Convergent clinical and epidemiological data have implicated omega-3 (n-3) fatty acids in the pathophysiology, prevention, and therapy of common and disabling conditions such as major depressive disorder (MDD) and cardiovascular disease. The intake of omega-3 fatty acids in the western diet has decreased dramatically relative to omega-6 (n-6) intake over the past century, causing a substantial increase in the ratio of omega-6 to omega-3 (n-6:n-3). Coincident with this change in diet, the incidence of major depressive disorder has markedly increased in western societies. It has been postulated that the 21st century western urban lifestyle characterized by high stress, little rest, and high intake of processed (i.e. omega-6- rich) foods, creates a baseline "pro-inflammatory" predisposition that may contribute to the development of mood disorders in some individuals. As has been demonstrated in the cardiology literature, omega-3 administration may correct the n-6:n-3 ratio, and reverse this pro-inflammatory state. Recent controlled trials suggest that dietary supplementation with omega-3 fatty acids at doses about five or more times the standard dietary intake in the U.S. may yield clinically significant antidepressant and/or mood stabilizing effects;however, there is little known about the mechanism of action underlying this effect. There is also a paucity of data comparing and contrasting the relative antidepressant efficacy of the two main omega-3 fatty acids, eicosapentanoic acid (EPA) and docosahexanoic acid (DHA). This five-year collaborative R01 application will focus primarily on comparing the antidepressant efficacy of monotherapy with EPA vs. DHA vs. placebo. We will also investigate potential lipid and immunological mediators and moderators of n-3 fatty acid antidepressant response. Our study will be the first to address the relative antidepressant efficacy of EPA and DHA in a placebo-controlled head-to-head trial, and also the first to investigate the potentially important relationship between lipid metabolism, immune parameters, and response to n-3 dietary supplementation in major depression. This application is consistent with recent statements from the leadership of NCCAM and NIMH, emphasizing the importance of research that has "traction," i.e. integrates biological findings with treatment in order to have a direct impact on the clinical practice of psychiatry.