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Aripiprazole Partial Agonism at 5-HT2C: A Comparison of Weight Gain Associated With Aripiprazole Adjunctive to Antidepressants With High Versus Low Serotonergic Activities

Charles T. Nguyen, MD; Jennifer A. Rosen, PharmD, BCPP; and Robert G. Bota, MD, MSG


Objective: 5-HT2C receptor antagonists are thought to contribute toward increased appetite and obesity. Aripiprazole acts as a partial agonist at the 5-HT2C receptor; hence, it is thought to cause little or no significant weight gain when used alone. We theorize that, in the presence of antidepressants with high serotonergic activity, aripiprazole acts as an antagonist at the 5-HT2C receptor, thus increasing the potential for weight gain. Conversely, in environments with low serotonergic activity, aripiprazole acts as an agonist at the 5-HT2C receptor, therefore having less potential for weight gain.

Method: A retrospective electronic medical record chart review of the Veterans Integrated Service Network 22 Veterans Affairs database was performed comparing patients’ weight and body mass index (BMI) while taking aripiprazole alone (n = 1,177), versus aripiprazole plus a high-serotonergic antidepressant (citalopram, fluoxetine, paroxetine, sertraline, or venlafaxine) (n = 145), versus aripiprazole plus a low-serotonergic antidepressant (bupropion) (n = 77) for a minimum continuous duration of 6 months of aripiprazole monotherapy or combination treatment. The study was conducted from January 2010 through June 2011.

Results: In our patient population, only the aripiprazole plus high-serotonergic antidepressants group had a statistically significant increase in weight (P = .0027) and BMI (P = .0016).

Conclusions: Our data suggest that, in the presence of antidepressants with high serotonergic activity, aripiprazole may act as an antagonist at the 5-HT2C receptor, resulting in weight gain. Conversely, when aripiprazole is used in the presence of antidepressants with low serotonergic activity, it may act as an agonist and result in little or no weight gain. This varying effect at the 5-HT2C receptor may explain why aripiprazole has not been associated with significant weight gain in previous studies focusing on schizophrenia and bipolar disorder.

Prim Care Companion CNS Disord 2012;14(5):doi:10.4088/PCC.12m01386

Submitted: March 29, 2012; accepted June 1, 2012.

Published online: October 18, 2012.

Corresponding author: Jennifer A. Rosen, PharmD, BCPP, VA Long Beach Healthcare System (600/119), Long Beach, CA 90822 (