Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial

Christoph U. Correll, Linmarie Sikich, Gloria Reeves, Jacqueline Johnson, Courtney Keeton, Marina Spanos, Sandeep Kapoor, Kristin Bussell, Leslie Miller, Tara Chandrasekhar, Eva M. Sheridan, Sara Pirmohamed, Shauna P. Reinblatt, Cheryl Alderman, Abigail Scheer, Irmgard Borner, Terrence C. Bethea, Sarah Edwards, Robert M. Hamer, Mark A. Riddle

Research output: Contribution to journalArticle

Abstract

Antipsychotics are used for many psychiatric conditions in youth. Although developmentally inappropriate weight gain and metabolic abnormalities, which are risk factors for premature cardiovascular mortality, are especially frequent in youth, optimal strategies to reduce pediatric antipsychotic-induced overweight/obesity are unclear. The Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) was a randomized, parallel group, 24-week clinical trial which enrolled overweight/obese, psychiatrically stable youth, aged 8-19 years, with a DSM-IV diagnosis of severe mental illness (schizophrenia spectrum disorder, bipolar spectrum disorder or psychotic depression), at four US universities. All of them had developed substantial weight gain following treatment with a second-generation antipsychotic. The centralized, computer-based randomization system assigned participants to unmasked treatment groups: metformin (MET); antipsychotic switch (aripiprazole or, if already exposed to that drug, perphenazine or molindone; SWITCH); or continued baseline antipsychotic (CONTROL). All participants received healthy lifestyle education. The primary outcome was body mass index (BMI) z-score change from baseline, analyzed using estimated least squares means. Altogether, 127 participants were randomized: 49 to MET, 31 to SWITCH, and 47 to CONTROL. BMI z-score decreased significantly with MET (week 24: –0.09±0.03, p=0.002) and SWITCH (week 24: –0.11±0.04, p=0.003), while it increased non-significantly with CONTROL (week 24: +0.04±0.03). On 3-way comparison, BMI z-score changes differed significantly (p=0.001). MET and SWITCH were each superior to CONTROL (p=0.002), with effect sizes of 0.68 and 0.81 respectively, while MET and SWITCH did not differ. More gastrointestinal problems occurred in MET than in SWITCH or CONTROL. The data safety monitoring board closed the perphenazine-SWITCH arm because 35.2% of subjects discontinued treatment due to psychiatric worsening. These data suggest that pediatric antipsychotic-related overweight/obesity can be reduced by adding metformin or switching to a lower risk antipsychotic. Healthy lifestyle education is not sufficient to prevent ongoing BMI z-score increase.

Original languageEnglish (US)
Pages (from-to)69-80
Number of pages12
JournalWorld Psychiatry
Volume19
Issue number1
DOIs
StatePublished - Feb 1 2020

Fingerprint

Metformin
Antipsychotic Agents
Education
Body Mass Index
Perphenazine
Therapeutics
Weight Gain
Psychiatry
Molindone
Obesity
Clinical Trials Data Monitoring Committees
Premature Mortality
Random Allocation
Healthy Lifestyle
Least-Squares Analysis
Bipolar Disorder
Diagnostic and Statistical Manual of Mental Disorders
Psychotic Disorders
Schizophrenia
Clinical Trials

Keywords

  • antipsychotic switch
  • Antipsychotics
  • healthy lifestyle education
  • IMPACT
  • metformin
  • obesity
  • weight gain
  • youth

ASJC Scopus subject areas

  • Phychiatric Mental Health
  • Psychiatry and Mental health

Cite this

Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness : results from the IMPACT trial. / Correll, Christoph U.; Sikich, Linmarie; Reeves, Gloria; Johnson, Jacqueline; Keeton, Courtney; Spanos, Marina; Kapoor, Sandeep; Bussell, Kristin; Miller, Leslie; Chandrasekhar, Tara; Sheridan, Eva M.; Pirmohamed, Sara; Reinblatt, Shauna P.; Alderman, Cheryl; Scheer, Abigail; Borner, Irmgard; Bethea, Terrence C.; Edwards, Sarah; Hamer, Robert M.; Riddle, Mark A.

In: World Psychiatry, Vol. 19, No. 1, 01.02.2020, p. 69-80.

