these first-episode patients, 80% achieved remission within 1 year (79% CPZ, 81% CLZ). The Kaplan-Meier estimated median time to first remission was 8 weeks for CLZ vs 12 weeks for CPZ (chi(2)(1)=5.56, p=0.02). Both the rate of first achieving remission and the odds for being in remission during the trial were almost doubled for the CLZ group in comparison with the CPZ group. At 12 weeks, CLZ was superior on many rating scale measures of symptom severity while CPZ was not superior on any. These symptom differences remained significant when controlling for EPS differences. By 52 weeks many of the symptom differences between groups were no longer significantly different. Generally, CLZ produced fewer side effects than CPZ, particularly extrapyramidal side effects. There was no significant difference between treatments in weight change or glucose metabolism. For each prior year of untreated psychosis, there was a 15% decrease in the odds of achieving remission (OR=0.85; CI 0.75-0.95). A high proportion of first-episode patients remitted within 1 year. We detected no difference in the proportion of first-episode patients receiving CLZ or CPZ that achieved remission. However, first-episode patients receiving CLZ remitted significantly faster and remained in remission longer than subjects receiving CPZ. While the CLZ group showed significantly less symptomatology on some measures and fewer side effects at 12 weeks, the two treatment groups seemed to converge by 1 year. Longer duration of untreated psychosis was associated with lower odds of achieving remission.",2003.0,0,0
670,12702892,The efficacy of olanzapine monotherapy for acute hypomania or mania in an outpatient setting.,Ellen B Dennehy; Kimberly Doyle; Trisha Suppes,"Randomized controlled trials have demonstrated the efficacy of olanzapine for treating acute mania or depression symptoms in patients with bipolar disorder. We aimed to evaluate the effectiveness of this medication in more usual care outpatient settings. A consecutive series of 15 patients entered an open, uncontrolled 8-week trial of olanzapine monotherapy. Inclusion criteria included significant hypomanic or manic symptoms greater than or equal to 15 on the Young Mania Rating Scale and no psychotic symptoms. The majority of patients experienced significant decreases in mania ratings and more limited improvement on depression ratings. Most patients reported adverse events consistent with other studies, but few discontinued due to these complaints. This case series highlights the individual variation in response to a proven medication. Furthermore, it highlights that those medications effective at one end of the mood spectrum may not be equally or simultaneously effective with other symptoms, emphasizing the complexity of treating bipolar illness.",2003.0,0,0
671,12716270,Divalproex sodium versus olanzapine in the treatment of acute mania in bipolar disorder: health-related quality of life and medical cost outcomes.,Dennis A Revicki; L Clark Paramore; Kenneth W Sommerville; Alan C Swann; John M Zajecka; Depakote Comparator Study Group,"Divalproex sodium is a mood stabilizer used in the United States for the treatment of acute mania associated with bipolar disorder. Recently, olanzapine, an atypical antipsychotic, was approved for the treatment of acute mania. This study compares the clinical, health-related quality of life (HRQL), and economic outcomes of divalproex and olanzapine in the treatment of acute mania associated with bipolar disorder. This 12-week, double-blind, double-dummy, randomized clinical trial included 120 subjects with DSM-IV bipolar disorder type I hospitalized for an acute manic episode recruited from 21 U.S. clinical centers. Subjects were randomly assigned to treatment with either divalproex or olanzapine and were followed in hospital for up to 21 days. If after 21 days clinical improvements (based on the Mania Rating Scale [MRS]) were not observed, subjects were discontinued. Subjects showing clinical improvement were treated for up to 12 weeks. HRQL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) after hospital discharge (baseline) and at 6 and 12 weeks. Medical resource use and costs were collected over the 12-week study. A total of 120 subjects (N = 63 divalproex, N = 57 olanzapine) were randomized, and 78 (65%) were followed beyond 21 days. No statistically significant differences between the treatment groups for baseline-to-endpoint MRS or Q-LES-Q scores were observed. Total 12-week outpatient medical costs were significantly lower for the divalproex-treated group (541 US dollars) compared with the olanzapine-treated group (1080 US dollars) (p =.004). There was no significant difference in total medical costs between the 2 groups (divalproex = 13,703 US dollars; olanzapine = 15,180 US dollars; p =.88). Divalproex is associated with lower 12-week outpatient costs compared with olanzapine. Divalproex and olanzapine have similar short-term effects on clinical or HRQL outcomes in bipolar disorder subjects.",2003.0,0,0
672,12716824,Patients on atypical antipsychotic drugs: another high-risk group for type 2 diabetes.,Michael E J Lean; Frank-Gerald Pajonk,"Patients with schizophrenia are more likely than the general population to develop diabetes, which contributes to a high risk of cardiovascular complications; individuals with schizophrenia are two to three times more likely to die from cardiovascular disease than the general population. The risk of diabetes, and hence cardiovascular disease, is particularly increased by some of the new atypical antipsychotic drugs. Individuals taking an atypical antipsychotic drug, particularly younger patients under 40 years of age (odds ratio 1.63, 95% CI 1.23-2.16), represent an underrecognized group at high risk of type 2 diabetes. The mechanisms responsible for antipsychotic-induced diabetes remain unclear. Hypotheses include these drugs' potential to cause weight gain, possibly through antagonism at the H(1), 5-HT(2A), or 5-HT(2C) receptors. Other mechanisms independent of weight gain lead to elevation of serum leptin and insulin resistance. Patients with psychoses have difficulties with diet and lifestyle interventions for diabetes and weight management. If hyperglycemia develops, withdrawal from antipsychotic medication will often be inappropriate, and a change to an atypical antipsychotic drug with lower diabetogenic potential should be considered, especially in younger patients. Management of psychoses should routinely include body weight and blood glucose monitoring and steps to promote exercise and minimize weight gain. Careful collaboration between the psychiatric and diabetology teams is essential to minimize the risk of diabetes in patients taking atypical antipsychotic medication and for effective management when it develops. This collaboration will also help minimize the already high risk of cardiovascular disease in individuals with schizophrenia.",2003.0,0,1
673,12721815,"Olanzapine, risperidone and haloperidol in the treatment of adolescent patients with schizophrenia.",D Gothelf; A Apter; J Reidman; A Brand-Gothelf; Y Bloch; G Gal; L Kikinzon; S Tyano; R Weizman; G Ratzoni,"To evaluate and compare the drug response and side effects of adolescents with schizophrenia treated with olanzapine, risperidone, and haloperidol. Forty-three patients were treated with olanzapine (n = 19), risperidone (n = 17) and haloperidol (n = 7) for 8 weeks in an open clinical trial. Clinical improvement was evaluated with the Positive and Negative Syndrome Scale (PANSS), and side effects with the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Significant clinical improvement was observed by week 4 for all medications. Olanzapine and haloperidol induced fatigability more frequently than risperidone. Haloperidol was associated with a higher frequency of depression and more severe extrapyramidal symptoms. To the best of our knowledge this is the first study in adolescents to compare the efficacy and side effects of three most commonly prescribed antipsychotic medications. Olanzapine, risperidone and haloperidol appear to be equally effective for the treatment of schizophrenia in adolescent inpatients but have different side effect profiles.",2003.0,0,0
674,12724254,Lithium augmentation in treatment-refractory unipolar depression.,W Lee; A Cleare,,2003.0,0,0
675,12725017,[Current concepts of pharmacological treatment in schizophrenia].,Marek Jarema,"The modern concepts of pharmacotherapy of schizophrenia, with the special emphasis put on new antipsychotic drugs were presented. The attention was put on the need for careful evaluation of the patient's state: the diagnosis, treatment which the patient receives and compliance with the treatment. It was stated that modern concepts of treatment of schizophrenia do not solely rely on the use of modern drugs, but include the multidirectional therapeutic actions with an active participation of the patient and his/her relatives.",2003.0,0,0
676,12725025,[Effect of olanzapine treatment on cognitive functions in patients with schizophrenia].,Piotr Radziwiłłowicz; Wioletta Radziwiłłowicz; Joanna Lis,"The aim of this study was to assess whether olanzapine treatment results in an improvement of cognitive functions that became impaired by the schizophrenic process. The correlation of the intensity of schizophrenic symptoms and duration of the disease with the level of cognitive functions were also examined. The schizophrenic patients were examined in three steps: before beginning of olanzapine treatment, after 6 weeks of treatment, and after approximately 12 months since the beginning of the olanzapine treatment, 36 patients were examined (9 female, 27 male) aged 20-53 (X = 25.4). The following tests were applied: Positive and Negative Syndromes Scale--PANSS, Squire's Memory Questionnaire, sub-scales: Digit span and Similarities of the Wechsler's Intelligence Scale, Long-term memory sub-test of the Choynowski's Memory Scale, Diagnosis of Brain Damages, Clock Completion Test, Decroly's Box. The olanzapine treatment of schizophrenia was characterised by significant antipsychotic efficacy including both positive and negative symptoms. The positive symptoms were associated with the attention range, the planning process context and the immediate memory with the tendency towards loosing remembrance in the process of non-verbal learning. The negative symptoms were associated with concrete conceptual thinking. Improvement of cognitive functions was noted for almost all of the examined functions. The effect of olanzapine therapy in schizophrenic patients may be regarded as personality integrating.",2003.0,0,0
677,12725026,[Subjective and objective assessment of memory functions in patients with schizophrenia treated with olanzapine].,Wioletta Radziwiłłowicz; Piotr Radziwiłłowicz,"Schizophrenic patients often complain of intellectual functioning impairment. The aim of this survey was to define the subjective memory loss by means of objective tests. The tests were carried out in three steps: before the admission to the clinic, after 6 weeks of hospitalisation, and after approximately 12 months from the beginning of the olanzapine treatment, 36 patients were examined (9 female, 27 male) aged 20-53 (X = 25.4). The following tests were applied: PANSS, Memory Questionnaire (Squire, Zouzounis 1988), subscales: Digit span and Similarities of the Wechsler Intelligence Scale, subtest for Long-term memory of the Choynowski's Memory Scale, Diagnosis of Brain Damages (Weidlich, Lamberti), Clock Completion Test, Decroly Box. The subjective assessment of memory functioning improved during the treatment with olanzapine. Before the hospitalisation and after 6 weeks of treatment patients' memory complaints were associated with the visuospatial memory. After 12 month of the olanzapine therapy the memory complaints were associated with audioverbal memory. Age, level of education and objective intensity of psychopathological symptoms did not influence patients' subjective assessment of memory functioning.",2003.0,0,0
678,12728743,"A random-assignment, double-blind, clinical trial of once- vs twice-daily administration of quetiapine fumarate in patients with schizophrenia or schizoaffective disorder: a pilot study.",K N Roy Chengappa; Haranath Parepally; Jaspreet S Brar; Jamie Mullen; Ann Shilling; Jeffrey M Goldstein,"To evaluate the efficacy and safety of administering quetiapine once vs twice daily. Utilizing a double-blind design, 21 hospitalized adult men or women with DSM-IV schizophrenia or schizoaffective disorder, who had received unchanged doses (for 2 weeks) of either 400 or 600 mg daily of quetiapine administered in 2 doses, were randomly assigned to once- or twice-daily administration for 4 weeks and then crossed over to the opposite dosing regimen for an additional 4 weeks. Standard psychopathology and safety measures were used in the study. Nearly 70% (15/21) of the subjects met the a priori efficacy responder criteria with no statistical differences in response between those assigned to once- or twice-daily quetiapine administration. Statistical analyses confirmed that most subjects maintained efficacy during the switch to once- or twice-daily administration with quetiapine. A minority (15%) did experience worsening of symptoms or orthostatic hypotension during the crossover. Quetiapine was generally well tolerated at either twice- or once-daily administration. These pilot data suggest that it is clinically feasible to switch most quetiapine-treated subjects receiving a therapeutic twice-daily dosing schedule to a once-daily regimen. A minority may experience worsening of symptoms or orthostatic hypotension during the switch. This strategy of administering quetiapine entirely at bedtime may promote improved adherence to treatment.",2003.0,0,0
679,12729864,"Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials.",Stephen R Marder; Robert D McQuade; Elyse Stock; Stephen Kaplita; Ronald Marcus; Allan Z Safferman; Anutosh Saha; Mirza Ali; Taro Iwamoto,"Aripiprazole is a novel antipsychotic with a unique mechanism of action. Presented here is a pooled analysis of safety and tolerability data from all completed short-term, placebo-controlled trials in schizophrenia from the aripiprazole clinical development program. Data were analyzed from five 4- to 6-week double-blind multicenter studies of patients hospitalized with acute relapse of schizophrenia or schizoaffective disorder randomized to aripiprazole (n=932), placebo (n=416), or haloperidol (n=201). Daily aripiprazole doses ranged from 2 to 30 mg. Safety assessments included adverse event (AE) reports, EPS scales, ECGs, weight, and prolactin, glucose and cholesterol levels. Aripiprazole was well tolerated, with similar AE incidence rates to placebo, and lower rates than haloperidol for akathisia, extrapyramidal syndrome and somnolence. Objective EPS assessments demonstrated no significant differences between aripiprazole and placebo on Simpson-Angus Scale (SAS) scores, no dose-dependent effects on Barnes Akathisia scores, and significant reductions in Abnormal Involuntary Movement Scale (AIMS) scores from baseline vs. placebo (p</=0.01). Haloperidol showed increased SAS and Barnes Akathisia scores over placebo (p</=0.01). There was minimal mean weight change with aripiprazole (+0.71 kg) and haloperidol (+0.56 kg), and a lack of QT(c) prolongation. Serum prolactin increased with haloperidol, but not aripiprazole. In conclusion, aripiprazole shows a favorable safety and tolerability profile with low potential for EPS, weight gain, prolactin elevation, QT(c) prolongation, and sedation. Aripiprazole's safety profile may offer benefits in schizophrenia treatment.",2003.0,0,1
680,12729866,Are patients enrolled in first episode psychosis drug trials representative of patients treated in routine clinical practice?,Jonathan Rabinowitz; Evelyn J Bromet; Michael Davidson,"Evidence on efficacy of antipsychotic medications comes primarily from controlled trials which select eligible consenting patients for experimental and regimented treatments, who do not abuse drugs, and are in good general health. Thus, it is not clear to what extent results are generalizable to most individuals treated for a psychotic illness who may not be eligible for such trials. This study compared characteristics of patients treated in a large randomized trial of persons with early psychosis to a cohort from a large epidemiological study of first episode psychosis. Included were the 535 patients enrolled in a controlled trial of antipsychotic medication and 179 similarly diagnosed persons from the Suffolk County Mental Health epidemiological study. Drug trial exclusion criteria were used to estimate the number of patients from the epidemiological study who would have been ineligible for the drug trial. The two samples were compared on key characteristics. Thirty-three percent (n=59) of the epidemiological sample did not meet inclusion criteria for the drug trial (due to antidepressant treatment, n=26; current substance abuse, n=18; recent suicide attempt, n=9; and for more than one reason, n=6). There were no significant differences between the two study samples on age of onset, age, gender and premorbid functioning. Drug trial patients had higher Brief Psychiatric Rating Scale (BPRS), slightly lower Clinical Global Impression (CGI), and less formal education than those in the epidemiological study. While some patients in the epidemiological sample would have been excluded from the drug trial, patients in the two studies were similar on several key variables.",2003.0,0,0
681,12729882,Olanzapine vs risperidone in the management of schizophrenia: a randomized double-blind trial in Australia and New Zealand.,Oye Gureje; Wayne Miles; Nicholas Keks; David Grainger; Timothy Lambert; John McGrath; Pierre Tran; Stanley Catts; Allen Fraser; Harry Hustig; Scott Andersen; Ann Marie Crawford,"Improved drug therapy for schizophrenia may represent the best strategy for reducing the costs of schizophrenia and the recurrent chronic course of the disease. Olanzapine and risperidone are atypical antipsychotic agents developed to meet this need. We report a multicenter, double-blind, parallel, 30-week study designed to compare the efficacy, safety, and associated resource use for olanzapine and risperidone in Australia and New Zealand. The study sample consisted of 65 patients who met DSM-IV criteria for schizophrenia, schizoaffective disorder, or schizophreniform disorder. Olanzapine-treated patients showed a significantly greater reduction in Positive and Negative Syndrome Scale (PANSS) total, Brief Psychiatric Rating Scale (BPRS) total, and PANSS General Psychopathology scores at endpoint compared to the risperidone-treated patients. Response rates through 30 weeks showed a significantly greater proportion of olanzapine-treated patients had achieved a 20% or greater improvement in their PANSS total score compared to risperidone-treated patients. Olanzapine and risperidone were equivalent in their improvement of PANSS positive and negative scores and Clinical Global Impression-Severity of Illness scale (CGI-S) at endpoint. Using generic and disease-specific measures of quality of life, olanzapine-treated patients showed significant within-group improvement in most measures, and significant differences were observed in favor of olanzapine over risperidone in Quality of Life Scale (QLS) Intrapsychic Foundation and Medical Outcomes Study Short Form 36-item instrument (SF-36) Role Functioning Limitations-Emotional subscale scores. Despite the relatively small sample size, our study suggests that olanzapine has a superior risk:benefit profile compared to risperidone.",2003.0,1,1
682,12734761,Long-term treatment of schizoaffective disorder: review and recommendations.,C Baethge,"To provide an overview of long-term treatment studies in schizoaffective disorder (SAD) and to draw conclusions for clinical decision-making. Literature was identified by searches in Medline, Embase, and the Cochrane Controlled Trials Register as well as a hand-search of handbook and journal articles. Studies were considered relevant if they reported on trials of at least 6 months duration and if they presented data for the SAD patients in particular. Thirty-nine studies met the criteria and 18 used modern diagnostic criteria, i. e., RDC, DSM-III-R, -IV, or ICD-10. The studies focused on lithium, anticonvulsants, and antipsychotics. The scientific evidence for prophylactic efficacy of the different substances is poor. Nevertheless, the data encourage the use of lithium and carbamazepine in primarily affective patients and clozapine in primarily schizophrenic patients and possibly in mainly affective patients as well. There is a considerable need for prospective and controlled studies on the long-term treatment of SAD. However, it seems to be useful to subtype the disorder of the patients into primarily affective vs. schizophrenic schizoaffective disorder and schizodepressive vs. schizobipolar and to treat accordingly.",2003.0,0,0
683,12734763,"Antipsychotic efficacy of the antidepressant trimipramine: a randomized, double-blind comparison with the phenothiazine perazine.",S Bender; H M Olbrich; W Fischer; C Hornstein; W Schoene; P Falkai; C Haarmann; M Berger; M Gastpar; Trimipramine Study Group,"The tricyclic antidepressant trimipramine exhibits several features (e. g., dopaminergic effect, molecular structure similar to a neuroleptic, receptor-binding profile similar to clozapine) that suggest its potential as an antipsychotic medication. The aim of the study was to investigate the antipsychotic potential of trimipramine in a controlled clinical trial comparing its antipsychotic efficacy with that of a neuroleptic. In a German multi-center, randomized, double-blind trial, the antipsychotic efficacy of trimipramine was compared with that of the phenothiazine neuroleptic perazine, using the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impressions (CGI). Antidepressant efficacy of both agents was measured by use of the Bech-Rafaelsen Melancholia Scale (BRMES). Ninety-five patients with acute schizophrenia (DSM-III-R) and a BPRS total score > 40 at baseline were treated with either 300-400 mg trimipramine or 450-600 mg perazine for 5 weeks. Therapeutic equivalence of both treatments (in the dosages used) could not be demonstrated (change in BPRS total score, per-protocol [PP] analysis, one-sided equivalence testing). However, intention-to-treat (ITT) as well as PP analysis showed a statistically significant decrease in the BPRS total scores in both treatment groups (PP: trimipramine, 56.5 +/- 9.8 to 44.1 +/- 17.9; perazine, 56.4 +/- 10.8 to 37.9 +/- 12.9). Significant decreases in all BPRS and PANSS subscores as well as CGI results and response rate support the antipsychotic efficacy of trimipramine. The BRMES total scores significantly decreased in both treatment groups without showing a significant difference between the two agents. Trimipramine was better tolerated than perazine and did not elicit extrapyramidal symptoms. Trimipramine failed to exhibit therapeutic equivalence to perazine in the dosages used. However, there was evidence of a substantial antipsychotic effect of trimipramine. It may be a useful medication if depressive symptoms in psychotic patients require antidepressant treatment or if other antipsychotics cannot be administered.",2003.0,0,0
684,12736282,"Effect of a mental health ""carve-out"" program on the continuity of antipsychotic therapy.",Wayne A Ray; James R Daugherty; Keith G Meador,"On July 1, 1996, as a cost-containment strategy, Tennessee's expanded Medicaid program, TennCare, rapidly shifted the provision of mental health services to a fully capitated, specialty ""carve-out"" program, TennCare Partners. We studied the effect of this transition on the continuity of antipsychotic therapy among patients with severe mental illness who had previously adhered to treatment. Study patients were 21 to 64 years of age, were enrolled throughout the study period, and had adhered to antipsychotic therapy during a 6-month base-line period that preceded the 12 months of study follow-up. The study population included 4507 patients whose follow-up began on the day the change was implemented (the post-transition cohort) and 3644 patients whose follow-up began one year earlier (the pretransition cohort). We compared the two cohorts in terms of the loss of continuity of antipsychotic therapy (missed treatment for more than 60 days during follow-up) and the mean number of days of antipsychotic therapy during follow-up. As compared with the pretransition cohort, the post-transition cohort had increased odds of loss of continuity (a multivariate odds ratio of 1.18 [95 percent confidence interval, 1.07 to 1.30], P=0.001) and a shorter mean duration of antipsychotic therapy (a mean reduction of 4.2 days [95 percent confidence interval, 1.7 to 6.7], P=0.001) during follow-up. This difference was most pronounced among high-risk patients (those requiring the administration of extended-release [depot] injections of antipsychotic medications or who had been hospitalized for psychosis) at base line, for whom continuity was most important (odds ratio for loss of continuity, 1.79 [95 percent confidence interval, 1.45 to 2.22]; P<0.001; mean reduction in the number of days of antipsychotic therapy, 14.4 days [95 percent confidence interval, 9.4 to 19.4]; P<0.001). These patients had decreased use of antipsychotic drugs immediately after the transition; the lower level persisted throughout the 12 months of follow-up. These findings underscore the need to ensure that shifts to widely used carve-out programs, which are designed primarily to contain costs, do not adversely affect clinical outcomes.",2003.0,0,0
685,12739903,"Cognitive rehabilitation with patients having persistent, severe psychiatric disabilities.",Lisa Lewis; Evelyn P Unkefer; Shaun Kelley O'Neal; Carol J Crith; Jim Fultz,"The effectiveness of cognitive rehabilitation in ameliorating the symptomatic, cognitive, and functional deficits associated with schizophrenia and schizoaffective disorders was assessed in this prospective study. Thirty-eight participants who met DSM-IV criteria were assigned to cognitive rehabilitation treatment or treatment as usual (TAU) groups, using the method of minimization to equalize groups on prognostic variables believed to affect outcome (i.e., duration and severity of illness, Clozapine). Participants were assessed at baseline, treatment end, and 3-month follow-up. Improvement across time was found for both groups in delayed visuospatial memory and visual information processing speed, and the participant's status on the prognostic variables was found to be related to level of performance on measures of delayed visuospatial memory, negative symptoms, and speech disturbance. However, the findings did not provide evidence that cognitive rehabilitation is associated with greater improvement than TAU. Nor did the findings indicate that prognosis interacted with treatment to produce differential treatment outcomes.",2003.0,0,0
686,12739998,Atypical antipsychotics in the treatment of bipolar disorder.,Stephen M Strakowski; Melissa P Del Bello; Caleb M Adler; Paul E Keck,"Atypical antipsychotic medications are widely used for the treatment of bipolar disorder. Most empirical support suggests that these medications are efficacious in the treatment of acute mania, but there is considerably less support for the utility of these drugs in other phases of bipolar disorder. However, it is likely that several of these drugs will demonstrate efficacy in relapse prevention, and perhaps antidepressant efficacy in bipolar disorder as more studies are conducted. Atypical antipsychotics offer different side effect profiles than older antipsychotics, which may be of benefit for some patients. Consequently, atypical antipsychotics provide an important treatment option for bipolar patients.",2003.0,0,0
687,12742866,Placebo or active control trials of antipsychotic drugs?,W Wolfgang Fleischhacker; Pal Czobor; Martina Hummer; Georg Kemmler; Ralf Kohnen; Jan Volavka,"The placebo-controlled trial has been the standard method to demonstrate efficacy and safety of antipsychotic drugs. We reviewed the scientific and ethical advantages and disadvantages of the placebo-controlled trial and an alternative method, the active-control trial, focusing more specifically on the active-control noninferiority trial. Recent meta-analyses indicate that a therapeutic dose of second-generation antipsychotic will very likely be statistically superior to placebo in an adequate trial, and that the average improvement of schizophrenia symptoms in a placebo arm will be small. These findings strengthen the scientific and ethical justification for the active-control noninferiority trial. New drugs in the pharmacotherapy for schizophrenia are often claimed to differ from their marketed competitors in their safety profile rather than in antipsychotic efficacy. Thus, in many cases, it appears sufficient to demonstrate mere noninferiority (rather than superiority) of antipsychotic efficacy in comparison with a standard antipsychotic. The active-control noninferiority trial is suitable for such demonstration. Sample size requirements for various equivalence margins in noninferiority trials are provided. Scientific and ethical arguments should lead to a more frequent use of the active-control noninferiority trial design.",2003.0,0,1
688,12747876,New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis.,Stefan Leucht; Kristian Wahlbeck; Johannes Hamann; Werner Kissling,"The clearest advantage of new generation, atypical antipsychotics is a reduced risk of extrapyramidal side-effects (EPS), compared with conventional compounds. These findings might have been biased by the use of the high-potency antipsychotic haloperidol as a comparator in most of the trials. We aimed to establish whether the new drugs induce fewer EPS than low-potency conventional antipsychotics. We did a meta-analysis of all randomised controlled trials in which new generation antipsychotics had been compared with low-potency (equivalent or less potent than chlorpromazine) conventional drugs. We included studies that met quality criteria A or B in the Cochrane Collaboration Handbook, and assessed quality with the Jadad scale. The primary outcome of interest was the number of patients who had at least one EPS. We used risk differences and 95% CIs as measures of effect size. We identified 31 studies with a total of 2320 participants. Of the new generation drugs, only clozapine was associated with significantly fewer EPS (RD=-0.15, 95% CI -0.26 to -0.4, p=0.008) and higher efficacy than low-potency conventional drugs. Reduced frequency of EPS seen with olanzapine was of borderline significance (-0.15, -0.31 to -0.01, p=0.07). Only one inconclusive trial of amisulpride, quetiapine, and risperidone and no investigations of ziprasidone and sertindole were identified, but some evidence indicates that zotepine and remoxipride do not lead to fewer EPS than low-potency antipsychotics. Mean doses less than 600 mg/day of chlorpromazine or its equivalent had no higher risk of EPS than new generation drugs. As a group, new generation drugs were moderately more efficacious than low-potency antipsychotics, largely irrespective of the comparator doses used. Optimum doses of low-potency conventional antipsychotics might not induce more EPS than new generation drugs. Potential advantages in efficacy of the new generation drugs should be a factor in clinical treatment decisions to use these rather than conventional drugs.",2003.0,1,1
689,12749512,A post hoc analysis of the impact on hostility and agitation of quetiapine and haloperidol among patients with schizophrenia.,K N Roy Chengappa; Jeffrey M Goldstein; Mike Greenwood; Vineeth John; Joseph Levine,"Quetiapine, a drug with a broad pharmacologic profile (similar to that of clozapine), may show benefits for agitation in patients with psychoses. Also, quetiapine may be superior to placebo and either equal or superior to haloperidol in treating this symptom. Available data for other second-generation antipsychotic agents show that quetiapine may have better efficacy in improving agitation compared with haloperidol. This reanalysis of a previously reported pivotal clinical trial assessed whether quetiapine or haloperidol has benefits for the treatment of hostility and agitation among patients experiencing an acute exacerbation of schizophrenia. Patients aged 18 to 65 years of either sex and any ethnicity who had a diagnosis of schizophrenia based on the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria and who were experiencing an acute exacerbation were recruited into the study. A priori, data from patients assigned to 4 therapeutically effective quetiapine treatment groups (150, 300, 600, and 750 mg) in a previously reported 6-week, double-blind, placebo-controlled clinical trial were combined and compared with data from patients given haloperidol 12 mg or placebo on an agitation measure derived from the Brief Psychiatric Rating Scale (BPRS). Patients who received at least 2 weeks of treatment who had a baseline assessment and at least 1 postbaseline assessment after the 2 weeks of treatment were included. An analysis of variance with the baseline hostility score and center as covariates was used to assess treatment effects of quetiapine or haloperidol versus placebo for changes in agitation scores. A path analysis was used to separate the direct from the indirect effects (via improvements in psychoses and/or overall psychopathology) on agitation scores of quetiapine relative to haloperidol. A total of 257 patients (193 men, 64 women) were studied. The combined quetiapine groups comprised 175 patients; the haloperidol group, 42 patients; and the placebo group, 40 patients. Quetiapine treatment reduced agitation scores significantly among patients with acute psychoses compared with placebo. A slight reduction in agitation scores was found when haloperidol treatment was compared with placebo, but this difference was not statistically significant. Compared with haloperidol, quetiapine treatment had a direct and significant effect on agitation that was independent of the improvement in psychotic symptoms. The data in this study suggest that quetiapine treatment has benefits for hostility and agitation among patients experiencing an acute exacerbation of schizophrenia. Furthermore, the path analysis indicated that, relative to haloperidol, quetiapine appeared to have direct effects on agitation that were independent of improvements in psychoses or overall psychopathology, as assessed by the BPRS.",2003.0,0,1
690,12755654,The effectiveness of quetiapine versus conventional antipsychotics in improving cognitive and functional outcomes in standard treatment settings.,Dawn I Velligan; Thomas J Prihoda; Dawen Sui; Janice L Ritch; Natalie Maples; Alexander L Miller,"To examine the effectiveness of quetiapine versus conventional antipsychotics in improving cognitive and functional outcomes. Forty stable outpatients with DSM-IV schizophrenia treated in public outpatient clinics were randomly assigned to continue taking conventional antipsychotic medications or switch to quetiapine for 6 months, beginning September 1998 and ending July 2000. Neurocognitive and functional measures were obtained at study entry, 3 months, and 6 months by raters blinded to treatment. Group differences were examined using repeated-measures analyses of covariance for mixed models. The mean (SD) dose of conventional antipsychotics in chlorpromazine equivalents was 348.00 (348.28) mg/day; the mean (SD) dose of quetiapine was 319.25 (142.55) mg/day. A cognitive function summary score improved in the quetiapine group relative to the group treated with conventional antipsychotics over the 6-month period (F = 5.80, df = 1,28.9; p <.023). Patients taking quetiapine did better with respect to both verbal fluency (initiation) and verbal memory. There were also statistically significant group differences with respect to quality of life favoring the quetiapine group (F = 4.87, df = 1,29; p <.04). Differences were not found with respect to adaptive functioning. Quetiapine improved cognition relative to conventional agents. After 6 months, groups differed by more than 1 standard deviation when baseline cognitive functioning was taken into account. No group differences were found with respect to improvements in community functioning. Improvements in adaptive functioning may lag behind improvements in cognition. Psychosocial programming may be necessary to translate gains in cognition into improvements in adaptive functioning.",2003.0,1,1
691,12755663,Effectiveness of switching to ziprasidone for stable but symptomatic outpatients with schizophrenia.,Peter J Weiden; George M Simpson; Steven G Potkin; Richard L O'Sullivan,"Many outpatients with schizophrenia experience persistent symptoms or side effects on their current antipsychotic regimen. Few studies have prospectively examined the effects of the prior medication or switching method on the safety and efficacy of a newly available antipsychotic. Efficacy and tolerability of ziprasidone were evaluated in patients with DSM-IV schizophrenia or schizoaffective disorder who were switched from conventional or atypical antipsychotics in three 6-week, multicenter, randomized, open-label, parallel-group trials. Stable outpatients with persistent symptoms or troublesome side effects on (1) conventional antipsychotic (N = 108), (2) olanzapine (N = 104), or (3) risperidone (N = 58) therapy were switched to an open-label, 6-week, flexible-dose trial of ziprasidone (40-160 mg/day). Patients were randomly assigned at baseline to 1 of 3 switching schedules during the first week of ziprasidone therapy. Baseline and outcome assessments included Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions of Severity (CGI-S) ratings. All 3 switching strategies were well tolerated for all 3 patient groups. After 6 weeks on ziprasidone therapy, significant (p <.05) improvements were observed on all major symptom measures and almost all subscales for all switched subgroups. Switching stable but symptomatic outpatients from their previous antipsychotic to ziprasidone was generally well tolerated and was associated with symptom improvements 6 weeks later. Improvements occurred in patients recently on other first-line atypical antipsychotic, as well as in those on conventional antipsychotic, treatment. While limitations of switching study designs do not permit interpretation of comparative efficacy, these studies suggest that outpatients who partially respond to conventional antipsychotics, risperidone, or olanzapine may experience improved control of psychotic symptoms following a switch to ziprasidone.",2003.0,0,0
692,12755664,Risperidone compared with olanzapine in a naturalistic clinical study: a cost analysis.,David M Taylor; Tim Wright; Susan E Libretto; Risperidone Olanzapine Drug Outcomes Studies in Schizophrenia (RODOS) U.K. Investigator Group,"Risperidone and olanzapine are thought to have broadly similar clinical effects. This study was designed as a cost analysis study comparing costs and basic clinical outcomes of treatment with risperidone or olanzapine in a naturalistic setting. The U.K. Risperidone Olanzapine Drug Outcomes Studies in Schizophrenia (RODOS-UK) program consisted of a retrospective review of medical notes and prescription charts for 501 patients with schizophrenia or schizoaffective disorder who had been admitted to the hospital for the treatment of psychosis. The main outcome measure was cost of inpatient drug treatment. Clinical outcomes (clinician-assessed and -documented effectiveness, time to discharge) were also evaluated. Data were collected and verified between June and September 2000. Clinical outcomes were similar for risperidone and olanzapine. Clinician-assessed effectiveness was similar for both treatments (78% risperidone, 74% olanzapine; p =.39), but mean time to documented onset of effectiveness was significantly shorter for those treated with risperidone versus olanzapine (17.6 vs. 22.4 days; p =.01). Risperidone-treated patients stayed a mean of 9 fewer days in the hospital compared with olanzapine-treated patients (49 vs. 58 days; p =.007). The possibility that these observed differences were a result of different baseline characteristics could not be entirely discounted. Mean +/- SD doses of risperidone and olanzapine were 5.5 +/- 2.4 mg/day and 14.1 +/- 4.7 mg/day, respectively. The mean daily cost of all inpatient drugs was significantly higher for olanzapine than for risperidone (pound 5.63 vs. pound 3.92; p <.0001). Mean total costs of all inpatient drugs were significantly higher for olanzapine than for risperidone (pound 164 vs. pound 96; p <.0001), which partly reflected the longer mean treatment duration for olanzapine compared with risperidone (44 vs. 37 days). Concomitant antipsychotic use was similar for both groups (66% risperidone, 67% olanzapine). The number of patients documented as experiencing adverse events was not different between groups (22% risperidone, 19% olanzapine; p =.32). Risperidone and olanzapine produced broadly comparable clinical outcome in this cohort of hospitalized patients, but the use of risperidone was associated with significantly lower drug treatment costs.",2003.0,0,0
693,12755665,Serum leptin and triglyceride levels in patients on treatment with atypical antipsychotics.,Murad Atmaca; Murat Kuloglu; Ertan Tezcan; Bilal Ustundag,"Weight gain is a common adverse effect associated with the use of most antipsychotic drugs. Leptin has been reported to be associated with antipsychotic-induced weight gain. Previous studies have demonstrated a relationship between the atypical antipsychotics clozapine and olanzapine and serum leptin levels. We planned to comparatively investigate the effects of the atypical antipsychotics quetiapine, olanzapine, risperidone, and clozapine on leptin and triglyceride levels and weight gain. The study population comprised 56 patients with DSM-IV schizophrenia, who were divided into 4 treatment groups: quetiapine (N = 14), olanzapine (N = 14), risperidone (N = 14), or clozapine (N = 14) monotherapy, and a control group of 11 patients receiving no psychopharmacologic treatment. The patients were evaluated at baseline and at the sixth week according to the Positive and Negative Syndrome Scale (PANSS), body mass index (BMI), weight, and fasting serum leptin and triglyceride levels. Data were gathered in 2001 and 2002. Olanzapine and clozapine caused a marked increase in weight and serum triglyceride and leptin levels, though increases in these variables were modest in the patients receiving quetiapine and minimal in those receiving risperidone. There were positive correlations between serum leptin levels and BMI and triglyceride levels. Clinical efficacy, as indicated by decrease in total PANSS scores, was associated with leptin levels in all atypical antipsychotic groups. Our results suggest that leptin may be associated with olanzapine- and clozapine-induced weight gain and that quetiapine appears to have modest influence and risperidone appears to have minimal influence on leptin and triglyceride levels and weight gain compared with olanzapine and clozapine.",2003.0,0,1
694,12755666,Undiagnosed hyperglycemia in clozapine-treated patients with schizophrenia.,Michael J Sernyak; Barbara Gulanski; Douglas L Leslie; Robert Rosenheck,"Clozapine has been demonstrated to be superior to typical neuroleptics in reducing refractory symptoms in patients with schizophrenia, but it has also been associated with hyperglycemia and diabetes mellitus. This study was designed to investigate the proportion of undiagnosed impaired fasting glucose and diabetes mellitus in patients prescribed clozapine at 8 Department of Veterans Affairs (VA) medical centers. All patients diagnosed by the VA in New England with ICD-9 schizophrenia from Oct. 1, 1999, to Sept. 30, 2000, who received a prescription for clozapine were identified, and an attempt was made to obtain a fasting plasma glucose (FPG) test. All patients were also characterized as to whether they were diagnosed as diabetic prior to the screening FPG. Patients not previously diagnosed as diabetic were divided into 2 groups: normal FPG (< 110 mg/dL) and elevated FPG (>or= 110 mg/dL). Clinical and sociodemographic characteristics of the 2 groups were compared using chi-square and t tests. Overall, 121 patients were not previously diagnosed as diabetic and received an FPG. Ninety-three (77%) had a normal FPG, and 28 (23%) had an elevated plasma glucose-including 17% with impaired fasting glucose and 6% with diabetes. Patients with hyperglycemia were significantly older (p =.007) and more commonly codiagnosed with bipolar disorder (p =.04). Hyperglycemia was common in patients receiving clozapine who had not been previously diagnosed as diabetic. These patients should be considered a group at high risk to develop diabetes mellitus and deserve both close monitoring and early intervention at the first sign of the onset of either diabetes or impaired glucose tolerance.",2003.0,0,1
695,12766915,The early stage of vascular dementia: significance of a complete therapeutic program.,L S Kruglov,"Mild manifestations of vascular dementia are relatively widespread among the old-age population. Drug therapy for this disorder is insufficiently effective at present, making it necessary to improve the treatment of such patients by means of an adequate psychotherapeutic and rehabilitation program. To assess the role of psychotherapeutic and rehabilitation measures in improving outcome in the early stage of vascular dementia. The test and control cohorts (each n = 95) were matched for characteristics found to be significant for outcome of treatment (the relevant predictors were found using Multiple Regression Analysis). The cohorts differed in the amount of the psychotherapy and rehabilitation received. To assess the effects of treatment the SCAG scale and a special scale for evaluating the level of activity in the household were used. In the test cohort the patients' condition improved significantly compared with the controls. Even in case of only slight therapeutic reduction of psychopathologic symptoms the systematic use of psychotherapeutic and rehabilitation methods favoured preserving a certain level of activity in the household and for some patients even improving it. The results of therapy at the early stage of vascular dementia to a great extent depend on carrying out a full-scale psychotherapeutic and rehabilitation program. The positive significance of the latter is connected not only with improvement of clinical indices but also with direct optimizing the every day life activity level.",2003.0,0,0
696,12766921,"The impact upon extra-pyramidal side effects, clinical symptoms and quality of life of a switch from conventional to atypical antipsychotics (risperidone or olanzapine) in elderly patients with schizophrenia.",C W Ritchie; E Chiu; S Harrigan; K Hall; A Hassett; S Macfarlane; M Mastwyk; D W O'Connor; J Opie; D Ames,"Atypical antipsychotics are commonly used in the management of schizophrenia in late life with evidence suggesting they induce lower rates of motor disturbance, but have similar efficacy to conventional antipsychotics. Trials in the elderly have been either retrospective, small, of short duration or of a single-arm design. To demonstrate the effects upon motor side-effects, efficacy, safety and quality of life (QOL) of switching elderly patients with schizophrenia from conventional antipsychotics to olanzapine or risperidone. Elderly patients with schizophrenia were randomly allocated to olanzapine or risperidone and followed through an open-label crossover period. Between and within group intention to treat analyses were conducted. 66 patients were randomised (mean age 69.6 [SD +/- 6.2]). Four (11.8%) patients on olanzapine and 8 (26.7%) patients on risperidone failed to complete the crossover because of treatment failure [Odds Ratio (OR) = 2.73[0.73-10.2] p = 0.14]. The mean doses upon completion of switching in each arm were 9.9 mg (SD = 4.2) and 1.7 mg (SD = 1.2) for olanzapine and risperidone respectively. In both arms there was improvement in Parkinsonism, though only olanzapine was associated with a reduction in dyskinetic symptoms. The Brief Psychiatric Rating Scale, Scale for the assessment of Negative Symptoms and Montgomery and Asberg Depression Rating Scale scores all improved through the crossover period in both arms with no between group differences. Treatment with olanzapine was associated with a better response over risperidone on the psychological domain of the World Health Organisation-Quality Of Life [Brief] (WHO-QOL-BREF) scale ( p = 0.02). Patients in the olanzapine arm also demonstrated improvement from baseline in the WHO-QOL-BREF physical, psychological and health satisfaction domains, but risperidone had no effect on any Quality of Life (QOL) measure. After switching from a conventional antipsychotic, olanzapine and risperidone were associated with improvement in core symptoms of schizophrenia and motor side effects. Subjects switched to olanzapine were more likely to complete the switching process and show an improvement in psychological QOL.",2003.0,1,1
697,12766931,Efficacy of nefazodone in the treatment of neuroleptic induced extrapyramidal side effects: a double-blind randomised parallel group placebo-controlled trial.,Dora Wynchank; Michael Berk,"Many atypical antipsychotics show antagonism at both serotonergic and dopaminergic neurones and show fewer extrapyramidal side effects (EPS). Nefazodone blocks postsynaptic 5HT2A receptors and weakly inhibits serotonin reuptake. This study aimed to elucidate the role of nefazodone in the treatment of antipsychotic-induced EPS. The trial was a double-blind, randomised, placebo-controlled trial of patients requiring antipsychotic treatment with haloperidol 10mg daily; from which a subgroup of patients who developed EPS were selected for the study. Patients were randomised to add-on therapy with either placebo (n=24) or nefazodone (n=25) 100mg bd. EPS were measured on days 0, 3 and 7 using the Simpson Angus, Barnes akathisia, abnormal involuntary movement and Chouinard scales. Nefazodone significantly reduced EPS as measured by both the Simpson Angus scale and CGI (p=0.007 and 0.0247, respectively). Akathisia and tardive dyskinesia did not differ between the two groups (p=0.601; p=0.507, respectively). These results suggest the role of 5HT2 antagonism in the mechanism of action of atypical antipsychotics with respect to lowering rates of drug-induced EPS. In addition, a therapeutic role for nefazodone is suggested in the treatment of antipsychotic-induced EPS.",2003.0,0,0
698,12777271,,,,,0,1
699,12777272,Effect size of symptom status in withdrawal of typical antipsychotics and subsequent clozapine treatment in patients with treatment-resistant schizophrenia.,David Pickar; John J Bartko,"In light of the efficacy of newer antipsychotic agents and the possibility that drug withdrawal may negatively affect subsequent drug response, concern has arisen that the use of placebo in schizophrenia research may be unethical. This study examines the effect size of symptom exacerbation during drug washout with placebo and the effects of drug washout on the efficacy of subsequent drug treatment. Fifty patients with treatment-resistant schizophrenia hospitalized on a research unit participated in a double-blind longitudinal study of the effects of drug washout after chronic treatment with a typical antipsychotic and before prospective treatment with clozapine. Brief Psychiatric Rating Scale (BPRS) scores were analyzed to examine drug effects and effect sizes for baseline treatment with a typical antipsychotic (>6 months treatment), drug washout with placebo (mean=34 days), early treatment with clozapine (mean=42 days, mean dose=345.0 mg/day), and optimal clozapine treatment (mean=83 days, mean dose=450.5 mg/day). Patients' BPRS total, positive, and negative symptom scores significantly increased during placebo washout, compared with baseline treatment, and significantly decreased with administration of clozapine, compared with placebo washout and baseline treatment. However, 30% of patients showed some symptom improvement during placebo washout. The effect sizes for the BPRS total score were 0.63 for baseline treatment versus placebo washout, 1.10 for optimal clozapine treatment versus placebo washout, and 0.82 for optimal clozapine treatment versus baseline treatment. Symptom exacerbation induced by drug withdrawal in patients with treatment-resistant schizophrenia did not impede subsequent responsiveness to clozapine. The effect size for clozapine, compared with typical antipsychotics, suggests that the drug-washout longitudinal design is useful for establishing a drug-free baseline and for investigating drug response, while requiring relatively few subjects.",2003.0,0,1
700,12787855,"Safety, effectiveness, and quality of life of olanzapine in first-episode schizophrenia: a naturalistic study.",José Manuel Montes; Antonio Ciudad; Josep Gascón; Juan Carlos Gómez; EFESO Study Group,"This study evaluated the effectiveness, safety, and quality of life (Qol) offered by olanzapine in first-episode schizophrenia. One hundred and eighty-two patients with first-episode schizophrenia (ICD-10) drawn from a larger, naturalistic, study were evaluated after 6 months of treatment with olanzapine, risperidone, or conventional antipsychotics (CA). Clinical status was assessed using the Clinical Global Impression-Severity (CGI-S) and Global Assessment of Function (GAF). AWAD and EuroQol scales were used to evaluate patients' attitude towards medication and Qol, respectively. Subjects treated with olanzapine, risperidone, and CA showed similar improvements on CGI-S and GAF. Treatment-emergent, extrapyramidal symptoms were significantly lower in olanzapine-treated patients (17.8%) than in the risperidone (46.4%) and CA (62.2%) groups. Compared to CA, olanzapine and risperidone showed significantly greater improvement on the visual analog scale of EuroQol. Olanzapine-treated patients also showed significantly improved AWAD scores. In first-episode schizophrenia, atypical antipsychotics were effective, and improved Qol. Olanzapine had a lower incidence of extrapyramidal symptoms and better subjective acceptance of medication.",2003.0,1,1
701,12788243,Combination pharmacotherapy in children and adolescents with bipolar disorder.,Robert A Kowatch; Gopalan Sethuraman; Judith H Hume; Michelle Kromelis; Warren A Weinberg,"The purpose of this study was to develop prospective data on the effectiveness of combination pharmacotherapy of children and adolescents with bipolar disorder during a 6-month period of prospective, semi-naturalistic treatment. Thirty-five subjects, with a mean age of 11 years, were treated in the extension phase of this study after having received 6-8 weeks of acute treatment with a single mood stabilizer. The extension phase of this study lasted for another 16 weeks, for a total of 24 weeks of prospective treatment. During this study phase, subjects were openly treated, and they could have their acute-phase mood stabilizer switched or augmented with another mood stabilizer, a stimulant, an antidepressant agent, or antipsychotic agent, if they were assessed to be a nonresponder to monotherapy with their initial mood stabilizer. During the extension phase of treatment, 20 of 35 subjects (58%) required treatment with one or two mood stabilizers and either a stimulant, an atypical antipsychotic agent, or an antidepressant agent. The response rate to combination therapy was very good, with 80% of subjects treated responding to combination therapy with two mood stabilizers after not responding to monotherapy with a mood stabilizer. This study suggests that children and adolescents with bipolar disorder are similar to adults with bipolar disorder, who also frequently require combination therapy.",2003.0,0,0
702,12788248,"Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD).",Gary S Sachs; Michael E Thase; Michael W Otto; Mark Bauer; David Miklowitz; Stephen R Wisniewski; Philip Lavori; Barry Lebowitz; Mathew Rudorfer; Ellen Frank; Andrew A Nierenberg; Maurizio Fava; Charles Bowden; Terence Ketter; Lauren Marangell; Joseph Calabrese; David Kupfer; Jerrold F Rosenbaum,"The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was conceived in response to a National Institute of Mental Health initiative seeking a public health intervention model that could generate externally valid answers to treatment effectiveness questions related to bipolar disorder. STEP-BD, like all effectiveness research, faces many design challenges, including how to do the following: recruit a representative sample of patients for studies of readily available treatments; implement a common intervention strategy across diverse settings; determine outcomes for patients in multiple phases of illness; make provisions for testing as yet undetermined new treatments; integrate adjunctive psychosocial interventions; and avoid biases due to subject drop-out and last-observation-carried-forward data analyses. To meet these challenges, STEP-BD uses a hybrid design to collect longitudinal data as patients make transitions between naturalistic studies and randomized clinical trials. Bipolar patients of every subtype with age >/= 15 years are accessioned into a study registry. All patients receive a systematic assessment battery at entry and are treated by a psychiatrist (trained to deliver care and measure outcomes in patients with bipolar disorder) using a series of model practice procedures consistent with expert recommendations. At every follow-up visit, the treating psychiatrist completes a standardized assessment and assigns an operationalized clinical status based on DSM-IV criteria. Patients have independent evaluations at regular intervals throughout the study and remain under the care of the same treating psychiatrist while making transitions between randomized care studies and the standard care treatment pathways. This article reviews the methodology used for the selection and certification of the clinical treatment centers, training study personnel, the general approach to clinical management, and the sequential treatment strategies offered in the STEP-BD standard and randomized care pathways for bipolar depression and relapse prevention.",2003.0,0,0
703,12795493,"Cost-effectiveness of risperidone, olanzapine, and conventional antipsychotic medications.",Jeanette M Jerrell,"To assess the cost and effectiveness of risperidone, olanzapine, and conventional antipsychotic medications under ""usual practice"" conditions in a large, public mental health system, 108 persons diagnosed with schizophrenia or schizoaffective disorder were randomly assigned to one of these three medication groups and followed prospectively over a 12-month period using standard instruments and procedures. Psychiatric medication costs increased more over time in both the olanzapine and risperidone groups than in the conventional medication group. Compliance with the prescribed medication was higher in the olanzapine group than in the conventional group. No differential effects by medication group were evident in this sample on the symptoms of schizophrenia, side effects, psychosocial functioning, time to discharge for index hospitalization, survival to initial rehospitalization, or client satisfaction with services. These results extend findings from previous efficacy and naturalistic studies in several ways but are limited chiefly by the small number of subjects who completed 6 to 12 months of the clinical trial, and the resulting power to detect differences in the statistical analyses.",2003.0,1,1
704,12795495,Estimating the costs and benefits of new drug therapies: atypical antipsychotic drugs for schizophrenia.,Josephine Mauskopf; Matthew Muroff; P Joseph Gibson; David L Grainger,"This article presents an analytic tool populated with data from published studies to illustrate the likely impacts of a switch from typical to atypical antipsychotic drugs over a 3-year period on individual, family, and societal outcomes for a U.S. schizophrenia population. Data taken from clinical trials and observational data studies are used. Changes in annual health care costs, schizophrenia symptom days, extrapyramidal symptom (EPS) days, suicide rates, and employment days are estimated. For each 1,000 people treated with typical drugs, the base case scenario gives estimates of annual medical care costs of dollar 28.9 million with 80,253 moderate/severe schizophrenia symptom days and 92,006 EPS days. In the base case scenario, after switching to atypical drugs, schizophrenia symptom days are estimated to decrease up to 33 percent, EPS days up to 50 percent, and total medical care costs up to 19 percent over the 3-year period. Suicide rates fall and employment rates increase. The direction of the impacts remain the same for a wide range of input parameter values used in sensitivity analyses. Thus, switching to atypical drugs will likely reduce total medical care costs and decrease other disease burdens for people with schizophrenia, their families, and society.",2003.0,0,0
705,12796218,A meta-analysis of the efficacy of second-generation antipsychotics.,John M Davis; Nancy Chen; Ira D Glick,"Consensus panel recommendations regarding choice of an antipsychotic agent for schizophrenia differ markedly, but most consider second-generation antipsychotics (SGAs) as a homogeneous group. It has been suggested that SGAs seem falsely more efficacious than first-generation antipsychotics (FGAs) as a result of reduced efficacy due to use of a high-dose comparator, haloperidol. We performed (1) a meta-analysis of randomized efficacy trials comparing SGAs and FGAs, (2) comparisons between SGAs, (3) a dose-response analysis of FGAs and SGAs, and (4) an analysis of the effect on efficacy of an overly high dose of an FGA comparator. Literature search of clinical trials between January 1953 and May 2002 of patients with schizophrenia from electronic databases, reference lists, posters, the Food and Drug Administration, and other unpublished data. We included 124 randomized controlled trials with efficacy data on 10 SGAs vs FGAs and 18 studies of comparisons between SGAs. Two of us independently extracted the sample sizes, means, and standard deviation of the efficacy data. Using the Hedges-Olkin algorithm, the effect sizes of clozapine, amisulpride, risperidone, and olanzapine were 0.49, 0.29, 0.25, and 0.21 greater than those of FGAs, with P values of 2 x 10-8, 3 x 10-7, 2 x 10-12, and 3 x 10-9, respectively. The remaining 6 SGAs were not significantly different from FGAs, although zotepine was marginally different. No efficacy difference was detected among amisulpride, risperidone, and olanzapine. We found no evidence that the haloperidol dose (or all FGA comparators converted to haloperidol-equivalent doses) affected these results when we examined its effect by drug or in a 2-way analysis of variance model in which SGA effectiveness is entered as a second factor. Some SGAs are more efficacious than FGAs, and, therefore, SGAs are not a homogeneous group.",2003.0,1,1
706,12799617,Comparison of cognitive performances during a placebo period and an atypical antipsychotic treatment period in schizophrenia: critical examination of confounds.,Thomas W Weickert; Terry E Goldberg; Stefano Marenco; Llewellyn B Bigelow; Michael F Egan; Daniel R Weinberger,"Although previous studies report cognitive improvement following atypical antipsychotic administration in schizophrenia (SC), few placebo-controlled within-subject studies with examination of confounds (symptom reduction, cooperation, learning, and outliers) have been reported. The present study examines the effects of atypicals and confounds upon cognition in SC. The hypothesis tested was that relative to placebo, atypicals as a general class of medication would elicit cognitive improvement in SC. In all, 19 patients with SC (15 males) completed the double-blind, counterbalanced, randomized within-subject study of the effects of atypical antipsychotics (risperidone, clozapine, olanzapine, or quetiapine) vs placebo administration upon cognitive performance in the domains of executive function, attention, memory, language, visual perception, and general intellect. Significant cognitive improvement during atypical antipsychotic administration relative to placebo withdrawal occurred in most cognitive domains with robust improvements in intelligence (p=0.001), memory (p=0.0009), and fluency (p <0.002) even after outliers and unmotivated performances were excluded. These findings suggest that relative to placebo withdrawal, atypicals improve cognitive performance in SC. However, this finding may not be specific to atypicals, since analogous studies of typicals have not been performed.",2003.0,0,1
707,12801428,Classification and treatment of tardive syndromes.,Hubert H Fernandez; Joseph H Friedman,"Tardive syndromes are a group of delayed-onset abnormal involuntary movement disorders induced by a dopamine receptor blocking agent. There are several phenomenologically distinct types of TS. The term tardive dyskinesia has been used to refer to the TS that presents with rapid, repetitive, stereotypic movements mostly involving the oral, buccal, and lingual areas. Tardive dystonia can be focal, segmental, or generalized. It commonly affects the face and neck followed by the arms and trunk. It usually results in retrocollis when it involves the neck and trunk arching backwards when it involves the trunk. Tardive akathisia is characterized by a feeling of inner restlessness and jitteriness with an inability to sit or stand still. Other tardive syndromes include tardive tics, myoclonus, tremor, and withdrawal-emergent syndrome. It remains unclear whether tardive parkinsonism truly exists. The only way to prevent TS is to avoid its etiologic agents. Chronic use of dopamine receptor blocking agents should be limited as much as possible to patients with chronic psychoses. In general, for mild TS, reducing the neuroleptic dose, switching to an atypical agent, or discontinuing antipsychotic treatment altogether in the hope of facilitating remission is recommended. For moderate to severe TS, tetrabenazine or reserpine may be the most effective agent. Neuroleptics should be resumed to treat TD in the absence of active psychosis only as a last resort for persistent, disabling, and treatment-resistant TD. The severity of the TS and the absolute need for antipsychotic therapy often dictate the treatment approach for this disorder.",2003.0,0,0
708,12802226,The use of atypical antipsychotics in traumatic brain injury.,Elie Paul Elovic; Ramon Lansang; Yali Li; Joseph H Ricker,"The use of antipsychotic medication in treating individuals with traumatic brain injury (TBI) has been controversial. Much of the caution derives from animal studies (and limited human data) with regard to typical antipsychotics. Of note, however, is that similar assumptions have been made about the newer generation of atypical antipsychotics as well. Because these agents have different mechanisms of action as well as different neurotransmitter targets, this may very well be unwarranted. In this article, mechanisms of action of typical and atypical antipsychotics are discussed, with particular attention paid to their use in TBI. Indications and contraindications are presented, and recommendations are made for the responsible prescribing of antipsychotic medications after TBI.",2003.0,0,0
709,12811711,Calming versus sedative effects of intramuscular olanzapine in agitated patients.,John Battaglia; Stacy R Lindborg; Karla Alaka; Karena Meehan; Padraig Wright,"Distinct calming rather than nonspecific sedation is desirable for the treatment of acute agitation. In 3 double-blind studies, acutely agitated patients with schizophrenia (N = 311), bipolar mania (N = 201), or dementia (N = 206) were treated with intramuscular (1-3 injections/24 hrs) olanzapine (2.5-10.0 mg), haloperidol (7.5 mg), lorazepam (2.0 mg), or placebo. The Agitation-Calmness Evaluation Scale (ACES; Eli Lilly and Co.) and treatment-emergent adverse events assessed sedation. Across all studies, 1 patient (lorazepam-treated, bipolar) became unarousable. There were no significant between-group differences in ACES scores of deep sleep or unarousable at any time across. Excluding asleep patients, agitation remained significantly more reduced with olanzapine than placebo (P <.05). The incidences of adverse events indicative of sedation were not significantly different with olanzapine versus comparators. For the treatment of acute agitation associated with schizophrenia, bipolar mania, or dementia, intramuscular olanzapine-treated patients experienced no more sedation than haloperidol- or lorazepam-treated patients and experienced distinct calming rather than nonspecific sedation.",2003.0,0,0
710,12817157,Risperidone in acute and continuation treatment of mania.,Lakshmi N Yatham; Carin Binder; Rosanna Riccardelli; Jean Leblanc; Mary Connolly; Vivek Kusumakar; RIS-CAN 25 Study Group,"In a prospective study, we examined the efficacy of risperidone added-on to mood stabilizers in the acute and continuation treatment of mania over a 12-week period. Patients (n=108) with a DSM-IV diagnosis of bipolar disorder, manic or mixed episode requiring treatment with an antipsychotic were recruited. All subjects were on one or two mood stabilizers at the time of initiation of risperidone (range 0.5-4 mg). No other antipsychotic medication or ongoing benzodiazepine therapy was allowed. There was a significant decrease in mean Young Mania Rating Scale (YMRS) scores from baseline (27.5+/-7.5) to week 1 (-10.8, P<0.0001), week 3 (-17.7, P<0.0001) and to week 12(-22.6, P<0.0001). When response was defined as > or = 50% reduction in YMRS scores from baseline, 32%, 68% and 90% of patients met criteria at week 1, week 3 and week 12, respectively. Significant decreases in mean 21-item Hamilton Depression Rating Scale scores from baseline (12.2+/-7.7) to week 3 (-5.7, P<0.0001) and week 12 (-5.7, P<0.0001) were also observed. No significant changes in extrapyramidal symptoms were noted between baseline and endpoint. The mean daily dose of risperidone was 2 mg with a median of 1.8 mg. These findings support the results of the two previous double-blind, randomized trials and indicate that the addition of risperidone to mood stabilizers is a safe and effective treatment for acute and continuation treatment of mania. Risperidone add-on does not induce depressive symptoms and, furthermore, risperidone may have efficacy in treating comorbid depressive symptoms in bipolar patients.",2003.0,0,0
711,12820816,,,,,0,1
712,12823076,Ethnic differences in use of antipsychotic medication among Texas medicaid clients with schizophrenia.,Jayme L Opolka; Karen L Rascati; Carolyn M Brown; Jamie C Barner; Michael T Johnsrud; P Joseph Gibson,"Culture and ethnicity have been suggested to influence the presentation of patients with schizophrenia. These factors are thought to affect the diagnoses, courses of treatment, and medical utilization patterns of patients with schizophrenia. Specifically, the differences between whites, African Americans, and Mexican Americans are of particular importance, as these groups comprise the majority of the population in the United States today. The traditional course of treatment for many patients with schizophrenia is the drug haloperidol. However, research has shown that some ethnic groups (African Americans and Mexican Americans) may respond better to atypical drugs, such as olanzapine, but may be less likely to receive these drugs. A better response to the course of treatment results in improved medical utilization patterns. The purpose of this study was to examine if ethnicity helped predict whether Texas Medicaid patients were prescribed haloperidol versus olanzapine when other factors were controlled for. The study population consisted of 726 patients whose index drug was haloperidol and 1875 patients whose index drug was olanzapine. Patients had an ICD-9-CM diagnosis of schizophrenia or schizoaffective disorder. Texas medical and prescription claims data were used in a logistic regression analysis to determine significant predictors of the type of antipsychotic (haloperidol vs. olanzapine) patients were prescribed. Variables included in the analysis were ethnicity, gender, age, region, other mental illness comorbidities, and previous utilization of medications and resources. Data were collected from Jan. 1, 1996, to Aug. 31, 1998. The results show that when other demographic and utilization factors were controlled for, African Americans were less likely than whites to receive olanzapine rather than haloperidol. Ethnicity is a significant predictor of the type of antipsychotic that is prescribed.",2003.0,0,1
713,12823080,Chlorpromazine equivalent doses for the newer atypical antipsychotics.,Scott W Woods,"Several clinical and research applications require an estimation of therapeutic dose equivalence across antipsychotic medications. Since the advent of the newer atypical antipsychotics, new dose equivalent estimations have been needed. The reported minimum effective dose was identified for each newer atypical antipsychotic medication and for haloperidol across all available fixed-dose placebo-controlled studies. Reported minimum effective dose equivalence ratios to haloperidol were then converted to chlorpromazine equivalents using the ""2 mg of haloperidol equals 100 mg of chlorpromazine"" convention. To identify the fixed-dose studies, the following sources were searched until June 2002: MEDLINE, the bibliographies of identified reports, published meta-analyses and reviews, Cochrane reviews, Freedom of Information Act material available from the Food and Drug Administration, and abstracts from several scientific meetings from 1997 to 2002. Doses equivalent to 100 mg/day of chlorpromazine were 2 mg/day for risperidone, 5 mg/day for olanzapine, 75 mg/day for quetiapine, 60 mg/day for ziprasidone, and 7.5 mg/day for aripiprazole. These equivalency estimates may be useful for clinical and research purposes. The source of the dose equivalency estimation is evidence-based and consistent across medication.",2003.0,0,0
714,12823090,A double-blind comparison of olanzapine versus risperidone in the acute treatment of dementia-related behavioral disturbances in extended care facilities.,Catherine S Fontaine; Linda S Hynan; Kathleen Koch; Kristin Martin-Cook; Doris Svetlik; Myron F Weiner,"In addition to demonstrating their superiority to placebo, there is a need to compare the relative efficacy and side effects of atypical neuroleptics for the acute treatment of dementia-related behavioral disturbances in residents of long-term care facilities. In a double-blind parallel study allowing dose titration over 14 days, 39 agitated persons with DSM-IV dementia who were residing in long-term care facilities were administered olanzapine (N = 20) or risperidone (N = 19) as acute treatment. Drug was administered once a day at bedtime. The initial dosages were olanzapine, 2.5 mg/day, and risperidone, 0.5 mg/day. Titration was allowed to maximum doses of olanzapine, 10 mg/day, and risperidone, 2.0 mg/day. The primary outcome measures were the Clinical Global Impressions scale (CGI) and the Neuropsychiatric Inventory (NPI). Data were gathered from 2000 to 2002. Both drugs produced significant reductions in CGI and NPI scores (p <.0001), but there was no significant difference between drugs. The mean olanzapine dose was 6.65 mg/day; for risperidone, the dose was 1.47 mg/day. The positive drug effect was not accompanied by decreased mobility, and there was improvement on a quality-of-life measure. The chief adverse events were drowsiness and falls. At baseline, 42% (16/38) of subjects in both groups had extrapyramidal symptoms that increased slightly, but not significantly, by the end of the study. Low-dose, once-a-day olanzapine and risperidone appear to be equally safe and equally effective in the treatment of dementia-related behavioral disturbances in residents of extended care facilities.",2003.0,1,1
715,12826983,Tolerability and efficacy of clozapine combined with lithium in schizophrenia and schizoaffective disorder.,Joyce G Small; Marietta H Klapper; Frederick W Malloy; Timothy M Steadman,"The safety and tolerability of clozapine combined with lithium were investigated because of potential additive risks as well as frequent usage in clinical practice. Ten hospitalized schizophrenic and 10 schizoaffective patients receiving clozapine maintenance therapy with partial therapeutic response were studied in a randomized controlled trial. CGI and PANSS outcome ratings were employed and a cognitive battery was administered at baseline and after 4 weeks of lithium and placebo administration. Barnes and UKU side effect ratings and laboratory safety data were obtained. Combined lithium-clozapine treatment was well tolerated except for reversible neurotoxic reactions in two schizophrenic patients. Safety measures showed no significant variations, even during lithium toxicity. Total WBC and absolute granulocyte counts increased with lithium and declined with placebo. Schizoaffective patients improved with lithium on CGI and PANSS total and negative symptom scales and the cognitive measures, whereas schizophrenic patients did not. Lithium added to clozapine in treatment regimens for hospitalized, treatment-resistant, schizoaffective patients appears to afford potential benefit without harmful effects; for schizophrenic patients, however, it did not afford improvement but posed a risk of lithium toxicity.",2003.0,0,0
