Depression and Antidepressant Use Linked to Sudden Cardiac Death in Women
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March 9, 2009 (New York, New York) — A new analysis has found that major depression predicted cardiovascular morbidity and mortality in women participating in the Nurses' Health Study [1]. The hazard ratios were strongest for fatal events and were driven by the association of depression--in particular, antidepressant use--with sudden cardiac death (SCD). Dr William Whang (Columbia University, New York, NY) and colleagues report their findings in the March 17, 2009 issue of the Journal of the American College of Cardiology.
But the authors and accompanying editorialists conclude that, at the present time, the benefits of appropriately prescribed antidepressant use likely outweigh the risk of SCD.
"The absence of proof that antidepressants might cause cardiac events is more relevant than conclusive proof that this effect is absent. Nevertheless, these findings are sufficiently sobering to warrant heightened clinical surveillance and to initiate studies to definitively address this relationship," say Drs Sanjiv M Narayan and Murray B Stein (University of California, San Diego [UCSD]) in an accompanying editorial comment [2].
Whang told heartwire that he believes the biggest clinical implication of this new study "is that management of coronary heart disease risk factors may be especially important among women with depressive symptoms."
Those Using Antidepressants Three Times More Likely to Suffer SCD
Whang et al prospectively studied 63 469 women in the Nurses' Health Study without baseline coronary disease, stroke, or malignancy. They studied depressive symptoms and a proxy variable for clinical depression consisting of severe symptoms and/or antidepressant use and their relationship to cardiovascular events.
Questionnaires in 1992, 1996, and 2000 assessed depressive symptoms, with major depression defined by a validated five-point mental-health-index score (MHI-5) of <53, and antidepressant use was assessed in 1996 and 2000. Primary end points included SCD, fatal coronary heart disease (CHD), and nonfatal MI.
Of the women, 7.9% had MHI-5 scores of <53, previously found to predict clinical depression. Depressive symptoms were associated with CHD events, and the relationship was strongest for fatal CHD, with the association remaining significant even after researchers controlled for CHD risk factors (hazard ratio 1.49).
From 1996 onward, the proxy variable of severe symptoms and/or antidepressant use was most associated with SCD in multivariable models (HR 2.33), and the risk was primarily due to a specific relationship between antidepressant use and SCD (HR 3.34).
Narayan and Stein say the work of Whang et al stands out from previous research of this kind: "[This research] is particularly exciting. The authors should be congratulated for these important data on the etiologic role of depression and its treatment on cardiovascular outcomes in a very large cohort of healthy individuals."
Arrhythmia a Possible Mechanism, But Further Study Needed
"This surprising results merits scrutiny," the editorialists say. Numerous pharmaceutical agents might contribute to arrhythmic mortality, and in the present study, 61% of subjects were using selective serotonin-reuptake inhibitors (SSRIs), while 39% used other, nonspecified antidepressants.
"Our study raises questions about the mechanism by which depression is associated with sudden cardiac death," Whang told heartwire. "This is not the first study to link risk of SCD to depression. Our study is consistent with prior analyses that have found an association between depressive symptoms and a higher mortality in patients with CHD, and it points to arrhythmia as a possible mechanism for this worse prognosis."
Narayan and Stein say: "It is unclear whether SSRI agents might cause [sudden cardiac arrest]. While cardiac events are well documented with . . . tricyclic antidepressants, evidence for a link with SSRIs is mixed."
"Moreover, it is quite possible that antidepressant use merely indicates that depression is of sufficient severity to merit treatment." It is well established that patients with depression after acute coronary syndrome, for example, are less likely to adhere to their cardiac medication regimens, note the UCSD doctors, although treating the depression improves adherence.
"Clearly, the burden of proof rests on confirming this association. There are abundant data attesting to the safety and efficacy of SSRIs in particular, and a relative paucity showing adverse cardiac effects," they conclude.
Whang et al agree: "Although antidepressant medication use might be a marker of worse depression, its specific association with elevated risk of SCD merits further study."
Twin Study Shows Depression Itself Independently Associated With Heart Disease
Chicago, IL – Separately, new research suggests that depression itself remains a significant contributor to incident heart disease after genetics and environmental, mental, and physical factors are controlled for [3]. The study, performed in 1200 male twins who served in the US military during the Vietnam War, was reported by Dr Jeffrey F Scherrer (Washington University School of Medicine and St Louis Veterans Affairs Medical Center) at the American Psychosomatic Society meeting last week
"In this study, we have demonstrated that exposure to depression is contributing to heart disease only in twins who have high genetic risk and who actually develop clinical depression," says Scherrer in a Washington University School of Medicine statement.
"In twins with high genetic risk common to depression and heart disease but who never develop depression itself, there was no increased risk for heart disease. The findings strongly suggest that depression itself independently contributes to risk for heart disease," he notes.
Narayan reports receiving speaking honoraria or serving as a consultant for St Jude Medical, Boston Scientific, Medtronic, Biosense-Webster, and Cambridge Heart. Stein receives or has received in the past three years research support from Eli Lilly and GlaxoSmithKline and is currently or in the past three years has been a consultant for BrainCells, Bristol-Myers Squibb, Eli Lilly, EPI-Q, Forest Laboratories, Hoffman La-Roche Pharmaceuticals, Integral Health Decisions, Jazz Pharmaceuticals, Johnson & Johnson, Mindsite, Pfizer, Sanofi-Aventis, Sepracor, Transcept Pharmaceuticals, and Virtual Reality Medical Center.
- Whang W, Kubzansky LD, Kawachi I, et al. Depression and risk of sudden cardiac death and coronary heart disease in women. Results from the Nurses' Health Study. J Am Coll Cardiol 2009; 53:950-958
- Narayan SM and Stein MB. Do depression or antidepressants increase cardiovascular mortality? The absence of proof might be more important than the proof of absence. J Am Coll Cardiol 2009; 53:959-961
- Dryden J. Depression increases risk for heart disease more than genetics or environment [press release]. March 3, 2009. Available at: http://mednews.wustl.edu/news/page/normal/13643.html?emailID=23300.
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