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Invited Commentary
December 14, 2009

Antidepressant Use, Depression, and Poor Cardiovascular Outcomes: The Chicken or the Egg?Comment on “Antidepressant Use and Risk of Incident Cardiovascular Morbidity and Mortality Among Postmenopausal Women in the Women's Health Initiative Study”

Arch Intern Med. 2009;169(22):2140-2141. doi:10.1001/archinternmed.2009.437

Depression is a common comorbidity in patients with chronic heart failure, with reported incidence as high as approximately 48% in this patient population.1-4 Studies have shown that depression in patients with heart failure is strongly associated with worse outcomes and is an independent predictor of increased mortality and hospitalization.5-9 As a result, the use of antidepressants in this population has become more prevalent.

Some studies have shown improvements in cardiovascular outcomes and functional status with the use of selective serotonin reuptake inhibitors (SSRIs) with no adverse safety signals observed.6,10,11 However, other studies of tricyclic antidepressants (TCAs) and SSRIs have raised questions regarding the safety of these antidepressants for use in patients with cardiac disease because treatment with these agents was associated with increased risk of myocardial infarction or cardiovascular death.12,13 Most notably, in the Cardiac Arrhythmia Suppression Trial,14 TCAs were found to be associated with an increase in mortality. This long-standing controversy has been fueled by studies with insufficient power to properly address the question.

The study by Smoller et al is an important addition to the literature. It prospectively examines the relationship between antidepressant use and cardiovascular morbidity and mortality in a large cohort of postmenopausal women in the Women's Health Initiative (WHI) study.15-20 The findings, in the largest cohort of women yet studied, provide additional warning that antidepressant therapy may in fact be detrimental with respect to stroke and total mortality in this demographic population. In this study of 136 293 community-dwelling postmenopausal women enrolled in the WHI from 1993 to 1998, the authors found that antidepressant use was not associated with incident coronary heart disease. However, SSRI use was associated with an increased risk of stroke and all-cause mortality, and TCA use was associated with an increased risk of all-cause mortality. There were no significant differences between SSRI and TCA use in risk of any of the outcomes. In secondary analyses by stroke type, SSRI use was associated with incident hemorrhagic stroke. This is an interesting finding because SSRIs have been shown to inhibit platelet function, although the clinical relevance of this property has not been established.21

The authors address the limitations and potential confounding aspects of the use of antidepressants by using a propensity score from a logistic regression model to predict incident antidepressant use. Perhaps the most difficult aspect of these trials is that, as others have shown, the patients who are likely to be treated with antidepressants have additional risk factors for mortality and cardiovascular risks that are difficult to control for. The modest C statistic of 0.69 by logistic regression suggests that the ability to discriminate incident use was not strong. Also, the study cannot fully address cases in which antidepressant therapy fails (ie, patients who begin treatment with antidepressants but experience no remission of their depression symptoms); these patients may represent the highest-risk mortality group.

While questions remain on the safety and efficacy of antidepressant use in patients with both depression and heart failure, Smoller et al add important information to the body of literature on this topic. As the authors have concluded, their findings should be considered by physicians to help determine the potential benefit in quality of life and the potential mitigation of morbidity and mortality risk associated with untreated depression in patients with cardiovascular disease.

Depression remains an important and underrecognized risk factor for cardiovascular morbidity and mortality in men and women with existing heart disease and/or cardiovascular risk factors. Depression is known to be associated with lower quality of life, unhealthy lifestyle choices, poor adherence to medication regimens, and poor outcomes. Unfortunately, therapies used to alleviate depressive symptoms and depression have not been associated with clear-cut cardiovascular benefits. Cognitive behavioral therapy has been shown to not improve cardiovascular outcomes; in fact it potentially worsens outcomes in women.22 Although smaller studies of SSRIs in patients with cardiovascular disease have suggested that SSRIs are safe, these studies have been significantly underpowered and could not be used to evaluate cardiovascular outcomes. Therefore, an important step in this field would be to embark on a national effort to endorse a large-scale simple trial of antidepressant therapy in patients with cardiovascular disease and to evaluate the influence of this therapy on cardiovascular outcomes such as cardiovascular quality of life, nonfatal cardiovascular events, and mortality. Until then, we are left with the chicken or the egg dilemma.

Correspondence: Dr O’Connor, Duke University Medical Center, Division of Cardiology and Clinical Pharmacology, PO Box 3356, Durham, NC 27710 (oconn002@mc.duke.edu).

Financial Disclosure: None reported.

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