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Cited by 123Pharmacology and Obesity TreatmentSchizophrenia research and treatmentAutism Spectrum Disorder Research

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

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Anagnostou, Evdokia, Aman, Michael G., Handen, Benjamin L., Sanders, Kevin B., Shui, Amy, Hollway, Jill A., Brian, Jessica, Arnold, L. Eugene +17 more·2016·JAMA Psychiatry
DOI 10.1001/jamapsychiatry.2016.1232
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Abstract

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.

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  • Underpowered studies of intranasal oxytocin have demonstrated mixed results that are overall not supportive of a large effect size.

    “Underpowered studies of intranasal oxytocin have demonstrated mixed results that are overall not supportive of a large effect size 209,210”

    From Autism spectrum disorder (2020) · cites this paper as [209]

    The Secondary Outcomes section reports weight and BMI effects in a metformin trial, not findings from intranasal oxytocin studies. Searches for intranasal oxytocin, mixed trial results, and oxytocin effect sizes found no passage addressing the claim; page numbers were unavailable in our copy. (LLM, conf=0.78)

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  1. Guy W. Dosage Record and Treatment Emergent Symptoms Scale, ECDEU Assessment Manual for Psychopharmacology (Revised). Washington, DC: US Dept of Health Education & Human Welfare; 1976:223-244.

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Authors
Anagnostou, E., Aman, M. G., Handen, B. L., Sanders, K. B., Shui, A., Hollway, J. A., Brian, J., Arnold, L. E., Capano, L., Hellings, J. A., Butter, E., Mankad, D., Tumuluru, R., Kettel, J., Newsom, C. R., Hadjiyannakis, S., Peleg, N., Odrobina, D., McAuliffe-Bellin, S., Zakroysky, P., Marler, S., Wagner, A., Wong, T., Macklin, E. A., & Veenstra-VanderWeele, J.
Affiliations
  • University of Toronto (CA)
  • The Ohio State University (US)
  • University of Pittsburgh (US)
  • Vanderbilt University (US)
  • Massachusetts General Hospital (US)
  • Nationwide Children's Hospital (US)
  • University of Ottawa (CA)
  • Holland Bloorview Kids Rehabilitation Hospital (CA)
  • Harvard University (US)
  • NewYork–Presbyterian Hospital (US)
Corresponding author
Anagnostou, Evdokia
ORCID
Venue
JAMA Psychiatry
Publisher
American Medical Association (AMA)
Published
2016-09-01
Volume
73
Issue
9
Pages
928
ISSN
2168-622X (ISSN-L)
DOI
10.1001/jamapsychiatry.2016.1232
OpenAlex
W2513067294
Cited by
123
References
50
Citations by year
2026: 11 · 2025: 8 · 2024: 11 · 2023: 9 · 2022: 8 · 2021: 13 · 2020: 20 · 2019: 11 · 2018: 20 · 2017: 9 · 2016: 3
FWCI
11.59
Type
journal article
Language
en
Open access
Locations
  • JAMA Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Defense
  • U.S. Department of Health and Human Services (UA3 MC11054)
  • Autism Speaks (UA3 MC 11054)
  • Abbott Laboratories
  • Eli Lilly and Company
  • Pfizer
  • Muscular Dystrophy Association
  • ALS Therapy Alliance
  • Vanderbilt University
  • Sunovion
  • Acorda Therapeutics
  • National Institutes of Health
  • Health Resources and Services Administration (UA3 MC11054)
  • Canadian Institutes of Health Research
  • National Institute on Aging
  • National Institute of Mental Health
Topics
  • Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
metformin, atypical antipsychotics, autism spectrum disorder, medication-induced weight gain, childhood obesity, body mass index, body composition, metabolic complications, irritability, adolescents, children, weight loss interventions, drug safety and tolerability, adverse events, serious adverse events, medication adherence, antipsychotic-induced metabolic syndrome, Asperger syndrome
MeSH terms
Autism Spectrum Disorder, Adolescent, Child, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Metformin, Antipsychotic Agents, Weight Gain, Body Mass Index, Overweight, Intention to Treat Analysis

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