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Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder
L. Fredrik Jarskog, M.D.; Robert M. Hamer, Ph.D.; Diane J. Catellier, Dr.P.H.; Dawn D. Stewart, M.S.; Lisa LaVange, Ph.D.; Neepa Ray, M.S.; Lauren H. Golden, M.D.; Jeffrey A. Lieberman, M.D.; T. Scott Stroup, M.D., M.P.H.; for the METS Investigators
Am J Psychiatry 2013;170:1032-1040. doi:10.1176/appi.ajp.2013.12010127
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Dr. Jarskog has served as a consultant for AstraZeneca, has received research grant support from GlaxoSmithKline, Novartis, Roche, and Sunovion, and has served on a data and safety monitoring board for Janssen. Dr. Hamer has served on an advisory board for, consulted with, served on a data and safety monitoring board/data monitoring committee with, or participated as an expert witness in patent lawsuits involving Abbott, Acadia, Allergan, Alpharma, Anesta, AstraZeneca, Barr, Biolinerx, Caraco, Cenerx, Cephalon, Edo, Epix, Eurand, Fidopharm, Forest, Johnson & Johnson, Lilly, Lundbeck, Marial, Mylan, NeuroPharmaBoost, Novartis, Pfizer, Proctor and Gamble, Roche, Solvay, Sun, Teva, Titan, and Velcera. Dr. LaVange has received an honorarium from GlaxoSmithKline and research grant support from Sanofi-Aventis. Dr. Lieberman serves on the advisory boards of Bioline, Intracellular Therapies, and PsychoGenics; he receives research grant support from Allon, F. Hoffman-La Roche, GlaxoSmithKline, Eli Lilly, Merck, Novartis, Pfizer, PsychoGenics, Sepracor (Sunovion), and Targacept; and he holds a patent with Repligen. Dr. Stroup has served as a consultant for Janssen and Eli Lilly. All other authors report no financial relationships with commercial interests.

ClinicalTrials.gov identifier: NCT00816907.

Supported by NIMH contract N01MH-90001 to Drs. Stroup and Lieberman.

The Metformin in the Treatment of Antipsychotic-Induced Weight Gain in Schizophrenia (METS) Study investigators and sites were as follows: Lawrence Adler, M.D., Clinical Insights, Glen Burnie, Md.; Michael Barber, M.D., Baylor College of Medicine, Houston; Matthew Byerly, M.D., University of Texas-Southwestern, Dallas; Jose M. Canive, M.D., New Mexico VA Health Care System, Albuquerque, N.Mex.; Ira Glick, M.D., Stanford University, Palo Alto, Calif.; David C. Henderson, M.D., Massachusetts General Hospital/Freedom Trail Clinic, Boston; L. Fredrik Jarskog, M.D. (during subject enrollment period), New York State Psychiatric Institute/Columbia University, New York; J. Steven Lamberti, M.D., University of Rochester Medical Center, Rochester, N.Y.; Ahsan Khan, M.D., Clinical Research Institute, Wichita, Kan.; Joseph P. McEvoy, M.D., Duke University, Durham, N.C.; Herbert Meltzer, M.D., Vanderbilt University, Nashville; Alexander Miller, M.D., University of Texas Health Science Center at San Antonio; Del D. Miller, M.D., University of Iowa, Iowa City; Henry A. Nasrallah, M.D., University of Cincinnati; Stephen Olson, M.D., University of Minnesota, Minneapolis; Jayendra K. Patel, M.D., University of Massachusetts Medical School, Worcester; and Bruce L. Saltz, M.D., Mental Health Advocates, Boca Raton, Fla.

From the Departments of Psychiatry and Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill; North Carolina Psychiatric Research Center, Raleigh; Departments of Psychiatry and Medicine, Columbia University, College of Physicians and Surgeons, New York; and New York State Psychiatric Institute, New York.

Presented at the 65th annual meeting of the Society of Biological Psychiatry, New Orleans, May 20–22, 2010, and the 49th annual meeting of the American College of Neuropsychopharmacology, Miami Beach, Fla., Dec. 5–9, 2010.

Address correspondence to Dr. Jarskog (jarskog@med.unc.edu).

Copyright © 2013 by the American Psychiatric Association

Received January 26, 2012; Revised December 05, 2012; Revised January 27, 2013; Accepted February 25, 2013.

Abstract

Objective  The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder.

Method  In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16.

Results  Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was −3.0 kg (95% CI=−4.0 to −2.0) for the metformin group and −1.0 kg (95% CI=−2.0 to 0.0) for the placebo group, with a between-group difference of −2.0 kg (95% CI=−3.4 to −0.6). Metformin also demonstrated a significant between-group advantage for BMI (−0.7; 95% CI=−1.1 to −0.2), triglyceride level (−20.2 mg/dL; 95% CI=−39.2 to −1.3), and hemoglobin A1c level (−0.07%; 95% CI=−0.14 to −0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation.

Conclusions  Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.

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FIGURE 1. Weight Change Across 16 Weeks of Treatment With Metformin or Placebo in Overweight Outpatients With Schizophrenia or Schizoaffective Disordera

a Error bars represent 95% confidence intervals. Significantly different between groups, p=0.007.

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TABLE 1.Baseline Demographic and Clinical Characteristics of Overweight Outpatients With Schizophrenia or Schizoaffective Disorder Treated With Metformin or Placebo
Table Footer Note

a Antipsychotics categorized a priori as higher-risk agents for weight gain are clozapine, olanzapine, paliperidone, quetiapine, and risperidone.

Table Footer Note

b Antipsychotics categorized a priori as lower-risk agents for weight gain are aripiprazole, fluphenazine, haloperidol, loxitane, perphenazine, thiothixene, and ziprasidone.

Table Footer Note

c Data are for patients receiving a combination of one higher- and one lower-risk agent.

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TABLE 2.Mean Change From Baseline to 16 Weeks for Primary and Secondary Outcome Variables Among Overweight Outpatients With Schizophrenia or Schizoaffective Disorder Treated With Metformin or Placebo
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TABLE 3.Adverse Events From Systematic Inquiry in Overweight Outpatients With Schizophrenia or Schizoaffective Disorder Treated With Metformin or Placebo
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TABLE 4.Exploratory Moderators of Metformin-Placebo Weight Change in Overweight Outpatients With Schizophrenia or Schizoaffective Disorder
Table Footer Note

a Analyzed using a median split.

Table Footer Note

b Participants receiving one higher- and one lower-risk agent (N=16) were not included in this analysis. (For a list of higher- and lower-risk agents, see Table 1 footnotes.)

Table Footer Note

c Data refer to the presence or absence of nausea, vomiting, or diarrhea within the first 2 weeks of study medication.

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1.
Weight loss over the course of 16 weeks of metformin treatment in overweight people with schizophrenia and schizoaffective disorder followed which pattern?
2.
Compared to placebo, metformin improved which fasting metabolic measure in overweight people with schizophrenia and schizoaffective disorder?
3.
What side effect was most common in people who received metformin?
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