716,12826992,Efficacy of low-dose mirtazapine in neuroleptic-induced akathisia: a double-blind randomized placebo-controlled pilot study.,Michael Poyurovsky; Svetlana Epshtein; Camil Fuchs; Michael Schneidman; Ronit Weizman; Abraham Weizman,"The nonselective serotonin (5-HT)-2A antagonists ritanserin, mianserin, and cyproheptadine were found efficacious in neuroleptic-induced akathisia (NIA). Mirtazapine is structurally and pharmacologically similar to mianserin, and the authors sought to determine its anti-NIA activity. Twenty-six neuroleptic-treated schizophrenic patients with DSM-IV diagnosis of NIA received add-on mirtazapine (15 mg/day) or placebo for 5 days in a double-blind design. Patients were assessed at baseline and days 3 and 5 with the Barnes Akathisia Scale (BAS), Positive and Negative Symptom Scale, Hamilton Rating Scale for Depression, and Simpson-Angus Scale for parkinsonism. Analysis of covariance with repeated measurements revealed significant group x time effects in favor of the mirtazapine group in both completers (n = 10 in each group) and intent-to-treat analysis (n = 13 in each group) for the BAS global subscale (F [1, 17] = 14.87, p = 0.001, and F [1, 23] = 13.24, p = 0.01, respectively) and objective subscale (F [1, 17] = 8.25, p = 0.011, and F [1, 23] = 7.35, p = 0.012, respectively) and borderline significant superiority for the BAS subjective subscale (F [1, 17] = 4.39, p = 0.051, and F [1, 23] = 4.12, p = 0.054, respectively) and distress subscale (F [1, 17] = 4.21, p = 0.056, and F [1, 23] = 3.80, p = 0.064, respectively). Significantly more mirtazapine-than placebo-treated patients (53.8% [7/13] vs. 7.7% [1/13], respectively; chi2 = 8.3, p = 0.004) met operational response criterion, a reduction of at least two points on the BAS global subscale. Mirtazapine treatment was associated with modest improvement of psychotic and parkinsonian symptoms. Mild sedation was the only side effect. Our study demonstrated that mirtazapine (15 mg/day) is an efficacious and well-tolerated therapeutic option in NIA. Marked 5HT2A/2C antagonistic activity of mirtazapine apparently accounts for its anti-NIA activity. The role of mirtazapine in the treatment of akathisia induced by atypical antipsychotic agents merits further investigation.",2003.0,0,0
717,12832232,"Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials.",Stefan Leucht; Thomas R E Barnes; Werner Kissling; Rolf R Engel; Christoph Correll; John M Kane,"The authors performed a systematic review and meta-analysis of studies of the potential of new-generation antipsychotic drugs to improve adherence and decrease relapse rates in patients with schizophrenia. Randomized, controlled trials comparing new-generation antipsychotic drugs with placebo and/or conventional antipsychotics were identified. Data on relapse, general treatment failure, and dropout due to adverse events were extracted and combined in a meta-analysis. Because few trials were available for each individual drug, the effects of new-generation antipsychotic drugs as a group were analyzed. The analysis of six placebo comparisons, involving a total of 983 patients, clearly demonstrated that new-generation antipsychotic drugs are effective for relapse prevention. Eleven studies with a total of 2,032 patients provided comparative data on relapse/treatment failure for new-generation and conventional antipsychotics. The analysis revealed that rates of relapse and overall treatment failure were modestly but significantly lower with the newer drugs. Whether this advantage was partly mediated by improved adherence to treatment remains unclear. No significant superiority in terms of fewer dropouts due to adverse events was found for the newer drugs. Furthermore, a number of methodological problems were identified. Overall, the currently available data suggest that new-generation antipsychotics have the potential to reduce relapse rates. Methodological issues to be addressed in future trials include the choice of comparator, use of appropriate doses, application of clinically relevant relapse criteria, monitoring of adherence, and minimization of dropouts.",2003.0,1,1
718,12832240,Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study.,Mauricio Tohen; Terence A Ketter; Carlos A Zarate; Trisha Suppes; Mark Frye; Lori Altshuler; John Zajecka; Leslie M Schuh; Richard C Risser; Eileen Brown; Robert W Baker,"Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder. The authors report a 47-week comparison of olanzapine and divalproex. This 47-week, randomized, double-blind study compared flexibly dosed olanzapine (5-20 mg/day) to divalproex (500-2500 mg/day) for manic or mixed episodes of bipolar disorder (N=251). The only other psychoactive medication allowed was lorazepam for agitation. The primary efficacy instrument was the Young Mania Rating Scale; a priori protocol-defined threshold scores were > or =20 for inclusion, < or =12 for remission, and > or = 15 for relapse. Analytical techniques included mixed model repeated-measures analysis of variance for change from baseline, Fisher's exact test (two-tailed) for categorical comparisons, and Kaplan-Meier estimates of time to events of interest. Over 47 weeks, mean improvement in Young Mania Rating Scale score was significantly greater for the olanzapine group. Median time to symptomatic mania remission was significantly shorter for olanzapine, 14 days, than for divalproex, 62 days. There were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% and 45.5%, respectively) and subsequent relapse into mania or depression (42.3% and 56.5%). Treatment-emergent adverse events occurring significantly more frequently during olanzapine treatment were somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels; those for divalproex were nausea and nervousness. In this 47-week study of acute bipolar mania, symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ.",2003.0,1,1
719,12837139,The effects of antipsychotic drug treatment on prolactin concentrations in elderly patients.,Bruce J Kinon; Virginia L Stauffer; Hillary C McGuire; Christopher J Kaiser; Ruth A Dickson; John S Kennedy,"To describe the change in serum prolactin concentrations in elderly agitated nursing home patients with dementia who were newly initiated on olanzapine or switched to olanzapine treatment from either conventional antipsychotics or risperidone. During an 8-week open-label olanzapine efficacy trial in elderly nursing home patients demonstrating clinically significant behavioral and psychological symptoms of dementia, serum prolactin concentrations were drawn on four occasions: at time of consent, following a washout period from previous therapy, midway through the study, and at endpoint. To assess post-hoc the effects of prolactin concentrations upon switching to olanzapine treatment, patients were divided into three different groups, based upon status at time of consent: those not taking antipsychotic medication, those taking any conventional antipsychotic, and those taking risperidone. Prolactin concentrations were assessed using a mixed-effect repeated-measures model. Symptom severity was measured using the Brief Psychiatric Rating Scale (BPRS), the Cohen-Mansfield Agitation Inventory (CMAI), the Clinical Global Impression (CGI)-Severity scale, and the Mini-Mental State Examination (MMSE), and the same repeated measures analysis was performed on these scales. Patients not on antipsychotic medication at study entry (29 females, 7 males) experienced a significant increase in prolactin concentration baseline to endpoint (P < 0.05) but remained below upper limit of normal for prolactin for both males and females. There was a nonsignificant increase in prolactin concentrations when patients were switched from conventional antipsychotic medications (mean dose 152.41 +/- 192.48 mg/day chlorpromazine equivalents) to olanzapine (2.5 to 10 mg/day) (22 females, 9 males). Patients who entered the study on risperidone (mean dose 1.31 +/- 0.91 mg/day) (13 females, 4 males) experienced a significant decrease in prolactin concentration (P < 0.001). While 62.5% of risperidone-treated patients had above-normal prolactin concentrations at baseline, only 21.4% had above-normal concentrations at endpoint (P = 0.033). Clear correlations between prolactin concentrations and clinical outcomes could not be determined. Consistent with previous findings in younger patients, olanzapine appeared to be a prolactin-sparing antipsychotic medication in the elderly with only modest prolactin increases observed. In addition, patients who were receiving risperidone and then switched to olanzapine experienced a significant reduction in prolactin concentrations that was sustained over the 8-week treatment course with olanzapine. One possible explanation for olanzapine's relatively modest increase in prolactin is that, unlike conventionals or risperidone, olanzapine binds less tightly with the dopamine D(2) receptor.",2003.0,0,0
720,12837670,Psychosis of Alzheimer disease: validity of the construct and response to risperidone.,Lon S Schneider; Ira R Katz; Sohee Park; Judy Napolitano; Rick A Martinez; Stanley P Azen,"The authors evaluated the efficacy of risperidone in reducing psychotic and aggressive symptoms in a subgroup of patients who fulfilled operationalized criteria for psychosis of dementia. Authors conducted a subgroup analysis of patients in the risperidone database arising from a previous double-blind, randomized, placebo-controlled study. In the primary study, patients age 55 or older, with a DSM-IV diagnosis of Alzheimer disease and/or vascular dementia were randomized to placebo or 0.5 mg, 1.0 mg, or 2.0 mg/day of risperidone. For this analysis, patients were selected who fulfilled operationalized criteria for psychosis of dementia. These criteria were then validated. The primary outcome measures were the newly developed Psychosis and Aggression Severity Indices, derived from Parts 1 and 2 of the BEHAVE-AD rating scale. At Week 12 and endpoint, patients with psychosis of dementia receiving 1 mg or 2 mg/day of risperidone showed significantly more improvement on the Psychosis Severity and Aggressiveness Severity Indices than those receiving placebo. The construct of psychosis of dementia was validated, and the severity of both psychosis and aggressiveness was reduced with risperidone treatment in a robust and dose-related way, with a continuing response over the 12-week trial period.",2003.0,0,1
721,12839431,Clozapine: a clinical review of adverse effects and management.,Mohammad Masud Iqbal; Atiq Rahman; Zahid Husain; Syed Zaber Mahmud; Wlliam G Ryan; Jacqueline M Feldman,"Clozapine (Clozaril) is a novel and unique prototype atypical, tricyclic, dibenzodiazepine-derivative, antipsychotic agent. It has been proven effective and significantly superior to placebo, as well as to conventional neuroleptics, in several placebo-controlled, double-blind studies in treatment-resistant schizophrenia. It has also been found to produce an incidence of extrapyramidal symptoms (EPS) as low as that found with placebo. Approximately 30-60% of all schizophrenic patients who fail to respond to typical antipsychotics may respond to clozapine. It was the first major advance that marked a turning point in the treatment of schizophrenia and other psychotic disorders since the introduction of the typical antipsychotic agents, i.e., chlorpromazine and haloperidol in the 1950s and 1960s, respectively. After its introduction in clinical studies in the United States in the early 1970s, it was withdrawn in 1974, and was not approved for clinical use in the United States until February 1990, because of the risk of agranulocytosis. Its novel pharmacological profile, lack of propensity to cause EPS in both short- and long-term uses, lack of effects on serum prolactin, and ameliorative effects on tardive dyskinesia have resulted in the expansion of its use from refractory schizophrenia to schizoaffective disorders, affective disorders, some neurological disorders, aggression, as well as psychosis in patients with dementia and parkinsonism. This review covers the history, pharmacology, management of side effects, and fetal and neonatal effects of clozapine.",2003.0,0,0
722,12844280,"[Benzodiazepines, typical and atypical antipsychotics in the management of acute agitation: a review].",Ayşegül Yildiz,"Given the diversity of clinical entities from which agitation may arise, it is not surprising that it is among the most commonly encountered clinical problems in psychiatric facilities and hospital emergency services. However, quite surprisingly this area has received very little attention and has not been studied in clinical trials until recently. Thus, tremendous variability exists in approaches to agitation. In this work, we review what is known about the pharmacologic management of agitation; first, by examining published studies comparing conventional antipsychotics, benzodiazepines, and/or a combination of both to achieve calm in acutely agitated psychiatric patients; and second, by reviewing available data on the use of atypical antipsychotic medications for the acute treatment of agitation associated with psychiatric illness. In our first review, we identified 11 trials meeting our inclusion criteria, 8 with a blind design. These studies taken together suggest that combination treatment may be superior to either agent alone, with higher improvement rates and lower incidence of extrapyramidal side effects. In our review of atypical antipsychotic agents as acute antiagitation compounds, we identified 5 studies, 3 with a blind design. This review found atypical antipsychotics to be as effective as the classical ones and more advantageous. Based on the data available to date, among the present novel antipsychotic agents, ziprasidone, risperidone, and olanzapine seem to be the best acute antiagitation compounds.",2003.0,0,0
723,12850662,Treatment for delirium with risperidone: results of a prospective open trial with 10 patients.,Naoshi Horikawa; Tomoko Yamazaki; Kazuko Miyamoto; Akiko Kurosawa; Hiroaki Oiso; Fumi Matsumoto; Katsuji Nishimura; Kumiko Karasawa; Kiyoshi Takamatsu,"Delirium is a common psychiatric illness among medically compromised patients. There is an increasing opportunity to use atypical antipsychotics to treat delirium. The effects of these drugs on delirium, however, the most appropriate way to use them, and the associated adverse effects remain unclear. To clarify these points, a prospective open trial on risperidone was carried out in 10 patients with delirium. At a low dose of 1.7 mg/d, on average, risperidone was effective in 80% of patients, and the effect appeared within a few days. There were no serious adverse effects. However, sleepiness (30%) and mild drug-induced parkinsonism (10%) were observed; the symptom of sleepiness was a reason for not increasing the dose. One patient responded to a dose as low as 0.5 mg/d, so it is recommended that treatment start at a low dose, which may then be increased gradually. This trial is a preliminary open study with a small sample size, and further controlled studies will be necessary.",2003.0,0,0
724,12854942,Olanzapine for intractable nausea in palliative care patients.,W Clay Jackson; Laura Tavernier,"Nausea is a common problem among palliative care patients, which is often undertreated. Olanzapine, an atypical antipsychotic, possesses a unique neurotransmitter binding profile that is similar to methotrimeprazine, an anti-emetic widely used in Europe for recalcitrant nausea. We report a case series of six patients who suffered nausea which was resistant to initial treatment with traditional antiemetics; each patient exhibited marked improvement when treated with olanzapine.",2003.0,0,0
725,12860772,"Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder.",Steven G Potkin; Anutosh R Saha; Mary J Kujawa; William H Carson; Mirza Ali; Elyse Stock; Joseph Stringfellow; Gary Ingenito; Stephen R Marder,"Aripiprazole is a dopamine D2 receptor partial agonist with partial agonist activity at serotonin 5HT1A receptors and antagonist activity at 5HT2A receptors. This multicenter trial examined the efficacy, safety, and tolerability of aripiprazole in patients with acute exacerbation of schizophrenia or schizoaffective disorder. In this 4-week double-blind study, 404 patients were randomized to 20 mg/d (n = 101) or 30 mg/d (n = 101) of aripiprazole, placebo (n = 103), or 6 mg/d of risperidone (n = 99). Efficacy assessments included Positive and Negative Syndrome Scale (PANSS) scores and Clinical Global Impression scores. Safety and tolerability evaluations included extrapyramidal symptoms and effects on weight, prolactin, and corrected QT (QTc) interval. Aripiprazole (20 and 30 mg/d) and risperidone (6 mg/d) were significantly better than placebo on all efficacy measures. Separation from placebo occurred at week 1 for PANSS total and positive scores with aripiprazole and risperidone and for PANSS negative scores with aripiprazole. There were no significant differences between aripiprazole and placebo in mean change from baseline in the extrapyramidal symptom rating scales. Mean prolactin levels decreased with aripiprazole but significantly increased 5-fold with risperidone. Mean change in QTc interval did not differ significantly from placebo with any active treatment group. Aripiprazole and risperidone groups showed a similar low incidence of clinically significant weight gain. Aripiprazole is effective, safe, and well tolerated for the positive and negative symptoms in schizophrenia and schizoaffective disorder. It is the first non-D2 receptor antagonist with clear antipsychotic effects and represents a novel treatment development for psychotic disorders.",2003.0,0,1
726,12867218,A comparison of the efficacy and safety of olanzapine versus haloperidol during transition from intramuscular to oral therapy.,Padraig Wright; Karena Meehan; Martin Birkett; Stacy R Lindborg; Cindy C Taylor; Philip Morris; Alan Breier,"Acutely agitated patients with schizophrenia who receive intramuscular (IM) medications typically are switched to oral (PO) antipsychotic maintenance therapy. The goal of this study was to assess the efficacy and safety of olanzapine versus those of haloperidol during transition from IM to PO therapy. We used additional data from a previously reported trial to test the hypothesis that the reduction in agitation achieved by IM olanzapine 10 mg or IM haloperidol 7.5 mg would be maintained following transition to 4 days of PO olanzapine or PO haloperidol (5-20 mg/d for both). We also hypothesized that olanzapine would maintain its more favorable extrapyramidal symptom (EPS) safety profile. This was a multinational (hospitals in 13 countries), double-blind, randomized, controlled trial. Acutely agitated inpatients with schizophrenia were treated with 1 to 3 IM injections to olanzapine 10 mg or haloperidol 7.5 mg over 24 hours and were entered into a 4-day PO treatment period with the same medication (5-20 mg/d for both). The primary efficacy measurement was reduction in agitation, as measured by the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score. Adverse events and scores on EPS rating scales were assessed. A total of 311 patients (204 men, 107 women; mean [SD] age, 38.2 [11.6] years) were enrolled (131, 126, and 54 patients in the olanzapine, haloperidol, and placebo groups, respectively). In all, 93.1% (122/131) of olanzapine-treated patients and 92.1% (116/126) of haloperidol-treated patients completed the IM period and entered the PO period; 85.5% (112/131) of olanzapine-treated patients and 84.1% (106/126) of haloperidol-treated patients completed the PO period. IM olanzapine and IM haloperidol effectively reduced agitation over 24 hours (mean [SD] PANSS-EC change, -7.1 [4.81 vs -6.7 [4.3], respectively). Reductions in agitation were sustained throughout the PO period with both study drugs (mean [SD] change from PO period baseline, -0.6 [4.8] vs -1.3 [4.4], respectively). During PO treatment, haloperidol-treated patients spontaneously reported significantly more acute dystonia than olanzapine-treated patients (4.3%[5/116] vs 0% [0/122], respectively; P = 0.026) and akathisia (5.2% [6/116] vs 0% [0/122], respectively; P = 0.013). Significantly more haloperidol-treated patients than olanzapine-treated patients met categorical criteria for treatment-emergent akathisia (18.5% [17/92] vs 6.5% [7/107], respectively; P = 0.015). In the acutely agitated patients with schizophrenia in this study, both IM olanzapine 10 mg and IM haloperidol 7.5 mg effectively reduced agitation over 24 hours. This alleviation of agitation was sustained following transition from IM therapy to 4 days of PO treatment (5-20 mg/d for both). During the 4 days of PO treatment, olanzapine-treated patients did not spontaneously report any incidences of acute dystonia, and olanzapine had a superior EPS safety profile to that of haloperidol. The combination of IM and PO olanzapine may help improve the treatment of acutely agitated patients with schizophrenia.",2003.0,0,0
727,12870569,Differential effect of quetiapine on depressive symptoms in patients with partially responsive schizophrenia.,Robin A Emsley; Peter Buckley; A Martin Jones; Michael R Greenwood,"While atypical antipsychotics appear to be effective in reducing depressive symptoms in the acute phase of schizophrenia, little is known about their efficacy in patients with ongoing symptoms. The present study assessed whether quetiapine (Seroquel) is more effective than haloperidol in treating depressive symptoms in patients with persistent positive symptoms, and investigated whether this effect is independent, or secondary to, reductions in other symptoms such as positive, negative or extrapyramidal symptoms. Patients with schizophrenia and a history of partial refractoriness to conventional antipsychotics who had not responded to 4 weeks of fluphenazine treatment (20 mg/day) were randomized to receive either quetiapine (600 mg/day) or haloperidol (20 mg/day) for a further 8 weeks. Change in the Positive and Negative Syndrome Scale depression factor score from baseline to endpoint was calculated and path analyses were performed on data from 269 patients. Quetiapine produced a greater reduction in depressive scores than haloperidol (-1.60 versus -0.54; p = 0.006). The path analyses indicated that this was a direct effect on depressive symptoms. These findings extend the evidence for an antidepressant effect for the novel antipsychotics in schizophrenia, and suggest that this is not limited to acutely psychotic patients.",2003.0,1,1
728,12879814,[Comparative bioavailability study of two formulations of risperidone available in the Chilean market].,Leonardo E Gaete; Jaime Solís; Pablo Venegas; Mitzy J Carrillo; Oscar Schatloff; Iván Saavedra,"Bioavailability of a particular drug can vary according to the formulation used. Therefore, studies of comparative bioavailability of different formulations of a same drug are worthwhile. To compare the bioavailability of two risperidone formulations available in the Chilean market. The bioavailability of a local risperidone formulation (Spiron) was compared with the original formulation of the drug (Risperdal) in 12 healthy volunteers, aged 19 +/- 1 years. A single dose of 3 mg was given orally, using a randomized double blind protocol in two periods. Fifteen blood samples were obtained at regular intervals, until 24 h after drug administration. Risperidone plasma levels were measured by high pressure liquid chromatography. pharmacokinetic parameters were calculated using a computer program that is independent of compartmental analysis. The area under the curve of plasma concentration versus time, from 0 to infinite (ABC0-infinity) and from 0 to 24 h (ABC0-24), early exposure (ABC from 0 to maximal time) and maximal plasma concentrations were significantly lower for Spiron. Half life time and time to achieve the maximal concentration were similar for the two formulations. According to bioequivalence tests suggested by the Food and Drug Administration (FDA) of the United States (90% confidence interval for the difference of long transformed mean pharmacokinetic parameters), the formulations Risperdal and Spiron, cannot be considered interchangeable.",2003.0,0,0
729,12888781,Olanzapine reduces craving for alcohol: a DRD4 VNTR polymorphism by pharmacotherapy interaction.,Kent E Hutchison; Angela Wooden; Robert M Swift; Andrew Smolen; John McGeary; Lawrence Adler; Lyndee Paris,"Separate investigations have suggested that olanzapine, a D4 antagonist, decreases craving after a priming dose of alcohol and that the DRD4 variable number of tandem repeats (VNTR) polymorphism influences the expression of craving after a priming dose of alcohol. The present study tested the hypothesis that olanzapine may be differentially effective at reducing cue-elicited craving based on individual differences in DRD4 VNTR in a sample of heavy social drinkers. Participants were randomly assigned to receive olanzapine (5 mg) or a control medication (cyproheptadine, 4 mg) prior to consuming three alcoholic drinks. Participants completed subjective measures of craving and euphoria after each drink. Participants who were homozygous or heterozygous for the 7 (or longer) repeat allele of the DRD4 VNTR were classified as DRD4 L, while the other participants were classified as DRD4 S. The findings indicated that olanzapine reduces craving for alcohol at baseline for both DRD4 S and DRD4 L individuals, but only reduces craving after exposure to alcohol cues and after a priming dose of alcohol for DRD4 L individuals.",2003.0,0,0
730,12892048,Vitamin E treatment for tardive dyskinesia. Veterans Affairs Cooperative Study #394 Study Group.,L A Adler; J Rotrosen; R Edson; P Lavori; J Lohr; R Hitzemann; D Raisch; M Caligiuri; K Tracy,"Several short-term, controlled trials have documented the efficacy of vitamin E in treating tardive dyskinesia. However, the persistent nature of the disease prompted us to perform a multicenter, longer-term trial of vitamin E. The study was a prospective, randomized, 9-site trial of up to 2 years of treatment with d-vitamin E (1600 IU/d) vs matching placebo. One hundred fifty-eight subjects with tardive dyskinesia who were receiving neuroleptic medications were enrolled. The blinded assessments performed were clinical (Abnormal Involuntary Movements Scale, Barnes Akathisia Scale, and Modified Simpson-Angus [for Extrapyramidal Symptoms] Scale) and electromechanical assessments of movement disorders, psychiatric status (Brief Psychiatric Rating Scale), and functioning (Global Assessment of Functioning). There were no significant differences in baseline demographic characteristics or in study assessments between the group that received vitamin E and the group that received placebo. Vitamin E was well tolerated and subject compliance with medication was good and similar between treatment groups. One hundred seven subjects (70% of those receiving vitamin E and 66% of subjects receiving placebo) completed at least 1 year of treatment. There were no significant effects of vitamin E on total scores or subscale scores for the AIMS, electromechanical measures of dyskinesia, or scores from the other 4 scales. This long-term, randomized trial of vitamin E vs placebo found no evidence for efficacy of vitamin E in the treatment of tardive dyskinesia.",2003.0,0,0
731,12893670,Clozapine v. conventional antipsychotic drugs for treatment-resistant schizophrenia: a re-examination.,Joanna Moncrieff,"Although there is a consensus that clozapine is more effective than conventional antipsychotic drugs for treatment-resistant schizophrenia, there is great heterogeneity among results of relevant trials. To re-evaluate the evidence comparing clozapine with conventional antipsychotics and to investigate sources of heterogeneity. Individual studies were inspected with assessment of clinical relevance of results. Meta-regression analysis was performed to investigate sources of heterogeneity. Ten trials were examined. Recent large-scale studies have not found a substantial advantage for clozapine, especially in terms of a clinically relevant effect. Meta-regression showed that shorter study duration, financial support from a drug company and higher baseline symptom score consistently predicted greater advantage of clozapine. It may be inappropriate to combine studies in meta-analysis, given the degree of heterogeneity between their findings. The benefits of clozapine compared with conventional treatment may not be substantial.",2003.0,0,0
732,12900300,"Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol.",Jeffrey A Lieberman; Gary Tollefson; Mauricio Tohen; Alan I Green; Raquel E Gur; Rene Kahn; Joseph McEvoy; Diana Perkins; Tonmoy Sharma; Robert Zipursky; Hank Wei; Robert M Hamer; HGDH Study Group,"Few long-term studies have compared the efficacy and safety of typical and atypical antipsychotic medications directly in patients with a first episode of psychosis who met the criteria for schizophrenia or a related psychotic disorder. This study compared the acute and long-term effectiveness of haloperidol with that of olanzapine in patients with first-episode psychosis in a large, controlled clinical trial. Patients with first-episode psychosis (N=263) were randomly assigned under double-blind conditions to receive haloperidol or olanzapine and were followed for up to 104 weeks. Domains measured included psychopathology, psychosocial variables, neurocognitive functioning, and brain morphology and metabolism. This report presents data from clinical measures of treatment response and safety data from the 12-week acute treatment phase. Haloperidol and olanzapine were associated with substantial and comparable baseline-to-endpoint reductions in symptom severity, which did not differ significantly in last-observation-carried-forward analyses. However, in a mixed-model analysis, olanzapine-treated subjects had significantly greater decreases in symptom severity as measured by the Positive and Negative Syndrome Scale total score and negative and general scales and by the Montgomery-Asberg Depression Rating Scale but not as measured by the Positive and Negative Syndrome Scale positive scale and by the Clinical Global Impression severity rating. Olanzapine-treated patients experienced a lower rate of treatment-emergent parkinsonism and akathisia but had significantly more weight gain, compared with the haloperidol-treated patients. Overall, significantly more olanzapine-treated subjects than haloperidol-treated subjects completed the 12-week acute phase of the study (67% versus 54%). As expected on the basis of previous studies, both olanzapine and haloperidol were effective in the acute reduction of psychopathological symptoms in this group of patients with first-episode psychosis. However, olanzapine had several relative advantages in therapeutic response. Although the nature of adverse events differed between the two agents, retention in the study was greater with olanzapine. Retention in treatment is important in this patient population, given their risk of relapse. Longer-term results are needed to determine whether treatment with atypical antipsychotics results in superior outcomes for a first episode of schizophrenia.",2003.0,1,1
733,12900301,Maintenance treatment of schizophrenia with risperidone or haloperidol: 2-year outcomes.,Stephen R Marder; Shirley M Glynn; William C Wirshing; Donna A Wirshing; Doreen Ross; Clifford Widmark; Jim Mintz; Robert P Liberman; Karen E Blair,"Most controlled studies comparing second-generation and conventional antipsychotics have focused on the acute treatment of schizophrenia. The authors compared symptom outcomes, side effects, and social adjustment in stable schizophrenia outpatients who received 2 years of maintenance treatment with risperidone or haloperidol. This was a 2-year, randomized, double-blind comparison of 6 mg of risperidone versus haloperidol in 63 patients with stabilized DSM-IV schizophrenia. Study patients also received 15 months of standard behavioral skills training or enhanced training with a case manager who promoted patients' use of their skills in the community. The risk of psychotic exacerbations and the risk of leaving the study were similar for both drug treatment groups. However, patients who received both risperidone and the enhanced community-based skills training were more likely to remain in the study than those in the other treatment groups. Patients demonstrated significant improvement in score on the Brief Psychiatric Rating Scale over time with both medications. There were no between-group differences in cluster scores for thought disturbance, hostile-suspiciousness, and withdrawal-retardation. A significant between-group difference favoring risperidone was found for the anxious-depression cluster. Risperidone resulted in significantly greater reductions in tremor and akathisia and greater improvements in most items on the SCL-90-R. When compared with patients given a low dose of haloperidol, risperidone-treated patients experienced similar improvements in positive and negative symptoms and similar risks of psychotic exacerbations. However, risperidone-treated patients appeared to feel subjectively better, as indicated by less anxiety and depression and fewer extrapyramidal side effects.",2003.0,1,1
734,12900303,,,,,0,1
735,12906345,Quetiapine in the successful treatment of schizophrenia with comorbid alcohol and drug dependence: a case report.,Robert L Weisman,"Excluding nicotine and caffeine dependence, almost 50% of individuals with schizophrenia also meet the criteria for substance abuse or dependence. Comorbid drug abuse presents complications to the effective treatment of these patients because they have increased psychotic symptoms and poorer treatment compliance. This report describes thecase of a young man with schizophrenia and comorbid alcohol and cocaine abuse who was successfully treated with quetiapine. The patient was previously treated with olanzapine and developed priapism, which required emergency medical treatment. The possible utility of atypical antipsychotics in the treatment of patients with schizophrenia and comorbid substance abuse needs to be confirmed in clinical trials.",2003.0,0,0
736,12908658,The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development.,T Scott Stroup; Joseph P McEvoy; Marvin S Swartz; Matthew J Byerly; Ira D Glick; Jose M Canive; Mark F McGee; George M Simpson; Michael C Stevens; Jeffrey A Lieberman,"The National Institute of Mental Health initiated the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) program to evaluate the effectiveness of antipsychotic drugs in typical settings and populations so that the study results will be maximally useful in routine clinical situations. The CATIE schizophrenia trial blends features of efficacy studies and large, simple trials to create a pragmatic trial that will provide extensive information about antipsychotic drug effectiveness over at least 18 months. The protocol allows for subjects who receive a study drug that is not effective to receive subsequent treatments within the context of the study. Medication dosages are adjusted within a defined range according to clinical judgment. The primary outcome is all-cause treatment discontinuation because it represents an important clinical endpoint that reflects both clinician and patient judgments about efficacy and tolerability. Secondary outcomes include symptoms, side effects, neurocognitive functioning, and cost-effectiveness. Approximately 50 clinical sites across the United States are seeking to enroll a total of 1,500 persons with schizophrenia. Phase 1 is a double-blinded randomized clinical trial comparing treatment with the second generation antipsychotics olanzapine, quetiapine, risperidone, and ziprasidone to perphenazine, a midpotency first generation antipsychotic. If the initially assigned medication is not effective, subjects may choose one of the following phase 2 trials: (1) randomization to open-label clozapine or a double-blinded second generation drug that was available but not assigned in phase 1; or (2) double-blinded randomization to ziprasidone or another second generation drug that was available but not assigned in phase 1. If the phase 2 study drug is discontinued, subjects may enter phase 3, in which clinicians help subjects select an open-label treatment based on individuals' experiences in phases 1 and 2.",2003.0,1,1
737,12908661,Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE): Alzheimer's disease trial.,Lon S Schneider; M Saleem Ismail; Karen Dagerman; Sonia Davis; Jason Olin; Dennis McManus; Eric Pfeiffer; J Michael Ryan; David L Sultzer; Pierre N Tariot,"This article describes the development of the protocol for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Alzheimer's disease trial, which was developed in collaboration with the National Institute of Mental Health to assess the effectiveness of atypical antipsychotics for psychosis and/or agitation occurring in outpatients with Alzheimer's disease. The article provides a detailed description of the methodology used in the trial as well as the clinical outcomes and effectiveness measures incorporated into it, discussing the most salient issues encountered in developing the design of the trial, as well as the unique features of the trial.",2003.0,1,1
738,12908663,Changing environments and alternative perspectives in evaluating the cost-effectiveness of new antipsychotic drugs.,Robert Rosenheck; Jefferson Doyle; Douglas Leslie; Alan Fontana,"This article examines the ways in which changes in the treatment environment and in measurement perspectives can affect the evaluation of cost-effectiveness of new medications. In three studies we reexamined data from a clinical trial of haloperidol and clozapine conducted from 1993 to 1996. The results of the studies are as follows: Study 1 found that clozapine treatment was associated with significantly reduced inpatient costs, and increased outpatient costs, suggesting that as systems use less inpatient care and more outpatient care, more effective medications may increase, rather than decrease, costs in sicker patients. Study 2 found that while provider assessments and standard measures favored clozapine over haloperidol, patient responses showed little evidence of a clinical advantage for clozapine and a less favorable side-effect profile. Study 3 found that while annual drug costs in the published trial were estimated to be dollars 4,545 for a full year of clozapine treatment, atypical antipsychotic costs in 2000 were estimated to range from dollars 1,254 to dollars 3,016 in the Department of Veterans Affairs system, and from dollars 2,221 to dollars 8,147 in the private sector. In conclusion, cost-effectiveness, as evaluated in studies like CATIE, will increasingly need to be tied to service system contingencies, environments, and evaluation perspectives.",2003.0,0,0
739,12908665,"Generating evidence to inform policy and practice: the example of the second generation ""atypical"" antipsychotics.",John Geddes,"The introduction of the second generation ""atypical"" antipsychotics has been heralded as a major advance in the treatment of schizophrenia and other psychotic disorders. Systematic reviews have revealed only modest advantages over conventional antipsychotics and uncertainty about long-term efficacy and safety, yet the second generation antipsychotic drugs have been widely accepted into clinical practice. Although the existing evidence of the benefits and harms of atypical antipsychotics can facilitate decision making about individual patients, the randomized evidence remains inadequate to make valid and fully evidence-based policy statements such as clinical practice guidelines that are designed to apply to groups of patients. Further large randomized trials are needed, but these require patients and clinicians to be in equipoise, or substantially uncertain, about alternative therapies. Premature clinical practice guidelines or expert opinion can lead to changes in clinical practice that make it difficult or impossible to conduct the required trials and are therefore a disservice to patients.",2003.0,0,0
740,12915289,Predicting suicidal risk in schizophrenic and schizoaffective patients in a prospective two-year trial.,Steven G Potkin; Larry Alphs; Chuanchieh Hsu; K Ranga Rama Krishnan; Ravi Anand; Frederick K Young; Herbert Meltzer; Alan Green; InterSePT Study Group,"Enhanced ability to reliably identify risk factors for suicidal behavior permits more focused decisions concerning treatment interventions and support services, with potential reduction in lives lost to suicide. This study followed 980 patients at high risk for suicide in a multicenter prospective study for 2 years after randomization to clozapine or olanzapine. A priori predictors related to diagnosis, treatment resistance, and clinical constructs of disease symptoms were evaluated as possible predictors of subsequent suicide-related events. Ten baseline univariate predictors were identified. Historical predictors were diagnosis of schizoaffective disorder, history or current use at baseline of alcohol or substance abuse, cigarette smoking, number of lifetime suicide attempts, and the number of hospitalizations in the previous 36 months to prevent suicide. Predictive clinical features included greater baseline scores on the InterSePT scale for suicidal thinking, the Covi Anxiety Scale, the Calgary Depression Scale (CDS), and severity of Parkinsonism. Subsequent multivariate analysis revealed the number of hospitalizations in the previous 36 months, baseline CDS, severity of Parkinson's, history of substance abuse, and lifetime suicide attempts. Clozapine, in general, was more effective than olanzapine in decreasing the risk of suicidality, regardless of risk factors present. This is the first prospective analysis of predictors of suicide risk in a large schizophrenic and schizoaffective population judged to be at high risk for suicide. Assessment of these risk factors may aid clinicians in evaluating risk for suicidal behaviors so that appropriate interventions can be made.",2003.0,1,1
741,12915290,Randomized trial of olanzapine versus placebo in the symptomatic acute treatment of the schizophrenic prodrome.,Scott W Woods; Alan Breier; Robert B Zipursky; Diana O Perkins; Jean Addington; Tandy J Miller; Keith A Hawkins; Eva Marquez; Stacy R Lindborg; Mauricio Tohen; Thomas H McGlashan,"The prodromal phase of schizophrenic disorders has been described prospectively. The present study aimed to determine the short-term efficacy and safety of olanzapine treatment of prodromal symptoms compared with placebo. This was a double-blind, randomized, parallel-groups, placebo-controlled trial with fixed-flexible dosing conducted at four sites. Sixty patients met prodromal diagnostic criteria, including attenuated psychotic symptoms, as determined by structured interviews. Olanzapine 5-15 mg daily or placebo was prescribed for 8 weeks. In the mixed-effects, repeated-measures analysis, the treatment x time interaction for the change from baseline on the Scale of Prodromal Symptoms total score was statistically significant, and post hoc analyses revealed that the olanzapine-placebo difference reached p<.10 by week 6 and p<.05 at week 8. Ratings of extrapyramidal symptoms remained low in each group and were not significantly different. Olanzapine patients gained 9.9 lb versus.7 lb for placebo patients (p<.001). This short-term analysis suggests olanzapine is associated with significantly greater symptomatic improvement but significantly greater weight gain than is placebo in prodromal patients. Extrapyramidal symptoms with olanzapine were minimal and similar to those with placebo. Future research over the longer term with more patients will be needed before recommendations can be made regarding routine treatment.",2003.0,1,1
742,12920408,Serum antimuscarinic activity during clozapine treatment.,Jose de Leon; Aruby Odom-White; Richard C Josiassen; Francisco J Diaz; Thomas B Cooper; George M Simpson,"This study attempts: (1) to verify that serum antimuscarinic activity is related to clozapine dose, and more importantly to clozapine plasma concentrations; (2) to explore whether norclozapine has serum antimuscarinic activity; (3) to explore whether antimuscarinic activity is related to clozapine side effects; and (4) to compare the serum antimuscarinic activities of clozapine with those of antiparkinsonian drugs and other antipsychotics. In 39 patients participating in a double-blind clozapine study, the [3H]QNB assay was used to measure serum antimuscarinic activity: (1) on baseline medications; (2) after a 4-week haloperidol trial; (3) after a 16-week clozapine trial of either 100, 300, or 600 mg/d; and (4) after 1 or 2 consecutive 16-week clozapine trials with remaining doses in nonresponders. Clozapine levels predicted serum antimuscarinic activity better than clozapine dose. At the end of the 1st clozapine trial, the correlation with the levels explained 69% of the variance of serum antimuscarinic activity (r = 0.83, P < 0.001, N = 34). Clozapine levels were good predictors of serum antimuscarinic activity only in patients taking 300 or 600 mg/d. After correcting for clozapine levels, the within-subject correlation between norclozapine levels and serum antimuscarinic activity was relatively high and significant (r = 0.54, F = 26.7, df = 1.65, P < 0.001). Constipation was significantly associated with higher serum antimuscarinic activity during the 1st clozapine trial. Clozapine was associated with clearly higher antimuscarinic activity than other antipsychotics or low doses of antiparkinsonians. In vitro studies and new clinical studies are needed to verify whether norclozapine may significantly contribute to antimuscarinic activity during clozapine treatment.",2003.0,0,0
743,12920409,Effectiveness of rapid initial dose escalation of up to forty milligrams per day of oral olanzapine in acute agitation.,Robert W Baker; Bruce J Kinon; Gerald A Maguire; Hong Liu; Angela L Hill,"Patients experiencing an acute decompensation of schizophrenia or bipolar disorder often present in an agitated state. Agitation presents a barrier to therapy, interrupting the typical physician-patient alliance and creating a disruptive, even hazardous, environment. Rapid assessment and effective treatment are necessary to manage agitation and, potentially, to shorten the time to recovery. One hundred forty-eight acutely agitated patients received either: rapid initial dose escalation (RIDE) in which up to 40 mg of oral olanzapine was allowed on days 1 and 2, up to 30 mg on days 3 and 4, and 5 to 20 mg thereafter; or usual clinical practice (UCP) in which patients received 10 mg/d olanzapine plus up to 4 mg lorazepam on days 1 and 2, up to 2 mg on days 3 and 4, and olanzapine 5 to 20 mg/d thereafter. The Positive and Negative Syndrome Scale-Excited Component (PANSS-EC: poor impulse control, tension, hostility, uncooperativeness, and excitement) measured at 24 hours was the primary measure. Secondary assessments of agitation and safety were also performed. Agitation improved significantly from baseline for both treatment groups; however, improvement with the RIDE strategy was superior to UCP. The RIDE group improvement was superior on the primary efficacy measure (PANSS-Excited) at 24 hours; it was superior on all agitation measures at the end of double-blind treatment. Both treatments were well tolerated, with no clinically significant differences in safety measures. Treatment was not limited by oversedation and attention improved from baseline in both groups. This study demonstrates the value of olanzapine in the treatment of acutely agitated patients. A new approach to olanzapine dosing that expands the initial dose range up to 40 mg/d may offer superior efficacy in rapidly and effectively controlling the symptoms of agitation.",2003.0,0,0
744,12920413,Olanzapine versus placebo in acute mania: treatment responses in subgroups.,Ross J Baldessarini; John Hennen; Michael Wilson; Joseph Calabrese; Roy Chengappa; Paul E Keck; Susan L McElroy; Gary Sachs; Eduard Vieta; Jeffrey A Welge; Lakshmi N Yatham; Carlos A Zarate; Robert W Baker; Mauricio Tohen,"Two double-blind, placebo-controlled trials of olanzapine in acute mania showed significant overall antimanic efficacy, based on reductions in mania ratings. Their subject-level data were pooled to increase statistical power to test for differences in treatment responses among 10 subgroup pairs of interest using generalized estimating equations methods. Similar drug/placebo superiority and responsiveness to olanzapine was found in men versus women, psychotic versus nonpsychotic subjects, and those presenting in mania versus mixed states, and responses were independent of onset age, current age, or prior illness based on episodes, hospitalizations, recent rapid cycling, lifetime substance use, or previous antipsychotic treatment. Olanzapine and placebo responses paralleled closely (r(s) = 0.73). Patients were relatively more responsive to olanzapine who were younger at illness onset, lacked prior substance abuse, and had not previously received antipsychotic treatment (efficacy ratios 1.5-1.7, all P < 0.01). These well-powered comparisons of subgroups of interest indicate broad efficacy of olanzapine in the treatment of acute mania.",2003.0,0,0
745,12920421,Treatment-emergent tardive dyskinesia with quetiapine in mood disorders.,Verinder Sharma,,2003.0,0,0
746,12921224,Actigraphic measurement of the effects of single-dose haloperidol and olanzapine on spontaneous motor activity in normal subjects.,Michael Kiang; Z Jeff Daskalakis; Bruce K Christensen; Gary Remington; Shitij Kapur,"To quantitatively examine the effects of haloperidol and olanzapine on spontaneous motor activity in normal subjects. Randomized, double-blind, placebo-controlled medication study. Normal volunteers (n = 30). Subjects received 1 dose of either haloperidol 2 mg (n = 9), olanzapine 10 mg (n = 10) or placebo (n = 10) and were admitted to hospital for the next 24 hours. Subjects wore an actigraphic monitor, which recorded movement in 15-second epochs. The Simpson-Angus Extrapyramidal Side Effect Scale (SAS) and the Barnes Akathisia Scale (BAS) were administered before and 7 and 24 hours after medication was given. Compared with placebo, total motor activity was decreased by 41% with olanzapine (p = 0.004) and by 12% with haloperidol (NS). There were significantly more epochs with zero movement with olanzapine than with haloperidol or placebo. For non-zero epochs, the mean activity count and the distribution of activity counts did not differ significantly among groups. There were no positive findings on the SAS or the BAS. Olanzapine decreased total motor activity by increasing the amount of time during which subjects were immobile, rather than by affecting the magnitude of movement during periods in which there was activity. This effect occurred at a dose of olanzapine low enough not to cause clinically observed extrapyramidal side effects. Our results suggest that actigraphy is useful as a sensitive, noninvasive tool for measuring the effect of antipsychotics on spontaneous motor activity.",2003.0,0,0
747,12921492,Management of the negative symptoms of schizophrenia: new treatment options.,Hans-Jürgen Möller,"This article presents a systematic review of pharmacological treatment for negative symptoms of schizophrenia, based on MEDLINE searches from 1995 to September 2002 to identify pertinent clinical trials. The pharmacotherapy of negative symptoms in schizophrenia includes novel/atypical antipsychotics and classical antipsychotics, as well as antidepressants, glutamatergic compounds, antiepileptic drugs and estrogens. In the assessment of therapy for negative symptoms of schizophrenia, it is imperative that better studies of sound methodology are performed. In such studies, some important aspects to be considered include an accurate definition and assessment of negative symptoms (including well designed, valid and reliable rating scales), the differentiation between primary and secondary negative symptoms, an appropriate selection of standard comparators, adequate dosages of comparators (e.g. haloperidol dosages) and an overall optimal study design. Most of the available studies on treating negative symptoms in schizophrenia have focused on the atypical antipsychotics, while other potential candidates, mostly in the context of add-on therapy, have not been so intensively investigated. Atypical antipsychotics have been proven in placebo-controlled trials to be effective in treating negative symptoms of acute schizophrenic episodes. In many of the comparator studies, they showed efficacy in treating negative symptoms that was superior to that of typical antipsychotics. Data on stable, predominant negative symptoms in subchronic or chronic cases of schizophrenia, although limited, have demonstrated the efficacy of atypical antipsychotics. If the beneficial tolerability profile with respect to extrapyramidal symptoms is also taken into account during clinical decision making, the atypical antipsychotics should be preferred for the treatment of negative symptoms. It is also worth noting that the traditional antipsychotics have the risk of inducing negative symptoms in the context of akinesia. The benefits of add-on therapy with SSRIs or a glutamatergic compound are well documented. Estrogen add-on therapy seems promising. Other traditionally suggested approaches, such as comedication with an antiepileptic drug, lithium or beta-adrenoceptor antagonist, cannot generally be recommended on the basis of the available data.",2003.0,0,0
748,12921516,Olanzapine for psychotic and behavioral disturbances in Alzheimer disease.,Robin A Schatz,"To evaluate the efficacy and safety of olanzapine for the treatment of psychotic and behavioral disturbances in Alzheimer disease. MEDLINE (1966-January 2003) and Science Citation Index searches were performed. Key search terms included olanzapine, Alzheimer(s), and dementia. Four trials of olanzapine and subsequent post hoc analyses were reviewed. Three trials found a benefit associated with olanzapine use, but a fourth trial did not. Olanzapine appears to be effective in treating psychotic and behavioral disturbances associated with Alzheimer disease. However, the most appropriate dose remains to be determined. The benefit of olanzapine therapy must be weighed against the adverse effect profiles of olanzapine and alternative treatment options.",2003.0,0,1
749,12925933,Augmenting atypical antipsychotics with a cognitive enhancer (donepezil) improves regional brain activity in schizophrenia patients: a pilot double-blind placebo controlled BOLD fMRI study.,Ziad Nahas; Mark S George; Michael D Horner; John S Markowitz; Xingbao Li; Jeffrey P Lorberbaum; Susan D Owens; Susan McGurk; Lindsay DeVane; S Craig Risch,"Cognitive impairments are cardinal features of schizophrenia and predictors of poor vocational and social outcome. Imaging studies with verbal fluency tasks (VFT) lead some to suggest that in schizophrenia, the combination of a failure to deactivate the left temporal lobe and a hypoactive frontal lobe reflects a functional disconnectivity between the left prefrontal cortex and temporal lobe. Others have theorized that an abnormal cingulate gyrus modulates such fronto-temporal connectivity. Thus addition of a cognitive enhancing medication to current antipsychotic therapy might improve functionality of networks necessary in working memory and internal concept generation. To test this hypothesis, we serially measured brain activity in 6 subjects on stable atypical antipsychotics performing a VFT, using BOLD fMRI. Measurements were made at baseline and again after groups were randomized to receive 12 weeks of donepezil (an acetylcholinesterase inhibitor) and placebo in a blind cross-over design. Donepezil addition provided a functional normalization with an increase in left frontal lobe and cingulate activity when compared to placebo and from baseline scans. This pilot study supports the cingulate's role in modulating cognition and neuronal connectivity in schizophrenia.",2003.0,0,0
750,12927004,"An integrated analysis of acute treatment-emergent extrapyramidal syndrome in patients with schizophrenia during olanzapine clinical trials: comparisons with placebo, haloperidol, risperidone, or clozapine.",Christopher D Carlson; Patrizia A Cavazzoni; Paul H Berg; Hank Wei; Charles M Beasley; John M Kane,"The frequency and severity of extrapyramidal syndrome (EPS) were evaluated in patients with DSM-III or DSM-IV schizophrenia in the acute phase (- 8 weeks) of randomized, double-blind, controlled trials from the integrated olanzapine clinical trial database. This retrospective analysis included 23 clinical trials and 4611 patients from November 11, 1991, through July 31, 2001. Incidences of dystonic, parkinsonian, and akathisia events were compared using treatment-emergent adverse-event data. Categorical analyses of Simpson-Angus Scale and Barnes Akathisia Scale (BAS) scores, use of anticholinergic medications, and baseline-to-endpoint changes in Simpson-Angus Scale and BAS scores were compared. A significantly smaller percentage of olanzapine-treated patients experienced dystonic events than did haloperidol- (p <.001) or risperidone-treated patients (p =.047). A significantly greater percentage of haloperidol-treated patients experienced parkinsonian (p <.001) and akathisia (p <.001) events than did olanzapine-treated patients. Categorical analysis of Simpson-Angus Scale scores showed significantly more haloperidol- (p <.001) or risperidone-treated patients (p =.004) developed parkinsonism than did olanzapine-treated patients. Olanzapine-treated patients experienced significantly greater reductions in Simpson-Angus Scale scores than did haloperidol- (p <.001), risperidone- (p <.001), or clozapine-treated (p =.032) patients. Categorical analysis of BAS scores showed significantly more haloperidol-treated patients experienced treatment-emergent akathisia versus olanzapine-treated patients (p <.001). Significantly greater reductions in BAS scores were experienced during olanzapine treatment versus placebo (p =.007), haloperidol (p <.001), and risperidone (p =.004) treatments. A significantly smaller percentage of olanzapine-treated patients received anticholinergic medications compared with that of haloperidol- (p <.001) or risperidone-treated patients (p =.018). Compared with that in olanzapine-treated patients, the duration of anticholinergic cotreatment was significantly longer among haloperidol- (p <.001) or risperidone-treated patients (p =.040) and significantly shorter among clozapine-treated patients (p =.021). This analysis of available data from olanzapine clinical trials lends additional support to olanzapine's favorable EPS profile.",2003.0,0,1
751,12934987,"The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder.",Robert M A Hirschfeld; Jeffrey D Baker; Patricia Wozniak; Katherine Tracy; Kenneth W Sommerville,"Previous studies have examined the safety and tolerability of oral-loaded divalproex sodium in the treatment of acute mania, but not the early efficacy of this dosing strategy. The purpose of this study was to evaluate the early efficacy of oral-loaded divalproex. In this pooled analysis, 348 subjects from 3 randomized, double-blind, parallel-group, active- or placebo-controlled studies were used to compare the efficacy, safety, and tolerability of oral-loaded divalproex with standard-titration divalproex, lithium, olanzapine, or placebo. Subjects were inpatients diagnosed with acute mania associated with bipolar I disorder (DSM-III-R or -IV and SADS-Change Version). Patients were administered oral-loaded divalproex (20 or 30 mg/kg/day on days 1 and 2 followed by 20 mg/kg/day, and increased at physician's discretion), standard-titration divalproex initiated at 250 mg t.i.d. and titrated to 40-150 microg/mL, lithium (300 mg t.i.d. initial dose) titrated to 0.4 to 1.5 mEq/L, olanzapine (10 mg q.d. initial dose) up to 20 mg/day, or placebo. The results demonstrate an early efficacy advantage for oral-loaded divalproex compared to standard-titration divalproex at days 5, 7/8, and 10. Efficacy was improved over lithium on day 7/8. There were no efficacy differences between divalproex loading and olanzapine. Divalproex loading showed greater efficacy than placebo at all time points. Divalproex loading was as well tolerated or better tolerated than the other active treatments as measured by adverse events and changes in laboratory parameters. These results suggest the oral loading of divalproex leads to a more rapid antimanic effect when compared with standard-titration divalproex, lithium, or placebo and is better tolerated than olanzapine and as well tolerated as lithium or standard-titration divalproex.",2003.0,0,1
752,12944341,"A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania.",Paul E Keck; Ronald Marcus; Stavros Tourkodimitris; Mirza Ali; Amy Liebeskind; Anutosh Saha; Gary Ingenito; Aripiprazole Study Group,"The authors compared the efficacy and safety of aripiprazole, a novel antipsychotic, to placebo for treatment of patients in an acute manic or mixed episode of bipolar disorder. This 3-week, multicenter, double-blind study randomly assigned 262 bipolar disorder patients in an acute manic or mixed episode to aripiprazole, 30 mg/day (reduced to 15 mg/day if needed for tolerability), or placebo. Patients remained hospitalized for at least 2 of the weeks. The primary efficacy measure was mean change from baseline in total score on the Young Mania Rating Scale; response was defined as a decrease in score of > or =50%. Aripiprazole produced statistically significant mean improvements in total score on the Young Mania Rating Scale compared with placebo (-8.2 versus -3.4, respectively) and produced a significantly higher response rate (40% versus 19%). For key efficacy variables (response per Young Mania Rating Scale; Clinical Global Impression-Bipolar Version scores for severity of illness [mania] and change from preceding phase [mania]), aripiprazole separated from placebo by day 4. The completion rate was significantly higher with aripiprazole than with placebo (42% versus 21%). Discontinuations due to adverse events did not differ significantly between the aripiprazole and placebo groups. There were no significant changes in body weight versus placebo, and aripiprazole was not associated with elevated serum prolactin or QTc prolongation. Aripiprazole had significantly greater efficacy than placebo for the treatment of bipolar disorder patients in acute manic or mixed episodes and was safe and well tolerated in this randomized controlled trial.",2003.0,1,1
753,12951204,An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients.,Chen-Jee Hong; Younger W-Y Yu; Ching-Hua Lin; Shih-Jen Tsai,"A growing body of evidence suggests the involvement of brain-derived neurotrophic factor (BDNF) in both antipsychotic action and schizophrenia pathogenesis. The present study tested the hypothesis that the BDNF-gene Val66Met polymorphism is associated with schizophrenia and clozapine's therapeutic response. To identify any genetic predisposition to schizophrenia, we studied the BDNF-gene Val66Met polymorphism in 93 schizophrenic patients and 198 normal controls. Statistical analysis was used to test the association between this polymorphism and clozapine response the schizophrenic group. A trend (P=0.055) was demonstrated between genetic predisposition and Val66Met genotypes in 93 schizophrenic patients, especially for those with good response to clozapine (P=0.023). No significant difference in clozapine therapeutic response was demonstrated comparing the three Val66Met-genotype subgroups. Our finding suggests that this BDNF-gene Val66Met polymorphism may be related to schizophrenia pathogenesis in patients responsive to clozapine treatment.",2003.0,0,0
754,12973385,Quetiapine fumarate (Seroquel): a new atypical antipsychotic.,J M Goldstein,"The goal of antipsychotic drug development efforts over the past 10 years has been to develop agents with increased efficacy and safety and fewer of the side effects commonly associated with the older antipsychotic medications. The newer agents, often called atypical antipsychotics, are effective in treating both the positive and negative symptoms of schizophrenia and are associated with fewer neurological- and endocrine-related side effects compared to the older agents. As a result, patients are likely to remain on therapy longer, preventing relapses and costly hospitalizations. Quetiapine fumarate (Seroquel) is the most recently introduced atypical antipsychotic and is indicated for the management of the manifestations of psychotic disorders and schizophrenia. Quetiapine, like clozapine (the archetypal atypical antipsychotic), interacts with a broad range of neurotransmitter receptors and has a higher affinity for serotonin (5-HT(2A)) receptors relative to dopamine (D(2)) receptors in the brain. Further, quetiapine's pharmacological effects appear selective for the mesolimbic and mesocortical dopamine systems, which are believed to be the areas of the brain responsible for the therapeutic effects of antipsychotics. In contrast to most standard antipsychotics and some atypical antipsychotics, quetiapine's effects on the nigrostriatal dopamine system, which is responsible for the extrapyramidal (or motor) side effects, are minimal. Quetiapine also has minimal activity on dopamine receptors in the tuberoinfundibular dopamine system, thereby avoiding the problem of hyperprolactinemia, common with the standard antipsychotics and some atypical antipsychotics. Because of these properties, quetiapine is an effective antipsychotic agent with a relatively benign side effect profile. Several large, placebo- and active-controlled, multicenter trials have shown quetiapine to be effective against both positive (e.g., hallucinations, delusions) and negative symptoms (e.g., emotional withdrawal, apathy) and to have benefits in reducing hostility, aggression and affective symptoms. Patients on long-term treatment report high compliance, good satisfaction, increased ability to function and improvements consistent with a better quality of life. Because of quetiapine's excellent tolerability profile, its use is particularly appropriate in patients especially sensitive to adverse effects, e.g., elderly patients with psychotic symptoms and other neurological disorders such as Parkinson's and Alzheimer's disease.",2003.0,0,0
755,12975676,Randomized controlled trial of occupational therapy in patients with treatment-resistant schizophrenia.,Patrícia Cardoso Buchain; Adriana Dias Barbosa Vizzotto; Jorge Henna Neto; Helio Elkis,"It is well established that the combination of psychopharmacological treatment and psychosocial interventions, such as psychotherapy, family orientation and occupational therapy (OT), represent the best strategy for treating patients with schizophrenia. However, in terms of treatment-resistant schizophrenia (TRS) almost only psychopharmacological treatments are available and psychosocial interventions such as OT had not proved to be effective. The aim of this study is to investigate if OT is effective when added to a psychopharmacological treatment in TRS. Two groups of patients with TRS were compared: The experimental group (EG) received psychopharmacological treatment with clozapine plus sessions of occupational therapy (OT) and the control group (CG) received only clozapine. The Scale for Interactive Observation in Occupational Therapy (EOITO) was employed to evaluate the outcome. The duration of the study was 6 months and patients were rated at baseline and monthly totaling 7 assessments. EOITO was independently applied by two occupational therapists with high reliability rates (Kappa=0.90, p=0.001). Repeated measures of analyses of variance and the evaluation of the standardized effect sizes were used for statistical analyses. The EG showed that the OT intervention was effective along the whole period of observation, mainly from the 4th month to the end of the study. In patients with TRS the combination of OT and clozapine showed to be more effective than the use of clozapine alone. OT may represent an additional therapeutic option for patients with TRS.",2003.0,0,0
756,13129658,Schizophrenia is not associated with DRD4 48-base-pair-repeat length or individual alleles: results of a meta-analysis.,Stephen J Glatt; Stephen V Faraone; Ming T Tsuang,"The gene DRD4, coding for dopamine receptor D4, was considered a candidate for association with schizophrenia based on its upregulation in postmortem schizophrenic brain and affinity for clozapine. Many studies sought allelic association of a 48-base-pair repeat in DRD4 exon 3 with schizophrenia, but found no strong evidence for a relationship. The present work sought to determine if this observation reflected the true absence of association or the low power of individual studies. We performed four meta-analyses, sequentially considering the two-, four-, and seven-repeat alleles as risk alleles, and then considering repeat length of the 48-base-pair segment as a risk factor. Each meta-analysis included at least 2,300 cases and 2,100 controls from 14-16 studies. The pooled odds ratio from each analysis approximated 1.0, and none were significant. Heterogeneity was not observed, although gender moderated the effects of repeat length and the seven-repeat allele. Despite over 90% power to detect a significant odds ratio of 1.4 or less, none was observed. This polymorphism seems not to influence risk for most schizophrenia cases; however, a sex-dependent relationship, or a role in some clinical features of the disorder, cannot be excluded and should be pursued experimentally.",2003.0,0,0
757,13129986,Suicide risk in bipolar disorder during treatment with lithium and divalproex.,Frederick K Goodwin; Bruce Fireman; Gregory E Simon; Enid M Hunkeler; Janelle Lee; Dennis Revicki,"Several studies have suggested that lithium treatment reduces risk of suicide in bipolar disorder, but no research has examined suicide risk during treatment with divalproex, the most commonly prescribed mood-stabilizing drug in the United States. To compare risk of suicide attempt and suicide death during treatment with lithium with that during treatment with divalproex. Retrospective cohort study conducted at 2 large integrated health plans in California and Washington. Population-based sample of 20 638 health plan members aged 14 years or older who had at least 1 outpatient diagnosis of bipolar disorder and at least 1 filled prescription for lithium, divalproex, or carbamazepine between January 1, 1994, and December 31, 2001. Follow-up for each individual began with first qualifying prescription and ended with death, disenrollment from the health plan, or end of the study period. Suicide attempt, recorded as a hospital discharge diagnosis or an emergency department diagnosis; suicide death, recorded on death certificate. In both health plans, unadjusted rates were greater during treatment with divalproex than during treatment with lithium for emergency department suicide attempt (31.3 vs 10.8 per 1000 person-years; P<.001), suicide attempt resulting in hospitalization (10.5 vs 4.2 per 1000 person-years; P<.001), and suicide death (1.7 vs 0.7 per 1000 person-years; P =.04). After adjustment for age, sex, health plan, year of diagnosis, comorbid medical and psychiatric conditions, and concomitant use of other psychotropic drugs, risk of suicide death was 2.7 times higher (95% confidence interval [CI], 1.1-6.3; P =.03) during treatment with divalproex than during treatment with lithium. Corresponding hazard ratios for nonfatal attempts were 1.7 (95% CI, 1.2-2.3; P =.002) for attempts resulting in hospitalization and 1.8 (95% CI, 1.4-2.2; P<.001) for attempts diagnosed in the emergency department. Among patients treated for bipolar disorder, risk of suicide attempt and suicide death is lower during treatment with lithium than during treatment with divalproex.",2003.0,0,0
758,13129995,Suicide risk and treatments for patients with bipolar disorder.,Ross J Baldessarini; Leonardo Tondo,,2003.0,0,1
759,14514482,"Schizophrenia, VI: Treatments.",Jeffrey A Lieberman; T Scott Stroup,,2003.0,0,0
760,14521477,Towards the pharmacotherapy of eating disorders.,Kristine J Pederson; James L Roerig; James E Mitchell,"The purpose of this review is to discuss pharmacological options for the treatment of patients with eating disorders. Sequentially described are pharmacotherapy studies of anorexia nervosa (AN), bulimia nervosa (BN) and binge-eating disorder (BED). The quantity of drug trials performed with AN patients has been very limited. While the majority of studies have failed to show medication efficacy for the acute treatment of AN, there is data which suggests that fluoxetine hydrochloride may play a role in preventing relapse during maintenance therapy. Atypical antipsychotics, most often olanzapine, have shown promise in a number of uncontrolled studies. BN has been most extensively studied, with the majority of pharmacological trials focusing on antidepressants. Fluoxetine, at a dose of 60 mg/day, is FDA-approved for the treatment of BN. Psychotherapy, particularly cognitive behavioural therapy (CBT) is of well-established utility in BN and data suggests that the combination of an antidepressant plus CBT is superior to either treatment alone. Recently, there has been interest in the 5-HT3 antagonist, ondansetron, and the anticonvulsant, topiramate. BED investigators have focused largely on antidepressants, which may reduce symptoms of depression and augment psychotherapy. While sibutramine and topiramate have both been associated with weight loss in controlled trials, the former appears to be fairly well-tolerated and the latter appears to be responsible for the emergence of significant cognitive and peripheral nervous system side effects in some patients. Further pharmacological research with eating disorder patients is needed, particularly in the areas of AN and BED. Also, pharmacological augmentation strategies for those not responding to primary therapies should be explored.",2003.0,0,0
761,14521482,Cannabinoids reduce symptoms of Tourette's syndrome.,Kirsten R Müller-Vahl,"Currently, the treatment of Tourette's syndrome (TS) is unsatisfactory. Therefore, there is expanding interest in new therapeutical strategies. Anecdotal reports suggested that the use of cannabis might improve not only tics, but also behavioural problems in patients with TS. A single-dose, cross-over study in 12 patients, as well as a 6-week, randomised trial in 24 patients, demonstrated that Delta9-tetrahydrocannabinol (THC), the most psychoactive ingredient of cannabis, reduces tics in TS patients. No serious adverse effects occurred and no impairment on neuropsychological performance was observed. If well-established drugs either fail to improve tics or cause significant adverse effects, in adult patients, therapy with Delta9-THC should be tried. At present, it remains unclear whether herbal cannabis, different natural or synthetic cannabinoid CB1-receptor agonists or agents that interfere with the inactivation of endocannabinoids, may have the best adverse effect profile in TS.",2003.0,0,0
762,14525551,An overview of recent findings of the Stanley Foundation Bipolar Network (Part I).,Robert M Post; Gabriele S Leverich; Lori L Altshuler; Mark A Frye; Trisha M Suppes; Paul E Keck; Susan L McElroy; Ralph Kupka; Willem A Nolen; Heinz Grunze; Jorg Walden,"Selected recent findings of the Stanley Foundation Bipolar Network are briefly reviewed and their clinical implications discussed. Daily prospective ratings on the NIMH-LCM indicate a high degree of residual depressive morbidity (three times that of hypomania or mania) despite active psychopharmacological treatment with a variety of modalities including mood stabilizers, antidepressants, and benzodiazepines, as well as antipsychotics as necessary. The rates of switching into brief to full hypomania or mania during the use of antidepressants is described, and new data suggesting the potential utility of continuing antidepressants in the small group of patients showing an initial acute and persistent response is noted. Bipolar patients with a history of major environmental adversities in childhood have a more severe course of illness and an increased incidence of suicide attempts compared with those without. Preliminary open data suggest useful antidepressant effects of the atypical antipsychotic quetiapine, while a double-blind randomized controlled study failed to show efficacy of omega-3 fatty acids (6 g of eicosapentaenoic acid compared with placebo for 4 months) in the treatment of either acute depression or rapid cycling. The high prevalence of overweight and increased incidence of antithyroid antibodies in patients with bipolar illness is highlighted. Together, these findings suggest a very high degree of comorbidity and treatment resistance in outpatients with bipolar illness treated in academic settings and the need to develop not only new treatment approaches, but also much earlier illness recognition, diagnosis, and intervention in an attempt to reverse or prevent this illness burden.",2003.0,0,0
763,14525555,"Subsyndromal symptoms assessed in longitudinal, prospective follow-up of a cohort of patients with bipolar disorder.",Glenda M MacQueen; Michael Marriott; Helen Begin; Janine Robb; Russell T Joffe; L Trevor Young,"Many patients with bipolar disorder (BD) do not regain full function following an acute illness episode, but the extent to which this impairment is the result of persistent symptoms has not been well established. This study examined factors associated with persistent subsyndromal symptoms in a well characterized group of BD patients who were prospectively followed for an average of 3 years. Detailed life charting data from 138 patients with BD were reviewed. Patients were categorized into euthymic, subsyndromal or syndromal groups according to the clinical state during their most recent year of follow-up. The three groups were then examined with respect to comorbidity, function and treatment received. Patients with subsyndromal symptoms had high rates of comorbid anxiety disorders, and were more likely to have increased rates of eating disorders as well. Patients with subsyndromal symptoms had lower global assessment of function (GAF) scores than euthymic patients, and had as many clinic contacts and medication trials as patients with full episodes of illness. Persistent subsyndromal symptoms in BD patients are associated with high rates of comorbidity that is important to recognize and treat in order to optimize mood and functioning.",2003.0,0,0
