Off-Label Antipsychotic Use Triggers Adverse Metabolic Effects in Kids

Batya Swift Yasgur, MA, LSW

June 19, 2018

Off-label antipsychotic use in children and adolescents with behavioral disorders triggers rapid and significant metabolic effects, including weight gain and decreased insulin sensitivity, new research shows.

Investigators studied persons aged 6 to 18 years who were randomly assigned to receive aripiprazole (multiple brands), olanzapine (multiple brands), or risperidone (Risperdal, Janssen) for disruptive behavior disorders.

The number of overweight or obese participants rose from roughly one third at baseline to almost one half after just 12 weeks of treatment, especially in those taking olanzapine. There were also significant decreases in insulin sensitivity.

"This study augments previous research tying antipsychotic use to weight gain and sheds additional light on the risk-benefit calculation of prescribing them for nonpsychotic behaviors," John Newcomer, MD, professor of integrated medical science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, told Medscape Medical News.

"We hope that clinicians working with families and patients would include this information in shared decision making and suggest that, unlike in schizophrenia, where antipsychotic medications can be lifesaving and are the mainstay of treatment, in youngsters with disruptive behaviors, there are other approaches," he said.

The study was published online June 13 in JAMA Psychiatry.

Connecting the Dots

Antipsychotics, which are associated with risks for weight gain and type 2 diabetes, are increasingly prescribed off label for attention-deficit/hyperactivity disorder (ADHD) and disruptive behavior disorders, the authors write.

Previous studies of the effects of these agents in children have relied on weight-based surrogate or indirect measures of adiposity (eg, weight, body mass index [BMI] percentile, or z score) and insulin sensitivity (eg, fasting plasma insulin or triglyceride levels) in children who were not antipsychotic naive.

"We knew beforehand that youths who are exposed to antipsychotics show increased incidence of type 2 diabetes in periods as short as 6 months following onset of treatment," said Newcomer.

But "what was missing was that increases in body weight were not necessarily attributable to fat, so we weren't sure how this connected to the risk of diabetes," he said.

"We wanted to connect the dots between prior knowledge of weight gain and epidemiologically demonstrated increased incidence of diabetes, increased body fat, and related reduction in tissue insulin sensitivity as a result of these agents in youth," Newcomer added.

In addition, he pointed out that in the past 2 decades, there has been a rise in antipsychotic prescriptions in children without psychosis. Given the known metabolic risks of antipsychotics, this was a cause for concern. The primary endpoints selected for this study had never been used in previous research, he said.

These endpoints utilized "gold standard measures" of body fat — dual-energy x-ray absorptiometry (DXA) and MRI of the abdomen, visceral fat, and subcutaneous fat. In addition, a hyperinsulinemic-euglycemic clamp procedure was used to measure glucose uptake in muscle (glucose rate of disappearance) and hepatic glucose production (glucose rate of appearance).

The researchers studied 144 antipsychotic-naive youths, (61% males, 31.9% female, aged 6 to 18 years; mean age, 11.4 years [SD, 2.8 years]).

Participants were required to have ≥1 DSM-IV-TR diagnoses and significant aggression (defined by a score of ≥18 on the Irritability subscale of the Aberrant Behavior checklist).

Patients who had a substance use disorder, an IQ of <70, a lifetime exposure to antipsychotics of >1 week, and diabetes were excluded.

Overweight, Obese

Participants underwent an array of clinical laboratory tests, including fasting metabolic and plasma lipid panels, hemoglobin A1c assessment, and measurements of height, weight, and waist circumference.

The percentage of total body fat and total lean body mass was determined by DXA at baseline and 6 and 12 weeks.

Abdominal 1.5-Tesla MRI scans, performed at baseline and 12 weeks, were used to quantify subcutaneous and visceral abdominal adiposity.

The primary outcomes measures were to evaluate antipsychotic treatment effects on total body fat and insulin sensitivity at muscle (glucose disposal) over 12 weeks.

Secondary outcomes included the effects on abdominal fat and insulin sensitivity at lipid and adipose tissues (glucose production and lipolysis, respectively).

