APA 2009: Atypical Antipsychotics Linked to Rapid, Adverse Metabolic Changes in Children

Caroline Cassels

June 03, 2009

June 3, 2009 (San Francisco, California) — Early findings from a study linking initial exposure to atypical antipsychotics in children show that concurrent with significant improvement in behavioral symptoms, including severe aggression, irritability, and disruptive behavior across multiple childhood-onset psychiatric disorders, these medications are associated with rapid, adverse metabolic changes.

Presented here at the American Psychiatric Association 162nd Annual Meeting, preliminary results from the Metabolic Effects of Antipsychotics in Children (MEAC) study show that 12 weeks of initial antipsychotic treatment was associated with significant mean increases in overall adiposity and percentage of body fat, as well as a decrease in whole-body insulin sensitivity.

Further, the investigators found antipsychotic treatment was also linked to significant increases in body-mass index (BMI) percentile and fasting plasma triglyceride levels, both clinically available indicators of adverse metabolic changes associated with increased adiposity.

Dr. Ginger E. Nicol

"The reason we wanted to present these preliminary results is that we saw such striking changes in these [metabolic] parameters in the entire group of patients. Weight gain is something that many of us see clinically with these medications in our pediatric patients, and it is of great concern. However, these preliminary results suggest that weight gain is associated with a significant decrease in insulin sensitivity," study investigator Ginger E. Nicol, MD, from Washington University School of Medicine, in St. Louis, Missouri, told Medscape Psychiatry.

A 5-year study funded by the National Institute of Mental Health (NIMH), under the direction of John Newcomer, MD, from Washington University School of Medicine, MEAC's purpose is to quantify antipsychotic treatment–related changes in adiposity and insulin sensitivity in antipsychotic-naive children and adolescents with irritability, aggression, and disruptive behaviors, which are common presenting symptoms for many mental disorders in this population.

Study subjects included children age 6 to 18 years with Aberrant Behavior Checklist (ABC) irritability subscale scores of more than 18 who were randomized to 12 weeks of open-label treatment with olanzapine (Zyprexa, Lilly), risperidone (Risperdal, Janssen), or aripiprazole (Abilify, Otsuko/Bristol-Myers Squibb).

"We used 18 as the cutoff score on the ABC irritability subscale because it is consistent with what has been used in other antipsychotic-treatment studies of irritability and aggression. Many of these children are very physically aggressive and as a result have frequently been suspended from school or are on the verge of hospitalization," said Dr. Nicol.

The MEAC study seeks to enroll only children in whom other approaches have failed and who are already under clinical consideration for antipsychotic treatment.

Children are screened for a variety of potential diagnoses that have associated symptoms of aggression and irritability, including depression and attention-deficit/hyperactivity disorder (ADHD), that may have previously gone undetected or were inadequately treated. In such cases, patients are referred back to their primary clinician with recommendations to pursue appropriate first-line treatments.

"The risk/benefit ratio is very carefully considered for each individual participant in terms of whether they are likely to derive benefit from being placed on an antipsychotic," said Dr. Nichol.

Treatment-Naive Population

Following randomization to 1 of the 3 study medications, subjects received weekly monitoring and scheduled assessments to detect any metabolic change. The study's primary end points include measures of body composition with dual-energy X-ray absorptiometry (DEXA), abdominal magnetic resonance imaging (MRI), and insulin sensitivity with stable isotopomer tracing during hyperinsulinemic-euglycemic clamp conditions.

According to Dr. Nicol, MEAC is 1 of the first studies to look at a treatment-naive pediatric population and is the only study in children taking antipsychotics to date that is using gold-standard measures of adiposity and insulin sensitivity.

The preliminary pooled-groups analysis of the first 57 study completers revealed that 12 weeks of initial antipsychotic treatment was associated with significant mean increases from baseline in DEXA total fat (2.74 kg) and DEXA total percent body fat (2.97%),  with an associated mean decrease in whole-body insulin sensitivity.

Similarly, change in clinically available indicators of adiposity and insulin sensitivity were also observed, with significant increases in BMI percentile of 14.8 percentile points and a mean increase in fasting plasma triglycerides of 18.1 mg/dL.

In a positive light, the study also showed treatment with antipsychotics was associated with marked reductions in the ABC irritability score, with a mean drop of 15.37 points.

Study Sheds New Light on Everyday Problem

Asked by Medscape Psychiatry to comment on the study, Lawrence Maayan, MD, an expert in the metabolic effects of psychotropic medications and treatment and evaluation of pediatric psychosis, said these early findings shed new light on the metabolic effects of these medications in children — a problem that child psychiatrists "see every day."

"There have been findings from randomized controlled trials showing these agents cause weight gain, especially with risperidone and olanzapine, but this study really looks at this group [of agents] broadly and has a number of different features that haven't been looked at in children previously," said Dr. Maayan, director of outpatient research at the Nathan S. Kline Institute for Psychiatric Research at New York University.

Dr. Maayan said he looks forward to the final study findings, which will demonstrate whether there are differences between the 3 agents in terms of their adverse metabolic effects.

"Certainly there are good data out there showing that olanzapine is most likely to cause weight gain in susceptible individuals; risperidone seems to be somewhere in the middle, although it appears it is more likely to cause weight gain in kids; and the picture for aripiprazole is not clear. But to have a study like this that is NIMH-funded that really looks at this question will be very valuable, whatever way it comes out," said Dr. Maayan.

A number of studies have tested potential interventions to help offset the metabolic effects of these medications. These include behavioral interventions that run the gamut of cognitive behavioral therapy to nutrition counseling, most of which do appear to have at least a modest effect on weight gain.

Other studies have shown pharmacological interventions, including the use of the oral antidiabetic agent metformin, can help slow weight gain. Dr. Maayan said in his own practice he routinely counsels children taking antipsychotics about the value of exercise and healthy eating choices.

Dr. Nicol reports no disclosures.

American Psychiatric Association 162nd Annual Meeting: Abstract NR5-030. Presented May 19, 2009.

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