The prevalence of childhood obesity has more than tripled from 1971 to 2011 and is now at epidemic proportions, contributing to rising rates of type 2 diabetes in youths. A new study is the first to show that even short-term treatment with antipsychotic medications commonly prescribed off-label to treat nonpsychotic disorders associated with disruptive behavior, such as ADHD, in youths can increase body fat and decrease the body’s sensitivity to insulin, important early steps in the development of risk for diabetes.

Researchers from Florida Atlantic University and Washington University in St. Louis, conducted a randomized. prospective clinical trial of children aged 6 to 18 years to test the hypothesis that antipsychotic treatment adversely increases body fat and decreases insulin sensitivity—important stages in the development of type 2 diabetes. While antipsychotic treatment is known to increase risk for diabetes, the mechanism underlying this risk has been unclear, as most prior studies did not directly measure key factors like changes in body fat and insulin sensitivity. In addition, prior studies have almost always been conducted in adults with years of prior antipsychotic exposure, making it difficult to attribute observed changes only to the medications under study and leaving unanswered questions about the effects of treatment in children.

The study, published in JAMA Psychiatry, is the first to use gold-standard methods to directly measure changes in whole body and abdominal fat as well as insulin sensitivity together in children taking antipsychotics for the first time, providing the researchers with a “clean slate” on which to measure the effects of the medications they studied.

“Over the past two decades, the US has seen a dramatic increase in the use of antipsychotic medications in children and it’s not due to an epidemic of childhood schizophrenia or other conditions where antipsychotics may be lifesaving. Rather, it is part of a national phenomenon where children who have nonpsychotic disorders with disruptive behaviors are increasingly being treated with antipsychotic medications,” said John W. Newcomer, MD, principal investigator and senior author of the study who is a psychiatrist and a professor of integrated medical science in FAU’s Charles E. Schmidt College of Medicine, as well as an adjunct professor of psychiatry at Washington University School of Medicine. “There was certainly reason to worry about the metabolic risks of using antipsychotic medications in children, and that prompted us to do this study.”

Researchers enrolled 144 children diagnosed with one or more psychiatric disorders involving clinically significant aggression who were already being considered for treatment with antipsychotic medications. Study participants were randomized to 12 weeks of treatment with one of three antipsychotics: oral aripiprazole, olanzapine, or risperidone. The study and related data analysis took place between 2006 and 2017.

Results from the study found that while one drug in particular—olanzapine—produced the greatest increases in body fat, body fat also increased significantly with all the antipsychotic medications tested. Increases were observed not only with total body fat, but also with visceral and subcutaneous abdominal fat, where increases have previously been associated with long-term risk for cardiovascular disease, high blood pressure, and type 2 diabetes.

“While antipsychotic medications are first-line treatments for conditions like pediatric-onset schizophrenia, bipolar disorder, and autism, it is imperative for psychiatrists treating children—especially for off-label conditions where less safety data is available—to carefully evaluate risk-benefit considerations,” said Ginger E. Nicol, MD, first author of the study and an associate professor of psychiatry at Washington University School of Medicine. “And if we do treat children with antipsychotics, we have to be diligent in monitoring body weight as well as blood sugar, cholesterol, and triglyceride levels and then be prepared to change course if we see adverse medication effects that could increase long-term risk for diabetes, cardiovascular disease, and other conditions.”

Researchers measured whole body fat using DXA (dual-energy x-ray absorptiometry), with abdominal fat measured by MRI. The body’s sensitivity to the hormone insulin was measured in muscle, fat tissue, and liver tissue using a procedure called a hyperinsulinemic clamp with stable isotopically labeled tracers. These measures have never been used together as primary outcomes in any published studies of prospective randomized antipsychotic treatment in youth, limiting understanding of key treatment-induced risks in children and adolescents, a population in whom antipsychotics are most often used “off-label” (ie, medication use for conditions not reviewed and approved by the FDA).

Newcomer, Nicol, and collaborators expect that the results from this study may be a “wake-up call” for psychiatrists and other clinicians that even short-term antipsychotic treatment can begin to adversely change important disease risk factors.

“It is a challenge for clinicians because we know that antipsychotic medications can produce rapid improvements in disruptive behavioral symptoms in children, but not without serious health consequences,” said Newcomer. “Therefore, we believe it is time to really hit the brakes on the common first-line use of these medications in children with nonpsychotic behavior disorders and to implement more consistent front-line use of behavioral treatment options that are available and effective.”