Research output: Contribution to journalArticle

Correll, CU, Sikich, L, Reeves, G, Johnson, J, Keeton, C, Spanos, M, Kapoor, S, Bussell, K, Miller, L, Chandrasekhar, T, Sheridan, EM, Pirmohamed, S, Reinblatt, SP, Alderman, C, Scheer, A, Borner, I, Bethea, TC, Edwards, S, Hamer, RM & Riddle, MA 2020, 'Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness: results from the IMPACT trial', World Psychiatry, vol. 19, no. 1, pp. 69-80. https://doi.org/10.1002/wps.20714
Correll, Christoph U. ; Sikich, Linmarie ; Reeves, Gloria ; Johnson, Jacqueline ; Keeton, Courtney ; Spanos, Marina ; Kapoor, Sandeep ; Bussell, Kristin ; Miller, Leslie ; Chandrasekhar, Tara ; Sheridan, Eva M. ; Pirmohamed, Sara ; Reinblatt, Shauna P. ; Alderman, Cheryl ; Scheer, Abigail ; Borner, Irmgard ; Bethea, Terrence C. ; Edwards, Sarah ; Hamer, Robert M. ; Riddle, Mark A. / Metformin add-on vs. antipsychotic switch vs. continued antipsychotic treatment plus healthy lifestyle education in overweight or obese youth with severe mental illness : results from the IMPACT trial. In: World Psychiatry. 2020 ; Vol. 19, No. 1. pp. 69-80.
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AU - Correll, Christoph U.

AU - Sikich, Linmarie

AU - Reeves, Gloria

AU - Johnson, Jacqueline

AU - Keeton, Courtney

AU - Spanos, Marina

AU - Kapoor, Sandeep

AU - Bussell, Kristin

AU - Miller, Leslie

AU - Chandrasekhar, Tara

AU - Sheridan, Eva M.

AU - Pirmohamed, Sara

AU - Reinblatt, Shauna P.

AU - Alderman, Cheryl

AU - Scheer, Abigail

AU - Borner, Irmgard

AU - Bethea, Terrence C.

AU - Edwards, Sarah

AU - Hamer, Robert M.

AU - Riddle, Mark A.

PY - 2020/2/1

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N2 - Antipsychotics are used for many psychiatric conditions in youth. Although developmentally inappropriate weight gain and metabolic abnormalities, which are risk factors for premature cardiovascular mortality, are especially frequent in youth, optimal strategies to reduce pediatric antipsychotic-induced overweight/obesity are unclear. The Improving Metabolic Parameters in Antipsychotic Child Treatment (IMPACT) was a randomized, parallel group, 24-week clinical trial which enrolled overweight/obese, psychiatrically stable youth, aged 8-19 years, with a DSM-IV diagnosis of severe mental illness (schizophrenia spectrum disorder, bipolar spectrum disorder or psychotic depression), at four US universities. All of them had developed substantial weight gain following treatment with a second-generation antipsychotic. The centralized, computer-based randomization system assigned participants to unmasked treatment groups: metformin (MET); antipsychotic switch (aripiprazole or, if already exposed to that drug, perphenazine or molindone; SWITCH); or continued baseline antipsychotic (CONTROL). All participants received healthy lifestyle education. The primary outcome was body mass index (BMI) z-score change from baseline, analyzed using estimated least squares means. Altogether, 127 participants were randomized: 49 to MET, 31 to SWITCH, and 47 to CONTROL. BMI z-score decreased significantly with MET (week 24: –0.09±0.03, p=0.002) and SWITCH (week 24: –0.11±0.04, p=0.003), while it increased non-significantly with CONTROL (week 24: +0.04±0.03). On 3-way comparison, BMI z-score changes differed significantly (p=0.001). MET and SWITCH were each superior to CONTROL (p=0.002), with effect sizes of 0.68 and 0.81 respectively, while MET and SWITCH did not differ. More gastrointestinal problems occurred in MET than in SWITCH or CONTROL. The data safety monitoring board closed the perphenazine-SWITCH arm because 35.2% of subjects discontinued treatment due to psychiatric worsening. These data suggest that pediatric antipsychotic-related overweight/obesity can be reduced by adding metformin or switching to a lower risk antipsychotic. Healthy lifestyle education is not sufficient to prevent ongoing BMI z-score increase.

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