Atypical antipsychotic

About: Atypical antipsychotic is a research topic. Over the lifetime, 6228 publications have been published within this topic receiving 282637 citations. The topic is also known as: atypical neuroleptic & atypical neuroleptic drug.

Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine

Abstract: • The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptics is a major challenge. Clozapine, an atypical antipsychotic drug, has long been of scientific interest, but its clinical development has been delayed because of an associated risk of agranulocytosis. This report describes a multicenter clinical trial to assess clozapine's efficacy in the treatment of patients who are refractory to neuroleptics.DSM-IIIschizophrenics who had failed to respond to at least three different neuroleptics underwent a prospective, single-blind trial of haloperidol (mean dosage, 61 ±14 mg/d) for six weeks. Patients whose condition remained unimproved were then randomly assigned, in a double-blind manner, to clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d) for six weeks. Two hundred sixty-eight patients were entered in the doubleblind comparison. When a priori criteria were used, 30% of the clozapine-treated patients were categorized as responders compared with 4% of chlorpromazine-treated patients. Clozapine produced significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Although no cases of agranulocytosis occurred during this relatively brief study, in our view, the apparently increased comparative risk requires that the use of clozapine be limited to selected treatment-resistant patients.

Chlorpromazine equivalent doses for the newer atypical antipsychotics

Abstract: Background 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. Method 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. Data sources and study selection 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. Results 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. Conclusion 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.

Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials.

Abstract: ContextAtypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with Alzheimer disease and other dementia; however, concerns have arisen about the increased risk for cerebrovascular adverse events, rapid cognitive decline, and mortality with their use.ObjectiveTo assess the evidence for increased mortality from atypical antipsychotic drug treatment for people with dementia.Data SourcesMEDLINE (1966 to April 2005), the Cochrane Controlled Trials Register (2005, Issue 1), meetings presentations (1997-2004), and information from the sponsors were searched using the terms for atypical antipsychotic drugs (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone), dementia, Alzheimer disease, and clinical trial.Study SelectionPublished and unpublished randomized placebo-controlled, parallel-group clinical trials of atypical antipsychotic drugs marketed in the United States to treat patients with Alzheimer disease or dementia were selected by consensus of the authors.Data ExtractionTrials, baseline characteristics, outcomes, all-cause dropouts, and deaths were extracted by one reviewer; treatment exposure was obtained or estimated. Data were checked by a second reviewer.Data SynthesisFifteen trials (9 unpublished), generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugs with placebo met criteria (aripiprazole [n = 3], olanzapine [n = 5], quetiapine [n = 3], risperidone [n = 5]). A total of 3353 patients were randomized to study drug and 1757 were randomized to placebo. Outcomes were assessed using standard methods (with random- or fixed-effects models) to calculate odds ratios (ORs) and risk differences based on patients randomized and relative risks based on total exposure to treatment. There were no differences in dropouts. Death occurred more often among patients randomized to drugs (118 [3.5%] vs 40 [2.3%]. The OR by meta-analysis was 1.54; 95% confidence interval [CI], 1.06-2.23; P = .02; and risk difference was 0.01; 95% CI, 0.004-0.02; P = .01). Sensitivity analyses did not show evidence for differential risks for individual drugs, severity, sample selection, or diagnosis.ConclusionsAtypical antipsychotic drugs may be associated with a small increased risk for death compared with placebo. This risk should be considered within the context of medical need for the drugs, efficacy evidence, medical comorbidity, and the efficacy and safety of alternatives. Individual patient analyses modeling survival and causes of death are needed.

Second-Generation (Atypical) Antipsychotics and Metabolic Effects: A Comprehensive Literature Review.

