The Use of Metformin in the Treatment of Antipsychotic-Induced Weight Gain in Schizophrenia (The METS Study) (METS)

Metformin in the Treatment of Antipsychotic-Induced Weight Gain in Schizophrenia (METS) - Pilot Study

This study will test the usefulness of the medication metformin in treating people with schizophrenia or schizoaffective disorder who are overweight and also taking antipsychotic medications.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Metformin; Drug: Placebo

Detailed Description

Schizophrenia is a chronic mental disorder that is characterized, in part, by psychotic symptoms. Psychotic symptoms include hallucinations and delusions, in which a person has abnormal experiences or beliefs, and are commonly treated with antipsychotic medications. Unfortunately, a side effect of many antipsychotics is unwanted weight gain, which can lead to physical illness. Use of the drug metformin has resulted in weight loss among diabetics. Metformin has also been shown to cause weight loss in preliminary studies of people taking atypical antipsychotics-a newer, second generation of antipsychotic medications. Metformin is currently approved by the Food and Drug Administration to treat only people with diabetes. This study will test the usefulness of prescribing metformin as a second medication to treat people with schizophrenia or schizoaffective disorder who are overweight and taking antipsychotics. The study will also provide important feasibility information for future larger studies.

Participation in this study will last 16 weeks. After undergoing baseline assessments, participants will be randomly assigned to receive either metformin or placebo, both of which will be taken twice daily for the duration of the study. All participants will also receive behavioral therapy that will teach them about reducing their weight through diet and exercise. Participants will undergo assessments at 11 study visits: the first 2 will include screening and baseline testing, the next 2 visits will take place after the first and second weeks of receiving treatment, and the last 7 visits will take place every 2 weeks until the end of the study. Assessments will include measurements of body weight, waist-to-hip ratio, and vital signs; clinical interviews about medication adherence, side effects, and alcohol use; and monthly blood tests to assess levels of lipids, glucose, insulin, and hemoglobin A1c.

• Study Type: Interventional
• Enrollment (Actual): 146
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94305
      • Stanford University
  • Florida
    • Boca Raton, Florida, United States, 33431
      • Mental Health Advocates
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Wichita, Kansas, United States, 67207
      • Clinical Research Institute
  • Maryland
    • Glen Burnie, Maryland, United States, 21061
      • Clinical Insights
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Freedom Trail Clinic
    • Worcester, Massachusetts, United States, 01605
      • University of Massachusetts
  • Minnesota
    • Minneapolis, Minnesota, United States, 55454
      • University of Minnesota School of Medicine
  • New Mexico
    • Albuquerque, New Mexico, United States, 87108
      • New Mexico VA Healthcare System
  • New York
    • New York, New York, United States, 10032
      • Research Foundation for Mental Hygiene
    • Rochester, New York, United States, 14623
      • University of Rochester
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Schizophrenia Research
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Outpatients with a diagnosis of schizophrenia or schizoaffective disorder, as defined by DSM-IV-TR criteria and confirmed by the Structured Clinical Interview for DSM-IV (SCID)
• Duration of illness greater than 1 year, as defined by having initiated antipsychotic treatment at least 1 year prior to study entry
• Adequate decisional capacity to make a choice about participating in this research study
• Body mass index (BMI) at or greater than 27
• Currently being treated with one or a combination of two antipsychotic medications (typical or atypical) and on that drug regimen for at least 2 months prior to study entry, with stable dosages for at least 1 month
• If taking antidepressants, mood stabilizers, or anxiolytics, the dose must be stable for at least 1 month prior to study entry
• Willing to use an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the study. Acceptable methods include oral, injectable, or implanted contraceptives; intrauterine devices or barrier methods such as condoms; and diaphragms and spermicides.

