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Original Investigation
September 2016

Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial

Author Affiliations
  • 1Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada
  • 2Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
  • 3Nisonger Center, The Ohio State University, Columbus
  • 4Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 5Department of Psychiatry, Vanderbilt University, Nashville, Tennessee
  • 6Biostatistics Center, Massachusetts General Hospital, Boston
  • 7Department of Psychology, Nationwide Children's Hospital, Columbus, Ohio
  • 8Department of Pediatrics and Psychology, The Ohio State University, Columbus
  • 9Department of Pediatrics, Vanderbilt University, Nashville, Tennessee
  • 10Department of Pediatrics, CHEO Research Institute, University of Ottawa, Ottawa, Ontario, Canada
  • 11Department of Medicine, Harvard Medical School, Boston, Massachusetts
  • 12Department of Psychiatry and Sackler Institute for Developmental Psychobiology, Columbia University, New York, New York
  • 13New York State Psychiatric Institute, New York
  • 14Center for Autism and the Developing Brain, New York Presbyterian Hospital, White Plains, New York
JAMA Psychiatry. 2016;73(9):928-937. doi:10.1001/jamapsychiatry.2016.1232
Key Points

Question  What is the effect of metformin hydrochloride on weight gain associated with the use of atypical antipsychotics in children and adolescents with autism spectrum disorders?

Findings  In this randomized clinical trial of 60 participants, metformin significantly reduced weight gain compared with placebo. Overall, metformin was well tolerated during 16 weeks of treatment.

Meaning  In children and youth with autism spectrum disorder who are receiving atypical antipsychotics, metformin may be effective in decreasing weight gain.


Importance  Atypical antipsychotic medications are indicated for the treatment of irritability and agitation symptoms in children with autism spectrum disorder (ASD). Unfortunately, these medications are associated with weight gain and metabolic complications that are especially troubling in children and with long-term use.

Objective  To evaluate the efficacy of metformin for weight gain associated with atypical antipsychotic medications in children and adolescents with ASD (defined in the protocol as DSM-IV diagnosis of autistic disorder, Asperger disorder, or pervasive developmental disorder not otherwise specified), aged 6 to 17 years.

Design, Setting, and Participants  A 16-week, double-blind, placebo-controlled, randomized clinical trial was conducted at 4 centers in Toronto, Ontario, Canada; Columbus, Ohio; Pittsburgh, Pennsylvania; and Nashville, Tennessee. In all, 209 potential participants were screened by telephone, 69 individuals provided consent, and 61 participants were randomized to receive metformin or placebo between April 26, 2013, and June 24, 2015.

Interventions  Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years.

Main Outcomes and Measures  The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication.

Results  Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, −0.10 [95% CI, −0.16 to −0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, −0.95 [95% CI, −1.46 to −0.45] and raw weight, −2.73 [95% CI, −4.04 to −1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005).

Conclusions and Relevance  Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD.

Trial Registration  clinicaltrials.gov Identifier: NCT01825798