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Metabolic Dysregulation With Atypical Antipsychotics Occurs in the Absence of Underlying Disease A Placebo-Controlled Study of Olanzapine and Risperidone in Dogs

From the Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California

Atypical antipsychotics have been linked to weight gain, hyperglycemia, and diabetes. We examined the effects of atypical antipsychotics olanzapine (OLZ) and risperidone (RIS) versus placebo on adiposity, insulin sensitivity (S_I), and pancreatic ß-cell compensation. Dogs were fed ad libitum and given OLZ (15 mg/day; n = 10), RIS (5 mg/day; n = 10), or gelatin capsules (n = 6) for 4–6 weeks. OLZ resulted in substantial increases in adiposity: increased total body fat (+91 ± 20%; P = 0.000001) reflecting marked increases in subcutaneous (+106 ± 24%; P = 0.0001) and visceral (+84 ± 22%; P = 0.000001) adipose stores. Changes in adiposity with RIS were not different from that observed in the placebo group (P > 0.33). Only OLZ resulted in marked hepatic insulin resistance (hepatic S_I [pre- versus postdrug]: 6.05 ± 0.98 vs. 1.53 ± 0.93 dl · min^–1 · kg^–1/[µU/ml], respectively; P = 0.009). ß-Cell sensitivity failed to upregulate during OLZ (pre-drug: 1.24 ± 0.15, post-drug: 1.07 ± 0.25 µU · ml^–1/[mg/dl]; P = 0.6). OLZ-induced ß-cell dysfunction was further demonstrated when ß-cell compensation was compared with a group of animals with adiposity and insulin resistance induced by moderate fat feeding alone (+8% of calories from fat; n = 6). These results may explain the diabetogenic effects of atypical antipsychotics and suggest that ß-cell compensation is under neural control.

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