SGAs Increase Teens’ Abdominal Fat, Decrease Insulin Sensitivity

Treatment with certain second-generation antipsychotic (SGA) medications in SGA-naïve youth for disruptive behavior disorders appears to result in increases in abdominal fat and reductions in insulin sensitivity within just 12 weeks of treatment, according to a report posted June 13 in JAMA Psychiatry.

All three of the antipsychotic medications compared in the study—aripiprazole, olanzapine, and risperidone—resulted in significant increases in whole body and abdominal fat. Further, when results for the entire cohort were pooled, treatments with these drugs resulted in reductions in insulin sensitivity in a remarkably short period.

“We have known for a while that antipsychotics cause weight gain, and we have known for a while that in large epidemiologic samples—such as studies of Medicaid patients—antipsychotic exposure was associated with increased risk for diabetes,” said principal investigator and senior author John Newcomer, M.D., a professor of integrated medical science at the Charles E. Schmidt College of Medicine at Florida Atlantic University.

“The usual pathway to developing diabetes is to have increased abdominal fat mass, which a vast amount of evidence has shown increases the risk for insulin resistance,” he said. “When your body develops insulin resistance, that’s when you develop the risk for type 2 diabetes. What we were trying to do in this study is identify in antipsychotic-naïve young people if antipsychotic exposure increased body fat, if the increase occurred in the abdominal compartment, and whether treatment also led to a decrease in insulin sensitivity. That’s exactly what we saw.”

Newcomer and colleagues recruited young people from the St. Louis metropolitan area between June 2006 and November 2010 whose clinicians and parents had already decided to initiate antipsychotic treatment, so that participation in the study offered safety monitoring not typically available in clinical practice. Researchers enrolled 144 antipsychotic-naïve youth aged 6 to 18 years; all participants had one or more Axis I DSM IV-TR diagnosis and clinically significant aggression defined by a score of at least 18 on the irritability subscale of the Aberrant Behavior Checklist.

The youth were randomized to receive aripiprazole, olanzapine, or risperidone for 12 weeks. Primary outcome measures were treatment effects over 12 weeks on total body fat, measured by dual-energy X-ray absorptiometry (DXA), as well as insulin sensitivity at muscle (glucose disposal). Secondary outcomes included effects over 12 weeks on abdominal fat and insulin sensitivity, measured by magnetic resonance imaging (MRI) at the liver (glucose production) and adipose tissue (lipolysis).

Newcomer and colleagues found that the primary outcome of mean percentage total body fat increased significantly during 12 weeks for all study treatments. The largest increase was for olanzapine (4.12 percent) followed by aripiprazole (1.66 percent) and risperidone (1.18 percent). When results for the entire cohort were pooled, insulin sensitivity decreased significantly during the 12 weeks, and there was no significant difference between treatments.

The secondary outcome of abdominal fat measured by MRI increased significantly in visceral and subcutaneous compartments, with a similar mean increase in visceral fat during all treatments, but greater subcutaneous mean fat increase with olanzapine.

“Olanzapine led to more fat,” Newcomer said, “but all three drugs produced significant increases. But to me, the really important observation is that all three drugs increased visceral abdominal fat and that treated youths on average experienced decreases in insulin sensitivity.”

Newcomer noted that off-label prescribing of antipsychotics for children and adolescents for behavioral disorders is far higher in the United States than in other parts of the world, while psychotherapy or cognitive-behavioral therapy are vastly underused.

“Medications have become the easy go-to fix,” he said.

He said that although the risks of weight gain and metabolic disease have been relatively well known and publicized, clinicians may have believed they could make a rapid clinical intervention with antipsychotics to improve behavior without significant risk to metabolic health and that they could switch to lower-risk medications over the long term. The results of the JAMA Psychiatry study call those assumptions into question.

“An important finding from the study is how quickly the mechanism that leads to risk for diabetes kicks in,” he told Psychiatric News. “The take-home message for clinicians is that the decision to prescribe antipsychotics in the first place is as important as the drug you choose. We’ve been telling clinicians to choose the lower-risk agent, but maybe for off-label uses, the risk-benefit equation is different when you are treating schizophrenia or bipolar disorder. In the instance of disruptive behavior disorder, when there are other nonpharmaceutical options, perhaps we should be rethinking the decision to go down this road at all.”

In an editorial accompanying the study, Belgian researchers Marc De Hert, M.D., Ph.D., and John Detrax, M.Psy., wrote that despite the existing guidelines and recommendations that highlight the importance of monitoring for metabolic abnormalities, glucose and lipid-monitoring rates continue to be “disappointingly low” in children and in adults.

“In the case of off-label prescribing, psychosocial interventions should be tried before initiating antipsychotic medication,” they wrote. “If antipsychotic medication is started, psychoeducation and health lifestyle advice are essential and can be helpful.”

The study was supported by grants from NIMH and NIH. ■