A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00741026.

Figure 1. CONSORT 2010 Flow Diagram.

The schema graphically outlines the design and conduct of the clinical study.

Figure 2. Effect of olanzapine on plasma leptin.

Baseline fasting blood samples were drawn approximately 10–12 h following the final dose of olanzapine or placebo tablets. Plasma leptin was measured at the conclusion of the study for each subject under placebo- and olanzapine-treated conditions. Data are expressed as a box plot for placebo and olanzapine-treated subjects. An asterisk indicates (P = 0.02) a significant difference between the medians of the placebo and olanzapine groups using a Wilcoxon matched-pairs signed rank test (n = 15).

Figure 3. Effects of olanzapine on the glucose and insulin responses during oral glucose challenge.

Blinded olanzapine or placebo tablets were self-administered by healthy volunteers for three days prior to conduction of a standard oral glucose tolerance test. In the morning, approximately 10–12 h following the final dose of placebo or drug compound, baseline blood samples were collected and then volunteers self-administered an oral glucose-containing solution. Serial blood samples were drawn at 30 min intervals for two hours. Plasma glucose and insulin concentrations were determined for each time point of the tolerance test. Area under the curve for (A) Glucose and (B) Insulin were calculated for each individual oral glucose tolerance test under placebo and active drug conditions. Data are expressed as box plots for the placebo and olanzapine-treated subjects. An asterisk indicates (P = 0.011) a significant difference between the medians of the placebo and olanzapine groups using a Wilcoxon matched-pairs signed rank test (n = 14).

Figure 4. Effect of olanzapine on plasma fasting free fatty acids.

Baseline blood samples were collected approximately 10–12 h following the final dose of olanzapine or placebo tablets prior to beginning an oral glucose tolerance test for hormone and metabolite analyses. Plasma free fatty acid concentrations were measured for all subjects under placebo- and olanzapine-treated conditions. Data are expressed as a box plot for placebo and olanzapine-treated groups. An asterisk indicates (P = 0.016) a significant difference between the medians of the placebo and olanzapine groups (n = 15).

Figure 5. Effect of olanzapine on plasma triglycerides.

For each subject baseline blood samples were drawn 10–12 h following the final dose of placebo or olanzapine tablets prior to beginning an oral glucose tolerance test for hormone and metabolite analyses. Plasma triglyceride concentration was measured for all subjects under placebo- and olanzapine-treated conditions. Data are expressed as a box plot for placebo and olanzapine-treated groups. An asterisk indicates (P = 0.017) a significant difference between the medians of the placebo and olanzapine groups (n = 15).

Figure 6. Effect of olanzapine on plasma cholesterol.

Plasma concentrations of (A) Total cholesterol, (B) High-density lipoprotein, and (C) Low-density lipoprotein cholesterol were measured for all subjects under placebo- and olanzapine-treated conditions. Data are expressed as box plots for comparison of placebo and olanzapine-treated groups. An asterisk indicates (P = 0.018) a significant difference between the medians of the placebo and olanzapine groups. NS = not significantly different (n = 15).