Depression: A Risk Factor and Two Riddles about Poor Prognosis in ACS

Depression is prevalent in acute coronary syndrome (ACS) and has been associated with increased morbidity and mortality.^1-3 Yet, despite the many prospective studies that link depression to poor outcome after ACS, depression has not been formally recognized in national health guidelines as a poor prognostic indicator. The Writing Group for this Scientific Statement undertook a systematic review to evaluate whether change is warranted.⁴

A search protocol was implemented to identify all English language publications in MEDLINE, Current Contents, and PsycINFO through July 24, 2011 that examined the association between depression and all-cause mortality, cardiac mortality, and composite outcomes for mortality and nonfatal events after ACS (myocardial infarction or unstable angina). A total of 53 individual studies and 4 meta-analyses met inclusion criteria and showed heterogeneity in terms of the sample demographics, the definition and measurement of depression, and length of follow-up. Positive studies identified associations of varying magnitudes, and a minority of the studies showed negative findings. The Writing Group’s appraisal, reflected in the Scientific Statement, is that the preponderance of evidence supports the recommendation that the AHA should elevate depression to the status of a risk factor for adverse medical outcomes in patients with ACS.

The Writing Group applied rigorous definitional criteria when interpreting depression as risk factor. Specifically, they analyzed only prospective studies and required that depression be linked to cardiac events and mortality, rather than only to intermediate outcomes. Two important riddles remain, however. The first riddle concerns whether there is a plausible biological mechanism to account for the observed association between depression and post-ACS mortality. The second riddle concerns whether there are practical clinical implications of the association between depression and adverse outcomes following ACS.

Confidence that depression is causally important for coronary disease outcome would be enhanced by evidence that the risk factor meets the Bradford Hill criterion of having a biologically plausible mechanism to explain its association to disease outcome.⁵ As Hill noted, the ability to comprehend or shed light on causal mechanisms inevitably is limited by the current state of biomedical knowledge. In the case of potential causal mechanisms to link depression and coronary heart disease, the list of contenders is very long indeed. As the Statement suggests, potential biological mediators of depression’s effects on adverse outcomes include neuroendocrine dysfunction, disturbances in autonomic cardiac control, enhanced platelet activity in depression, endothelial dysfunction, and inflammation. Another suggestion is that depression may contribute to poor cardiac outcomes by potentiating the adverse metabolic effects of diabetes and obesity on the heart. Equally likely is the prospect that depression fosters untoward effects by increasing the odds that health risk behaviors such as smoking, physical inactivity, and treatment non-adherence will indirectly mar the process of recovery from ACS.

Even more challenging than the riddle of what mechanism links depression to poor ACS outcome is the riddle regarding any practical implications of the association. To date, there is no compelling evidence that treating depression improves survival after ACS.⁶ The premise of the Statement is that such evidence is not yet available, but will be forthcoming. Let us hope this proves to be the case and that we will eventually learn how to treat post-ACS depression sufficiently well to improve survival. If so, depression may emerge as a genuinely “causal risk factor” for ACS outcome.⁷ Until then, we might wish to consider whether intervening positively to foster wellness, well-being, or resilience, rather than solely to alleviate depression could hold added potential to improve disease outcomes.^8,9