Abstract: Increasing numbers of reports concerning diabetes, ketoacidosis, hyperglycaemia and lipid dysregulation in patients treated with second-generation (or atypical) antipsychotics have raised concerns about a possible association between these metabolic effects and treatment with these medications. This comprehensive literature review considers the evidence for and against an association between glucose or lipid dysregulation and eight separate second-generation antipsychotics currently available in the US and/or Europe, specifically clozapine, olanzapine, risperi-done, quetiapine, zotepine, amisulpride, ziprasidone and aripiprazole. This review also includes an assessment of the potential contributory role of treatment-induced weight gain in conferring risk for hyperglycaemia and dyslipidaemia during treatment with different antipsychotic medications. Substantial evidence from a variety of human populations, including some recent confirmatory evidence in treated psychiatric patients, indicates that increased adiposity is associated with a variety of adverse physiological effects, including decreases in insulin sensitivity and changes in plasma glucose and lipid levels. Comparison of mean weight changes and relative percentages of patients experiencing specific levels of weight increase from controlled, randomised clinical trials indicates that weight gain liability varies significantly across the different second-generation antipsychotic agents. Clozapine and olanzapine treatment are associated with the greatest risk of clinically significant weight gain, with other agents producing relatively lower levels of risk. Risperidone, quetiapine, amisulpride and zotepine generally show low to moderate levels of mean weight gain and a modest risk of clinically significant increases in weight. Ziprasidone and aripiprazole treatment are generally associated with minimal mean weight gain and the lowest risk of more significant increases. Published studies including uncontrolled observations, large retrospective database analyses and controlled experimental studies, including randomised clinical trials, indicate that the different second-generation antipsychotics are associated with differing effects on glucose and lipid metabolism. These studies offer generally consistent evidence that clozapine and olanzapine treatment are associated with an increased risk of diabetes mellitus and dyslipidaemia. Inconsistent results, and a generally smaller effect in studies where an effect is reported, suggest limited if any increased risk for treatment-induced diabetes mellitus and dyslipidaemia during risperidone treatment, despite a comparable volume of published data. A similarly smaller and inconsistent signal suggests limited if any increased risk of diabetes or dyslipidaemia during quetiapine treatment, but this is based on less published data than is available for risperidone. The absence of retrospective database studies, and little or no relevant published data from clinical trials, makes it difficult to draw conclusions concerning risk for zotepine or amisulpride, although amisulpride appears to have less risk of treatment-emergent dyslipidaemia in comparison to olanzapine. With increasing data from clinical trials but little or no currently published data from large retrospective database analyses, there is no evidence at this time to suggest that ziprasidone and aripiprazole treatment are associated with an increase in risk for diabetes, dyslipidaemia or other adverse effects on glucose or lipid metabolism. In general, the rank order of risk observed for the second-generation antipsychotic medications suggests that the differing weight gain liability of atypical agents contributes to the differing relative risk of insulin resistance, dyslipidaemia and hyperglycaemia. This would be consistent with effects observed in nonpsychiatric samples, where risk for adverse metabolic changes tends to increase with increasing adiposity. From this perspective, a possible increase in risk would be predicted to occur in association with any treatment that produces increases in weight and adiposity. However, case reports tentatively suggest that substantial weight gain or obesity may not be a factor in up to one-quarter of cases of new-onset diabetes that occur during treatment. Pending further testing from preclinical and clinical studies, limited controlled studies support the hypothesis that clozapine and olanzapine may have a direct effect on glucose regulation independent of adiposity. The results of studies in this area are relevant to primary and secondary prevention efforts that aim to address the multiple factors that contribute to increased prevalence of type 2 diabetes mellitus and cardiovascular disease in populations that are often treated with second-generation antipsychotic medications.

Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review.

Abstract: Rationale: Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. Similar deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearly not animal models of schizophrenia per se, but appear to provide models of sensorimotor gating deficits in schizophrenia patients that have face, predictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D2 dopamine (DA) receptors, produced by amphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin receptors; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drugs such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied to the identification of potential antipsychotic treatments. In addition, some developmental manipulations, such as isolation rearing, have provided non-pharmacological animal models of the PPI deficits seen in schizophrenia. Objective: This review summarizes and evaluates studies assessing the effects of systemic drug administrations on PPI in rats. Methods: Studies examining systemic drug effects on PPI in rats prior to January 15, 2001 were compiled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four main PPI models used in the study of antipsychotic drugs were critically evaluated. Results: Despite some notable inconsistencies, the literature provides strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT2 agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medications. While the PPI model based on the effects of direct DA agonists is the most well-validated for the identification of known antipsychotics, the isolation rearing model also appears to be sensitive to both typical and atypical antipsychotics. The 5-HT PPI model is less generally sensitive to antipsychotic medications, but can provide insight into the contribution of serotonergic systems to the actions of newer antipsychotics that act upon multiple receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical antipsychotics. Hence, despite some exceptions to this generalization, the NMDA PPI model might aid in the identification of novel or atypical antipsychotic medications. Conclusions: Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification of antipsychotic medications. Because each of these models has specific advantages and disadvantages, the choice of model to be used depends upon the question being addressed. This review should help to guide such decisions.