In this prospective study among women without known cardiovascular disease at baseline, symptoms of depression were directly associated with risk of CHD events in age-adjusted and multivariable models excluding potential biologic intermediates. Symptoms were most strongly related to fatal CHD events, where the association remained significant even after controlling for all CHD risk factors. However, depressive symptoms were also associated with multiple risk factors for CHD, and the relationships between depressive symptoms and all three endpoints, including fatal CHD, were attenuated in multivariable analyses that adjusted for updated CHD risk factor status. These CHD risk factors may act as biologic intermediates in the relationship between depressive symptoms and cardiac events, given their strong association with depression in this and prior studies.20
When we examined a proxy variable for clinical depression that consisted of either MHI-5 score<53 or use of antidepressant medication, a strong association with risk of SCD emerged that was not attenuated in multivariable models. When examined separately, this increased risk appeared to result primarily from a specific elevation in the risk of SCD among women who reported antidepressant use. Neither depression score nor antidepressant use was significantly associated with non-fatal events in multivariable models.
Prior studies have examined the association between depression and incident cardiac events, with varying results. Two meta-analyses of observational studies both estimated that depression conferred a 1.6 fold increased risk of CHD;21–22
and similar to the relationship observed here for SCD, clinically relevant depression appeared to be a stronger predictor than depressive symptoms.22
With respect to prior large scale data among women, investigators from the Women’s Health Initiative (WHI) also found that depressive symptoms were associated with a significantly higher risk of fatal cardiovascular events (adjusted risk ratio 1.5, 95% CI 1.10–2.03) among 73,098 women without a history of cardiovascular disease over four years of follow-up.23
As observed in our study, relationships appeared stronger for fatal versus nonfatal events; however, separate risks were not reported for antidepressant use and SCD was not specifically examined.
Part of the association with fatal events observed in this and previous studies could be explained if part of the elevated mortality risk associated with depression were due to an increased risk of fatal ventricular arrhythmias. The strong association between our proxy measure of clinical depression and SCD supports this possibility. A large case control study also found a significant association between a diagnosis of clinical depression and out-of-hospital cardiac arrest independent of established CHD risk factors.2
Depressive symptoms have also been specifically associated with ventricular arrhythmias among individuals with implantable defibrillators.3
Possible mechanisms for the elevated risk of ventricular arrhythmias and SCD associated with depression include greater sympathetic nervous system activation,9
higher resting heart rates, increases in QT dispersion,24
and reduced heart rate variability8
among individuals with depression. Another possibility is that treatments for depression may elevate risk of ventricular arrhythmias. When examined separately, we found an elevated risk of SCD associated with antidepressant use, and not with more severe depressive symptoms according to MHI-5 score<53. It is also noteworthy that as opposed to the hazard ratio corresponding to MHI-5 score, the hazard ratio for SCD corresponding to antidepressant use was minimally attenuated despite adjustment for multiple coronary risk factors (HR in fully adjusted model 3.34, 95% CI 2.03–5.50).
In addition to our own study, prior observational studies have noted a higher mortality risk associated with antidepressant use in patients with heart failure25
and in patients undergoing coronary artery bypass graft surgery.26
Fluoxetine, which has been shown to cause direct and indirect reductions in the hERG potassium current in a human embryonic kidney cell model,27
has been reported to result in QT prolongation and torsades de pointes.28–29
Tricyclic antidepressants are also known to cause QT prolongation and ventricular arrhythmias in overdose, and in doses greater than 100 mg have been associated with SCD risk in a retrospective cohort study.30
In this same study, standard doses of SSRIs and TCAs were not associated with increased risk; however, the study was unable to control for other confounding factors.