Mean final antipsychotic doses for risperidone, olanzapine, and aripiprazole, which are representative of pediatric practice patterns (and which were lower than the doses typically used to treat psychosis) were 1.0 mg (SD, 0.6 mg), 6.3 mg (SD, 3.2 mg), and 6.0 mg (SD, 4.5 mg), respectively.

Of the participants, 55.6% had a primary diagnosis of ADHD, with irritability and aggression insufficiently responsive to prior therapy; and 60% had reported ≥1 school suspensions during the 12 months preceding the study.

All study participants showed similar "clinically and statistically significant improvements" in behavioral symptoms, including irritability and aggression, during the treatment period, with school suspensions decreasing by 43%.

In all study treatments, mean DXA percentage total body fat (primary outcome) increased significantly (by 1.18% for risperidone, 4.12% for olanzapine, and 1.66% for aripiprazole) during the 12 weeks (F = 6.17; P < .001).

The olanzapine group showed greater mean increases in fat, compared with the risperidone and aripiprazole groups (time by treatment interaction, P < .001).

Abdominal fat, as measured by MRI (secondary outcome), increased significantly viscerally and subcutaneously; the greatest increase in subcutaneous fat occurred in patients treated with olanzapine.

Baseline rates of overweight (BMI 85th to 94th percentiles) and obesity (BMI ≥ 95th percentile) among those who completed the study were 13.2% and 17.8%, respectively, similar to rates in the general population.

However, at 12 weeks, 20.9% and 25.6%, respectively, met criteria for overweight or obesity (46.5% combined).

Reduced Insulin Sensitivity

Reductions in insulin sensitivity from baseline were larger in those with higher baseline sensitivity.

Insulin-stimulated change in glucose rate of disappearance between baseline and week 12 increased in patients who received risperidone (by 2.30%) and decreased in those who received olanzapine and aripiprazole (by 29.34% and 30.26%, respectively). There were no significant differences across treatment groups (time by treatment interaction, P < .07).

On the pooled study sample, this primary measure of insulin sensitivity decreased significantly during the study period (effect of time, F = 17.38; P < .001).

Younger patients experienced greater increases of change than did older patients.

"We are in the middle of a childhood obesity epidemic, and our sample at baseline looked like the general pediatric population, with roughly a third overweight or obese, but after 12 weeks of treatment, almost half were overweight and obese" Newcomer commented.

"A significant percentage had experienced school suspension prior to the study, which is a catastrophic event from an educational standpoint," he noted.

"I understand why clinicians might be motivated to seek rapidly acting options to target the disruptive behaviors and get children back into the education pathway as quickly as possible," he said.

However, there are "other evidence-based interventions for these kinds of behaviors, and in a perfect world, they would be deployed first, although availability of therapists trained in these modalities is limited, and there are long wait lists, with the clock ticking in terms of school performance," he said.

Screen and Monitor

Commenting on the study for Medscape Medical News, Marc De Hert, MD, PhD, of the Department of Neurosciences, Katholieke Universiteit Leuven, Kortenberg, Belgium, who was not involved with the study, observed that off-label use of antipsychotics for nonpsychotic indications is common both in the United States and Europe.

"Metabolic side effects are a real concern — or should be — in antipsychotic use, and they are more pronounced in first-time users and young people," he said.

The study uses "state-of-the-art gold standard measurements to confirm and highlight this problem in nonpsychotic disorders," noted De Hert, who is the coauthor of an accompanying editorial.

He recommended "good screening and monitoring for these side effects in all antipsychotic users, especially children and youngsters."

Newcomer echoed the "critical importance" of monitoring body weight, BMI, and blood parameters in children taking antipsychotics.

"If you're going to use these medications, buckle your seat belt and do all the steps that need to be done," he said.

The study was supported by the National Institute of Mental Health, the National Center for Research Resources, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health. Additional funding was provided by the Sidney R. Bear Jr Foundation and the Health Mind Lab at Washington University. The study authors' relevant financial relationships are listed in the original article. Dr De Hert has disclosed no relevant financial relationships.

JAMA Psychiatry. Published online June 13, 2018. Abstract, Editorial

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