Metformin Mitigates Antipsychotic Weight Gain in Autism

Megan Brooks

August 25, 2016

Metformin may counteract atypical antipsychotic–induced weight gain in children with autism spectrum disorder (ASD).

In a controlled trial, metformin was significantly more effective than placebo in decreasing weight gain associated with the use of atypical antipsychotics in this population.

"Based on our findings, we recommend that physicians consider using metformin in children and youth with ASD who have to stay on their atypical antipsychotics for management of irritability/aggression but experience significant weight gain," Evdokia Anagnostou, MD, of the Holland Bloorview Kids Rehabilitation Hospital Autism Research Center, Toronto, Ontario, Canada, told Medscape Medical News.

The study was published online August 24 in JAMA Psychiatry.

The atypical antipsychotics risperidone (Risperdal, Janssen Pharmaceuticals), and aripiprazole (Abilify, Otsuka Pharmaceuticals) are approved by the US Food and Drug Administration to manage irritability in children and adolescents with ASD, but increased appetite and weight gain are well-known side effects.

Dr Anagnostou and a multicenter team tested the safety, tolerability, and efficacy of metformin in decreasing weight gain associated with their use in 60 children and adolescents aged 6 to 17 years (mean age, 12.8 years) with ASD.

All participants had been receiving a stable dose of an atypical antipsychotic, most commonly risperidone and aripiprazole, for at least 1 month with no plans to change. To be included in the study, the children also had to have had at least a 7% increase in body mass index (BMI) since starting the medication or, if the BMI was in the 85th percentile or higher, a greater than 5% increase in body weight per year since starting the medication.

Metformin or matching placebo was titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those aged 10 to 17 years. There were 28 children in the metformin group and 32 in the placebo group.

The primary outcome measure was change in BMI z score over 16 weeks of treatment. On this measure, metformin was superior to placebo (difference in 16-week change in scores vs placebo, -0.10; 95% confidence interval [CI] -0.16 to -0.04; P = .003).

Children receiving placebo experienced no change over 16 weeks in BMI z scores (0.02; 95% CI, -0.03 to 0.06), whereas children taking metformin saw a substantial reduction from baseline (-0.08; 95% CI, -0.13 to -0.04).

Metformin also led to statistically significant improvements in secondary body composition measures of raw BMI (-0.95; 95% CI, -1.46 to -0.45) and raw weight (-2.73; 95% CI, -4.04 to -1.43).

Three children taking metformin (11%) saw declines of 8% to 9% in BMI. No other children experienced declines of more than 5% in BMI during the 16-week treatment period.

No significant between-group differences were noted in metabolic parameters measured in blood, including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, glucose, fasting insulin, or hemoglobin A1c levels.

The authors note that the length of metformin treatment may have been too short to capture metabolic benefits and to evaluate whether initial improvements will be maintained.

Five children stopped metformin owing to adverse events (agitation in four and sedation in one). Gastrointestinal side effects were reported during a significantly higher percentage of treatment days with metformin than placebo (25.1% vs 6.8%; P = .005).

"Metformin was well tolerated overall," Dr Anagnostou told Medscape Medical News. "However, the most common side effects were related to gastrointestinal symptoms. Given that children and youth with ASD experience more GI distress than typically developing children, that's something to keep in mind when prescribing. Also, metformin requires blood monitoring of liver enzymes, and as such, children and youth prescribed this medication would have to tolerate blood work."

"Effective Approach to Consider"

"These findings have important implications for children in whom the benefits of atypical antipsychotics for treating irritability and agitation symptoms are difficult to balance with the substantial weight gain that often accompanies their use," the authors conclude.

"Where we need more study," Dr Anagnostou said, "is to answer the question whether adding metformin at the onset of treatment with atypical antipsychotics may prevent weight gain altogether."

"Clearly, Anagnostou et al understand the dilemma our field faces in balancing the risk-benefit ratio of treating youths with ASD with atypical antipsychotics," Christopher J. McDougle, MD, Lurie Center for Autism, Massachusetts General Hospital and Harvard Medical School, Lexington, Massachusetts, writes in a related editorial.

With this study, they have made a "significant contribution to the literature and provided clinicians with an effective approach to consider for managing weight gain in youths with ASD treated with atypical antipsychotics," Dr McDougle says.

"In addition to more studies of this approach, alternative strategies that warrant investigation include the coadministration of topiramate, monotherapy with ziprasidone, and undoubtedly others."

Dr Anagnostou has received consultation fees and has served on advisory boards for Roche and has received industry funding from SynapDx and Aventis. A complete list of author disclosures is available with the original article. Dr McDougle has disclosed no relevant financial relationships.

JAMA Psychiatry. Published online August 24, 2016. Full text, Editorial

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