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Are Weight Gain and Metabolic Side Effects of Atypical Antipsychotics Dose Dependent? A Literature Review

Background: Numerous publications have provided evidence for clinically important metabolic adverse effects of antipsychotics, but there is no systematic evaluation as to whether weight gain and other metabolic changes are dose dependent.

Objective: This review of the available literature aimed to explore a possible relationship between dosage of second-generation antipsychotics (SGAs) and the degree of metabolic side effects.

Data Sources: A literature review was conducted in 3 steps: (1) Articles published between 1975 and 2004 were identified on the basis of the bibliography of an extensive review of the metabolic effects of SGAs. (2) Articles published between 2004 and 2008 were identified by a PubMed search with the keywords weight gain, metabolic, glucose, insulin, and lipid AND dose combined with amisulpride, aripiprazole, clozapine, quetiapine, risperidone, sertindole, and ziprasidone. (3) A hand search was conducted based on the bibliography of the identified articles.

Study Selection and Data Extraction: All studies that provided information on metabolic side-effects in different dose ranges were selected. Data extraction was carried out independently by 2 observers.

Data Synthesis: Preliminary evidence suggests a dose-response relationship between clozapine and olanzapine serum concentrations and metabolic outcomes, although the association between administered daily dose and metabolic outcomes is not clear. Data are controversial with regard to risperidone, and no study has as yet assessed risperidone serum concentrations in association with metabolic outcomes. For the other SGAs, there was little evidence to suggest a dose-response relationship, although, in these agents also, no assessment of serum concentrations was conducted.

Conclusions: The finding that metabolic complications may be associated with clozapine and olanzapine plasma concentrations provides further evidence for a causal contribution to the metabolic disturbances observed with these agents. Further well-designed, prospective studies investigating a possible association between SGA serum concentrations and metabolic outcomes are needed.

J Clin Psychiatry 2009;70(7):1041–1050. doi:10.4088/JCP.08r04392

Received May 20, 2008; accepted Dec. 8, 2008. From the Department of Psychiatry and Psychotherapy, Semmelweis University Budapest, Hungary (Dr. Simon); the Department of Psychiatry and Neuropsychology, European Graduate School of Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht University Medical Centre, The Netherlands (Dr. van Winkel); and University Psychiatric Center, Catholic University Leuven, Kortenberg, Belgium (Drs. van Winkel and De Hert).

Dr. van Winkel has been a consultant for Eli Lilly and has received honoraria from Eli Lilly and Janssen-Cilag. Dr. De Hert has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory boards of AstraZeneca, Lundbeck JA, Janssen-Cilag, Eli Lilly, Pfizer, Sanofi, and Bristol-Myers Squibb. Dr. Simon has no conflicts of interest to declare relative to this article.

Corresponding author: Marc De Hert, M.D., Ph.D., University Psychiatric Center, Catholic University Leuven, Leuvensesteenweg 517, 3070 Kortenberg, Belgium (e-mail: