Antipsychotic-Induced Insulin Resistance and Postprandial Hormonal Dysregulation Independent of Weight Gain or Psychiatric Disease

Atypical antipsychotic (AAP) medications that have revolution-ized the treatment of mental illness have become stigmatized by metabolic side effects, including obesity and diabetes. It remains controversial whether the defects are treatment induced or disease related. Although the mechanisms underlying these metabolic defects are not understood, it is assumed that the initiating pathophysiology is weight gain, secondary to centrally mediated increases in appetite. To determine if the AAPs have detrimental metabolic effects independent of weight gain or psychiatric disease, we administered olanzapine, aripiprazole, or placebo for 9 days to healthy subjects (n = 10, each group) under controlled in-patient conditions while maintaining activity levels. Prior to and after the interventions, we conducted a meal chal-lenge and a euglycemic-hyperinsulinemic clamp to evaluate in-sulin sensitivity and glucose disposal. We found that olanzapine