Metformin for treatment of overweight induced by atypical antipsychotic medication in young people with autism spectrum disorder: A randomized clinical trial

Evdokia Anagnostou, Michael G. Aman, Benjamin L. Handen, Kevin B. Sanders, Amy Shui, Jill A. Hollway, Jessica Brian, L. Eugene Arnold, Lucia Capano, Jessica A. Hellings, Eric Butter, Deepali Mankad, Rameshwari Tumuluru, Jessica Kettel, Cassandra R. Newsom, Stasia Hadjiyannakis, Naomi Peleg, Dina Odrobina, Sarah McAuliffe-Bellin, Pearl ZakroyskySarah Marler, Alexis Wagner, Taylor Wong, Eric A. Macklin, Jeremy Veenstra-Vander Weele

Research output: Contribution to journalArticle

38 Citations (Scopus)

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 ofmetformin 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 receivemetformin or placebo between April 26, 2013, and June 24, 2015. INTERVENTIONS Metformin or matching placebo titrated up to 500mg twice daily for children aged 6 to 9 years and 850mg twice daily for those 10 to 17 years. MAIN OUTCOMES AND MEASURES The primary outcome measurewas 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). CONCLUSIONSANDRELEVANCE Metforminmaybe effective in decreasingweight gain associated with atypical antipsychotic use and iswell tolerated by children and adolescents with ASD.

Original languageEnglish (US)
Pages (from-to)928-937
Number of pages10
JournalJAMA Psychiatry
Volume73
Issue number9
DOIs
StatePublished - Sep 1 2016

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Metformin
Antipsychotic Agents
Randomized Controlled Trials
Placebos
Body Mass Index
Body Composition
Weight Gain
Therapeutics
Asperger Syndrome
Body Weights and Measures
Ontario
Autistic Disorder
Telephone
Diagnostic and Statistical Manual of Mental Disorders
Canada
Autism Spectrum Disorder
Safety
Weights and Measures

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Metformin for treatment of overweight induced by atypical antipsychotic medication in young people with autism spectrum disorder : A randomized clinical trial. / Anagnostou, Evdokia; Aman, Michael G.; Handen, Benjamin L.; Sanders, Kevin B.; Shui, Amy; Hollway, Jill A.; Brian, Jessica; Arnold, L. Eugene; Capano, Lucia; Hellings, Jessica A.; Butter, Eric; Mankad, Deepali; Tumuluru, Rameshwari; Kettel, Jessica; Newsom, Cassandra R.; Hadjiyannakis, Stasia; Peleg, Naomi; Odrobina, Dina; McAuliffe-Bellin, Sarah; Zakroysky, Pearl; Marler, Sarah; Wagner, Alexis; Wong, Taylor; Macklin, Eric A.; Veenstra-Vander Weele, Jeremy.

In: JAMA Psychiatry, Vol. 73, No. 9, 01.09.2016, p. 928-937.

Research output: Contribution to journalArticle

Anagnostou, E, Aman, MG, Handen, BL, Sanders, KB, Shui, A, Hollway, JA, Brian, J, Arnold, LE, Capano, L, Hellings, JA, Butter, E, Mankad, D, Tumuluru, R, Kettel, J, Newsom, CR, Hadjiyannakis, S, Peleg, N, Odrobina, D, McAuliffe-Bellin, S, Zakroysky, P, Marler, S, Wagner, A, Wong, T, Macklin, EA & Veenstra-Vander Weele, J 2016, 'Metformin for treatment of overweight induced by atypical antipsychotic medication in young people with autism spectrum disorder: A randomized clinical trial', JAMA Psychiatry, vol. 73, no. 9, pp. 928-937. https://doi.org/10.1001/jamapsychiatry.2016.1232
Anagnostou, Evdokia ; Aman, Michael G. ; Handen, Benjamin L. ; Sanders, Kevin B. ; Shui, Amy ; Hollway, Jill A. ; Brian, Jessica ; Arnold, L. Eugene ; Capano, Lucia ; Hellings, Jessica A. ; Butter, Eric ; Mankad, Deepali ; Tumuluru, Rameshwari ; Kettel, Jessica ; Newsom, Cassandra R. ; Hadjiyannakis, Stasia ; Peleg, Naomi ; Odrobina, Dina ; McAuliffe-Bellin, Sarah ; Zakroysky, Pearl ; Marler, Sarah ; Wagner, Alexis ; Wong, Taylor ; Macklin, Eric A. ; Veenstra-Vander Weele, Jeremy. / Metformin for treatment of overweight induced by atypical antipsychotic medication in young people with autism spectrum disorder : A randomized clinical trial. In: JAMA Psychiatry. 2016 ; Vol. 73, No. 9. pp. 928-937.
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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 ofmetformin 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 receivemetformin or placebo between April 26, 2013, and June 24, 2015. INTERVENTIONS Metformin or matching placebo titrated up to 500mg twice daily for children aged 6 to 9 years and 850mg twice daily for those 10 to 17 years. MAIN OUTCOMES AND MEASURES The primary outcome measurewas 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). CONCLUSIONSANDRELEVANCE Metforminmaybe effective in decreasingweight gain associated with atypical antipsychotic use and iswell tolerated by children and adolescents with ASD.",
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T1 - Metformin for treatment of overweight induced by atypical antipsychotic medication in young people with autism spectrum disorder

T2 - A randomized clinical trial

AU - Anagnostou, Evdokia

AU - Aman, Michael G.

AU - Handen, Benjamin L.

AU - Sanders, Kevin B.

AU - Shui, Amy

AU - Hollway, Jill A.

AU - Brian, Jessica

AU - Arnold, L. Eugene

AU - Capano, Lucia

AU - Hellings, Jessica A.

AU - Butter, Eric

AU - Mankad, Deepali

AU - Tumuluru, Rameshwari

AU - Kettel, Jessica

AU - Newsom, Cassandra R.

AU - Hadjiyannakis, Stasia

AU - Peleg, Naomi

AU - Odrobina, Dina

AU - McAuliffe-Bellin, Sarah

AU - Zakroysky, Pearl

AU - Marler, Sarah

AU - Wagner, Alexis

AU - Wong, Taylor

AU - Macklin, Eric A.

AU - Veenstra-Vander Weele, Jeremy

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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 ofmetformin 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 receivemetformin or placebo between April 26, 2013, and June 24, 2015. INTERVENTIONS Metformin or matching placebo titrated up to 500mg twice daily for children aged 6 to 9 years and 850mg twice daily for those 10 to 17 years. MAIN OUTCOMES AND MEASURES The primary outcome measurewas 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). CONCLUSIONSANDRELEVANCE Metforminmaybe effective in decreasingweight gain associated with atypical antipsychotic use and iswell tolerated by children and adolescents with ASD.

AB - 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 ofmetformin 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 receivemetformin or placebo between April 26, 2013, and June 24, 2015. INTERVENTIONS Metformin or matching placebo titrated up to 500mg twice daily for children aged 6 to 9 years and 850mg twice daily for those 10 to 17 years. MAIN OUTCOMES AND MEASURES The primary outcome measurewas 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). CONCLUSIONSANDRELEVANCE Metforminmaybe effective in decreasingweight gain associated with atypical antipsychotic use and iswell tolerated by children and adolescents with ASD.

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