Antipsychotics May Increase Risk for Diabetes, Heart Disease in Young People

June 21, 2018

By Marilynn Larkin

NEW YORK—Pediatric antipsychotic use is associated with an increase in body fat and decreases in insulin sensitivity, potentially raising the risk of premature cardiometabolic morbidity and mortality, researchers say.

"Although antipsychotics are first-line treatments for conditions like pediatric-onset schizophrenia, they are more commonly prescribed off-label for attention-deficit/hyperactivity disorder and disruptive behavior disorders, with greater use in publicly insured youths," according to Dr. John Newcomer of Florida Atlantic University in Boca Raton and colleagues.

"Although youths with these most commonly treated disorders might benefit from antipsychotic treatment," they note, "careful consideration of risks and benefits is warranted."

"We already knew from clinical trials that antipsychotics can increase body weight in adults, with potentially larger effects in children," Dr. Newcomer said in an email to Reuters Health. What wasn't clear, he said, was how much of the weight gain represented an increase in body fat (versus muscle and water), which could increase risk for diabetes and other conditions.

Dr. Newcomer's previous work had linked antipsychotic use with an increased incidence of new-onset type 2 diabetes in adults as well as children (

"What we did not know is how to connect those observations," he said, "and specifically whether antipsychotic treatment in children activated the usual pathway for risk for diabetes that includes increases in total and abdominal body fat, along with decreases in insulin sensitivity."

To investigate, the team randomly assigned 144 young people diagnosed with one or more psychiatric disorders and clinically significant aggression to 12 weeks of oral risperidone, (mean dose, 1.0 mg); olanzapine (6.3 mg); or aripiprazole (6.0 mg). The mean age was 11.4 years; 68% were male and 51.4% were African American.

Eighty participants (55.6%) had a primary diagnosis of attention-deficit/hyperactivity disorder with irritability and aggression insufficiently responsive to previous therapy. All were taking antipsychotics for the first time. Doses, though representative of pediatric practice patterns, were below those typically used to treat psychosis.

As reported online June 13 in JAMA Psychiatry, all treatments resulted in behavioral improvement. However, from baseline to week 12, the percentage of total body fat as measured by DXA increased by 1.18% for risperidone, 4.12% for olanzapine, and 1.66% for aripiprazole. The increase for olanzapine was significant compared to the other treatments.

Similarly, MRI-measured abdominal fat increased overall, with a significantly greater increase in subcutaneous fat for olanzapine compared with risperidone or aripiprazole.

In the pooled study sample, insulin sensitivity decreased significantly at muscle, liver and fat tissue, (measured by hyperinsulinemic clamp with stable isotopically-labeled tracers) over the 12-week trial, Dr. Newcomer noted.

"These results," he said, "should be taken in the context of prior knowledge that the development of cardiometabolic risk factors like increased body fat and reduced insulin sensitivity earlier - rather than later - in life can have a larger long-term adverse impact on disease outcomes."

"We hope that the results will lead to a recalibration or recalculation of this risk-benefit ratio, especially in non-psychotic children for whom there are alternative first-line treatment approaches," he concluded.

Dr. Marc De Hert of Katholieke Universiteit Leuven in Kortenberg, Belgium, coauthor of a related editorial, told Reuters Health by email, "Off-label antipsychotic use is frequent for different indications both in the U.S. and Europe."

"Metabolic side effects are - or should be - a real concern with antipsychotic use," he said. "These side effects are more pronounced in first-time users and young people. This study, using gold-standard measurements, confirms and highlights the problem in those with non-psychotic disorders."

"Prescribers should ensure that all antipsychotic drug users, especially young people, are (regularly) screened and monitored for these side effects," he concluded.


JAMA Psychiatry 2018.

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