Although proarrhythmic effects from antidepressant medications may have resulted in a higher risk of SCD in our study, it must be emphasized that observational studies cannot prove causality, and confounding by indication can never be completely ruled out. Since antidepressant use was more significantly correlated with a diagnosis of clinical depression than the MHI-5 score, it is entirely possible that antidepressant use identified participants with more severe depression that was not fully captured by the MHI-5 questionnaire. In addition, these risks need to be put in perspective and balanced against known benefits of these medications on depression. SCD among healthy women is an uncommon event, and although elevated, the absolute risk among women who reported antidepressant use in this study was still very low (46 SCDs per 100,000 person-years).
Although the individual risk is low, the possible public health implications of an arrhythmic risk from these commonly prescribed medications at a societal level remain large. This potential risk coupled with recent data suggesting that the clinical benefit of newer antidepressant agents may be less than previously thought31
highlights the need for large-scale randomized trials of antidepressant medications that are adequately designed and powered to detect important adverse cardiovascular outcomes such as proarrhythmia as well as efficacy. Although the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) trial was specifically designed to examine cardiovascular safety in patients with acute MI or unstable angina, the primary study endpoints were intermediate endpoints such as left ventricular ejection fraction and significant QTc prolongation.32
With only 369 patients enrolled, the trial had minimal power to examine hard endpoints such as SCD or fatal CHD. The largest randomized trial thus far, the ENRICHD trial, enrolled 2481 post-MI patients and did not find an increase or decrease in the risk of death or recurrent MI associated with cognitive behavioral therapy supplemented with SSRI, but raised the possibility of an interaction by sex, with higher risks of cardiovascular events among women treated with the intervention.12
Strengths of our study include the relatively large sample size, the long follow up period, rigorously documented CHD endpoints, and the updated measures of depression and cardiac risk factors over the course of follow-up. There are also additional limitations of the present study that warrant consideration. First, reverse causality may account for at least part of the association observed between depression and cardiovascular disease in this and other observational studies. Individuals who are diagnosed with CHD or with conditions that predispose them to coronary disease such as diabetes or hypertension may develop depression, and therefore, would also be at higher risk for fatal cardiac events. Our study excluded women with known CHD at baseline, and sensitivity analyses that excluded participants who reported CHD in follow-up did not significantly change our results, arguing that reverse causality by symptomatic CHD is less likely to be a significant source of bias. Although we attempted to adjust for as many potential confounding factors as possible in our multivariable analyses, there may still be residual confounding from CHD risk factors and prevalent CHD. Also, for the non-fatal MI analysis, women who are depressed my be more likely to self-report MI, and this could inflate the detection of MI, particularly with respect to the probable cases not confirmed by medical records. However, analyses excluding these probable cases revealed similar results.
Second, we did not have a measure of adherence to medications in our data. Because depression has previously been associated with reduced adherence to medications,33
adherence may be a confounder in our results. Also, we did not collect information on antidepressant dose, and therefore, it is not possible to analyze our data for a dose-response relationship between antidepressants and SCD. In addition, our analysis does not include other comorbid psychologic factors, such as anxiety, which may be collinear with depression and which has been correlated with arrhythmia.35
Another limitation is the relatively small number SCD events in our analyses (138 SCDs for analyses starting in 1992, 99 SCDs for analyses starting in 1996), compared with the fatal CHD and non-fatal MI endpoints. Finally, the Nurses’ Health study represents a relatively healthy group of mostly Caucasian females, and findings from this analysis may not be generalizable to other populations. However, the estimated 7.9% prevalence of depression as measured by an MHI-5 score <53 is comparable to the prevalence of major depression (4.8%) estimated among white women aged 45–54 years using a structured interview in the National Comorbidity Survey.36
In summary, in this prospective cohort of women without baseline cardiovascular disease, we found that symptoms of depression are associated with higher risks of cardiac events, and at least part of this association appears to be explained by differences in coronary risk factors, which may act as causal intermediates in the risk conferred by depression. When we utilized a proxy for clinical depression, which included antidepressant medication use, we observed a stronger association for SCD suggesting a possible pro-arrhythmic mechanism. Although antidepressant medication use may be a marker of worse depression, its specific association with elevated risk of SCD merits further study.