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

doi:10.1002/wps.20714

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. 2020 Feb;19(1):69-80. doi: 10.1002/wps.20714.

Authors

Christoph U Correll^{1

2

3}, Linmarie Sikich⁴, Gloria Reeves⁵, Jacqueline Johnson⁶, Courtney Keeton⁷, Marina Spanos⁴, Sandeep Kapoor^{1

2

3}, Kristin Bussell⁵, Leslie Miller⁷, Tara Chandrasekhar⁴, Eva M Sheridan⁸, Sara Pirmohamed⁵, Shauna P Reinblatt^{5

7}, Cheryl Alderman⁹, Abigail Scheer⁴, Irmgard Borner¹, Terrence C Bethea^{4

10}, Sarah Edwards⁵, Robert M Hamer¹¹, Mark A Riddle⁷

Affiliations

¹ Division of Psychiatric Research, Zucker Hillside Hospital, NY, USA.
² Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
³ Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany.
⁴ Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, USA.
⁵ Division of Child and Adolescent Psychiatry, School of Medicine, University of Maryland, Baltimore, MD, USA.
⁶ SAS Institute, Cary, NC, USA.
⁷ Division of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA.
⁸ Department of Science Education, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
⁹ Duke Clinical Research Institute, Durham, NC, USA.
¹⁰ Hughes Center, Danville, VA, USA.
¹¹ Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA.

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.

Keywords: Antipsychotics; IMPACT; antipsychotic switch; healthy lifestyle education; metformin; obesity; weight gain; youth.