Introduction: Antipsychotic medications are associated with significant weight gain, type 2 diabetes mellitus, dyslipidemia, and increased cardiovascular risk. Suggested mechanisms of weight gain from antipsychotic medication include antagonism of histamine and serotonin receptors, and effects on the hypothalamic-pituitary-adrenal axis. The objective of this study was to determine if mifepristone, a glucocorticoid receptor antagonist, could prevent olanzapine-induced weight gain.
Methods: This was a randomized, double-blind trial. Fifty-seven lean, healthy men (body mass index 18-25 kg/m(2)) aged 19-38 years were randomized to olanzapine (7.5 mg) (n=22), olanzapine (7.5 mg) plus mifepristone (600 mg) (n=24), or mifepristone (600 mg) (n=11) daily for 2 weeks in an institutional setting. Subjects were provided food ad libitum to accentuate weight gain. Body weight was measured daily.
Results: The mean change in baseline weight was +3.2+/-0.9 kg in subjects receiving olanzapine versus +2.0+/-1.2 kg in those receiving olanzapine plus mifepristone (P<0.0001). Subjects receiving mifepristone alone had a similar degree of weight gain compared to those receiving olanzapine plus mifepristone. The olanzapine group had significant increases in waist circumference when compared with the olanzapine plus mifepristone group (3.7+/-1.3 cm vs. 2.2+/-1.9 cm, respectively; P=0.006). Fasting insulin and triglycerides increased more in the olanzapine group, although differences were not statistically significant.
Conclusion: Mifepristone was effective in attenuating the increase in weight associated with olanzapine treatment over a 2-week period. Longer-term studies are required to examine the durability and full magnitude of this response.