Antipsychotics May Put Kids on the Fast Track to CVD

Drugs Improve Kids' Psychiatric Outcomes but at What Cost?

Fran Lowry

June 20, 2011

June 20, 2011 (Boca Raton, Florida) — Antipsychotic-naive children who receive these medications for the first time experience rapid cardiometabolic changes — including increased adiposity and insulin resistance — just weeks after use of these drugs is initiated.

Lead investigator, John W. Newcomer, MD, professor of psychiatry at the University of Miami Miller School of Medicine in Florida, presented the results of the National Institutes of Mental Health–funded Metabolic Effects of Antipsychotics in Children study here at the New Clinical Drug Evaluation Unit 51st Annual Meeting, sponsored by the American Society of Clinical Psychopharmacology.

Dr. John W. Newcomer

The study was undertaken to characterize changes in adiposity and insulin sensitivity in children receiving their first course of antipsychotic treatment.

"I had been chairing the Drug Utilization Review Board for Missouri Medicaid for the last 14 years, and we saw rising rates of antipsychotic prescription in children and clearly no epidemic of schizophrenia in children," Dr. Newcomer, who led the study while he was at Washington University School of Medicine in St. Louis, Missouri, told Medscape Medical News. "The increase was due to the rising use of antipsychotics for disruptive behavior disorders."

Having studied the metabolic effects of antipsychotics in adults, Dr. Newcomer and his team were curious to see what was happening in children.

Greatest Weight Gain With Olanzapine

The investigators randomized 125 antipsychotic-naive children aged 6 to 18 years (mean age, 11.5 years) with target symptoms of aggression, as determined by an Aberrant Behavior Checklist (ABC) irritability subscale score of at least 18, to 12 weeks of treatment with aripiprazole, risperidone, or olanzapine.

There was a robust improvement in ABC scores with all 3 medications, with a mean decrease of 16.64 points (SD, 7.98).

"They got a lot better. I was actually stunned at how much better they got. It gave me some margin of sympathy that I didn't have before for why the child psychiatrists and the pediatricians are using so much of these drugs," said Dr. Newcomer.

But the improvement came at the cost of increased body weight and adverse changes in insulin sensitivity. Body fat, as measured by dual energy x-ray absorptiometry, increased by a mean of 8.98% (range, 2% – 119%; P < .0001) and whole-body insulin sensitivity, as measured by stable isotopomer tracing during hyperinsulinemic-euglycemic clamps, was decreased by a mean of 2.99 (P = .055).

"There was quite a bit of variability among the treatments in terms of increased fat, but just about everybody sloped upwards," Dr. Newcomer said.

Children treated with olanzapine had the biggest increase in fat mass. The weight gain with risperidone and aripiprazole was much less, he added.

Explore All Options

The results open up an "interesting" policy question, he said.

"In my time on Missouri Medicaid, risperidone at the doses that were used in the study would be something under $50 per user per month, and aripiprazole at those doses would be $300 or so per user per month; so at least from the metabolic perspective, you are getting a lot of clinical benefit and doing much better with a generic second-generation antipsychotic."

The changes in insulin sensitivity paralleled the fat mass changes, he added.

"This study wasn't about cost benefit, it was about risk benefit, but it provokes some thinking about the costs of these drugs. But if you have to use antipsychotics, with the emphasis on the 'have to,' then you want to pick the agents with the lower risk for metabolic outcomes,” Dr. Newcomer said.

"If the child has schizophrenia, not using an antipsychotic is really not an option, but if the child has a disruptive behaviour disorder, you should explore all the other options," he said.

Risk Reduction Strategies 'Sorely Needed'

"Results of this study will generally support promulgated recommendations to select and start treatment with antpsychotics that have the lowest cardiovascular risk potential whenever possible," said Christoph U. Correll, MD, of the Zucker Hillside Hospital, Glen Oaks, New York, who was not part of the study.

"This is particularly relevant in children and adolescents and in treatment-naive and first episode, early-phase patients as these populations appear to be at greatest risk for fast and dramatic adverse changes in body weight, adiposity, lipid metabolism, and insulin sensitivity, adverse effects that have been related to increased and premature cardiovascular morbidity and mortality," Dr. Correll told Medscape Medical News.

"Given the potentially serious consequences of this cardiovasvcular risk accumulation, novel treatment strategies with lower cardiometabolic adverse event potential and strategies that can successfully reduce these side effects are sorely needed," he said.

Dr. Newcomer reported financial relationships with the National Institute of Mental Health, NARSAD, Britsol-Myers Squibb, Janssen, Pfizer, AztraZeneca, BioVail, H. Lundbeck, Obecure, Sepracor, Sunovion, Dainippon Sumitomo Pharma, and Vivus, Inc. Dr. Correll reported financial relationships with Actelion, AstraZeneca, BMS/Otsuka, Boehringer-Ingelheim, Cephalon, Eli Lilly, GSK, Hoffmann-La Roche, Intra-Cellular Therapy, Lundbeck, Medicure, OrthoMcNeill-Janssen, Pfizer, Sepracor/Sunovion, and Takeda.

New Clinical Drug Evaluation Unit (NCDEU) 51st Annual Meeting: Abstract 18. Presented June 15, 2011.