In this prospective cohort study of more than 1000 outpatients with stable coronary heart disease, we found that participants with baseline depressive symptoms had a 50% greater rate of subsequent cardiovascular events (heart failure, myocardial infarction, stroke, transient ischemic attack, or death) than participants without depressive symptoms. After adjustment for comorbid conditions and cardiac disease severity, depressive symptoms remained associated with a 31% increased rate of cardiovascular events. Inflammation (as measured by C-reactive protein) explained a small part of this association. However, no significant association between depressive symptoms and cardiovascular events remained after adjustment for physical activity and other health behaviors. These findings raise the hypothesis that the increased risk of cardiovascular events associated with depression could potentially be preventable with behavior modification, especially exercise.
Given the relatively modest effects of traditional therapies on depressive symptoms in patients with heart disease,55–58
there is increasing urgency to identify interventions that not only reduce depressive symptoms but also directly target the mechanisms by which depression leads to cardiovascular events.59
Several large-scale studies have clearly documented that increased physical activity reduces cardiovascular events,60–62
but whether exercise interventions can eliminate the excess risk of cardiovascular events associated with depressive symptoms has not been studied. Patients with depressive symptoms are less likely to adhere to dietary, exercise, and medication recommendations,13–15
and poor health behaviors can lead to cardiovascular events.36,62
Exercise training can improve both depressive symptoms and markers of cardiovascular risk.63,64
It is therefore possible that the combination of exercise therapy plus antidepressant medication may reduce the risk of cardiovascular events in patients with depression.
Our study evaluated depression and physical activity at the same point in time, and thus we cannot determine whether physical inactivity was the cause or result of depression. Indeed, the association is almost certainly bidirectional because depression leads to physical inactivity,14,65–68
and physical inactivity exacerbates depression.69–72
This can result in a downward spiral in which depression and physical inactivity become mutually reinforcing. Likewise, treating depression can increase physical activity, and physical activity can elevate mood.64,73–75
To the extent that physical inactivity precedes depression, it would be acting as a confounder rather than as a mediator of the association between depression and cardiovascular events. Regardless of whether physical inactivity was the cause (a confounder) or the result (a mediator) of depressive symptoms, it appeared to account for almost half of the association between depressive symptoms and cardiovascular events in our sample. These findings raise the possibility that increased exercise may decrease the risk of cardiovascular events associated with depression.
Because we measured the potential behavioral mediators by self-report, it is possible that participants with depressive symptoms were more likely to underreport medication adherence and physical activity. We attempted to address this possibility by substituting exercise capacity (instead of self-reported physical activity) as an objective measure of physical fitness. Although exercise capacity may also have been influenced by worse underlying cardiac disease severity that was not otherwise accounted for in our models, adjusting for this gold standard measure of physical fitness resulted in the same findings as adjusting for self-reported physical activity.
Many cross-sectional studies have examined potential mediators of the association between depression and cardiovascular disease. However, only a few prospective studies have evaluated whether adjusting for any of these candidate mechanisms actually changes the effect size for depression on cardiovascular events. Carney et al17
found that low heart rate variability partially mediated the effect of depression on survival among 311 depressed patients after an acute myocardial infarction. In light of the present results, an intriguing possibility is that the mediating effects of heart rate variability may have been related to a less physically active lifestyle among the depressed participants. Vaccarino and colleagues24
reported that inflammatory biomarkers explained a small portion of the association between depression and cardiovascular disease incidence among 559 women with suspected coronary ischemia, but Empana et al76
found that adjustment for inflammatory markers did not change the strength of association between depressive symptoms and incident cardiovascular disease in a nested case-control study of 1005 healthy middle-aged men. In the present study, we found that adjusting for C-reactive protein was associated with a decrease in the strength of association between depressive symptoms and cardiovascular events. However, it is unclear whether inflammation was functioning as a mediator between depressive symptoms and cardiovascular events or as a marker of worse cardiac disease severity.
