Depression in coronary artery disease: Does treatment help?

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In the ENRICHD trial, cognitive behavior therapy–based psychosocial intervention did not result in lower rates of recurrent MI or mortality compared with usual medical care, but the (nonrandomized) use of selective serotonin reuptake inhibitors (SSRIs) by some patients in the study was associated with a 42% reduction in the risk of death.33,35

Likewise, depression intervention had no significant effect on cardiac outcome in SADHART, although this 369-patient study was not powered to demonstrate such a benefit.31 Deaths were reduced by more than 50% with sertraline compared with placebo, but there were only 5 and 2 deaths in the placebo and sertraline groups, respectively. The point estimate for sertraline’s effect on major adverse cardiac events was a 23% reduction in events (ie, relative risk of 0.77), but the 95% confidence interval corresponding to this relative risk was 0.51 to 1.16, indicating a lack of statistical significance.

Still, this 23% reduction from SADHART was suggestive—certainly enough to interest the cardiologists associated with the study. Together with the ENRICHD trial findings and results from case-control studies indicating that SSRI therapy reduces the risk of incident MI,36,37 the SADHART findings have encouraged other investigators to suggest additional studies of the effects of antidepressant therapy on CAD outcomes.38,39

Notably, in both the ENRICHD trial40 and SADHART (unpublished data, manuscript in preparation), patients who recovered from depression (regardless of treatment assignment) had better long­term survival, and this was also true in a long-term longitudinal study of patients following coronary artery bypass graft (CABG) surgery.12 This suggests that interventions to promote recovery from depression should be useful in improving cardiac prognosis, but it does not prove it. It may be that patients whose depression improves are in some way healthier, regardless of their depression intervention.

As noted above, data from observational case-control studies of patients admitted to coronary care units suggest that SSRI therapy reduces incident MI.36,37 On the other hand, a study of mortality among patients undergoing CABG surgery revealed worse outcomes in those taking SSRIs than in those who were not.41 Because this study was observational and not randomized, its findings must be interpreted with caution. The effect observed could be due to an adverse effect of SSRI treatment, an adverse effect of depression, or some other mechanism.


The answer to this question depends on the specific mechanism being considered.

Platelet activation. In the case of platelet activation, the answer may be yes. In a randomized study of depressed patients with ischemic heart disease, paroxetine but not nortriptyline reduced elevated biomarkers of platelet activation.42 In a substudy of SADHART, blood levels of sertraline and desmethylsertraline were inversely correlated with platelelet activation.43 Moreover, serotonin reuptake inhibitors appear to reduce platelet activation in proportion to their affinity for the serotonin transporter.37,44

Heart rate variability. There is little evidence that depression therapy influences heart rate variability. In SADHART, for instance, sertraline and placebo did not differ in their effects on heart rate variability.31

Nonadherence to CAD therapy. It is clear that nonadherence to therapy is more common in depressed patients with cardiac disease than in their nondepressed counterparts45,46 and that poor adherence is associated with worse cardiac outcomes.47 But no study in depressed patients has yet demonstrated that depression treatment per se results in improved adherence. One study has demonstrated, however, that adherence tends to “travel with” depression over the course of treatment: as symptoms of depression declined, adherence improved.48


In the future, a more efficient way to improve cardiac outcomes associated with depression may be to target interventions directly at intermediary mechanisms rather than at depression itself. For example, if depression is robustly associated with a deleterious effect on platelet function that heightens the risk of thrombus formation, it might be helpful to optimize antiplatelet therapy in patients with depression, independent of the depression treatment. Similarly, anti-inflammatory treatments might have added benefit in those cardiac patients who are depressed, because these patients tend to have abnormally elevated inflammatory activity, which is associated with worse outcomes. These hypotheses would need to be specifically tested in randomized controlled trials, of course.

Because depression is associated with smoking, a recent study of a 3-month smoking cessation intervention in patients admitted to a coronary care unit provides an instructive example.49 At 2-year follow-up, significantly more patients had continuously abstained from smoking in the intervention group than in a usual-care control group (33% vs 9%, respectively), and significantly fewer patients had died in the intervention group compared with the control group (2.8% vs 12%, respectively).

Another desirable objective is the development of treatments that are more robust in their effects on depression for patients with CAD than the interventions tested so far. Higher rates of response and remission of depression would be highly desirable in their own right. Moreover, only with more potent interventions, whose effects separate more robustly from those seen with placebo or usual care, is it likely that depression treatments themselves could affect cardiac outcomes.

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