background The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. methods A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. results Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. conclusions The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.

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Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia

OBJECTIVE: 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. METHOD: 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. RESULTS: 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....

https://ajp.psychiatryonline.org/doi/pdf/10.1176/ajp.156.11.1686

Antipsychotic-Induced Weight Gain: A Comprehensive Research Synthesis

https://onlinelibrary.wiley.com/doi/pdf/10.1002/j.2051-5545.2011.tb00014.x

Physical illness in patients with severe mental disorders.I. Prevalence, impact of medications and disparities in health care

https://www.thelancet.com/pdfs/journals/lancet/PIIS014067360861764X.pdf

Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis

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.

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

The Hamilton Anxiety Rating Scale, a widely used clinical interview assessment tool, lacks instructions for administration and clear anchor points for the assignment of severity ratings. We developed a Structured Interview Guide for the Hamilton Anxiety Scale (SIGH-A) and report on a study comparing this version to the traditional form of this scale. Experienced interviewers from three Anxiety Disorders research sites conducted videotaped interviews using both traditional and structured instruments in 89 participants. A subset of the tapes was co-rated by all raters. Participants completed self-report symptom questionnaires. We observed high inter-rater and test-retest reliability using both formats. The structured format produced similar but consistently higher (+ 4.2) scores. Correlation with a self-report measure of overall anxiety was also high and virtually identical for the two versions. We conclude that in settings where extensive training is not practical, the structured scale is an acceptable alternative to the traditional Hamilton Anxiety instrument.

Reliability and validity of a structured interview guide for the Hamilton Anxiety Rating Scale (SIGH‐A)

Objective: The objective of this study was to estimate and compare the distributions of body mass index (BMI: kg/m 2 ) among individuals with and without schizophrenia, and, thereby, place the weight gain-inducing effects of antipsychotic drugs into context. Method: 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 antipsychotic 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. Results: After age-adjusting BMI in each data set, the NHIS data revealed that men with schizophrenia have mean BMls 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 BMls 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). Conclusion: 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.

L.P. Chandler

Papers

Antipsychotic-Induced Weight Gain: A Comprehensive Research Synthesis

Reliability and validity of a structured interview guide for the Hamilton Anxiety Rating Scale (SIGH‐A)

The distribution of body mass index among individuals with and without schizophrenia.

Validation of the behavioural activity rating scale (BARS): a novel measure of activity in agitated patients.

Validation of the behavioural activity rating scale (BARS): A novel measure of activity in agitated patients