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

• Feasibility of enrolling a cohort of participants meeting the inclusion and exclusion criteria of the study [ Time Frame: Measured pre- and post-treatment ] [ Designated as safety issue: No ]
• Identification of appropriate clinical sites to mount the proposed clinical trial [ Time Frame: Measured pre- and post-treatment ] [ Designated as safety issue: No ]
• Feasibility of protocol implementation with a high level of protocol adherence and low participant attrition [ Time Frame: Measured over 16 weeks of study visits ] [ Designated as safety issue: No ]

• Change in Total Cholesterol From Baseline to 16 Weeks [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  Total cholesterol
• Change in HDL Cholesterol From Baseline to 16 Weeks [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  high-density lipoprotein
• Change in LDL Cholesterol From Baseline to 16 Weeks [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  low-density lipoprotein
• Change in Triglycerides From Baseline to 16 Weeks [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  serum triglycerides
• Change in Fasting Glucose From Baseline to 16 Weeks [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  fasting blood glucose
• Change in Fasting Insulin From Baseline to 16 Weeks [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  Fasting insulin
• Change in Hemoglobin A1c From Baseline to 16 Weeks [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  glycosylated hemoglobin

• Mean difference in body weight between participants assigned to metformin and participants assigned to placebo [ Time Frame: Measured at the last study visit ] [ Designated as safety issue: No ]
• Effect of metformin on waist-hip ratio, fasting lipid levels (including total cholesterol, HDL, LDL, triglycerides), fasting glucose, fasting insulin, and hemoglobin A1c [ Time Frame: Measured over 16 weeks of study visits ] [ Designated as safety issue: No ]

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.

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.

• Drug: Metformin
  500 mg to 1,000 mg taken twice daily for 16 weeks
  Other Name: Glucophage
• Drug: Placebo
  1 to 2 placebo capsules taken twice daily for 16 weeks
  Other Name: Placebo

• Experimental: Metformin
  Encapsulated metformin 1000-2000 mg/day
  Intervention: Drug: Metformin
• Placebo Comparator: Placebo
  Matching placebo capsules 2-4 daily
  Intervention: Drug: Placebo

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.