764,14533126,"Cognitive, psychiatric and motor response to galantamine in Parkinson's disease with dementia.",D Aarsland; M Hutchinson; J P Larsen,"Cholinesterase inhibitors with additional nicotinic activity, such as galantamine, may be useful in PD patients with dementia (PDD) since stimulation of nicotinic receptors may prevent the down-regulation that is likely to accompany cholinesterase inhibition and facilitate dopamine release in the striatum. Sixteen PDD patients (six female) with onset of cognitive impairment after at least one year with parkinsonism participated in this open-label trial of galantamine. Cognitive, psychiatric, and motor symptoms were assessed before and after 8 weeks of treatment with galantamine using unstructured clinical assessment as well as rating scales including the Mini-Mental State Examination (MMSE), clock drawing test, verbal fluency and selected items from the Neuropsychiatric Inventory (NPI). Age (mean, SD) was 75.6 (5.2) years, duration of PD 13.4 (5.9), duration of dementia 2.1 (1.7) years, Hoehn and Yahr score was 3.8 (0.8) and baseline MMSE score was 17.7 (6.7). Side-effects caused discontinuation in three patients, but were rare and mild in the remaining 13. Improvement of global mental symptoms was noted in eight patients, whereas worsening was reported in four. Hallucinations improved in seven of the nine patients with hallucinations before treatment. Parkinsonism improved in six patients, but a mild worsening of tremor was noted in three. Clock-drawing improved (p=0.016), and trends towards improvement on MMSE (p=0.09) and verbal fluency (p=0.16) were found. Although controlled trials are needed, the findings suggest that galantamine is useful in patients with PDD.",2003.0,0,0
765,14562491,The effects of an educational intervention on antipsychotic-induced weight gain.,Kimberly H Littrell; Nicole M Hilligoss; Carol D Kirshner; Richard G Petty; Craig G Johnson,"To assess the effect of an educational intervention on antipsychotic-induced weight gain among patients with schizophrenia. Quasi-experimental. Seventy patients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder entered this 6-month study condicted in the United States. All participants began receiving olanzapine treatment when they entered the study. The patients were then randomly assigned to an intervention group or a standard care group. Over the next 4-months, the intervention group participated in weekly psychoeducation classes focused on nutrition, exercise, and living a healthy lifestyle. Patients were followed for an additional 2 months to assess weight change. A statistically significant difference in weight change between the two groups was observed post-treatment and at endpoint. At endpoint, the mean weight change of the intervention group was -.06 pounds, while the mean weight change in the standard care group was 9.57 pounds. In both groups, men gained significantly more weight than did women. The results indicate that a structured educational intervention might have a positive effect on antipsychotic-induced weight gain among patients with schizophrenia.",2003.0,0,0
766,14567163,[Clozapine and pregnancy].,H N Nguyen; P Lalonde,"This article reviews the relations between clozapine and pregnancy. Six case reports are identified in the literature of pregnant patients who received clozapine. Novartis at Basle, Switzerland, through its pharmacovigilance and epidemiology, service, has data on nearly 200 cases summarized in this article. We also describe the case of a patient with paranoid schizophrenia who was hospitalized 10 times between the age of 22 to 32. She received clozapine when she was 29 years old and, with a daily dosage of 350 mg, she became asymptomatic. At the age of 33 and 37, she became pregnant and continued clozapine during her 2 pregnancies. During her first pregnancy, she received insulin due to gestational diabetes associated with a body weight mass (BWM) of 30.4 (N = 20 to 25). During her second pregnancy, the BWM was 23.7 and she did not develop diabetes. She delivered at term 2 daughters who are at the time of this report 5 and 3 years old. The two girls are doing well and have no developmental delay. Psychotic symptoms exacerbation: the plasma concentration of clozapine diminishes during pregnancy due to a higher hepatic metabolism and distribution volume. Monitoring plasma concentration of clozapine can help to adjust its dosage. In case of psychotic symptoms exacerbation, the following can be recommended: 1) Increase the clozapine dosage; 2) Add a classic antipsychotic like perphenazine, trifluoperazine or haloperidol. Diabetes: obesity, glucose intolerance or a family history of diabetes are risk factors to develop gestational diabetes. The follow-up of patients, who take an atypical antipsychotic, should include constant monitoring of the blood glucose or Hb1A and lipid dosages. Complications at labor: Clozapine increases the secretion of oxytocine and the contraction of the uterine muscle. But, no studies can explain how clozapine affects the labor exactly. Some case studies report use of forceps, vacuum or cesarean. Stoner (1997) described neonatal convulsions 8 days after birth. The mother was receiving 350 mg of clozapine, but also lorazepam and haloperidol during her pregnancy. The newborn withdrawal of lorazepam can increase the risk of convulsions and also haloperidol can diminish the convulsion threshold. Floppy infant syndrome: in the case described by Dimichele (1996), the mother received a daily dosage of 300 mg of clozapine and 2.5 mg of lorazepam 3 to 5 times a day. This can explain hypotonia. Stoner (1997) reports a second case where a mother, who received 600 mg of clozapine during pregnancy, gave birth to a child who had no convulsions neither hypotonia. The cases described concerning studies of children until age 2 to 3 years by Stoner (1997) and Dickson (1998) and until 6 years old by Barnas (1994), do not mention any developmental problem, similar to the two daughters of our patient. The pharmacovigilance service of Novarits reports 6% of malformations. But these reports must be considered with caution since they represent only the pregnancies reported spontaneously to the pharmaceutical company. This is only a portion of all pregnancies associated with clozapine. No specific risks for the mother and children can be attributed to the use of clozapine during pregnancy. However, the plasma concentration of clozapine is higher in the fetus compared to the mother (Barnas, 1994); therefore, a minimal dosage should be used. Since clozapine is present in the maternal milk, breast feeding should be avoided. The advantages to use clozapine during pregnancy must exceed the risks. It is justified to continue the use of this medication even if data on classic antipsychotics (e.g.: haloperidol) are more extensive. Because the risk of psychotic exacerbation is higher, the substitution of clozapine is not recommended. The psychosocial support and the obstetrical follow-up must be intensive too. An institutional pharmacovigilance service should complement the one provided by the industry. Also, further case-control and cohort studies are essential to better estimate the long-term risks.",2003.0,0,0
767,14587227,[Methodological and regulatory features of clinical trials for behavioral and psychological symptoms in the course of dementia].,Giovanni Diana,"During the last few years there has been a growing awareness of behavioral and psychological symptoms of dementia (BPSD). These symptoms are usually classified in syndromes, which include psychosis, depression, agitation and sleep disturbances. BPSD have a major impact on the clinical course, prognosis and the quality of life of patients and caregivers. Moreover, BPSD considerably increase the social costs of dementia, since they often result in institutionalization. The therapy of BPSD was initially based on an empirical syndromic approach. However, in more recent years the efficacy and safety of treatments for these conditions have been tested in several controlled clinical trials. This paper addresses some of the methodological and regulatory issues that are relevant to the conducting of clinical trials for BPSD.",2003.0,0,0
768,14593007,The management of acute mania.,Paul E Keck,,2003.0,0,0
769,14645311,Effectiveness and cost of olanzapine and haloperidol in the treatment of schizophrenia: a randomized controlled trial.,Robert Rosenheck; Deborah Perlick; Stephen Bingham; Wen Liu-Mares; Joseph Collins; Stuart Warren; Douglas Leslie; Edward Allan; E Cabrina Campbell; Stanley Caroff; June Corwin; Lori Davis; Richard Douyon; Lawrence Dunn; Denise Evans; Ede Frecska; John Grabowski; David Graeber; Lawrence Herz; Kong Kwon; William Lawson; Felicitas Mena; Javaid Sheikh; David Smelson; Valerie Smith-Gamble; Department of Veterans Affairs Cooperative Study Group on the Cost-Effectiveness of Olanzapine,"Although olanzapine has been widely adopted as a treatment of choice for schizophrenia, its long-term effectiveness and costs have not been evaluated in a controlled trial in comparison with a standard antipsychotic drug. To evaluate the effectiveness and cost impact of olanzapine compared with haloperidol in the treatment of schizophrenia. Double-blind, randomized controlled trial with randomization conducted between June 1998 and June 2000 at 17 US Department of Veterans Affairs medical centers. Three hundred nine patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia or schizoaffective disorder, serious symptoms, and serious dysfunction for the previous 2 years. Fifty-nine percent fully completed and 36% partially completed follow-up assessments. Patients were randomly assigned to receive flexibly dosed olanzapine, 5 to 20 mg/d, with prophylactic benztropine, 1 to 4 mg/d (n = 159); or haloperidol, 5 to 20 mg/d (n = 150), for 12 months. Standardized measures of symptoms, quality of life, neurocognitive status, and adverse effects of medication. Veterans Affairs administrative data and interviews concerning non-VA service use were used to estimate costs from the perspective of the VA health care system and society as a whole (ie, consumption of all resources on behalf of these patients). There were no significant differences between groups in study retention; positive, negative, or total symptoms of schizophrenia; quality of life; or extrapyramidal symptoms. Olanzapine was associated with reduced akathisia in the intention-to-treat analysis (P<.001) and with lower symptoms of tardive dyskinesia in a secondary analysis including only observations during blinded treatment with study drug. Small but significant advantages were also observed on measures of memory and motor function. Olanzapine was also associated with more frequent reports of weight gain and significantly greater VA costs, ranging from 3000 dollars to 9000 dollars annually. Differences in societal costs were somewhat smaller and were not significant. Olanzapine does not demonstrate advantages compared with haloperidol (in combination with prophylactic benztropine) in compliance, symptoms, extrapyramidal symptoms, or overall quality of life, and its benefits in reducing akathisia and improving cognition must be balanced with the problems of weight gain and higher cost.",2003.0,1,1
770,7481376,[Clozapine in the treatment of mental manifestations of Parkinson disease].,N Diederich; M Keipes; M Graas; H Metz,"Medical treatment of Parkinsonian syndromes is often complicated by psychiatric side effects such as confusional states, hallucinations and psychosis. Recent pilot studies report good clinical results with the atypical neuroleptic clozapine. We report on 15 patients with Parkinsonian syndromes: 11 with idiopathic Parkinson's disease (IPD), 3 with multiple system atrophy (MSA) and 1 with postencephalitic Parkinsonism (SPP). The mean age was 68.8 +/- 10 years; the mean duration of Parkinsonian symptoms was 6.8 +/- 5.7 years. The Hoehn & Yahr grade was: 3.5 +/- 0.8. Eleven patients were suffering from psychotic episodes, 10 from hallucinations, 8 from confusional states. Clozpine was introduced at nighttime and dosage was modified until the appearance of clinical effect or intolerable side effects. We report on an observed cumulative duration of clozapine treatment of 13 patient-years. The average treatment duration was 10.5 +/- 10.4 months. The mean daily dose was 33.3 +/- 30 mg (range: 6.2-100). There was at least transitory improvement of psychiatric symptoms in all patients. There was constant and complete improvement in 7 patients (46%) and satisfactory improvement in 5 patients (33.3%). The levodopa dosage was unchanged (mean dosage 563 +/- 232 mg), and the dosage of dopamine agonists was significantly increased. None of our patients experienced motor deterioration. Side effects comprised sialorrhoea, sedation, orthostatic hypotension, and delirium tremens and an epileptic seizure in one patient each. Two patients died suddenly at the 63rd and at the 86th day of treatment respectively, outside the hospital. These deaths seemed to be unrelated to the treatment. There was no agranulocytosis. Clozapine is an efficient antipsychotic drug in Parkinsonian patients with no motor side effects in the dosages used. The effective dosage is very low in comparison to psychiatric patients. However various side effects may occur and close monitoring is required.",1995.0,0,0
771,7491385,A comparison of European and American dosing regimens of schizophrenic patients on clozapine: efficacy and side effects.,S Pollack; J A Lieberman; W W Fleischhacker; M Borenstein; A Z Safferman; M Hummer; M Kurz,"We present a comparison of the results from two studies of patients on clozapine. The American study (n = 84; Hillside Hospital, Glen Oaks, NY) and the European study (n = 63; Innsbruck University Clinics, Innsbruck, Austria) both examine efficacy and side effects in schizophrenic patients on this atypical neuroleptic. There is a very substantial difference in the dosing regimen used on both continents and this is reflected in the studies reported. A question with major clinical implications is whether the higher doses commonly used in the United States lead to a better outcome or a different profile of side effects. Outcome as a function of serum concentration will be examined. Results confirm a lower dose, lower clozapine blood level, and a lesser degree of side effects in the Austrian cohort when compared to the American sample. Surprisingly, the clinical efficacy of the lower dosing regimen was superior to the higher dose. Reasons for this anomaly are explored.",1995.0,0,0
772,7508541,Risperidone.,M G Livingston,,1994.0,0,0
773,7508675,Risperidone versus perphenazine in the treatment of chronic schizophrenic patients with acute exacerbations.,O J Høyberg; C Fensbo; J Remvig; O Lingjaerde; M Sloth-Nielsen; I Salvesen,"Risperidone (RIS), a new neuroleptic with 5-HT2- and dopamine D2 receptor-blocking properties, was compared with perphenazine (PER) in a double-blind, multicentre, parallel-group study in 107 chronic schizophrenics with acute exacerbation. RIS 5-15 mg or PER 16-48 mg daily was given for 8 weeks. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression. Seventy-eight patients completed the trial; there was an equal number of dropouts on both drugs. The mean daily dose at endpoint was 8.5 mg RIS and 28 mg PER. The reduction in total PANSS score to endpoint did not differ significantly, although there was a tendency in favour of RIS. The number of patients with predominantly negative symptoms who showed at least 20% reduction in total PANSS score was significantly larger in the RIS group. Furthermore, the number of patients showing at least 20% reduction in Brief Psychiatric Rating Scale (BPRS) score (BPRS being a subscale of PANSS) was significantly larger in the RIS group. The hostility cluster of BPRS improved more on RIS than on PER in the endpoint analysis. The overall prevalence of side effects was fairly similar in the two groups.",1993.0,1,1
774,7509495,"Risperidone versus clozapine in the treatment of schizophrenic patients with acute symptoms: a double blind, randomized trial.",K Heinrich; E Klieser; E Lehmann; E Kinzler; H Hruschka,"1. In order to verify the hypothesis that risperidone is a useful therapeutic alternative to clozapine the authors carried out a randomized double blind trial in 59 patients with paranoid hallucinatory psychoses. 2. In a treatment lasting 28 days three groups of patients received either 4 mg risperidone (N = 20), 8 mg risperidone (N = 19), or 400 mg clozapine (N = 20) daily. 3. The tolerance of 4 mg risperidone was globally assessed as being better than that of 400 mg clozapine. Drop-outs under clozapine were mostly caused by side effects, whereas under risperidone they tended to occur for therapeutic inefficacy. 4. The antipsychotic effect was highly significant and clinically relevant under both risperidone and clozapine.",1994.0,0,1
775,7514366,Risperidone in the treatment of schizophrenia.,S R Marder; R C Meibach,"The purpose of this study was to investigate the safety and efficacy of risperidone in the treatment of schizophrenic patients and determine its optimal dose. This double-blind study included 388 schizophrenic patients drawn from 20 sites in the United States. Patients were randomly assigned to 8 weeks' treatment with placebo, one of four doses of risperidone (2, 6, 10, or 16 mg), or 20 mg of haloperidol daily. Clinical improvement (20% reduction in total scores on the Positive and Negative Syndrome Scale for Schizophrenia) at the study end point was shown by 35% of the patients receiving 2 mg of risperidone, 57% receiving 6 mg, 40% receiving 10 mg, and 51% receiving 16 mg; and by 30% receiving haloperidol and 22% receiving placebo. Statistically significant differences in clinical improvement were found between 6 and 16 mg of risperidone versus placebo and versus haloperidol. Positive symptom scores were significantly lower after 6, 10, and 16 mg of risperidone and 20 mg of haloperidol than placebo; negative symptom scores, however, were reduced significantly, compared with placebo, only after 6 and 16 mg of risperidone. The incidence of extra-pyramidal side effects (measured by the Extrapyramidal Symptom Rating Scale) was significantly higher in patients treated with 16 mg of risperidone or 20 mg of haloperidol than placebo. The results indicate that the optimal daily dose of risperidone for most schizophrenic patients in this study was 6 mg; this dose was as effective as 16 mg, and the incidence of extrapyramidal symptoms in patients receiving 6 mg of risperidone was no higher than that in patients receiving placebo. Risperidone is a safe antipsychotic that is effective against both the positive and negative symptoms of schizophrenia.",1994.0,0,1
776,7514873,Is it possible to predict the clinical effects of neuroleptics from animal data? Part V: From haloperidol and pipamperone to risperidone.,P A Janssen; F H Awouters,"In 1965 the first study of this series reported different effects of neuroleptics in rats, supporting clinical differences. At the one end, haloperidol presented as a potent and specific antagonist of the psychostimulants amphetamine and apomorphine. Haloperidol-like neuroleptics have marked effects on psychomotor agitation, delusions and hallucinations and bind with high affinity to dopamine-D2 receptors. Pipamperone, at the other end, presented with weak ""dopamine"" antagonism and more striking tryptamine antagonism. Pipamperone is known to improve disturbed sleep, social withdrawal and other symptoms of chronic schizophrenia in the relative absence of extrapyramidal symptoms. These effects have been attributed to central serotonin-S2 antagonism, on the basis of the clinical effects of ritanserin. As shown by the present analysis of relative tryptamine versus apomorphine antagonism of 57 neuroleptics, in comparison to relative S2 vs. D2 binding, there is a continuity in the series. About 30% of the compounds can be considered to act primarily as serotonin antagonists, but few are markedly more potent than pipamperone. In amphetamine-challenged rats pipamperone-like activity is reflected in preferential inhibition of the excessive oxygen consumption rather than of agitation. Risperidone inhibits oxygen consumption (0.016 mg/kg) at the same dose as haloperidol inhibits agitation. Other low-dose effects of risperidone include reversal of amphetamine-induced withdrawal, antagonism of agitation induced by a sequential tryptamine and apomorphine challenge and LSD-antagonism. In dogs, the antiemetic activity of risperidone is characterized by high oral effectiveness which lasts one day and agrees with pharmacokinetic data when allowance is made for the active metabolite 9-hydroxyrisperidone.(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0
777,7520110,Antidepressant activity and mania associated with risperidone treatment of schizoaffective disorder.,M M Dwight; P E Keck; S P Stanton; S M Strakowski; S L McElroy,,2001.0,0,1
778,7521534,Changes in single symptoms and separate factors of the schizophrenic syndrome after treatment with risperidone or haloperidol.,E Lindström; L von Knorring,"Risperidone, a rather selective blocker of D-2 and 5-HT-2 receptors, was, in the doses 1 mg, 4 mg, 8 mg, 12 mg and 16 mg a day, compared to the rather selective D-2 blocker haloperidol in the dose of 10 mg a day, in 88 chronic schizophrenic patients. After one week placebo wash-out, the patients were randomly assigned to one of the six treatment groups and the study was performed as a double blind parallel-group study for 8 weeks. In the present analysis, a special emphasis has been laid on the effects on single symptoms and separate factors in the schizophrenic syndrome. Overall, risperidone in a dose of 4 mg a day was comparable to haloperidol in a dose of 10 mg a day. Risperidone was found to have a curvilinear dose-response curve with an optimum effect of 4 mg day on the negative, anxious/depressive and cognitive factors and with an optimum effect of 8 mg day on the positive and excited factors. While haloperidol had significant effects on the negative and anxious/depressive factors, risperidone had significant effects on all five factors - the positive, the negative, the excited, the anxious/depressive and the cognitive. The fact that the novel drug had significant effects on the cognitive factor might be of great importance as concerns the possibilities for rehabilitation of chronic schizophrenic patients.",1994.0,1,1
779,7525541,Predictors of clozapine response in schizophrenia.,D Pickar; R R Owen; R E Litman; J K Hsiao; T P Su,"The introduction of the atypical neuroleptic, clozapine, has had widespread influence not only on the treatment of the seriously mentally ill patient, but also on new drug development and on hypotheses of the pathophysiology of schizophrenia. While clozapine differs from traditional neuroleptics in its lack of extrapyramidal side effects (EPS), it also is distinct in its profile of neurotransmitter receptor affinities. In our work examining the clinical and biological effects of clozapine in patients with schizophrenia, we have identified the presence of EPS during typical neuroleptic treatment as a consistent predictor of subsequent good response to clozapine. Further, our data suggest that clozapine should not be reserved for the most chronically ill patients, but rather be utilized in patients with less chronic courses of schizophrenia. Biological predictors of clozapine response are consistent with dopaminergic, serotonergic, and noradrenergic facets to its mechanism of action.",2001.0,0,0
780,7525543,The effects of clozapine on neurocognition: an overview.,T E Goldberg; D R Weinberger,"Clozapine has proved effective in alleviating a wide range of psychiatric symptoms in schizophrenia. Its effects on cognitive function in schizophrenia are more variable. Clozapine appears to have a salutary effect on some aspects of attention, response speed, and fluency, whereas it appears to have a mild but adverse effect on visual memory and some executive functions. This profile may be related to the affinity of clozapine for dopaminergic type I and muscarinic receptors and relative lack of affinity for dopaminergic type II receptors.",1994.0,0,0
781,7527327,Risperidone. A review of its pharmacology and therapeutic potential in the treatment of schizophrenia.,S Grant; A Fitton,"Risperidone, a benzisoxazol derivative, is a novel antipsychotic agent which combines potent serotonin (5-hydroxytryptamine) 5-HT2 and dopamine D2 receptor antagonism. Development of the drug was stimulated by reports that the selective serotonin 5-HT2 antagonist ritanserin improved the negative symptoms of schizophrenia and decreased extrapyramidal symptoms when combined with haloperidol. The relatively low incidence of extrapyramidal symptoms with risperidone may reflect a preferential action on mesolimbic rather than nigrostriatal dopaminergic pathways. Recent clinical investigation suggests that risperidone is of at least comparable efficacy to haloperidol and perphenazine in improving the symptoms of acute and chronic schizophrenia on short term administration. Advantages offered by risperidone over haloperidol include a faster onset of antipsychotic action, a lower incidence of extrapyramidal effects and possibly greater efficacy against the negative symptoms of schizophrenia. If these benefits prove to be maintained during long term therapy, risperidone is likely to make a significant contribution to the treatment of schizophrenia.",1994.0,0,0
782,7528602,Desmopressin for risperidone-induced enuresis.,J A Bennett; P E Keck; L J Wallhausser,,2001.0,0,0
783,7530379,Pharmacokinetics of risperidone in chronic schizophrenic patients.,R L Borison; B Diamond; A Pathiraja; R C Meibach,"In a randomized, crossover study, 24 schizophrenic patients received a single 4-mg dose of risperidone in caplet or tablet form. Each of the two study periods lasted 5 days. Blood samples to determine (by radioimmunoassay) plasma levels of risperidone and its major metabolite, 9-hydroxy-risperidone (9-OH-risperidone), were obtained each day. The two formulations of risperidone were bioequivalent. Following are the mean pharmacokinetics of risperidone and risperidone + 9-OH-risperidone: area under the plasma concentration curve (AUC) from 0 to 96 hours; 278.0 and 716.9 ng.hr/mL; AUC from 0 to infinity, 291.9 and 762.4 ng.hr/mL; peak plasma concentration, 33.0 and 44.5 ng/mL; time to peak concentration, 1.39 and 1.78 hours; and elimination half-life, 14.93 and 23.04 hours. These results demonstrate that the active moiety (risperidone plus 9-OH-risperidone) has a half-life of 23 hours and reveal a pool of risperidone (terminal half-life, 14.9 hours) that may allow twice-daily or even once-daily dosing.",1994.0,0,0
784,7531355,Risperidone and clozapine in the treatment of drug-resistant schizophrenia and neuroleptic-induced supersensitivity psychosis.,G Chouinard; J L Vainer; M C Bélanger; L Turnier; P Beaudry; J Y Roy; R Miller,"1. Supersensitivity psychosis (SSP) has emerged as a potential side effect of long-term neuroleptic therapy similar to tardive dyskinesia (TD). 2. Six schizophrenic patients with SSP, considered to be drug-resistant, were treated with risperidone, while another 5 were treated with clozapine. 3. The 6 risperidone-treated patients (all women) were rated on the Clinical Global Impression Improvement Scale as at least very much improved. Among the 5 clozapine-treated patients, all 4 men were found to have a marked response to clozapine, while the female patient was judged to be minimally improved. 4. It is hypothesized that not only TD but also SSP arise from destruction of cholinergic interneurons in the striatum as a consequence of prolonged neuroleptic administration. Thus, the drug-induced parkinsonism, which was proposed as mediating the antipsychotic effect of dopamine D2 blocking drugs, depends on the integrity of these cholinergic neurons. If these neurons are destroyed, drugs such as haloperidol lose their therapeutic effect. 5. In contrast, atypical neuroleptics like clozapine and risperidone reduce dopamine release in the striatum independently of prior production of extrapyramidal symptoms and, in this way, may be effective in psychotic illnesses unresponsive to classical anti-D2 neuroleptics. 6. In the present sample of patients, it is worth noting that schizophrenic men were good responders to clozapine. In comparison, risperidone was found to be efficacious in schizophrenic women.",1994.0,0,0
785,7533585,Risperidone: review of its pharmacology and therapeutic use in schizophrenia.,S Gupta; D W Black; D A Smith,"The discovery of antipsychotic medications has revolutionized the treatment of schizophrenia and other psychotic disorders. However, side effects such as extrapyramidal symptoms (EPS) and tardive dyskinesia have been limiting factors in treatment. The introduction of atypical drugs such as clozapine and risperidone has ushered in a new era. This article provides an overview of the pharmacology, efficacy, and techniques for the clinical use of risperidone, which has recently become available.",1994.0,0,0
786,7536945,,,,,0,0
787,7539272,A risk-benefit assessment of risperidone in schizophrenia.,V A Curtis; R W Kerwin,"The atypical antipsychotic risperidone combines dopaminergic and serotonergic antagonism. This results in a drug that is both clinically effective, reducing positive and negative symptoms of schizophrenia, and has a low incidence of adverse effects. At a dosage of 4 to 8 mg/day, risperidone is comparable to 10 mg/day of haloperidol. This dosage has a low incidence of extrapyramidal adverse effects and is nonsedative, although it may cause orthostatic hypotension. There is no current evidence for specific biochemical and haematological abnormalities associated with risperidone. Although the clinical benefits appear to outweigh the risks, this drug continues to be a relatively expensive treatment option in the UK. There is therefore a need for a formal cost-utility assessment of risperidone and for comparisons between this drug and other atypical neuroleptics.",1995.0,0,0
788,7542829,Risperidone versus zuclopenthixol in the treatment of acute schizophrenic episodes: a double-blind parallel-group trial.,M O Huttunen; T Piepponen; H Rantanen; I Larmo; R Nyholm; V Raitasuo,"A double-blind, randomized, multi-center, parallel-group study was conducted in Finland to compare the efficacy and safety of risperidone with zuclopenthixol in patients with acute exacerbations of schizophrenia or schizophreniform disorder. Ninety-eight patients were randomly assigned to treatment with risperidone (n = 48) or zuclopenthixol (n = 50), in variable doses, for 6 weeks. The mean daily doses of risperidone and zuclopenthixol at the end of the trial were 8 mg and 38 mg respectively. Efficacy was assessed throughout by the Positive and Negative Syndrome Scale for schizophrenia and Clinical Global Impression. Safety assessments included the Extrapyramidal Symptom Rating Scale, UKU Side-Effect Rating Scale, vital signs, body weight and laboratory screening. The results indicate that risperidone is at least as effective as zuclopenthixol for the treatment of acute schizophrenic episodes, with a trend towards greater improvement in the overall severity of symptoms. The onset of action was significantly shorter with risperidone than with zuclopenthixol. Although the general tolerability of the two drugs was comparable, fewer patients experienced extrapyramidal symptoms with risperidone, so that significantly fewer risperidone-treated patients required antiparkinsonian medication.",1995.0,1,1
789,7543500,Critique of the Canadian Multicenter Placebo-Controlled Study of Risperidone and Haloperidol.,W S Musser; L Kirisci,,1995.0,0,0
790,7545060,"Risperidone in the treatment of patients with chronic schizophrenia: a multi-national, multi-centre, double-blind, parallel-group study versus haloperidol. Risperidone Study Group.",J Peuskens,"This study was performed in order to evaluate the short-term efficacy and safety of fixed risperidone doses compared to haloperidol. In a multi-national, parallel-group, double-blind study, patients with chronic schizophrenia (DSM-III-R) were randomly assigned to risperidone 1, 4, 8, 12 or 16 mg or haloperidol 10 mg daily for 8 weeks. Efficacy was assessed by the Positive and Negative Syndrome Scale for schizophrenia (PANSS) and clinical global impression (CGI), and safety primarily by the Extrapyramidal Symptom Rating Scale (ESRS). One thousand three hundred and sixty-two patients were evaluated. The optimum risperidone doses were 4 mg and 8 mg, with response rates of 63.4% (56.8%; 69.7%) and 65.8% (59.2%; 71.9%) respectively. Response rate in haloperidol-treated patients was 58.7% (52.0%; 65.3%); the 95% confidence intervals (CI) of the differences between risperidone 4 mg or 8 mg and haloperidol were (- 4.3%; 13.7%) and (- 1.9%; 16.0%) respectively. There were no significant differences in CGI scores at endpoint between risperidone 4 mg, 8 mg, 12 mg and 16 mg and haloperidol (3.0, 3.0, 3.2, 3.1 and 3.1 respectively); the 95% CI of the differences between risperidone 4 mg or 8 mg and haloperidol were ( - 0.4; 0.1) and ( - 0.3; 0.2) respectively. Mean shifts to the maximum total ESRS scores versus baseline (mean (confidence interval)) were significantly greater in haloperidol-treated patients (5.1 (4.0; 6.2)) than in the risperidone 1, 4, 8 and 12 mg groups (1.1 (0.3; 1.9); 1.8 (0.9; 2.7); 2.7 (1.8; 3.6) and 3.2 (2.3; 4.1) respectively (P < 0.05)). Risperidone is an effective antipsychotic for the treatment of chronic schizophrenia; doses of 4 and 8 mg seem to be optimal and have a lower incidence of side-effects than haloperidol.",1995.0,1,1
791,7559380,Highlight of the 1995 Psychiatry Global Medical Conference.,,,1995.0,0,0
792,7560252,"Safety, tolerability, and effect of food on the pharmacokinetics of iloperidone (HP 873), a potential atypical antipsychotic.",S M Sainati; J W Hubbard; E Chi; K Grasing; M B Brecher,"Iloperidone (HP 873) is a D2 and 5-HT2 receptor-antagonist that is under development as a potential atypical antipsychotic agent. Two studies on iloperidone evaluated its safety and tolerability, made a preliminary pharmacokinetic assessment of single 3- and 5-mg doses, and determined the effect of food on its tolerability and pharmacokinetics in healthy volunteers after single 3-mg doses. Iloperidone was well absorbed orally in fasted subjects. The Cmax occurred approximately 2 to 3 hours after administration of a single 3- or 5-mg dose. The pharmacokinetic parameters increased with the dose between 3 and 5 mg (from 2.2 to 5.2 ng/mL for Cmax, and 16 to 50 ng/mL.h for AUC). Iloperidone was eliminated slowly, with a mean t1/2 of 13.5 to 14.0 hours. Coadministration with food did not significantly affect AUC, tmax, or Cmax. These results indicate that the rate of iloperidone's absorption is decreased, but the overall bioavailability is unchanged, when the drug is taken with food. Orthostatic hypotension, dizziness, and somnolence were the most commonly reported adverse events. Coadministration of food reduced the incidence and severity of these events.",1995.0,0,0
793,7575109,Clozapine-induced increase in plasma levels of soluble interleukin-2 receptors.,T Pollmächer; D Hinze-Selch; J Mullington; F Holsboer,,1995.0,0,0
794,7585841,"ICI 204,636, a novel, atypical antipsychotic: early indication of safety and efficacy in patients with chronic and subchronic schizophrenia.",L F Fabre; L Arvanitis; J Pultz; V M Jones; J B Malick; V B Slotnick,"We evaluated the effects of ICI 204,636 in 12 hospitalized patients with schizophrenia in a double-blind, placebo-controlled, parallel-group, rising-dose study. Patients met the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria for chronic or subchronic schizophrenia and had a total score > or = 30 on the 18-item Brief Psychiatric Rating Scale (BPRS) and a score > or = 3 on the Clinical Global Impression (CGI) Severity of Illness item. Patients received 21 days of double-blind treatment with increasing doses of ICI 204,636 (25 to 250 mg/d) or placebo. Efficacy was assessed using the BPRS and CGI. Response to treatment was defined as a > or = 30% decrease in the BPRS total score from baseline. Extrapyramidal symptoms and abnormal involuntary movements were assessed using the Simpson Scale and Abnormal Involuntary Movement Scale. Changes from baseline in the BPRS and CGI were significantly greater at end point for patients who received ICI 204,636 versus placebo (BPRS, -20.9 vs -4.8; CGI, -2.9 vs -1.0; P < 0.05, analysis of covariance; P < or = 0.06, Wilcoxon rank sum test). All patients in the ICI 204,636 group responded to treatment (P < 0.10) versus only two patients in the placebo group. Mild somnolence occurred in 50% of ICI 204,636-treated patients. No treatment-emergent extrapyramidal symptoms or dystonic reactions were observed. ICI 204,636 showed efficacy in the positive and negative symptoms of schizophrenia and was well tolerated.",2001.0,0,1
795,7585844,Efficacy and safety of risperidone in the long-term treatment of patients with schizophrenia.,E Lindström; B Eriksson; A Hellgren; L von Knorring; G Eberhard,"The long-term efficacy and safety of risperidone were evaluated in patients with chronic schizophrenia in an open-label study. Thirty-two patients received risperidone for 1 year and 19 of the 32 received risperidone for 2 years. The mean dose of risperidone was 9.4 mg/d in the 1-year follow-up. At the end of 1 and 2 years, improvements were found in total scores on the Positive and Negative Syndrome Scale (PANSS), on four PANSS factors (positive, negative, excited, and cognitive), and the Clinical Global Impression scale. Severity of extrapyramidal symptoms (based on scores on the Extrapyramidal Symptom Rating Scale) was also reduced. Clinical improvement (defined as a 20% or more reduction in total PANSS scores) was shown by 54% of the patients at end point. Social functioning (as assessed by using the modified Strauss/Carpenter scale) was significantly improved after 2 years. Number of days spent in hospitals was significantly reduced during the 2 years of treatment, and the number of days in treatment (group) homes significantly increased. It is concluded that treatment with risperidone for 1 and 2 years is associated with significant reductions in symptoms of schizophrenia, improved social functioning, and reduction in days spent in the hospital.",1995.0,0,1
796,7592504,"Efficacy of risperidone treatment for psychoses associated with schizophrenia, schizoaffective disorder, bipolar disorder, or senile dementia in 11 geriatric patients: a case series.",S Madhusoodanan; R Brenner; L Araujo; A Abaza,"Clinical trials of risperidone, a recently approved novel antipsychotic, included elderly healthy patients, but more data are needed on the effects of risperidone in this population, especially those with comorbid medical illnesses. Risperidone was used to treat 11 elderly hospitalized patients between 61 and 79 years of age who manifested signs of psychoses related to schizophrenia, schizoaffective disorder, bipolar disorder, or senile dementia. All patients had been treated previously with classic antipsychotics. Response was assessed by clinical observation of the patients' behavior. Eight patients responded to treatment, 1 did not respond, and 2 had treatment discontinued because of hypotension or dizziness. Positive and negative symptoms decreased markedly in 7 of the responding patients. Four patients had preexisting extrapyramidal symptoms (EPS) and symptoms of tardive dyskinesia that also decreased in response to risperidone treatment. In addition, 4 patients were able to discontinue anti-parkinsonian medications, and 2 were able to discontinue antihypertensive medications. Side effects related to blockade of dopamine, histamine, and serotonin were negligible. No adverse consequences occurred when electroconvulsive therapy, carbamazepine, or lithium was given concurrently. The reduction of both positive and negative symptoms of schizophrenia and the lack of significant EPS, tardive dyskinesia, sedation, and anticholinergic side effects indicate that risperidone is a safe and effective medication for the elderly.",1995.0,0,0
797,7592511,Plasma clozapine levels and clinical benefit.,W M Greenberg,,1995.0,0,0
798,7593706,Effect of risperidone on hostility in schizophrenia.,P Czobor; J Volavka; R C Meibach,"The objective was to examine effects of risperidone on hostility and compare these effects with those of haloperidol. On the basis of risperidone's pharmacologic profile, we hypothesized that risperidone has a selective effect on hostility and that this effect is greater than that of haloperidol. The data were obtained in a multicenter clinical trial of risperidone under placebo-controlled, double-blind conditions (duration, 9 weeks). The patients were 139 patients with the diagnosis of DSM-III-R schizophrenia. Hostility was measured by the ""hostility"" item of the Positive and Negative Syndrome Scale. Change in hostility served as a dependent variable in the analyses. Change in ""psychosis"" was applied as a covariate; it helped us examine changes in hostility that were unrelated to change in psychosis (selective effect). Risperidone had a greater selective effect on hostility than did haloperidol or placebo. This finding should encourage tests of risperidone as a treatment for patients who show frequent overt physical aggression.",1995.0,0,1
799,7597122,Extrapyramidal side effects of clozapine and haloperidol.,M Kurz; M Hummer; H Oberbauer; W W Fleischhacker,"Neuroleptic-induced extrapyramidal side effects (EPS) were evaluated in 92 patients treated with clozapine for the first time and 59 patients treated with haloperidol followed in a drug monitoring program. Side effects were measured by the Columbia University Rating Scale, the Simpson Dyskinesia Scale and the Hillside Akathisia Scale. The cumulative incidence rate for tremor was found to be 24.4% in the clozapine group and 39.3% in the haloperidol group. This did not amount to a statistically significant group difference. Bradykinesia was observed in 21.8% of the patients treated with clozapine and in 47.7% of the patients of haloperidol (P = 0.011). In the clozapine group the akathisia incidence rate was 5.6%, whereas haloperidol patients showed a higher rate of 31.7% (P = 0.005). Our results show higher incidence rates of tremor and bradykinesia during clozapine treatment than previous studies. We conclude that clozapine is not entirely free of EPS, but they are usually less severe and of a different quality than side effects induced by typical antipsychotics.",1995.0,1,1
800,7619979,Clozapine decreases smoking in patients with chronic schizophrenia.,J McEvoy; O Freudenreich; M McGee; C VanderZwaag; E Levin; J Rose,,1995.0,0,0
801,7621385,,,,,0,0
802,7621391,A clinical study of clozapine treatment and predictors of response in a Canadian sample.,W G Honer; G W MacEwan; L Kopala; S Altman; S Chisholm-Hay; K Singh; G N Smith; T Ehmann; S Ganesan; M Lang,"To study the clinical response to clozapine in patients with refractory schizophrenia. Open trial of clozapine in 61 consecutively-treated patients. Following clozapine, the level of function of patients was improved relative to admission (p = 0.0001) and to the highest level in the previous year (p = 0.0001). Severity of illness was decreased (p = 0.0001). Overall, 31% of the patients were classified as responders to clozapine and the responders were all identified by 32 weeks of treatment. Poor functioning in the previous year was associated with less favourable response. At a mean interval of 26 months following discharge, 72% of the patients were continuing clozapine treatment. This open trial of patients who were treated consecutively indicates a comparable degree of response to clozapine as observed in controlled clinical trials, and that level of functioning in the previous year was the best predictor of response.",1995.0,0,1
803,7624901,Can low-dose clozapine pharmacokinetics predict steady-state plasma concentration?,L K Oyewumi; D J Freeman; D Vollick,"Plasma concentrations of clozapine at a given dose vary considerably between patients, but drug levels are not routinely monitored during the normal 4- to 8-week dose escalation period at the beginning of therapy. We hypothesized that the dose required to give a putative threshold therapeutic concentration of 350 micrograms/L could be individualized using pharmacokinetic predictions made at the beginning of normal dose escalation. Low-dose clozapine (25-75 mg every 12 h) was administered to 21 treatment-resistant patients with schizophrenia who had been split into three groups. In group A (six patients), individual target doses were predicted from area under the concentration-time curve data after a single 50-mg dose. In group B (five patients), predictions were made as in group A but at steady state. In group C (10 patients), predictions were based on trough clozapine levels obtained at steady state immediately before dose increase. Dosage was increased, if tolerated, by 25 mg twice daily three times a week for 4-8 weeks according to established clinical practice. Clozapine concentrations were measured weekly, and actual target doses were determined for each patient from dose-concentration plots. In groups A and B, the correlation between actual and predicted target dose was not significant (r = 0.18, p = 0.59). In group C, however, it was significant (r = 0.86, p = 0.0016). These results suggest that individualized doses of clozapine for treatment-resistant patients with schizophrenia can be conveniently predicted from trough drug levels at the start of therapy. Such information would facilitate a more rapid, individualized, and consistent attainment of therapeutic doses than is now the case in clinical practice.",1995.0,0,0
804,7659771,"Seroquel (ICI 204 636), a putative ""atypical"" antipsychotic, in schizophrenia with positive symptomatology: results of an open clinical trial and changes of neuroendocrinological and EEG parameters.",H Wetzel; A Szegedi; C Hain; J Wiesner; S Schlegel; O Benkert,"Preclinical data indicated that seroquel (ICI 204 636), a dibenzothiazepine with 5-HT2 and D2-like receptor antagonistic properties, might be an effective antipsychotic agent, causing fewer extrapyramidal side effects than typical neuroleptics. In the present study, 12 patients suffering from schizophrenia or schizophreniform disorder with predominantly positive symptomatology were treated in an open clinical trial for 4 weeks with seroquel at a maximum dosage of 750 mg/day. The drug was generally well tolerated, and virtually no adverse extrapyramidal side effects such as acute dystonia, parkinsonism or akathisia were observed. Total scores for BPRS (item score 0-6; baseline: 42.0 +/- 2.3; mean +/- SEM), SAPS (64.5 +/- 4.8) and SANS (55.0 +/- 4.3) showed a moderate decrease at the end of treatment (BPRS: 30.0 +/- 3.5; SAPS: 36.1 +/- 6.7; SANS: 42.5 +/- 5.9), when intention-to-treat analysis was applied. There were considerable interindividual differences in treatment response, with some subjects showing almost full remission of positive symptoms, in contrast to about half of the patients who showed no satisfactory clinical improvement. Interestingly, patients showing good antipsychotic response reported slight initial side effects like mild sedation. Prolactin and TSH levels were not altered during seroquel administration. As to pharmaco-EEG investigations, seroquel caused a moderate increase of the absolute power in the alpha, theta, and beta frequency bands, paralleled by a decrease of delta activity. There were no signs of paroxysmal EEG activity under seroquel.(ABSTRACT TRUNCATED AT 250 WORDS)",1995.0,0,0
805,7665540,Clozapine in severe mood disorders.,C A Zarate; M Tohen; R J Baldessarini,"A growing literature suggests that the atypical antipsychotic agent clozapine may be effective in schizoaffective and psychotic mood disorders. To evaluate the efficacy and tolerability of clozapine in severe mood disorders, we reviewed published studies on clozapine in schizophrenia, bipolar disorder, schizoaffective disorder, major depression, and organic disorders with psychotic or major affective syndromes, identified through the MEDLINE data base. Patients in manic or psychotic phases of schizoaffective or bipolar disorder were significantly more likely to respond to clozapine than patients with schizophrenia (p = .006) or severe depressive syndromes (unipolar, bipolar, and schizoaffective depression combined; p = .001). There was no significant difference in the side effect profile secondary to clozapine in patients with severe mood disorders compared to patients with schizophrenia. Clozapine appears to be effective and well-tolerated in the short-term and maintenance treatment of severe or psychotic mood disorders, particularly in the manic-excited phases of schizoaffective and bipolar disorders, even in patients who have not responded well to conventional pharmacotherapies.",2001.0,0,1
806,7665549,Seroquel: a putative atypical antipsychotic drug with serotonin- and dopamine-receptor antagonist properties. Preclinical and early clinical trials in schizophrenia.,,,1995.0,0,0
807,7694912,Relation of leukocyte counts during clozapine treatment to serum concentrations of clozapine and metabolites.,F Centorrino; R J Baldessarini; J G Flood; J C Kando; F R Frankenburg,"This study was done to test the hypothesis that serum concentration of norclozapine is a risk factor for leukopenia during treatment with clozapine. Maximum decreases in leukocyte counts in 44 unselected patients treated with clozapine were determined and then correlated with drug doses and serum concentrations of clozapine, norclozapine, and clozapine-N-oxide. White cell and granulocyte counts decreased by up to 60%-73%, but there were no positive correlations between these decrements and drug dose, drug level, ratio of drug level to drug dose, or ratio of norclozapine level to clozapine level, nor were the decreases related to age or gender. While these results do not suggest in vivo hemotoxicity of norclozapine, further study of patients with clinically significant leukopenia is required.",1995.0,0,0
808,7696728,Selective serotonin reuptake inhibitors: pharmacologic profiles and potential therapeutic distinctions.,P R Finley,"To review the respective pharmacologic profiles of the selective serotonin reuptake inhibitors (SSRIs), with particular emphasis placed on clinically relevant distinctions. A MEDLINE search was conducted to identify English language literature published within the last five years on the four SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine). Previous review articles were scrutinized for additional citations, and manufacturers provided a contemporary bibliography of more recent material. Studies were selected for specific citation on the basis of comparative research merit and the contribution of this original literature to the pharmacologic profile(s) described. All SSRIs appear to be more efficacious than placebo for the acute treatment of major depressive disorder (MDD). Short-term (six-week) efficacy was comparable with that of tricyclic antidepressants for the amelioration of MDD regarded as moderate in severity. Further comparative trials are clearly indicated to demonstrate the therapeutic benefits of SSRIs in specific populations (e.g., geriatric, severely ill) and to demonstrate sustained benefit with long-term prophylaxis. Other potential indications for SSRIs include obsessive-compulsive disorder, panic disorder, bulimia, and chronic pain syndromes. Pharmacokinetic profiles of the four SSRIs reveal similar parametric values, and most quantitative differences are of limited clinical significance. Adverse effects are common but ordinarily mild and transient, primarily restricted to the gastrointestinal tract and central nervous system. Important differences in the prevalence or severity of these adverse effects await the accumulation of further clinical experience and the completion of additional comparative trials. Similarly, the relative propensity of SSRIs to inhibit the metabolism of other medications is currently under investigation. The four SSRIs studied appear to be more similar than they are different. Slowly, important distinctions are beginning to emerge with regard to adverse effect profiles and potential drug interactions. Given that the costs of these respective medications are comparable, such differences may ultimately serve to establish the preferential selection of individual agents in specific clinical situations.",1994.0,0,0
809,7701277,Childhood-onset schizophrenia: an NIMH study in progress.,C T Gordon; J A Frazier; K McKenna; J Giedd; A Zametkin; T Zahn; D Hommer; W Hong; D Kaysen; K E Albus,"An ongoing study of the phenomenology, genetics, neuropsychology, physiology (eye tracking, autonomic responsivity), neuroimaging, biochemistry, and pharmacology of childhood-onset schizophrenia is described, and pilot data are presented for the first 22 subjects. Differentiation from autism ""spectrum"" disorders and other poorly defined, severe neurodevelopmental disorders is needed. Eye tracking and autonomic results are similar to patterns seen in later-onset schizophrenia and possibly more striking. Magnetic resonance imaging showed larger left frontal ventricular horn area for the schizophrenia subjects, larger left caudate, and lack of normal caudate asymmetry. Fluorodeoxyglucose positron emission tomography during an auditory continuous performance task revealed decreased right parietal/occipital glucose metabolic rate in the schizophrenia subjects, which may be secondary to poor attentional performance, and increased glucose metabolic rate in three left frontal regions, a left parietal region, and the right putamen. Clozapine has been effective and well tolerated in an open trial with 12 adolescents who responded poorly to typical neuroleptics; 16 subjects have been enrolled in a double-blind comparison of haloperidol and clozapine. Longitudinal study of this narrowly defined and possibly more homogeneous group of very early-onset schizophrenia subjects will be relevant to current neurodevelopmental theories addressing the role of puberty, progression of pathology, and continuity or discontinuity with later-onset schizophrenia.",1994.0,0,0
810,7746841,Determination of clozapine and its major metabolites in serum samples of adolescent schizophrenic patients by high-performance liquid chromatography. Data from a prospective clinical trial.,E Schulz; C Fleischhaker; H Remschmidt,"This report describes a method for determination of clozapine and its major metabolites N-desmethylclozapine and clozapine N-oxide in serum samples of adolescent schizophrenic patients during maintenance therapy. The method includes deproteinization and subsequent high-performance liquid chromatography with electrochemical detection. The method shows sufficient sensitivity to quantitate clozapine, clozapine N-oxide and N-desmethylclozapine accurately at 0.5, 5, and 0.5 ng/ml, respectively. We were able to demonstrate for 16 patients receiving fixed doses of clozapine that the individual mean values calculated from six consecutive measurements revealed a strong linear dosage and serum level relationship (Pearson's coefficient of correlation): clozapine (r = 0.82, p = 0.0001); N-desmethylclozapine (r = 0.81, p = 0.0001); clozapine N-oxide (r = 0.91; p = 0.0001). Preliminary pharmacokinetic data are presented and dose-response relationship are discussed.",1995.0,0,0
811,7751421,Intra- and interethnic variability in reduced haloperidol to haloperidol ratios.,Y W Lam; M W Jann; W H Chang; H S Yu; S K Lin; H Chen; C M Davis,"Steady-state haloperidol and reduced haloperidol concentrations were measured in 250 schizophrenic patients from 4 ethnic groups: 39 Blacks, 66 Caucasians, 82 Chinese, and 63 Mexican Americans. The distribution of the reduced haloperidol to haloperidol concentration (RH/HL) ratios was bimodal in all ethnic groups, with the antimode determined by probit plot as 0.46, 0.51, 0.36, and 0.76, respectively. With these antimodes, the proportion of patients with low RH/HL ratios were 41%, 42%, 73%, and 57% in the four ethnic groups, respectively. Compared with the other three ethnic groups, in the Chinese patients the ratio was lower. The mean RH/HL ratio in the Chinese was 0.34 compared with 0.81 to 0.87 in the non-Chinese groups. In 53 patients who were treated with two or more haloperidol dosage regimens, steady-state haloperidol and reduced haloperidol drug concentrations obtained from the different regimens were positively correlated with the haloperidol dose (R = .79 and R = .62, respectively). Our data suggest not only the existence of a bimodal distribution in the RH/HL ratio, but also that the antimode separating the low and high ratio subgroups is different among the various ethnic groups.",1995.0,0,0
812,7766534,Five factor model of schizophrenia: replication across samples.,J P Lindenmayer; S Grochowski; R B Hyman,"In order to examine the effect of neuroleptic medication on the factor structure of schizophrenic symptomatology, 517 DSM-III-R schizophrenic in-patients enrolled in a multicenter phase II drug study were evaluated on their pre-existing neuroleptic at screening on the Positive and Negative Syndrome Scale (PANSS) and after a one-week drug-free period. Separate principal components analyses of the PANSS were done at each time point. PANSS total and component scores were assessed for differences utilizing paired t-tests. Both factor analyses confirmed the five factor model (negative, positive, cognitive, excitement and depression components) explaining 51.7 and 56.2% of the variances at each time point. After medication wash-out psychopathology significantly worsened as measured by total PANSS score and by each of the components. The overall worsening of component scores appeared global and uniform, as evidenced by the fact that at washout, the proportion of individual component scores to total psychopathology remained constant for most components. The lack of change of most components in proportion to the psychopathology total is evidence for the stability of these individual psychopathological dimensions of patients while on and off neuroleptics. The results further support the validity of the five-factor model of schizophrenic psychopathology as measured by the PANSS.",1995.0,0,0
813,7770613,Clozapine serum levels and side effects during steady state treatment of schizophrenic patients: a cross-sectional study.,O V Olesen; K Thomsen; P N Jensen; C H Wulff; N A Rasmussen; C Refshammer; J Sørensen; M Bysted; J Christensen; R Rosenberg,"Serum clozapine (S-Cloza) and serum desmethyl-clozapine concentrations (S-Descloza) were measured in 30 chronic schizophrenic in- and out-patients on a variable dose regimen. All patients were in steady state with respect to clozapine therapy and in a stable condition with respect to psychotic illness. The 24-h clozapine dose (median with interquartile range in parenthesis) was 350 (228-425) mg/24 h (range 100-700). There was a weak positive correlation between doses and the BPRS total score (r = 0.44, P < 0.05). The median S-Cloza was 1076 (706-1882) nmol/l (range 196-5581 corresponding to 64-1824 ng/ml). The S-Cloza was linearly correlated to dose but with a high interindividual variation at equal doses, e.g. a factor of 8 at 400 mg/24 h, but a low intraindividual variability of 20%. The S-Descloza averaged 77% of the S-Cloza and was highly correlated to S-Cloza (r = 0.90; P < 0.001). The S-Descloza/dose ratio increased with age and duration of treatment. The side effects registered were EEG abnormalities (83%), tachycardia (23%), increased liver enzyme activity (60%), orthostatic hypotension (17%), and moderate leucocytosis (17%). Only EEG changes were correlated to S-Cloza (r = 0.43; P < 0.05). The score values of the UKU Side Effect Scale were weakly (r = 0.36) correlated to S-Cloza. No side effects were correlated to S-Descloza, doses, or treatment duration. The frequency of side effects was higher than in studies using lower mean doses indicating a correlation between doses or S-Cloza and the frequency of side effects. It is concluded that clozapine fulfils the criteria for therapeutic drug monitoring. TDM may contribute to finding the lowest effective dose with the fewest possible side effects.",1995.0,0,0
814,7775371,Current concepts in schizophrenia: international symposia report new standards for assessment and treatment. Part II: Treatment issues and broadening options.,,,1995.0,0,0
815,7779241,Treatment of polydipsia and hyponatremia in psychiatric patients. Can clozapine be a new option?,J de Leon; C Verghese; J K Stanilla; T Lawrence; G M Simpson,"Polydipsia occurs frequently in chronic schizophrenic patients, some of whom develop intermittent hyponatremia. Most therapeutic efforts have tried to control the hyponatremia. Four schizophrenic patients, followed for more than one year, showed improvement on clozapine. Case 1 was an outpatient without history of hyponatremia who improved from polydipsia and psychosis. The last three were inpatients with polydipsia, intermittent hyponatremia, and psychosis who showed minimal improvement of psychosis but significant decrease in polydipsia and water intoxication. Case 2 relapsed to polydipsia when clozapine was discontinued on two occasions. Case 3 demonstrated polyuria during 39% of days before clozapine and in 0% of days after two weeks of clozapine. In case 4, most baseline sodium levels were abnormal, but all became normal after clozapine. A time-series analysis for intervention effects showed a significant effect of clozapine (p = .017). The limited information provided by these case reports suggest the need for controlled studies of the clozapine effect on polydipsic patients.",1995.0,0,0
816,7831416,A new five factor model of schizophrenia.,J P Lindenmayer; R Bernstein-Hyman; S Grochowski,"Schizophrenic psychopathology is heterogeneous and multidimensional. Various strategies have been developed over the past several years to assess and measure more accurately discrete domains of psychopathology. One of the more fruitful strategies to investigate more homogenous domains of psychopathology has been the positive-negative syndrome approach. However, this approach is unable to address a number of important issues. Most schizophrenics present a mixed syndrome; the criteria for what constitutes a positive and negative syndrome are variable; distinguishing primary from secondary negative symptoms can be difficult. In order to address some of these problems, we propose the introduction of a five syndrome model based on a reanalysis of factor analytic procedures used on 240 schizophrenics assessed with the Positive and Negative Syndrome Scale (PANSS). We present data on a 5-factor solution which appears to best fit the psychopathological data and which is supported by three independent and comparable factor analyses; negative, positive, excitement, cognitive and depression/anxiety domains of psychopathology give patients their individual mark. Data on internal consistency of the five factors and on initial validation using demographic and clinical variables are presented.",1994.0,0,0
817,7840350,Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment.,H Y Meltzer; G Okayli,"Suicide has been reported to occur in 9%-13% of schizophrenic patients. It has been suggested that neuroleptic-resistant or neuroleptic-intolerant schizophrenic patients are at higher risk for suicide than neuroleptic-responsive patients. Clozapine is the treatment of choice for neuroleptic-resistant patients, but its use has been greatly limited because of its ability to cause potentially fatal agranulocytosis. The purpose of this study was to compare the suicidality of neuroleptic-resistant and neuroleptic-responsive patients and to determine if clozapine treatment decreased suicidality in the former group. Prior episodes of suicidality were assessed in a total of 237 neuroleptic-responsive and 184 neuroleptic-resistant patients with schizophrenia or schizoaffective disorder. Eighty-eight of the neuroleptic-resistant patients were treated with clozapine and prospectively evaluated for suicidality for periods of 6 months to 7 years. There was no significant difference in prior suicidal episodes between neuroleptic-responsive and neuroleptic-resistant patients. Clozapine treatment of the neuroleptic-resistant patients during the follow-up period resulted in markedly less suicidality. The number of suicide attempts with a high-probability of success decreased from five to zero. This decrease in suicidality was associated with improvement in depression and hopelessness. These results suggest a basis for reevaluation of the risk-benefit assessment of clozapine, i.e., that the overall morbidity and mortality of patients with neuroleptic-resistant schizophrenia are less with clozapine treatment than with typical neuroleptic drugs because of less suicidality. This conclusion also has implications for increasing the use of clozapine with neuroleptic-responsive patients.",1995.0,1,1
818,7846212,EEG alterations in patients treated with clozapine in relation to plasma levels.,C Haring; C Neudorfer; J Schwitzer; M Hummer; A Saria; H Hinterhuber; W W Fleischhacker,"It is well known that psychotropic drugs can induce EEG alterations. Dose dependence seems established; however, there are no data concerning the impact of plasma levels. The authors investigated the influence of clozapine plasma levels on the frequency of EEG alterations. Data from 29 inpatients (18 male, 11 female, 31.7 +/- 10.2 years) receiving clozapine in a dose range between 25 and 600 mg were collected prospectively. There was no psychotropic or anticholinergic comedication. All patients had normal EEGs before taking clozapine. Fifteen patients showed pathological changes (group 2) and 14 no changes (group 1). Discriminant analysis showed that EEG changes are dependent on plasma levels (P = 0.0009, plasma levels in group 1 mean 81.6 ng/ml, +/- SD 64.6, in group 2 235.7 ng/ml, +/- 169.8). A total of 72.4% of the patients were correctly classified as having either pathological EEG changes or none by this analysis. Variables such as dose, age, sex, weight and duration of treatment were not statistically relevant. It can therefore be suggested that clozapine plasma levels are a valid indicator for the appearance of electrophysiological reactions.",1994.0,0,0
819,7855214,Pharmacologic treatment of schizoaffective disorder.,P E Keck; S L McElroy; S M Strakowski; S A West,"In contrast to the considerable systematic study of the pharmacologic treatment of schizophrenia and mood disorders, the pharmacologic treatment of schizoaffective disorder has been relatively ignored. The authors reviewed the available literature regarding the pharmacologic treatment of schizoaffective disorder. The total number of controlled studies of the acute and prophylactic treatment of schizoaffective disorder was small and few used modern criteria to define the disorder. In studies of schizoaffective disorder, bipolar type (manic), lithium and antipsychotics produced comparable albeit incomplete responses, except in highly agitated patients when antipsychotics exerted superior efficacy. The combination of lithium and antipsychotics appeared to be superior to antipsychotics alone for schizoaffective, bipolar type patients. In the only controlled study of schizoaffective disorder, depressed type, the presumed superiority of combined antidepressant and antipsychotic treatment to antipsychotic alone was not found. Although combined antipsychotic and thymoleptic treatment represents common prophylactic management of schizoaffective disorder in clinical practice, the efficacy of this strategy has not been studied in controlled trials. Advances in the nosology of schizoaffective disorder, emerging epidemiologic data demonstrating large numbers of patients with this disorder in clinical populations, and preliminary evidence that clozapine may have combined antipsychotic and thymoleptic properties as well as efficacy in both the psychotic and affective components of schizoaffective disorder, suggest that renewed interest in the diagnosis and treatment of this disorder may lead to improved delivery of care for this understudied but seriously ill group of patients.",2001.0,0,0
820,7856324,[Effect of clozapine on biogenic amines within the scope of drug treatment of schizophrenic psychoses in adolescence].,E Schulz; H Remschmidt; C Fleischhaker,"Longitudinal assessments (every six weeks for one year) were made of plasma norepinephrine, dopamine, epinephrine and 3-methoxy-4-hydroxyphenylglycol (MHPG) in 40 adolescents with schizophrenia, 20 on clozapine therapy and 20 on conventional medication. In addition to the plasma catecholamine determinations, serum levels of 5-HT were determined as a measure of serotoninergic status. All analyses were performed by HPLC-ECD (high-performance liquid chromatography with electrochemical detection). Clinical ratings of symptomatology were obtained with the Brief Psychiatric Rating Scale (BPRS) and the Andreasen scales for negative and positive symptoms (SANS and SAPS). Compared with the typical neuroleptic medication, clozapine administration was accompanied by a significant increase in plasma norepinephrine and MPHG and serum serotonin levels. The fluctuations in the biogenic amines were closely associated with the observed symptomatology. Plasma MHPG was linked to depressive symptoms (BPRS), and negative symptoms (SANS) were related to changes in the serum serotonin levels. The pathophysiological implications and clinical consequences of these findings are discussed.",1994.0,0,0
821,7856623,Clozapine therapy for Parkinson's disease and other movement disorders.,C Pfeiffer; M L Wagner,"Recent research on the role of clozapine in the treatment of Parkinson's disease and other movement disorders is discussed. Most clinical trials have shown resolution of or improvement in psychotic symptoms accompanying Parkinson's disease without worsening of parkinsonian symptoms. Adverse effects appear to be mild at dosages of < 100 mg/day; sedation is the most frequent problem. Most of these studies have serious limitations, however; until better studies have been completed, the decision to use clozapine for Parkinson's disease-related psychosis should be made on a case-by-case basis, with thorough evaluation of risks, benefits, and other therapeutic options. Some patients with Parkinson's disease have shown improvement in tremor and other abnormal movements when given clozapine. Clozapine cannot be recommended for treating tardive dyskinesia on the basis of the research done so far; some trials show dramatic resolution of symptoms, others no benefit. Anticholinergics or dopamine-reuptake inhibitors should be considered before clozapine is given to patients with tardive dyskinesia because of clozapine's potential for serious adverse effects. A few patients with Huntington's disease have responded to clozapine, but again no conclusions can be drawn. Clozapine appears to offer no real advantage over haloperidol for treating choreiform movements in Huntington's disease. The frequency of tics in Tourette's syndrome does not seem to be reduced by clozapine. Clozapine has shown some efficacy as a treatment for psychosis and abnormal movements in Parkinson's disease. Results have been less promising for other movement disorders. Further study in larger populations is needed before any definitive conclusions about clozapine's place in movement disorder therapy can be made.",1994.0,0,0
822,7858067,The comparative efficacy and long-term effect of clozapine treatment on neuropsychological test performance.,R W Buchanan; C Holstein; A Breier,"Previous studies have suggested that clozapine may improve neuropsychological test performance. The current study was designed to examine the comparative efficacy and the long-term effect of clozapine (versus haloperidol), on neuropsychological test performance. Neuropsychological measures of executive/attention, visuospatial, and memory function were administered to schizophrenic patients at baseline, at the end of a 10-week double-blind study, and after 1 year of open clozapine treatment. Symptoms and function ratings were obtained at the same time points. The 10-week double-blind study revealed significant group-by-time interactions for two measures: Categorical Fluency and WAIS-R Block Design. At the end of 1 year of open treatment there were significant improvements in Verbal Fluency, Mooney Faces Closure, and WAIS-R Block Design performance, and trend improvements in Stroop Color-Word Interference, Category Fluency, and WMS-R Logical Memory performance. Improvements in neuropsychological performance were unrelated to symptom changes. Change in selected neuropsychological measures were significantly correlated with improvement in quality of life. The results suggest that long-term clozapine treatment may have beneficial effects on a broad range of cognitive functions.",1994.0,1,1
823,7862923,Effect of switching carbamazepine to oxcarbazepine on the plasma levels of neuroleptics. A case report.,V Raitasuo; R Lehtovaara; M O Huttunen,"Carbamazepine was switched to its 10-keto analogue oxcarbazepine among six difficult-to-treat schizophrenic or organic psychotic patients using concomitantly haloperidol, chlorpromazine or clozapine. This change resulted within 2-4 weeks in the 50-200% increase in the plasma levels of these neuroleptics and the appearance of extrapyramidal symptoms. None of the patients showed any clinical deteriotation during the following 3-6 months. The results of this case report support the idea that in contrast with carbamazepine oxcarbazepine does not induce the hepatic microsomal enzyme systems regulating the inactivation of antipsychotic drugs.",1994.0,0,0
824,7870880,,,,,0,0
825,7875111,[Clozapine and refractory schizophrenia. Long-term prospective study of 20 patients].,I Jalenques; A J Coudert,"Clozapine, a dibenzodiazepine derivative, has potent antipsychotic activity. But bone marrow suppression resulting in agranulocytosis has been associated with clozapine treatment; thus its clinical development has been delayed and the administration of this drug has been restricted to treatment-resistant schizophrenic patient. This report describes an open prospective study of the effects of clozapine on symptomatology of patients who are refractory to neuroleptics. Authors prospectively followed up until 36 months, 20 DSM III-R schizophrenic patients who had failed to respond to various neuroleptics (7.7 +/- 3.0). When clozapine treatment was initiated, the mean duration of the illness was 17 +/- 10 years. Various scales were used for evaluation: total BPRS, BPRS ""positive symptoms"", BPRS ""negative symptoms"", PANSS positive and PANSS negative were realized at days 0 and 15, months 1, 2 and 3 and then every 3 months. Significative improvements in total BPRS, BPRS positive symptoms and PANSS positive were noted at day 15 (p < 0.005, p < 0.026, p < 0.02, respectively); clozapine produced significant improvement on the BPRS negative symptoms and the PANSS negative at 1 month (p < 0.03 and p < 0.008, respectively). Side effects were studied: dry mouth was more prominent in the first month after wash-out (15%), while salivation was more and more prevalent (20% within the first month; 53% beyond). There was no agranulocytosis in this cohort; 2 cases (10%) of eosinophilia occurred during the first month; 20% of the patients experienced an increase in total white blood cell count (> 12.000/mm3). Weight gain (> 5 kg) affected 32% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)",1994.0,0,0
826,7883728,Is clozapine a mood stabilizer?,C A Zarate; M Tohen; M D Banov; M K Weiss; J O Cole,"Clozapine has been increasingly shown to be effective in the acute and maintenance treatment of bipolar disorders. For this reason, we studied whether clozapine alone is effective as a mood stabilizer in patients with refractory bipolar disorders. Subjects were part of a long-term follow-up study cohort of 193 patients with refractory mood disorders who were treated with clozapine at McLean Hospital prior to July 1, 1992. Patients included in this study were those older than 16 years with bipolar disorder (manic or mixed) and schizoaffective disorder, bipolar type, discharged taking clozapine alone (N = 17). Hospital records on all patients were reviewed by trained raters blind to ""best-estimate"" diagnoses. Response to clozapine was determined by the Clinical Global Impressions-Improvement (CGI-I) scale. Patients were contacted at least 6 months after clozapine initiation for semistructured follow-up interviews by raters blind to diagnosis and baseline information. Seventeen subjects were contacted 16.1 +/- 5.6 months after clozapine initiation. Most of the 17 patients had previously failed trials of lithium, valproate, carbamazepine, neuroleptics, combinations of these, and electroconvulsive therapy; or had tardive dyskinesia. Of these patients, 65% (11/17) continued to be on clozapine therapy alone at follow-up and had no subsequent rehospitalization or affective episode. At follow-up, there was a significant decrease in the rehospitalization rate (p = .025) than before starting clozapine and a significant improvement in CGI-I scores (p = .02). Clozapine monotherapy is an effective mood stabilizer, reducing both the number of affective episodes and rehospitalizations in patients with severe refractory bipolar illness.",2001.0,0,0
827,7898690,Low-dose clozapine in the treatment of levodopa-induced mental disturbances in Parkinson's disease.,J M Rabey; T A Treves; M Y Neufeld; E Orlov; A D Korczyn,"Delusions and other manifestations of psychotic behavior are common side effects in Parkinson's disease (PD) patients chronically treated with dopaminergic drugs. Clozapine, a dibenzodiazepine derivative, is an antipsychotic drug largely devoid of extrapyramidal side effects. We evaluated the effects of low doses of clozapine on the mental and motor functions in PD patients requiring antipsychotic treatment. Twenty-seven PD patients taking dopaminergic drugs and who had psychotic behavior received clozapine at 12.5 to 75 mg/d. Fifteen patients received clozapine for 1 to 11 months (mean, 6.8 months) and seven received it for 12 to 24 months (mean, 18 months). No patient exhibited motor deterioration, and the psychotic features disappeared immediately, allowing discontinuation of clozapine after several months in 10 patients. Fifteen patients are still receiving clozapine and are free of psychiatric symptoms. The clozapine treatment was discontinued after 5 days (25 mg/d) in two patients because of somnolence. No patient developed neutropenia. Clozapine in low doses is effective in the treatment of drug-induced delusions and hallucinations in PD.",1995.0,0,0
828,7908618,Psychopharmacologic treatment of negative schizophrenic symptoms.,L A Opler; D Albert; P M Ramirez,"Diverse pharmacologic agents have been reported to be effective in treating negative schizophrenic symptoms (NSS). In light of this large and growing literature, as well as of reconceptualizations of the underlying pathophysiology of NSS, the time may have come to reject models that assume ""irreversibility"" of NSS. However, flaws in existing studies prevent closure regarding the reversibility of, and by inference the treatability of, NSS. Guidelines for future studies are articulated, e.g., the need to distinguish primary from secondary NSS, to include drug-free subjects with a predominance of NSS in clinical trials, and to use well-validated and psychometrically sound instruments for assessing NSS.",1994.0,0,0
