Major depression is a now well-established risk factor for cardiovascular disease (CVD), comparable in potency with conventional risk factors (1). Epidemiological study has demonstrated a proportional relationship between the severity of depressive symptoms and the likelihood of subsequent cardiac events, and patients with even mild depressive symptoms have been noted to have an increase in mortality risk compared with patients without depression (2). The mechanisms by which depression causes CVD fall into 2 general categories: a higher concentration of poor health habits such as smoking, physical inactivity, and medication noncompliance in depressed patients and direct pathophysiological effects (4). Chronic depression is associated with persistent activation of both the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, with resultant development of autonomic, endothelial, platelet, and ovarian dysfunction, elevation in inflammatory proteins, and increased risk for diabetes (1). Depression also impairs cognitive function and adversely alters brain plasticity, although there are indications that these changes are not irreversible.

The relationship between depression and CVD is bidirectional. Just as depression increases the risk for CVD, the development of CVD increases the risk for depression. As a consequence, the prevalence of depressive symptoms in cardiac populations is more than 30%, and approximately 15% of cardiac patients manifest major depression, a rate that is 3-fold higher than the point prevalence for depression within the general community (4).

Consequently, there has been growing interest in developing treatment strategies that effectively reduce depression among cardiac patients. In general, patients with depression can be treated by specific types of psychotherapy, such as cognitive therapy or interpersonal psychotherapy, and/or by use of antidepressant medications, primarily selective serotonin reuptake inhibitors (SSRIs). Whereas psychotherapies have been shown to be effective for treating mild to moderate depression, their use among cardiac patients with comorbid depression is in need of further study. Cognitive therapy, which is based on the concept that the quality of our thoughts affects our emotions, focuses on identifying present distortions in thoughts and behavior patterns and acquiring tools to change them. Whereas cognitive therapy may be particularly apt for short-term therapy, to date, only 1 large study, the ENRICHD (Enhancing Recovery in Coronary Heart Disease) trial, studied cognitive therapy in cardiac patients, with randomization of 2,481 post–myocardial infarction patients to either cognitive therapy or usual care. During a mean follow-up period of 29 months, no mortality difference was noted with cognitive therapy versus usual care, and cognitive therapy produced only modestly greater reduction in depression symptoms (5). A second randomized study did not find improvement in depressive symptoms with interpersonal psychotherapy versus usual care in cardiac patients (6).

SSRIs are widely used by internists, general practitioners, and psychiatrists to treat both mild and severe depression and have been demonstrated to have an acceptable safety profile among cardiac patients (7). However, there is limited evidence that cardiac outcomes in patients with depression and cardiac disease are improved by SSRIs. In the ENRICHD study, a secondary ad hoc analysis found that SSRI use was associated with reduced mortality during follow-up (8). The few other prospective studies have involved small sample sizes and yielded conflicting results, and a meta-analysis of randomized trials to date demonstrated no significant prognostic benefit for SSRI use (9). Thus, more study in this arena is also required.

In this issue of the Journal, Blumenthal et al. (10) now assess exercise training as a third way to treat depression in cardiac patients. Physiologically, exercise training can increase prefrontal cortex blood flow (11) and hippocampal volume (12) and increase brain mediators such as brain-derived neutrotrophic factor (which may be a key feature of depression) (13). Regular exercise enhances executive function, learning, and retention and serves as a protector against the development of dementia (11). Epidemiologically, cross-sectional studies, such as the Alameda County Study (15), have found a lower frequency of depressive symptoms among community dwellers who exercise versus those who do not. Longitudinal studies that have measured physical activity levels at baseline and then followed subjects over time have also found relatively lower levels of subsequent depressive symptoms among those who were physically active at baseline (16). Subsequent studies have assessed the prospective reduction in depression after formal exercise training. A recent meta-analysis of 25 randomized studies that compared exercise with standard treatment for depression, no treatment, or placebo found a large treatment effect for exercise (17). However, the investigators also noted the relatively poor design of many of the studies included in this meta-analysis. Hence, there is a need for more well-designed prospective studies, such as the present study by Blumenthal et al. (10).

