Weight effects associated with antipsychotics: A comprehensive database analysis

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Abstract

Background

Available data on atypical antipsychotic-induced weight gain are limited by a number of methodological factors. The objective of this report is to evaluate short-term (N = 1742) and long-term (N = 1649) weight effects in patients receiving standard doses of amisulpride, haloperidol, olanzapine, risperidone, ziprasidone, and placebo based on 21 randomized, placebo-controlled, parallel-group studies from an integrated clinical trial database.

Method

Analyses of the integrated ziprasidone schizophrenia trials database were performed to estimate the weighted average of weight change and the percentage of subjects experiencing weight gain (or weight loss) across studies for each agent studied, based on fixed- and random-effects models. Durations of treatment exposure in long-term trials were controlled by well-defined time windows (6 month: 150 to 210 days; 1 year: 330 to 390 days). Weight gain or loss was defined using a 7% change from baseline threshold.

Results

During long-term therapy with 1-year treatment duration, incidence of weight gain for subjects treated with ziprasidone (17%) was not significantly different from the placebo (13%) or haloperidol (41%) groups based on 95% confidence interval. In contrast, significantly greater weight gain incidence was observed for the olanzapine (57%) and risperidone (39%) groups compared to placebo. Median weight change of + 0.49, − 0.18, + 1.50 and + 0.55 lb/month was observed for haloperidol, ziprasidone, olanzapine and risperidone subjects, respectively, indicating differential weight change patterns compared to placebo (− 0.32). Similar results were observed for the short-term (4–12 weeks) and 6-month treatment exposure cohorts.

Conclusions

Our results confirm significant differences in long-term weight effects among atypical antipsychotics, consistent with findings from prior meta-analysis of antipsychotic-induced weight gain [Allison, D.B., Mentore, J.L., Heo, M., Chandler, L.P., Capelleri, J.C., Infante, M.C., Weiden, P.J., 1999. Antipsychotic induced weight gain: a comprehensive research synthesis. Am J Psychiatry 156, 1686–1696] and the CATIE schizophrenia study [Lieberman, J.A., Stroup, T.S., McEvoy, J.P., et al., 2005. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353, 1209–1223].

Introduction

Schizophrenia is a chronic, debilitating illness requiring long-term treatment with antipsychotic medications. Patients with schizophrenia are at increased risk for developing obesity (Fontaine et al., 2001, Myer and Nasrallah, 2003, Wirshing, 2004) and some atypical antipsychotics have been reported to be associated with undesirable metabolic side effects and weight gain. Clozapine, olanzapine, and to a lesser extent, risperidone and quetiapine, have all been implicated in causing weight gain (Allison et al., 1999, Newcomer, 2005, Newcomer and Hennekens, 2007). In contrast, previous reports suggest that aripiprazole and ziprasidone are associated with lower overall risks for weight gain, diabetes, and worsening lipid profiles (American Diabetes Association et al., 2004, Newcomer, 2005).

Despite heightened interest in the health implications and clinical importance of atypical antipsychotic-induced weight gain, most studies that assess weight change are short-term in duration (< 6 months). Long-term data, beyond 6 months, have been typically limited by a number of methodological and design factors, and the conclusions are thus less definitive. These limiting factors have included small sample sizes, lack of a control group, biasing effects of individual variations in treatment exposure and prior antipsychotic use, and the use of study designs that are less rigorous than randomized, double-blind trials. Such factors render comparison and interpretation of long-term weight change difficult, if not impossible (Wetterling, 2001, Gentile, 2006). Beyond recognizing clozapine on the one hand and both ziprasidone and aripiprazole on the other as representing opposite poles on the weight-gain spectrum, review of existing literature shows contradictory results for the degree of weight gain associated with long-term use of other atypical agents (American Diabetes Association et al., 2004, Gentile, 2006).

The recently published National Institute of Mental Health (NIMH) sponsored Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study addressed some of the methodological issues in existing studies by making systematic, direct comparisons of several atypical antipsychotics with the conventional agent, perphenazine. Among the antipsychotics examined, ziprasidone was associated with no meaningful weight gain (mean ± SE: − 0.3 ± 0.3 lb per month of treatment), and was the only study drug associated with improvement in all metabolic variables (glycosylated hemoglobin, total cholesterol and triglycerides) evaluated (Lieberman et al., 2005).

Although CATIE provides useful information on the relative safety and efficacy of different atypical antipsychotic treatments, the large variations in treatment duration among subjects participating in this study make it difficult to interpret or generalize from its long-term results. The number of evaluable subjects available for long-term analysis was considerably smaller than the full analysis dataset due to the high dropout rate. Among the 1432 patients analyzed, 1061 (74%) discontinued before 18 months (McEvoy et al., 2005).

The objective of this post-hoc, integrated database analysis was to evaluate the exposure-controlled weight effects across treatment groups, using well-defined treatment time windows to control for variations in exposure duration. We examined weight changes during short- and long-term treatments of schizophrenia, in subjects receiving amisulpride (short-term trial only), haloperidol, olanzapine, risperidone, ziprasidone, and placebo treatment in 21 randomized, controlled trials.

Section snippets

Database description

The analysis database consisted of a total of 3507 patients in 21 placebo- and active-controlled studies conducted in the United States, Canada, South America, Australia, New Zealand, Eastern and Western Europe (Table 1, Table 2). The data described in this report were based on duration of exposure to a) amisulpride (N = 55), haloperidol (N = 230), olanzapine (N = 92), risperidone (N = 112), ziprasidone (N = 1066) and placebo (N = 187) in short-term 4- to 12-week trials (Table 1); and b) haloperidol (N = 

Discussion

Our comprehensive analysis of a large schizophrenia clinical trial database examining body weight changes during short- and long-term treatments of patients randomized to placebo or antipsychotic agents confirms that there are substantial differences among antipsychotics in their effects on body weight. In short-term, 4- to 12-week studies, ziprasidone-treated subjects experienced the lowest clinically significant weight gain (i.e., > 7% increase compared to baseline) in comparison to

Role of funding source

This study was sponsored by Pfizer Inc. The sponsor was involved in all stages from conception, analysis to review of the manuscript. Data analysis was supported by Pfizer Inc., and interpreted collectively by all of the authors.

Contributors

All authors contributed to the analysis of data and writing of this manuscript. Analysis and interpretation of data: authors Parsons, Allison, Loebel, Giller, Williams, Romano and Siu. Drafting of the manuscript: authors Parsons, Allison, Loebel, Giller, and Siu. Statistical analysis: Allison and Siu. Critical revision of the manuscript for important intellectual content and approval of the final version for publication: authors Parsons, Allison, Loebel, Giller, Williams, Romano and Siu.

Conflict of interest

David Allison has received grants, honoraria, consulting fees, and contributions from multiple food, pharmaceutical, and for profit and not-for-profit entities concerned with obesity and/or antipsychotic drugs. Bruce Parsons, Antony Loebel, Kathryn Williams, Earl Giller, and Steven Romano were employees of Pfizer, Inc. during development and writing of the manuscript. Cynthia Siu was a paid consultant to Pfizer, Inc., in connection with the development and analysis of this manuscript. She

Acknowledgements

This study was supported by Pfizer Inc.

This study was previously presented as a poster at the American Psychiatric Association 159th Annual Meeting, Toronto, Canada, 20–25 May, 2006.

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