829,7909917,[Electroconvulsive therapy in comorbidity of treatment refractory paranoid hallucinatory psychoses with Parkinson disease].,G Höflich; K W Burghof; S Kasper; H J Möller,"We report the case of a 49-year-old woman with a therapy resistant paranoid hallucinatory psychosis and coexisting severe symptoms of Parkinson's disease. Over a 3-week period she received electroconvulsive therapy (ECT) 10 times, while the medication of haloperidol 8 mg/day, thioridazin 90 mg/day, metixen 17.5 mg/day and biperiden 6 mg/day was continued. There was a general improvement of the clinical picture, more pronounced for the parkinson symptomatology than for the psychotic disorder.",1994.0,0,0
830,7910931,Increased serum IgE in schizophrenic patients who responded poorly to neuroleptic treatment.,R Ramchand; J Wei; C N Ramchand; G P Hemmings,"Total serum IgE and plasma Interleukin (IL)-4 have been determined in patients with schizophrenia, 26 neuroleptic-free, and 81 neuroleptic-treated, and in 46 healthy control subjects. The total serum IgE was significantly higher in the patients who responded poorly to neuroleptic treatment compared with the other four groups (F = 4.27, df = 4, 148, P < 0.003). No significant changes were found in plasma IL-4 levels between any of the five groups. It is possible that raised serum IgE levels may characterise a subgroup of schizophrenia.",1994.0,0,0
831,7944879,,,,,0,0
832,7948457,Stability of neurological signs with clozapine treatment.,R W Buchanan; P Koeppl; A Breier,,1994.0,0,0
833,7961550,Clozapine in tardive dyskinesia: observations from human and animal model studies.,C A Tamminga; G K Thaker; M Moran; T Kakigi; X M Gao,"Clozapine has long been considered a useful treatment in patients who have schizophrenia with the neuroleptic-induced delayed-onset side effect tardive dyskinesia. We present data in support of the clinical impression using both an animal model of the disorder and dyskinetic patients themselves. Clozapine produces a lower rate of oral dyskinesia in laboratory rats after 6 months of chronic treatment than does haloperidol (8.6 +/- 1.3 vs. 13.6 +/- 1.4 vacuous chewing movements every 5 minutes, respectively), suggesting a lower propensity to cause tardive dyskinesia. In the human, when clozapine was compared with haloperidol in the treatment of patients with tardive dyskinesia, clozapine produced significantly greater benefit for motor symptoms after 12 months of treatment than did haloperidol (p < .001). Moreover, the dyskinesia rebound, which occurred equally in both drug groups at the beginning of the study, was sustained in the haloperidol group but lost in the clozapine-treated patients. These data suggest that dyskinetic patients lose their symptoms of tardive dyskinesia, along with dopaminergic hypersensitivity, with long-term clozapine treatment.",1994.0,0,0
834,7961554,Plasma clozapine concentrations as a predictor of clinical response: a follow-up study.,D D Miller; F Fleming; T L Holman; P J Perry,"We investigated the relationship between plasma clozapine concentrations and clinical response in treatment-refractory schizophrenic patients. In a previous study, we found that plasma drug concentrations above 350 ng/mL maximized clinical response in a group of 29 patients. This study represents a follow-up of these original 29 patients over approximately 2 1/2 years of clozapine treatment. We found that during the initial 6-week trial of clozapine, 38% (N = 11) of the patients were considered to be responders. With continued treatment, we found that 58% (14 of 24) were classified as responders. Consistent with our previous study, we observed that plasma concentrations were helpful in predicting response. Five of 7 patients who had unsatisfactory response became responders when their plasma clozapine concentrations increased to above 350 ng/mL. We conclude that the assessment of plasma clozapine concentrations as a guide to dose adjustment may be useful in maximizing response.",1994.0,0,0
835,7961555,Clozapine and noradrenergic function: support for a novel hypothesis for superior efficacy.,A Breier,"Because of its superior clinical efficacy, clozapine is considered the new ""reference"" antipsychotic agent. Currently, there is an intensive investigational effort attempting to delineate which of clozapine's many biochemical effects are important for its impressive clinical profile. In this paper, the effects of clozapine on noradrenergic function are examined. Preclinical and clinical studies indicate that clozapine selectively increases noradrenergic activity and norepinephrine outflow. Moreover, data are presented demonstrating that clozapine causes fivefold increases in plasma norepinephrine in schizophrenic patients and that these increases are related to its superior clinical efficacy. A novel hypothesis for its superior efficacy is proposed that involves complex actions on noradrenergic systems that result in robust norepinephrine outflow. Implications of heightened norepinephrine outflow are discussed.",1994.0,0,0
836,7961556,Predictors of response to clozapine.,J A Lieberman; J M Kane; A Z Safferman; S Pollack; A Howard; S Szymanski; S J Masiar; M H Kronig; T Cooper; H Novacenko,"Clinical and biological measures were examined for their relationship to clinical response to clozapine. Associations were found between therapeutic response and the following variables: male gender, paranoid schizophrenia subtype diagnosis, older age at onset of illness, shorter duration of illness, higher levels of pretreatment acute EPS, low pretreatment CSF HVA/5-HIAA, greater decrease in prolactin (PRL) and increase in growth hormone (GH) response to apomorphine stimulation pretreatment and greater inhibition by clozapine treatment of PRL and GH response to apomorphine, and plasma clozapine levels above 350 ng/mL. These results are consistent with other investigators' findings and have practical and heuristic implications for the use of clozapine and understanding its mechanism of action.",1994.0,0,0
837,7961557,Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia.,S G Potkin; R Bera; B Gulasekaram; J Costa; S Hayes; Y Jin; G Richmond; D Carreon; K Sitanggan; B Gerber,"Steady-state blood clozapine concentrations in 58 schizophrenic patients varied more than 45-fold (40-1911 ng/mL) after fixed-dose treatment (400 mg/day). Discriminant function analysis determined that a blood clozapine concentration of 420 ng/mL optimally distinguished responders from nonresponders. After 4 weeks of treatment, only 8% of those patients with a blood clozapine concentration < 420 ng/mL responded compared with 60% of those who had a blood clozapine concentration > 420 ng/mL. When plasma concentrations were increased above 420 ng/mL (by a double-blind random assignment procedure), nonresponders increased their response rate to 73% if their plasma concentrations at Week 12 exceeded 420 ng/mL compared with a response rate of 29% if their Week 12 levels remained below 420 ng/mL (chi 2 = 4.2, p < .04).",1994.0,0,0
838,7961559,51Cr release assay of clozapine-induced cytotoxicity: evidence for immunogenic mechanism.,A V Pisciotta; S A Konings,"Serum drawn from patients during clozapine-induced agranulocytosis was toxic to human polymorphonuclear leukocytes (PMNs). Toxicity was produced by an immunoglobulin fraction, predominantly of the IgM class. The offending drug was not necessary at this stage to produce cytotoxicity. These effects were observed by inhibiting post-phagocytosis glycolysis, by ejection of trypan blue, or by enhanced release of 51Cr from lysed-labeled PMNs. Direct chemical toxicity, produced by clozapine or its metabolites, was tested by similar procedures. At a concentration of 10(-5) M in a colloidal milieu produced by dilution with AB serum, no cytotoxicity was observed; however, in aqueous medium. N-desmethylclozapine was toxic to PMNs and proliferating lymphocytes. Post-recovery serum appeared to be inert, but cytotoxicity was restored by adding clozapine or N-desmethylclozapine to the sensitive patient's serum. At this stage, cytotoxicity as measured by 51Cr release was abrogated by anti-IgG or anti-IgM. These relationships favor an immunologic mechanism that damages peripheral PMNs. Development of colony-forming units-granulocyte (CFU-G) was similarly inhibited in normal marrow cultures by cytotoxic serum alone, whereas no metabolite had such an effect at the same concentration (10(-5) M).",1994.0,0,0
839,7961563,Clozapine and weight gain.,D S Umbricht; S Pollack; J M Kane,"To investigate the association of clozapine treatment and weight gain, we studied short- and long-term weight gain, correlation of weight gain with treatment response, and risk factors for weight gain in 82 patients with chronic schizophrenia who received clozapine treatment for up to 90 months. Weight values were obtained through retrospective chart review. Clozapine was titrated over an average of 3 to 5 weeks up to a dose of 500 to 600 mg/day. Psychopathology was assessed with the Brief Psychiatric Rating Scale and the Clinical Global Impressions scale. A clinically significant weight gain occurred mostly during the first 6 to 12 months, but continued well into the third year of treatment. Weight gain and treatment response were not correlated, and early weight gain was not a predictor of response. The cumulative incidence of patients becoming substantially overweight exceeded 50%. Being underweight at baseline correlated with maximum amount gained (p = .000), and being overweight at baseline correlated with percentage above ideal weight (p = .006). Treatment with clozapine is associated with a high incidence of substantial weight gain, posing a potential long-term health risk. Studies are needed of the underlying mechanisms of weight gain, as well as the treatment for this side effect.",1994.0,1,1
840,7961575,Functional neuroimaging and pharmacogenetic studies of clozapine's action at dopamine receptors.,R W Kerwin; L Pilowsky; J Munro; S Shaikh; M Gill; D Collier,"The factors that influence response to neuroleptic drugs are poorly understood. These factors may include clinical variables such as length of illness before treatment, age at onset, and the presence of negative symptoms; and pharmacologic factors such as rates of drug metabolism. For example, pharmacodynamic differences in therapeutic response to haloperidol have been observed between Chinese and Caucasian patients. Response rates may also reflect clinical heterogeneity, although familiality, history of obstetric trauma, or ventricular enlargement have been not shown to be significant factors. It is also possible that genetic differences in receptors that are targets for these drugs may influence response.",1994.0,0,0
841,7961576,Clozapine effects on glucose metabolic rate in striatum and frontal cortex.,S G Potkin; M S Buchsbaum; Y Jin; C Tang; J Telford; G Friedman; S Lottenberg; A Najafi; B Gulasekaram; J Costa,"Eighteen patients with schizophrenia had cerebral metabolic rates assessed with positron emission tomography during a double-blind, placebo-controlled crossover study of clozapine treatment. Relative metabolic rates were increased in the basal ganglia, especially on the right side. In the frontal lobe, metabolic rates were lowered, more on the left than on the right. The anterior nuclei of the thalamus also showed lower metabolic rates after clozapine. We have previously observed patients with schizophrenia to have low metabolic rates in the basal ganglia and to lack the normal right > left asymmetry; in this study, clozapine normalized striatal activity. In the frontal lobe, asymmetry was normalized, but hypofrontal function was, if anything, exaggerated. This effect in the frontal lobe was not observed with haloperidol in earlier studies. The cortical effects of clozapine may be related to its unique clinical properties and suggest important differences between typical and atypical antipsychotic drugs.",1994.0,0,0
842,7961579,"Clozapine, negative symptoms, and extrapyramidal side effects.",J M Kane; A Z Safferman; S Pollack; C Johns; S Szymanski; M Kronig; J A Lieberman,"The importance of persistent negative symptoms in schizophrenia as a limiting factor in psychosocial and vocational rehabilitation has been increasingly emphasized. As a result, treatment trials and new drug development programs are focusing more attention on negative symptoms. Unfortunately, there is enormous phenomenological overlap between negative symptoms and neuroleptic-induced parkinsonism. We report data from a cohort of 56 clozapine-treated patients demonstrating significant correlations between measures of akinesia and anergia. Despite an average drug washout of over 2 weeks, the persistence of drug-induced parkinsonism can confound the assessment of therapeutic drug effects on negative symptoms.",1994.0,0,0
843,7961582,Effects of clozapine on cognitive function in schizophrenia.,M A Lee; P A Thompson; H Y Meltzer,"Cognitive dysfunction may underlie some of the psychopathology of schizophrenia as well as contribute to impaired social and vocational function in this disorder. Chronic treatment with typical neuroleptics has been reported to produce only minimal improvement in and may impair cognitive function in schizophrenia. We have studied the effect of clozapine, an atypical antipsychotic drug, on cognitive function in 36 patients with treatment-resistant schizophrenia. In addition, patients with non-treatment-resistant schizophrenia were randomly assigned to clozapine (N = 24) or typical neuroleptics (N = 23). Cognitive function in the treatment-resistant schizophrenia group was studied after 6 weeks and 6 months of treatment, while the non-treatment-resistant patients were also studied at 12 months of treatment. Clozapine treatment improved several domains of cognitive function, especially attention and verbal fluency in both treatment-resistant schizophrenia and non-treatment-resistant schizophrenia. On the other hand, typical neuroleptic treatment produced minimal improvement in cognitive function. The effect of clozapine on some tests of attention and verbal fluency was significantly greater than that of typical neuroleptic treatment in non-treatment-resistant schizophrenia. These data suggest that clozapine treatment was superior to typical neuroleptics in improving cognitive function in schizophrenia. The possibility that this is related to normalization of dopaminergic function by clozapine is discussed.",1994.0,0,1
844,7961583,Clozapine in treatment-refractory mood disorders.,S E Kimmel; J R Calabrese; M J Woyshville; H Y Meltzer,"Lithium remains the mainstay of treatment for patients with bipolar affective disorder; however, nearly half of patients with bipolar disorder fail to respond to lithium. Recently, there have been an increasing number of preliminary clinical reports that clozapine, an atypical antipsychotic agent, has potential efficacy in patients with mood disorders. We review the available clinical data supporting the potential use of clozapine in these psychiatric disorders and report our preliminary data from a study that used clozapine in the acute treatment of mania in treatment-refractory patients. Twenty-five patients meeting the DSM-III-R criteria for the manic phase of either bipolar or schizoaffective disorder entered a 13-week open prospective trial of clozapine. These patients either had failed to respond to or had been intolerant to treatment with lithium, an anticonvulsant, and at least two typical neuroleptics. Eighteen of 25 patients demonstrated a greater than 50% decrease in the Young Mania Rating Scale score. These preliminary data as well as the clinical reports reviewed indicate that the efficacy of clozapine in treatment-resistant patients is not limited to patients with schizophrenia.",1994.0,0,0
845,7961584,Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response.,S C Piscitelli; J A Frazier; K McKenna; K E Albus; D R Grothe; C T Gordon; J L Rapoport,"Plasma clozapine and haloperidol concentrations were studied in adolescents being treated for childhood-onset schizophrenia. Eleven patients (9 boys, 2 girls; mean age = 14.1 +/- 2.1 years) received a 6-week blinded or open trial of clozapine. Five patients also received 6 weeks of blinded or open haloperidol. Doses were increased on an individual basis to a mean 6-week dose of 5.99 +/- 2.6 mg/kg/day for clozapine and 0.24 +/- 0.20 mg/kg/day for haloperidol. The Brief Psychiatric Rating Scale and Bunney Hamburg Rating Scale were completed weekly for each subject. Weekly blood samples were obtained during therapy and assayed by high performance liquid chromatography. The mean clozapine level at Week 6 was 378.3 ng/mL and ranged from 77.5 to 1050 ng/mL. The mean Week 6 haloperidol level was 23.0 ng/mL (range, 6.2-44.3 ng/mL). The clozapine desmethyl and N-oxide metabolites achieved mean concentrations of 77% and 18%, respectively, of those of the parent compound. The mean ratio of haloperidol/reduced haloperidol was 4.48 (range, 0.76-8.76). Clozapine concentrations versus clinical benefit exhibited a consistent linear relationship among patients (correlation range, 0.26-0.96). Conversely, poor and inconsistent correlations between haloperidol concentrations and clinical effects were observed. No relationships were noted between clozapine or haloperidol dose and clinical effects. Adolescents with schizophrenia produce a greater amount of desmethylclozapine than previously seen in adults. Plasma clozapine concentrations appear to be related in a linear fashion to clinical improvement.",1994.0,0,0
846,7979877,Clinical action of remoxipride.,R Conley; C A Tamminga; J A Nguyen,,1994.0,0,0
847,7986770,"Effects of clozapine, fluphenazine, and placebo on reaction time measures of attention and sensory dominance in schizophrenia.",T P Zahn; D Pickar; R J Haier,"Two reaction time (RT) paradigms were used to study clozapine's effects on sustained and selective attention compared to fluphenazine and placebo in 25 chronic schizophrenic patients. Sensory dominance was studied via simple and choice RTs to lights and tones, and on double-stimulus trials in which the two stimuli were presented simultaneously. Although 8 of the 25 patients could not perform the RT tasks when taking placebo, there were no effects of clozapine on simple or choice RT compared to placebo or fluphenazine. Subjects on all 3 treatments showed visual dominance: faster RT to lights than to tones on choice and double-stimulus trials. However, clozapine reduced this by means of a selective increase in RT to lights. Clozapine reduced failures to respond to the tone on double-stimulus trials. This was shown to be due to reductions in hallucinations. Clozapine does not generally improve attention, but it may increase the ability of schizophrenic persons to process nondominant or unattended stimuli possibly by increasing the efficiency of resource allocation. This may be partially mediated by a reduction in hallucinations.",1994.0,0,1
848,7991106,"Clozapine-related seizures: experience with 5,629 patients.",S V Pacia; O Devinsky,"We reviewed the incidence, clinical features, and management of all clozapine-related seizures in 5,629 patients monitored by the Clozaril Patient Management System, during the first 6 months after marketing. Seventy-one patients had generalized tonic-clonic seizures yielding a frequency of 1.3%. One patient had myoclonic seizures prior to generalization. Seizures tended to occur at low doses (< 300 mg/d) during the titration phase, and at high doses (> or = 600 mg/d) during the maintenance phase. Patients with a history of seizures or epilepsy were more likely to have seizures soon after initiation of therapy, on low doses. Twenty-nine of 37 patients (78%) who had seizures and were rechallenged with clozapine were able to continue the medication with dose reduction and more-gradual dose titration, or with the addition of an antiepileptic medication.",1994.0,1,1
849,7991117,The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia.,J L Cummings; M Mega; K Gray; S Rosenberg-Thompson; D A Carusi; J Gornbein,"We developed a new instrument, the Neuropsychiatric Inventory (NPI), to assess 10 behavioral disturbances occurring in dementia patients: delusions, hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, and aberrant motor activity. The NPI uses a screening strategy to minimize administration time, examining and scoring only those behavioral domains with positive responses to screening questions. Both the frequency and the severity of each behavior are determined. Information for the NPI is obtained from a caregiver familiar with the patient's behavior. Studies reported here demonstrate the content and concurrent validity as well as between-rater, test-retest, and internal consistency reliability; the instrument is both valid and reliable. The NPI has the advantages of evaluating a wider range of psychopathology than existing instruments, soliciting information that may distinguish among different etiologies of dementia, differentiating between severity and frequency of behavioral changes, and minimizing administration time.",1994.0,0,0
850,8006199,Disposition of clozapine and desmethylclozapine in schizophrenic patients.,S K Lin; W H Chang; M C Chung; Y W Lam; M W Jann,"The disposition of the atypical clozapine and its desmethyl metabolite were evaluated in fourteen male chronic patients. A single 100 mg dose of clozapine was administered and blood sampling performed over the following 72 hours. The mean (SD) oral clearance and half-life of clozapine were 55.4 (29.7) L/hr and 13.7 (9.9) hours, respectively. The mean (SD) AUC for clozapine and desmethylclozapine was 2389.9 (1406) and 751.1 (622.9) ng.hr/mL, respectively. The elimination of the metabolite is rate limited by its formation from cloza-pine. A wide interpatient variability in clozapine and desmethylclozapine pharmacokinetics was observed.",1994.0,0,0
851,8021328,Teaching clinical psychopharmacology on an inpatient psychiatric research center.,P A Santy; S G Bryant,"In this article we have shown how an inpatient Psychiatric Clinical Research Center has been used successfully to teach medical students and residents some basic principles of clinical psychopharmacology. Although teaching effectiveness and resident acceptance of the program have not been measured objectively (we intend to do this in the next 2 years), informal feedback about the CRC rotation has been enthusiastic. The clinical psychopharmacology curriculum in our department has been enhanced by the experience of trainees on a research unit. In the rapidly expanding area of psychopharmacology, where new drugs are continually coming on the market, the CRC provides an opportunity to demonstrate the biopsychosocial model and to explore the interface between the research and clinical aspects of psychopharmacology.",1994.0,0,0
852,8043521,Quantitative effects of typical and atypical neuroleptics on smooth pursuit eye tracking in schizophrenia.,R E Litman; D W Hommer; A Radant; T Clem; D Pickar,"Smooth pursuit eye movement (SPEM) gain, total saccades, and subtypes of saccades were quantified from the visual pursuit tracking of 26 fluphenazine-treated patients with schizophrenia and 42 normal controls. Tracking was repeated in 16 patients who underwent a placebo-controlled, double-blind crossover comparison of fluphenazine and clozapine. Fluphenazine-treated patients showed significant reduction in SPEM gain and significant increases in both total, intrusive, and anticipatory saccades and in saccadic amplitude, when compared to controls. Clozapine significantly reduced SPEM gain and significantly increased total and catch-up saccades, when compared to placebo or fluphenazine. High amplitude of intrusive saccades in drug-free patients predicted poor response to clozapine, suggesting that intact frontal cortical function may enable optimal clozapine response.",1994.0,0,0
853,8052275,Effects of a limiting Medicaid drug-reimbursement benefits on the use of psychotropic agents and acute mental health services by patients with schizophrenia.,S B Soumerai; T J McLaughlin; D Ross-Degnan; C S Casteris; P Bollini,"We examined the effects of a three-prescription monthly payment limit (cap) on the use of psychotropic drugs and acute mental health care by noninstitutionalized patients with schizophrenia. We hypothesized that reducing access to such drugs would increase the use of emergency mental health services and the rate of partial hospitalizations (full-day or half-day treatment programs) and psychiatric-hospital admissions. We linked Medicaid claims data for a period of 42 months with clinical records from two community mental health centers (CMHCs) and the single state psychiatric hospital in New Hampshire, where Medicaid imposed a three-prescription limit on reimbursement for drugs during 11 months (months 15 through 25) of the study. For comparison, we used Medicaid claims for a period of 42 months in New Jersey, which had no limit on drug reimbursement. The study patients (n = 268) and the comparison patients (n = 1959) were permanently disabled, noninstitutionalized patients with schizophrenia, 19 through 60 years of age, who were insured by Medicaid. We conducted interrupted time-series regression analyses to estimate the effects of the cap on the use of medications and mental health services. The cap resulted in immediate reductions (range, 15 to 49 percent) in the use of antipsychotic drugs, antidepressants and lithium, and anxiolytic and hypnotic drugs (P < 0.01). It also resulted in coincident increases of one to two visits per patient per month in visits to CMHCs (range of increase, 43 to 57 percent; P < 0.001) and sharp increases in the use of emergency mental health services and partial hospitalization (1.2 to 1.4 episodes per patient per month), but no change in the frequency of hospital admissions. After the cap was discontinued, the use of medications and most mental health services reverted to base-line levels (measured in the first 14 months of the study). The estimated average increase in mental health care costs per patient during the cap ($1,530) exceeded the savings in drug costs to Medicaid by a factor of 17. Limits on coverage for the costs of prescription drugs can increase the use of acute mental health services among low-income patients with chronic mental illnesses and increase costs to the government, even aside from the increases caused in pain and suffering on the part of patients.",1994.0,0,0
854,8071267,Seizures associated with clozapine treatment in a state hospital.,W H Wilson; A M Claussen,"The seizures associated with the atypical antipsychotic medication clozapine represent a serious side effect of treatment. In premarketing studies, seizures occurred at a crude rate of 3.5%. It is possible that the rate and character of seizures would vary in clinical settings because of differences in patient populations or differences in the manner in which treatment is administered. We studied the seizures that occurred during clozapine treatment in a state psychiatric hospital. We reviewed the medical charts and pharmacy records of 100 sequential patients who were to start clozapine treatment. The review period covered 6 months pretreatment through 1 year of follow-up. The patients were 55 men and 45 women, aged 20 to 61 years. Ten (5 men, 5 women) had at least one seizure during clozapine treatment. Seizures occurred at all dose ranges (0-299 mg/day, N = 6; 300-599 mg/day, N = 2; 600-900 mg/day, N = 2). Of 12 patients with histories of previous seizures, 4 (33%) had a seizure while taking clozapine and anticonvulsants. Of 9 patients with histories of head trauma but no seizures, 1 (11%) had a seizure. Of 79 patients without seizure disorder or a history of head trauma, 5 (6.3%) had a seizure. Nine of the patients who had a seizure continued on clozapine treatment with temporary dose reduction and/or addition of an anticonvulsant, 2 having one additional seizure. Clozapine-associated seizures were more frequent in this group of state hospital patients than they were in premarketing studies. Clozapine-related seizures did not preclude successful treatment with clozapine.",1994.0,0,1
855,8080889,"Clozapine treatment and its effect on neuroendocrine responses induced by the serotonin agonist, m-chlorophenylpiperazine.",R S Kahn; M Davidson; L J Siever; S Sevy; K L Davis,"The effects of clozapine treatment on neuroendocrine responses induced by the serotonin agonist, m-chlorophenylpiperazine (mCPP) were examined. mCPP and placebo were administered after a 2-week drug-free period and again after 5 weeks of clozapine treatment in nine schizophrenic inpatients. Adrenocorticotropic hormone (ACTH), prolactin, and mCPP levels were measured. Clozapine treatment completely blocked mCPP-induced ACTH and prolactin release suggesting that clozapine blocks serotonin receptors that mediate these hormone responses.",1994.0,0,0
856,8132186,Clozapine treatment of outpatients with schizophrenia: outcome and long-term response patterns.,A Breier; R W Buchanan; D Irish; W T Carpenter,"The purpose of the study was to examine the effects of clozapine in treating moderately ill schizophrenic outpatients and to determine the length of medication trial needed to identify responders and nonresponders. Rates of clinical responses, relapses and hospitalizations, and levels of symptomatology and functioning were assessed for 30 chronic schizophrenic outpatients who received clozapine for one year. For some patients, data on relapse and hospitalization during treatment were compared with data from the year before treatment. Eighteen of the 30 patients met criteria for sustained response; 17 of the responders were identified within the first four months of treatment. Patients experienced significantly fewer relapses and hospitalizations during treatment than in the previous year. Improvement in positive symptoms, general symptomatology, and levels of functioning reached a plateau during the first six months of treatment and remained at that level during the second six months. Negative symptoms and quality of life showed nonsignificant improvements at 12 months. Results support the use of clozapine in treating chronic, residually symptomatic schizophrenic outpatients. A four-month clozapine trial may be adequate to detect clinical responders in this population.",2001.0,0,1
857,8179790,The effect of clozapine on plasma norepinephrine: relationship to clinical efficacy.,A Breier; R W Buchanan; R W Waltrip; S Listwak; C Holmes; D S Goldstein,"Clozapine is an atypical neuroleptic medication with superior efficacy to conventional antipsychotic agents for patients with chronic, symptomatic schizophrenia. Neurochemical characteristics that distinguish clozapine from other neuroleptics and contribute to its differential efficacy are not known. We assessed the effects of clozapine on plasma levels of norepinephrine (NE) in a double-blind, parallel groups comparison of clozapine (n = 11) and haloperidol (n = 15) in chronic schizophrenic outpatients who had been previously treated with fluphenazine. Simultaneous measurements were obtained for plasma levels of the catecholamine precursor dopa, the dopamine metabolite dihydroxyphenylacetic acid (DOPAC), the NE metabolite 3,4-dihydroxyphenylglycol (DHPG), adrenocorticotropin (ACTH), cortisol, and hemodynamic parameters. Clozapine produced marked increases (471%) in plasma NE levels, whereas haloperidol had no significant effects on plasma NE levels. Clozapine also increased dopa and tended to increase DOPAC levels, without effects on DHPG, ACTH, or cortisol levels and without consistent changes in blood pressure. Across patients, the magnitude of clozapine-induced increments in plasma NE levels was positively related to improvement in positive symptoms and global symptomatology and was unrelated to the occurrence of extrapyramidal symptoms. The results suggest that clozapine differs importantly from other neuroleptics in increasing plasma NE levels, with the peripheral noradrenergic stimulation related to its superior efficacy profile. The unchanged DHPG levels and absence of hypertension suggest a more complex mechanism of action of clozapine than heightened NE release alone.",2001.0,0,0
858,8186332,Clozapine response in treatment-refractory first-episode schizophrenia.,S Szymanski; S Masiar; D Mayerhoff; A Loebel; S Geisler; S Pollack; J Kane; J Lieberman,,1994.0,0,0
859,8195452,Clozapine and metabolites: concentrations in serum and clinical findings during treatment of chronically psychotic patients.,F Centorrino; R J Baldessarini; J C Kando; F R Frankenburg; S A Volpicelli; J G Flood,"Clozapine (CLZ) and metabolites norclozapine and clozapine-N-oxide were assayed with a new, sensitive (2 pmol), and selective method in 68 serum samples from 44 psychotic subjects, 20 to 54 years old, ill 16 years, and treated with CLZ for 2.2 years (currently at 294 mg, 3.4 mg/kg daily). CLZ levels averaged 239 ng/ml (0.73 microM; 92 ng/ml per mg/kg dose) or 48% of total analytes (norclozapine = 41% [91% of CLZ] and clozapine-N-oxide = 11%); metabolite and CLZ levels were highly correlated (rs = 0.9), and CLZ levels varied with daily dose (rs = 0.7). Sampling twice yielded similar within-subject analyte levels (r = 0.8 to 0.9; difference = 24% to 33%). Range and variance narrowed when levels were expressed per weight-corrected dose (ng/ml per mg/kg). Levels per dose were 40% higher in nonsmoking women than men, despite a 60% lower milligram per kilogram dose in women, and did not vary by diagnosis or age in this limited sample. Fluoxetine increased serum CLZ analytes by 60%; valproate had less effect. Patients rated treatment very positively; observer-assessed benefits typically were more moderate. Common late side effects were sialorrhea (80%), excess sedation (58%), obesity (55% > 200 lb), mild tachycardia (51%), constipation (32%), and enuresis (27%); there were no seizures or leukopenia. There was little evident relationship of drug dose or serum level to current clinical measures or side effect risks.",1994.0,0,0
860,8251696,Pharmacoepidemiology of clozapine in 202 inpatients with schizophrenia.,J M Zito; J Volavka; T J Craig; P Czobor; S Banks; J Vitrai,"To evaluate clozapine in a field trial for hospitalized patients with treatment-resistant schizophrenia. The setting consisted of a large, state-operated, public psychiatric system. The protocol called for the treating psychiatrist to provide symptom- and adverse-effect ratings at four times following the start of drug therapy. The outcome criteria included the Sandoz study outcome measure of symptom improvement as well as discharge status for one year of follow-up. To assess the validity of the ratings, several measures of internal consistency were determined. Clozapine therapy was started in 227 patients, and symptom data are available for 202. Overall, 33 percent (n = 66) of the patients were improved at the end of one year of treatment; 12 percent (n = 24) maintained symptom improvement at all three evaluation times. Modest, statistically significant improvement after 12 weeks compared with baseline Brief Psychiatric Rating Scale (BPRS) total scores was observed for the patients continuing medication (n = 152); the emergence of a previously unimproved group (n = 26) explains this modest improvement. However, in the analysis of all patients (n = 202), (including dropouts), there was no significant symptom improvement after 12 weeks. Lower baseline BPRS scores predicted significant symptom improvement after 12 weeks of treatment. Among those medicated for one year, the pattern of symptom improvement showed that the probability of late improvement was 0.26 for those previously unimproved, and the probability of a 12-week responder losing improvement was 0.23, resulting in a net group gain of 3 cases in 100. By the end of one year, 8 percent (n = 17) of the cohort was discharged, and 3 percent (n = 7) was transferred to another facility while continuing to receive clozapine. Of the 227 original patients started on clozapine therapy, medication was discontinued for adverse effects in 11 percent (n = 25): white blood cell count (WBC) decrease (but no agranulocytosis) in 5 percent (n = 12), seizures in 1 percent (n = 3), one patient with seizures and decreased WBC count, and other events (e.g., cardiovascular changes, fever, or possible neuroleptic malignant syndrome) in 4 percent (n = 9). Patient refusal was reported for 6 percent (n = 13) of those starting treatment. Although only 19 percent of the patients exhibited improvement at 6 weeks, the response rate at 12 weeks (29 percent) for this naturalistic study cohort was similar to that in the major, double-blind, six-week, controlled, clinical trial of clozapine. The impersistence of response as symptoms were followed for up to one year is a finding that deserves rigorous evaluation.",1993.0,0,0
861,8251698,Meaningful interpretation of risk reduction from clinical drug trials.,J P McCormack; M Levine,"To illustrate the concepts of relative and absolute risk reduction, and by example, present and discuss the results of prevention trials that have evaluated the impact of drug therapy on cardiovascular disease. Additional approaches to evaluating the results of prevention trials are also presented. Data were gathered from eight frequently quoted major cardiovascular intervention trials. Reference to large reductions in relative risk in review papers, newspapers, and at professional meetings can lead to false expectations among clinicians and patients regarding the potential impact of the treatment in individual patients. When making decisions about preventive drug therapy, clinicians are encouraged to examine measures other than relative risk reduction and to include the patient in the decision process. Educators should emphasize these other measures of outcome and not rely solely on relative risk reduction in discussing particular areas of therapeutics.",1993.0,0,1
862,8260445,,,,,0,0
863,8267110,Serum concentrations of clozapine and its major metabolites: effects of cotreatment with fluoxetine or valproate.,F Centorrino; R J Baldessarini; J Kando; F R Frankenburg; S A Volpicelli; P R Puopolo; J G Flood,"Serum concentrations of clozapine, norclozapine, and clozapine-N-oxide were assayed in psychotic patients treated with clozapine alone (N = 17), clozapine with fluoxetine added (N = 6), or clozapine with valproic acid added (N = 11). Subjects were matched for age and other treatments, and concentrations were corrected for daily dose of clozapine (milligrams per kilogram of body weight). With valproic acid, there was a minor increase in total clozapine metabolites, which was even less with dose correction. Fluoxetine increased all clozapine analytes, in some cases to twice the levels in the subjects given only clozapine.",1994.0,0,0
864,8268334,Clozapine attenuates meta-chlorophenylpiperazine (mCPP)-induced plasma cortisol increases in schizophrenia.,A Breier; B Kirkpatrick; R W Buchanan,,1993.0,0,0
865,8297214,Clinical response to clozapine in patients with schizophrenia.,D Pickar; R E Litman; W W Hong; T P Su; E M Weissman; J K Hsiao; W Z Potter,,1994.0,0,1
866,8599400,Course of treatment response in first-episode and chronic schizophrenia.,S R Szymanski; T D Cannon; F Gallacher; R J Erwin; R E Gur,"The timing and clinical correlates of symptom change following antipsychotic treatment were examined in first-episode and chronic schizophrenia. The subjects were 36 first-episode schizophrenic patients who had received minimal or no neuroleptics and 34 patients with chronic illness whose neuroleptics had been withdrawn. They were followed for 2 years and assessed with the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms. Treatment decisions during follow-up were made clinically by the treating physicians. At 6-month follow-up, both the neuroleptic-naive and previously treated patients showed significant improvement in positive symptoms (52% and 44% reductions from baseline, respectively). The previously treated but not the neuroleptic-naive patients also showed a significant reduction in negative symptoms (19% from baseline). A longer duration of illness before baseline assessment and inconsistent treatment during follow-up were independently associated with poorer treatment outcome in terms of positive symptoms in both groups. There were no significant changes on the outcome measures in either group after the 6-month follow-up. The results suggest that maximum symptomatic improvement occurs within the first 6 months of treatment and that disease progression may blunt treatment efficacy in both first-episode and chronic schizophrenia.",1996.0,0,0
867,8610833,Different side effect profiles of risperidone and clozapine in 20 outpatients with schizophrenia or schizoaffective disorder: a pilot study.,D G Daniel; T E Goldberg; D R Weinberger; J E Kleinman; D Pickar; L J Lubick; T S Williams,"The purpose of this study was to compare the side effect +profiles of clozapine and risperidone. The subjects were 20 outpatients with schizophrenia or schizoaffective disorder who were clinically stable on a regimen of clozapine at the time of screening. They underwent a randomized-order crossover comparison of 6 weeks of risperidone treatment and 6 weeks of clozapine treatment. Clinical and neurocognitive variables were assessed by raters blind to medication status, and severity of side effects was determined from patients' self-reports. Side effect measures, but not clinical ratings, were significantly different after 6 weeks of treatment with the two drugs. Patients required more benztropine for motor effects and complained of more insomnia with risperidone and more sedation with clozapine. Body weight was higher at the end of clozapine treatment than at the end of risperidone treatment. In this exploratory study, the side effect profiles of clozapine and risperidone were consistent with the different pharmacodynamic profiles of the two drugs.",1996.0,1,1
868,8623040,Dose related response to clozapine in a state psychiatric hospital population: a naturalistic study.,B J Gordon; D J Milke,"After noting a striking difference in the dosing practices of two treating psychiatrists, each responsible for the operation of a clozapine unit in a state psychiatric hospital, the authors conducted a retrospective chart review to assess the clinical efficacy of low dose x = 294 mg. per day) versus high dose (x = 525 mg. per day) clozapine treatment for a cohort of 31 inpatients. Levels of psychopathology, behavior, and social functioning were assessed six months pre and during clozapine treatment for 16 patients who received low dose clozapine treatment and 15 patients who received high dose clozapine treatment. Patients on both units demonstrated significant reductions in their levels of psychopathology, improved social functioning and improvement in their behavior following six months clozapine treatment. This naturalistic study suggests that the use of low dose clozapine provides effective treatment for chronic, severely treatment resistant inpatients with schizophrenia or schizo-affective illness, at the same time reducing the potential for significant side effects.",1996.0,0,0
869,8633697,Differential effect of clozapine on weight: a controlled study.,J R Bustillo; R W Buchanan; D Irish; A Breier,This study examined whether clozapine induces more weight gain than haloperidol and whether weight gain is related to clinical improvement. The weight and symptoms of 39 outpatients with schizophrenia who were randomly assigned to double-blind treatment with either clozapine or haloperidol were assessed. The weight and symptoms of 33 of the patients who chose to take clozapine during a 1-year follow-up after the study ended were also assessed. The patients treated with clozapine gained significantly more weight over baseline (7%) than the haloperidol-treated patients (1%). Weight gain was not significantly correlated with improvements in either positive or negative symptoms. Fifty-eight percent of the patients followed for 1 year gained at least 10% over their baseline weight. Weight gain is an important side effect of clozapine and is unrelated to the drug's differential antipsychotic efficacy.,1996.0,1,1
870,8641685,Allelic association between a Ser-9-Gly polymorphism in the dopamine D3 receptor gene and schizophrenia.,S Shaikh; D A Collier; P C Sham; D Ball; K Aitchison; H Vallada; I Smith; M Gill; R W Kerwin,"We examined a Ser-9-Gly polymorphism in the dopamine D3 receptor gene for allelic association with schizophrenia in 133 patients currently treated with clozapine and 109 controls. Allele 1 (Ser-9) was significantly more frequent in the patients (69%) than in the controls (56%) (P = 0.004). The 1-1 genotype was more common (43% vs 30%) and the 2-2 genotype less common (5% vs 18%) in patients than in controls. When the patient group was subdivided on the basis of clinical response to clozapine, using a 20-point improvement in the global assessment scale as cut-off, genotype 1-1 was found to be more frequent among the non-responders (53% vs 36%, P = 0.04). To place our results in the context of previous studies of this polymorphism and schizophrenia, we performed a meta-analysis of all published data including the present sample. The combined analysis shows evidence for a modest association between genotype 1-1 and schizophrenia (odds ratio 1.25, 95% confidence interval 1.05-1.49, P = 0.01). These results suggest that the Ser-9 allele, or a nearby polymorphism in linkage disequilibrium, results in a small increase in susceptibility to schizophrenia.",1996.0,0,0
871,8657050,[Maintenance therapy with low doses of clozapine in schizophrenia].,R Lisulov; A Nedić,"A sample of 27 schizophrenic outpatients, who were or had been in maintenance therapy with clozapine, were studied for the last 2 years, in an open clinical trial. Two groups were followed: group 1-with low maintenance doses of clozapine, and with a concomitant neuroleptic therapy, and group 2-where clozapine was switched to classical neuroleptics. Therapy strategies in group 1 have been significantly more effective than those in group 2.",1995.0,0,0
872,8666580,Advances in CNS Drugs. Recent advances and considerations in the treatment of schizophrenia.,,,1996.0,0,0
873,8678181,Lack of association between polymorphisms in the 5-HT2A receptor gene and the antipsychotic response to clozapine.,A K Malhotra; D Goldman; N Ozaki; A Breier; R Buchanan; D Pickar,"The authors' goal was to determine whether either of two 5-HT2A receptor polymorphisms, 102-T/C and 452-His/Tyr, are associated with clozapine response. Brief Psychiatric Rating Scale (BPRS) ratings were obtained in 70 patients with schizophrenia or schizoaffective disorder to determine their response to clozapine compared with a typical neuroleptic. Patients were genotyped with the polymerase chain reaction and restriction fragment length polymorphism analysis. Neither 102-T/C nor 452-His/Tyr was associated with clozapine response. There were no significant differences in BPRS scores among patients with different 5-HT2A genotypes at week 10 of clozapine administration. Allelic variation in the 5-HT2A gene is not associated with individual differences in clozapine response.",1996.0,0,0
874,8685657,Clozapine eligibility among state hospital patients.,S M Essock; W A Hargreaves; F A Dohm; J Goethe; L Carver; L Hipshman,"Connecticut State Hospital's entire resident population (n = 1,300) was screened on an arbitrary target day to determine eligibility for clozapine. Sixty percent of 803 patients with schizophrenia or schizoaffective disorder diagnoses met Food and Drug Administration (FDA)- approved criteria for clozapine use as judged by review of past medication trial records and by the responsible physicians. Eighty-eight percent of these patients were medically cleared, and of those cleared, 63 percent agreed to clozapine treatment. Of the patients who began a clozapine trial, 76 percent were still taking the drug 12 months later. Preliminary findings from a randomized trial of clozapine versus usual care (n = 227) indicate that discharge rates associated with clozapine and usual care do not differ. Once discharged, however, patients assigned to clozapine are less likely to be readmitted. Hence, clozapine may be more cost-effective than usual care. However, before savings can be realized, State governments will have to make up-front investments of approximately $140 million simply to give patients hospitalized on a single day a year's access to clozapine.",1996.0,0,0
875,8690831,"ICI 204,636, an atypical antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial in patients with schizophrenia. U.S. SEROQUEL Study Group.",R L Borison; L A Arvanitis; B G Miller,"ICI 204,636 is a new, potentially atypical antipsychotic. In early phase II trials, the antipsychotic was well tolerated and results suggested efficacy in the treatment of the positive and negative symptoms of schizophrenia. The efficacy and safety of ICI 204,636 were evaluated on a larger scale in a 6-week, multicenter, double-blind trial. Hospitalized patients who met DSM-III-R criteria for chronic or subchronic schizophrenia with acute exacerbation, as well as other criteria, were randomized to ICI 204,636 (75 to 750 mg daily) (N = 54) or placebo (N = 55). Patients were assessed weekly by use of the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Negative Symptoms (SANS), and Clinical Global Impression Scale (CGI) for efficacy and the Simpson Scale and Abnormal Involuntary Movement Scale for extrapyramidal side effects (EPS). Significant differences (p < or = 0.05) between treatment groups, which favored ICI 204,636, were identified throughout the trial. Endpoint differences were significant (by analysis of covariance) for BPRS factor IV (activation) and SANS scores and were marginally significant for total BPRS, BPRS factor III (thought disturbance), BPRS positive-symptom cluster, and CGI Severity of Illness item scores (p = 0.07, 0.09, 0.06, and 0.09, respectively). ICI 204,636 was well tolerated, although it was associated with mild transient increases in alanine aminotransferase and a higher incidence of somnolence and anticholinergic effects compared with placebo. In the dose range studied, treatment with ICI 204,636 did not induce EPS as determined by analysis of Simpson Scale total scores and lack of treatment-emergent acute dystonic reactions. Furthermore, ICI 204,636 did not produce sustained levels of prolactin; the mean change from baseline at endpoint (-7.2 micrograms/L) was comparable (p = 0.44) to that for placebo (-8.2 micrograms/L). These findings distinguish ICI 204,636 from standard antipsychotics and confirm preclinical predictions that ICI 204,636 is an atypical antipsychotic.",1996.0,0,1
876,8721896,Risperidone: a once-daily dosage schedule.,S Gupta; W R Gilroy,,2001.0,0,1
877,8725991,Efficacy and safety of risperidone in psychotic patients: an open study.,T K Daradkeh; F Reda; L Karim,"This open prospective study was undertaken to determine the efficacy and safety of a fixed dose (6 mg) of risperidone in psychotic patients. Hospital in-patients who fulfilled DSM-111-R criteria for schizophrenia, schizoaffective and bipolar disorders were eligible for entry into the study (n = 15). Patients who were on other antipsychotics had a washout period of 1 week before they were started on the drug. A fixed dose of risperidone was administered (6 mg). The Brief Psychiatric Rating Scale (BPRS), Negative Symptom Rating Scale (NSRS) and Abnormal Involuntary Movement Scale were used to measure psychopathology and extrapyramidal side-effects. Five patients dropped out of the study. Two patients became very agitated and potentially aggressive, one patient became very restless and did not respond to benzodiazepines, and one dropped out because of restlessness that did not respond to clonazepam. Of the 10 patients who completed the study, 50 per cent reduction on BPRS and NSRS was achieved by five and six patients respectively. There was a marginally significant trend towards a greater reduction in the magnitude of negative symptoms. Four patients required treatment with anticholinergic drugs. Risperidone was effective in resistent psychotic patients, but agitated and impulsive psychotic patients with positive symptoms may not be best candidates for treatment with risperidone. On average, negative symptoms respond better than positive symptoms.",1996.0,0,0
878,8726548,Smooth pursuit eye movements in the evaluation of famotidine adjunctive therapy of schizophrenia: a preliminary report.,P B Rosenberg; R B Rosse; S K Johri; K Kendrick; M Fay-McCarthy; J P Collins; L C Tsui; R J Wyatt; S I Deutsch,"Smooth pursuit eye movements (SPEM) are often abnormal in schizophrenic patients and have been proposed as a trait marker of the disorder. We explored the use of SPEM as an outcome measure in an open-label clinical trial of famotidine, an H-2 antagonist, in patients with schizophrenia; famotidine has been proposed as an adjunctive medication, particularly for negative symptoms. Prior studies using SPEM as an outcome measure have not found a significant effect with ""typical"" neuroleptic medication, and one study found greater SPEM dysfunction with clozapine treatment. In this study, 19 schizophrenic subjects were stabilized for at least 1 week on conventional neuroleptic medications and then administered oral famotidine, 100 mg daily, for an additional 3 weeks. SPEM and clinical measures were assessed. Whereas Brief Psychiatric Rating Scale (BPRS) and Schedule for Assessment of Negative Symptoms (SANS) scores decreased significantly with famotidine administration, there was no significant change in SPEM performance over the course of the study. Two subjects (11%) doubled their signal/noise ratio and maintained this increase after famotidine discontinuation, whereas three subjects (17%) approximately halved this ratio and returned to baseline after famotidine discontinuation. SPEM changes were not found to correlate significantly with changes in BPRS or SANS scores. These findings suggest that SPEM dysfunction reflects a ""trait"" rather than clinical ""state"" in schizophrenia, and changes in SPEM performance might not be expected always to parallel changes in clinical ratings.",2001.0,0,0
879,8732909,Using the proportional odds model to assess the relationship between a multi-item and a global item efficacy scale in a psychiatric clinical trial.,R N Tamura; Y Tanaka; K Satoh; M Takahashi,"The proportional odds model is illustrated in the analysis of two efficacy scales used in a phase II clinical trial involving 81 schizophrenic patients. The proportional odds model preserves the discrete, ordinal nature of one of the scales. The analysis of this data suggested that the relationship between the two scales is not captured by a linear proportional odds model. A linear model and a piecewise linear model for the explanatory variable were therefore compared using likelihood-based analyses. Residuals from both models were compared. Predicted probabilities for the ordinal categories were constructed from the estimated model. Extensions and limitations of the model for interpretation of other trials and for the planning of future trials are discussed.",1996.0,0,0
880,8733795,"Idazoxan and response to typical neuroleptics in treatment-resistant schizophrenia. Comparison with the atypical neuroleptic, clozapine.",R E Litman; T P Su; W Z Potter; W W Hong; D Pickar,"We investigated whether antagonism of alpha 2 adrenergic receptors would augment treatment response in schizophrenia, by administering idazoxan, an alpha 2 antagonist drug, to treatment-resistant patients on typical neuroleptics. Seventeen hospitalised treatment-resistant patients with DSM-III-R schizophrenia or schizoaffective disorder were studied on typical neuroleptic treatment, on treatment with idazoxan plus typical neuroleptic, and after discontinuation of idazoxan, in fixed, non-random order, and under double-blind, placebo-controlled conditions. The addition of idazoxan to fluphenazine treatment resulted in significant reductions of global psychosis and total, positive and negative symptoms on the Brief Psychiatric Rating Scale, compared to neuroleptic treatment alone. Symptom improvement significantly correlated with idazoxan-induced changes in indices of noradrenergic function. In a subgroup of patients, idazoxan plus typical neuroleptic treatment compared favourably with clozapine treatment, when both were compared to typical neuroleptic treatment alone. The antagonism of alpha 2 receptors augmented therapeutic response to typical neuroleptic treatment in treatment-resistant patients with schizophrenia. This antagonism may contribute to clozapine's superior antipsychotic effects.",1996.0,0,0
881,8736614,Adverse effects of antipsychotic agents. Do newer agents offer advantages?,D G Owens,"Although antipsychotic drugs are effective in treating the so-called positive features of schizophrenia, between one-quarter and one-third of patients respond poorly. Furthermore, the incidence of adverse effects is high, especially those reflecting disruption of extrapyramidal function, and is a major source of non-compliance. There is a clear need for new compounds that are more efficacious and/or better tolerated. Until recently, the classical dopamine hypothesis, with its emphasis on D2 blockade as the key mechanism of antipsychotic action, dominated drug development, though the emphasis is now shifting. Three 'new' antipsychotics have reached the international market in the past 5 years-the newly rehabilitated clozapine and the genuinely new remoxipride and risperidone. Claims of enhanced tolerability have been made for each of these, but as none is free from adverse effects, their place in treatment can only be meaningfully established in relation to the efficacy of each in different clinical situations. Clozapine has an extensive profile of general, nonhaematological adverse effects which is slightly different in emphasis from, but comparable in incidence to, that of chlorpromazine. There is a 0.8% risk of agranulocytosis in the first year of exposure, which can be fatal, though the boundary separating it from other (especially phenothiazine) antipsychotics in this regard is becoming increasingly blurred. It has a clearly diminished liability to cause extrapyramidal adverse effects. Its proven efficacy in operationally defined treatment-resistant schizophrenia and in patients intolerant to the extrapyramidal adverse effects of standard drugs establishes its credentials for advantage in these groups. There is on present evidence, however, only a hint of enhanced efficacy in acute schizophrenia: this requires further investigation. Open maintenance studies provide impressive data on long term outcome, especially in terms of quality-of-life parameters, but this issue requires to be addressed in blind, randomised trials. Until such additional information is forthcoming the risks and consequent costs would not justify extension of its use. The evidence to date is that reported benefits in so-called negative features probably reflect its favourable neurological profile. While the advantages of clozapine are undoubted, they remain as yet restricted to selected patient groups. Remoxipride has a good general tolerability profile, its special strength being its low sedative effect. However, its reported association with aplastic anaemia has severely restricted its use, and regular haematological monitoring is required. Although remoxipride appears to have a lower liability to produce extrapyramidal adverse effects than the high potency haloperidol, its benefits relative to other low potency compounds in this regard remain unproven. The only obvious situation in which its risks and consequent costs would be justified would seem to be patients with established compliance problems as a result of intrusive sedation with standard drugs. The position of other benzamides such as raclopride and amisulpride remains to be established. Risperidone, perhaps from its antiadrenergic actions, has more in the way of cardiovascular adverse effects than haloperidol, though these can be obviated by graded early exposure. It may also be associated with greater weight gain. Otherwise it appears to be well tolerated. In comparison with haloperidol, it appears to be associated with a lower prevalence of acute extrapyramidal adverse effects in dosages < or = 10 mg/day, the most potentially important component of which is its reportedly insignificant likelihood of promoting akathisia. These conclusions emerge from comparisons with haloperidol in doses many might consider somewhat high. The question of the advantage of risperidone over low or milligram-equivalent haloperidol regimens remains open.(ABSTRACT TRUNCATED)",1996.0,0,0
882,8739553,Diurnal and weekly variation of tardive dyskinesia measured by digital image processing.,J K Stanilla; C Büchel; J Alarcon; J de Leon; G M Simpson,"The diurnal and weekly variability of tardive dyskinesia (TD) was assessed instrumentally by digital image processing. Weekly assessments were obtained in ten patients over a 6-week period. In six of the ten patients, assessments were obtained four times over a single 12-h period. Results indicate that TD movements measured by instrumental assessment vary from week to week and throughout the day. Factors that appear to have affected the variability were changes in medications and the time of day when the assessments were conducted.",1996.0,0,0
883,8742444,Association between clozapine response and allelic variation in the 5-HT2C receptor gene.,M S Sodhi; M J Arranz; D Curtis; D M Ball; P Sham; G W Roberts; J Price; D A Collier; R W Kerwin,"A cysteine to serine substitution at amino acid 23 in the 5-HT2C receptor gene alters the pharmacological properties of the protein. We investigated this polymorphism in subjects with schizophrenia resistant to conventional neuroleptic drugs, and analysed our data for allelic association between the disease state or clinical response to the atypical antipsychotic drug, clozapine. Ninety percent of subjects who had one or more 5-HT2Cser alleles (19/21) were classified as clozapine responders compared with 59% (84/141) without this allele (chi 2 = 7.7, p = 0.005), suggesting that this mutation is a predictor of good response to clozapine. There was no association between schizophrenia and the 5-HT2Cser allele, but our results indicate that the 5-HT2C receptor may contain the major site of action through which clozapine mediates its antipsychotic effects.",1995.0,0,0
884,8748041,Risperidone in the treatment of negative symptoms of schizophrenia: a meta-analysis.,J Carman; J Peuskens; A Vangeneugden,"Risperidone has antiserotonergic and antidopaminergic properties that may make it more effective than conventional antipsychotic agents in the treatment of the negative symptoms of schizophrenia. Clinical trials in chronic schizophrenic patients have shown trends in favor of risperidone in the control of negative symptoms compared with haloperidol, perphenazine or zuclopenthixol, but the differences were not consistently statistically significant. A meta-analysis of the pooled results from six double-blind trials showed that risperidone at doses ranging from 4 to 8 mg/day had a significantly (p < 0.004) higher negative symptom response rate, defined as the percentage of patients with a 20% or more reduction in scores on the negative subscale of the Positive and Negative Syndrome Scale, than patients receiving active controls. The combined patient population treated with 4-8 mg/day of risperidone was 1.43 times more likely to have had a clinical response on the negative symptom subscale than the combined population treated with haloperidol, perphenazine or zuclopenthixol.",1995.0,0,1
885,8749886,Clozapine: efficacy and safety.,R W Buchanan,"Clozapine (Clozaril) represents the first major advance in the pharmacological treatment of schizophrenia since the introduction of antipsychotics into clinical practice in the 1950s. Studies consistently support its efficacy for reducing positive symptoms in acutely psychotic patients and in treatment-resistant patients, for preventing positive symptom exacerbations as a maintenance treatment, and for reducing symptoms of hostility and violence. There is evidence to suggest that clozapine may improve social and occupational functioning and quality of life and may reduce affective symptoms, hospitalizations, secondary negative symptoms, and tardive dyskinesia. Its most significant side effects include agranulocytosis, seizures, weight gain, hypotension and tachycardia, sedation, and perhaps rebound psychosis (with abrupt discontinuation of medication).",1995.0,0,0
886,8749887,Risperidone: efficacy and safety.,D Umbricht; J M Kane,This article reviews the evidence for the efficacy and effectiveness of risperidone in persons with schizophrenia. Nine published double-blind studies compare risperidone with another antipsychotic medication and/or placebo. All were conducted in the acute phase of illness. Risperidone's antipsychotic efficacy is shown to be consistently superior to that of placebo and at least comparable to that of haloperidol and perphenazine for patients in the acute phase of schizophrenia. Further research is necessary to determine the effectiveness of risperidone and its efficacy both as a maintenance treatment and in treatment-refractory and deficit-state patients.,1995.0,0,0
887,8750075,The Nisonger CBRF: a child behavior rating form for children with developmental disabilities.,M G Aman; M J Tassé; J Rojahn; D Hammer,"Although the rate of behavior and emotional problems of children with mental retardation is considerably higher than the rate among typically developing children, there is a shortage of tools for assessing persons with mental retardation. The Child Behavior Rating Form (CBRF) was modified by altering instructions and adding new items describing behavior problems known to occur in children with mental retardation. The adapted scale was named the Nisonger CBRF. Three hundred sixty-nine children being assessed at a University Affiliated Program for MR/DD were rated on the CBRF by their parents and teachers. Independent factor analyses of parent and teacher ratings produced two Social Competence subscales and six Problem Behavior subscales. These results were largely consistent across rater types and similar to prior findings with the CBRF. Internal consistency was generally high, parent-teacher agreement was satisfactory, and subscales from the Nisonger CBRF correlated highly with analogous subscales from the Aberrant Behavior Checklist. The Nisonger CBRF appears to be a promising new tool for assessing behavioral and emotional problems in children with mental retardation; however, further psychometric work is warranted.",1996.0,0,0
888,8761867,Observation of metabolic changes in chronic schizophrenia after neuroleptic treatment by in vivo hydrogen magnetic resonance spectroscopy.,B Y Choe; T S Suh; K S Shinn; C W Lee; C Lee; I H Paik,"The authors investigate: (1) whether there is a lateral effect of hydrogen (1H) magnetic resonance (MR) spectroscopy observable metabolite ratios between the right and the left prefrontal lobe in chronic schizophrenia; (2) whether there is a change of proton metabolite ratios in chronic schizophrenia after neuroleptic treatment; (3) whether there is a relation between changes in 1H MR spectra and the clinical assessment of Brief Psychiatric Rating Scale (BPRS); and (4) to investigate a hypofrontality hypothesis in schizophrenia in terms of neurochemical aspects. Localized in vivo 1H MR spectroscopy was used to measure the metabolite levels in the prefrontal lobes of control persons (n = 20) and of chronic patients before and after neuroleptic treatment (n = 34). The MR spectra of 8 cm3 voxels were compared with clinical assessment of BPRS in each subject. No significant metabolic lateral effect was established in both schizophrenia and control groups (P > 0.05). After neuroleptic treatment, chronic schizophrenic patients generally demonstrated a decrease of the complex of gamma-aminobutyric acid (GABA) and glutamate (Glu) containing (GABA + Glu)/creatine (Cr) ratio. The current follow-up 1H MR spectroscopy study shows a significant correlation between alterations of (GABA + Glu)/Cr ratio and BPRS, and supports a hypofrontality hypothesis in chronic schizophrenia. The reduction of (GABA + Glu)/Cr ratio after neuroleptic treatment may implicate the recovery of normal neuronal function in neurotransmitters. In vivo 1H MR spectroscopy may be a useful modality in follow-up evaluation of neuroleptic treatment in chronic schizophrenia.",1996.0,0,0
889,8822534,Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial.,C M Beasley; G Tollefson; P Tran; W Satterlee; T Sanger; S Hamilton,"Olanzapine is a potential new ""atypical"" antipsychotic agent. The double-blind acute phase of this study compared three dosage ranges of olanzapine (5 +/- 2.5 mg/day [Olz-L], 10 +/- 2.5 mg/day [Olz-M], 15 +/- 2.5 mg/day [Olz-H]) to a dosage range of haloperidol (15 +/- 5 mg/day [Hal]) and to placebo in the treatment of 335 patients who met the DSM-III-R criteria for schizophrenia. In overall symptomatology improvement (Brief Psychiatric Rating Scale [BPRS]-total), Olz-M, Olz-H, and Hal were significantly superior to placebo. In positive symptom improvement (BPRS-positive), Olz-M, Olz-H, and Hal were comparable and significantly superior to placebo. In negative symptom improvement (Scale for the Assessment of Negative Symptoms [SANS]-composite), Olz-L and Olz-H were significantly superior to placebo and Olz-H was also significantly superior to Hal. The most common treatment-emergent adverse events included somnolence, agitation, asthenia, and nervousness. No acute dystonia was observed with olanzapine. Treatment-emergent parkinsonism occurred with Olz-H at approximately one-third the rate of Hal, and akathisia occurred with Olz-H at approximately one-half the rate of Hal. Prolactin elevations associated with olanzapine were not significantly greater than those observed with placebo and were also significantly less than those seen with haloperidol.",2001.0,1,1
890,8823348,Treatment-resistant schizophrenic patients.,J M Kane,"Despite the proven efficacy of antipsychotic medication in the treatment of schizophrenia, a substantial proportion of patients derive little if any benefit from traditional medications. Though alternative strategies (e.g., increasing dosage, switching antipsychotic, or adding adjunctive medication) are frequently employed, success rates are often disappointing. Clozapine has shown to be effective in some poor or partially responsive patients in three prospective, random assignment, double-blind trials. Risperidone has not yet been extensively studied in treatment-resistant patients, but may also be a useful alternative.",1996.0,0,0
891,8823352,Clinical experience with risperidone.,S R Marder,"Recent clinical experiences with risperidone including controlled trials, clinical observations, and reports of side effects are reviewed. The controlled trials indicate that risperidone is an effective anti-psychotic that may have advantages over conventional antipsychotics for treating both positive and negative symptoms of schizophrenia. A number of clinical reports indicate that risperidone is also effective for psychotic illnesses that result from other disorders. Risperidone has a relatively mild side effect profile when compared with conventional antipsychotics.",1996.0,0,0
892,8830067,Free radical scavenging enzyme activity and related trace metals in clozapine-induced agranulocytosis: a pilot study.,L A Linday; C E Pippenger; A Howard; J A Lieberman,"We hypothesized that patients who had experienced clozapine-induced agranulocytosis would have abnormalities in their free radical scavenging enzyme activity (FRESA) and levels of related trace metals. We therefore measured FRESA profiles and related trace metals in four groups: post-clozapine agranulocytosis (POST CLOZ AGRAN) (N = 9); clozapine no agranulocytosis (CLOZ NO AGRAN) (N = 12); West Coast controls (WC CONTROLS) (N = 14); and Long Island Jewish Medical Center controls (LIJ CONTROLS) (N = 12). Glutathione peroxidase (GSH-Px, P1) levels in plasma were slowest in the POST CLOZ AGRAN group (34.3 +/- 6.9 IU/dl [standard deviation; SD]; p < 0.002); red blood cell glutathione peroxidase (GSH-Px, RBC) was highest in the WC CONTROLS (38.7 +/- 4.7 IU/g hemoglobin [Hgb]; p < 0.008); and selenium (SE) levels in plasma were lower in both the POST CLOZ AGRAN group (111.6 +/- 14.7 ng/ml) and the CLOZ NO AGRAN group(115.0 +/- 17.8) than in the WC CONTROLS (142.5 +/- 18.3; p < 0.0006). SE was also lower in the POST CLOZ AGRAN group than in the LIJ CONTROLS (129.1 +/- 21.6; p < 0.04). The presence of at least one of the following: (1) GSH-Px, P1 < 37.6 IU/dl; (2) GSH-Px, RBC < 31.0 IU/g Hgb; or (3) SE < 112.4 ng/ml, distinguished POST CLOZ AGRAN subjects from the WC CONTROLS, but not from the LIJ CONTROLS. Data from this cross-sectional pilot study suggest that abnormalities in the body's antioxidant defense system may be involved in the pathogenesis of clozapine-associated agranulocytosis. If confirmed in large-scale, prospective studies, these preliminary findings have potential clinical application in the screening and prophylaxis of clozapine agranulocytosis.",1995.0,0,0
893,8834417,"Antipsychotic and anxiolytic properties of risperidone, haloperidol, and methotrimeprazine in schizophrenic patients.",O Blin; J M Azorin; P Bouhours,"The subjects were 62 patients hospitalized for acute exacerbations of schizophrenia and were randomly assigned to receive risperidone (mean dose, 7.4 mg/day), haloperidol (7.6 mg/day), or methotrimeprazine (100 mg/day) for 4 weeks. Clinical improvement, defined a priori as a 20% reduction in total Positive and Negative Syndrome Scale (PANSS) scores at end point, was attained by 81% of the risperidone patients, 60% of the haloperidol patients, and 52% of the methotrimeprazine patients (p < 0.05). The reductions in total PANSS and Clinical Global Impression Scale severity scores from baseline to end point were significantly greater in the risperidone patients than in the other two groups. Reductions in scores on the Psychotic Anxiety Scale were significantly greater in the risperidone patients than the methotrimeprazine patients; the difference between haloperidol and methotrimeprazine was not significant. Extrapyramidal symptoms (scores on the Extrapyramidal Symptom Rating Scale) were more severe in the haloperidol patients than in the other two groups, but few differences were apparent between risperidone and methotrimeprazine patients. It is concluded that risperidone is an effective antipsychotic and anxiolytic agent in schizophrenic patients.",1996.0,0,1
894,8851645,Risperidone use in a teaching hospital during its first year after market approval: economic and clinical implications.,C S Carter; B H Mulsant; R A Sweet; R A Maxwell; K Coley; R Ganguli; R Branch,"Risperidone, a new antipsychotic drug, was recently approved by the Food and Drug Administration (FDA) on the basis of its having comparable efficacy and less toxicity than haloperidol. In a preliminary study to evaluate the therapeutic efficiency of this drug, we conducted a survey of resperidone utilization, cost, and safety during its first year of availability at an academic psychiatric hospital. Data were obtained from a computerized, centralized medical record system, from an adverse drug reaction monitoring system, and from pharmacy purchasing records. In its first year of availability, risperidone became the second most widely used antipsychotic agent at our institution. Most of this use extended beyond the adult schizophrenia population, for whom pre-marketing safety and efficacy data are available. The direct institutional cost of risperidone treatment exceeded the entire budget for antipsychotic drugs during the year before its release. Results from the adverse drug reaction reporting system did not indicate a strong advantage of risperidone over more established antipsychotic agents with respect to extrapyramidal side effects. Furthermore, the mean dose of risperidone associated with extrapyramidal symptoms was 3.5 mg/day, considerably lower than that suggested by pre-marketing studies in a more select patient group. These results confirm that new pharmacological agents are generally used in much broader patient populations than those for which efficacy and safety have been established prior to FDA approval. This study also raises questions about the therapeutic efficiency of risperidone compared with other antipsychotic drugs. We conclude that systematic studies of outcome, safety, and cost of new pharmaceuticals in naturalistic settings are needed to provide the data necessary to establish local standards of cost-effective care.",1995.0,0,0
895,8851647,Pharmaceutical decisionmaking: pharmacoepidemiology or pharmacoeconomics--who's in the driver's seat?,J M Zito; G Provenzano,"Although it is well known that clinical trial findings and actual clinical experience can differ substantially in pharmaceutical decisionmaking, it is our working hypothesis that this divergence is critically important in the area of psychopharmacology. We support this contention with a discussion of recent findings from post-marketing pharmacoepidemiologic and pharmacoeconomic investigations of clozapine. The pharmacoeconomic evaluations purport to show cost savings of clozapine versus standard neuroleptic therapy but these conclusions are flawed, in large part because the epidemiologic investigations on which they are based are inadequate. To correct this situation, long-term, randomized field trials (usual practice settings) are needed to compare costs and outcomes of clozapine versus standard therapy. The design of these studies should incorporate multidimensional outcomes, including social function, employment, and rehospitalization, as well as measures of symptoms and self-reported quality of life. Pharmacoeconomic evaluations that adopt the designs of typical clinical trials with limited outcome measures, such as symptoms or self-reported quality of life measures, will not be sufficient to determine cost-effectiveness for psychopharmacologic therapies of severe mental disorders.",1995.0,0,0
