Major depressive disorder (MDD) is one of the most common mental disorders in the United States. An estimated 6.7 percent of adults 18 years or older in the United States in 2015 had at least one major depressive episode in the past year. Depression often accompanies other psychiatric and medical conditions and contributes to challenges of being on multiple medications and drug interactions. An estimated 44 percent of those with MDD stop their medications within three months of initiation and 50 percent discontinue by the end of the first year. Untreated depression results in costly hospitalizations and emergency room visits and poor psychiatric and medical outcomes, including suicide attempts and even deaths. Depression is also considered an independent risk factor for nonadherence to other medical treatments. Community pharmacists are accessible yet underutilized members of the healthcare team who can help optimize medication regimens. There is much evidence of community pharmacists having impact on medication therapy management (MTM) across several disease states. However, there is insufficient data as to which ways of delivering MTM would be most effective in the optimization of medication use for individuals with MDD. Through our advisory panel discussions and literature review, we have identified key comparative effectiveness research questions that test different MTM delivery approaches. Our objective is to conduct a comparative effectiveness trial in New England, examining which MTM approach for individuals with MDD yields better patient outcomes. We anticipate the findings will be applicable to how MTM is delivered across other disease states and settings.