Exclusion Criteria:

• Inpatient status
• Clinical Global Impression Severity (CGI-S) score greater than 6
• Currently being treated with more than two antipsychotic medications
• Fasting glucose greater than 125
• Diagnosis of diabetes mellitus or treatment with insulin or oral hypoglycemics
• Previous or current treatment with metformin
• Diagnosis of congestive heart failure
• Renal impairment, as defined by a serum creatinine level greater than 1.5 in males or greater than 1.4 in females, or creatinine estimated glomerular filtration rate (GFR) outside of normal limits
• Hepatic disease, as defined by aspartate transaminase (AST), alanine transaminase (ALT), or c-glutamyl transferase (CGT) greater than 1.5 times upper limit of normal (ULN), or total bilirubin greater than 1.2 times ULN
• Metabolic acidosis, as defined by serum carbon dioxide less than the lower limit of normal
• Known hypersensitivity to metformin
• Pregnant or breastfeeding
• Recent (in the past 30 days) or scheduled radiological studies involving iodinated contrast material
• Alcohol abuse or dependence within the past month, as determined by the SCID
• Other serious and unstable medical condition in the judgment of the investigator
• Diagnosis of mental retardation, delirium, or dementia, as defined by DSM-IV-TR
• Failed to discontinue 4 weeks prior to study entry any medication used for weight loss
• Concurrent treatment with certain drugs that are known to increase metformin blood levels should be discussed with the Project Medical Officer.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin; Encapsulated metformin 1000-2000 mg/day	Drug: Metformin; 500 mg to 1,000 mg taken twice daily for 16 weeks; Other Names: Glucophage
Placebo Comparator: Placebo; Matching placebo capsules 2-4 daily	Drug: Placebo; 1 to 2 placebo capsules taken twice daily for 16 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Difference in Body Weight Change Between Participants Assigned to Metformin and Participants Assigned to Placebo	Mean difference in body weight change between participants assigned to metformin and participants assigned to placebo from baseline to last study visit (up to 16 weeks)	Measured at the last study visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Total Cholesterol From Baseline to 16 Weeks	Total cholesterol	16 weeks
Change in HDL Cholesterol From Baseline to 16 Weeks	high-density lipoprotein	16 weeks
Change in LDL Cholesterol From Baseline to 16 Weeks	low-density lipoprotein	16 weeks
Change in Triglycerides From Baseline to 16 Weeks	serum triglycerides	16 weeks
Change in Fasting Glucose From Baseline to 16 Weeks	fasting blood glucose	16 weeks
Change in Fasting Insulin From Baseline to 16 Weeks	Fasting insulin	16 weeks
Change in Hemoglobin A1c From Baseline to 16 Weeks	glycosylated hemoglobin	16 weeks

Collaborators and Investigators

• Sponsor: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: L. Fredrik Jarskog, MD, Columbia University; Principal Investigator: Jeffrey A. Lieberman, MD, Columbia University

Publications and helpful links

General Publications

• Wang B, Ogburn EL, Rosenblum M. Analysis of covariance in randomized trials: More precision and valid confidence intervals, without model assumptions. Biometrics. 2019 Dec;75(4):1391-1400. doi: 10.1111/biom.13062. Epub 2019 Jun 3.
• Jarskog LF, Hamer RM, Catellier DJ, Stewart DD, Lavange L, Ray N, Golden LH, Lieberman JA, Stroup TS; METS Investigators. Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder. Am J Psychiatry. 2013 Sep;170(9):1032-40. doi: 10.1176/appi.ajp.2013.12010127.
• Khan AY, Macaluso M, McHale RJ, Dahmen MM, Girrens K, Ali F. The adjunctive use of metformin to treat or prevent atypical antipsychotic-induced weight gain: a review. J Psychiatr Pract. 2010 Sep;16(5):289-96. doi: 10.1097/01.pra.0000388624.91039.a3.

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: January 2, 2009
• First Submitted That Met QC Criteria: January 2, 2009
• First Posted (Estimate): January 5, 2009

Study Record Updates

• Last Update Posted (Estimate): March 27, 2013
• Last Update Submitted That Met QC Criteria: February 13, 2013
• Last Verified: November 1, 2010

More Information

Terms related to this study

• Keywords: Schizoaffective Disorder
• Additional Relevant MeSH Terms: Mental Disorders; Body Weight; Schizophrenia Spectrum and Other Psychotic Disorders; Body Weight Changes; Schizophrenia; Weight Gain; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: N01 MH090001-03; N01MH90001 DSIR AT (Other Identifier: National Institute of Mental Health)