896,8866933,"A controlled trial with ORG 2766, an ACTH-(4-9) analog, in 50 relatively able children with autism.",J K Buitelaar; M E Dekker; J M van Ree; H van Engeland,"The aim of the present study was to replicate earlier findings of beneficial effects of ORG 2766, an ACTH-(4-9) analog, in autistic children. Fifty children with autism, 7-15 years old and with a Performance IQ of more than 60, participated in a double-blind placebo controlled parallel trial. Active treatment was 40 mg ORG 2766 for 6 weeks. The outcome was assessed on the basis of the Aberrant Behavior Checklist completed by parents and teachers, and by means of a detailed behavioral observation (30 subjects). ORG 2766 failed to improve social and communicative behavior at a group level. The rate of individual response, defined as a reliable change in social withdrawal at home and at school, to ORG 2766 (10 out of 30) and placebo (4 out of 20) was not significant either. The children who responded to ORG 2766, but not those who responded to placebo, manifested significant improvements outside the changes in the defining variables, including a decrease in hyperactivity at school. The responders to ORG 2766 were characterized mainly by a relatively lower PIQ; further by more initial hyperactivity, stereotypies and abnormal speech, and less initial eye contact. The responders to placebo could not be differentiated from the non-responders to placebo. Future studies should examine whether ORG 2766 differentially affects various subtypes of autism.",1996.0,0,1
897,8866934,Mechanical lesions of the fimbria fornix in rat brain studied by 1H-magnetic resonance imaging. Evidence for long-lasting dynamic alterations in the ipsilateral ventricular system.,R M Dijkhuizen; H J Muller; M Josephy; B M Spruijt; K Nicolay,"In vivo 1H-NMR imaging was employed to study dynamic changes in the status of tissue water as a function of time after mechanical brain injury induced by partial unilateral transection of the fimbria fornix (FF) in the rat brain and was correlated with histology. Changes in the brain tissue were reproducibly found in distinct regions which were exclusively located in the lesioned hemisphere. The most pronounced changes concerned the lateral ventricle. Ventricular enlargement became evident posterior to the site of transection after a few hours and was maximal after 2-4 days. At later time points the posterior ventricular expansion was reduced. The lateral ventricle anterior to the site of transection was significantly enlarged from day 1 and continued to expand for up to 7 months. Tissue response at the site of transection, mainly involving the hippocampal formation and the thalamus, was first manifested after 24 h, while signs of progressive tissue degeneration were apparent in the long term.",1996.0,0,1
898,8867521,Electroencephalographic findings with low-dose clozapine treatment in psychotic Parkinsonian patients.,M Y Neufeld; J M Rabey; E Orlov; A D Korczyn,"Twenty patients with Parkinson's disease (PD), who developed delusions and psychotic behavior, underwent electroencephalogram (EEG) recordings before and during treatment with low-dose clozapine. Resolution of the psychotic features was observed in all cases. The EEG was unaltered in 15, whereas five patients exhibited increased generalized or focal slowing when compared with the pretreatment tracings. These findings contrast with the high incidence of EEG abnormalities, including epileptiform activity, which are observed when larger doses of clozapine are used in schizophrenic patients, but they underscore that even in low doses, clozapine may cause EEG changes.",1996.0,0,0
899,8894200,Neutropenia and agranulocytosis in patients receiving clozapine in the UK and Ireland.,K Atkin; F Kendall; D Gould; H Freeman; J Liberman; D O'Sullivan,"Clozapine can cause reversible agranulocytosis and neutropenia. This study documents the occurrence of blood dyscrasias and identifies predisposing risk factors. An analysis was made of the haematological, demographic, and dosage data from a central database on 6316 patients receiving clozapine over four and a half years in the UK and Ireland. During the study period, 2.9% of the patients developed neutropenia and 0.8% developed agranulocytosis. The peak incidence of both disorders was in the first 6-18 weeks of treatment. Fatal agranulocytosis occurred in 0.03% of patients. After the first year of treatment, the incidence of agranulocytosis significantly decreased to the order noted with some phenothiazines. The use of a patient monitoring service kept the haematological risks associated with using clozapine within acceptable limits, particularly in view of the benefits of this medication in treatment-resistant schizophrenia.",1996.0,1,1
900,8916101,Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine.,M J Arranz; D A Collier; J Munro; P Sham; G Kirov; M Sodhi; G Roberts; J Price; R W Kerwin,"Clozapine is an atypical antipsychotic with affinity for a broad range of receptors, including serotonin (5-HT) and dopamine receptors. It is successful in treating about 60% of patients refractory to other antipsychotic drugs. Since genetic variation in clozapine's neurotransmitter receptor targets may affect clinical response through altering drug binding or receptor expression, we have studied a His452Tyr polymorphism in the 5-HT2A receptor (HTR2A) in a sample of 153 schizophrenic patients undergoing clozapine treatment and 178 normal controls. An association was found between the allele Tyr452 and poor clinical response.",1996.0,0,1
901,8925346,Effects of the clozapine national registry system on incidence of deaths related to agranulocytosis.,G Honigfeld,"Clozapine is the only medication distributed in the U.S. through a national patient registry system that provides the medication only if results of patients' weekly blood tests show no evidence of significant white blood cell suppression, an effect that can be fatal if it progresses to advanced agranulocytosis. This study assessed morbidity and mortality related to agranulocytosis during the first five years of the national registry system. Data from the national registry database maintained by the U.S. manufacturer of clozapine was used to determine the level of treating systems' adherence to the mandated program of weekly white blood cell counts, number of instances in which clozapine treatment was denied because of prior determination of white blood cell suppression, and number of cases of agranulocytosis and deaths related to agranulocytosis among treated patients from February 1990, when clozapine was commercially introduced in the U.S., through December 1994. The actual numbers of cases of agranulocytosis and related deaths were compared with expected outcomes based on clinical research done before the drug became available commercially. Approximately 97 percent of treating systems had a high overall level of adherence to the registry protocol. In 28 instances, the pretreatment authorization requirement resulted in denial of clozapine; after additional data were considered, 15 of the patients were cleared for treatment. The actual incidences of 382 cases of agranulocytosis and 12 related deaths were lower than the expected 995 cases and 149 deaths. The clozapine national registry system fostered early detection of white blood cell suppression, prevented retreatment with clozapine of patients who had previously developed white blood cell suppression, and brought about lower than expected rates of agranulocytosis and associated deaths.",1996.0,1,1
902,8927657,Serotonin-mediated increase in cytosolic [Ca++] in platelets of risperidone-treated schizophrenia patients.,L Ereshefsky; C Riesenman; J E True; M Javors,"Stimulating the platelet 5HT2 receptor generates the second messenger IP3, and results in an increase in cytosolic [Ca++] ([Ca++]cyt). Platelets from risperidone-treated patients would be expected to respond less effectively, as measured by decreased [Ca++]cyt, after 5HT2 receptor stimulation. We report the data on 6 risperidone-treated patients and 6 normal controls evaluated at our site using the Fura-2 method for determining platelet [Ca++]. Data analysis was performed by unpaired two-tailed Student's t-test. No significant differences between groups were found for ED50 5HT-stimulated [Ca++]cyt (ED50 5HT delta [Ca++]cyt). Significant differences were found for maximal change [Ca++]cyt (Max delta [Ca+2]cyt) between risperidone-treated patients and normal controls (p = .03). These preliminary data suggest that measurement of 5HT-stimulated changes in platelet cytosolic [Ca+2] might be a useful marker for in vivo risperidone inhibition of 5HT2 function.",1996.0,0,0
903,8927658,"Plasma prolactin in schizophrenia subjects treated with Seroquel (ICI 204,636).",M B Hamner; L A Arvanitis; B G Miller; C G Link; W W Hong,"Treatment with standard antipsychotic medications causes side effects such as hyperprolactinemia and extrapyramidal symptoms. Because these side effects can cause noncompliance with antipsychotic medication and consequent relapse, they add to the morbidity of schizophrenia. A compound with antipsychotic efficacy but without the side effects of standard antipsychotic agents would improve compliance and treatment outcomes and enhance quality of life. Improved compliance, reduced relapse, and decreased hospitalization would also reduce the cost of treatment of schizophrenia. Seroquel (ICI 204,636), an atypical antipsychotic compound in Phase III development, was found to be well tolerated and effective in treating subjects with DSM-III-R schizophrenia in three Phase II clinical trials. Analysis of plasma prolactin concentrations obtained during these trials revealed that ICI 204,636 did not differ from placebo in its effect on plasma prolactin after up to 6 weeks of treatment; no significant difference was found in the degree of decline of plasma prolactin levels when subjects treated with ICI 204,636 and placebo were compared. A significant difference was found, however, between ICI 204,636- and chlorpromazine-treated subjects; prolactin levels in ICI 204,636-treated subjects fell to a greater degree than they did in chlorpromazine-treated subjects, however in all three trials, ICI 204,636 did not cause sustained elevation of prolactin.",1996.0,0,0
904,8927680,"A comparison of an atypical and typical antipsychotic, zotepine versus haloperidol in patients with acute exacerbation of schizophrenia: a parallel-group double-blind trial.",M Petit; J Raniwalla; J Tweed; E Leutenegger; S Dollfus; F Kelly,"The atypical antipsychotic zotepine was compared to haloperidol in 126 patients suffering from acute exacerbation of schizophrenia (DSM-III-R) in a randomized, double-blind study. After 8-weeks, 150 to 300 mg zotepine improved scores on the Brief Psychiatric Rating Scale (BPRS) more than 10 to 20 mg haloperidol (-17.03 versus -13.45; 95%CI for zotepine-haloperidol -9.34/2.04). BPRS subscores and Clinical Global impressions (CGI) Severity and improvement subscales showed comparable gains, but scores on the Scale for the Assessment of Negative Symptoms (SANS) improved significantly more with zotepine (-23.82) than haloperidol (-15.15; P < .05; 95%CI for zotepine haloperidol -18.03/-0.18). Adverse events were reported by 71 percent of zotepine and 78 percent of haloperidol patients. Extrapyramidal side effect (EPMS) scores decreased with zotepine (-0.34) but increased with haloperidol (+2.32; P < .05). Seven haloperidol patients reported akathisia but no zotepine patients did (p < .05). Uric acid reductions (which appear to have no clinical consequence) and transient raised liver enzymes were recorded with zotepine. Weight increased on zotepine (2.32 kg; P < .001) and a small increase in pulse rate occurred (P < .05). Both drugs were effective in reducing positive symptoms of schizophrenia; zotepine was significantly more effective against negative symptoms and reduced EPMS.",1996.0,0,0
905,8927681,Obsessive-compulsive symptoms in schizophrenia: a comparison of olanzapine and placebo.,R W Baker; D Ames; D S Umbricht; K N Chengappa; N R Schooler,"The antipsychotic drug olanzapine is similar to clozapine and risperidone in potent serotonergic antagonism. We assessed obsessive-compulsive symptoms during olanzapine treatment because these symptoms have been reported during risperidone and clozapine treatment. Obsessions and compulsions were measured in 25 subjects with schizophrenia before and after a 6-week double-blind trial comparing two olanzapine doses to placebo. At baseline, 8 subjects had mild or moderate obsessions, and 6 had mild compulsions. There was no significant difference in the course of obsessive-compulsive symptoms among the three treatment groups. We found that olanzapine did not appear to cause obsessive-compulsive symptoms in patients with schizophrenia. Our sample size, the dose and duration of olanzapine treatment, and assessment methods limit the extent to which this finding can be generalized. Though emerging obsessive-compulsive symptoms have been reported for 13 clozapine-treated and 2 risperidone-treated patients with schizophrenia, this phenomenon has not yet been demonstrated in a controlled study.",1996.0,0,0
906,8930967,Clozapine response and the 5HT2C Cys23Ser polymorphism.,A K Malhotra; D Goldman; N Ozaki; W Rooney; A Clifton; R W Buchanan; A Breier; D Pickar,"The presence of the 5HT2C receptor allele, Ser23, has recently been reported to predict favorable response to the antipsychotic drug, clozapine. This finding is of interest as Ser23, compared with the more abundant Cys23, alters pharmacological characteristics of the receptor and therefore may provide insights into the mechanism of action of antipsychotic drugs. We determined 5HT2C receptor genotype at the Cys23Ser locus in 66 subjects participating in double-blind studies of clozapine. There was no relationship between Ser23 and clozapine response (p = 0.30, Fisher's exact) nor was there any effect of Ser23 upon absolute levels of psychiatric symptoms after 10 weeks of clozapine treatment (t = -0.57, p = 0.57). These data suggest that this 5HT2C receptor polymorphism is not associated with clozapine response.",1996.0,0,0
907,8932891,"Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia.",U Heresco-Levy; D C Javitt; M Ermilov; C Mordel; A Horowitz; D Kelly,"It has been proposed that schizophrenia is associated with underactivity of brain glutamatergic neurotransmission, especially at the level of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Glycine potentiates NMDA receptor-mediated neurotransmission, indicating that it may serve as an effective therapeutic agent in the treatment of schizophrenia. Eleven treatment-resistant patients with chronic schizophrenia completed a double-blind, placebo-controlled, six-week, randomly assigned, crossover treatment trial of 0.8 g/kg body weight/day of glycine, added to their prior antipsychotic treatment. Glycine was well tolerated, resulted in significantly increased serum glycine levels and induced a mean 36 (7%) reduction in negative symptoms (P < 0.0001). Significant improvements were also induced in depressive and cognitive symptoms. The greatest reduction in negative symptoms was registered in the patients who had the lowest baseline serum glycine levels. These results extend previous findings and suggest an additional approach to the pharmacotherapy of negative symptoms and cognitive deficits in schizophrenia.",1996.0,0,0
908,8934152,Melperone in the treatment of iatrogenic psychosis in Parkinson's disease.,L Barbato; A Monge; F Stocchi; G Nordera,"The pharmacological management of Parkinson's disease (PD) can be complicated by psychiatric disorders induced by antiparkinsonian drugs. The reduction or withdrawal of levodopa (l-dopa) and other drugs commonly used in the treatment of PD may attenuate the psychosis but exacerbate motor impairment and disability. Melperone is an atypical antipsychotic drug showing in vivo a greater relative affinity for the 5-HT2 than the D2 receptors. A two-year study to assess the clinical efficacy and the safety of melperone in the management of iatrogenic psychosis in 30 parkinsonian patients was carried out. Neurological evaluation was performed with patients in the ""off"" and in the ""on"" state using the motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS). Time spent in ""on"" state was evaluated using the self-evaluation diary of daily life. To assess psychiatric disturbances the modified version of the Brief Psychiatric Rating Scale (BPRS) was used. The mean BPRS score was significantly reduced when comparing baseline with individual examinations; no statistically significant differences were found between subsequent examinations. UPDRS motor score and time spent in ""on"" state during daily life showed no statistically significant differences when comparing baseline with subsequent examinations. Two patients dropped out because of excessive sedation problems but in the remaining 28 patients melperone proved to be optimally tolerated.",1996.0,0,0
909,8935810,Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine--a 123I IBZM single photon emission tomography (SPET) study.,L S Pilowsky; G F Busatto; M Taylor; D C Costa; T Sharma; T Sigmundsson; P J Ell; V Nohria; R W Kerwin,"We have studied striatal D2 dopamine binding in schizophrenic patients treated with the novel atypical antipsychotic drug, olanzapine. 123I iodobenzamide (IBZM) single photon emission tomography (SPET) was used to estimate striatal dopamine D2 receptor binding in vivo. Patients were recruited from a prospective, double blind controlled trial of olanzapine versus haloperidol treatment. In vivo striatal D2 binding data from olanzapine treated patients (n = 6) were compared with previously reported data from typical antipsychotic responsive (n = 10); clozapine (n = 10); and risperidone (n = 6) treated patient groups. Mean % Brief Psychiatric Rating Scale score (BPRS) improvement following olanzapine treatment was 49% (SD 44). The hypothesis that clinical improvement in olanzapine treated patients would be associated with higher mean striatal D2 binding of 123I IBZM (reflecting lower levels of D2 occupancy) than typical antipsychotic (1.25 +/- 0.05) or risperidone (1.24 +/- 0.04) treatment was confirmed. Olanzapine treated patients had similar levels of striatal D2 binding in vivo (1.41 +/- 0.06) as those treated with clozapine (1.49 +/- 0.04). This preliminary evidence suggests olanzapine is another atypical antipsychotic drug in which therapeutic response is not associated with a high degree of striatal D2 receptor occupancy in vivo.",1996.0,0,0
910,8935812,"Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial.",C M Beasley; T Sanger; W Satterlee; G Tollefson; P Tran; S Hamilton,"Olanzapine is a potential new ""atypical"" antipsychotic agent. This double-blind, acute phase study compared two doses of olanzapine [1 mg/day (Olz1.0); 10 mg/day (Olz10.0)] with placebo in the treatment of 152 patients who met the DSM-III-R criteria for schizophrenia and had a Brief Psychiatric Rating Scale (BPRS)-total score (items scored 0-6) > or = 24. In overall symptomatology improvement [BPRS-total score and Positive and Negative Syndrome Scale (PANSS)-total score], Olz10.0 was statistically significantly superior to placebo. In positive symptom improvement (PANSS-positive score, BPRS-positive score), Olz10.0 was statistically significantly superior to placebo. In negative symptom improvement (PANSS-negative score), Olz10.0 was statistically superior to placebo. Olz 1.0 was clinically comparable to placebo in all efficacy comparisons. The only adverse event to show an overall statistically significant incidence difference was anorexia (reported for 10% of placebo-treated and 0% of Olz10.0-treated patients). The Olz10.0-treated patients improved over baseline with respect to parkinsonian and akathisia symptoms, and these changes were comparable with those observed with placebo. There were no dystonias associated with Olz10.0 treatment. At endpoint, the incidence of patients with elevated prolactin values did not differ statistically significantly between placebo-treated and Olz10.0-treated patients. Olanzapine appears to be not only safe and effective, but a promising atypical antipsychotic candidate.",2001.0,0,1
911,8935814,Relapse following clozapine withdrawal: effect of neuroleptic drugs and cyproheptadine.,H Y Meltzer; M A Lee; R Ranjan; E A Mason; P A Cola,"The objective of this study was to report the effect of the slow withdrawal of clozapine from 19 patients with neuroleptic-responsive schizophrenia at the end of a 2-year clinical trial of clozapine and to compare this with the results of naturalistic discontinuation of clozapine treatment in 64 neuroleptic-resistant schizophrenic patients. Nineteen neuroleptic-responsive schizophrenic patients who received clozapine were withdrawn from clozapine by tapering it over 3-week period with and without the addition of a typical neuroleptic. Fifteen of the 19 neuroleptic-responsive patients experienced the return of psychotic symptoms during or after the clozapine taper, which were most severe in the ten patients in whom the withdrawal of clozapine was carried out without prior addition of neuroleptic treatment. Addition of a neuroleptic prior to clozapine withdrawal prevented the emergence of positive symptoms during clozapine withdrawal in each of eight patients. Nevertheless, psychotic symptoms emerged, usually within a week after discontinuing clozapine, in six of the eight patients. Neuroleptic treatment, with or without an anticholingergic drug, was much less effective in treating positive symptoms in these patients immediately after the clozapine withdrawal than it had been 2 years previously. Cyproheptadine, a non-selective serotonin receptor antagonist, augmented the antipsychotic effect of neuroleptics in each of four patients who relapsed following withdrawal from clozapine and relieved extrapyramidal symptoms in a fifth patient. The frequency of relapse following withdrawal of clozapine in 64 neuroleptic-resistant patients was significantly lower (25/64, 39.1%) than in the neuroleptic-responsive patients.",1996.0,0,0
912,8935817,Does eosinophilia predict clozapine induced neutropenia?,M Hummer; B Sperner-Unterweger; G Kemmler; M Falk; M Kurz; H Oberbauer; W W Fleischhacker,The atypical antipsychotic clozapine carries a high risk of inducing agranulocytosis. We attempted to investigate whether eosinophilia during clozapine treatment has predictive value for subsequent neutropenia/agranulocytosis. One hundred and seventy-seven patients were studied in a prospective naturalistic design using haloperidol as the reference compound. Clozapine was found to differ from haloperidol in respect to their influence on neutrophil granulocytes. In the clozapine group patients with eosinophilia showed a decrease in neutrophil count (less than 2000/mm3 neutrophil granulocytes) significantly more often than patients without eosinophilia.,1996.0,0,1
913,8938913,Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal.,T M Shiovitz; T L Welke; P D Tigel; R Anand; R D Hartman; J J Sramek; N M Kurtz; N R Cutler,"Following the conduct of a 28-day inpatient bioequivalence study of clozapine in schizophrenia patients, withdrawal effects after abrupt discontinuation from clozapine were assessed. Thirty patients who met DSM-III-R criteria for schizophrenia, residual type, or schizophrenia in remission were enrolled in the study. Patients were evaluated for symptoms of withdrawal effects for 7 days after clozapine 200 mg/day was abruptly withdrawn. Of 28 patients who completed the study, 11 had no withdrawal symptoms; 12 had mild withdrawal adverse events of agitation, headache, or nausea; four patients experienced moderate withdrawal adverse events of nausea, vomiting, or diarrhea; and one patient experienced a rapid-onset psychotic episode requiring hospitalization. Cholinergic rebound is a likely explanation for the mild to moderate withdrawal symptoms and is easily treated with an anticholinergic agent. Mesolimbic supersensitivity, as well as specific properties of clozapine, are discussed as likely causes for rapidonset psychosis. Our findings are consistent with previous reports of withdrawal reactions associated with clozapine, further reminding clinicians to monitor patients closely following abrupt discontinuation of clozapine.",1996.0,0,0
914,8942454,Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges.,C VanderZwaag; M McGee; J P McEvoy; O Freudenreich; W H Wilson; T B Cooper,"This study sought to determine the relationships between serum clozapine levels and therapeutic response. Fifty-six inpatients who met the DSM-III-R criteria for chronic schizophrenia and who had not responded to extended treatment with classical antipsychotics were randomly assigned to 12 weeks of double-blind treatment with clozapine at one of three serum level ranges: low (50-150 ng/ml), medium (200-300 ng/ml), or high (350-450 ng/ml). Baseline clinical assessments were completed before the patients' regular antipsychotic and anticholinergic drugs were discontinued. During clozapine treatment, serum levels were ascertained weekly to allow adjustment of clozapine doses so as to maintain each patient near the midpoint of his or her assigned serum level range. Clinical assessments were completed after 6 and 12 weeks of treatment. The analyses of the results of treatment supported the superior efficacy of the 200-300 ng/ml and 350-450 ng/ml serum clozapine level ranges over the 50-150 ng/ml range, with no advantage for 350-450 ng/ml over 200-300 ng/ml. Sleepiness increased with increasing serum levels. Serum clozapine levels per unit of daily dose were at the lower end of the range noted in previous reports, possibly reflecting the current study's dosing schedules of twice or three times a day, the 11- to 13-hour postdose sampling time, and the moderate doses given. Serum clozapine levels, if interpreted in relation to daily clozapine dosing schedules, postdose sampling time, and total daily dose, may help to guide dosing to provide adequate opportunities for therapeutic response and to limit certain side effects of clozapine treatment.",1996.0,0,0
915,8942462,Fluoxetine augmentation of clozapine treatment in patients with schizophrenia.,R W Buchanan; B Kirkpatrick; N Bryant; P Ball; A Breier,"The authors examined the efficacy of fluoxetine augmentation of clozapine treatment response in schizophrenic outpatients who, despite adequate treatment with clozapine, continued to exhibit persistent positive or negative symptoms. Thirty-three patients completed on 8-week, double-blind, parallel-groups comparison of adjunctive fluoxetine and placebo. There were no significant differences in positive, negative, depressive, or obsessive-compulsive symptoms between patients given adjunctive fluoxetine or placebo. These results suggest that fluoxetine is not effective in augmenting clozapine treatment response.",1996.0,0,0
916,8942463,D-cycloserine added to clozapine for patients with schizophrenia.,D C Goff; G Tsai; D S Manoach; J Flood; D G Darby; J T Coyle,"The effects of D-cycloserine added to clozapine were assessed and compared with previous results for D-cycloserine plus conventional neuroleptics. Ten schizophrenic outpatients receiving clozapine entered consecutive 2-week trials of placebo and D-cycloserine at 5, 15, 50, and 250 mg/day. Clinical evaluations were videotaped and scored by a rater blind to the sequence of assessments. There was a significant dose effect of D-cycloserine on scores on the Scale for the Assessment of Negative Symptoms (SANS); the 50-mg dose produced a mean 21% increase in SANS score. The patients had significantly higher baseline serum glutamate concentrations than the patients receiving typical neuroleptics in the previous trial. Baseline glutamate level and change in glycine level significantly correlated with response of negative symptoms to 50-mg D-cycloserine. The improvement of negative symptoms with D-cycloserine previously observed in patients receiving typical neuroleptics did not occur in patients treated with clozapine.",1996.0,0,0
917,8956674,Childhood-onset schizophrenia. A double-blind clozapine-haloperidol comparison.,S Kumra; J A Frazier; L K Jacobsen; K McKenna; C T Gordon; M C Lenane; S D Hamburger; A K Smith; K E Albus; J Alaghband-Rad; J L Rapoport,"Childhood-onset schizophrenia is a rare but severe form of the disorder that is often treatment-refractory. In this study, the efficacy and adverse effects of clozapine and haloperidol were compared for children and adolescents with early-onset schizophrenia. Twenty-one patients (mean [+/-SD] age, 14.0 +/- 2.3 years) with onset of Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition-defined schizophrenia that began by age 12 years and who had been nonresponsive to typical neuroleptics participated in the study. Patients were randomized to a 6-week double-blind parallel comparison of clozapine (mean [+/-SD] final dose, 176 +/- 149 mg/d), or haloperidol, (16 +/- 8 mg/d). Clozapine was superior to haloperidol on all measures of psychosis (P = .04-.002). Positive and negative symptoms of schizophrenia improved. However, neutropenia and seizures were major concerns. To date, one third of the group has discontinued using clozapine. Clozapine has striking superiority for positive and negative symptoms in treatment-refractory childhood-onset schizophrenia. However, due to possibly increased toxic effects in this pediatric population, close monitoring for adverse events is essential.",1996.0,0,0
918,8959478,Effects of 'Seroquel' (quetiapine) on platelet serotonin-2 binding in schizophrenia.,W O Faustman; D L Ringo; J Lauriello; K O Lim; A Pfefferbaum,,1996.0,0,0
919,8984849,[Risperidone in the treatment of chronic schizophrenia: multicenter study comparative to haloperidol].,J J López Ibor; J L Ayuso; M Gutiérrez; J Guimon; M L Herraiz; A Chinchilla; J L Ayuso; A González Pinto; I Eguiluz; A Fernández,"This study was designed to compare the efficacy and safety of five different doses of risperidone with a fixed dose of haloperidol in patients with chronic schizophrenia. After a 1-week single-blind, placebo washout phase, 99 chronic schizophrenic patients were randomly assigned to double-blind treatment with 1, 4, 8, 12 or 16 mg risperidone or 10 mg haloperidol daily for 8 weeks. Efficacy was assessed throughout the study by the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, and Clinical Global Impression (CGI). Safety assessments included the Extrapyramidal Symptom Ratinf Scale (ESRS) UKU Side Effect Rating Scale, vital signs, body weight, ECG and laboratory screening. Risperidone had a bell-shaped dose-response curve, with optimal therapeutic responses occurring at a daily dose of 8 mg. The therapeutic response to haloperidol was similar to that seen with risperidone 16 mg. Risperidone was associated with significantly less extrapyramidal symptoms than haloperidol, as assessed by the ESRS. The effect was mirrored by the requirement for antiparkinson rescue medication. Furthermore, the overall incidence of adverse events was markedly lower with the optimum dose of risperidone than with haloperidol. Risperidone is at least as effective as haloperidol for the treatment of chronic schizophrenia. Moreover, risperidone is associated with an improved adverse event profile and significantly less extrapyramidal symptoms which will have beneficial implications on patient quality of life and compliance. These results are in agreement with the results from the international multicenter trial.",2001.0,0,0
920,8986313,Adjunctive loxapine in a clozapine-resistant cohort of schizophrenic patients.,S Mowerman; S G Siris,"The purpose of this trial was to assess the potential utility of adjunctive treatment with a typical neuroleptic for patients with refractory psychosis insufficiently responsive to clozapine alone. Seven chronic schizophrenic or schizoaffective patients who remained stabilized for at least 9 months on clozapine received open clinical trials with adjunctive loxapine lasting from 18 to 50 weeks. Their symptoms were documented with periodic Brief Psychiatric Rating Scale assessments. All patients improved at least somewhat and two improved remarkably. In the four cases in which the assessment was made, the loxapine had no apparent effect on plasma clozapine levels. We conclude that adjunctive treatment with typical neuroleptics for patients with an incomplete response to clozapine merits further investigation.",1996.0,0,0
921,8993078,Polypharmacy in bipolar I disorder.,D A Solomon; G I Keitner; C E Ryan; I W Miller,"There are currently three mood stabilizers available for the maintenance treatment of patients with bipolar I disorder: lithium, valproate, and carbamazepine. Unfortunately, monotherapy with each of these conventional agents often fails. To improve outcome, clinicians utilize polypharmacy. Although the efficacy of this practice is largely unknown, because of the lack of controlled studies, data from the United States and Europe indicate polypharmacy is the rule rather than the exception. The few controlled trials that have been conducted indicate that (1) the specific combination of lithium plus imipramine provides no advantage over lithium monotherapy (notwithstanding the inadequacy of lithium monotherapy); (2) the specific combination of lithium and the depot neuroleptic flupenthixol provides no advantage over lithium monotherapy; and (3) the combination of lithium plus carbamazepine may be as effective as lithium plus haloperidol for acute and continuation treatment. Most of the literature on polypharmacy consists of case reports, retrospective chart reviews, and open-label prospective studies, and describes the use of numerous combinations of medications, including lithium plus valproate, lithium plus carbamazepine, and valproate plus carbamazepine. Preliminary findings suggest these combinations may be effective, and that clozapine and high-dose levothyroxine may each be useful as well when combined with other drugs. Further research is necessary to formally evaluate whether these drug combinations are more effective than monotherapy. Until such studies are completed, certain general principles regarding side effects, pharmacodynamics, and pharmacokinetics should be kept in mind when prescribing two or more medications concurrently.",1996.0,0,0
922,8993091,Therapeutic effect and safety of adjunctive risperidone in refractory obsessive-compulsive disorder (OCD).,L Ravizza; G Barzega; S Bellino; F Bogetto; G Maina,"It has been well established that more than 40 percent of patients with obsessive-compulsive disorder (OCD) do not improve after an adequate trial with serotonin uptake inhibitors (SUIs). The first purpose of this trial was to compare the short-term efficacy and safety of two different strategies in a sample of treatment-refractory OCD patients: dose increase of the ongoing treatment versus the addition of another SUI. The second purpose was to investigate the short-term efficacy and safety of adjunctive risperidone in SUI-refractory OCD patients. Thirty-three OCD patients who were unimproved after a short-term treatment with clomipramine (150 mg/day) were admitted to the study. In the first part of the study, the dose increase of clomipramine was compared with sertraline addition, in an open-label manner. The addition of sertraline to the ongoing treatment appeared to be more effective and tolerable than the clomipramine dose increase. Seven (50%) of the 14 patients who were considered nonresponders after the first part of the study, showed good clinical improvement and good tolerability after risperidone augmentation. These results suggest that risperidone addition to ongoing SUIs may be useful in augmenting pharmacologic response in OCD.",1996.0,0,0
923,8993092,Clozapine's effectiveness for patients in state hospitals: results from a randomized trial.,S M Essock; W A Hargreaves; N H Covell; J Goethe,"In our study, we examined the effectiveness of clozapine and compared it to the array of medication alternatives typically used in the public sector. Long-term patients in Connecticut's state hospitals who met Food and Drug Administration criteria for clozapine use were invited to participate in this randomized open-label study. Participants (N = 227) were followed for 2 years. Compared with usual care, clozapine was associated with significantly greater reductions in side effects, disruptiveness, and hospitalization, but was not more effective in reducing symptoms or improving quality of life. The groups did not differ in likelihood of being discharged; however, once discharged, clozapine patients were less likely to be readmitted. The results of our study suggest that, compared with the flexible range of medication alternatives available, clozapine is an effective agent. However, at least with this patient population, clozapine did not produce the dramatic improvements is symptomatology or hospital utilization reported in clinical efficacy trials or suggested by mirror-image studies.",1996.0,0,1
924,8993093,Longitudinal analysis of abnormal involuntary movements in long-term clozapine-treated patients.,M T Bunker; R W Sommi; S C Stoner; J L Switzer,"As part of a prospective efficacy and safety monitoring system, patients receiving clozapine are assessed monthly for dyskinetic events (DE), using the Abnormal involuntary Movement Scale (AIMS). Longitudinal analysis of 45 patients revealed 20 with baseline DE, 7 who developed emergent DE after a negative baseline assessment, and 18 patients with no DE symptoms throughout treatment with clozapine. Eight of the 20 patients with baseline DE were assessed to resolution of symptoms, with an average time of 261 +/- 188 days; 5 were evaluated until complete resolution of symptoms (AIMS = 0), with an average time of 691 +/- 462 days. The average time to onset of DE in emergent DE patients was 238 +/- 179 days, and the average time to resolution was 347 +/- 179 days after diagnosis. Four patients attained complete resolution with an average time of 629 +/- 293 days after diagnosis. It appears this emergent type of dyskinesia is different from other currently described dyskinesias. Overall, of the 27 patients having DE at any point in treatment, 15 of 27 (56%) had resolution of symptoms and 10 of 27 (37%) had complete resolution of DE. Clinicians should be aware of the utility of clozapine in dyskinesia and the extended time frame of response.",1996.0,0,1
925,8998394,Weight gain induced by clozapine.,M Hummer; G Kemmler; M Kurz; I Kurzthaler; H Oberbauer; W W Fleischhacker,"Patients were investigated to gain more insight into the incidence and time course of clozapine induced weight gain (n = 81) and to compare weight gain in patients treated with clozapine (n = 31) with that of patients treated with standard antipsychotics (haloperidol, n = 11). 35.7% of the patients treated with clozapine gained weight according to our definition. If patients gained weight on clozapine this side effect was apparent within the first 12 weeks of treatment. Deviation from normal body weight at the beginning of treatment showed a significant influence on weight gain. Sex, severity of illness, comedication, mean clozapine dose and degree of improvement did not show an influence on this side effect. Weight increase was significantly higher in patients treated with clozapine than in patients treated with haloperidol.",1995.0,1,1
926,9004057,The effects of clozapine on symptom clusters in treatment-refractory patients.,G Abraham; C Nair; J I Tracy; G M Simpson; R C Josiassen,"Preliminary results of a double-blind clozapine study in a population of chronic psychotic patients at a state psychiatric facility are reported. Thirty ""treatment-refractory"" schizophrenic patients given a diagnosis according to DSM-III-R criteria (mean age of 44 +/- 9.1 years and a duration of illness of 24.9 +/- 8.8 years) who received 300 mg or 600 mg of clozapine and randomized in a double-blind fashion were analyzed. Subjects were evaluated using the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Impression (CGI) Scale on a weekly basis for 16 weeks. Based on the changes in their CGI scores at week 16 of clozapine treatment, subjects were retrospectively categorized as ""improvers"" (N = 12) and ""nonimprovers"" (N = 18). The two groups were compared for changes in total BPRS and BPRS factor scores. In terms of total BPRS scores, we expected a difference between the two groups because they were categorized based on changes in their CGI scores. However, the total BPRS scores in improvers showed a significant decrease by week 6 of clozapine treatment. On analyzing the four BPRS factors, the improvers showed improvement in the thinking disturbance factor by week 1 that remained steady from week 7. On the hostility-suspiciousness factor, the improvers showed an improvement across time when compared with nonimprovers. The withdrawal-retardation factor showed improvement in both groups across time, whereas the anxiety-depression factor was least influenced by clozapine. These observations suggested that all BPRS symptom factors did not uniformly contribute to improvement in overall psychopathology, which was observed as a decrease in total BPRS scores.",1997.0,0,0
927,9004341,"Clozapine eligibility: the effect of stringent criteria on ethnic, gender and age subgroups of schizophrenic patients.",M G Juarez-Reyes; M Shumway; C Battle; P Bacchetti; M S Hansen; W A Hargreaves,"1. The purpose of this retrospective chart review study was to determine whether broad and stringent criteria differentially impact clozapine eligibility in ethnic, gender, and age subgroups of schizophrenic patients. 2. 505 patients charts were selected from a random cluster sample of mental health patients known to the city and county of San Francisco. Information related to clozapine eligibility was abstracted by trained non-clinical personnel. The impact of subgroup membership on eligibility was examined using logistic regression procedures. 3. Even under the broadest interpretation of FDA requirements for clozapine use, Asian patients were less likely to be eligible, since fewer Asian patients met clozapine treatment requirements. Under more stringent eligibility criteria, older patients were more likely to be excluded from eligibility when TD does not automatically satisfy treatment criteria, and younger patients were more likely to lose eligibility if the number of required adequate medication trials increases to three. 4. Broad eligibility criteria tend to differentially exclude Asian patients while more stringent criteria differentially exclude younger and older patients.",1996.0,0,0
928,9010121,Predictive value of eosinophilia for neutropenia during clozapine treatment.,D Ames; W C Wirshing; R W Baker; D S Umbricht; A B Sun; J Carter; N R Schooler; J M Kane; S R Marder,Myelotoxicity continues to hinder the widespread use of clozapine in the United States. It has been theorized that eosinophilia predicts later agranulocytosis and that agranulocytosis occurs due to an immunologic mechanism. Our study compares the rates of these dyscrasias in clozapine-treated patients and a control group. Forty-one patients taking clozapine and 29 patients taking haloperidol were monitored for a period of 6 months. Rates of eosinophilia and neutropenia were compared between the two treatment groups. Treatment-emergent eosinophilia occurred frequently in both haloperidol- and clozapine-treated patients. No significant difference was seen between groups in the incidence of eosinophilia and neutropenia. We find no statistical difference between the rates of eosinophilia or neutropenia in haloperidol- and clozapine-treated patients. This study does not support the use of eosinophilia as a reliable predictor of neutropenia.,1996.0,0,0
929,9061775,Blood levels of reduced haloperidol versus clinical efficacy and extrapyramidal side effects of haloperidol.,H Y Lane; H N Lin; O Y Hu; C C Chen; M W Jann; W H Chang,"1. The studies of relationships between blood levels of reduced haloperidol HL (RH) and clinical efficacy in haloperidol (HL)-treated patients have yielded variable results. On the other hand, the contribution of RH upon HL's extrapyramidal side effects (EPS) had been suggested in animal models as well as in preliminary clinical studies with limited subjects. 2. This study explored the relationships between blood drug levels and clinical effects and EPS of HL in 48 Chinese acutely exacerbated schizophrenic inpatients. After a single-blind placebo period of one week, the patients were treated with a fixed dose 10 mg of HL for two weeks. Steady-state levels of HL and RH in plasma (n = 48) and in red blood cells (RBC) (n = 37) were measured by high performance liquid chromatography. 3. The mean RH/HL ratio in RBC in the Chinese (0.55) is lower than that in non-Chinese patients as reported in the literature (> 2), so is the RH/HL ratios in plasma. 4. No significant relationship emerged between percent improvement in BPRS total score and any of drug indices (HL, RH, sum of two compounds (HL+RH), and RH/HL ratio) in plasma and in RBC. Furthermore, the responders did not differ significantly from the nonresponders in each drug index. 5. Plasma RH levels were significantly higher in 30 patients experiencing EPS compared with the other 18 patients (mean 2.14 +/- 1.71 (S.D.) ng/ml vs. 1.38 +/- 0.37 ng/ml, p < 0.05). No significant differences in other drug indices were noted between subjects with or without EPS.",1997.0,0,0
930,9087885,Neural network based on adaptive resonance theory as compared to experts in suggesting treatment for schizophrenic and unipolar depressed in-patients.,I Modai; A Israel; S Mendel; E L Hines; R Weizman,"A modified neural network based on adaptive resonance theory (ART) was trained with the records of 211 psychiatric inpatients (74 schizophrenic, 50 unipolar depressed, 34 bipolar depressed, 20 bipolar manic, 33 other) who improved by at least 40 points on the GAFS during 8 weeks of treatment. Thereafter, a comparison was made between the clinical response of another 26 schizophrenic patients and 28 unipolar depressed inpatients, to treatment suggested by the trained ART (N = 21) and by the consensus of two senior psychiatrists (N = 33). The patients were allocated blindly and randomly to the two treatment groups. The BPRS (for the schizophrenic patients) or the HDRS (for the unipolar depressed patients) was completed weekly for 5 weeks. Results showed no difference between decisions regarding treatment by the ART network and by the experts. Length of hospital stay was also similar. All ART suggestions included supportive psychotherapy. High potency antipsychotics were suggested for 7 schizophrenic inpatients, clozapine for one and the addition of community therapy for another. Depressed patients got a variety of treatment suggestions. No contraindicated treatment was suggested by ART; however, two incomplete treatment suggestions were dropped from the study. In conclusion, in a prospective study ART was successful in learning treatment strategies and performed under supervision similar to experts.",1996.0,0,0
931,9090331,Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial.,G D Tollefson; C M Beasley; P V Tran; J S Street; J A Krueger; R N Tamura; K A Graffeo; M E Thieme,"This international, multicenter double-blind trial was designed to compare the therapeutic profile of an atypical antipsychotic, olanzapine, with that of a conventional dopamine D2 antagonist, haloperidol. A total of 1,996 patients at 174 sites in Europe and North America were randomly assigned to treatment with olanzapine (N = 1,336) or haloperidol (N = 660) over 6 weeks. The primary efficacy analysis involved the mean change from baseline to endpoint in total scores on the Brief Psychiatric Rating Scale (BPRS). Secondary analyses included comparisons of the mean change in positive and negative symptoms, comorbid depression, extrapyramidal symptoms, and overall drug safety. Olanzapine demonstrated clinical results superior to those of haloperidol on overall improvement according to the BPRS and on every secondary measure, including depression. Olanzapine was also associated with significantly fewer discontinuations of treatment due to lack of drug efficacy or adverse events. Substantially more olanzapine-treated patients (66.5%) than haloperidol-treated patients (46.8%) completed 6 weeks of therapy. Statistically significant advantages of olanzapine treatment were related to 1) change in negative symptoms, 2) extrapyramidal symptom profile, 3) effect on prolactin levels, and 4) response rate. Olanzapine shows a superior and broader spectrum of efficacy in the treatment of schizophrenic psychopathology, with a substantially more favorable safety profile, than haloperidol. It meets several of the criteria for a novel atypical antipsychotic agent.",2001.0,1,1
932,9090332,"Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine.",G D Tollefson; T M Sanger,"The authors investigated whether primary negative symptoms of schizophrenia are enduring or treatment-responsive. Previously, a double-blind, random-assignment trial of the novel antipsychotic olanzapine (in low, medium, and high dose ranges), placebo, or haloperidol (10-20 mg/day) for 335 schizophrenic inpatients was conducted for up to 52 weeks. Changes in the treatment groups from baseline to endpoint in summary scores on the Scale for the Assessment of Negative Symptoms (SANS) and several secondary measures were compared. This article describes a path analysis to determine to what extent the total treatment effect on negative symptoms was direct or indirect (i.e., mediated by differential effects on positive symptoms, extrapyramidal symptoms, or mood). Significantly greater improvement was achieved with high-dose olanzapine than with placebo or haloperidol. Olanzapine had a significantly greater direct effect than placebo on all SANS dimensions except anhedonia-asociality. Olanzapine also demonstrated a significantly greater direct effect than haloperidol on negative symptoms, especially on the dimensions of affective flattening and avolition-apathy. Olanzapine's superior effects were replicated in a subgroup with SANS-defined prominent negative symptoms (N = 116) and a subgroup with a BPRS-defined cross-sectional proxy for the deficit state (N = 117). These results suggest that the negative symptoms of schizophrenia are directly responsive to treatment. The significantly greater direct and indirect effects of olanzapine than of haloperidol on negative symptoms are likely related to olanzapine's pleotrophic pharmacology, which includes dopaminergic, serotonergic, muscarinic, and adrenergic activities. The results contribute to the hypothesis that negative symptoms may be under the influence of several neurotransmitters within one or more neuroanatomic circuits.",1997.0,0,0
933,9097896,Risperidone in the treatment of schizophrenia: a meta-analysis of randomized controlled trials.,F Song,"This study evaluates the relative effectiveness and side-effects of risperidone as compared with conventional neuroleptics in the treatment of schizophrenia, by meta-analysis of 11 double-blind, randomized controlled trials. The proportion of patients showing clinical improvement; use of medications for extrapyramidal side-effects (EPS); the treatment drop-out rates; and the changes in negative PANSS scores were measured. Compared with conventional neuroleptics, slightly more patients in the risperidone group showed clinical improvement [57 vs 52%; odds ratio 1.27, 95% confidence interval (CI): 1.04, 1.56]. The use of concomitant medications for EPS was significantly less in the risperidone group than in the conventional neuroleptic group (22.8 vs 38.4%; odds ratio 0.51, 95% CI: 0.41, 0.63). The overall drop-out rate was lower in the risperidone group than in other neuroleptic group (29.1 vs 33.9%; odds ratio 0.75, 95% CI: 0.61, 0.94). The difference in changes in negative PANSS score between the risperidone and the haloperidol group was -0.74 (95% CI: -1.50, 0.02). Weight gain and tachycardia are more common in patients treated with risperidone. Sensitivity analysis of different analytic approaches did not materially change the main estimates. It was concluded that the short-term efficacy of risperidone is comparable to other neuroleptics in the treatment of schizophrenia. It is associated with significantly fewer EPS than conventional neuroleptics (mainly haloperidol).",1997.0,0,0
934,9106913,,,,,0,0
935,9108812,Clozapine and associated diabetes mellitus.,A P Popli; P E Konicki; G J Jurjus; M A Fuller; G E Jaskiw,"Clozapine is an effective therapy for the treatment of refractory psychosis. Clozapine-associated adverse effects include sedation, weight gain, sialorrhea, palpitations, seizures, and hematologic changes such as agranulocytosis. We present a four-case series in which clozapine use was associated with either a de novo onset or severe exacerbation of preexisting diabetes mellitus. The change in glycemic control was not significantly related to weight gain. Three of the patients have been able to continue on clozapine therapy and have experienced a reduction in psychotic symptoms. Patients with a family history of diabetes mellitus or with preexisting diabetes mellitus may need to have blood sugar monitored closely during initiation of clozapine treatment.",1997.0,0,0
936,9109179,Prediction of short-term changes in symptom severity by baseline plasma homovanillic acid levels in schizophrenic patients receiving clozapine.,T Sumiyoshi; M Hasegawa; K Jayathilake; H Y Meltzer,"The relationship between pretreatment levels of plasma homovanillic acid (pHVA) and the outcome of clozapine treatment was studied in 18 male patients with schizophrenia who were resistant to treatment with conventional neuroleptics. After 6 months of clozapine treatment, 7 patients demonstrated > or = 20% decrease in the Brief Psychiatric Rating Scale (BPRS) (responders), while 11 patients did not (non-responders). Responders and non-responders did not differ with respect to the baseline pHVA level. The BPRS Positive Symptom scores at 6 weeks and 3 months, but not those at baseline and 6 months, following initiation of clozapine treatment negatively correlated with pHVA levels for all patients. The correlations became stronger when only responders were included. No significant correlation between Positive Symptom scores and pHVA levels was observed for non-responders. The BPRS Total and Negative Symptom scores did not correlate with pHVA for all patients, responders or non-responders at any time. The percent decrease in the BPRS Positive Symptom scores from baseline at 6 weeks following clozapine treatment correlated significantly with pHVA levels in responders. These results suggest that pretreatment levels of pHVA can be used to predict relatively short-term changes in the positive symptoms of patients with schizophrenia receiving clozapine treatment, particularly for clozapine responders.",1997.0,0,0
937,9109903,Benztropine versus clozapine for the treatment of tremor in Parkinson's disease.,J H Friedman; W C Koller; M C Lannon; K Busenbark; E Swanson-Hyland; D Smith,"Four open-label studies have reported beneficial effects of clozapine on the tremor of idiopathic Parkinson's disease (PD). We performed a double-blind crossover trial with a 2-week washout, comparing low-dose clozapine to benztropine for the treatment of tremor in PD. Twenty-two subjects enrolled and 19 completed the study. Benztropine and clozapine were equally effective in improving tremor and the motor score of the United Parkinson's Disease Rating Scale at mean doses of 3.0 and 39 mg/day, respectively. Significant adverse events were experienced with each drug, but leukopenia was not encountered. We conclude that the atypical antipsychotic drug clozapine is helpful in the treatment of tremor in PD and should be considered when all other drug therapies fail.",1997.0,0,0
938,9117479,Effects of switching inpatients with treatment-resistant schizophrenia from clozapine to risperidone.,D J Still; P G Dorson; M L Crismon; C Pousson,"A prospective, open-label study in a 400-bed state psychiatric hospital evaluated change in therapeutic response among ten patients with treatment-resistant schizophrenia who were switched from clozapine to risperidone. Drug effects were examined before discontinuation of clozapine and at three, six, nine, and 12 weeks of risperidone treatment. No patients improved, and five discontinued treatment due to exacerbation of psychosis or adverse effects. Changes in scores on the Positive and Negative Syndrome Scale, the Brief Psychiatric Rating Scale, and the Barnes Akathisia Scale indicated clinically significant worsening of symptoms. The findings do not support replacing clozapine with risperidone for patients with treatment-resistant schizophrenia.",1996.0,0,0
939,9133768,An open clinical trial of risperidone monotherapy in young children with autistic disorder.,R L Findling; K Maxwell; M Wiznitzer,"Autistic disorder (AD) may be associated with dysfunctional behaviors which significantly interfere with a child's functioning. Risperidone has been described as having salutary effects as an adjunctive pharmacotherapy in adult and pediatric patients with AD. The purpose of this 8-week, open-label study was to examine the effectiveness and tolerability of risperidone monotherapy in young patients with AD. Doses of risperidone were to be started at 0.25 mg qhs and were titrated to maximize clinical efficacy. Six patients (ages 5 to 9 years) were enrolled in this protocol, and all completed it. After 8 weeks of treatment, with a mean risperidone dose of 1.1 mg, improvement in symptomatology was demonstrated by reduced scores on both the Children's Psychiatric Rating Scale (p < .005) and the Clinical Global Impressions Scale (p < .001). The most common side effect were weight gain and sedation. This study provides preliminary evidence that risperidone monotherapy may be safe and effective in ameliorating dysfunctional behaviors in children with AD.",1997.0,0,1
940,9133772,"Substance abuse as a risk factor for tardive dyskinesia: a retrospective analysis of 1,027 patients.",L G Bailey; S Maxwell; M M Brandabur,"Tardive dyskinesia (TD) affects between 10 and 50 percent of all patients on long-term antipsychotic therapy, depending on the population studied. Various risk factors for TD have been reported; a correlation between TD and substance abuse has been suggested in some reports and not found in others. This study analyzes the association of substance abuse with the incidence of tardive dyskinesia in a schizophrenic population. All patients at the West Side Veterans Affairs Medical Center are evaluated prior to the initiation of neuroleptic therapy with the Dyskinesia identification System: Condensed User Scale (DISCUS); those with a diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder during the years 1986 through 1993 were included in this analysis. History of substance abuse was considered positive if there was clinician report or diagnosis of substance abuse. These data were collected and analyzed using ANOVA. In a sample of 1,027 subjects (97% male), 83.2 percent had a neuroleptic exposure of 10 or more years, and slightly more than half (50.8 percent) had a positive history of substance abuse. Using research diagnostic criteria, 28.9 percent of the sample had tardive dyskinesia. Analysis of variance showed history of substance abuse (p < .000) and years on neuroleptics (p < .000) to be strongly correlated to a diagnosis of TD. Age was less strongly correlated to the DISCUS score (p < .01), and there was no association of TD with diagnosis (p = .237). This study therefore demonstrates a robust correlation between TD and substance abuse. A mechanism of action involving N-methyl-D-aspartate (NMDA)-mediated excitotoxicity is proposed.",1997.0,0,1
941,9138438,Adverse effects of risperidone on eye movement activity: a comparison of risperidone and haloperidol in antipsychotic-naive schizophrenic patients.,J A Sweeney; K S Bauer; M S Keshavan; G L Haas; N R Schooler; P D Kroboth,"Risperidone is a novel and clinically effective atypical antipsychotic medication with a unique biochemical profile. To contrast the neurophysiological effects of this new medication with those of a typical antipsychotic medication, we performed quantitative measurements of saccadic eye movements in a series of antipsychotic-naive schizophrenic patients treated with either risperidone or haloperidol. Patients were tested before and after 1 month of treatment, and a matched group of healthy subjects was tested twice over a similar time interval. Risperidone, but not haloperidol, was associated with prolonged latency and decreased peak velocity and accuracy of saccadic eye movements that was detectable 4 weeks after treatment initiation. The adverse effects of risperidone may be due to the lack of development of acute tolerance to its powerful serotonergic (5-HT2A) antagonism, which could be responsible for the disruption of brainstem physiology in regions controlling saccadic eye movements.",1997.0,0,1
942,9154588,Antipsychotic treatment in outpatients with dementia.,D P Devanand,,1996.0,0,0
943,9154590,Nursing home research from industry's perspective.,M Brecher,,1996.0,0,0
944,9156369,New dimensions in the pharmacologic treatment of schizophrenia and related psychoses.,P F Buckley,"During the past 5 years unprecedented advances have taken place in the psychopharmacology of schizophrenia and related psychoses. Clozapine and risperidone, two prototypic novel antipsychotic drugs, have had a significant impact on the treatment of psychotic disorders. Additionally, they have ushered in another generation of antipsychotic drugs with complex pharmacologic profiles, potentially enhanced efficacy, and more benign side-effect profiles than previously associated with conventional antipsychotic medications. This review highlights these developments, implications for the management of psychotic disorders, and the use of novel antipsychotic drugs in specific clinical subgroups.",1997.0,0,0
945,9165565,Risperidone: effects of formulations on oral bioavailability.,R Gutierrez; P I Lee; M L Huang; R Woestenborghs,"The bioavailability of risperidone was evaluated in an open-label, randomized, two-way, crossover study comparing a 1-mg tablet with a 1-mg/ml oral solution. Both formulations were administered as a single 1-mg dose with a 10-day washout period between treatments. Of 26 healthy men who entered the study, 23 completed both treatment periods. Plasma concentrations of risperidone and the active moiety (risperidone plus its active metabolite, 9-hydroxyrisperidone) were determined by radioimmunoassays. For key pharmacokinetic values (Cmax, AUC), the 90% CIs on the relative bioequivalence of risperidone, 9-hydroxyrisperidone, and the active moiety were contained within the equivalence range of 80-120% (80-125% for log-transformed data). The results demonstrate that the 1-mg/ml oral solution and the 1-mg tablet are bioequivalent.",1997.0,0,0
946,9167506,"Relapse in young paranoid schizophrenic patients: a prospective study of stressful life events, P300 measures, and coping.",S Pallanti; L Quercioli; A Pazzagli,"The authors investigated the relationship of cognitive and coping characteristics to stressful life events at the time of relapse in patients with recent-onset paranoid schizophrenia. Over 6 years, the authors collected data on 41 schizophrenic outpatients aged 18-28 years at recruitment. The patients were rated prospectively every 2 weeks with the Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Scale for the Assessment of Positive Symptoms, Global Assessment of Functioning Scale, and life events measures. The Frankfurt Questionnaire of Complaints was used to analyze subjective complaints regarding cognitive and coping abilities. The P300 auditory event-related potential was measured at recruitment to provide an index of information-processing capability. Patients without severe life events during the 1 month before relapse had a smaller P300, more subjective complaints, and less coping capacity than did relapsed schizophrenic subjects who had severe life events in the month before relapse. Relapses in subjects without severe life events were associated with fewer cognitive resources and less coping ability. Patients with normal P300 and adequate coping resources seemed to be able to deal better with stressful life events.",1997.0,0,1
947,9167507,Does risperidone improve verbal working memory in treatment-resistant schizophrenia?,M F Green; B D Marshall; W C Wirshing; D Ames; S R Marder; S McGurk; R S Kern; J Mintz,"Treatment efficacy in schizophrenia is typically defined in terms of symptom reduction. However, new antipsychotic medications could potentially have an impact on aspects of disability, such as neurocognitive deficits. The authors evaluated the effects of risperidone on verbal working memory, a memory component of theoretical interest because of its link to prefrontal activity and of practical interest because of its link to psychosocial rehabilitation. Verbal working memory of 59 treatment-resistant schizophrenic patients was assessed as part of a randomized, double-blind comparison of treatment with risperidone and haloperidol. Verbal working memory was measured under both distracting and nondistracting conditions at baseline and after 4 weeks of both fixed- and flexible-dose pharmacotherapy. Risperidone treatment had a greater beneficial effect on verbal working memory than haloperidol treatment across testing conditions (with and without distraction) and study phases (fixed and flexible dose). The treatment effect remained significant after the effects of benztropine cotreatment, change in psychotic symptoms, and change in negative symptoms were controlled. Neither benztropine status nor symptom changes were significantly related to memory performance. Treatment with risperidone appears to exert a more favorable effect on verbal working memory than treatment with a conventional neuroleptic. The beneficial effect appears to be due, at least partially, to a direct effect of the drug, possibly through antagonism of the 5-HT2A receptor. Results from this study suggest that pharmacotherapeutic efficacy in schizophrenia treatment could be broadened to include impact on neurocognitive abilities.",2001.0,1,1
948,9169300,Olanzapine versus haloperidol: acute phase results of the international double-blind olanzapine trial.,C M Beasley; S H Hamilton; A M Crawford; M A Dellva; G D Tollefson; P V Tran; O Blin; J N Beuzen,"A 6-week acute phase of an international 1-year double-blind study was conducted comparing three dose ranges of olanzapine (5 +/- 2.5 mg/day, 10 +/- 2.5 mg/day, and 15 +/- 2.5 mg/day) with a fixed dose of olanzapine (1.0 mg/day) and with a dose range of haloperidol (15 +/- 5 mg/day) in the treatment of 431 patients with schizophrenia. The purpose was to determine whether olanzapine demonstrated a dose-related ability to decrease overall psychopathology with minimal associated extrapyramidal symptoms in patients with schizophrenia. The high-dose olanzapine group showed statistically significantly greater improvement in overall psychopathology based on mean change in the CGI Severity score and statistically significantly greater improvement in positive psychotic symptoms based on mean change in both the BPRS positive score and the PANSS positive score compared with the 1.0-mg/day olanzapine group. Analyses indicated that an increasing dose-response curve was observed across the range of all olanzapine dose groups. Acute extrapyramidal syndromes were reported less frequently among all olanzapine groups compared with the haloperidol group. Endpoint mean change on both the Simpson-Angus Scale and the Barnes Akathisia Scale reflected improvement for all olanzapine treatment groups compared with worsening for the haloperidol group. Olanzapine was associated with weight gain but did not appear to have any clinically meaningful effect on vital signs. Although olanzapine was associated with some increase in prolactin concentrations, increases were transient, occurred less often, and were of lesser magnitude than those observed with haloperidol.",2001.0,0,1
949,9169965,Extrapyramidal symptoms in patients treated with risperidone.,G M Simpson; J P Lindenmayer,"Data on extrapyramidal symptoms (EPS) from both arms of the North American multicenter comparative study of risperidone, placebo, and haloperidol were analyzed. The subjects were 523 patients with chronic schizophrenia who, after a 1-week washout period, received placebo, risperidone (2, 6, 10, or 16 mg/day), or haloperidol (20 mg/day) for 8 weeks; the trial was completed by 253 patients. Severity of EPS was assessed by means of the Extrapyramidal Symptom Rating Scale (ESRS). Mean changes (increases) in ESRS scores from baseline to worst score were significantly lower in each risperidone group than the haloperidol group on the total ESRS (parkinsonism + dystonia + dyskinesia), total parkinsonism, hypokinetic symptoms, and on the questionnaire (p < 0.001). On several of the subscales (dyskinesia, buccolinguomasticatory, and Clinical Global Impression severity of dyskinesia), mean change scores were significantly lower in some of the risperidone groups than in the placebo group (p < 0.05). At the clinically most effective risperidone dose (6 mg/day), the mean ESRS change score was not significantly different from that of the placebo group. A significant linear relationship was noted between mean change scores and increasing risperidone dose on 4 of the 12 ESRS subscales; nevertheless, even at 16 mg/day of risperidone, mean change scores were lower than in the haloperidol group. A linear relationship between increasing risperidone dose and use of antiparkinsonian medications was also apparent. Acute dystonic reactions occurred both in patients receiving risperidone and haloperidol. Patients with severe baseline EPS were at higher risk of EPS during the study than patients with low or moderate baseline EPS. It is concluded that low doses of risperidone cause few or no EPS and recommendations for initiation of risperidone treatment are made.",1997.0,0,1
950,9179524,Drug treatment of schizophrenia in the 1990s. Achievements and future possibilities in optimising outcomes.,W W Fleischhacker; M Hummer,"The current state of the art of the pharmacological treatment of schizophrenia, and a review of the latest findings in antipsychotic drug development are presented. A first step in optimising treatment is an increase in the awareness and implementation of existing treatment standards. The introduction of clozapine challenges the view that all antipsychotics are of similar efficacy; the drug has an established superiority over some of the traditional antipsychotics in treatment-resistant patients. Newer agents such as zotepine, risperidone, quetiapine, olanzapine and sertindole, which have a lower risk of producing extrapyramidal motor symptoms, have been developed in the wake of clozapine. While it is still common to switch nonresponding patients to an antipsychotic of a different chemical class, clozapine treatment remains the only strategy based on sound scientific evidence in these patients, although the novel antipsychotics give rise to hope. Alternatively, combination treatment with benzodiazepines, lithium or an anticonvulsant has been employed. If treatment with a depot antipsychotic is planned, it is advisable to start a patient on the oral form of the same drug in order to obtain dose requirements and tolerability information of the drug in that patient. Long term maintenance therapy is crucial and continuous monitoring for the development of adverse effects essential.",1997.0,0,0
951,9179630,Depression in the community: the first pan-European study DEPRES (Depression Research in European Society).,J P Lépine; M Gastpar; J Mendlewicz; A Tylee,"DEPRESS (Depression Research in European Society) is the first large pan-European survey of depression in the community. A total of 13359 of the 78463 adults who participated in screening interviews across six countries were identified as suffering from depression, a 6-month prevalence of 17%. Major depression accounted for 6.9% of the cases of depression and minor depression for 1.8%. Depressed subjects in both these categories perceived that their working or social lives were substantially impaired by depressive symptoms. The remaining 8.3% of depressed subjects considered that their functional impairment was not substantial. A significant proportion of sufferers from depression (43%) failed to seek treatment for their depressive symptoms. Of those who did seek help (57%), most consulted a primary care physician, the frequency of consultation increasing with the severity of depression. Sufferers from major depression imposed the greatest demand on healthcare resources, making almost three times as many visits to their GP or family doctor as non-sufferers (4.4 vs 1.5 visits over 6 months). More than two-thirds of depressed subjects (69%) were not prescribed any treatment and when drug therapy was prescribed (31%), only 25% of these subjects were given antidepressant drugs. The number of days of work lost due to illness increased with the severity of depression. Major depression had most impact on productive work, with sufferers losing four times as many working days over 6 months as non-sufferers. The results of the DEPRES survey confirm the high prevalence of depression in the community and the burden imposed on the individual sufferer in terms of impaired quality of life and on society in terms of healthcare utilization and lost productivity.",1997.0,0,0
952,9184614,Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the acute treatment of schizophrenia.,P V Tran; M A Dellva; G D Tollefson; C M Beasley; J H Potvin; G M Kiesler,"A relative lack of extrapyramidal symptoms (EPS, i.e., the syndromes of dystonia, parkinsonism, akathisia, dyskinesia) is one criterion used to determine whether an antipsychotic is ""atypical."" The extrapyramidal symptom profiles of the novel antipsychotic olanzapine and the conventional antipsychotic haloperidol were compared in a population of 2606 patients from three well-controlled prospective clinical trials. Extrapyramidal symptom data were analyzed for 1796 patients treated with olanzapine (5 to 20 mg/day) and 810 patients treated with haloperidol (5 to 20 mg/day) for up to 6 weeks of therapy. Patients were monitored weekly by three methods of extrapyramidal symptom assessment: (1) detection of extrapyramidal adverse events (signs and symptoms) by casual observation, nonprobing inquiry, and spontaneous report; (2) objective rating scale scores: and (3) use of concomitant anticholinergic medications. Emergence of EPS was assessed by (1) analysis of the incidence of extrapyramidal syndrome categories based on adverse events, (2) the incidence of extrapyramidal syndromes based on categorical analysis of rating scale scores, (3) analysis of mean maximum change in rating scale scores, and (4) categorical analysis of anticholinergic medication use. Outcome of EPS was assessed by (1) analysis of mean change in rating scale scores at endpoint and (2) mean anticholinergic use at endpoint. Olanzapine was statistically significantly (p = .014, p < .001) superior to haloperidol in all four analyses related to emergence of EPS and in the two analyses related to outcome. Furthermore, during acute treatment, statistically significantly fewer patients treated with olanzapine (0.3%) discontinued the study because of any extrapyramidal adverse event than patients treated with haloperidol (2.7%, p < .001). Olanzapine exhibited a statistically significantly lower extrapyramidal symptom profile than the conventional antipsychotic haloperidol at comparably effective antipsychotic doses. The lower extrapyramidal symptom profile with olanzapine was evident despite statistically significantly more frequent use of anticholinergic drugs among haloperidol-treated patients. Fewer olanzapine-treated than haloperidol-treated patients discontinued because of EPS, suggesting that olanzapine should contribute to better compliance with longer term maintenance treatment, with minimal anticholinergic-associated events.",2001.0,0,1
953,9193196,Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison with placebo. Seroquel Study Group.,J G Small; S R Hirsch; L A Arvanitis; B G Miller; C G Link,"Quetiapine fumarate (Seroquel [ICI 204,636]) is an atypical dibenzothiazepine antipsychotic with a greater affinity for 5-hydroxytryptamine2 (5-HT2) receptors than for D2 dopamine receptors; its efficacy in patients with schizophrenia was shown in early phase 2 trials (maximum dose, 750 mg/d). In this multicenter, double-blind, placebo-controlled trial, 286 patients hospitalized with chronic or subchronic schizophrenia (DSM-III-R) were randomized to 6 weeks of treatment with high-dose quetiapine fumarate (< or = 750 mg/d), n = 96; low-dose quetiapine fumarate (< or = 250 mg/d), n = 94; or placebo, n = 96. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression Severity of Illness item scores were the primary efficacy variables. Secondary efficacy variables included the BPRS positive-symptom cluster score, the Modified Scale for the Assessment of Negative Symptoms summary score (United States only), and the total score from the negative scale of the Positive and Negative Syndrome Scale (Europe only). Scores were analyzed using an analysis of covariance for change from baseline at end point with last observations carried forward. The model included baseline score (covariate), center, and treatment. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale and the Barnes Akathisia Scale; abnormal involuntary movements were assessed using the Abnormal Involuntary Movement Scale. Frequency distributions of grouped change-from-baseline scores were analyzed using chi 2 tests. Of 280 patients in whom the efficacy of quetiapine was evaluated, 159 (42% of those receiving high-dose treatment; 57%, low-dose treatment; and 59%, placebo) withdrew before trial completion, primarily because of treatment failure. Significant (P < .001, BPRS; P = .003, Clinical Global Impression Severity of Illness item; and P = .003, BPRS positive-symptom cluster) differences were identified between patients receiving high-dose quetiapine and placebo for both primary efficacy variables, with end point differences in the BPRS positive-symptom cluster score showing quetiapine's consistency in reducing positive symptoms. The reduction of negative symptoms was less consistent; high-dose quetiapine was superior on the Modified Scale for the Assessment of Negative Symptoms but not on the negative scale of the Positive and Negative Syndrome Scale. Quetiapine was well tolerated and did not induce extrapyramidal symptoms, sustained elevations of prolactin, or clinically significant changes in hematologic parameters. Quetiapine is an effective antipsychotic with a favorable safety profile. The optimum dose is probably greater than 250 mg/d.",1997.0,0,0
