Depression is widely recognized as having significant implications for both mental and physical health. More than 1 in 5 adults suffer from major depression (MDD) at some point in their lifetimes, and estimates are even higher for patients with coronary heart disease (CHD). Approximately 20% of patients suffer from MDD after a myocardial infarction (MI), and an additional 20% might experience elevated depressive symptoms without meeting diagnostic criteria for MDD. Depression is associated with poorer quality of life and increased medical expenditures and healthcare use. In addition, depression is one of the leading sources of disability in the United States and is associated with greater absenteeism and lowered work productivity. According to the World Health Organization, depression will soon become the second leading cause of disability-adjusted life years, after only CHD.

There also is a growing body of published data that have documented the association of depression with adverse health outcomes, particularly in patients with CHD. Numerous studies from multiple research teams have reported that depression is associated with a 2- to 4-fold increase in risk for death and nonfatal CHD events among patients with a variety of cardiac conditions, including recent MI, coronary disease requiring surgical revascularization, stable and unstable angina, and chronic heart failure ((1),(2),3). As a result of these findings, the American Heart Association commissioned a Scientific Advisory Panel to evaluate the risk with depression in CHD patients (4). Although recognizing that there was no direct evidence that screening for depression leads to improved outcomes, the Panel concluded that—because of the overwhelming evidence for the association of depression with worse prognosis—assessment of depression was important with the goal of “targeting those most in need of treatment and support services.”

One of the most critical issues now facing clinicians is how to best treat depressed cardiac patients. Current recommendations for depression treatment typically involve pharmacotherapy, usually with a selective serotonin reuptake inhibitor (SSRI), although treatments with tricyclic antidepressants, benzodiazepines, and combined therapies are also prescribed (5). It has been estimated that approximately 50% of patients will have a clinical “response” to treatment (i.e., a 50% reduction in symptoms), whereas many patients will require augmented treatment with >1 antidepressant agents (6). However, many patients do not respond to antidepressant medications or experience untoward side effects. Indeed, although data are limited, results from several randomized controlled trials of antidepressants in cardiac patients have provided negative or equivocal findings. For example, the SADHART (Sertraline Against Depression and Heart Disease) trial was a randomized, double-blind, placebo-controlled, 24-week trial of sertraline for MDD among patients hospitalized for acute MI (7). Improvement in depressive symptoms among participants treated with sertraline was observed only in a subset of patients with more severe depression; there was no difference between sertraline and placebo in the full sample. The study was not powered to examine clinical outcomes. A second study (SADHART-CHF [Sertraline Against Depression and Heart Disease in Chronic Heart Failure] trial) confirmed the safety of sertraline among patients with chronic heart failure, but sertraline did not reduce depressive symptoms any more than placebo (8). Moreover, participants treated with sertraline had no better clinical outcomes compared with those receiving placebo. The MIND-IT study (Myocardial INfarction and Depression-Intervention Trial) also failed to demonstrate improvement in either depressive symptoms or cardiac outcomes with antidepressant treatment (9). In one of the few positive trials, the CREATE (Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy) study (10) reported that depressive symptoms and remission rates were improved with citalopram compared with placebo, whereas no differences in depressive symptoms were observed between patients receiving interpersonal therapy and clinical management compared with patients receiving clinical management alone. The sample was too small to examine clinical outcomes, however. Meta-analyses of randomized, controlled trials of antidepressant medications in cardiac patients generally have reported no significant differences between antidepressant medication and placebo controls, but the authors still encouraged the use of antidepressant drugs because nonrandomized trials showed greater benefits with medication ((11),12).

One of the problems in developing effective treatments for depression in cardiac patients is that the mechanisms underlying the association between depression and worse outcomes are not fully understood. A number of potentially interrelated biobehavioral pathways have been studied, albeit often individually. Depressive symptoms have been linked to autonomic nervous system dysregulation, vascular endothelial dysfunction, abnormal inflammatory processes, and maladaptive health behaviors (13). Indeed, the Heart and Soul study noted that, among a variety of health behaviors, physical inactivity was especially important (14). Furthermore, there is mounting evidence that patients who exhibit a worsening of depression over time seem to be at especially increased risk for death or other adverse outcomes, including nonfatal MI or cardiac-related hospital stays ((15),16). It remains unclear whether depression is causally related to worse outcomes or whether depression is simply a marker for more severe CHD or some other factor associated with worse outcomes.

