Adverse changes in adiposity and insulin sensitivity in youths with psychiatric disorders could be associated with their first exposure to antipsychotic treatment, according to research published in JAMA Psychiatry. These changes might be further associated with increased risk for premature cardiometabolic morbidity and death.

Researchers conducted this randomized study in an effort to characterize the metabolic effects of antipsychotics in youths with clinically significant aggression. Assessments of body composition and insulin sensitivity were evaluated over 12 weeks using standard criteria. Patient demographics, medical history, anthropomorphic measurements, vital signs, and laboratory test results were obtained for all participants. Primary outcome measures included percentage of total body fat and insulin sensitivity taken at baseline, 6 weeks, and 12 weeks.

The study recruited 144 youths aged 6 to 18 who were diagnosed with at least 1 psychiatric disorder and were antipsychotic-naive. Participants were randomly assigned to receive 3 different antipsychotics commonly prescribed to children with disruptive behavioral disorders: oral aripiprazole (n=49), olanzapine (n=46), or risperidone (n=49). Total body fat was measured using dual-energy X-ray absorptiometry (DXA), and MRI was used to assess abdominal adiposity. Using hyperinsulinemic clamps with stable isotopically labeled tracers, insulin sensitivity was measured in muscle, adipose, and hepatic tissue. Adverse events were rated using relevant reporting scales at 0, 6, and 12 weeks.

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Researchers found a change in DXA-measured adiposity from baseline to week 12 across all study treatments, especially in the olanzapine group: 1.81% mean increase for risperidone, 4.12% increase for olanzapine, and 1.66% increase for aripiprazole. Secondary outcomes measuring abdominal fat through MRI showed worsening adiposity in visceral and subcutaneous compartments for all groups, with a significantly greater increase in subcutaneous fat for olanzapine than with risperdone or aripiprazole (time by treatment, P =.003). Clamp-derived insulin sensitivity (percentage change in the glucose rate of disappearance) decreased significantly in the overall study sample (effect of time, F=17.38; P <.001). Improvements in irritability, aggression, and overall symptoms during the course of treatment were clinically and statistically significant.

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Limitations of the study included a trial duration of 12 weeks, which is shorter than typical long-term treatment regimens required by psychiatric patients, and the lack of a placebo group for ethical reasons. While treatment effects on insulin sensitivity were observed in the pooled sample, a smaller study size might have limited the ability to detect differences between treatment groups. Additionally, a single rather than 2-stage clamp may have limited the ability to determine hepatic vs peripheral insulin sensitivity.

Metabolic risk and adverse effects on adiposity and insulin sensitivity were associated with antipsychotic treatments in youths, with the greatest increases in fat measures attributed to olanzapine. While antipsychotic treatments can improve behavioral symptoms, risk of hyperglycemia and weight gain should inform careful consideration of antipsychotic use in young patients.

Disclosures: See full study for a list of disclosures.


Nicol GE, Yingling MD, Flavin KS, et al. Metabolic effects of antipsychotics on adiposity and insulin sensitivity in youths: a randomized clinical trial [published online June 13, 2018]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2018.1088