954,9193198,"The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 Dopamine Antagonist Group.",M S Kramer; B Last; A Getson; S A Reines,"Based mainly on the selective antagonism of clozapine at D4 compared with D2 dopamine receptors, hopes have run high that a selective D4 dopamine receptor antagonist might improve the pharmacological treatment of patients with schizophrenia. We report, to our knowledge, the first multicenter study of the antipsychotic potential of a highly specific D4 dopamine receptor antagonist (ie, L-745,870) in patients with acute schizophrenia. Thirty-eight acutely psychotic and neuroleptic responsive (by history) newly admitted inpatients with schizophrenia were randomized to 4 weeks of double-blind treatment (2:1) with either L-745,870 (n = 26), 15 mg/d, or placebo (n = 12) after a 3- to 5-day placebo run-in period. Overall, a greater percentage of patients receiving L-745,870 compared with patients receiving placebo discontinued the study for insufficient therapeutic response (32% vs 16%). At the end of 4 weeks by last observation carried forward analysis, the mean change from baseline to week 4 on the total Brief Psychiatric Rating Scale favored placebo (i.e., -8 points [-15% change from baseline] vs -1 point [-2% change from baseline] for placebo vs L-745,870, P = .09). Similar differences in favor of placebo in changes from baseline mean scores were observed for the not carried forward analysis on the total Brief Psychiatric Rating Scale (P < .03), for not carried forward and last observation carried forward analyses on the sum of selected positive symptom items of the Brief Psychiatric Rating Scale, and for the Clinical Global Impression analysis (P = .03, last observation carried forward). A greater percentage of patients receiving L-745,870 had scores indicative of some level of worsening (compared with baseline) on the total Brief Psychiatric Rating Scale and the Clinical Global Impressions' Severity of Illness Scale as well as positive symptoms compared with those receiving placebo. The selective D4 dopamine receptor antagonist L-745,870 was ineffective as an antipsychotic for the treatment of neuroleptic responsive inpatients with acute schizophrenia.",1997.0,0,0
955,9193736,Heterogeneity of serotonergic response in treatment-refractory schizophrenia patients.,J P Lindenmayer; ; M Vital-Herne; N Bark; S Grochowski; N Moynihan,"Oral metachlorophenylpiperazine (m-CPP) as a direct-acting postsynaptic serotonergic agonist was used to study serotonergic dysfunction in treatment-refractory chronic schizophrenia based on the hypothesis that some patients may show central serotonergic hypersensitivity. Seventeen DSM-III-R chronic schizophrenic patients with a history of neuroleptic nonresponse underwent double-blind challenge with oral m-CPP (0.25 mg/kg body weight) and placebo after medication washout: m-CPP significantly elevated both prolactin and cortisol levels as compared to placebo. There was a significant relationship between change in cortisol level and change in psychopathology under m-CPP; a blunted cortisol response was associated with a decrease in total psychopathology, while an increase in cortisol response related to an increase in psychopathology. Similarly, decrease in severity of the activation factor and the hostility factor was associated with a smaller cortisol response in the m-CPP condition. These results point to heterogeneity in central serotonergic sensitivity within the context of different subpopulations of serotonergic receptors.",1997.0,0,0
956,9196923,Psychopharmacologic treatment of pathologic aggression.,M Fava,"Several drugs are apparently effective in treating pathologic anger and aggression. Because many of the studies on aggressive populations allowed the use of concomitant medications, it is unclear whether the efficacy of each drug in a particular population is dependent on the presence of other medications, such as antipsychotic agents. Finally, one needs to be circumspect in inferring efficacy of a particular drug in aggressive patients with neuropsychiatric conditions other than the ones in which some efficacy has been established. Lithium appears to be an effective treatment of aggression among nonepileptic prison inmates, mentally retarded and handicapped patients, and among conduct-disordered children with explosive behavior. Certainly, lithium would be the treatment of choice in bipolar patients with excessive irritability and anger outbursts, and it has been shown to be effective in this population. Anticonvulsant medications are the treatment of choice for patients with outbursts of rage and abnormal EEG findings. The efficacy of these drugs in patients without a seizure disorder, however, remains to be established, with the exception perhaps of valproate and carbamazepine. In fact, dyphenylhydantoin did not appear to be effective in treating aggressive behavior in children with temper tantrums and was found to be effective in only a prison population. There is some evidence for the efficacy of carbamazepine and valproate in treating pathologic aggression in patients with dementia, organic brain syndrome, psychosis, and personality disorders. As Yudofsky et al point out in their review of the literature, although traditional antipsychotic drugs have been used widely to treat aggression, there is little evidence for their effectiveness in treating aggression beyond their sedative effect in agitated patients or their antiaggressive effect among patients whose aggression is related to active psychosis. Antipsychotic agents appear to be effective in treating psychotic aggressive patients, conduct-disordered children, and mentally retarded patients, with only modest effects in the management of pathologic aggression in patients with dementia. Furthermore, at least in one study, these drugs were found to be associated with increased aggressiveness in mentally retarded subjects. On the other hand, atypical antipsychotic agents (i.e., clozapine, risperidone, and olanzapine) may be more effective than traditional antipsychotic drugs in aggressive and violent populations, as they have shown efficacy in patients with dementia, brain injury, mental retardation, and personality disorders. Similarly, benzodiazepines can reduce agitation and irritability in elderly and demented populations, but they also can induce behavioral disinhibition. Therefore, one should be careful in using this class of drugs in patients with pathologic aggression. Beta-blockers appear to be effective in many different neuropsychiatric conditions. These drugs seem effective in reducing violent and assaultive behavior in patients with dementia, brain injury, schizophrenia, mental retardation, and organic brain syndrome. As pointed out by Campbell et al in their review of the literature, however, systematic research is lacking, and little is known about the efficacy and safety of beta-blockers in children and adolescents with pathologic aggression. Although widely used in the management of pathologic aggression, the use of this class of drugs has been limited partially by marked hypotension and bradycardia, which are side effects common at the higher doses. The usefulness of the antihypertensive drug clonidine in the treatment of pathologic aggression has not been assessed adequately, and only marginal benefits were observed with this drug in irritable autistic and conduct disorder children. Psychostimulants seem to be effective in reducing aggressiveness in brain-injured patients as well as in violent adolescents with oppositional or conduct disorders, particu",1997.0,0,0
957,9197942,Low dose of clozapine in the treatment of dopaminergic psychosis in Parkinson's disease.,S Ruggieri; M F De Pandis; A Bonamartini; L Vacca; F Stocchi,"Dopaminergic psychosis frequently complicates the pharmacological treatment of Parkinson's disease. Dose reduction of dopaminomimetic therapy or treatment with conventional neuroleptics improves psychosis but worsens parkinsonism. In an open-label 12-month trial, the clinical antipsychotic efficacy of the atypical neuroleptic clozapine was investigated in 36 parkinsonian patients (age range 46-85 years) with symptoms of dopaminergic psychosis including delusions, vivid dreams, hallucinations, frank paranoid delirium, and hypersexuality. Clozapine, given orally at bedtime, was started at a dose of 6.25 mg and titrated upward to the minimal effective dose. In all patients, psychosis responded to very low clozapine doses (mean 10.59 +/- 6.48 mg/day). Clozapine doses correlated with the severity of psychosis. During clozapine treatment, parkinsonian disabilities and levodopa dosage remained statistically unchanged. During the 12-month study, no patient had clozapine-induced agranulocytosis or other severe side effects. These findings indicate that even at low doses, clozapine effectively controls dopaminergic psychosis in Parkinson's disease patients without compromising motor function.",1997.0,0,0
958,9201822,Psychotropics.,K G Goldaber,"The risks during pregnancy from commonly prescribed psychopharmacological agents are summarized in this article. Psychotropic agents included in this discussion are antidepressants, antianxiety agents, and antipsychotic agents. The focus of this review is to describe the association between these medications and the incidence of congenital malformations. Epidemiological studies, cohort studies, case reports, and animal studies are discussed.",1997.0,0,1
959,9209730,Clozapine-induced electroencephalogram changes as a function of clozapine serum levels.,O Freudenreich; R D Weiner; J P McEvoy,"Specific electroencephalogram (EEG) changes during clozapine therapy were prospectively studied in a cohort of 50 chronic state hospital patients with schizophrenia who were randomly assigned to one of three nonoverlapping clozapine serum level ranges (50-150 ng/mL, 200-300 ng/mL, and 350-450 ng/mL). EEGs were obtained before clozapine was instituted, and after 10 weeks of treatment. Fifty-three percent of patients showed EEG changes during the 10-week study period. We observed three seizures (6%), one in a patient on 900 mg (serum level 320 ng/mL) clozapine, and two in patients with lower clozapine serum levels (200-300 ng/mL) who had prior histories of seizures and inadequate valproate coverage. Thirteen percent of patients developed spikes with no relationship to dose or serum level of clozapine. Fifty-three percent of patients developed slowing on EEG. Compared to plasma levels below 300 ng/mL, a clozapine serum level between 350 and 450 ng/mL led to more frequent and more severe slowing. The EEG slowing correlated with observed sleepiness, although this factor was not sufficient to explain the severity of high-dose effects.",1997.0,0,0
960,9219046,Response to clozapine in acute mania is more rapid than that of chlorpromazine.,B Barbini; P Scherillo; F Benedetti; G Crespi; C Colombo; E Smeraldi,"The purpose of the present study was to compare the efficacy of clozapine with that of chlorpromazine in an open label manner (both given in association with lithium salts) in the treatment of acute mania. Thirty hospitalized manic patients were entered into the study. All patients met DSM-IV criteria for bipolar disorder, Manic Episode; 27 patients completed the study and three patients dropped for noncompliance. The duration of the study was 3 weeks. Patients were randomly assigned to two treatment groups; group 1 (n = 15) was treated with clozapine at a mean dose of 166 mg/day and group 2 (n = 12) was treated with chlorpromazine at a mean dose of 310 mg/day. Manic symptomatology was rated on Young Rating Scale for Mania (YRSM) each week; side effects were recorded on dosage records and treatment emergent symptoms; extrapyramidal acute side effects were rated on the Simpson-Angus Rating Scale performed at the beginning of the study and after 3 weeks of treatment. A two-way repeated measures analysis of variance on YRMS scores showed a significant time effect (p < 0.0001) and a significant time-group interaction (p < 0.0001). Post-hoc comparison between the two groups showed a significant difference after 2 weeks of treatment (p = 0.0001), with clozapine treated patients showing lower YRSM scores than chlorpromazine treated patients. YRSM scores at the end of the study were not significantly different. Patients treated with clozapine showed a more rapid trend toward amelioration. No clinically relevant side effect was observed during the study.",1997.0,0,0
961,9225889,Sertindole hydrochloride: a novel antipsychotic medication with a favorable side effect profile.,G R Brown; J M Radford,"Forty percent of all long-term care hospitalization days are accounted for by patients with schizophrenia. New approaches to managing this disorder are needed, including improved efficacy and better tolerability to enhance compliance with treatment. Sertindole hydrochloride is a novel antipsychotic medication soon to be available in the United States and Canada. As part of multisite phase II and III studies, we studied effects of this medication in five patients with chronic schizophrenia and examined the side effect profile. With more than 30 patient-months of exposure, sertindole treatment was not associated with neurologic side effects and was well tolerated in all patients studied. No evidence of hematologic abnormalities was found. Serial electrocardiograms revealed slight increases in QTc that were not considered clinically significant and did not lead to discontinuance of treatment. While data from larger samples are needed, in this small population sertindol hydrochloride was tolerated well with no evidence of acute neurologic side effects associated with traditional treatments for schizophrenia. Individuals with schizophrenia may benefit from enhanced compliance with treatment and a possible reduction in hospitalizations in the future.",1997.0,0,0
962,9241010,Economic and health state utility determinations for schizophrenic patients treated with risperidone or haloperidol.,G Chouinard; P S Albright,"The current study uses utility analysis to assess economic and quality-of-life benefits of risperidone in patients with chronic schizophrenia. A retrospective analysis was performed on Positive and Negative Syndrome Symptoms (PANSS) data obtained from the published Canadian multicenter risperidone trial (part of the North American trial). Cluster analysis applied to endpoint PANSS scores, including all patients (N = 135), identified three clusters representing 130 patients with mild, moderate, and severe symptomatology. A narrative health state profile was written for each cluster, and 100 psychiatric nurses from Washington, DC, were asked to assign preference ratings to each one using linear analog and standard gamble (SG) methods. Mean utility values (confidence interval 95%) obtained from the SG ratings for the three health state profiles were 0.61 +/- 0.069 (mild); 0.36 +/- 0.073 (moderate); and 0.29 +/- 0.071 (severe). The mild health state (including the majority of risperidone 6 mg-treated patients) was rated by nurses to have a 0.25 +/- 0.0501 greater utility than the moderate health state (composed of the majority of haloperidol-treated patients). The results of these utility evaluations (SG) by the nurses were related to the clinical outcome for three of the six drug treatment groups (N = 65) by multiplying the percentage of patients in each of the three clusters, both at baseline and end-point, who were receiving risperidone 6 mg/day, haloperidol, or placebo, by the utility value for the health state assigned to that cluster. The gain in utility for risperidone-treated patients was 2.6 times higher (0.125) compared with haloperidol-treated patients (0.049), and 7 times higher compared with placebo (-0.021). After multiplying the gain in utility of each treatment by the remaining expected life span for men and women, it was found that risperidone-treated patients obtained more than twice as many quality-adjusted years as haloperidol patients. The incremental drug treatment cost divided by the incremental benefit of risperidone versus haloperidol was found to yield a favorable, generally accepted cost-utility ratio.",1997.0,0,0
963,9241012,Hepatotoxicity of clozapine.,M Hummer; M Kurz; I Kurzthaler; H Oberbauer; C Miller; W W Fleischhacker,"Two hundred thirty-eight patients treated with either haloperidol or clozapine were investigated to shed more light on the incidence and severity of antipsychotic-induced liver enzyme increase. Serum glutamic-pyruvic transaminase (SGPT) increase was most frequently seen in both treatment groups. When analyzing the incidence rates for patients with increased liver enzyme values (serum glutamic-oxaloacetic transaminase, SGPT, gamma-glutamyl transpeptidase) that were higher than twice the upper limit of the normal range, clozapine-treated patients showed an SGPT increase (37.3%) significantly more frequently than patients treated with haloperidol (16.6%). Both patients with higher clozapine plasma levels and male patients were at a higher risk for an SGPT increase. At least 60% of the increase of the different enzymes remitted within the first 13 weeks of treatment. In general, the authors conclude that clozapine-induced liver enzyme elevation seems to be a common and mostly transient phenomenon.",1997.0,1,1
964,9241494,Antipsychotic use in pregnancy. What are the best treatment options?,M Trixler; T Tényi,"Both the rapid emergence of new antipsychotic medications and the increasing fertility rate among women with psychotic disorders have contributed to the growing clinical importance of the treatment of pregnant women who have psychotic illnesses. The treatment of this patient population must always take into consideration the effect of that treatment on the fetus. With regard to the high risk of decompensation during pregnancy and postpartum, continuous antipsychotic medication is needed using the minimum effective dose. The use of high-potency agents appears to be preferable for first-line management, as there are few data regarding the use of atypical agents such as clozapine in pregnancy. Guidelines for treating pregnant women with psychoses vary little from those for nonpregnant patients. Clinicians must always carefully weigh up the risks and benefits for each patient on an individual basis.",1997.0,0,0
965,9248867,A double-blind comparative study of clozapine versus chlorpromazine on Chinese patients with treatment-refractory schizophrenia.,C J Hong; J Y Chen; H J Chiu; C B Sim,"Clozapine has been shown to have superior effectiveness compared with classic neuroleptics in treating refractory schizophrenia in Caucasians, but its efficacy and safety in Chinese have not been adequately studied. Forty Chinese schizophrenic patients were recruited in a 12-week, double-blind, comparative trial. Twenty-one patients were randomly assigned to clozapine treatment and 19 to chlorpromazine treatment. The average dose was 543 +/- 157 and 1163 +/- 228 mg/day for clozapine and chlorpromazine, respectively. The results showed that six clozapine-treated patients (28.6%) had more than 20% improvement in Brief Psychiatric Rating Scale score and were classified as responders, whereas none of the chlorpromazine-treated patients was classified as a responder. The degree of improvement in positive symptoms, negative symptoms and Brief Psychiatric Rating Scale scores in the clozapine group was inversely correlated with the severity of negative symptoms at entry into the trial. Two clozapine-treated patients were withdrawn from the study, one because of leukopenia and nausea, and the other because of vomiting and hypotension. Chlorpromazine treatment was prematurely discontinued in two patients, because of jaundice and over sedation in one, and because of severe weight loss in the other (9 kg). The rate of moderate-to-severe sialorrhea was high in clozapine-treated patients (28.6%). Two clozapine-treated patients and two chlorpromazine-treated patients showed significant improvement in previously existing tardive dyskinesia and one chlorpromazine-treated patient exhibited aggravation of tardive dyskinesia. The results of this study indicate that clozapine treatment might have advantages over chlorpromazine for Chinese schizophrenic patients who are refractory to typical neuroleptic treatment.",1997.0,0,1
966,9260734,Methylene blue adjuvant therapy of schizophrenia.,S I Deutsch; R B Rosse; B L Schwartz; M Fay-McCarthy; P B Rosenberg; K Fearing,"There is growing interest in the role of the nitric oxide (NO) pathway in idiopathic psychotic disorders such as schizophrenia. In this preliminary study, we examined the therapeutic efficacy of methylene blue (MB), a ""downstream"" inhibitor of one of NO's actions, administered orally as an adjuvant to conventional neuroleptic medications. Specifically, MB blocks NO's activation of soluble guanylyl cyclase. MB has previously been reported to have therapeutic effects in the treatment of psychosis and mania. Preclinical data also suggest that MB might possess antipsychotic potential. Participants in the current study were eight patients with schizophrenia who had incomplete responses to conventional antipsychotics (as evidenced by a Brief Psychiatric Rating Scale [BPRS] total score of 35 or more). These patients completed a 4-week open-label study with a 1 week ""off"", 2 week ""on"", and one final week ""off"" design. Measures of treatment efficacy were the BPRS, Schedule for the Assessment of Negative Symptoms, and Clinical Global Improvement Scale administered weekly. Final scores for each outcome measure item were based on the consensus of at least two trained raters present during each rating interview. A statistically significant, albeit modest, decrease in the severity of psychopathology was observed while the subjects were taking MB, and psychopathology significantly worsened when MB was discontinued. The results suggest a need for further study with MB or perhaps other NO-dependent guanylyl cyclase-inhibiting medications.",1997.0,0,0
967,9262046,Quality of life and response of negative symptoms in schizophrenia to haloperidol and the atypical antipsychotic remoxipride. The Canadian Remoxipride Group.,A G Awad; Y D Lapierre; C Angus; A Rylander,"In a large, multicenter, double-blind study of the effect of haloperidol and the atypical antipsychotic remoxipride on improvement of negative symptoms in schizophrenia, quality of life was also assessed using a modified version of the Sickness Impact Profile (SIP). Compared with previous studies, this study had a longer duration (28 weeks), and the dose of the comparator, haloperidol, was much lower. At the end of the study, compared with the baseline, both treatment groups reported comparable improvement in negative symptoms as defined by the protocol (at least 20% improvement). Similarly, both groups showed comparable changes on global and multidimensional self-assessments of quality of life. All the subfactors of the modified version of the SIP were similar in both groups, except for the subfactor that relates to alertness behavior, which possibly reflects remoxipride's lack of any sedating properties compared with haloperidol. This study presents an approach for inclusion of quality of life as an outcome measure in the design of clinical trials of new antipsychotic medications.",1997.0,0,0
968,9264136,Lack of allelic association between 102T/C polymorphism of serotonin receptor type 2A gene and schizophrenia in Chinese.,C H Chen; Y R Lee; F C Wei; F J Koong; H G Hwu; K J Hsiao,"Recent studies have reported an association between a 102T/C polymorphism of serotonin receptor type 2A gene (5-HT2A) and schizophrenia. In addition, an association was detected between a 102T/C polymorphism of the 5-HT2A receptor gene and drug response to clozapine in the treatment of schizophrenic patients. These studies suggest an important role of the 5-HT2A gene in schizophrenia. To study the possible involvement of the 5-HT2A gene in the pathogenesis of schizophrenia, a case-control association study was carried out in a Chinese population from Taiwan. No significant differences of genotype distributions, allele frequencies and homozygosity were detected between schizophrenic patients (n = 177) and nonpsychiatric controls (n = 98). When subjects were divided into subgroups according to sex, still no differences of allele frequencies or genotype distributions were noted between patients and controls. Our data do not support an allelic association between the 102T/C polymorphism of the 5-HT2A receptor gene and schizophrenia in Chinese population.",1997.0,0,0
969,9265916,Dosing the antipsychotic medication olanzapine.,C B Nemeroff,"Olanzapine is a new antipsychotic agent with serotonin/dopamine antagonism action. Efficacy in treating overall psychopathology in acute schizophrenia as measured by the BPRS0-6 total score was demonstrated at 10 mg/day versus placebo; at doses in a 5-20 mg/day range, olanzapine was comparable or superior to haloperidol. Superior efficacy for negative and depressive symptoms was shown in comparison to haloperidol. Olanzapine has a favorable acute and tardive extrapyramidal symptom profile relative to haloperidol and caused substantially less elevation of serum prolactin. Dose-related weight gain and asymptomatic mild transaminase elevations occurred in olanzapine-treated patients.",1997.0,0,0
970,9270900,"Multiple fixed doses of ""Seroquel"" (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group.",L A Arvanitis; B G Miller,"Five fixed doses of the atypical antipsychotic ""Seroquel"" (quetiapine) were evaluated to delineate a dose-response relationship, as measured by changes from baseline in Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and Modified Scale for the Assessment of Negative Symptoms (SANS) summary scores, and to compare efficacy and tolerability opposite placebo and haloperidol. Three hundred sixty-one patients from 26 North American centers entered this double-blind, placebo-controlled trial with acute exacerbation of chronic schizophrenia (DSM-III-R). Patients who completed a single-blind, placebo washout phase were randomized to double-blind treatment with quetiapine (75, 150, 300, 600, or 750 mg daily), haloperidol (12 mg daily), or placebo and evaluated weekly for 6 weeks. At end point, significant differences (p < 0.05, analysis of covariance) in adjusted mean changes from baseline were identified between the four highest doses of quetiapine and placebo for BPRS total, BPRS positive-symptom cluster, and CGI Severity of Illness item scores and between quetiapine 300 mg and placebo for SANS summary score. Differences between quetiapine and haloperidol were not significant. Dose-response modeling showed significant linear and quadratic functions of quetiapine dose for all primary efficacy variables. Notably, no significant safety concerns were identified as dose increased. Quetiapine was no different from placebo across the dose range studied regarding incidence of extrapyramidal symptoms or change in prolactin concentrations. Quetiapine is well tolerated and clinically effective in the treatment of schizophrenia. It is both superior to placebo and comparable to haloperidol in reducing positive symptoms at doses ranging from 150 to 750 mg/day and in reducing negative symptoms at a dose of 300 mg/day.",1997.0,0,1
971,9271776,The influence of clozapine treatment on plasma granulocyte colony-stimulating (G-CSF) levels.,T Pollmächer; T Fenzel; J Mullington; D Hinze-Selch,"The antipsychotic drug clozapine frequently induces transient increases in white blood cell counts that have been found to be sensitive, but non-specific, predictors of subsequent life-threatening agranulocytosis. Granulocyte colony-stimulating factor (G-CSF) is an endogenous hematopoietic growth factor that plays a pivotal role in granulopoiesis. In addition, G-CSF has successfully been used to treat clozapine-induced agranulocytosis. We performed a longitudinal investigation of the plasma levels of G-CSF in 20 schizophrenic patients during six weeks of clozapine treatment. Clozapine transiently increased plasma G-CSF levels in 55% of the subjects studied. This effect was most prominent at the end of the second week of treatment. Increased G-CSF levels were accompanied by increased granulocyte and monocyte counts, increased rectal temperature and increased plasma levels of other cytokines and cytokine receptors. The results presented suggest that G-CSF is involved in clozapine-induced increases in granulocyte counts seen early during treatment. Like granulocytosis, granulocytopenia is known to occur in conjunction with increased systemic G-CSF levels. Therefore, we hypothesize that a persistent increase along with a decline in white cell counts following an early spike during clozapine treatment might predict the occurrence of agranulocytosis.",1997.0,0,0
972,9283512,Clozapine withdrawal: serotonergic or dopaminergic mechanisms?,H Y Meltzer,,1997.0,0,0
973,9286183,Time to clozapine response in a standardized trial.,R R Conley; W T Carpenter; C A Tamminga,"The authors sought to determine the time to clozapine response in treatment-refractory patients with schizophrenia. Antipsychotic response to a clozapine trial was examined in 50 treatment-refractory schizophrenic inpatients. Subjects were treated with clozapine for at least 12 months, regardless of response status, according to a standardized, increasing dose protocol. Behavioral changes were measured through monthly assessments with the Brief Psychiatric Rating Scale. Thirty-four subjects (68%) met clinical response criteria by the end of the trial. Response was achieved at a mean dose of 468 mg/day (SD = 168). The dose of 30 (88%) of the responding patients was 600 mg/day or less. The mean time to response was 82 days (SD = 100, range = 10-401). It took an average of 60 days (SD = 87) for subjects to reach the dose at which clozapine response was achieved. Once this dose was reached, the average response time was 17 days (SD = 14, range = 2-56). All 34 subjects who responded met criteria within 8 weeks of a clozapine dose escalation. No late response was found in the remaining 16 subjects despite a mean follow-up period of 75 weeks (SD = 50). In this study, all patients who responded to clozapine did so within 8 weeks of a change in dose. Thus, there appears to be little clinical gain in prolonging exposure to clozapine beyond 8 weeks at any particular dose if no response is seen.",2001.0,0,0
974,9286184,"Blind, controlled, long-term study of the comparative incidence of treatment-emergent tardive dyskinesia with olanzapine or haloperidol.",G D Tollefson; C M Beasley; R N Tamura; P V Tran; J H Potvin,"Tardive dyskinesia is a serious and common complication of neuroleptic treatment. Olanzapine is a novel antipsychotic agent exhibiting regional mesolimbic dopaminergic selectivity and a broad-based pharmacology encompassing serotonin, dopamine, muscarinic, and adrenergic receptor binding affinities. The authors' goal was to compare the incidence of tardive dyskinesia among patients receiving olanzapine and those receiving the conventional dopamine 2 antagonist haloperidol. Data were analyzed from three actively controlled and blind long-term responder studies of subjects meeting DSM-III-R criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder treated with olanzapine (N = 707, up to 20 mg/day, 237 median days of exposure) or haloperidol (N = 197, up to 20 mg/day, 203 median days of exposure) who did not have evidence of tardive dyskinesia at baseline. All of the subjects had a chronic disease course (mean greater than 10 years), and there were no significant between-treatment group differences in demographic or disease characteristics. The Abnormal Involuntary Movement Scale and research diagnostic criteria for tardive dyskinesia were used to define the comparative incidence rates of long-term treatment-emergent tardive dyskinesia. The incidence of newly emergent tardive dyskinesia at any visit after baseline, at the final visit, and at the final two clinical assessments was statistically significantly lower among olanzapine-treated patients than among haloperidol-treated patients. These findings support an atypical extrapyramidal symptom profile and the potential of a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol among patients requiring maintenance antipsychotic treatment.",2001.0,0,1
975,9295240,,,,,1,1
976,9315992,Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders.,P V Tran; S H Hamilton; A J Kuntz; J H Potvin; S W Andersen; C Beasley; G D Tollefson,"Olanzapine and risperidone, both second-generation antipsychotic agents, represent two different pharmacologic strategies. Although they share some in vitro properties, they differ by virtue of their chemical structure, spectrum of receptor binding affinities, animal neuropharmacology, pharmacokinetics, and in vivo neuroimaging profile. Based on such differences, it was hypothesized that the two compounds would show distinct safety and/or efficacy characteristics. To test this hypothesis, an international, multicenter, double-blind, parallel-group, 28-week prospective study was conducted with 339 patients who met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. Results of the study indicated that both olanzapine and risperidone were safe and effective in the management of psychotic symptoms. However, olanzapine demonstrated significantly greater efficacy in negative symptoms (Scale for Assessment of Negative Symptoms summary score), as well as overall response rate (> or = 40% decrease in the Positive and Negative Syndrome Scale total score). Furthermore, a statistically significantly greater proportion of the olanzapine-treated than risperidone-treated patients maintained their response at 28 weeks based on Kaplan-Meier survival curves. The incidence of extrapyramidal side effects, hyperprolactinemia, and sexual dysfunction was statistically significantly lower in olanzapine-treated than risperidone-treated patients. In addition, statistically significantly fewer adverse events were reported by olanzapine-treated patients than by their risperidone-treated counterparts. Thus, the differential preclinical profiles of these two drugs were also evident in a controlled, clinical investigation. Olanzapine seemed to have a risk-versus-benefit advantage.",2001.0,1,1
977,9316001,Effects of risperidone on polydipsia in chronic schizophrenia patients.,R S Kern; B D Marshall; T G Kuehnel; J Mintz; J L Hayden; M J Robertson; M F Green,,1997.0,0,0
978,9316002,Weight gain with risperidone.,M Brecher; W Geller,,1997.0,0,1
979,9323354,In vivo immunomodulatory effects of clozapine in schizophrenia.,M Maes; E Bosmans; G Kenis; R De Jong; R S Smith; H Y Meltzer,"Recently, there have been some reports that schizophrenia is accompanied by an immune-inflammatory response, characterized by increased secretion of interleukin-6 (IL-6), soluble IL-2 receptor (sIL-2) and lower plasma levels of CC16 (Clara cell protein), an endogenous anti-cytokine. It was shown that clozapine, an atypical antipsychotic drug, may increase the plasma levels of sIL-2R and pro-inflammatory cytokines. This study was carried out in order to examine serum IL-6, IL-6R, CC16, IL-1R antagonist (IL-1RA), transferrin receptor (TfR) and sCD8 antigen, both before and after treatment with clozapine in schizophrenic subjects versus normal controls. Schizophrenic patients showed significantly higher plasma IL-6R and IL-1RA and lower plasma CC16 than normal controls. Treatment with clozapine significantly increased plasma sCD8, IL-6, CC16 and IL-1RA concentrations. The clozapine-induced increments in plasma IL-6 and CC16 appeared during the first 2 weeks of treatment, whereas the increases in plasma sCD8 and IL-1RA appeared after 5 weeks. Clozapine appears to have complex in vivo immunomodulatory effects.",1997.0,0,0
980,9325559,Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: a study with ketamine.,A K Malhotra; C M Adler; S D Kennison; I Elman; D Pickar; A Breier,"Several lines of evidence suggest that the glutamatergic N-methyl-D-aspartate (NMDA) receptor is involved in the antipsychotic efficacy of the atypical antipsychotic agent clozapine. Clinical data on the interaction between clozapine's mechanism of action and NMDA receptor function have been lacking secondary to a paucity of pharmacologic probes of the NMDA system. We have utilized a double-blind, placebo-controlled infusion paradigm with subanesthetic doses of the NMDA antagonist ketamine to test the hypothesis that clozapine would blunt ketamine-induced psychotic symptoms in schizophrenic patients. Ten schizophrenic patients underwent ketamine infusions while antipsychotic drug free and also during treatment with clozapine. Antipsychotic drug-free patients experienced increases in ratings of positive and negative symptoms. Clozapine treatment significantly blunted the ketamine-induced increase in positive symptoms. These data suggest that NMDA receptor function may be involved in the unique antipsychotic efficacy of clozapine.",1997.0,0,0
981,9337781,,,,,0,0
982,9345668,Mortality in current and former users of clozapine.,A M Walker; L L Lanza; F Arellano; K J Rothman,"Clozapine (Clozaril), a tricyclic dibenzodiazepine, causes fewer extrapyramidal side effects than do other antipsychotic drugs. Because it can induce agranulocytosis, however, clozapine is indicated only for schizophrenia that is not responsive to other therapies. To describe the drug's effects on mortality, we compared rates of various causes of death in 67,072 current and former clozapine users. We linked data from a national registry of clozapine recipients to the National Death Index and Social Security Administration Death Master Files, obtained death certificates, and calculated mortality rates for underlying causes of death using standardization to adjust for age, sex, and race. During 1991-1993, there were 396 deaths in 85,399 person-years for patients ages 10-54 years. Mortality was lower during current clozapine use than during periods of non-use. Mortality from suicide was decreased in current clozapine users by comparison with past users [rate ratio (RR) = 0.17; 95% confidence interval (CI) = 0.10-0.30]. During clozapine use, there were elevations in mortality rates for less common causes of death, including pulmonary embolism (RR for current exposure compared with past clozapine use = 5.2) and respiratory disorders (RR = 2.9). Clozapine appears to reduce mortality in severe schizophrenics, mostly by decreasing suicide rates.",1997.0,0,1
983,9348547,Effects of clozapine on plasma catecholamines and relation to treatment response in schizophrenia: a within-subject comparison with haloperidol.,A S Brown; G Gewirtz; J Harkavy-Friedman; T Cooper; G Brébion; X F Amador; D Malaspina; J M Gorman,"We conducted a within-subject comparison of the effects of clozapine and haloperidol on plasma levels of neurotransmitters and metabolites, and related changes in specific plasma neurochemicals with clozapine response. The subjects were 14 inpatients with schizophrenia or schzoaffective disorder, who were refractory to haloperidol and at least one other typical antipsychotic medication. Subjects underwent, in the following order: a 6-week ""fixed, flexible dose"" haloperidol trial, followed by a 2-4 week medication-free phase, and a 6-week clozapine trial. Plasma levels of norepinephrine (NE), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), and objective clinical ratings of total, positive, negative, and depressive symptoms were obtained at the end of each phase. As expected, we found a substantial increase of plasma NE with clozapine but not with haloperidol. However, the increase in NE was not associated with improvement in total or positive symptomatology. There was some evidence for an association between improvement in negative symptoms and increased HVA on clozapine, as well as diminished HVA during the medication-free phase. The implications of these data for understanding the mechanisms of action of clozapine are discussed.",1997.0,0,0
984,9350955,A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia.,J Peuskens; C G Link,"A 6-week, double-blind, randomized, multicentre, parallel-group study was conducted to compare the efficacy of quetiapine ('Seroquel') (n=101) with that of chlorpromazine (n=100) in hospitalized patients with acute exacerbation of subchronic or chronic schizophrenia, or schizophreniform disorder. The tolerabilities of the two treatments were also compared. The mean daily doses of quetiapine and chlorpromazine at the end of the study were 407 mg and 384 mg, respectively. Both treatments were effective in the treatment of positive and negative symptoms, with a trend towards superior efficacy for quetiapine. The quetiapine group had a lower incidence of adverse events than the chlorpromazine group, and a low incidence of treatment-emergent extrapyramidal symptoms. Quetiapine was not associated with a sustained increase in serum prolactin. These clinical data support the preclinical profile of quetiapine as an atypical antipsychotic agent.",1997.0,0,1
985,9355136,"Assessment and treatment selection for ""revolving door"" inpatients with schizophrenia.",P Weiden; W Glazer,"The goals of this study are 1) to determine causes and patterns of relapse for a cohort of ""revolving door"" schizophrenia inpatients, and 2) to assess the feasibility of starting a new psychopharmacologic intervention before discharge, either depot therapy or an atypical antipsychotic. Consecutive admissions to an acute inpatient unit in New York City were screened for ""revolving door"" criteria. Patients had to have a primary diagnosis of schizophrenia or schizoaffective disorder and have either 1) two hospitalizations in the last year, or 2) three hospitalizations in the last three years. Patients were then assessed for probable causes of relapse for the index and prior two hospitalizations. Treatment selection, based on this information, was trichotomized to: 1) oral conventional antipsychotic, 2) depot conventional antipsychotic (either haloperidol or fluphenazine decanoate), or 3) atypical antipsychotic (either risperidone or clozapine). Sixty-three out of 131 screened admissions met the above revolving door criteria. They were indeed ""revolving"", having an average of 1.3 hospitalizations per year over the last 3 years and were only out of the hospital for five months (median) before index admission. The treatment selection process was hampered by lack of information about events leading to relapse, and by the lack of outpatient participation in the medication selection process. Of the 50 patients with complete histories about precipitants for the index episode, the most common reason for rehospitalization was judged to be medication noncompliance (n = 25; 50%), followed by medication nonresponse (n = 13; 26%). Not surprisingly, medication recommendations were closely linked to the assessed reason for relapse (depot therapy [n = 27; 49%] with medication noncompliance; atypical antipsychotic [n = 20; 37%] with medication nonresponse [X2 = 26.9, p < .001]). These two recommendations were implemented before discharge for about one-half of the cases. Patient refusal was a relatively greater problem for depot recommendation while constraints in the outpatient environment were more problematic for patients recommended for atypical antipsychotics. Medication noncompliance and medication nonresponse, in that order, were judged to be the most common causes of relapse for ""revolving door"" inpatients. Both depot therapy and atypical antipsychotics were commonly recommended and ultimately accepted by about 2/3rds of patients. Choice between depot and atypical was driven by the assessed cause of relapse. In summary, it seems possible to identify ""revolving door"" inpatients, and to target specific medication interventions within the time frame of an acute inpatient admission.",1997.0,0,0
986,9356559,PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia.,S Kapur; R Zipursky; G Remington; C Jones; G McKay; S Houle,"Loxapine, a dibenzoxazepine antipsychotic, is closely related to clozapine and shares clozapine's high affinity for binding to serotonin 5-HT2 and dopamine D4 receptors. The purpose of this study was to document loxapine's 5-HT2 and D2 receptor occupancy in vivo in patients with psychoses. Ten patients who were taking loxapine (10-100 mg/day) had their D2 and 5-HT2 receptors assessed by means of positron emission tomography with [11C]raclopride and [18F]setoperone, respectively. The D2 receptor occupancy ranged from 43% to 90%; 5-HT2 occupancy varied from 27% to near saturation. Statistical comparison of the results showed that loxapine was equipotent in blocking 5-HT2 and D2 receptors. Loxapine differs from typical neuroleptics in demonstrating a high degree of 5-HT2 receptor occupancy. However, it is not ""atypical"" like clozapine and risperidone, since its 5-HT2 occupancy is not higher than its D2 occupancy. The results demonstrate that a high level of 5-HT2 occupancy is not a sufficient condition for atypicality. If atypical antipsychotic action is predicated on a combination of 5-HT2 and D2 effects, then it requires > 80% 5-HT2 occupancy in conjunction with < 80% D2 occupancy.",1997.0,0,0
987,9363292,An open trial of valproate for agitation in geriatric neuropsychiatric disorders.,A P Porsteinsson; P N Tariot; R Erb; S Gaile,"The authors assessed the efficacy, tolerability and safety of open valproate administration in a group of elderly patients with agitation and neuropsychiatric disorders (N = 13), most of whom had dementia (n = 12). Dosing was individualized according to the response of target symptoms and side effects. Clinical Global Impression of Change (vs. baseline) measured efficacy. This open treatment suggested that valproate reduced agitated behaviors in some patients, and is well tolerated; thus, results warrant a larger, randomized, placebo-controlled study.",1997.0,0,0
988,9376336,The acute and long-term effect of olanzapine compared with placebo and haloperidol on serum prolactin concentrations.,A M Crawford; C M Beasley; G D Tollefson,"Prolactin elevation is both a common and a persistent event with the currently marketed antipsychotics, excluding clozapine. Elevations have been associated with both acute (galactorrhea, amenorrhea) and chronic (predisposition to osteoporosis) treatment-emergent adverse events. One of the defining criteria for an atypical antipsychotic is the relative lack of persistent prolactinemia. A double-blind, placebo- (N = 68) and haloperidol- (Hal: 15 +/- 5 mg/day, N = 69) controlled trial of three dose ranges of olanzapine (Olz-L: 5 +/- 2.5 mg/day, N = 65; Olz-M: 10 +/- 2.5 mg/day, N = 64; Olz-H: 15 +/- 2.5 mg/day, N = 69) in the treatment of schizophrenia afforded the opportunity to assess the temporal course of the influence of olanzapine and haloperidol on serum prolactin concentration. Consistent with its potent D2 antagonism, haloperidol was associated with a statistically significantly higher incidence of treatment-emergent prolactin elevation (72%) than seen with placebo (8%; p < 0.001) at week 2 of therapy. Expectedly, this elevation was also persistent at weeks 4 and 6. In contrast, olanzapine-associated treatment-emergent prolactin elevations were both lower in magnitude and transient. At week 2, 38% of the Olz-H, 24% of the Olz-M, and 13% of the Olz-L treatment groups exhibited a treatment-emergent prolactin elevation, with a mean increase of 0.35, 0.52, and 0.61 nmol/l, respectively; for haloperidol the mean increase was 1.23 nmol/l. For only the Olz-M and the Olz-H treatment groups did the week 2 incidence of treatment-emergent prolactin elevations differ statistically significantly from placebo. Both the incidence of elevations and the mean increase, in prolactin concentration were less than that seen with haloperidol. Furthermore, by treatment week 6, all three olanzapine groups exhibited incidences of treatment-emergent prolactin elevation that were comparable to placebo and were statistically significantly less than observed with haloperidol. Rapid adaptation was observed in the temporal course of prolactin elevations associated with olanzapine based on both the categorical analysis of treatment-emergent high values and the analyses of temporal change in mean concentrations. In contrast to haloperidol, the magnitudes of the treatment-emergent elevations associated with olanzapine were minimal. The rates of elevation were approximately one-half to one-third those observed with haloperidol and were significantly more transient. Olanzapine, even at the highest doses (15 +/- 2.5 mg/day) used, was not associated with persistent elevations of prolactin, consistent with an 'atypical' pharmacologic profile.",2001.0,0,0
989,9378688,Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder.,E Leibenluft; S Feldman-Naim; E H Turner; T A Wehr; N E Rosenthal,"The ready availability of exogenous melatonin means that its use in patients with mood disorders is probably not uncommon. Nonetheless, few controlled trials of exogenous melatonin in these patients have been conducted. Five patients with rapid-cycling DSM-III-R bipolar disorder were treated with melatonin 10 mg q.d. at 10:00 p.m. for 12 weeks. Melatonin was added to a stable regimen of medication and administered in a double-blind, placebo-controlled fashion. Melantonin administration had no positive effects. One patient developed a free-running (unentrained) sleep-wake cycle after melatonin withdrawal. In addition, in both this and a second patient, there is evidence that the administration of exogenous melatonin may have suppressed the secretion of endogenous melatonin. The administration of melatonin had no significant effects on mood or sleep. However, melatonin withdrawal delayed sleep onset time and may have had some mild mood-elevating effects.",1997.0,0,0
990,9384895,Uses of clozapine in nonschizophrenic patients.,F R Frankenburg; M C Zanarini,"Clozapine is a novel antipsychotic agent used in the treatment of schizophrenic patients who have not responded to or have been unable to tolerate conventional neuroleptic therapy. In this paper, the literature surveying the uses of clozapine in the treatment of patients with nonschizophrenic illnesses, in particular psychotic affective disorders (bipolar disorder and schizoaffective disorder), will be reviewed. (A Medline search was done for all papers concerning clozapine; those that represented major contributions to the literature were used.) Results from a prospective study at McLean Hospital assessing the effects of diagnosis on response will be presented. Several other uses in nonschizophrenic patients will also be discussed. Because of its relative freedom from extrapyramidal side effects, it is an important agent in the treatment of patients with Parkinson's disease who also have psychotic symptoms. It may be effective in the treatment of tardive dyskinesia in nearly 50% of patients with that symptom. In addition, the drug may be useful in treating violent patients and those with certain movement disorders, atypical borderline personality disorder, or chronic psychotic symptoms. Due to the risk of agranulocytosis, clozapine cannot yet be considered a first-choice treatment for psychotic symptoms, but many studies indicate it to be helpful with a wide variety of treatment-resistant ones.",1998.0,0,0
991,9391688,Olanzapine: a new antipsychotic agent with efficacy in the management of schizophrenia.,J C Kando; J C Shepski; W Satterlee; J K Patel; S G Reams; A I Green,"To review the pharmacology, pharmacokinetics, efficacy data, and adverse effects of olanzapine as a treatment for schizophrenia and to determine the advantages and disadvantages of this atypical antipsychotic agent compared with currently marketed agents. A MEDLINE computer literature search was conducted to retrieve all English-language studies and review articles involving olanzapine published as of October 1, 1996. The manufacturer of the drug, Eli Lilly and Company, provided the clinical investigator's brochure and abstracts of unpublished Phase III clinical trials. Animal studies evaluating the pharmacology of olanzapine were evaluated, as were all open-label and double-blind studies involving the evaluation of olanzapine for the treatment of patients with schizophrenia. All available clinical studies were reviewed and the interpretation of data for each study was influenced by the size of the study sample, the nature of the inclusion and exclusion criteria, and the data analysis techniques used. Olanzapine is a thienobenzodiazepine analog with an in vitro receptor affinity profile similar to that of clozapine. Olanzapine exhibits linear kinetics over the dosage range studied and is extensively metabolized in humans. Clinical evaluations to date have shown olanzapine to be at least as efficacious as typical antipsychotic agents in the treatment of the acute phase of schizophrenia. The drug was well tolerated, with significantly fewer extrapyramidal adverse effects than haloperidol. Current data suggest that olanzapine may be more effective than haloperidol for the treatment of negative symptoms; moreover, preliminary data suggest that fewer relapses occur over the course of treatment in patients treated with olanzapine compared with those taking haloperidol. The exact place of olanzapine in the therapy of psychotic patients remains unclear, as more data are needed to evaluate the long-term efficacy of this agent, its impact on negative symptoms, and its potential use in patients resistant to the standard agents. Despite limitations in the current database, olanzapine is a promising treatment option for patients with schizophrenia.",1997.0,0,1
992,9406266,Standard olanzapine versus placebo and ineffective-dose olanzapine in the maintenance treatment of schizophrenia.,M A Dellva; P Tran; G D Tollefson; A L Wentley; C M Beasley,"Two studies compared the efficacy of standard-dose oral olanzapine (5 to 15 mg a day) with placebo and with ineffective-dose olanzapine (1 mg a day) in maintenance therapy of schizophrenia. The studies were 46-week double-blind extensions of multicenter studies that assessed the efficacy of olanzapine in the acute treatment of schizophrenia. Subjects were 120 adults who met DSM-III-R criteria for schizophrenia with an acute exacerbation and who had a minimum score of 24 on the Brief Psychiatric Rating Scale, who had responded to acute therapy (defined as at least a 40 percent reduction in the BPRS score from baseline or a score of 18 or less during up to six weeks of treatment), and who were outpatients at their last acute-phase visit. Relapse was defined as hospitalization for psychopathology. Relapse risk was analyzed using Kaplan-Meier survival analysis and life table analysis. Patients who relapsed were discontinued from the studies. In the first study (N = 58), patients in the standard-dose olanzapine group experienced a significantly lower relapse risk (p = .002) over one year than patients treated with placebo. The estimated one-year risk of relapse with olanzapine was 28.6 percent, compared with 69.9 percent with placebo. Results were similar in the second study (N = 62); patients treated with standard-dose olanzapine had a significantly reduced risk of relapse (p = .018) over one year compared with patients treated with ineffective-dose olanzapine. The estimated one-year risks of relapse were 19.6 percent for standard-dose olanzapine and 45.5 percent for ineffective-dose olanzapine. Olanzapine is superior to placebo and ineffective-dose olanzapine in the maintenance therapy of schizophrenia.",2001.0,0,0
993,9408810,Olanzapine plasma concentrations and clinical response in acutely ill schizophrenic patients.,P J Perry; T Sanger; C Beasley,"Olanzapine is an atypical antipsychotic effective in the treatment of schizophrenic patients. After a 2- to 9-day placebo lead-in, 79 inpatients with schizophrenia according to DSM-III-R criteria were placed on an olanzapine dosage of 10 mg/day or 1 mg/day for up to 6 weeks. Blood samples were obtained weekly during this period. Receiver operating characteristic curve analyses of Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome Scale rating scale data suggested a minimum effective therapeutic concentration of 9 ng/mL. Using an intent-to treat analysis, 45% of the patients with olanzapine plasma concentrations > or = 9.3 ng/mL responded (> or = 20% decrease in BPRS), whereas only 13% of the patients with concentrations < 9.3 ng/mL responded. Use of olanzapine plasma concentrations of > 9 ng/mL as a predictor for treatment response in acutely ill schizophrenic patients is practicable because this therapeutic marker significantly increases the likelihood of a patient responding to olanzapine.",1997.0,0,0
994,9408917,Olanzapine versus placebo and haloperidol: quality of life and efficacy results of the North American double-blind trial.,S H Hamilton; D A Revicki; L A Genduso; C M Beasley,"This double-blind study evaluated the impact of treatment with olanzapine compared with haloperidol, and placebo on improvements in symptomatology and quality of life in patients with a DSM-III-R diagnosis of schizophrenia. A total of 335 patients was randomized to five treatment groups; olanzapine 5 +/- 2.5 mg/day, olanzapine 10 +/- 2.5 mg/day, olanzapine 15 +/- 2.5 mg/day, haloperidol 15 +/- 5 mg/day, and placebo. Patients responding to treatment during the 6-week acute phase were eligible to enter a 46-week extension. Efficacy measures included the brief psychiatric rating scale total, scale for assessment of negative symptoms summary, and clinical global impressions severity scores. Quality of life was evaluated using the quality of life scale. Data analyzed after 24 weeks of therapy showed that olanzapine was significantly superior to placebo in reducing clinical severity and significantly superior to haloperidol in reducing negative symptoms in patients responding to acute treatment. Furthermore, improvement in quality of life was observed in olanzapine-treated responders.",2001.0,1,1
995,9412161,[Cost effectiveness analysis of olanzapine versus haloperidol in the treatment of schizophrenia++ in Spain].,J A Sacristán; J C Gómez; L Salvador-Carulla,"Cost-effectiveness of olanzapine in comparison with haloperidol, in Spanish schizophrenic patients, was analysed using a clinical decision model. The model represents a simulation of the different clinical and therapeutic possibilities that an hypothetical cohort of patients could experienced in a 5-years period of treatment. Efficacy was measured as months with partial-complete remission. Most information was obtained from the HGAJ randomised clinical trial. Other information was estimated through literature reviews and the opinion of an expert panel. Average cost-effectiveness for olanzapine was lower (116,476 pesetas per month with partial-complete remission) than for haloperidol (134,762 pesetas per month with partial-complete remission). Olanzapine produced more than half year (6.7 months) with partial complete remission, in comparison with haloperidol, with antincrementar cost-effectiveness of 32,516 pesetas per month with partial-complete remission, in comparison with haloperidol. The results were not sensitive to changes in the values of the main variables used in the analysis. According to this analysis, olanzapine presents a good cost-effectiveness relationship in comparison with baloperidol, in Spanish schizophrenic patients. The analysis will be completed when new studies comparing olanzapine with other antipsychotics are available.",1997.0,0,0
996,9429073,Neurocognitive functioning in schizophrenia: a trial of risperidone versus haloperidol.,J Addington; D Addington,,1998.0,0,1
997,9429074,Risperidone diminishes cue-elicited craving in withdrawn cocaine-dependent patients.,D A Smelson; A Roy; M Roy,,1998.0,0,0
998,9433359,Olanzapine on trial.,J A Mattes,,1998.0,0,1
999,9435769,Childhood-onset schizophrenia.,V S Bhatara; S Gupta; M Flugsrud-Breckenridge,,1998.0,0,0
1000,9435993,,,,,0,0
1001,9442340,Differential effect of haloperidol and clozapine on plasma homovanillic acid in elderly schizophrenic patients with or without tardive dyskinesia.,I Andia; M Zumarraga; M J Zabalo; A Bulbena; R Davila,"Plasma homovanillic acid (HVA) changes in response to a challenge of several days with haloperidol have been found to be predictive of the therapeutic response to haloperidol over a longer period of treatment. Twenty-six elderly women who gave informed consent were divided into two groups, with or without tardive dyskinesia, and subjected to an 80-day washout, after which both the dyskinetic and nondyskinetic group was divided, and half of each group given haloperidol or clozapine. The nondyskinetic group had a brief rise in plasma HVA, then a decline. The dyskinetic group had no change in plasma HVA. Neither group challenged with clozapine had any change in plasma HVA.",1998.0,0,0
1002,9443524,A study of enhanced management in patients with treatment-resistant schizophrenia.,G Mercer; A Finlayson; E C Johnstone; C Murray; D G Owens,"The clinical efficacy of two intensive treatment packages (one including the new antipsychotic risperidone and the other not doing so) was compared with that of standard management in 43 patients with long-standing treatment-resistant schizophrenia. Significant differences between the groups in terms of total positive or total negative symptoms were not demonstrated, but the pattern of change between the treatment groups differed, so that benefit in positive symptomatology was seen in both intensive treatment groups and in negative symptomatology in the intensive treatment/risperidone group and the standard group. Changes in general psychopathology were most marked in the risperidone group and were compatible with a relatively non-sedative profile. Using the Disability Assessment Schedule, substantial significant advantages for the intensive treatment groups were found.",1998.0,1,1
1003,9443525,The use of videotaped assessment in relation to a study of enhanced management in treatment-resistant schizophrenia.,D G Owens; A Finlayson; G Mercer; E C Johnstone,"Videotaped assessments of standardized interviews were used to ensure blindness in relation to a clinical trial of multifaceted programmes of management in patients with treatment-resistant schizophrenia. The technique, although laborious, was feasible in all patients studied and offered advantages in relation not only to blindness but also to assessing the nature of psychopathological changes in patients with schizophrenic deficit syndrome of severe degree. The method is likely to be useful in further studies assessing the possible advantages of newer antipsychotic drugs.",1998.0,0,0
1004,9448657,The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials.,S R Marder; J M Davis; G Chouinard,"In two double-blind trials conducted in North America, 513 patients with chronic schizophrenia received risperidone, haloperidol, or placebo. In the present study, combined data from the two trials were analyzed. Patients were randomly assigned to receive placebo, fixed doses of risperidone (2, 6, 10, and 16 mg/day) or 20 mg/day of haloperidol for 8 weeks. Factor analysis of scores on the Positive and Negative Syndrome Scale (PANSS) produced five dimensions (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression), similar to the five dimensions of previous factor-analytic studies of PANSS data. Mean changes (symptom reductions) in PANSS factor scores from baseline to treatment Weeks 6 and 8 were significantly greater in patients receiving 6-16 mg/day of risperidone than in patients receiving placebo or haloperidol. The advantages of risperidone were greatest for negative symptoms, uncontrolled hostility/excitement, and anxiety/depression. Even at the lowest dose, 2 mg/day, risperidone was significantly (p < or = .05) superior to haloperidol in reducing negative symptoms. The differences in outcomes between risperidone and haloperidol on PANSS scores were not related to extrapyramidal symptoms. Risperidone produced significantly (p < or = .05) greater improvements than haloperidol on all five dimensions. The large between-group differences on negative symptoms, hostility/excitement, and anxiety/depression suggest that risperidone and other serotonin/dopamine antagonists have qualitatively different effects from those of conventional antipsychotic agents.",1998.0,0,1
1005,9453932,[Long-term clinical experience with clozapine].,F Gelly; O Chambon; M Marie-Cardine,"This study reports a clinical experience among twenty schizophrenic patients treated by clozapine during two years and eight months within a range extending from three months to seven years. These twenty patients had previously shown long-term resistance to usual neuroleptics but three out of them met the diagnosis of mental retardation or childhood disintegrative disorder (F.84.3-ICD 10). These patients were put under clozapine for their violent behavior. The methodology was retrospective, descriptive with intra-individual comparison, each patient being his own reference before and after treatment. Diagnosis met CD 10 criteria and were assessed without using standard examination. This study aimed at assessing once more clozapine efficacy and tolerance upon a long time follow up. Single therapy has been the rule and dosages have been progressively increased reaching a mean daily dosage of 350 mg per day. The efficacy, assessed by the way of BPRS, GAF (DSM III-R) and simplified form of CGIS, has been verified in approximately 30% of the patients, mainly concerning positive symptoms. Clozapine was also able to alleviate severe behavior troubles brought about by delusional states, without this latter being markedly softened when it was a long term one. Clozapine tolerance has shown it to be satisfactory, however we noticed the occurrence of a leucopenia with neutropenia after seventeen weeks of treatment, followed, some days later, by a Quincke oedema, which forced to interrupt the treatment. White blood cells came back in a normal range fifteen days later. The other side effects (transitory hypersialorrhea, tachycardia, without clinical and ECG perturbations) have been usually well tolerated and have never caused treatment interruption. No extrapyramidal side effect have been noticed among our twenty patients. The end of this paper consists in the presentation of four clinical cases: one about the efficacy of clozapine upon violent antisocial behaviour in a schizotypital disorder; one delusional chronic schizophrenic patient whose violence has been controlled despite of the delusion; one paranoid schizophrenic patient who has been able to maintain a satisfactory professional and family adaptation; and finally a childhood disintegrative disorder (F.84.3-ICD 10) in whom occurred the only leucopenia side effect of our study. These four clinical cases have seemed particularly meaningful regarding our clinical experience of clozapine which has been lasting for almost seven years now.",1998.0,0,0
1006,9468354,Factors influencing relapse in the long-term course of schizophrenia.,J L Ayuso-Gutiérrez; J M del Río Vega,"Highly effective neuroleptic drugs have been available for the past 40 years, but 50% of schizophrenic patients, under normal treatment conditions, relapse within 1 year after their latest episode, frequently spending 15-20% of their time in psychiatric institutions. The term relapse usually refers to a deterioration or recurrence of positive rather than negative features, and relapses appear to impair the course of the disease. Impairment is often longer than expected for those patients who discontinue antipsychotic medication and then relapse to their prediscontinuation clinical state of function. Drug therapy is an important defense against relapse. Marked differences in relapse rate between patients receiving placebo and neuroleptic drugs have been observed (approximately 69% after 1 year for the placebo group versus 26% for the neuroleptic group). First-year relapse rates can be reduced from 75% to 15% with prophylactic treatment with neuroleptics. Follow-up studies suggest that noncompliance with medication, pharmacological factors, psychosocial factors and alcohol and drug abuse contribute to setting off new psychotic episodes. The most important of these is noncompliance with medication. The overwhelming majority of schizophrenic patients who suffered a clinical exacerbation and required hospitalization (73%) did not comply with the treatment prescribed. The effect of new antipsychotic agents should be examined in patients who relapse despite maintenance treatment with conventional neuroleptics. We have found that the rate of current drug abuse among patients with schizophrenic relapse (44%) was significantly higher than that in schizophrenic patients who regularly attended outpatient clinics. Also, the rate of alcohol and substance abuse is higher in males (79%) than in females (21%). Psychiatric units should integrate addiction treatments with psychotic-relapse management.",1998.0,0,1
1007,9468355,"The new antipsychotics, and their potential for early intervention in schizophrenia.",J L Waddington; P J Scully; E O'Callaghan,"Over almost four decades, few fundamentally different antipsychotic drugs evolved to challenge classical neuroleptics as the mainstay of the pharmacotherapy of schizophrenia. However, the recent re-emergence of clozapine, together with the emergence of risperidone, portends an increasing number of new antipsychotics which are now either traversing the stages of regulatory approval or else well-advanced in clinical development. This article first evaluates the significance of clozapine and risperidone; it then reviews some of the new antipsychotics and how they might be classified vis-a-vis potential advantages for patients, outlines putative mechanisms and new therapeutic targets, and considers whether such agents may act on any disease process inherent to schizophrenia. One fundamental issue is the extent to which the new antipsychotics might shift materially the risk benefit balance towards intervention, not just at the earliest possible stage following the onset of psychosis but at a yet earlier, 'prodromal' phase of the disorder where there is a considerably greater likelihood of 'treating' behavioural disturbances that prove not to be the harbingers of psychotic illness.",1998.0,0,0
1008,9468359,Altered consciousness states and endogenous psychoses: a common molecular pathway?,J Ciprian-Ollivier; M G Cetkovich-Bakmas,"Interest in the role of indolamines in the pathogenesis of psychoses has been renewed in recent years by the development of atypical antipsychotic drugs such as clozapine, olanzapine, and risperidone, which act on serotonin receptors. Discovery of the hallucinogenic compounds called methylated indolealkyalamines (MIAs) (e.g. N,N-dimethylserotonin, or bufotenin, and N,N-dimethyltryptamine, or DMT) led proponents of the transmethylation hypothesis of schizophrenia to theorize that through some inborn error of metabolism, serotonin or tryptamine might undergo the addition of extra methyl radicals, thereby forming MIAs with hallucinogenic properties. Various studies have attempted to detect the excretion of MIAs, especially DMT, in the body fluids of psychotic patients and normal controls. Some of these studies have demonstrated elevated MIA concentrations in psychotic patients, including those with schizophrenia, compared with normal persons, and others have not. A number of variables may account for these contradictory findings. The mechanism whereby the beverage ayahuasca, which is used in certain cure and divination rituals in the Amazon Basin, exerts its hallucinogenic effects may serve as a model to explain the mechanism underlying hallucinogenic symptoms in schizophrenia and may lend support to the transmethylation hypothesis. Certain studies suggest that specific perceptual disturbances manifested by schizophrenic patients could contribute to progressive deterioration and negative symptomatology. All these findings point to the need for further study of the neurophysiology of MIAs and their pathogenetic role in endogenous psychoses.",1998.0,0,0
1009,9469675,The effect of timing of a standard meal on the pharmacokinetics and pharmacodynamics of the novel atypical antipsychotic agent ziprasidone.,B A Hamelin; S Allard; L Laplante; J Miceli; K D Wilner; J Tremblay; M LeBel,"To evaluate the influence of a high-fat meal on the pharmacokinetics and pharmacodynamics of the novel atypical antipsychotic drug ziprasidone. Open, randomized, three-way crossover study. University-based research facility. Eight healthy male volunteers. Ziprasidone 20 mg was administered under fasting conditions (treatment A), and directly after (treatment B) and 2 hours after (treatment C) a standard high-fat breakfast. Serial blood samples were obtained over 36 hours. Three objective psychometric tests were employed to evaluate daytime vigilance at baseline and 2 hours after each dose. Ziprasidone had a significant effect on area under the curve (AUC0-infinity), maximum serum concentration, and half-life (analysis of variance all p<0.05), with the mean AUC0-infinity being significantly greater (627.2 +/- 206.4 vs 371.0 +/- 126.5 ng x hr/ml, ANOVA with Bonferroni's criteria p<0.016) and half-life significantly shorter (4.7 +/- 0.8 vs 6.6 +/- 1.3 hrs, ANOVA with Bonferroni's criteria p<0.016) after treatment B compared with treatment A. Although similar trends were observed after treatment C compared with treatment A, the differences did not reach statistical significance when Bonferroni's correction criteria were applied (p>0.016). These data suggest an increase in systemic exposure to the highly lipophilic compound ziprasidone when taken after fatty foods, possibly due to improved drug dissolution and solubilization. The drug's longer half-life under fasting conditions may reflect dissolution-limited absorption, although this could not be directly assessed. Despite postprandial increases in ziprasidone AUC0-infinity and maximum concentration, daytime vigilance was not affected.",1998.0,0,0
1010,9469684,"Sertindole, a new atypical antipsychotic for the treatment of schizophrenia.",L A Brown; G M Levin,"The introduction of antipsychotics for the management of schizophrenia greatly improved the quality of life of many patients suffering from this debilitating disease. Although typical antipsychotic drugs represent a significant advancement in psychopharmacology, they carry a heavy side effect burden, have little efficacy in the management of negative symptoms, and are ineffective in about one-third of patients with schizophrenia. Atypical antipsychotic agents characterized the next major advancement in pharmacotherapy. They differ from typical antipsychotics in their mechanism of action, side effect profiles, and clinical efficacy. Sertindole is a new atypical antipsychotic.",1998.0,0,0
1011,9472836,Pharmacokinetic interactions of clozapine with selective serotonin reuptake inhibitors: differential effects of fluvoxamine and paroxetine in a prospective study.,H Wetzel; I Anghelescu; A Szegedi; J Wiesner; H Weigmann; S Härter; C Hiemke,"Pharmacokinetic interactions of clozapine and its metabolites N-desmethylclozapine and clozapine N-oxide with the selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and paroxetine were investigated in a prospective study in schizophrenic patients under steady-state conditions. Thirty patients were treated with clozapine at a target dose of 2.5 to 3.0 mg/kg of body weight. After gradual dose escalation, serum concentrations of clozapine and two metabolites were determined twice at 7-day intervals after steady-state conditions had been reached. Then, fluvoxamine (50 mg/day) or paroxetine (20 mg/day) was added in 16 and 14 patients, respectively. Serum concentrations of clozapine and its metabolites were measured after 1, 7, and 14 days of coadministration with the SSRI. Mean trough concentrations of steady-state serum concentrations of clozapine, N-desmethylclozapine, and clozapine N-oxide were markedly elevated under fluvoxamine by about threefold of baseline concentrations whereas paroxetine induced only minor, nonsignificant changes. Estimation of the mean elimination half-life of clozapine 2 weeks after start of fluvoxamine comedication revealed an increase from 17 hours to about 50 hours whereas there was no change under paroxetine coadministration. The N-desmethylclozapine/clozapine ratio did not change significantly with either SSRI. Under monotherapy, clozapine mean serum concentrations in smokers were significantly lower by 32% compared with nonsmokers. Similarly, N-demethylation ratios were about 20 to 50% higher in smokers. Thus, in all patients, fluvoxamine induced relevant increases in serum concentrations of clozapine and its metabolites, probably by the inhibition of enzymes catalyzing the degradation of clozapine and N-desmethylclozapine, whereas paroxetine, at a usual clinically effective dosage of 20 mg/day, did not cause significant pharmacokinetic interactions.",1998.0,0,0
1012,9481807,Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP.,M K Spearing; R M Post; G S Leverich; D Brandt; W Nolen,"The Clinical Global Impressions Scale (CGI) was modified specifically for use in assessing global illness severity and change in patients with bipolar disorder. Criticisms of the original CGI were addressed by correcting inconsistencies in scaling, identifying time frames for comparison, clarifying definitions of illness severity and change, and separating out assessment of treatment side effects from illness improvement during treatment. A Detailed User's Guide was developed to train clinicians in the use of the new CGI-Bipolar Version (CGI-BP) for rating severity of manic and depressive episodes and the degree of change from the immediately preceding phase and from the worst phase of illness. The revised scale and manual provide a focused set of instructions to facilitate the reliability of these ratings of mania, depression, and overall bipolar illness during treatment of an acute episode or in longer-term illness prophylaxis. Interrater reliability of the scale was demonstrated in preliminary analyses. Thus, the modified CGI-BP is anticipated to be more useful than the original CGI in studies of bipolar disorder.",1998.0,0,0
