Clozapine, Olanzapine Increases Risk of Insulin Resistance and Diabetes

"While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes," write David C. Henderson, MD, from Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues. "Although methodological issues related to nonrandom prescribing patterns and insensitive or nonuniform ascertainment of diabetes mellitus make these results difficult to interpret, clozapine and olanzapine have been most strongly implicated in pharmacoepidemiological studies."

Of 50 stable, treated patients with schizophrenia who were recruited from an urban community mental health clinic and who signed informed consent to be studied at a general clinical research center, 41 underwent a frequently sampled intravenous glucose tolerance test. These included 36 nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone.

Mean duration of treatment was 68.3 +/- 28.9 months for clozapine, 29.5 +/- 17.5 months for olanzapine, and 40.9 +/- 33.7 months for risperidone. Fasting serum insulin concentrations were highest for clozapine, followed by olanzapine and then risperidone, with significant differences between clozapine and risperidone (P = .03) and olanzapine and risperidone (P = .04).
Insulin sensitivity index followed a similar pattern (clozapine<olanzapine<risperidone; P < .001), as did the homeostasis model assessment of insulin resistance (clozapine>olanzapine>risperidone; clozapine vs. risperidone, P =.006; olanzapine vs. risperidone, P = .02) and glucose effectiveness (clozapine<olanzapine<risperidone; clozapine vs. risperidone, P = .02; olanzapine vs. risperidone; P = .03).

"Both nonobese clozapine- and olanzapine-treated groups displayed significant insulin resistance and impairment of glucose effectiveness compared with risperidone-treated subjects," the authors write. "Patients taking clozapine and olanzapine must be examined for insulin resistance and its consequences."
Archives of General Psychiatry. 2005;62:19-28