A Double Blind, Placebo-Controlled, Randomized Crossover Study of the Acute Metabolic Effects of Olanzapine in Healthy Volunteers

Background and Rationale: Atypical antipsychotics exhibit metabolic side effects including diabetes mellitus and obesity. The adverse events are preceded by acute worsening of oral glucose tolerance (oGTT) along with reduced plasma free fatty acids (FFA) and leptin in animal models. It is unclear whether the same acute effects occur in humans. Methodology/Principal Findings: A double blind, randomized, placebo-controlled crossover trial was conducted to examine the potential metabolic effects of olanzapine in healthy volunteers. Participants included male (8) and female (7) subjects [18-30 years old, BMI 18.5-25]. Subjects received placebo or olanzapine (10 mg/day) for three days prior to oGTT testing. Primary endpoints included measurement of plasma leptin, oral glucose tolerance, and plasma free fatty acids (FFA). Secondary metabolic endpoints included: triglycerides, total cholesterol, high-and low-density lipoprotein cholesterol, heart rate, blood pressure, body weight and BMI. Olanzapine increased glucose Area Under the Curve (AUC) by 42% (2808 +/- 474 vs. 3984 +/- 444 mg/dl.min; P = 0.0105) during an oGTT. Fasting plasma leptin and triglycerides were elevated 24% (Leptin: 6.8 +/- 1.3 vs. 8.4 +/- 1.7 ng/ml; P = 0.0203) and 22% (Triglycerides: 88.9 +/- 10.1 vs. 108.2 +/- 11.6 mg/dl; P = 0.0170), whereas FFA and HDL declined by 32% (FFA: 0.38 +/- 0.06 vs. 0.26 +/- 0.04 mM; P = 0.0166) and 11% (54.2 +/- 4.7 vs. 48.9 +/- 4.3 mg/dl; P = 0.0184), respectively after olanzapine. Other measures were unchanged. Conclusions/Significance: Olanzapine exerts some but not all of the early endocrine/metabolic changes observed in rodent models of the metabolic side effects, and this suggest that antipsychotic effects are not limited to perturbations in glucose metabolism alone. Future prospective clinical studies should focus on identifying which reliable metabolic alterations might be useful as potential screening tools in assessing patient susceptibility to weight gain and diabetes caused by atypical antipsychotics.