1013,9491816,The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response.,A K Malhotra; D Goldman; R W Buchanan; W Rooney; A Clifton; M H Kosmidis; A Breier; D Pickar,"Several lines of evidence suggest that the dopamine D3 receptor is involved in the pathophysiology of schizophrenia. The D3 receptor gene (DRD3) contains a polymorphism resulting in a serine-glycine substitution in the N-terminus of the receptor. Shaikh and colleagues have reported a significant association between the DRD3 Ser9 allele and the Ser9/Ser9 genotype with schizophrenia in 133 Caucasians. In a meta-analysis of previous studies, Ser9 and the Ser9/Ser9 genotype were found to be significantly associated with schizophrenia, although these investigators could not confirm reports of excess homozygosity at this locus in schizophrenia. These authors also report that, in an unblinded study, the Ser9/Ser9 genotype was more frequent in patients who did not respond to clozapine. These data represent the most comprehensive examination of DRD3 Ser9Gly in schizophrenia to date. We have therefore determined DRD3 Ser9Gly genotypes in 58 patients with schizophrenia and in their parents. Moreover, we have genotyped 68 schizophrenics participating in double-blind clozapine trials. We do not find that Ser9 is preferentially transmitted in schizophrenia, cannot confirm excess DRD3 homozygosity in schizophrenia, and do not replicate the association between DRD3 and clozapine response. These data suggest that allelic variation in DRD3 may not play a role in the pathophysiology of schizophrenia or in clozapine response.",1998.0,0,0
1014,9502542,Translating research into practice: the Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations.,A F Lehman; D M Steinwachs,"Beginning in 1992, the Agency for Health Care Policy and Research and the National Institute of Mental Health funded the Schizophrenia Patient Outcomes Research Team (PORT) to develop and disseminate recommendations for the treatment of schizophrenia based on existing scientific evidence. These Treatment Recommendations, presented here in final form for the first time, are based on exhaustive reviews of the treatment outcomes literature (previously published in Schizophrenia Bulletin, Vol. 21, No. 4, 1995) and focus on those treatments for which there is substantial evidence of efficacy. The recommendations address antipsychotic agents, adjunctive pharmacotherapies, electroconvulsive therapy, psychological interventions, family interventions, vocational rehabilitation, and assertive community treatment/intensive case management. Support for each recommendation is referenced to the previous PORT literature reviews, and the recommendations are rated according to the level of supporting evidence. The PORT Treatment Recommendations provide a basis for moving toward ""evidence-based"" practice for schizophrenia and identify both the strengths and limitations in our current knowledge base.",1998.0,0,0
1015,9502543,Patterns of usual care for schizophrenia: initial results from the Schizophrenia Patient Outcomes Research Team (PORT) Client Survey.,A F Lehman; D M Steinwachs,"To examine the conformance of current patterns of usual care for persons with schizophrenia to the Schizophrenia Patient Outcomes Research Team (PORT) Treatment Recommendations, the PORT surveyed a stratified random sample of 719 persons diagnosed with schizophrenia in two States. The types of treatment settings surveyed included acute inpatient programs and continuing outpatient programs in urban and rural locales. Using data from medical record reviews and patient interviews, the PORT assessed the conformance of current care with 12 of the Treatment Recommendations. The rates at which patients' treatment conformed to the recommendations were modest at best, generally below 50 percent. Conformance rates were higher for pharmacological than for psychosocial treatments and in rural areas than in urban ones. Rates of Treatment Recommendation conformance for minority patients were lower than those for Caucasians, and patterns of care varied between the two States. The findings indicate that current usual treatment practices likely fall substantially short of what would be recommended based on the best evidence on treatment efficacy. This disparity underscores the need for greater efforts to ensure that treatment research results are translated into practice.",1998.0,0,0
1016,9503259,Blood biogenic amines during clozapine treatment of early-onset schizophrenia.,E Schulz; C Fleischhaker; H W Clement; H Remschmidt,"The aims of this investigation were to evaluate long-term and short-term effects of clozapine-treatment on plasma biogenic amines and psychopathology measures in adolescents with schizophrenia (DSM-III-R criteria). The long-term study was conducted in a study sample of 40 young patients (age 14-22 years) following a mean of 3.4 years of neuroleptic treatment. During the study, 20 patients received clozapine, and the other 20 patients were treated with standard neuroleptic medications. At the beginning of the open clinical trials, the patients had already been receiving clozapine treatment for 24 +/- 15 months. Assessment of the biochemical and psychopathological measures was performed on six occasions at consecutive 6-week intervals during maintenance treatment with clozapine or conventional neuroleptics. Blood levels of serotonin, 3-methoxy-4-hydroxy-phenylglycol (MHPG), norepinephrine, and epinephrine were significantly higher in clozapine-treated patients than in conventionally treated patients. During long-term treatment, higher serotonin levels were associated with significantly fewer negative symptoms of schizophrenia, whereas higher MHPG levels were correlated with less depression. The short-term effects of clozapine were assessed in a second and independent study sample. After failing on conventional neuroleptics in clinical trials lasting a mean of 1.6 years, 15 inpatients (aged 11-20 years) received clozapine. Weekly ratings of psychopathological symptoms using standard rating scales were performed in parallel to blood samplings for measurements of biogenic amines and serum levels of clozapine. These measures were obtained for 6 weeks during conventional neuroleptic treatment and for 6 weeks during the open-label clozapine trial. Serum levels of serotonin and plasma norepinephrine levels were significantly higher during treatment with clozapine than during pretreatment with typical neuroleptics. A comparison of plasma epinephrine levels in responders (n = 7) and nonresponders (n = 8) to clozapine revealed that response to clozapine can be predicted by epinephrine levels prior to initiation of treatment with clozapine (responders ranging from 32.2 to 90.3 pg/ml; nonresponders ranging from 92.5 to 473.5 pg/ml). Additionally, subjects who responded to clozapine showed increased mean plasma concentrations of MHPG and epinephrine during treatment with this drug in comparison to the levels measured during pretreatment with typical neuroleptic medication. Nonresponders to clozapine failed to show this increase. Finally, in responders to clozapine a negative linear relationship between negative symptoms of schizophrenia and the concentrations of plasma norepinephrine and serum serotonin were observed. In conclusion, our results demonstrate that plasma epinephrine levels prior to initiation of clozapine therapy predict response to this atypical neuroleptic. Our findings derived from short-term and maintenance treatment with clozapine suggest involvement of norepinephrine, epinephrine and serotonin in the therapeutic actions of the atypical neuroleptic clozapine.",1998.0,0,1
1017,9505989,Olanzapine: interaction study with imipramine.,J T Callaghan; B J Cerimele; K J Kassahun; E H Nyhart; P J Hoyes-Beehler; G V Kondraske,"Olanzapine is an ""atypical"" antipsychotic agent with a high affinity for serotonin 5HT2A/C, 5HT3, 5HT6, and dopamine D1, D2, D3, D4 receptors. Depressed patients with psychotic disorders frequently require treatment with concomitant antipsychotic and antidepressant medications. Imipramine pharmacokinetics serve as a marker for hepatic CYP2D6, CYP1A2, CYP3A activity. An open-label, three-way randomized crossover study was done to determine the safety, pharmacokinetics, and potential for a drug interaction between olanzapine (5 mg) and imipramine (75 mg). Each drug was administered alone and in combination. Nine healthy men, ages 32 to 54 years, enrolled in the study. Psychomotor performance capacities, plasma olanzapine, imipramine, desipramine concentrations, and clinical laboratory tests were measured. Pharmacokinetic variables, vital signs, subjective tests for liveliness, and psychomotor outcomes were analyzed using a two-way ANOVA. Olanzapine was safe. Sedation, postural hypotension, and minor vital sign alterations occurred during all treatments. On the liveliness questionnaire, patients generally reported poorer (less lively) scores with olanzapine alone or coadministered with imipramine versus baseline scores. These effects disappeared within 24 hours after administration. Olanzapine alone and in combination decreased motor-speed tasks (finger tapping and visual-arm random reach) compared with baseline or imipramine treatment. Peak 6-hour changes were statistically significant but clinical importance was only marginal. Olanzapine concentrations were < 19% greater than with imipramine. But olanzapine did not affect the kinetics of imipramine or desipramine and, therefore, did not show a metabolic drug interaction involving CYP2D6.",2001.0,0,1
1018,9509290,New atypical antipsychotics. Experience and utility in the elderly.,R A Sweet; B G Pollock,"The atypical antipsychotics are a new class of agents with great promise for use in the elderly because of their reduced propensity to cause acute extrapyramidal adverse effects. Treatment of older patients with these agents, however, needs to take into consideration age-related changes in pharmacokinetics and the risks of drug-drug interactions. Additionally, current evidence of their efficacy in late-life psychoses is derived largely from case series and from the extrapolation of results obtained in studies of younger patients with schizophrenia. Controlled clinical studies of atypical antipsychotics in elderly patients are urgently needed.",1998.0,0,0
1019,9510219,Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol.,G D Tollefson; T M Sanger; Y Lu; M E Thieme,"Depressive signs and symptoms during the course of schizophrenia are common and have been associated with impaired recovery and a higher risk of self-harm. Novel antipsychotic agents introduce new pharmacological avenues that may differentially affect schizophrenic signs and symptoms, including depression. This was a 17-country investigation of 1996 patients with schizophrenia or a related diagnosis randomly assigned to a blinded, comparative trial of the novel antipsychotic agent olanzapine (5-20 mg/d) or the conventional D2 antagonist haloperidol (5-20 mg/d). Patients were evaluated with the Positive and Negative Syndrome Scale, the Montgomery-Asberg Depression Rating Scale, and the Simpson-Angus Rating Scale. The trial consisted of a 6-week and a 46-week masked responder maintenance period. At least moderate depressive signs and symptoms (Montgomery-Asberg Depression Rating Scale score, > or =16) were seen in slightly more than half of this sample. Although both treatments were associated with short-term baseline-to-end point improvement on the Montgomery-Asberg Depression Rating Scale, olanzapine-associated improvements were significantly superior to those observed with haloperidol (P=.001). Furthermore, the response rate for the group receiving olanzapine (> or =50% improvement on the Montgomery-Asberg Depression Rating Scale after at least 3 weeks of treatment) was also significantly higher (P=.008). Analysis demonstrated that improvement in positive, negative, and/or extrapyramidal symptoms was associated with mood improvement (indirect effect); however, most of the olanzapine treatment effect on mood was a primary direct effect (57%) that alone was significantly greater than that seen with haloperidol treatment (P<.001). Depressive signs and symptoms in schizophrenia are responsive to treatment. The pleotrophic pharmacological features of olanzapine, through 1 or more non-D2-mediated pathways, likely contribute to its superior treatment effect. Better control of the mood disorders accompanying schizophrenia holds the possibility for improved patient outcomes.",1998.0,1,1
1020,9511946,The effects of clozapine on negative symptoms in patients with schizophrenia with minimal positive symptoms.,J S Brar; K N Chengappa; H Parepally; A R Sandman; S B Kreinbrook; S A Sheth; R Ganguli,"The effectiveness of clozapine in the treatment of the negative symptoms of schizophrenia remains controversial, as improvements in negative symptoms are invariably accompanied by improvements in positive symptoms and neurological side effects. We examined the effectiveness of treatment with clozapine on negative symptoms in a cohort of patients with minimal positive symptoms. Improvements in positive and negative symptoms were measured by BPRS ratings in a subgroup of schizophrenic patients (n=17, from a state hospital cohort of 75) with minimal positive symptoms, who had received clozapine for 6 months. In this subgroup, significant improvements were noted by a composite score on the three negative symptom items of emotional withdrawal, blunted affect, and motor retardation. Positive and depressive symptoms remained unchanged. The remaining cohort (n=58) showed improvements in overall psychopathology including positive, negative, and depressive symptoms. Interestingly, nearly 50% of each group were discharged from the hospital. These findings suggest that clozapine may be beneficial in the treatment of core negative symptoms, even in the absence of other improvements in psychopathology. This effect of clozapine may be a function of its unique pharmacological profile.",1998.0,0,0
1021,9519099,"Sulpiride augmentation in people with schizophrenia partially responsive to clozapine. A double-blind, placebo-controlled study.",R Shiloh; Z Zemishlany; D Aizenberg; M Radwan; B Schwartz; P Dorfman-Etrog; I Modai; M Khaikin; A Weizman,"We hypothesised that a combined regimen of clozapine, a relatively weak D2-dopaminergic antagonist, and sulpiride, a selective D2 blocker, would demonstrate a greater antipsychotic efficacy by enhancing the D2 blockade of clozapine. Twenty-eight people with schizophrenia, previously unresponsive to typical antipsychotics and only partially responsive to current treatment with clozapine, received, double-blind, 600 mg/day sulpiride or placebo, in addition to an ongoing clozapine treatment. The clinical status was evaluated before, during, and at the end of 10 weeks of sulpiride addition using the Brief Psychiatric Rating Scale (BPRS), Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms, and Hamilton Rating Scale for Depression. The clozapine-sulpiride group exhibited substantially greater and significant improvements in positive and negative psychotic symptoms. About half of them, characterised by a younger age and lower baseline SAPS scores, had a mean reduction of 42.4 and 50.4% in their BPRS and SAPS scores, respectively. A subgroup of patients with chronic schizophrenia may substantially benefit from sulpiride addition to clozapine.",1998.0,0,0
1022,9522104,Risperidone versus haloperidol: I. Meta-analysis of efficacy and safety.,A Davies; M A Adena; N A Keks; S V Catts; T Lambert; I Schweitzer,"Haloperidol is widely considered a reference standard in antipsychotic therapy and is commonly used in comparative studies of the efficacy and safety of antipsychotic medication. Comparative clinical trials have shown that the novel antipsychotic agent risperidone tends to have greater efficacy (i.e., clinical response defined as a > or = 20% reduction in total scores on the Positive and Negative Syndrome Scale) than haloperidol in patients with chronic schizophrenia and poses less risk of extrapyramidal symptoms (EPS). We used DerSimonian and Laird's random-effects model to analyze pooled patient data from available randomized, double-masked, comparative trials of risperidone and haloperidol in patients with schizophrenia treated for at least 4 weeks at recommended doses. The purpose of the analysis was to determine whether there are significant overall differences in the rates of patient clinical response, prescription of anticholinergic agents, and treatment dropout. Six of the nine trials revealed in a literature search met all criteria for inclusion in the meta-analysis. The meta-analysis showed that in patients with chronic schizophrenia, risperidone therapy is associated with significantly higher response rates, significantly less prescribing of anticholinergic medication, and significantly lower treatment dropout rates than haloperidol. These results demonstrate the greater treatment efficacy associated with risperidone compared with haloperidol and suggest both a lower incidence of EPS and improved treatment compliance.",1998.0,0,1
1023,9522115,Risperidone versus haloperidol: II. Cost-effectiveness.,A Davies; P C Langley; N A Keks; S V Catts; T Lambert; I Schweitzer,"Australia and Canada are currently the only Western nations with government guidelines for analyzing the cost-effectiveness of drugs. We used guidelines issued by the Australian Pharmaceutical Benefits Advisory Committee to construct a model for comparing the cost-effectiveness of risperidone and haloperidol over a 2-year period in patients with chronic schizophrenia. Use of clozapine was also included in the analysis as an alternative treatment given to patients who proved unresponsive to therapy with haloperidol or risperidone. Results are expressed in Australian dollars. Cost-effectiveness was determined by using decision-analytic modeling to compare clinical outcomes and costs. The analytic model contained a decision tree for each of the compared agents that tracked the distribution of patients between treatment outcome pathways (i.e., scenarios). Distributions were based on probabilities derived from our meta-analysis results reported elsewhere and from other sources. Each scenario had an associated monetary cost that included all significant direct costs (i.e., hospital costs; outpatient costs; and the cost of drugs, the services of health care professionals, and government-subsidized hostel accommodation). The cost for a given outcome was the sum of costs for all scenarios leading to that outcome. Cost-effectiveness was expressed as the total cost per favorable outcome. The definition of a favorable outcome was one in which the patient was in a response phase at the end of the 2-year period. The probability of a patient experiencing a favorable outcome at the end of 2 years was 78.9% for risperidone versus 58.9% for haloperidol. The total cost of treatment for 2 years was $15,549.00 for risperidone versus $18,332.00 for haloperidol. The expected cost per favorable outcome was $19,709.00 for risperidone and $31,104.00 for haloperidol. Risperidone was more cost-effective than haloperidol and therefore was ""dominant"" in pharmacoeconomic terms because it produced a higher proportion of favorable outcomes at lower cost. Sensitivity analysis showed that the difference in clinical response rate was a key determinant of cost-effectiveness.",1998.0,0,0
1024,9524981,An open comparison of clozapine and risperidone in treatment-resistant schizophrenia.,S W Flynn; G W MacEwan; S Altman; L C Kopala; D H Fredrikson; G N Smith; W G Honer,"Clozapine and risperidone are used in treatment-resistant schizophrenia. At present, there are few reported comparisons of these drugs in this population. We report on a consecutive series of treatment-resistant schizophrenics given either clozapine or risperidone in open clinical trials. Subjects were treated with clozapine (n = 57) or risperidone (n = 29). Pretreatment GAF, CGI, and PANSS scores did not differ between the groups, nor did demographic variables including age, age at first hospitalization, years ill, number of previous hospitalizations, or gender. The mean treatment trial was 12.1 weeks, with mean doses of clozapine 420 mg, and risperidone 7.75 mg. The length of the trial did not differ significantly between the groups. Response was taken to be a 20% decrease in the PANSS score. Using repeated measures ANOVA, PANSS total scores (F = 5.3, p = 0.02) and positive subscore (F = 7.4, p = 0.008) showed greater improvement in the clozapine group than the risperidone group, while other PANSS subscores showed a trend toward greater improvement with clozapine. The PANSS-derived factors of excitement (F = 6.7, p = 0.01), psychosocial withdrawal (F = 3.8, p = 0.05), and psychomotor retardation (F = 3.9, p = 0.05) improved more in the group treated with clozapine. The GAF (F = 10.9, p = 0.0014), CGI (F = 11.5, p = 0.0011), and CGI improvement (p = 0.0001) scores also improved more in the clozapine group. Of the clozapine group, 25 (44%) responded, while 8 (28%) of the risperidone group responded to treatment. Clozapine had better efficacy in subjects with treatment-resistant schizophrenia compared to risperidone, although risperidone appears to yield better response rates than those previously reported for typical antipsychotics. Double-blind, controlled trials of risperidone are needed to establish its efficacy in treatment-resistant schizophrenia.",1998.0,0,0
1025,9539257,Correlation between plasma clozapine concentration and heart rate variability in schizophrenic patients.,T Rechlin; G Beck; M Weis; W P Kaschka,"Forty schizophrenic patients treated with 50-600 mg/day of clozapine as monotherapy and 40 normal control subjects were tested for heart rate variability (HRV) which is mediated by the vagus nerve using acetylcholine as neurotransmitter. As compared to the control subjects, the patients showed essentially reduced HRV parameters which were negatively correlated with the plasma clozapine levels. Therefore, clozapine's anticholinergic effect is correlated to the plasma clozapine level when measured by the decrease of HRV. We suggest that HRV data might be useful as a predictor for plasma clozapine levels.",1998.0,0,0
1026,9545995,Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. The Risperidone Study Group.,G Bondolfi; H Dufour; M Patris; J P May; U Billeter; C B Eap; P Baumann,"The purpose of this study was to compare the short-term efficacy and safety of risperidone and clozapine in treatment-resistant chronic schizophrenic patients. In a controlled double-blind, multicenter study, 86 inpatients with chronic schizophrenia (DSM-III-R), who were resistant to or intolerant of conventional neuroleptics, were randomly assigned to receive risperidone or clozapine for 8 weeks after a 7-day washout period. After a 1-week dose-titration phase, doses were fixed at 6 mg/day of risperidone and 300 mg/day of clozapine for 1 week and then adjusted according to each patient's response. The final mean doses were 6.4 mg/day of risperidone and 291.2 mg/day of clozapine. Treatment efficacy and safety were evaluated with several well-known rating scales. Both risperidone and clozapine significantly reduced the severity of psychotic symptoms (scores on the Positive and Negative Syndrome Scale and the Clinical Global Impression scale) from baseline, with no significant between-group differences. At endpoint, 67% of the risperidone group and 65% of the clozapine group were clinically improved (reduction of 20% or more in total Positive and Negative Syndrome Scale score). Risperidone appeared to have a faster onset of action. In both groups extrapyramidal symptoms and other adverse events were few, and their severity was generally mild. Neither group showed evidence of a relation between drug plasma concentrations and clinical effectiveness. Risperidone was well tolerated and as effective as medium doses of clozapine in patients with chronic schizophrenia who had been resistant to or intolerant of conventional neuroleptics.",1998.0,0,1
1027,9545996,"Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients.",C Trichard; M L Paillère-Martinot; D Attar-Levy; C Recassens; F Monnet; J L Martinot,"This study examined the binding to cortical serotonin 5-HT2A receptors of conventional doses of the typical neuroleptic chlorpromazine in comparison with clozapine, the prototype atypical antipsychotic, and amisulpride, a specific dopamine D2-D3 blocker. Seventeen schizophrenic patients treated with chlorpromazine (75-700 mg/day), four treated with clozapine (200-600 mg/day), and five treated with amisulpride (200-1200 mg/day) were studied. Cortical 5-HT2A binding was estimated by reference to the values for 14 antipsychotic-free schizophrenic subjects with the use of positron emission tomography and [18F]setoperone, a high-affinity radioligand for cortical 5-HT2A receptors. A dose-dependent decrease in the number of available cortical binding sites for [18F] setoperone was demonstrated in the chlorpromazine group; for the highest dose, there was a virtual lack of sites available for binding. A very low percentage of available binding sites was also observed in the clozapine-treated patients at all doses. This suggests a high level of 5-HT2A blockade with both clozapine and high doses of chlorpromazine. No significant binding of amisulpride to 5-HT2A receptors was detected. A high level of 5-HT2A receptor blockade does not appear specific to clozapine in comparison with high doses of chlorpromazine, suggesting that the distinct clinical profiles of both drugs are unrelated to 5-HT2A blockade itself.",1998.0,0,0
1028,9555595,Therapeutic equivalence of risperidone given once daily and twice daily in patients with schizophrenia. The Risperidone Study Group.,N P Nair,"A study was conducted to determine whether once-daily administration of risperidone was as effective and safe as twice-daily administration. In a double-blind 6-week trial, 211 patients with acute exacerbation according to DSM-III-R criteria were randomly assigned to receive risperidone at 8 mg once daily or 4 mg twice daily. The primary efficacy measure was the treatment response rate, defined as a 20% or greater reduction in total Positive and Negative Syndrome Scale (PANSS) scores. Severity of extrapyramidal symptoms was assessed by the Extrapyramidal Symptom Rating Scale. The percentage of patients who showed a treatment response at endpoint was not significantly different between groups (76%, once-daily; 72%, twice-daily), nor was the median time to first treatment response (14 days, both groups). Significant reductions in PANSS total and subscale scores and PANSS-derived Brief Psychiatric Rating Scale were observed in both groups, with no significant between-group differences. Extrapyramidal Symptom Rating Scale scores did not differ significantly between groups. There were no clinically relevant changes in vital signs, electrocardiograms, or clinical laboratory test results in either group. Gradual dosage titration over the first 3 days of treatment was well-tolerated in both groups. The median trough plasma concentrations of risperidone, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone were significantly lower with once-daily than with twice-daily administration; median plasma concentrations measured within the first 8 hours after administration tended to be higher with once-daily administration. These differences did not affect the safety and efficacy of risperidone. Risperidone given once daily at 8 mg is as effective as twice-daily administration of 4 mg in the treatment of acute exacerbations of schizophrenia. Both regimens were equally well-tolerated.",1998.0,0,0
1029,9555596,Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome.,F Müller-Siecheneder; M J Müller; A Hillert; A Szegedi; H Wetzel; O Benkert,"In a multicenter, double-blind, parallel group trial, the efficacy of risperidone (RIS) was compared with a combination of haloperidol and amitriptyline (HAL/AMI) over 6 weeks in patients with coexisting psychotic and depressive symptoms with either a schizoaffective disorder, depressive type, a major depression with psychotic features, or a nonresidual schizophrenia with major depressive symptoms according to DSM-III-R criteria. A total of 123 patients (62 RIS; 61 HAL/AMI) were included; the mean daily dosage at endpoint was 6.9 mg RIS versus 9 mg HAL combined with 180 mg AMI. Efficacy results for those 98 patients (47 RIS; 51 HAL/AMI) who completed at least 3 weeks of double-blind treatment revealed in both treatment groups large reductions in the Positive and Negative Syndrome Scale-derived Brief Psychiatric Rating Scale (RIS 37%; HAL/AMI 51%) and the Bech-Rafaelsen Melancholia Scale total scores (RIS 51%; HAL/AMI 70%). The reductions in the Brief Psychiatric Rating Scale and the Bech-Rafaelsen Melancholia Scale scores in the total group were significantly larger in the HAL/AMI group than in the RIS group (p < 0.01), mostly because of significant differences in the subgroup of patients suffering from depression with psychotic features, whereas treatment differences in the other diagnostic subgroups were not significant. The incidence of extrapyramidal side effects as assessed by the Extrapyramidal Symptom Rating Scale was slightly higher under RIS (37%) than under HAL/AMI (31%). Adverse events were reported by 66% of RIS and 75% of HAL/AMI patients. The results of this trial suggest that the therapeutic effect of HAL/AMI is superior to RIS in the total group of patients with combined psychotic and depressive symptoms. However, subgroup differences have to be considered.",1998.0,1,1
1030,9555605,"Comments on article by Tran and colleagues, ""Double-blind comparison of olanzapine versus risperidone in treatment of schizophrenia and other psychotic disorders"".",N R Schooler,,1998.0,0,1
1031,9555606,"Comments on article by Tran and associates, ""Double-blind comparison of olanzapine versus risperidone in treatment of schizophrenia and other psychotic disorders"".",J Gheuens; J A Grebb,,1998.0,0,1
1032,9564200,Long-term efficacy and safety comparison of sertindole and haloperidol in the treatment of schizophrenia. The Sertindole Study Group.,D G Daniel; P Wozniak; R J Mack; B G McCarthy,"Sertindole is an atypical antipsychotic that is efficacious in schizophrenia and is associated infrequently with extrapyramidal symptoms (EPS). This study assessed time to treatment failure with 24 mg/day sertindole or 10 mg/day haloperidol in 282 clinically stable neuroleptic-responsive outpatients with schizophrenia. During a 5-week transition period, patients were randomized to treatment with sertindole or haloperidol; other treatments were gradually discontinued. Patients then received treatment through Day 365. Time to treatment failure was numerically superior in sertindole-treated patients compared with haloperidol-treated patients, although this difference was not statistically significant. Sertindole-treated patients, however, remained free of hospitalization for exacerbation of schizophrenia and remained medically compliant significantly longer than did haloperidol-treated patients. In addition, there were significantly fewer reports of EPS in sertindole-treated patients and sertindole therapy was generally well tolerated. Patients transitioned well from other antipsychotic agents to sertindole. Sertindole appears to be an effective long-term treatment for schizophrenia.",1998.0,0,1
1033,9564201,The relationship between negative symptoms of schizophrenia and extrapyramidal side effects with haloperidol and olanzapine.,E R Allan; C E Sison; M Alpert; B Connolly; J Crichton,"Atypical neuroleptics present a unique opportunity to examine confounding by neuroleptic-induced extrapyramidal symptoms (EPS) in the assessment of negative signs of schizophrenia. EPS, such as facial bradykinesia and akinesia, involve some of the same response systems and phenomena as emotional display channels. EPS are attributed to the blockade of dopamine receptors in the striatum by traditional neuroleptics. Newer atypical neuroleptics target primarily mesolimbic and mesocortical areas, and receptors for other transmitters such as serotonin. Olanzapine has been reported as less likely to cause EPS and may improve some negative signs. We investigated the relationship between measures of EPS and negative symptoms in patients with schizophrenia treated with haloperidol or olanzapine. Patients were rated with the Positive and Negative Syndrome Scale (PANSS) and the Simpson-Angus Scale EPS scale. Results show that the two agents have comparable efficacy but different safety outcomes. A positive correlation between EPS and PANSS negative score was detected in the haloperidol group only. Stepwise multiple regression analysis shows that a big proportion of variability in PANSS negative symptoms is predicted by EPS in the haloperidol group, but not in the olanzapine group, even though EPS increased in patients treated with haloperidol but not in olanzapine patients.",1998.0,0,1
1034,9564202,Risperidone: clinical outcome predictors and cost-effectiveness in a naturalistic setting.,P R Finley; B R Sommer; J L Corbitt; G H Brunson; B L Lum,"Although risperidone seems to be a safe and effective treatment for the management of psychotic symptoms, its acquisition cost is considerably higher than that of conventional antipsychotics, and its precise role in managing psychiatric illnesses has yet to be defined. The purpose of this investigation was to examine the relationship of patient demographic variables to therapeutic outcomes and to analyze the financial impact of risperidone on the treatment of psychotic symptoms. Subjects included in this 2-year, retrospective cohort, intent-to-treat analysis were all patients initiated on risperidone therapy at an inpatient psychiatric treatment facility. Clinical outcomes were assessed from the absolute change in hospitalized days, total number of psychotropic medications prescribed, and historic Clinical Global Impression severity scores. Logistic regression analysis was conducted to analyze the potential relationship to certain demographic variables to therapeutic response. The cost-benefit analysis compared the direct treatment costs incurred by the institution before and after risperidone initiation. Of the 66 patients originally started on risperidone, 57 completed a therapeutic trial. A clinical response was evident in 54 percent of these patients overall. Logistic regression analysis identified previous treatment intolerance and a negative history of substance abuse as predictive of therapeutic success with risperidone (p = .0006 and p = .01, respectively). Hospitalization rates declined by 43 percent among treatment responders and by 1.3 percent among nonresponders resulting in a net annual savings of $147,962. Risperidone may be efficacious in many patients who had previously failed antipsychotic trials. Patients who had been unable to tolerate traditional antipsychotics and those who lacked a documented history of substance abuse were uniquely responsive to risperidone treatment. The significant decline in hospitalized days that was observed among responsive patients seems to indicate that risperidone may be a cost-effective approach to the management of psychotic symptoms.",1998.0,0,0
1035,9571294,Topographic analysis of EEG photic driving in patients with schizophrenia following clozapine treatment.,Y Jin; S G Potkin; C A Sandman; W E Bunney,"Reduced EEG photic driving has been found to be diagnostically sensitive and specific for schizophrenia. Thirty-one patients with schizophrenia were tested in this study to identify the typical and atypical neuroleptic effects on the photic driving. Compared with the placebo, clozapine significantly enhanced the photically driven EEG in theta and low alpha frequency band, while haloperidol did not have the same effect. These changes with clozapine appeared to be symmetrical and located primarily in the frontal, central and mid-parietal areas but not in the lateral parietal, temporal and occipital regions. Results were consistent with previous findings and suggested that the atypical EEG profile of clozapine might be associated with 5-HT2 antagonistic property.",2001.0,0,0
1036,9580382,Spontaneous brain magnetic activity in schizophrenia patients treated with aripiprazole.,J M Cañive; J D Lewine; J C Edgar; J T Davis; G A Miller; F Torres; V B Tuason,"This magnetoencaphalographic (MEG) study was conducted as part of a multicenter clinical trial to study the efficacy of aripiprazole. Participants included 5 DSM-IV schizophrenia subjects and 10 age-matched normal controls. The schizophrenia subjects underwent a second MEG recording after 8 weeks of open-label treatment with aripiprazole. Overall, control subjects showed no abnormal spontaneous magnetic brain activity. At washout, 3 patients showed increased delta and theta activity along with paraxosymal bitemporal slow waves. In 2 of these patients, the slow waves were generated in the superior temporal plane, as determined by dipole modeling. In the third patient, the slow waves appeared to have been generated at multiple regions throughout the temporal and inferior parietal lobes. As a group, schizophrenia patients, when compared with normal controls, demonstrated significant decreases in alpha peak frequency and power. Following treatment, aripiprazole had a significant normalizing effect on delta and theta activity. Patients on aripiprazole continued to demonstrate significant abnormalities in alpha frequency and power.",1998.0,0,0
1037,9589514,The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia.,D F Horrobin,"The neurodevelopmental hypothesis of schizophrenia is becoming an important feature of research in the field. However, its major drawback is that it lacks any biochemical basis which might draw the diverse observations together. It is suggested that the membrane phospholipid hypothesis can provide such a biochemical basis and that the neurodevelopmental phospholipid concept offers a powerful paradigm to guide future research.",1998.0,0,0
1038,9590670,Psychiatric hospital utilization in patients treated with clozapine for up to 4.5 years in a state mental health care system.,W H Reid; M Mason,"We wished to study long-term psychiatric hospital utilization in a large sample of patients with schizophrenia and/or schizoaffective disorders who were treated with clozapine for up to 4.5 years, and to determine whether or not the reduction in hospital utilization we previously observed in smaller groups for up to 2.5 years was sustained with larger groups and in the longer term. Patients in Texas state hospitals who had schizophrenia and/or schizoaffective disorder took either clozapine or traditional antipsychotics for 1.5 to 4.5 years. The number of patients in the clozapine group ranged from 383 (1.5 years of treatment) to 29 (4.5 years). The group of patients who took traditional antipsychotics was made up of all patients (N = 233) with similar diagnoses, symptom severity, and duration of illness present in Texas state hospitals on an index day. The clozapine group showed a rapid and continuing decrease in hospital bed-days compared with controls who took traditional antipsychotics. The number of clozapine-treated patients who required little or no hospitalization during successive 6-month periods became significant (p < .0001) within 1.5 years, and continued to increase. Conversely, the number of patients taking clozapine who required virtually continuous state hospitalization decreased markedly compared with those taking traditional antipsychotics. Potential hospital cost savings are substantial, even though overall group results are diluted by clozapine nonresponders. Most treatment costs for clozapine nonresponders were related to hospital care; most or all of such costs would have been present in any event had these patients remained on traditional antipsychotic therapy. We believe a trial of clozapine therapy provides a low-cost opportunity for a highly effective and highly cost-saving outcome in those patients who will favorably respond to this therapy. We discuss clinical, social, and economic advantages of modern pharmaceutical treatments over traditional drugs.",1998.0,0,0
1039,9609675,Olanzapine in treatment-resistant bipolar disorder.,S L McElroy; M Frye; K Denicoff; L Altshuler; W Nolen; R Kupka; T Suppes; P E Keck; G S Leverich; G F Kmetz; R M Post,"We evaluated the response to olanzapine in 14 consecutive patients with bipolar I disorder who were inadequately responsive to standard psychotropic agents. Fourteen patients with bipolar I disorder by DSM-IV criteria experiencing persistent affective symptoms inadequately responsive to at least one standard mood stabilizer were treated with open-label olanzapine by one of the authors. Response was assessed with the Clinical Global Impression Scale modified for use in bipolar disorder (CGI-BP). The 14 patients received olanzapine at a mean (SD dosage of 14.1+/-7.2 (range 5-30) mg/day for a mean+/-SD of 101.4+/-56.3 (range 30-217) days of treatment. Of the 14 patients, 8 (57%) displayed much or very much overall improvement in their illness. In general, olanzapine was well tolerated. The most common side effects were sedation, tremor, dry mouth, and appetite stimulation with weight gain. Data were obtained nonblindly and without a randomized control group, and olanzapine was added to ongoing psychotropic regimens. Olanzapine may have antimanic and mood-stabilizing effects in some patients with bipolar disorder, and is generally well tolerated. Controlled studies of olanzapine in bipolar disorder appear warranted.",2001.0,0,0
1040,9611669,"A double-blind, controlled comparison of the novel antipsychotic olanzapine versus haloperidol or placebo on anxious and depressive symptoms accompanying schizophrenia.",G D Tollefson; T M Sanger; C M Beasley; P V Tran,"Depressive symptoms are a common feature of schizophrenia and may represent a core part of the illness. Where present, it has been associated with greater overall morbidity and mortality. Monotherapy with conventional dopamine antagonists may either worsen or bestow a limited therapeutic benefit. Accordingly the use of adjunctive thymoleptics has been explored. In contrast, olanzapine (OLZ), an atypical antipsychotic agent, offers a distinctive and pleotropic pharmacology suggestive of a broader efficacy profile than conventional neuroleptic agents. In a 6-week placebo- and haloperidol (HAL)-controlled trial with 335 randomized subjects with chronic schizophrenia in an acute exacerbation, three fixed dose ranges of OLZ (5, 10, or 15 +/- 2.5 mg) were evaluated versus HAL (10-20 mg) or placebo. Baseline to endpoint change in the Brief Psychiatric Rating Scale including the anxiety-depression cluster (items 1, 2, 5, 9) was analyzed. Two dose ranges of OLZ (10 +/- 2.5, 15 +/- 2.5) were superior to placebo (p < 05) in improving mood status, whereas HAL was not. Contributions from a more selective mesolimbic dopaminergic profile, D1 or D4 activity, the release of dopamine/norepinephrine in the prefrontal cortex, and/or serotonin 5-HT2A,C antagonism may explain the differential benefit seen with OLZ in the treatment of comorbid anxious and depressive symptoms in schizophrenia.",1998.0,0,1
1041,9617509,Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial.,J Segal; M Berk; S Brook,"Case reports and studies of other neuroleptics suggest the efficacy of risperidone in the treatment of mania. Forty-five inpatients with DSM-IV mania were studied in a 28-day randomized, controlled, double-blind trial of either 6 mg daily of risperidone, 10 mg daily of haloperidol, or 800 to 1200 mg daily of lithium. The patients in all three groups showed a similar improvement on the total score for all rating scales at day 28 (Brief Psychiatric rating scale; lithium 9.1, haloperidol 4.9, risperidone 6.5, F = 1.01, df = 2, p = 0.37; Mania rating scale; lithium 15.7, haloperidol 10.2, risperidone 12.4, F = 1.07, df = 2, p = 0.35 [analysis of variance]). The Global Assessment of Functioning and Clinical Global Impression data showed a similar pattern of improvement. This study suggests that risperidone is of equivalent efficacy to lithium and haloperidol in the management of acute mania. The extrapyramidal side effects of risperidone and haloperidol were not significantly different.",1998.0,0,0
1042,9619146,Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome.,R W Buchanan; A Breier; B Kirkpatrick; P Ball; W T Carpenter,"In a preliminary report, the authors observed that clozapine was superior to haloperidol in the treatment of positive and negative symptoms in stable outpatients with schizophrenia. In this final report, they examine the effects of clozapine on positive and negative symptoms in patients with and without the deficit syndrome to determine which patients receive the positive symptom advantage of clozapine and the extent of clozapine's therapeutic effects on negative symptoms. In addition, they examine the long-term effects of clozapine on positive, negative, and affective symptoms, social and occupational functioning, and quality of life. Seventy-five outpatients with schizophrenia, who met retrospective and prospective criteria for residual positive or negative symptoms, were entered into a 10-week double-blind, parallel-groups comparison of clozapine and haloperidol. Patients who completed the double-blind study were then entered into a 1-year open-label clozapine study. For patients who completed the 10-week double-blind study, clozapine was superior to haloperidol in treating positive symptoms. This effect was not observed in the intent-to-treat analyses. There was no evidence of any superior efficacy or long-term effect of clozapine on primary or secondary negative symptoms. Long-term clozapine treatment was associated with significant improvements in social and occupational functioning but not in overall quality of life. For schizophrenic patients who are able to tolerate clozapine therapy, clozapine has superior efficacy for positive symptoms but not negative symptoms and is associated with long-term improvements in social and occupational functioning for patients with and without the deficit syndrome.",2001.0,1,1
1043,9620110,A review of anticonvulsants in treating agitated demented elderly patients.,F Grossman,"Agitation in the elderly, manifested by verbal and physical aggression, frequently results in increased morbidity and mortality for nursing home residents and reduced morale for the family and nursing home staff. It is also responsible for increased costs associated with caring for these residents. Pharmacologic interventions are often used but are frequently ineffective and associated with significant adverse effects. Few controlled studies of drug treatment are available, but divalproex sodium and carbamazepine are effective and well tolerated by this population. Divalproex sodium has advantages of fewer adverse side effects and drug-drug interactions.",1998.0,0,0
1044,9622049,Olanzapine-induced weight gain.,S Gupta; T Droney; S Al-Samarrai; P Keller; B Frank,,1998.0,0,1
1045,9623031,,,,,0,0
1046,9626923,Serum concentrations of clozapine and N-desmethylclozapine are unaffected by the potent CYP3A4 inhibitor itraconazole.,K Raaska; P J Neuvonen,"We studied a possible pharmacokinetic interaction between clozapine and itraconazole, a potent CYP3A4 inhibitor. A double-blind randomized study design was used. Seven schizophrenic inpatients volunteered to receive, in addition to their previous drug regimen, either 200 mg itraconazole or placebo for 7 days. For the next 7 days, itraconazole was changed to placebo and vice versa. Serum concentrations of clozapine and its main metabolite desmethylclozapine were measured on days 0, 3, 7, 10 and 14. Concomitant administration of itraconazole had no significant effect on serum concentrations of clozapine or desmethylclozapine. CYP3A4 seems to be of minor importance in clozapine metabolism in humans. Itraconazole, and probably also other inhibitors of CYP3A4, can be used concomitantly with clozapine.",1998.0,0,0
1047,9629565,Effects of clozapine on in vitro immune parameters: a longitudinal study in clozapine-treated schizophrenic patients.,D Hinze-Selch; E W Becker; G M Stein; P A Berg; J Mullington; F Holsboer; T Pollmächer,"Clozapine is an atypical antipsychotic agent with immunomodulatory properties. We hypothesized that in vitro immune parameters of peripheral blood mononuclear cells (PBMC) are affected in the course of clozapine treatment and that clozapine per se, added in vitro to PBMC cultures of clozapine-treated patients, exerts differential effects in the timecourse of treatment in vivo. We measured proliferation and cytokine secretion of PBMC, serum autoantibodies, and immunoglobulin levels in 17 patients before and during the first 6 weeks of clozapine treatment. Independent of clozapine dosage and rectal temperature, clozapine treatment in vivo suppressed proliferation and shedding of sIL-2r by PBMC, and the addition of clozapine in vitro induced, relative to unstimulated conditions, PBMC proliferation and secretion of IL-6 and sIL-2r. Serum IgG levels were increased; whereas, autoantibody pattern was unaffected. Thus, clozapine treatment and the addition of clozapine in vitro exert differential effects on various in vitro immune parameters independent of clozapine dosage and rectal temperature in the course of treatment.",1998.0,0,0
1048,9629566,Serotonin subtype 2 receptor genes and clinical response to clozapine in schizophrenia patients.,M Masellis; V Basile; H Y Meltzer; J A Lieberman; S Sevy; F M Macciardi; P Cola; A Howard; F Badri; M M Nöthen; W Kalow; J L Kennedy,"Using a pharmacogenetic approach in 185 schizophrenics who have been prospectively assessed for clozapine response, we have examined the hypothesis that polymorphisms in the 5-HT2A (HTR2A), and 5-HT2C (HTR2C) genes are involved in its variable response. A-1438 A-->G polymorphism in the putative promoter and a silent T-->C 102 substitution in HTR2A were in almost complete linkage disequilibrium, and neither was associated with response (T-->C. 102 allele: chi 2 = 0.02; 1 df, p = .90; genotype: chi 2 = 0.02, 2 df, p = .99). A his452tyr HTR2A polymorphism was found to be associated with clozapine response (his452tyr allele: chi 2 = 6.43, 1 df, p = .01 [p = .04, Bonferroni corrected]; genotype: chi 2 = 6.54, 2 df, p = .04 [p = .16, Bonferroni corrected]). No HTR2A haplotype was associated with response. Interethnic differences were observed in the frequencies of the cys23ser HTR2C polymorphism. This polymorphism was not significantly associated with response in either of the ethnic groups (Caucasian and African American genotype: chi 2 = 3.46, 2 df, p = .18; chi 2 = .31, 2 df, p = .86, respectively). Although replication is required, the overall results suggest that the his452tyr HTR2A polymorphism may be involved in clozapine response.",1998.0,0,0
1049,9633833,"Psychomotor slowing, negative symptoms and dopamine receptor availability--an IBZM SPECT study in neuroleptic-treated and drug-free schizophrenic patients.",A Heinz; M B Knable; R Coppola; J G Gorey; D W Jones; K S Lee; D R Weinberger,"Anhedonia and psychomotor slowing in schizophrenia have been attributed to a dysfunction of dopaminergic neurotransmission. To differentiate between disease and drug-induced negative symptoms, we examined eight drug-free and eight neuroleptic-treated schizophrenic patients. Positive and negative symptoms and extrapyramidal side effects were assessed using standardized rating scales (PSAS, AMDP, SANS). 'Reaction time' and 'motor speed' were measured using a computer-aided system and striatal dopamine D2/D3 receptor availability was assessed using [I-123]IBZM SPECT. Psychomotor reaction time, parkinsonism, affective flattening and avolition were increased in treated patients relative to the untreated cohort and were negatively correlated with dopamine D2/D3 receptor availability. Significant positive correlations were found between parkinsonism and affective flattening and between psychomotor slowing and avolition. Positive symptoms were not significantly associated with striatal IBZM binding. These findings support the hypothesis that neuroleptic-induced dopamine D2/D3 blockade in the striatum can mimic certain negative symptoms, such as affective flattening and avolition, and indicates that psychomotor testing may be helpful in differentiating between disease and drug-induced negative symptoms.",1998.0,0,1
1050,9659857,Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia.,R R Conley; C A Tamminga; J J Bartko; C Richardson; M Peszke; J Lingle; J Hegerty; R Love; C Gounaris; S Zaremba,"The purpose of this study was to compare the efficacy of olanzapine with that of chlorpromazine plus benztropine in patients with treatment-resistant schizophrenia. One hundred three previously treatment-resistant patients with schizophrenia diagnosed according to the DSM-III-R criteria were given a prospective 6-week trial of 10-40 mg/day of haloperidol. Eighty-four of them failed to respond to that trial and agreed to be randomly assigned to an 8-week fixed-dose trial of either 25 mg/day of olanzapine alone or 1200 mg/day of chlorpromazine plus 4 mg/day of benztropine mesylate. Fifty-nine (70%) of the 84 subjects completed the trial. The primary outcome measures were Brief Psychiatric Rating Scale total score and positive symptom score, Scale for the Assessment of Negative Symptoms global score, and Clinical Global Impression score. An analysis of variance for the subjects who completed the study showed no difference in efficacy between the two drugs. Seven percent of the olanzapine-treated patients responded according to a priori criteria; no chlorpromazine-treated patients responded. The olanzapine-treated patients had fewer motor and cardiovascular side effects than the chlorpromazine-treated patients. Extrapyramidal symptoms and akathisia were similar in the two groups, although no antiparkinsonian drugs were used in the olanzapine group. Olanzapine and chlorpromazine showed similar efficacy, and the total amount of improvement with either drug was modest. Olanzapine-treated patients had fewer side effects than chlorpromazine-treated patients.",1998.0,0,1
1051,9659858,5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation.,S Kapur; R B Zipursky; G Remington; C Jones; J DaSilva; A A Wilson; S Houle,"Olanzapine is a new atypical antipsychotic recently introduced for the treatment of schizophrenia. The purpose of this study was to investigate olanzapine's binding to the serotonin 5-HT2 and dopamine D2 receptors in schizophrenic patients being treated with clinically relevant doses. Twelve patients with schizophrenia were randomly assigned to 5, 10, 15, or 20 mg/day of olanzapine in a prospective fashion. Three other subjects taking 30-40 mg/day were also included. Once steady-state plasma levels were achieved, dopamine D2 and serotonin 5-HT2 receptors were assessed by using [11C]raclopride and [18F]setoperone positron emission tomography imaging, respectively. Ratings of clinical status, extrapyramidal side effects, and prolactin levels were also obtained. Olanzapine induced near saturation of the 5-HT2 receptors, even at 5 mg/day. Its D2 occupancy increased with dose: patients taking 5-20 mg/day showed 43%-80% D2 occupancy, while patients taking 30-40 mg/day showed 83%-88%. Olanzapine is a potent 5-HT2 blocker and shows a higher 5-HT2 than D2 occupancy at all doses. However, its D2 occupancy is higher than that of clozapine and similar to that of risperidone. In the usual clinical dose range of 10-20 mg/day, its occupancy varies from 71% to 80%, and this restricted range may explain its freedom from extrapyramidal side effects and prolactin elevation. However, doses of 30 mg/day and higher are associated with more than 80% D2 occupancy and may have a higher likelihood of prolactin elevation and extrapyramidal side effects.",1998.0,0,0
1052,9669187,Long-term outcome with clozapine: comparison of patients continuing and discontinuing treatment.,M K Laker; R S Duffett; J C Cookson,"The aim of this naturalistic study was to compare the outcome of patients who continued on clozapine with that of those who discontinued treatment with this drug. Data from 113 patients who commenced clozapine between January 1990 and June 1995 were available for analysis. The main outcome measures were hospitalization status at each anniversary since starting treatment, and the proportion of time spent in hospital by the survey endpoint. On average, patients had been ill for 11.8 years (SD 7.9) and had spent a total of 3.5 years (SD 5.3) in hospital, before treatment with clozapine. The mean duration of follow-up was 2.5 years (SD 1.25, range: 0.32-5.5), by which time 39 patients (35%) had discontinued clozapine. Patients who remained on clozapine (n = 74) were no more likely to have been discharged from hospital than those who discontinued it (n = 39) by the end of the first, second or third year of treatment (p < 0.05). Recent reports of the cost-effectiveness of clozapine treatment should be interpreted with caution.",1998.0,1,1
1053,9671341,Prevalence of diabetes and impaired glucose tolerance in patients treated with clozapine compared with patients treated with conventional depot neuroleptic medications.,S Hägg; L Joelsson; T Mjörndal; O Spigset; G Oja; R Dahlqvist,"Recent case reports suggest the association of the emergence of diabetes mellitus with clozapine treatment, although conventional neuroleptics have also been implicated. This study was conducted to determine if there is an increased risk of diabetes mellitus and/or impaired glucose tolerance (IGT) during clozapine treatment compared with treatment with conventional depot neuroleptics. In a district hospital in northern Sweden, blood glucose tests and, if necessary an oral glucose tolerance test were used to assess the prevalence of diabetes mellitus or IGT in 63 patients treated with clozapine compared with 67 patients treated with conventional depot neuroleptics (haloperidol, zuclopenthixol, fluphenazine, perphenazine, or flupenthixol). Diabetes mellitus and impaired glucose tolerance were classified according to World Health Organization criteria. There were 3 dropouts in the clozapine group and 4 in the control group. Of subjects treated with clozapine, 12% (7/60) had type 2 diabetes mellitus, and 10% (6/60) had IGT. Of subjects treated with depot injections of neuroleptics, 6% (4/63) had type 2 diabetes mellitus and 3% (2/63) had IGT. None in either group had type 1 diabetes mellitus. Subjects in the clozapine group were significantly (p < .001) younger than subjects in the control group, whereas the 2 groups did not differ with respect to body weight, body mass index, or prevalence of diabetes mellitus in first-degree relatives. Subjects treated with clozapine were more often classified as having type 2 diabetes mellitus or IGT compared with subjects in the control group. This difference did not, however, achieve statistical significance (p=.06).",1998.0,1,1
1054,9672052,Does participation in psychosocial treatment augment the benefit of clozapine? Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.,R Rosenheck; J Tekell; J Peters; J Cramer; A Fontana; W Xu; J Thomas; W Henderson; D Charney,"This study examines the role of participation in psychosocial treatment as a mediator of the clinical effectiveness of clozapine. Subjects participated in a 12-month double-blind random-assignment trial comparing clozapine and haloperidol in patients hospitalized 30 to 364 days for refractory schizophrenia at 15 Department of Veterans Affairs medical centers. A broker-advocate case management intervention was used to facilitate participation in psychosocial treatments and to document such participation. Between those who continued receiving clozapine (n=122) or a conventional antipsychotic drug (n=169) for 12 months, those receiving clozapine were more likely to participate in psychosocial rehabilitation treatment. Although they were no more likely to receive clinical recommendations for such treatments, they were more likely to both verbally accept recommendations and to act on them. Structural equation modeling shows that participation in psychosocial treatment did not play a mediating role in clozapine's effect on outcomes at 6 months, but was associated with both reduced symptoms and improved quality of life at 12 months. Clozapine facilitates participation in psychosocial treatment, and such enhanced participation is associated with improved quality-of-life and symptom outcomes. Psychosocial rehabilitation should be offered concomitantly with clozapine.",1998.0,0,0
1055,9672054,"A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders.",C J McDougle; J P Holmes; D C Carlson; G H Pelton; D J Cohen; L H Price,"Neurobiological research has implicated the dopamine and serotonin systems in the pathogenesis of autism. Open-label reports suggest that the serotonin2A-dopamine D2 antagonist risperidone may be safe and effective in reducing the interfering symptoms of patients with autism. Thirty-one adults (age [mean+/-SD], 28.1+/-7.3 years) with autistic disorder (n=17) or pervasive developmental disorder not otherwise specified (n=14) participated in a 12-week double-blind, placebo-controlled trial of risperidone. Patients treated with placebo subsequently received a 12-week open-label trial of risperidone. For persons completing the study, 8 (57%) of 14 patients treated with risperidone were categorized as responders (daily dose [mean+/-SD], 2.9+/-1.4 mg) compared with none of 16 in the placebo group (P<.002). Risperidone was superior to placebo in reducing repetitive behavior (P<.001), aggression (P<.001), anxiety or nervousness (P<.02), depression (P<.03), irritability (P<.01), and the overall behavioral symptoms of autism (P<.02). Objective, measurable change in social behavior and language did not occur. Nine (60%) of 15 patients who received treatment with open-label risperidone following the double-blind placebo phase responded. Other than mild, transient sedation, risperidone was well tolerated, with no evidence of extrapyramidal effects, cardiac events, or seizures. Risperidone is more effective than placebo in the short-term treatment of symptoms of autism in adults.",1998.0,0,0
1056,9672055,The irony of autism.,B L Leventhal; E H Cook; C Lord,,2001.0,0,0
1057,9689720,Risperidone versus haloperidol for perception of emotion in treatment-resistant schizophrenia: preliminary findings.,K S Kee; R S Kern; B D Marshall; M F Green,"Currently, little is known about the pharmacological effects of the new generation of antipsychotic medications on perception of emotion in schizophrenia. The present study was designed to compare the effects of risperidone versus haloperidol on the ability to perceive emotion in 20 treatment-resistant schizophrenia patients, using a double-blind design. Measures of emotion perception included a facial emotion identification test (still photographs presented on videotape), a voice emotion identification test (audiotape), and an affect perception test (brief interpersonal vignettes presented on videotape). These measures were administered during the final week of baseline and after 8 weeks of double-blind medication. Risperidone treatment produced a greater effect on patients' ability to perceive emotion compared with haloperidol treatment. Additionally, all patients who received risperidone demonstrated improvement in performance between baseline and retest, compared with four of the nine patients who received haloperidol. When changes in positive symptoms were statistically controlled, the results remained significant. These findings suggest that resperidone may facilitate patients' ability to accurately perceive emotion, an effect which may be mediated either directly by risperidone's pharmacological action or perhaps indirectly by its influence on basic neurocognition.",2001.0,0,1
1058,9690334,Medical-claims databases in the design of a health-outcomes comparison of quetiapine ('Seroquel') and usual-care antipsychotic medication.,W W Hong; I W Rak; V T Ciuryla; A M Wilson; J W Kylstra; H Y Meltzer; W T Carpenter; A Lehman; L A Arvanitis,"Treating schizophrenia is expensive. Preventing rehospitalization of patients with schizophrenia provides an attractive opportunity for cost savings, especially for patients with 'revolving-door' or multiple-episode schizophrenia. Reducing the occurrence of extrapyramidal symptoms and other adverse events associated with standard antipsychotic agents may increase compliance and reduce the rate of rehospitalization of patients with schizophrenia. Quetiapine ('Seroquel', ICI 204,636, Zeneca Pharmaceuticals) is a new dibenzothiazepine antipsychotic agent with a low propensity for extrapyramidal symptoms. We describe here a unique methodology to compare quetiapine with usual-care medications in real-world treatment settings. The trial objective is to determine if therapy with this new atypical antipsychotic agent can reduce the rate of rehospitalization and, therefore, treatment costs. Using two secondary medical-claims databases, we defined the minimal threshold for revolving-door status as 1.0 admission per year; this definition allows our trial to focus on the subpopulation of schizophrenic patients with the greatest potential for cost savings by either the new atypical antipsychotic quetiapine or usual-care therapy. We describe here the approach used in our trial.",2001.0,0,0
1059,9690695,An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder.,D C Goff; T Posever; L Herz; J Simmons; N Kletti; K Lapierre; K D Wilner; C G Law; G N Ko,"Ninety patients with schizophrenia or schizoaffective disorder according to DSM-III-R criteria participated in this double-blind, exploratory, dose-ranging trial. After a single-blind washout period of 4 to 7 days, patients were randomly assigned to receive one of four fixed doses of the new antipsychotic, ziprasidone 4 (N = 19), 10 (N = 17), 40 (N = 17), or 160 (N = 20) mg/day or haloperidol 15 mg/day (N = 17) for 4 weeks. A dose-response relationship among ziprasidone groups was established for improvements in Clinical Global Impression Severity (CGI-S) score (p = 0.002) but not in Brief Psychiatric Rating Scale (BPRS) total score (p = 0.08). The intent-to-treat analysis of mean changes from baseline in the BPRS total, BPRS Psychosis core, and CGI-S scores demonstrated that ziprasidone 160 mg/day was comparable with haloperidol in reducing overall psychopathology and positive symptoms and was superior to ziprasidone 4 mg/day. Despite the small sample size and short duration of the trial, the improvement in CGI-S with both ziprasidone 160 mg/day and haloperidol 15 mg/day was statistically significantly greater than with ziprasidone 4 mg/day (p = 0.001 andp = 0.005, respectively). The percentage of patients classified as responders on both the BPRS total (> or = 30% improvement) and CGI-Improvement (score of 1 or 2) scales in the ziprasidone 160 mg/day group was similar to that in the haloperidol group and nonsignificantly greater than that in the ziprasidone 4 mg/day group. On all assessments of clinical efficacy, the improvements associated with ziprasidone 4 mg/day, 10 mg/day, and 40 mg/day were similar. Concomitant benztropine use at any time during the study was less frequent with ziprasidone 160 mg/day (15%) than with haloperidol (53%). Haloperidol was associated with a sustained hyperprolactinemia, unlike ziprasidone, where only transient elevations in prolactin that returned to normal within the dosing interval were observed. Ziprasidone was well tolerated, and the incidence of adverse events was similar in all groups. The results of this study suggest that ziprasidone 160 mg/day is as effective as haloperidol 15 mg/day in reducing overall psychopathology and positive symptoms of an acute exacerbation of schizophrenia or schizoaffective disorder but has a lower potential to induce extrapyramidal symptoms.",1998.0,0,1
1060,9690708,Olanzapine-induced reversible priaprism: a case report.,J M Deirmenjian; S M Erhart; D A Wirshing; B J Spellberg; W C Wirshing,,1998.0,0,0
1061,9690975,"Long-term treatment of chronic schizophrenia with risperidone: an open-label, multicenter study of 386 patients.",H J Möller; C A Gagiano; D E Addington; L Von Knorring; J F Torres-Plank; C Gaussares,"An open-label, multicentre study was conducted to assess the long-term efficacy and safety of risperidone in patients with chronic schizophrenia. Three hundred and eighty-six patients at 70 centres in 11 countries received risperidone (2-16 mg/day) for up to 57 weeks; 247 patients were treated for at least 1 year. All but 48 patients had been treated with antipsychotic agents before entering the trial. The mean (+/- SD) daily risperidone dose at endpoint was 8.6 +/- 4.4 mg. The mean total Positive and Negative Syndrome Scale (PANSS) scores were reduced significantly from 76.7 at baseline to 67.4 at endpoint (p < 0.001). Even though no patients had acutely exacerbated symptoms at the start of the trial, mean scores on each of the PANSS positive, negative, and general psychopathology subscales were significantly reduced during the first month of open treatment, and these mean scores continued to improve over the course of the trial. At endpoint, 64% of patients were rated as improved on the Clinical Global Impression change scale. Extrapyramidal symptoms (scores on the Extrapyramidal Symptom Rating Scale) tended to decrease in severity or remained unchanged over the course of risperidone treatment; 27.7% of patients required antiparkinsonian medication during the study. The results demonstrate that risperidone's efficacy against the positive and negative symptoms of chronic schizophrenia can be maintained in long-term treatment with a low incidence of adverse experiences; moreover, the drug reduces preexisting extrapyramidal symptoms over time.",1998.0,1,1
1062,9694006,Early developmental differences between DSM-III-R schizophrenics treated with clozapine and typical neuroleptics.,T Mäkikyrö; E Leinonen; H Koponen; M R Järvelin; H Hakko; O Saarnisaari; M Isohanni,"Developmental deviance is known to be associated with schizophrenia. We tested the hypothesis that the most severe schizophrenia requiring treatment with clozapine would particularly show these effects. Therefore, associative factors from pregnancy, delivery, neonatal and socio-demographic characteristics were compared between the clozapine-treated schizophrenic cases (n = 17) and the remaining cases of schizophrenia treated with typical neuroleptics (n = 59) from an unselected, general population North Finland 1966 Birth Cohort, (n = 11,017). By the end of 1994, seventeen (22%) of a total 76 DSM-III-R schizophrenia patients, had received clozapine treatment. The mean length at birth was 52 cm in the clozapine group (in the non-clozapine group 50 cm) and correspondingly the mean one year weight 10.4 kg (9.8 kg), with the differences between the groups being statistically significant (P < 0.05). Other pregnancy, delivery, and socio-demographic characteristics were, however, similar in the clozapine-treated and the remaining cases with schizophrenia. There was no evidence that severe schizophrenia requiring treatment with clozapine was associated with impaired intrauterine or post-natal development. Indeed, during the first years of life the former group was larger in terms of weight and length than those treated with typical neuroleptics. These early developmental characteristics did not predict clinical severity of schizophrenia in adulthood.",1998.0,0,0
1063,9696517,"Amisulpride, and atypical antipsychotic, in the treatment of acute episodes of schizophrenia: a dose-ranging study vs. haloperidol. The Amisulpride Study Group.",A Puech; O Fleurot; W Rein,"This 4-week, double-blind, randomized study was undertaken to determine the dose-response relationship of amisulpride in 319 patients with acute exacerbation of schizophrenia. Fixed doses of amisulpride (400, 800 and 1200 mg/day) and haloperidol (16 mg/day) were compared to amisulpride, 100 mg/day, as a potentially subtherapeutic dose. Efficacy data (BPRS total score and PANSS positive subscale) in the amisulpride groups generated a bell-shaped dose-response curve, with 400 mg/day and 800 mg/day being the most effective treatments for positive symptoms. Parkinsonism did not increase significantly between baseline and endpoint with amisulpride 400, 800 and 1200 mg/day compared to the amisulpride 100 mg/day group, whereas the difference was significant for haloperidol (P<0.05). It is concluded that amisulpride 400 mg and 800 mg/day is highly effective in treating the positive symptoms of schizophrenia, with less extrapyramidal side-effects than haloperidol 16 mg/day.",1998.0,0,0
1064,9699711,Olanzapine for primary negative symptoms.,R W Licht,,1998.0,0,0
1065,9704166,"Diminished suicidal and aggressive behavior, high plasma norepinephrine levels, and serum triglyceride levels in chronic neuroleptic-resistant schizophrenic patients maintained on clozapine.",B Spivak; S Roitman; Y Vered; R Mester; E Graff; Y Talmon; N Guy; N Gonen; A Weizman,"Impulsiveness and aggressiveness may be the most common behavioral correlates of central serotonergic dysfunction. The aim of this study was to determine whether clozapine, an atypical antipsychotic agent with a potent serotonergic antagonistic activity, affects impulsiveness and aggression. Its effects on serum lipids, platelet-poor plasma serotonin (5-HT), and norepinephrine (NE) levels were also studied. Thirty neuroleptic-resistant chronic schizophrenic patients, maintained on clozapine for 1 year, were evaluated for aggressiveness, impulsiveness, and suicidality in comparison with 30 chronic schizophrenic patients maintained on classical antipsychotic agents for the same period of time. Clozapine treatment was associated with less impulsiveness (p < 0.05), aggressiveness (p < 0.01) and fewer suicidal attempts (p < 0.05). Serum triglycerides and plasma NE levels were significantly higher (p < 0.01 and p < 0.0001, respectively) in the patients treated with clozapine, as compared with patients treated with classical neuroleptic drugs. The authors conclude that long-term clozapine treatment may be effective in controlling aggressive, impulsive, and suicidal behavior in neuroleptic-resistant chronic schizophrenic patients. The elevated plasma NE levels in patients treated with clozapine as compared to those treated with classical neuroleptic drugs may be relevant for the anti-aggressive/antisuicidal activity of clozapine.",1998.0,1,1
1066,9704872,Immediate versus delayed visual memory task performance among schizophrenic patients and normal control subjects.,D M Dougherty; J L Steinberg; A A Wassef; D Medearis; D R Cherek; F G Moeller,"In an exploratory study, 10 schizophrenic patients and 10 normal control subjects performed immediate and delayed memory tasks, which were variants of previously developed continuous performance tests. Both tasks required participants to identify five-digit numbers which were repeated. Numbers were presented in series for 500 ms each and separated by a 500-ms time-out period. In the immediate memory task, subjects were to respond if a number was identical to the one that had immediately preceded it. The delayed memory task differed from the first task in that a longer delay (3.5 s) between stimuli was introduced, and during this delay distracter stimuli appeared. While normal control subjects performed accurately on both tasks (exceeding 80% correct detections), schizophrenic patients performed poorly, performing worse on the delayed memory task than on the immediate memory task. Rates of commission errors (responses made to similar, but not identical numbers) were nearly equal between groups on the immediate memory task, but on the delayed memory task normal control subjects made relatively more commission errors while schizophrenic patients made fewer commission errors. No differences in response latencies were observed between subject groups or tasks. This paradigm may prove useful in discriminating subtle differences in immediate and delayed memory capability among psychiatric populations and normal control subjects.",1998.0,0,0
1067,9712207,Suicide prevention effects associated with clozapine therapy in schizophrenia and schizoaffective disorder.,W H Reid; M Mason; T Hogan,"Suicide is a significant cause of death among patients with schizophrenia and schizoaffective disorder, affecting some 10 to 15 percent of these patients. This study examined annual suicide rates over a two-year period (1993-1995) among more than 30,000 patients with schizophrenia and schizoaffective disorder who received services from the Texas Department of Mental Health and Mental Retardation and suicide rates over a six-year period (1991-1996) among a subgroup of patients treated with clozapine. The annual suicide rate for all patients with schizophrenia and schizoaffective disorder was 63.1 per 100,000 patients, approximately five times higher than in the general population. In contrast, only one suicide occurred in six years among patients treated with clozapine who were of similar diagnosis, age, and sex, for a suicide rate of about 12.7 per 100,000 patients per year. This rate is similar to the 15.7 per 100,000 patients per year for all U.S. patients treated with clozapine, calculated from data reported as of June 1996 to the clozapine national registry system maintained by Novartis Pharmaceuticals Corporation, the U.S. manufacturer of clozapine. The study results suggest that clozapine therapy is associated with a reduced risk of suicide among patients with schizophrenia and schizoaffective disorder.",1998.0,1,1
1068,9713904,Meta-analysis of studies on genetic variation in 5-HT2A receptors and clozapine response.,M J Arranz; J Munro; P Sham; G Kirov; R M Murray; D A Collier; R W Kerwin,"Serotonin (5-HT) neurotransmitter receptors are targeted by atypical antipsychotic drugs. We hypothesized that genetic variation in these receptors may affect clinical response to the drugs targeting them. This hypothesis has been tested by several studies in which the correlation between polymorphic variants in the 5-HT2A receptor gene and clinical response to the atypical antipsychotic clozapine was investigated. The results of these studies either found association between 5-HT2A genetic variants and clozapine response or found differences in the same direction which did not reach statistical significance. Meta-analysis of these studies including 373 patients who responded to the treatment and 360 non-responders showed association between two 5-HT2A polymorphisms, 102-T/C and His452Tyr, and clozapine response. Statistical analysis of extreme responders showed a clearer association of the 102-T/C with clozapine response. These results reinforce the hypothesis and strengthen the candidacy of these receptors as important therapeutic targets.",1998.0,0,1
