[Skip to Content]
[Skip to Content Landing]
Original Investigation
August 2018

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

Author Affiliations
  • 1Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, Missouri
  • 2Department of Internal Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri
  • 3Department of Medicine, Washington University School of Medicine in St Louis, St Louis, Missouri
  • 4Department of Biostatistics, Washington University School of Medicine in St Louis, St Louis, Missouri
  • 5Department of Integrated Medical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton
JAMA Psychiatry. 2018;75(8):788-796. doi:10.1001/jamapsychiatry.2018.1088
Key Points

Question  What is the effect of first exposure to antipsychotics on adiposity and insulin sensitivity in youths?

Findings  In this randomized clinical trial, 144 youths aged 6 to 18 years with disruptive behavior disorders who were randomized to receive aripiprazole, olanzapine, or risperidone experienced clinically significant increases in total and abdominal adiposity during 12 weeks of treatment. Increases were greater for olanzapine vs risperidone or aripiprazole; decreases in insulin sensitivity and improvements in behavior were also noted.

Meaning  Antipsychotic medications are commonly used in children for the treatment of disruptive behavior disorders, but potential benefits should be carefully weighed against the risk for adverse changes in total and abdominal adiposity and insulin sensitivity, known contributors to the development of early-onset type 2 diabetes, cardiovascular disease, and other illnesses associated with premature morbidity and mortality.


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