• Treatment of major depressive disorder (MDD) (acute phase) and prevention of MDD recurrence (maintenance phase) [ Time Frame: Measured over 40 weeks ] [ Designated as safety issue: No ]
  

• Insulin resistance (IR), glycemic control, anthropometrics and body composition, and cortisol levels [ Time Frame: Measured over 40 weeks ] [ Designated as safety issue: No ]
  
• Value of reducing IR for predicting reduction in depression symptoms and time-to-recurrence (TTR) [ Time Frame: Measured over 40 weeks ] [ Designated as safety issue: No ]
  
• Sustained IR reduction during the depression-free interval following treatment [ Time Frame: Measured over 40 weeks ] [ Designated as safety issue: No ]
  

Current depression treatments are not effective for approximately one-half of overweight people, and depression eventually returns in approximately one-third of those overweight people whose initial treatment is effective. One possible reason for these treatment failures is that overweight people often experience a condition called insulin resistance (IR), which can lead to type 2 diabetes, an associated disease that might also affect depression treatment. IR results in elevated blood sugar levels that may interfere with medications used to treat depression. Metformin, a medication commonly used to treat diabetes, reduces blood sugar levels. This study will examine whether taking metformin with the antidepressant medication sertraline will enhance the effectiveness of sertraline in people who are overweight and depressed.

Participation in this study will be divided into two phases lasting a total of 40 weeks. Phase 1 will last 16 weeks and include baseline testing and seven scheduled study visits. During this phase, participants will be randomly assigned to receive either sertraline and metformin or sertraline and placebo on a daily basis. The baseline visit will include the following tests and measures: an electrocardiogram (EKG), which will measure the electrical activity in the heart; an oral glucose tolerance test (OGTT), which will measure how a person's body breaks down glucose; a blood test, which will measure lipids, hemoglobin A1C, and other cardiometabolic risk factors; a dual energy x-ray absorptimetry (DEXA) scan, which will measure body fat; a pregnancy test for women; measurements of vital signs, height, weight, waist-to-hip ratio, and waist circumference; and questionnaires concerning health, medication use, physical activity, diet, and mood. Some of the questionnaires will be administered through interviews with a researcher. During the study visits, which will occur every 2 weeks, participants will complete questionnaires, unused medication will be collected, and new medication will be handed out. At Week 8, participants will provide an additional blood sample by finger stick. At the end of Phase 1, participants will undergo repeat baseline testing.

Participants whose depression has improved after Phase 1 will be eligible to continue to Phase 2 of the study, which will determine the longer term effects of taking metformin with sertraline. Phase 2 of the study will last 24 weeks, with study visits occurring monthly. During the study visits, participants will complete questionnaires again, and medication will be collected and handed out. At Weeks 24 and 32, participants will provide blood samples by finger stick. After completing Phase 2, participants will again undergo repeat baseline testing.