1069,9718639,Expenditures for treating schizophrenia: a population-based study of Georgia Medicaid recipients.,B C Martin; L S Miller,"The study analyzed all claims data for reimbursable medical services and drugs rendered to 18- to 50-year-old Medicaid recipients in the State of Georgia over a 3-year period. A cohort of 6,443 schizophrenia patients were identified by inspecting the medical history data for claims indicative of schizophrenia (ICD-9-CM 295.xx). A crude prevalence of 6.02 percent was identified. Use patterns and charges associated with schizophrenia were stratified by major areas of service including ambulatory services, hospitalizations, and pharmacological treatment. The incidence of rehospitalization for chronic schizophrenia patients based on a 12-month hospitalization index format was also identified. Findings are discussed regarding using these data to focus strategies for assessing schizophrenia treatment outcome in relation to treatment cost.",1998.0,0,0
1070,9720968,Rodent data and general hypothesis: antipsychotic action exerted through 5-Ht2A receptor antagonism is dependent on increased serotonergic tone.,P Martin; N Waters; C J Schmidt; A Carlsson; M L Carlsson,"The locomotor stimulation induced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) in mice was regarded as a model of at least some aspects of schizophrenia. The serotonin synthesis inhibitor dl-p-chlorophenylalanine (PCPA) was used to evaluate the involvement of endogenous serotonin in (a) the induction of MK-801-induced hyperlocomotion in NMRI mice, and (b) the inhibition of MK-801-induced hyperlocomotion by each of five monoaminergic antagonists (M100907, clozapine, olanzapine, raclopride, SCH23390). Further, brain monoaminergic biochemistry was characterised in rats and mice after various drug treatments. PCPA pretreatment did not significantly reduce MK-801-induced hyperlocomotion in any of the experiments performed; however in a meta-analysis of six experiments, the locomotion displayed by MK-801-treated animals was diminished 17% by PCPA pretreatment. The selective 5-HT2A receptor antagonist M100907 exerted a dose-dependent inhibition of MK-801-induced hyperlocomotion. This effect was abolished in mice pretreated with PCPA, but could be restored in a dose-dependent manner by restitution of endogenous 5-HT by means of 5-hydroxytryptophan (5-HTP). On the other hand, the inhibition of MK-801-induced hyperlocomotion exerted by the selective dopamine D-2 receptor antagonist raclopride or the dopamine D-1 receptor antagonist SCH23390 was unaffected by PCPA pretreatment. The antipsychotics clozapine and olanzapine displayed a split profile. Hence, the inhibitory effect on MK-801-induced hyperlocomotion exerted by low doses of these compounds was diminished after PCPA pretreatment, while inhibition exerted by higher doses was unaffected by PCPA. These results suggest that (1) MK-801-induced hyperlocomotion is accompanied by an activation of, but is not fully dependent upon, brain serotonergic systems. (2) In the hypoglutamatergic state induced by MK-801, endogenous serotonin exerts a stimulatory effect on locomotion through an action at 5-HT2A receptors, an effect that is almost completely counterbalanced by a concomitant inhibitory impact on locomotion, mediated through stimulation of serotonin receptors other than 5-HT2A receptors. M100907, by blocking 5-HT2A receptors, unveils the inhibitory effect exerted on locomotion by these other serotonin receptors. (3) Dopamine D-2 receptor antagonistic properties of antipsychotic compounds, when they come into play, override 5-HT2A receptor antagonism. Possible implications for the treatment of schizophrenia with 5-HT2A receptor antagonists are discussed. It is hypothesized that treatment response to such agents is dependent on increased serotonergic tone.",1998.0,0,0
1071,9723115,Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients.,W H Chang; S K Lin; H Y Lane; F C Wei; W H Hu; Y W Lam; M W Jann,"1. To characterize the interconversion process between clozapine and its metabolite clozapine N-oxide (CNO), eight healthy male schizophrenics were administered a single dose of clozapine or CNO in a randomized crossover manner. 2. Using a general pharmacokinetic model for the interconversion process, the mean total clearances of clozapine and CNO were 28.45 L/hr and 45.30 L/hr, respectively. These values were similar to the values obtained by the usual model-independent method of pharmacokinetic analysis. 3. When administered clozapine, mean CNO plasma concentrations of 17.7 +/- 16.4 ng/ml were slightly lower than the other clozapine metabolite-desmethylclozapine (DCLOZ) plasma levels of 24.4 +/- 8.6 ng/ml at the 12 hour time point. When CNO was administered, plasma concentrations at the 12 hour time point of clozapine were twice the amount of CNO (28.1 +/- 8.9 ng/ml vs 14.4 +/- 8.8 ng/ml). 4. DCLOZ plasma concentrations were detected in all patients upon clozapine administration. Upon CNO administration, only one patient had detectable plasma DCLOZ levels. 5. The interconversion process of clozapine and CNO could partially account for the wide interpatient variability reported for clozapine plasma concentrations in schizophrenic patients.",1998.0,0,0
1072,9729687,"Typical and atypical antipsychotics in adolescent schizophrenia: efficacy, tolerability, and differential sensitivity to extrapyramidal symptoms.",R Lewis,"To review the existing literature on the efficacy and tolerability of antipsychotics for adolescent psychosis. The review focuses in particular on literature regarding adverse effects that are thought to have an increased incidence in young patients and on the possible neurobiological bases for such differential sensitivity. Pertinent studies were sought using Medline searches, supplemented by selected bibliographies, and reviewed. There is a relative paucity of research in this area; in particular, well-controlled trails are lacking. The existing literature suggests fairly good efficacy of both typical and atypical antipsychotics in the treatment of psychotic disorders in children and adolescents. However, the incidence of certain side effects, particularly extrapyramidal symptoms (EPS). is found to be higher in younger patients compared with adults. Positron emission tomography (PET) receptor studies in adults have demonstrated that the incidence of EPS is related to dose-dependent dopamine type-2 (D2) receptor occupancy and that there is a significant relationship between the number of these receptors and age. Improved tolerability is leading to the increasing us of atypical antipsychotics for adolescent patients, though these new drugs to have specific adverse effects of their own. There is a need for more controlled studies of atypical antipsychotics in children and adolescents. In particular, dose-finding studies are needed to determine the optimal dose range to produce the greatest improvement with the least side effects for each of these drugs.",1998.0,0,0
1073,9764967,Constipation as an adverse effect of drug use in nursing home patients: an overestimated risk.,K N van Dijk; C S de Vries; P B van den Berg; A M Dijkema; J R Brouwers; L T de Jong-van den Berg,"To investigate whether results from case control and cross sectional studies which suggest an association between laxative use and other drug use could be confirmed in a cohort study of nursing home patients. A prospective cohort study of 2355 nursing home patients aged 65 years and over was performed to estimate the incidence relative risk of constipation associated with drug use. The study was conducted with prescription sequence analysis of each resident's detailed pharmacy records and data on morbidity and mobility. Use of drugs, which according to the summaries of product characteristics (SPC) and the literature on adverse drug effects have moderately to strongly constipating properties, was associated with a relative risk of 1.59 (95% CI 1.24-2.04) for the occurrence of constipation during exposure time. Use of drugs with mildly to moderately constipating effects was not associated with laxative use (RR 1.13; 95% CI 0.93-1.38). Stratification on the level of age, gender, type of nursing (psychogeriatric or somatic), morbidity, number of medications taken and mobility showed no confounding effects of these variables on outcome measurements. These variables all acted as effect modifiers. Effect of age and number of medications taken on the relative risk was nonlinear. Although an association between drugs that exhibit moderately to strongly constipating effects and occurrence of constipation was found, the risk was not as high as seen in previous studies. The high prevalence of constipation in nursing home patients is only partly due to adverse drug effects.",1998.0,0,0
1074,9771823,Update on the management of bipolar illness.,R C Shelton; M E Thase; R Kowatch; R J Baldessarini,,1998.0,0,0
1075,9777179,Predictors of differential response to clozapine and haloperidol. Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.,R Rosenheck; W Lawson; J Crayton; J Cramer; W Xu; J Thomas; M Stolar; D Charney,"We sought to identify baseline predictors of response to clozapine. Data were from a 15-site randomized clinical trial comparing clozapine and haloperidol in hospitalized patients with refractory schizophrenia (n = 423). Three-month outcomes were analyzed with the full sample (n = 368 due to attrition). Because of crossovers, analyses of 12-month outcomes were conducted with crossovers excluded (n = 291). Clinical predictors included age, race, diagnosis (current substance abuse, paranoid subtype of schizophrenia, or depressive syndrome), severity of symptoms, quality of life, age at onset of schizophrenia, extrapyramidal symptoms, and VA compensation payment. Multiple regression analysis was used to examine the interaction of treatment condition and each of these variables in predicting outcomes for symptoms, quality of life, side effects, and days hospitalized. Patients with higher quality of life at baseline (p = .04) and higher symptoms (p = .02) had relatively smaller declines in hospital days at 6 months. In the 12-month sample patients with higher levels of symptoms had greater symptom reductions at 12 months (p = .03) and greater improvement in quality of life (p = .004). Although high levels of symptoms were associated with greater improvement on clozapine, these findings are not robust enough to suggest that any specific, clinically defined subgroup of refractory patients should be preferentially targeted for clozapine treatment.",1998.0,0,0
1076,9781474,Olanzapine augmentation of clozapine.,S Gupta; S J Sonnenberg; B Frank,"In clinical practice, patients are encountered who are partial responders or nonresponders to clozapine. There are others who are unable to tolerate a high dosage of clozapine. In the two cases presented, we propose an alternative strategy using olanzapine in combination with clozapine in treatment-refractory patients. Olanzapine was found to be helpful in these patients, however, controlled studies are needed.",1998.0,0,0
1077,9783349,Olanzapine response in treatment-refractory schizophrenic patients with a history of substance abuse.,R R Conley; D L Kelly; E A Gale,"As many as half of all schizophrenic patients have abused alcohol or illicit drugs. This study determines the extent of substance abuse in a treatment-resistant population and assesses the response of this population to olanzapine treatment. Sixty patients with a DSM-III-R diagnosis of schizophrenia were included in an open 7-week trial of up to 25 mg/day of olanzapine. A history of substance abuse was present in 23 (38%) of the patients. At baseline evaluation, patients with a history of substance abuse had lower CGI scores and less negative symptomatology while having a higher rate of tardive dyskinesia. The overall group improved significantly over time. There were no differences in response between the substance-abusing (SA) and non-substance-abusing (NSA) patients as measured by the total BPRS, GGI and SANS ratings. The NSA group had significantly greater improvement in negative symptoms as measured by the BPRS negative symptom factor. Sixty-nine per cent (16/23) of the SA group and 60% (22/37) of the NSA were considered olanzapine responders by a priori criteria (p = NS). Extrapyramidal symptoms declined significantly in the overall group, but did not significantly differ between the SA and NSA groups. Treatment-refractory patients with prior substance abuse had a comparable outcome on olanzapine therapy to those with no history of abuse, as well as no increase in adverse effects. This suggests that olanzapine may be of benefit to SA patients who have a greater tendency for antipsychotic side effects and tardive dyskinesia.",1998.0,0,0
1078,9789907,Attentional improvement following quetiapine fumarate treatment in schizophrenia.,K W Sax; S M Strakowski; P E Keck,"This study examined changes in attentional performance in patients with schizophrenia during the 2 months after initiating treatment with quetiapine fumarate. Prior to treatment, attentional performance in patients with schizophrenia (n = 10) was significantly (p < 0.01) worse than in matched controls (n = 12). During treatment with quetiapine, performance in patients with schizophrenia improved, and by 2 months, did not differ significantly from that of the controls. These results suggest that quetiapine produces a significant improvement in attentional functioning in patients with schizophrenia.",2001.0,0,0
1079,9798075,Effects of clozapine on auditory event-related potentials in schizophrenia.,D Umbricht; D Javitt; G Novak; J Bates; S Pollack; J Lieberman; J Kane,"Schizophrenia is associated with cognitive deficits that are an intrinsic component of the disorder. Clozapine is an atypical antipsychotic that is superior to typical agents in the treatment of positive symptoms. The degree to which clozapine ameliorates cognitive deficits, however, is still controversial. Mismatch negativity (MMN), N200 (N2), and P300 (P3) are cognitive event-related potentials (ERPs) that index preattentive (MMN) and attention-dependent information processing (N2, P3) and provide a measure of cognitive deficits associated with schizophrenia. In schizophrenic patients deficient generation of MMN, N2, and P3 has been observed, suggesting impairments of discrete stages of information processing. This study investigates the effects of clozapine treatment on MMN, N2, and P3 generation. Patients were recruited from a haloperidol-controlled, double-blind treatment study of clozapine in chronic schizophrenia. ERPs were obtained at the beginning of the study and after 9 weeks (4 patients) and 16 weeks (13 patients) of treatment. Clozapine treatment was associated with a significant increase of P3 amplitude, which was not observed in the haloperidol group; however, clozapine treatment did not affect deficits in MMN and N2. These findings suggest that clozapine--in contrast to conventional antipsychotics--improves electrophysiological measures of attention-dependent information processing, but does not ameliorate preattentive deficits.",1998.0,0,0
1080,9798076,"Risperidone vs. haloperidol on reaction time, manual dexterity, and motor learning in treatment-resistant schizophrenia patients.",R S Kern; M F Green; B D Marshall; W C Wirshing; D Wirshing; S McGurk; S R Marder; J Mintz,"The present study compared the effects of risperidone vs. haloperidol on reaction time, manual dexterity, and two types of motor learning in a sample of treatment-resistant schizophrenia patients. Fifty-six DSM-III-R diagnosed schizophrenia inpatients participated in a randomized, double-blind comparison of risperidone vs. haloperidol. Measures of reaction time, manual dexterity, motor sequence learning, and gross motor learning were administered at baseline, after 4 weeks of fixed-dose medication, and after 4 weeks of flexible-dose medication. The results indicated that patients receiving risperidone showed greater improvement in reaction time and manual dexterity than patients receiving haloperidol. After covarying symptom changes and movement disorder ratings, the results remained significant. The two treatment groups did not differ on either measure of motor learning. The differences in performance in reaction time and manual dexterity may be due to a specific beneficial effect of risperidone, as opposed to a general reduction in extrapyramidal symptom liability, compared to haloperidol.",2001.0,0,0
1081,9798077,Relationship between patient variables and plasma clozapine concentrations: a dosing nomogram.,P J Perry; K A Bever; S Arndt; M D Combs,"Previous work has suggested factors such as gender, smoking behavior, dose, and age affect the amount of drug a patient requires to achieve a desired plasma concentration of clozapine. Plasma clozapine concentrations ranging from 350 to 504 ng/mL in treatment-refractory schizophrenics and schizoaffective patients produce response rates ranging approximately 55-80%. Without the aid of clozapine plasma concentration monitoring, 3-6 months are recommended for a therapeutic clozapine trial. Data suggest that the lag time to response can be reduced by administering a dose that produces a therapeutic clozapine concentration. To generate a clozapine dosing nomogram to predict clozapine steady-state plasma concentrations, a cohort of 71 patients was collected via retrospective chart review and/or patient interview. Clozapine steady-state plasma concentrations and demographic variables were obtained. Multiple-linear regression was utilized to examine the relationship between the plasma clozapine concentration and the independent variables. The dosing model that optimally predicted steady-state clozapine plasma concentrations included the variables dose (mg/day), smoking (yes = 0 and no = 1), gender, and a dose-gender interaction variable. The model explained 47% of the variance in the clozapine concentrations (F = 14.42, p < .001, r2 = .47). Two equations, one for male subjects, i.e., clozapine (ng/mL) = 111 (smoke) + 0.464 (dose) + 145, and one for female subjects, i.e., clozapine (ng/mL) = 111 (smoke) + 1.590 (dose)-149, were derived to predict clozapine steady-state plasma concentrations to serve as a clozapine dosing guide for clinicians. A clozapine dosing nomogram was constructed as a clinical aid to facilitate clozapine dosing.",1998.0,0,0
1082,9803771,Economic outcomes of antipsychotic agents in a Medicaid population: traditional agents vs. risperidone.,B S Nightengale; J M Crumly; J Liao; B J Lawrence; E W Jacobs,"Clinical trials reveal that the newer atypical antipsychotic agents are more effective and have fewer side effects than traditional agents. However, these newer agents have a higher acquisition cost than traditional agents. This study assessed the differential impact of risperidone and traditional agents on the total schizophrenia-related cost of care for Medicaid patients suffering from schizophrenia. This was a retrospective longitudinal pretest-posttest analysis of Medicaid claims data covering January 1992 to August 1996. Continuously eligible patients (n = 150) with a documented diagnosis of schizophrenia were evaluated. Medical claims were analyzed for patients treated with traditional antipsychotics for at least 12 months and then switched to risperidone and followed for at least 12 months. Patients who failed on at least one traditional agent and who remained on other traditional agents throughout the study timeframe served as a control group. Monthly costs per patient were estimated using mixed model linear regression with age and gender serving as covariates. The total monthly costs per patient for the risperidone and traditional cohorts were similar ($1,050.52 and $946.24, respectively; p = .5438) during the pretest phase of the study. For patients treated with risperidone, drug costs were $177.35 higher (CL0.95 +/- $7.64; p = .0001) per patient per month in the posttest period compared with the pretest period. However inpatient hospital costs were $312.04 lower (CL0.95 +/- $146.76; p = .001) per patient per month in the posttest period compared with the pretest period. In addition, physician costs were $9.55 lower (CL0.95 +/- $5.31; p = .0004) per patient per month in the posttest period. The difference from the pretest to posttest period for outpatient mental health clinic costs was statistically similar. For those in the risperidone cohort, total estimated costs decreased by $204.87 per patient per month during treatment with risperidone (CL0.95 +/- $161.01; p = .0127). Over the same time-frame, total costs increased $160.68 per patient per month (CL0.95 +/- $196.04; n.s.; p = .1082) in the control cohort. While the mean monthly drug cost was significantly higher during treatment with risperidone, this increase was offset by cost reductions elsewhere in the system.",1998.0,0,0
1083,9817624,Risperidone is associated with blunting of D-fenfluramine evoked serotonergic responses in schizophrenia.,H Jones; V A Curtis; P A Wright; J V Lucey,"The high 5-HT affinity of some atypical antipsychotic agents is thought to contribute to their clinical efficacy. We examined central 5-HT responses in two groups of ten schizophrenic patients by measuring serum prolactin and cortisol responses to the neuroendocrine challenge D-fenfluramine. One group of patients with schizophrenia was tested after a 2-week neuroleptic free period. A similar group were tested after a mean of 12 weeks treatment with the atypical antipsychotic risperidone. A significant elevation of baseline serum prolactin levels, consistent with dopaminergic antagonism was seen after risperidone treatment. Significantly reduced 5-HT mediated serum prolactin responses were seen in risperidone treated patients. D-fenfluramine evoked serum prolactin responses were positively correlated with positive but not negative schizophrenic symptoms for all 20 patients. Risperidone treatment was associated with a significant functional in-vivo 5-HT antagonism similar to clozapine. 5-HT antagonism may contribute to the efficacy of risperidone against positive schizophrenic symptoms.",1998.0,0,0
1084,9818633,Clinical and neurocognitive effects of clozapine and risperidone in treatment-refractory schizophrenic patients: a prospective study.,J P Lindenmayer; A Iskander; M Park; F S Apergi; P Czobor; R Smith; D Allen,"Few controlled studies have compared the efficacy of clozapine and risperidone in treatment-refractory schizophrenic patients. The present study investigates the efficacy of both clozapine and risperidone on psychopathologic and neurocognitive measures in a prospective 12-week open-label trial in treatment-refractory schizophrenic patients from state psychiatric hospitals. Thirty-five DSM-IV schizophrenic patients with a documented history of nonresponse to typical neuroleptics were treated with either clozapine or risperidone. Response was assessed every 2 weeks by independent raters with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) scale, neurologic rating scales, and plasma drug levels. Neurocognitive tests were administered at baseline and week 12. Both clozapine and risperidone brought about significant (p < .003) overall improvement in psychopathology. However, clozapine was numerically superior to risperidone on PANSS total scores and PANSS positive, negative, excitement, and cognitive factors. Extrapyramidal side effects were minimal for clozapine, whereas some were present for risperidone. Patients taking risperidone improved significantly in the beginning stages of the study and remained stable thereafter. Patients taking clozapine showed a gradual improvement that occurred over the entire length of the trial. Neurocognitive measures showed minimal improvement and did not differentiate between the 2 medication groups. Both clozapine and risperidone were comparably effective across a wide spectrum of psychopathologic measures. While the efficacy of clozapine was only numerically superior to that of risperidone, it was associated with fewer extrapyramidal side effects and with progressive improvement over the 12-week treatment period, suggesting that in longer trials clozapine may prove to be superior to risperidone in neuroleptic-refractory patients.",1998.0,0,1
1085,9818639,Efficacy and safety of neuroleptics in behavioral disorders associated with dementia.,K L Lanctôt; T S Best; N Mittmann; B A Liu; P I Oh; T R Einarson; C A Naranjo,"Neuroleptics are commonly used to treat behavioral disorders associated with dementia. However, their safety and efficacy have not been well established in these patients. A meta-analysis of randomized, controlled (either placebo or active drug), double-blind trials published since 1966 (N = 16; 499 treated, 112 active controls, and 123 placebo) was conducted. Data were collected on proportion of patients with clinically significant improvement, significant side effects, and dropout rates. Pooled mean percentages of patients who improved (95% CI): all neuroleptics, 64% (54% to 74%); low potency, 63% (54% to 72%); moderate potency, 70% (56% to 85%); moderate-high potency, 62% (49% to 75%); and high potency, 69% (49% to 90%). Thus, no differences in efficacy existed between different potencies of neuroleptics. Therapeutic effect (neuroleptic minus placebo) was only 26% (14% to 38%). Treatment-emergent side effects were more common for neuroleptics vs. placebo (mean difference = 25%, 13% to 37%), but pooled mean dropout rates were not different (mean difference = 4%, -7% to 14%). Neither weighting by clinical trial quality (3 raters; weighted agreement, 83% to 92%) nor exclusion of poor quality trials changed the results. Neuroleptics have small but significant efficacy over placebo in this population, and the efficacy rate is equivalent to the side effect rate. Comparing different neuroleptics shows they have similar efficacy, side effects, and dropout rates. Further study to determine more specific drug-responsive behaviors is needed to maximize benefits of these drugs.",1998.0,0,1
1086,9824875,Clozapine effects on force control in schizophrenic patients.,P B Vrtunski; P E Konicki; G E Jaskiw; D W Brescan; K Y Kwon; G Jurjus,"We previously reported significant differences in force control (FC) function between schizophrenics treated with typical antipsychotic drugs (APD) and those treated with clozapine. Clozapine treatment was associated with an attenuation of the capacity for fine motor control. We now report that a test-retest study with 41 treatment-refractory patients confirms our earlier finding; the FC deficit is due primarily to clozapine treatment. An additional comparison was made with 10 patients who were administered the FC test repeatedly through the initial clozapine titration interval of 6-8 weeks. The results suggest that two distinct clozapine effects can be distinguished, an initial transient stage characterized by 'drowsiness' and a subsequent stage with dose-dependent emerging myoclonic features.",1998.0,0,0
1087,9825948,Post-marketing studies: the work of the Drug Safety Research Unit.,F J Mackay,"The Drug Safety Research Unit (DSRU) is the centre for prescription-event monitoring (PEM) in England. PEM studies are noninterventional observational cohort studies which monitor the safety of newly marketed drugs. The need for post-marketing surveillance is well recognised in the UK and general practice is an ideal source of data. PEM studies are general practitioner (community)-based and exposure is based on dispensed prescription data in England. To date, 65 PEM studies have been completed with a mean cohort size of 10 979 patients and the DSRU database has clinical information on over 700000 patients prescribed new drugs. Unlike spontaneous reporting schemes, PEM produces incidence rates for events reported during treatment. Comparative studies can be conducted for drugs in the same class. The DSRU aggregates outcome data for pregnancies exposed to new drugs. Data for children and the elderly can also be specifically examined. PEM data have a number of advantages over data from computerised general practice databases in the UK. PEM is the only technique within the UK capable of monitoring newly marketed drugs in such a comprehensive and systematic way.",1998.0,0,0
1088,9828990,Oral olanzapine versus oral haloperidol in the maintenance treatment of schizophrenia and related psychoses.,P V Tran; M A Dellva; G D Tollefson; A L Wentley; C M Beasley,"Three studies compared olanzapine and haloperidol given orally in maintenance therapy for schizophrenia and related psychoses. Data were from double-blind extensions of acute studies. The subjects met criteria for schizophrenia, schizophreniform disorder or schizoaffective disorder. Subjects had responded to acute therapy (Brief Psychiatric Rating Scale total score decreased > or = 40% from baseline (Studies 1, 2, and 3) or was < or = 18 (Studies 1 and 2)) and were out-patients at their last acute phase visit. Relapse was defined as hospitalisation for psychopathology. Subjects treated with olanzapine in the three studies were pooled to form the olanzapine group and subjects treated with haloperidol were pooled to form the haloperidol group. Olanzapine-treated subjects experienced less relapse (P = 0.034). The Kaplan-Meier estimated one-year risk of relapse was 19.7% with olanzapine and 28% with haloperidol. Olanzapine was superior to haloperidol in the maintenance therapy of schizophrenia and related psychoses. This work was sponsored by Eli Lilly and Company.",2001.0,0,1
1089,9828992,Nithsdale schizophrenia surveys. 17. Fifteen year review.,C Kelly; R G McCreadie; T MacEwan; S Carey,"In recent years there has been a shift to 'community care' and the introduction of several 'atypical' antipsychotic drugs. We report the impact of these changes. In Nithsdale, Dumfries and Galloway, Scotland, the population of patients with schizophrenia was identified in 1996. This census replicated a study carried out in 1981. The population with schizophrenia were compared on clinical and social variables. The whereabouts in 1996 of the 1981 population was determined. In comparison with the 1981 population, more patients in 1996 had positive, negative and non-schizophrenic symptoms. More showed tardive dyskinesia. Social adjustment had not changed. They had spent less time in hospital; fewer (13%) were living with their parents; and fewer (8%) were employed. By 1996, 35% of the 1981 cohort had died (standardised mortality rate male-154; female-162). The mental health of a community of people with schizophrenia living in a rural area in 1996 was poorer than in 1981.",1998.0,0,0
1090,9830258,P50 suppression in recent-onset schizophrenia: clinical correlates and risperidone effects.,C M Yee; K H Nuechterlein; S E Morris; P M White,"Chronic schizophrenic patients often do not suppress the auditory P50 component of the event-related potential to the second of 2 clicks, presented 500 ms apart, suggesting a loss of normal inhibition. This study attempted to replicate the P50 suppression deficit in patients with recent-onset schizophrenia and to examine whether P50 is related to clinical symptoms or is affected by an atypical antipsychotic medication. Data from 22 recent-onset schizophrenia patients and 11 normal controls revealed that disruption in P50 suppression is present during the early stages of illness. In addition, impaired P50 suppression covaried with clinical ratings of anxiety, depression, and anergia; results also suggested that the P50 inhibitory deficit may be related to the degree of patients' attentional impairment. Finally, risperidone, compared with a typical antipsychotic medication, improved inhibition of P50 to the second click. These results support P50 suppression as a measure of disordered neurocognition in schizophrenia.",1998.0,0,0
1091,9832346,D2-dopamine receptor occupancy measured by IBZM-SPECT in relation to extrapyramidal side effects.,K Broich; F Grünwald; S Kasper; E Klemm; H J Biersack; H J Möller,"The purpose of this study was to compare striatal D2 dopamine receptor occupancy of various typical neuroleptics and clozapine in relation to the occurrence of extrapyramidal side effects (EPS). Forty-four inpatients with schizophrenia, including 12 patients with schizodominant schizoaffective disorder, were evaluated using 123I-iodobenzamide (IBZM) and single photon emission computed tomography. Striatal D2 dopamine receptor occupancy was estimated by use of a striatal/frontal cortex ratio (ST/FC) of IBZM binding. Fourteen patients were neuroleptic-free and served as controls. Six patients were treated with clozapine and 24 patients were treated with various typical neuroleptics. ST/FC ratios in patients taking typical neuroleptics were significantly lower than those who were neuroleptic free or treated with clozapine. Patients with EPS had lower ST/FC ratios than those without EPS. A significant linear relationship between ST/FC ratios and severity of EPS estimated by the Simpson-Angus-Scale was established (r=-0.51, p=0.041).",1998.0,0,0
1092,9836012,D-serine added to antipsychotics for the treatment of schizophrenia.,G Tsai; P Yang; L C Chung; N Lange; J T Coyle,"Hypofunction of N-methyl-D-aspartate (NMDA) subtype glutamate receptor has been implicated in the pathophysiology of schizophrenia. D-serine is a full agonist of the glycine site of NMDA receptor, an endogenous cotransmitter enriched in corticolimbic regions and distributed in parallel with NMDA receptor. Supplementation of D-serine may improve the symptoms of schizophrenia. Thirty-one Taiwanese schizophrenic patients enrolled in a 6-week double-blind, placebo-controlled trial of D-serine (30 mg/kg/day), which was added to their stable antipsychotic regimens. Of these, 28 completed the trial. Measures of clinical efficacy, side effects, and serum levels of amino acids and D-serine were determined every other week. Wisconsin Card Sorting Test (WCST) was performed at the beginning and end of the trial. Patients who received D-serine treatment revealed significant improvements in their positive, negative, and cognitive symptoms as well as some performance in WCST. D-serine levels at week 4 and 6 significantly predicted the improvements. D-serine was well tolerated and no significant side effects were noted. The significant improvement with the D-serine further supports the hypothesis of NMDA receptor hypofunction in schizophrenia. Given the effects of D-serine on positive symptoms, a trial of D-serine alone in schizophrenia should be considered.",1998.0,0,0
1093,9850205,London-east Anglia randomised controlled trial of cognitive-behavioural therapy for psychosis. III: Follow-up and economic evaluation at 18 months.,E Kuipers; D Fowler; P Garety; D Chisholm; D Freeman; G Dunn; P Bebbington; C Hadley,"A randomised controlled trial of cognitive-behavioural therapy (CBT) for people with medication-resistant psychosis showed improvements in overall symptomatology after nine months of treatment; good outcome was strongly predicted by a measure of cognitive flexibility concerning delusions. The present paper presents a follow-up evaluation 18 months after baseline. Forty-seven (78% of original n = 60) participants were available for follow-up at 18 months, and were reassessed on all the original outcome measures (see Part I). An economic evaluation was also completed. Those in the CBT treatment group showed a significant and continuing improvement in Brief Psychiatric Rating Scale scores, whereas the control group did not change from baseline. Delusional distress and the frequency of hallucinations were also significantly reduced in the CBT group. The costs of CBT appear to have been offset by reductions in service utilisation and associated costs during follow-up. Improvement in overall symptoms was maintained in the CBT group 18 months after baseline and nine months after intensive therapy was completed. CBT may be a specific and cost-effective intervention in medication-resistant psychosis.",1998.0,0,0
1094,9854654,Treatment with risperidone of an acute psychotic episode in a patient with AIDS.,N Zilikis; I Nimatoudis; V Kiosses; C Ierodiakonou,,1998.0,0,0
1095,9855322,Lack of effect of olanzapine on the pharmacokinetics of a single aminophylline dose in healthy men.,W L Macias; R F Bergstrom; B J Cerimele; K Kassahun; D E Tatum; J T Callaghan,"To test whether olanzapine, an atypical antipsychotic, is an inhibitor of cytochrome P450 (CYP) 1A2 activity, we conducted a drug interaction study with theophylline, a known CYP1A2 substrate. Two-way, randomized, crossover study. Clinical research laboratory. Nineteen healthy males (16 smokers, 3 nonsmokers). Because the a priori expectation was no effect of olanzapine on theophylline pharmacokinetics, a parallel study using cimetidine was included as a positive control. In group 1, 12 healthy subjects received a 30-minute intravenous infusion of aminophylline 350 mg after 9 consecutive days of either olanzapine or placebo. In group 2, seven healthy subjects received a similar aminophylline infusion after 9 consecutive days of either cimetidine or placebo. Concentrations of theophylline and its metabolites in serum and urine were measured for 24 and 72 hours, respectively. Plasma concentrations of olanzapine and its metabolites were measured for 24 hours after the next to last dose and 168 hours after the last olanzapine dose. Olanzapine did not affect theophylline pharmacokinetics. However, cimetidine significantly decreased theophylline clearance and the corresponding formation of its metabolites. Urinary excretion of theophylline and its metabolites was unaffected by olanzapine but was reduced significantly by cimetidine. Steady-state concentrations of olanzapine (15.3 ng/ml), 10-N-glucuronide (4.9 ng/ml), and 4'-N-desmethyl olanzapine (2.5 ng/ml) were observed after olanzapine 10 mg once/day and were unaffected by coadministration of theophylline. As predicted by in vitro studies, steady-state concentrations of olanzapine and its metabolites did not affect theophylline pharmacokinetics and should not affect the pharmacokinetics of other agents metabolized by the CYP1A2 isozyme.",1998.0,0,0
1096,9859115,[Significance of hepatic cytochrome P450 enzymes for psychopharmacology].,C Normann; B Hesslinger; J Bauer; M Berger; J Walden,"Nearly all psychotropic drugs are metabolized by hepatic cytochrome P450-enzymes. In humans, there are 5 isoenzymes involved in this process. The activity of these enzymes can be modulated by a number of commonly used drugs, yielding potentially hazardous interactions. Most of the recently introduced selective serotonin reuptake inhibitors are potent inhibitors of cytochrome P450 enzymes. Thus, the plasma concentrations of tricyclic antidepressants or clozapine might be elevated into toxic levels. In contrast, carbamazepine induces most of the isoenzymes. This potentiates the elimination of tricyclics and antipsychotics and might cause a serious risk for the recurrence of depressive or psychotic symptoms. Moreover, 5-10% of the population are slow metabolizers of CYP2D6. This group is prone to increased adverse effects of moderately dosed medication. This review systematically points out the reported or predicted pharmacokinetic drug interactions in psychopharmacology focussing on clinical significance.",1998.0,0,0
1097,9860108,Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial.,P Keck; A Buffenstein; J Ferguson; J Feighner; W Jaffe; E P Harrigan; M R Morrissey,"A double-blind, placebo-controlled, multicenter study, was performed to evaluate the efficacy and safety of ziprasidone in 139 patients with an acute exacerbation of schizophrenia or schizoaffective disorder. Patients were randomized to receive ziprasidone 40 mg/day, 120 mg/day or placebo for 28 days. Ziprasidone 120 mg/day was significantly more effective than placebo in improving the BPRS total, CGI-S. BPRS depression cluster and BPRS anergia cluster scores (all P < 0.05). Similarly, the percentages of patients classified as responders on the BPRS (> or = 30% reduction) and the CGI improvement (score < or = 2) were significantly greater with ziprasidone 120 mg/day compared with placebo (P < 0.05). The number of patients who experienced an adverse event was similar in all three treatment groups, and discontinuation due to adverse events was rare (five of 91 ziprasidone-treated patients). The most frequently reported adverse events, that were more common in either ziprasidone group than in the placebo group, were dyspepsia, constipation, nausea and abdominal pain. There was a notably low incidence extrapyramidal side-effects (including akathisia) and postural hypotension and no pattern of laboratory abnormalities or apparent weight gain. Ziprasidone-treated patients were not clinically different from placebo-treated patients on the Simpson-Angus Rating scale, Barnes Akathisia scale and AIMS assessments. These results indicate that ziprasidone 120 mg/day is effective in the treatment of the positive, negative and affective symptoms of schizophrenia and schizoaffective disorder with a very low side-effect burden.",2001.0,1,1
1098,9860152,A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism.,R A Lucas; D J Gilfillan; R F Bergstrom,"Olanzapine is a novel antipsychotic, which is effective against both the positive and negative symptoms of schizophrenia and causes fewer extrapyramidal adverse effects than conventional antipsychotics. The purpose of the present study was to assess the potential for a pharmacokinetic interaction between olanzapine and carbamazepine, since these agents are likely to be used concomitantly in the treatment of manic psychotic disorder. The pharmacokinetics of two single therapeutic doses of olanzapine were determined in 11 healthy volunteers. The first dose of olanzapine (10 mg) was taken alone and the second dose (10 mg) after 2 weeks of treatment with carbamazepine (200 mg BID). Measurement of urinary 6beta-hydroxycortisol/cortisol excretion was used as an endogenous marker to confirm that induction of CYP3A4 by carbamazepine had occurred. The dose of olanzapine given after a 2-week pretreatment with carbamazepine was cleared more rapidly than olanzapine given alone. Olanzapine pharmacokinetic values for Cmax and AUC were significantly lower after the second dose, the elimination half-life was significantly shorter, and the clearance and volume of distribution were significantly increased. Carbamazepine has been shown to induce several P450 cytochromes including CYP3A4 and CYP1A2. Since CYP1A2 plays a role in the metabolic clearance of olanzapine, the interaction may be attributed to induction of CYP1A2 by carbamazepine, leading to increased first-pass and systemic metabolism of olanzapine. The interaction is not considered to be of clinical significance because olanzapine has a wide therapeutic index, and the changes in plasma concentration of olanzapine are within the fourfold variation that occurs without concern for safety in a patient population.",1998.0,0,0
1099,9861575,Risperidone and olanzapine: optimal dosing for efficacy and tolerability in patients with schizophrenia.,S Kasper,"Schizophrenia is a chronic and debilitating disorder whose effective pharmacological management is often less than optimal. For several decades, pharmaceutical treatment for this disorder consisted of conventional neuroleptics such as haloperidol and chlorpromazine. However, the limitations of these drugs have driven the development of newer antipsychotics that are designed to be more efficacious and more tolerable than conventional agents. Newer agents available for consideration as first-line treatment options now include risperidone, olanzapine, sertindole and, more recently, quetiapine. Proper dosing has emerged as a vital factor in the effective use of these newer drugs. This report examines data derived from clinical trials and market research with risperidone and olanzapine to help clinicians determine the appropriate dose for efficacy and to appraise the adverse events associated with that efficacious dose. Current information suggests that, for most patients with schizophrenia, the optimal dose with respect to efficacy and tolerability of risperidone is < or = 6 mg/day. The optimal dose of olanzapine is less clear and may be 15 mg/day or higher. With the advent of these newer antipsychotics, clinicians now have more treatment options for the management of patients with psychotic disorders. Knowledge gained through clinical experience is needed to augment clinical trial results and to help define the most effective use of each of these agents.",1998.0,0,0
1100,9861577,Elevated serum creatine kinase activity in adolescent psychiatric inpatients on admission.,R Blumensohn; R Yoran-Hegesh; P Golubchik; R Mester; H Fluhr; H Hermesh; A Weizman,"Studies in adults have indicated a significant relationship between high serum creatine kinase levels on admission and acute psychosis. However, data on children are sparse. The files of 183 hospitalized children and adolescents (93 boys, 90 girls) with severe psychiatric disorders were reviewed for serum creatine kinase activity on admission, psychomotor agitation, Clinical Global Impression Score, need for intramuscular injection, number of neuroleptic medications and presence of neuroleptic malignant syndrome. Serum creatine kinase levels > 201 IU/ml were considered abnormal. Boys had significantly higher creatine kinase activity than girls. Division of the cohort by diagnosis yielded significantly higher levels in those with schizophrenia, affective disorders and mental retardation. Higher levels were also associated with higher Clinical Global Impression score on admission, use of injections and physical restraint, and nonresponse to neuroleptic medication. There were no cases of neuroleptic malignant syndrome. This first large-scale investigation of serum creatine kinase activity in young psychiatric inpatients shows a significant association between high creatine kinase activity and acute psychosis, similar to that in adults. Furthermore, high creatine kinase levels on admission are predictive of the severity of the psychosis, but are not associated with neuroleptic malignant syndrome. Because psychotic adolescents with high admission creatine kinase levels tend to be nonresponders, clinicians should consider the early use of atypical antipsychotics in this subgroup.",1998.0,0,0
1101,9862604,"Switching from clozapine to olanzapine in treatment-refractory schizophrenia: safety, clinical efficacy, and predictors of response.",D C Henderson; R A Nasrallah; D C Goff,"In our experience, many of our schizophrenic patients treated with clozapine request the newer atypical antipsychotic agents in order to eliminate the weekly blood monitoring. However, there are few guidelines available to clinicians interested in switching patients successfully treated with clozapine to olanzapine. The goal of this study was to collect preliminary data on the safety, clinical effectiveness, and predictors of response of switching clozapine patients to olanzapine. In an open trial, 19 patients receiving clozapine were switched to olanzapine. Eight (42%) of 19 patients were considered responders. Seven patients decompensated seriously enough to require hospitalization. All 7 of these patients were restabilized on clozapine treatment in the hospital, and olanzapine was discontinued. In an additional 4 patients, clinical status worsened, and clozapine doses were titrated upwards and olanzapine was slowly discontinued. Overall, mean total Brief Psychiatric Rating Scale (BPRS) scores increased significantly from baseline to final assessment (p = .02). Responders had been treated for a significantly shorter period of time with clozapine prior to the switch compared to nonresponders (p = .04) and were receiving a lower dose of clozapine (p = .05). The final olanzapine dose did not differ between responders and nonresponders. All responders have remained on olanzapine treatment and are stable. In this open trial, the crossover from clozapine to olanzapine was generally well tolerated and resulted in a successful transition for 8 of the 19 patients. However, mean scores on the total BPRS and negative symptom and depressive symptom subscales significantly increased. Caution must be taken in determining which patients may benefit from the switch to olanzapine because of the risk of decompensation and hospitalization. Because this was an open trial, these findings require replication in a controlled trial.",1998.0,0,1
1102,9865219,Multiple outcome assessment in a study of the cost-effectiveness of clozapine in the treatment of refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.,R Rosenheck; J Cramer; W Xu; J Grabowski; R Douyon; J Thomas; W Henderson; D Charney,"To develop new methods for combining results from multiple outcome domains and to demonstrate their application in a study of the cost-effectiveness of clozapine in treating hospitalized patients with refractory schizophrenia. Interview assessments, and administrative utilization and cost data, concerning 423 patients with refractory schizophrenia who had been hospitalized for 30-364 days during the year before study entry, at 15 VA medical centers. A 12-month double-blind trial compared clozapine (n = 205) and haloperidol (n = 218) in the treatment of refractory schizophrenia. Data from standard assessment instruments, gathered at baseline and at 6 weeks, and at 3, 6, 9, and 12 months, were used to develop a Composite Health Index for Schizophrenia, a measure that addresses outcome in six domains, weighted by patient or provider preferences. Cumulative improvement was estimated by computing the area under the improvement curve. This measure was then combined with cost data, reflecting consumption of societal resources to estimate incremental cost-effectiveness ratios. Clozapine was significantly more effective than haloperidol on measures of symptoms (p = .02) and side effects (p < .0001), with nonsignificant trends in the positive direction on community role functioning (p = .06), family relationships (p = .23), social relationships (p = .30), and daily activities (p = .20). Clozapine was also more effective than haloperidol on the one-year cumulative Composite Health Index for Schizophrenia (p < .0001 for all weighting schemes). After converting this measure to a 0-1 Worst Health-Good Health Scale analogous to Quality Adjusted Life Years, clozapine was found to yield a small improvement of .049 Worst Health-Good Health Units as compared to an improvement of only .027 Units for haloperidol (p < .0001). Average annual costs were $2,733 lower for clozapine (95% C.I. = -$9,220 to $3,754). Although clozapine was significantly more effective than haloperidol, the summary cost-effectiveness ratio had a wide 95 percent confidence interval ranging from -$431,585 to $177,352. Methods demonstrate an approach to using conventional disease-specific measures to evaluate the cumulative effectiveness of novel treatments for psychotic disorders and for expressing their economic effect as cost-effectiveness ratios. Among high hospital users with refractory schizophrenia, clozapine is more cost-effective than standard treatment, although the magnitude of its effect is small and there is considerable uncertainty about the cost estimates.",1998.0,0,0
1103,9875725,Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action.,F X Vollenweider; M F Vollenweider-Scherpenhuyzen; A Bäbler; H Vogel; D Hell,"Psilocybin, an indoleamine hallucinogen, produces a psychosis-like syndrome in humans that resembles first episodes of schizophrenia. In healthy human volunteers, the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol. These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation, independently of dopamine stimulation. Thus, serotonin-2A overactivity may be involved in the pathophysiology of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics.",1999.0,0,0
1104,9884683,The antipsychotics. A pediatric perspective.,R L Findling; S C Schulz; M D Reed; J L Blumer,"As can be discerned from this article, antipsychotics are commonly prescribed, and they are not used to treat only psychosis. Although some data support the use of typical antipsychotics in pediatric patients with a variety of psychiatric syndromes, concerns about the safety and tolerability of these agents often complicated their use and probably even interfered with case identification. A fundamentally new group of medications, the atypicals, have now become available and may not only have improved tolerability but also may have greater ability to reduce some target symptoms. Because of their superior side-effect profile in adults, some of these atypical treatments probably will be commonly prescribed despite a relative paucity of data about their use in the young. Moreover, although frequently prescribed in this age group, the overall prescription rate for antipsychotics will probably increase because of the putative improved safety profile of the newer agents. However, it is possible that serious side effects, such as tardive dyskinesia or neuroleptic malignant syndrome, may occur with these atypical agents. For this reason, the enthusiasm for prescribing these newer treatments should be tempered with the understanding that these agents, although they may in some ways be superior to their predecessors, still possess the potential for significant adverse events. Four atypical antipsychotics are currently marketed in the United States (see Table 2). One additional agent, ziprasodone, is undergoing clinical investigation. Ziprasodone has been shown to be superior to placebo in adults suffering from schizophrenia. Ziprasodone will probably be marketed in the United States in the near future. Whether all of these atypical drugs will have a place in the clinical armamentarium of the pediatric psychopharmacologist remains to be determined. Because the receptor binding profile of the atypical agents differ, it is not possible to assume that what is true for one of these agents is true for the others. Although results from most preliminary studies with atypical antipsychotics indicate that these are promising agents for pediatric patients, further research is needed to define just how these medications may be most judiciously used.",1999.0,0,0
1105,9885782,Mechanism of peripheral noradrenergic stimulation by clozapine.,I Elman; D S Goldstein; G Eisenhofer; J Folio; A K Malhotra; C M Adler; D Pickar; A Breier,"Elevated plasma norepinephrine (NE) levels is a relatively consistent clinical effect of clozapine. Plasma NE levels reflect an interplay of release, reuptake, metabolism, and excretion. To explore the mechanism of clozapine-induced plasma NE elevation, we measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE (3H-NE) in schizophrenic patients treated with clozapine, fluphenazine, or placebo. Clozapine-treated patients had markedly higher levels of NE than did the patients treated with fluphenazine or placebo. NE spillover averaged more than three times higher in clozapine-treated patients; whereas NE clearance did not differ among the groups. Production of 3H-dihydroxyphenylglycol (3H-DHPG), a purely intraneuronal metabolite of 3H-NE in clozapine-treated patients was normal, indicating that clozapine did not affect neuronal uptake of NE. Because plasma levels of DHPG and dihydroxyphenylacetic acid (DOPAC), deaminated metabolites of catecholamines, in clozapine-treated patients were normal, clozapine also did not seem to inhibit intraneuronal monoamine oxidase (MAO). High plasma NE levels in clozapine-treated patients, therefore, resulted from increased NE spillover rather than decreased reuptake, metabolism, or clearance.",1999.0,0,0
1106,9890595,Clozapine and hospitalization.,R Rosenheck; D Charney; J Cramer,,1999.0,0,0
1107,9892301,Olanzapine versus haloperidol treatment in first-episode psychosis.,T M Sanger; J A Lieberman; M Tohen; S Grundy; C Beasley; G D Tollefson,"It has been hypothesized that the morbidity and mortality associated with schizophrenia can be prevented by providing effective treatment during the first episode of psychosis. Hence, the authors examined patients with first-episode psychosis to determine the efficacy and safety of olanzapine and haloperidol treatment. A subpopulation of first-episode patients (N=83) from a large prospective, multicenter, international, double-blind, 6-week acute treatment study was evaluated. These patients were selected from a pool of 1,996 patients who had a DSM-III-R diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder and who also met the following criteria: 1) the length of their current psychotic episode had to be 5 or fewer years, and 2) patients had to be 45 years of age or younger at onset of first psychotic symptoms. Compared to haloperidol, olanzapine showed a statistically significantly greater reduction in the Brief Psychiatric Rating Scale (BPRS) total and negative scores and in the Positive and Negative Syndrome Scale total and positive scores. Clinical response (defined as 40% or greater improvement in BPRS total score from baseline) was also statistically significantly higher in olanzapine-treated patients (67.2%) than in haloperidol-treated patients (29.2%). Olanzapine-treated patients further showed statistically significant improvements in the Simpson-Angus scale and Barnes Akathisia Scale scores, while haloperidol-treated patients showed a worsening on both measures. Compared to olanzapine-treated multiple-episode patients in the parent study, olanzapine-treated first-episode patients achieved an even statistically significantly higher response. Haloperidol-treated first-episode patients experienced statistically significantly more extrapyramidal symptoms than haloperidol-treated multiple-episode patients. In patients experiencing first-episode psychosis, olanzapine had a risk-benefit profile significantly superior to that of haloperidol. The study results suggest that novel antipsychotic agents such as olanzapine should be considered as a preferred option in first-episode psychosis, on the basis of both safety and efficacy advantages.",2001.0,1,1
1108,9892302,Impact of clozapine on negative symptoms and on the deficit syndrome in refractory schizophrenia. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia.,R Rosenheck; L Dunn; M Peszke; J Cramer; W Xu; J Thomas; D Charney,"This study compared the effect of clozapine and haloperidol on positive and negative symptoms of schizophrenia and in patients with high levels of negative symptoms or the deficit syndrome. Patients were participants in a 15-site double-blind, random-assignment Veterans Administration trial comparing clozapine (N=205) and haloperidol (N=217) in hospitalized patients with refractory schizophrenia. Analysis of covariance examining change at 6 weeks, 3 months, and 1 year evaluated 1) clozapine's effect on positive and negative syndromes; 2) clozapine's effect on each syndrome, statistically controlling for the other; and 3) the interaction of clozapine treatment and the presence or absence of high levels of negative symptoms at baseline and the deficit syndrome. Patients treated with clozapine showed significantly greater improvement than control subjects on positive symptoms at all time points and on negative symptoms at 3 months. Clozapine had no independent effect on negative symptoms at any time after control for positive symptoms, but its effects on positive symptoms persisted after control for negative symptoms at 6 weeks only. There were no significant differences in response to clozapine between patients with high and low levels of negative symptoms at baseline or between patients with and without the deficit syndrome. The greater effectiveness of clozapine as compared to conventional medications in refractory schizophrenia is not specific to either negative clinical symptoms or clinical subtypes defined by prominent negative symptoms or evidence of the deficit syndrome.",1999.0,0,0
1109,9892314,Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia.,S G Potkin; Y Jin; B G Bunney; J Costa; B Gulasekaram,"The focus of this study was the systematic evaluation of the clinical effects of glycine as an adjunct to the atypical antipsychotic clozapine in the treatment of schizophrenia. In a double-blind, placebo-controlled study, 19 patients with chronic, treatment-resistant schizophrenia who were maintained on optimal doses of clozapine (400-1200 mg/day) were administered either 30 g/day of glycine (N=9) or placebo (N=10) for 12 weeks. Clinical evaluations with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, and the Simpson-Angus movement scale were completed biweekly. The use of glycine as an adjunct to clozapine was not effective in decreasing positive or negative symptoms. In contrast, the patients treated with clozapine without glycine had a 35% reduction in positive symptoms. These preliminary data suggest that glycine may interfere with the antipsychotic efficacy of atypical neuroleptics such as clozapine.",1999.0,0,0
1110,9916613,Drug utilization patterns and outcomes associated with in-hospital treatment with risperidone or olanzapine.,R M Procyshyn; S Zerjav,"This study compared the drug-utilization costs and indicators of clinical outcomes associated with the use of risperidone and olanzapine in a hospital setting. We conducted a nonrandomized, retrospective chart review of consecutive patients identified as presenting with psychotic symptoms on inpatient wards at Riverview Hospital in British Columbia and given either risperidone or olanzapine as their first new drug after reassessment (n = 30 per treatment group). Data were collected for up to 120 days. No significant differences were observed between groups in terms of sex, age, duration of illness, or diagnosis. The mean dosage of risperidone for responders was 4.89 +/- 2.56 mg/d, whereas that for olanzapine was 17.19 +/- 3.88 mg/d. The associated daily drug-acquisition costs were significantly different, at CA$4.69 for risperidone and CA$11.52 for olanzapine. Notes in patient charts indicated that a significantly greater proportion of risperidone-treated patients (60.0%) than olanzapine-treated patients (26.7%) responded to therapy, as indicated by improvement in at least one target symptom (P < 0.01). Forty percent of patients initially treated with risperidone were discharged on their original therapy, compared with 13.3% of patients treated with olanzapine (P < 0.05). These results were not substantially affected by correction for markers of illness severity or treatment resistance. Overall, no significant differences in side effects were recorded in the patient records of the two groups. Within this cohort of patients, risperidone treatment was associated with lower drug-acquisition cost and better treatment outcomes than olanzapine.",1999.0,0,0
1111,9918355,Pilot study with clozapine in patients with HIV-associated psychosis and drug-induced parkinsonism.,G Lera; J Zirulnik,"Clozapine (CZP) is an atypical antipsychotic drug that does not appear to block striatal dopamine receptors. In six patients who met the criteria of HIV-associated psychosis and who had previously developed moderate parkinsonism as a result of the use of typical neuroleptic agents, CZP was added in an open, rising dose study. Subjects were evaluated at baseline after at least 7 days without neuroleptic drugs and then monthly for 3 months of the experimental treatment using three rating scales: Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS). A significant reduction in psychopathology as represented in the BPRS total score (54.2 at baseline versus 23.9 at month 3) and CGI (2 and 8, respectively) was obtained with a mean CZP dose of 27.08 mg/day. Parkinsonism also improved by an average of 76.5% at the end of the study. One patient did not complete the study as a result of a progressive decrease in leukocyte count while on CZP. These preliminary results suggest that the pharmacologic properties of CZP may be of value in the management of HIV-psychotic patients.",1999.0,0,0
1112,9919323,Conventional vs. newer antipsychotics in elderly patients.,D V Jeste; E Rockwell; M J Harris; J B Lohr; J Lacro,"Elderly patients with schizophrenia and dementia patients with agitation are frequently candidates for antipsychotic treatment. Conventional neuroleptics have relatively little effect on negative symptoms and may cause considerable side effects, especially in elderly patients. The authors have found a 29% cumulative annual incidence of tardive dyskinesia (TD) in middle-aged and elderly outpatients treated with relatively low doses of conventional neuroleptics Newer antipsychotics are less likely to cause extrapyramidal symptoms and may be associated with a lower risk of TD. They are generally effective for both positive and negative symptoms and may also improve some aspects of cognition, but these drugs have their own side effects. Dosing requirements for elderly patients tend to be much lower than those for younger adults.",1999.0,0,0
1113,9921698,Use of atypical neuroleptics in child and adolescent psychiatry.,P Toren; N Laor; A Weizman,"This article reviews the published clinical experience with atypical neuroleptics in children and adolescents. A computerized literature search was conducted (MEDLINE, 1974-1998) to retrieve all reports on the use of atypical neuroleptics in children and adolescents. A hand search was performed as well. All relevant clinical data were collated by type of drug. We found 5 blind placebo-controlled clinical trials (105 patients), 24 open-label clinical trials (387 patients), and 33 case series (115 patients) describing the use of the atypical neuroleptics clozapine, risperidone, olanzapine, sulpiride, tiapride, amisulpride, remoxipride, and clothiapine in children and adolescents. Some of these agents, especially clozapine, risperidone, and olanzapine, were found to be efficacious in the treatment of schizophrenia, bipolar disorders, and pervasive developmental disorders. The role of atypical neuroleptics as augmenters of serotonin reuptake inhibitors in obsessive-compulsive disorder is unclear. Risperidone appears to possess anti-tic properties in patients with Tourette's disorder. The most convincing evidence of the efficacy of atypical neuroleptics in children and adolescents concerns clozapine in the treatment of schizophrenia. Data on other atypical neuroleptics in other disorders are still sparse, and further research is needed. Some of the atypical neuroleptics may become the first-line treatment for childhood schizophrenia and pervasive developmental disorders.",1999.0,0,1
1114,9928917,Schizophrenia: do we really need placebo-controlled studies?,J G Storosum; A J Elferink; B J van Zwieten,"To investigate whether placebo control is necessary to prove efficacy in short-term studies in schizophrenia. This study compares the efficacy results of placebo-controlled studies versus positive controlled studies, that is controlled studies without a placebo control, in the short-term treatment of chronic schizophrenia. Concerning mean improvement on the BPRS, the placebo arms showed in two cases a worsening, in one case almost no change, and in the remaining studies (6) the improvement was between 1 and 5%. The percentage mean improvement in the haloperidol arms of the placebo-controlled studies was comparable to the percentage mean improvement in the corresponding arms of the non-placebo-controlled studies. The highest percentage responders in the placebo-groups was 43% and the lowest was 6%. Moreover the responder rates in the atypical antipsychotic and haloperidol arms of the non-placebo-controlled studies were, in two of the three studies, in the same order of magnitude as the responder rates of the placebo arms in the placebo-controlled studies. The overall dropout rates in the placebo arms was between 48% and 80% and were higher than the drop out rates in the atypical neuroleptic arms and haloperidol arms of the placebo-controlled studies. The dropout rates due to an insufficient response in the atypical neuroleptic arms and haloperidol arms of the non-placebo-controlled studies were lower when compared to corresponding treatment arms of the placebo-controlled studies. In contrast to the mean improvement on the BPRS, responder rates in the placebo arms varied considerably from study to study. Responder rates in the atypical antipsychotic and haloperidol arms of the non-placebo-controlled studies were, in two of the three studies, of the same order of magnitude as the responder rates of the placebo arms in the placebo-controlled studies. These results indicate that placebo control is necessary. Moreover as responders are a more clinically relevant outcome measure when compared to mean improvement on a rating scale, placebo-controlled studies are still needed. However, consensus on responder definition should be agreed upon. For the moment, alternatives to placebo-controlled studies are inadequate in demonstrating efficacy in studies with schizophrenic patients.",1999.0,0,0
1115,9928923,Combination treatment with clozapine and paroxetine in schizophrenia: safety and tolerability data from a prospective open clinical trial.,I Anghelescu; A Szegedi; S Schlegel; H Weigmann; C Hiemke; H Wetzel,"Clozapine is a drug with many side effects, some of them with potentially hazardous outcome (e.g. seizures, agranulocytosis), if not carefully monitored. It has been shown that the metabolism of clozapine may be affected by concomitant treatment with selective serotonin reuptake inhibitors (SSRIs), while there have been reports of improved efficacy on negative symptomatology of clozapine in combination with SSRIs. Therefore, this prospective open clinical trial was performed to investigate the safety and tolerability of the coadministration of clozapine and paroxetine under control of serum concentrations of clozapine and its metabolites and the effect of this combination treatment on psychopathological outcome was evaluated. A total of 14 patients suffering from schizophrenia or schizodepressive disorder with predominant negative symptomatology were included. The duration of the study was at least 6 weeks for each patient. Initial treatment was a monotherapy with clozapine at a daily dose of 2.5 mg/kg weight. After two measurements of serum concentrations of clozapine and metabolites during steady state conditions, an add-on therapy with 20 mg paroxetine was initiated. No concomitant medication was allowed. The main finding of our prospective study was that addition of paroxetine to a monotherapy with clozapine was a well tolerated medication that did not give rise to new clinically relevant side effects. After addition of paroxetine the serum concentrations of clozapine and its major metabolites remained virtually constant. The results of the psychopathological measurements indicated a further clinical improvement, although the small open study could not test for efficacy.",1999.0,0,0
1116,9934944,Prolactin levels and adverse events in patients treated with risperidone.,D L Kleinberg; J M Davis; R de Coster; B Van Baelen; M Brecher,"Hyperprolactinemia is a common clinical disorder that may lead to sexual dysfunction or galactorrhea. It may arise from a variety of etiologies, including the use of antipsychotic agents, presumably because of a dopamine receptor blockade. This analysis was designed to characterize the relationship between risperidone, serum prolactin levels, and possible clinical sequelae. All data from randomized, double-blind studies of risperidone in patients with chronic schizophrenia were analyzed. The two largest studies (the North American and multinational trials) included 841 patients (259 women, 582 men) with paired prolactin level data and 1,884 patients (554 women, 1,330 men) with data on six adverse events possibly associated with increased prolactin levels (amenorrhea, galactorrhea, and decreased libido in women; erectile dysfunction, ejaculatory dysfunction, gynecomastia, and decreased libido in men). Both risperidone and haloperidol produced dose-related increases in plasma prolactin levels in men and women. Among women, the risperidone dose was not correlated with adverse events, nor were the adverse events correlated with endpoint prolactin levels. Among men, the incidence of adverse events was positively correlated with risperidone dose; however, at risperidone doses of 4 to 10 mg/day the incidence of adverse events was not significantly higher than that observed in patients receiving placebo. Furthermore, adverse events in men were unrelated to plasma prolactin levels. Risperidone-associated increase in serum prolactin levels was not significantly correlated to the emergence of possible prolactin-related side effects.",1999.0,0,0
1117,9987204,Obsessive-compulsive disorder in schizophrenia: epidemiologic and biologic overlap.,P Tibbo; L Warneke,"To examine the co-existence of obsessive-compulsive disorder (OCD) with schizophrenia in terms of epidemiology and overlapping biologic substrates. Review of the relevant literature. There appears to be a significant prevalence of OCD in schizophrenia--higher than what would be expected on the basis of calculated comorbidity figures. There is significant overlap in the proposed functional circuits of OCD and schizophrenia, which may lead to co-expression of symptoms. Although there is overlap in neurotransmitter dysfunction, the interactions are complex, especially in regard to the serotonin and dopamine systems. The expression of OCD in schizophrenia is complex but very intriguing. Theoretical hypotheses of the pathology of the 2 disorders now need to be tested in larger controlled trials.",1999.0,0,0
1118,9988841,"Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials.",S Leucht; G Pitschel-Walz; D Abraham; W Kissling,"The objective of this meta-analysis is to summarize the efficacy and tolerability of the new antipsychotics risperidone, olanzapine, sertindole and quetiapine in schizophrenia compared to placebo and conventional antipsychotics. The main results are: (1) All of the 4 new drugs are more effective than placebo, but the magnitude of the effect is only moderate [mean effect size, r, of all antipsychotics vs. placebo = 0.25, with a 95% confidence interval (CI) = 0.22-0.28, n = 2477]. (2) According to the studies published to date, sertindole and quetiapine are as effective as haloperidol, and risperidone and olanzapine are slightly more effective than haloperidol in the treatment of global schizophrenic symptomatology. (3) With respect to negative symptoms, all new antipsychotics are more effective than placebo. However, contrary to widespread opinion, so is the 'conventional' antipsychotic haloperidol. Risperidone and olanzapine are slightly superior, sertindole is as effective and--according to the only study fully published to date--quetiapine is even slightly less effective than haloperidol in this regard. (4) All new antipsychotics are associated with less frequent use of antiparkinson medication than haloperidol, with risperidone appearing to have a slightly less favourable EPS-profile than the other new antipsychotics. The methodological limitations of this review, the generalizability of the results and expectations from future research are discussed.",1999.0,1,1
1119,9989566,"Clozapine and risperidone in chronic schizophrenia: effects on symptoms, parkinsonian side effects, and neuroendocrine response.",A F Breier; A K Malhotra; T P Su; D A Pinals; I Elman; C M Adler; R T Lafargue; A Clifton; D Pickar,"Clozapine and risperidone were the first two ""second-generation"" antipsychotic drugs approved for schizophrenia. There is currently little information about their comparative efficacy from head-to-head clinical trials. The purpose of this study was to examine the comparative efficacy of clozapine and risperidone for positive and negative symptoms, depression, parkinsonian side effects, and indexes of neuroendocrine function in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents. After a baseline fluphenazine treatment period, 29 patients participated in a 6-week, double-blind, parallel-group comparison of the effects of these agents. Clozapine was superior to risperidone for positive symptoms and parkinsonian side effects, but there were no significant differences between the drugs on two measures of negative symptoms, Brief Psychiatric Rating Scale total scores, and depression scores. The clozapine patients, but not the risperidone patients, demonstrated significant reductions from the fluphenazine baseline in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than risperidone or fluphenazine. The mean daily doses during week 6 of the trial were 403.6 mg of clozapine and 5.9 mg of risperidone. The findings from this study indicate that these drugs have both important differences and similarities in their comparative efficacy in chronically ill, partially responsive patients with schizophrenia. Further research on second-generation antipsychotic drugs in this patient population that addresses key methodological issues, such as optimal dose and treatment duration, are needed.",2000.0,1,1
1120,9989571,Body weight and leptin plasma levels during treatment with antipsychotic drugs.,T Kraus; M Haack; A Schuld; D Hinze-Selch; M Kühn; M Uhr; T Pollmächer,"Leptin is produced by fat cells and is presumed to signal the size of the adipose tissue to the brain. The authors investigated whether antipsychotic drugs that often induce weight gain affect circulating levels of leptin. Weight, body mass index, and leptin plasma level were measured weekly over 4 weeks in psychiatric inpatients who received clozapine (N = 11), olanzapine (N = 8), haloperidol (N = 13), or no psychopharmacological treatment (N = 12). In patients receiving clozapine or olanzapine, significant increases in weight, body mass index, and leptin level were found, whereas these measures remained stable in patients who received haloperidol or no pharmacological treatment. Weight gain induced by clozapine or olanzapine appears to be associated with an increase in leptin level that cannot be attributed to dietary changes upon hospitalization.",1999.0,0,1