Depression is a risk factor for morbidity and mortality after acute myocardial infarction (MI) and unstable angina. 2 recent clinical trials (sertaline vs. placebo, sertraline plus cognitive therapy vs. usual care) reported only modest reductions in depression following an acute MI or unstable angina, and many treated patients remained depressed. Neither study reported better medical outcomes in the treated patients. Earlier studies found that even subclinical depression increases the risk of mortality in cardiac patients. Thus, more effective treatments are needed to eliminate depression and improve medical outcomes in patients following an acute MI or unstable angina. Omega-3 fatty acids (FAs) have been shown to augment the efficacy of antidepressants for major depression and to improve several cardiac risk factors. However, these findings have evolved in separate lines of research. No previous study has investigated whether omega-3 FAs can simultaneously improve depression and reduce cardiovascular risk factors in post-MI patients. This study will test a novel approach to the treatment of comorbid major depression in CHD. 170 patients who meet the DSM-IV criteria for a current major depressive episode and who score 19 or higher on the Hamilton Rating Scale for Depression 3-4 months after an acute MI or unstable angina will be enrolled in a randomized, double-blind, placebo-controlled trial of omega-3 augmentation of sertraline. The participants will be randomly assigned to receive sertraline plus omega-3 or sertraline plus placebo for 10 weeks. At baseline and again after 10 weeks, the subjects will complete 1) assessments of depression and psychosocial functioning; 2) 24 hour ECG monitoring for heart rate variability analysis; and 3) blood draws to measure procoagulant and proinflammatory markers and plasma levels of sertraline and omega-3. If this study shows that omega-3 reduces depression and improves cardiovascular disease markers, we will have a basis for proposing a larger clinical trial to determine whether it can also improve survival after hospitalization for acute MI or unstable angina.