In this issue of the Journal, Ye et al. (17) seek to examine this question by prospectively studying the relationship between depressive symptoms and nonfatal MI or all-cause mortality in a subset of participants in the REGARDS (Reasons for the Geographic And Racial Differences in Stroke) study. The REGARDS study is a population-based, longitudinal study of 30,000 African-American and white men and women ≥45 years designed to determine the reasons for the higher incidence of stroke mortality in the southeastern “stroke belt” region of the United States and among African Americans (18). Individuals were identified from commercially available lists of residents and were recruited with an initial mailing followed by telephone screening calls. The present study was limited to 4,676 participants with a history of CHD at baseline and complete data. Over a median follow-up period of 3.8 years, 125 of 638 (19.6%) participants with elevated depressive symptoms experienced a clinical event, compared with 657 of 4,038 (16.3%) participants without elevated depressive symptoms. After adjustment for medical comorbidities, medications, and lifestyle factors, the association of depression and worse clinical outcomes was no longer statistically significant, and the authors emphasized the importance of lifestyle factors in explaining the prognostic value of depression and CHD and in guiding intervention efforts to reduce the elevated risk of depression in cardiac patients.

The authors are to be congratulated for their contribution to the published literature with this interesting analysis of a large and important dataset. Several important limitations of the study should be acknowledged, however. As with many substudies in which the variables under investigation are of secondary importance to the parent study, the assessment measures were not optimal, and only a limited number of potential mediators were examined. Depression was assessed by a seldom-used 4-item self-report measure of depressive symptoms that might not accurately classify depression in all patients, while the 4 behavioral factors relied on brief measures of self-reported alcohol use, medication adherence, smoking, and physical activity. This lack of precision might help to explain the lower-than-expected rates of depression in this CHD population and also some unexpected results, such as trends for better outcomes in patients with high alcohol consumption and poor medication adherence. Smoking and physical activity explained a substantial proportion of the association of depression and the combined endpoint of MI and death, leading the authors to recommend smoking cessation and increasing physical activity in this population.

These lifestyle recommendations should come as little surprise to readers of the Journal. Cigarette smoking is not uncommon in patients with MDD (19), and patients who continue to smoke, despite having CHD, might be engaged in a highly maladaptive effort to treat their depression. Similarly, a number of cross-sectional and observational studies have shown that physical inactivity is associated with depression. For example, in the Alameda County Study, Camacho et al. (20) measured activity level and depressive symptoms of subjects in 1965, 1974, and 1983. Compared with men and women who reported higher activity levels, those who were inactive at baseline were at greater risk for higher depression scores at the first follow-up. Participants who increased their physical activity level between 1965 and 1974, however, were at no greater risk for depression in 1983 than those who were active throughout the period. Conversely, those who became more inactive by 1974 were more likely to have higher depression scores in 1983 compared with those who maintained a high level of physical activity. Of course, observational studies are limited in that it cannot be determined whether people are inactive because they are depressed or whether they are depressed because they are inactive.

The effect of exercise on depression now has been examined in over 2 dozen randomized trials and has been the topic of several meta-analyses and systematic reviews ((21),22). Existing studies vary substantially in size, type of control group, methodological rigor, length of follow-up, and type of exercise. In a recent Cochrane review (21), the primary analyses were limited to 25 clinical trials comparing exercise treatment with no treatment or a control intervention. There were large, clinically meaningful improvements in depressive symptoms associated with exercise in comparison with controls (standardized mean difference = −0.82, 95% confidence interval: −1.12 to −0.51), which was somewhat diminished when the analyses were limited to those trials with intention-to-treat analyses and blinded outcome assessments. In addition, when analyses were conducted among the 5 trials that collected long-term follow-up data, the effects of treatment were slightly weaker, consistent with a moderate clinical improvement (standardized mean difference = −0.44, 95% confidence interval: −0.71 to −0.18).

Three randomized trials ((23),(24),25), including a recent trial of 101 CHD patients (25), now have compared exercise with antidepressant medication. In these studies, exercise training resulted in significant reductions in depressive symptoms that were greater than placebo and comparable or even superior to antidepressant medications. For example, in the UPBEAT (Understanding the Prognostic Benefits of Exercise and Antidepressant Therapy) study (25), after 4 months of treatment, scores on the Hamilton Rating Scale for Depression were 3.3 points lower among exercisers compared with patients receiving placebo, whereas the average score was 1.7 points lower in patients receiving sertraline compared with placebo. Furthermore, exercise was even more effective in reducing clinical depression in the subset of patients who were diagnosed with MDD at study entry. Although the sample was small, 40% of patients with MDD at the time of randomization were remitted at the end of 4 months of exercise, compared with 10% of those who received sertraline and none of the patients who received placebo. A recent substudy from the HF-ACTION trial (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) (26) also found exercise to be superior to guideline-based usual care in reducing depressive symptoms in over 2,300 heart failure patients.

So what is the take-home message? The term “cardiovascular vulnerable patient” has been used to describe patients susceptible to acute coronary events on the basis of plaque, blood, or myocardial characteristics ((27),28). It now has become clear that depression is another of those characteristics that also increases the vulnerability of CHD patients to adverse events. In their report, Ye et al. (17) provide support for the prognostic importance of elevated depressive symptoms in CHD patients. Moreover, by identifying smoking and physical inactivity as mediators of the relationship between depression and adverse health outcomes, they remind us of the value of promoting healthy lifestyle changes and specifically smoking cessation and exercise training to improve clinical outcomes in this vulnerable population.

⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.