The investigators randomized 101 patients with various degrees of depression into 3 treatment groups: sertraline (50 to 200 mg), group exercise 3 times per week, or placebo. Baseline depressive symptoms were assessed both by the Hamilton Rating Scale for Depression and a structured interview. Approximately one-half of the patients had major depression. At 4-month follow-up, there were comparable reductions in depressive symptoms among the patients who received sertraline and those who underwent exercise, and both groups had greater reductions in depressive symptoms compared with placebo. These results are concordant with those of 2 prior randomized studies these investigators performed to compare exercise with antidepressant medication in noncardiac subjects with depression (18).

The chief limitation of the present study is its lack of generalizability. The study population consisted of volunteers, who may thus not be typical of depressed patients in general. The nearly complete compliance with exercise and prescribed medication in this study is certainly atypical and suggests that these volunteers were particularly motivated and less severely depressed than many clinic patients. The study population was also skewed toward those of higher socioeconomic status and was ethnically narrow. In addition, the 3 randomized trials that have now been conducted by Blumenthal et al. (10) represent the experience garnered at only 1 medical center. Thus, there is a need to perform further multicenter studies that would enroll broader spectra of patients. It is also notable that the present study was not an assessment of exercise per se but rather, supervised group exercise. As such, it is possible that the social support or the sense of purpose provided by being part of a group study were important determinants of the improved mood of the patients assigned to group exercise. However, in 1 study, Blumenthal et al. (19) found that both home-based exercise and group exercise served to reduce depressive symptoms, thus mitigating this concern. Finally, it is somewhat surprising that exercise was as effective as sertraline among the subgroup of subjects with severe depression. This finding, however, is based on a very small sample size and, given the volunteer status of this population, would need to be reproduced in more real-life settings to assess the applicability of this finding

If further study continues to reproduce these present findings, there would be strong clinical appeal for developing exercise as treatment for depression in cardiac patients. First, on a practical basis, the use of SSRIs is not without side effects, which, beyond transient effects involved with medication initiation, can include sexual dysfunction, a tendency to polypharmacy in some patients, and a need to be watchful for drug interactions among patients on multiple cardiac medications. Indeed, in the present study, 25% of patients randomized to sertraline experienced sexual dysfunction, and 18% experienced fatigue, while such symptoms were rare in the group randomized to group exercise. Second, in contrast to the current paucity of prognostic benefit associated with SSRI use in cardiac patients, exercise training is of known prognostic benefit among patients with heart disease. Of interest, a secondary analysis of the ENRICHD trial found that depressed patients who exercised had a 40% reduction in mortality compared with depressed patients who did not engage in exercise (20). Third, the occurrence of acute cardiac events may heighten not only the risk for depression but also associated fear and anxiety. Prescribing exercise for such patients may convey a message of empowerment.

The findings of Blumenthal et al. (10) raise a practical question. Overall, current American society is highly sedentary and depressed patients even more so. Comorbid depression and cardiac disease make exercise instruction and maintenance more complex. Although some depressed patients may simply respond to their physician instructions concerning exercise, many will require more assistance than practicing doctors can provide in constrained medical practice. In the present study, group exercise for cardiac patients was freely sponsored through funded research. But in the real world, there is currently no third-party payer support for exercise training programs for cardiac patients besides conventional cardiac rehabilitation, which is relatively costly, limited in geographic availability, and narrow in its patient eligibility requirements. Thus, future research should address the realities of this situation. A practical line of exploration lies in the medical testing of inexpensive hospital or community exercise programs that provide either home-based and/or group-based exercise and adherence assistance, such as that provided by peer-based and professional social support, pedometer-based self-monitoring, and coaching assistance designed to increase patient autonomy, self-efficacy, and stress management (21). Such exercise programs can be tested versus conventional medical practice for their ability to reduce depression and important sequelae, such as medication noncompliance, work absenteeism, and the high utilization of medical resources that is associated with depression. The clinical reasons for developing such exercise programs are already compelling, but by demonstrating the efficacy of exercise versus antidepressant medication for reducing depressive symptoms, Blumenthal et al. (10) have now provided an important additional incentive for developing practical exercise programs for medical patients.

⁎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