Metabolic Effects of Antipsychotics on Adiposity and Insulin Sensitivity in Youths: A Randomized Clinical Trial

Abstract

Importance: Antipsychotic medications are commonly used to treat nonpsychotic disruptive behavioral disorders in youths.

Objective: To characterize the metabolic effects of first exposure to antipsychotics in youths using criterion standard assessments of body composition and insulin sensitivity.

Design, setting, and participants: This randomized clinical trial recruited antipsychotic-naive youths aged 6 to 18 years in the St Louis, Missouri, metropolitan area who were diagnosed with 1 or more psychiatric disorders and clinically significant aggression and in whom antipsychotic treatment was considered. Participants were enrolled from June 12, 2006, through November 10, 2010. Enrolled participants were randomized (1:1:1) to 1 of 3 antipsychotics commonly used in children with disruptive behavioral disorders and evaluated for 12 weeks. Data were analyzed from January 17, 2011, through August 9, 2017.

Interventions: Twelve weeks of treatment with oral aripiprazole (n = 49), olanzapine (n = 46), or risperidone (n = 49).

Main outcomes and measures: Primary outcomes included percentage total body fat measured by dual-energy x-ray absorptiometry (DXA) and insulin sensitivity in muscle measured via hyperinsulinemic clamps with stable isotopically labeled tracers. Secondary outcomes included abdominal adiposity measured by magnetic resonance imaging (MRI) and adipose and hepatic tissue insulin sensitivity measured via clamps with tracers.

Results: The intention-to-treat sample included 144 participants (98 males [68.1%]; mean [SD] age, 11.3 [2.8] years); 74 (51.4%) were African American, and 43 (29.9%) were overweight or obese at baseline. For the primary outcomes, from baseline to week 12, DXA percentage total body fat increased by 1.18% for risperidone, 4.12% for olanzapine, and 1.66% for aripiprazole and was significantly greater for olanzapine than risperidone or aripiprazole (time by treatment interaction P < .001). From baseline to week 12, insulin-stimulated change in glucose rate of disappearance increased by 2.30% for risperidone and decreased by 29.34% for olanzapine and 30.26% for aripiprazole, with no significant difference across medications (time by treatment interaction, P < .07). This primary measure of insulin sensitivity decreased significantly during 12 weeks in the pooled study sample (effect of time, F = 17.38; P < .001). For the secondary outcomes from baseline to week 12, MRI measured abdominal fat increased, with subcutaneous fat increase significantly greater for olanzapine than risperdone or aripiprazole (time by treatment, P = .003). Behavioral improvements occurred with all treatments.

Conclusions and relevance: Adverse changes in adiposity and insulin sensitivity were observed during 12 weeks of antipsychotic treatment in youths, with the greatest fat increases on olanzapine. Such changes, likely attributable to treatment, may be associated with risk for premature cardiometabolic morbidity and mortality. The results inform risk-benefit considerations for antipsychotic use in youths.

Trial registration: ClinicalTrials.gov identifier: NCT00205699.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Nicol reported research funding from the National Institute of Mental Health (NIMH), Otsuka America Pharmaceutical Inc, Alkermes PLC, The Sidney R. Baer Jr Foundation, and the Center for Brain Research in Mood Disorders at Washington University in St Louis. Dr Schechtman reported research funding from the NIMH, the National Heart, Lung, and Blood Institute, the National Institute of Aging, the National Cancer Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Allergy and Infectious Diseases. Dr Newcomer reported research funding from the National Institutes of Health (NIH) and Otsuka America Pharmaceutical Inc, in the 3 years before this study; serving as a consultant for Reviva Pharmaceuticals, Sunovion Pharmaceuticals Inc, Indivior, Otsuka America Pharmaceutical Inc, and Alkermes PLC, and serving as a consultant to litigation; serving on a data safety monitoring board for Amgen Inc; and receiving honoraria for continuing medical education from the American Society for Clinical Psychopharmacology. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

Figure 2.. Change in Adiposity During Initial Antipsychotic Exposure in the Study Participants

A, Baseline and 6- and 12-week mean percentage total body fat measured by dual-energy x-ray absorptiometry (DXA) for each group treated with risperidone, olanzapine, or aripiprazole. B, Baseline and 12-week end points of mean subcutaneous and visceral fat measured using magnetic resonance imaging (MRI) for each treatment group. Error bars indicate SE. aIndicates time by treatment condition. bIndicates time by treatment condition by compartment.

Figure 3.. Insulin Sensitivity During Initial Antipsychotic Exposure in the Study Participants

Data are represented by baseline and 12-week mean values for insulin-stimulated percentage change in glucose rates of disappearance (A) and appearance (B) and glycerol rate of appearance (C) for the total study sample. Error bars indicate SE.