title: Metformin for Treatment of Overweight Induced by Atypical Antipsychotic Medication in Young People With Autism Spectrum Disorder: A Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01825798.
authors.affiliation: Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada2Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Evdokia
authors.initials: E
authors.lastname: Anagnostou
authors.affiliation: Nisonger Center, The Ohio State University, Columbus.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Aman
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Handen
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Sanders
authors.affiliation: Biostatistics Center, Massachusetts General Hospital, Boston.
authors.forename: Amy
authors.initials: A
authors.lastname: Shui
authors.affiliation: Nisonger Center, The Ohio State University, Columbus.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Hollway
authors.affiliation: Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada2Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Brian
authors.affiliation: Nisonger Center, The Ohio State University, Columbus.
authors.forename: L Eugene
authors.initials: LE
authors.lastname: Arnold
authors.affiliation: Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada2Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lucia
authors.initials: L
authors.lastname: Capano
authors.affiliation: Nisonger Center, The Ohio State University, Columbus.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Hellings
authors.affiliation: Department of Psychology, Nationwide Children's Hospital, Columbus, Ohio8Department of Pediatrics and Psychology, The Ohio State University, Columbus.
authors.forename: Eric
authors.initials: E
authors.lastname: Butter
authors.affiliation: Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada2Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Deepali
authors.initials: D
authors.lastname: Mankad
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Rameshwari
authors.initials: R
authors.lastname: Tumuluru
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jessica
authors.initials: J
authors.lastname: Kettel
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, Tennessee.
authors.forename: Cassandra R
authors.initials: CR
authors.lastname: Newsom
authors.affiliation: Department of Pediatrics, CHEO Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Stasia
authors.initials: S
authors.lastname: Hadjiyannakis
authors.affiliation: Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.
authors.forename: Naomi
authors.initials: N
authors.lastname: Peleg
authors.affiliation: Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario, Canada.
authors.forename: Dina
authors.initials: D
authors.lastname: Odrobina
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Sarah
authors.initials: S
authors.lastname: McAuliffe-Bellin
authors.affiliation: Biostatistics Center, Massachusetts General Hospital, Boston.
authors.forename: Pearl
authors.initials: P
authors.lastname: Zakroysky
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Sarah
authors.initials: S
authors.lastname: Marler
authors.affiliation: Nisonger Center, The Ohio State University, Columbus.
authors.forename: Alexis
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Nisonger Center, The Ohio State University, Columbus.
authors.forename: Taylor
authors.initials: T
authors.lastname: Wong
authors.affiliation: Biostatistics Center, Massachusetts General Hospital, Boston11Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Macklin
authors.affiliation: Department of Psychiatry and Sackler Institute for Developmental Psychobiology, Columbia University, New York, New York13New York State Psychiatric Institute, New York14Center for Autism and the Developing Brain, New York Presbyterian Hospital, White Plains, New York.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Veenstra-VanderWeele
mesh_terms: D000293:Adolescent; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D000067877:Autism Spectrum Disorder / Q000188:drug therapy*; D015992:Body Mass Index; D002648:Child; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D050177:Overweight / Q000139:chemically induced* / Q000188:drug therapy*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D008687:Metformin