Mifepristone treatment of olanzapine-induced weight gain in healthy men.
BACKGROUND
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.


CONCLUSIONS
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.
Gross
Coleman
C
Corcept Therapeutics, Menlo Park, CA 94025, USA. cgross@corcept.com
Blasey
Christine M
CM
Roe
Robert L
RL
Allen
Kate
K
Block
Thaddeus S
TS
Belanoff
Joseph K
JK
D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000009:adverse effects / Q000627:therapeutic use*; D001786:Blood Glucose / Q000187:drug effects; D015992:Body Mass Index; D001837:Body Weights and Measures; D004311:Double-Blind Method; D006727:Hormone Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D015735:Mifepristone / Q000009:adverse effects / Q000627:therapeutic use*; D000077152:Olanzapine; D015430:Weight Gain / Q000187:drug effects*; D055815:Young Adult
D014150:Antipsychotic Agents; D001786:Blood Glucose; D006727:Hormone Antagonists; D007328:Insulin; D008055:Lipids; D001569:Benzodiazepines; D015735:Mifepristone; D000077152:Olanzapine