In January, 2015, the White House identified Veterans Affairs (VA) as a participating agency in the Precision Medicine Initiative, an effort to “enable a new era of medicine through research, technology, and policies that empower patients, researchers, and providers to work together toward development of individualized care” that takes into account individual differences in people's genes, environments, and lifestyles. To inform this initiative, the VA Office of Research and Development (ORD) is developing a clinical study to implement precision medicine in mental health (PMH). This study will supplement the Million Veteran Program's (MVP) capabilities to (1) understand the lifestyle, genomics and pharmacogenomics of depression in Veterans, (2) develop individualized approaches to treat depression in Veterans, and (3) develop and implement a responsible and efficient process of returning genetic data to providers and patients to determine how to use genetic findings in the clinical setting. The PMH planning committee identified depression as a relevant focus because of its high prevalence, the continuing need for better treatment strategies, and the growing use of genetic testing for decision making. As funding for this study is arranged for FY17, ORD is convening a planning committee meeting for April 2016 to discuss study development. To inform their meeting, ORD commissioned the Evidence-based Synthesis Program Coordinating Center (ESP CC) to conduct an evidence brief on the comparative effectiveness, harms, and cost-effectiveness of pharmacogenomics-guided antidepressant treatment versus usual care for major depressive disorder.