Others have raised the possibility that antidepressant toxicity may be responsible for the adverse cardiovascular outcomes associated with depressive symptoms. Cohen et al77
reported an excess risk of myocardial infarction in users of tricyclic antidepressants, and Sherwood et al18
found that use of antidepressant medication was associated with an increased risk of cardiovascular hospitalization or death in patients with heart failure. In contrast, Taylor and colleagues evaluated 2481 patients after experiencing a myocardial infarction and found that users of selective serotonin re-uptake inhibitors were at lower risk of death or recurrent myocardial infarction than nonusers.78
To evaluate the antidepressant toxicity hypothesis, we compared the effect size for depressive symptoms on cardiovascular events before and after adjustment for use of antidepressant medications. Although adjusting for use of selective serotonin reuptake inhibitors or tricyclic agents did not change the effect size for depressive symptoms, adjusting for use of “other antidepressants” reduced the effect size for depressive symptoms by 8.8%. One potential interpretation of these findings is that antidepressant toxicity may (at least partly) be responsible for the increased risk of cardiovascular events associated with depressive symptoms. However, a more likely explanation is that use of “other antidepressants” was a marker of more severe (or treatment-resistant) depression and that the effect size for depressive symptoms on cardiovascular events was reduced because adjusting for use of “other antidepressants” was tantamount to adjusting for depression severity. This interpretation is supported by previous studies identifying treatment-resistant depression as a high-risk subtype for cardiovascular events.59,79
We found that major depressive disorder as measured by the C DIS-IV was not associated with cardiovascular events, whereas depressive symptoms as measured by the PHQ were. It is possible that some participants may have felt more comfortable endorsing depressive symptoms on an anonymous questionnaire than in a face-to-face interview, making the interview a less accurate measure of depression. Assuming the interview was accurate, however, this discrepancy could inform our understanding of the mechanisms of association between depression and cardiovascular disease. An interview diagnosis of major depressive disorder was based on endorsing a minimum of 5 symptoms during the past month.
In contrast, the continuous PHQ-9 score captured both the number and frequency of depressive symptoms experienced in the past 2 weeks. Some patients with a major depressive episode in the past month may not have reported substantial depressive symptoms within the past 2 weeks. Likewise, some patients who did not meet interview criteria for major depressive disorder because they did not have 5 or more symptoms of depression may have had elevated PHQ-9 scores because they were experiencing fewer depressive symptoms more frequently or more recently than patients who did meet interview criteria. This would suggest that the frequency of depressive symptoms may be a stronger risk factor for physical inactivity and cardiovascular events than whether the patient meets criteria for major depressive disorder.
Our study has several strengths, including detailed assessments of depression and cardiac disease severity, careful measurement of potential biological and behavioral mediators, and comprehensive assessment of cardiovascular events. However, several limitations must also be considered. First, most of our participants were older men, and almost half were recruited from VA medical centers. Therefore, our results may not generalize to women or to other patient populations. Second, low physical activity and exercise capacity may have been the result of greater cardiac disease severity. We attempted to address this possibility by carefully measuring and adjusting for comorbid conditions and cardiovascular disease severity. However, no observational study can completely eliminate confounding, and it remains possible that the effect of physical inactivity on cardiovascular outcomes may have been influenced by worse underlying cardiac disease severity that was not otherwise accounted for in our models. Third, we did not assess dietary factors other than blood levels of omega-3 fatty acids. Finally, our study was limited to outpatients with stable coronary heart disease, and thus we cannot comment on the mechanisms of association between depression and cardiovascular outcomes in healthy populations or in patients following acute coronary syndrome.
In summary, we found that the association between depressive symptoms and cardiovascular events was largely explained by health behaviors, especially physical inactivity. These results suggest that the relationship between depression and cardiovascular events may be modifiable with behavioral interventions. The ongoing Understanding Prognostic Benefits of Exercise and Antidepressant Therapy (UPBEAT) study is comparing the effects of exercise vs antidepressant medication on depression and biomarkers of cardiovascular risk in patients with depressive symptoms and coronary heart disease.80
The longer-term goal is to identify an intervention that will improve both depression and cardiovascular disease outcomes. Regardless of whether physical inactivity causes depressive symptoms or vice-versa, increased activity has the potential to reduce the excess risk of cardiovascular events associated with depressive symptoms in patients with stable coronary heart disease.