Antipsychotics Increase Body Weight in Children with Behavioral Conditions

John W. Newcomer, MD

For the past 13 years, John W. Newcomer, MD, has watched the rise of antipsychotic medication overprescribing firsthand. As a member of the Missouri Medicaid Drug Utilization Review Board, Newcomer observed an influx of cases wherein a physician prescribed antipsychotics to children diagnosed with nonpsychotic behavioral conditions, such as attention deficit hyperactivity disorder (ADHD).

It wasn’t until recent that Newcomer saw how such prescribing fed into another pediatric epidemic: the national obesity rate.

A new study conducted by researchers from Florida Atlantic University and Washington University, St. Louis, MO, reported that even short-term antipsychotic treatment for a nonpsychotic condition in children can increase body fat and decrease the body’s sensitivity to insulin — leaving pediatric patients at greater risk of developing diabetes.

Newcomer, principal investigator and corresponding author of the study, told MD Magazine there was already considerable evidence to the thought that antipsychotic medication considerably affected patient body weight and lipid status prior to the study’s start.

“We wouldn’t have embarked on this long study and (the National Institutes of Health) wouldn’t have given us the funding if we didn’t have a high index of understanding that there was an influence,” Newcomer said. “But it needed to be put to the test, and unfortunately the findings confirm our hypothesis.”

From June 2006 through November 2010, researchers recruited 144 antipsychotic-naïve children and adolescents aged 6-18 years old from the St. Louis metropolitan area who had been diagnosed with 1 or more psychiatric disorders and clinically significant aggression. Researchers randomized the participants 1:1:1 to receive 12-week regimen of oral aripiprazole (n= 49), olanzapine (n= 46), or risperidone (n= 49).

Each of the therapies are common antipsychotics prescribed to children with disruptive behavioral disorders. Among the patients, mean age was 11.3 years, a majority (51.4%) were African American, and 29.9% were overweight or obese at baseline.

Researchers measured for percentage total body fat as per dual-energy x-ray absorptiometry (DXA), and insulin sensitivity in muscle via hyperinsulinemic clamps with stable isotopically labeled tracers. From baseline to week 12, DXA percentage total body fat increased 4.12% in patients receiving olanzapine, 1.66% in patients on aripiprazole, and 1.18% in patients on risperidone (P < 0.001).

Insulin-stimulated change in glucose rate of disappearance increased 30.26% in patients on aripiprazole, 29.34% in patients on olanzapine, and 2.3% for patients on risperidone, with no significant difference across medications. However, Newcomer theorized this may have been due to the smaller patient population.

For secondary outcomes such as MRI-measured abdominal fat increase, patients on olanzapine reported significantly greater fat gains than patients on risperidone or aripiprazole (P = 0.003). Overall, patients reported improvements in behavior.

The study broke from a consistent issue in clinical research into the correlation between weight gain and antipsychotic medication, Newcomer said, in that it compared different antipsychotic medications rather than compare one drug versus placebo. It was also an added benefit to observe a patient population that was recommended for antipsychotic treatment, but never administered.

“All prior literature was commonly complicated by patients from prior studies being treated with antipsychotics and then receiving another medication,” Newcomer said. “This is associated with certain metabolic effects.”

Researchers concluded the results were worse than previously hypothesized. Olanzapine, a second-generation antipsychotic that rebalances dopamine and serotonin levels in patients, was characterized for reporting the greatest fat increases in patients. What’s next is characterizing the patients most susceptible to such effects, Newcomer said.

“There’s been a lot of interest in identifying clinical risk factors,” Newcomer said. “The search is certainly still on for that, and we’ll be conducting some second-leg analyses.”

Though there aren’t any obvious leads to draw from current analysis, Newcomer said they may start their search at genomic risk factors. Progress in secondary research may eventually lead to what he called a “recalibration” of physician’s benefit-risk criteria when treating non-psychotic pediatric patients with behavioral conditions.

The end-result could be a direct effect on pediatric antipsychotic prescription and obesity rates — which Newcomer noted affect US children notably more than any other countries.

“You get these poor kids, already suffering from psychiatric challenges,” Newcomer said. “The last thing we want to do is give them metabolic issues that could complicate not only their youth but their adult life.”

The study, "Metabolic Effects of Antipsychotics on Adiposity and Insulin Sensitivity in Youths," was published online in JAMA today.