Impacts of depression and emotional distress on cardiac disease

INSIGHTS FROM STUDIES OF DEPRESSION THERAPY IN CARDIAC PATIENTS

Among antidepressants, selective serotonin reuptake inhibitors (SSRIs) have been uniformly demonstrated to be effective in improving depressive symptoms and relatively safe for cardiac patients.^21–24 Not surprisingly, tricyclic antidepressants have been found to cause more cardiac problems.²¹ Mirtazapine, a central nervous system alpha-2 antagonist, failed to improve depressive symptoms in depressed post-MI patients in the Myocardial Infarction and Depression Intervention Trial (MIND-IT),^25,26 but because the results from this study have been presented only in abstract form, more details will be necessary to gain insight into explanations for this failure.

Although psychotherapy has been found to be quite effective among depressed patients without other medical illnesses, its effectiveness among patients with cardiac disease has not been impressive to date (Table 1).

No evidence of prognostic benefit from psychotherapy

Results from evaluations of psychotherapeutic interventions on cardiac prognosis have been rather disappointing (Table 1). The Enhancing Recovery In Coronary Heart Disease Patients (ENRICHD) study,²⁷ which involved randomization of 2,481 post-MI patients with depression and/or low perceived social support to usual care or cognitive behavior therapy, failed to show an impact of cognitive behavior therapy on the combined end point of death or nonfatal MI. Similarly, the Montreal Heart Attack Readjustment Trial (M-HART)²⁸ failed to demonstrate a benefit from home-based psychosocial nursing intervention on cardiac prognosis in IHD patients. These studies suggested that psychotherapeutic intervention might have differing or even opposite effects on the two genders.

Potential prognostic benefit from antidepressant therapy

In theory, adequate treatment of depression could affect dysregulated physiologic factors as well as dysregulated psychosocial factors, thereby leading to improved cardiac outcomes. There is physiologic evidence to support beneficial pleiotropic effects of antidepressant medications in IHD, such as reduced platelet activity^29–31 and improvement in low heart rate variability^32–34 with both sertraline and paroxetine.

The MIND-IT study evaluated mirtazapine for post-MI depression using a randomized placebo-controlled design.²⁵ However, this trial failed to find a significant treatment effect for either depression or cardiac outcomes.²⁶ These results may have been related to a lack of statistical power, as only 209 treated patients were compared with 122 patients receiving usual care. This trial also raises the question whether any nontricyclic antidepressant (other than SSRIs) might have beneficial effects on cardiovascular outcomes, or whether such an effect might be limited to SSRIs alone.

Provocative results emerged from the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART),²³ a randomized, double-blind, placebo-controlled investigation of the safety and efficacy of sertraline for major depressive disorder among 369 patients with recent MI or unstable angina. Patients receiving sertraline had fewer cardiac events (death, MI, stroke, worsened angina, or onset of HF) compared with patients taking placebo. The relative risk ratio for having at least one cardiac event was 0.77 with sertraline therapy, but this reduction in risk was not statistically significant (95% CI, 0.51 to 1.16). Although these findings suggest that sertraline may improve cardiac outcomes, the study was not adequately powered to detect differences on this measure. Power calculations indicate that in order to confirm a 20% reduction in relative risk in a randomized trial, a sample of at least 4,000 depressed patients with acute coronary syndrome would be required.²³ Based on the cost of SADHART, the estimated expense to complete such a study is approximately $200 million.

The SADHART-CHF trial is a randomized, double-blind, placebo-controlled study examining sertraline’s efficacy for major depressive disorder among patients with HF, as well as its effects on mortality and cardiac outcomes. This trial is in its last year of enrollment, and results will be forthcoming in 2008.

FUTURE DIRECTIONS

These recent insights into depression’s impact on cardiac disease give rise to several new questions to consider:

• Expand research to patients with depressive symptoms? To date, investigations into treatment effects have focused only on patients with cardiac disease who have major depressive disorder. However, depressive symptoms as reported on self-administered questionnaires consistently have been shown to be a risk for poor cardiac outcomes. Should we expand our interventional studies to patients with self-reported depressive symptoms?
• How thoroughly to test for differences among antidepressants? Three of the six SSRIs have been studied among depressed cardiac patients. Based on the available findings, can we assume that all SSRIs have the same efficacy and safety profiles and are similarly cardiovascularly protective? Should every antidepressant or SSRI be tested? Should head-to-head comparison studies be conducted? Tricyclic antidepressants are cardiotoxic, and central nervous system alpha-2 antagonists like mirtazapine may not be effective, but what about other types of antidepressants for depressed cardiac patients?
• Is there a role for studying surrogate end points? Studies examining the effects of an intervention on mortality and/or morbidity can be very expensive. As research budgets tighten, can we instead test the effects of depression therapy on some surrogate end points?

Our laboratory has been funded by the National Heart, Lung, and Blood Institute to compare the effects of escitalopram with those of placebo on MSIMI in patients with stable IHD and a score of 5 or greater on the Beck Depression Inventory. This study, the Responses of Myocardial Ischemia to Escitalopram Treatment (REMIT) trial, will provide SSRI therapy to patients with a broad spectrum of depressive symptoms (not just major depressive disorder), assess the ischemic activity induced by mental stress testing as its primary end point, and explore the effects on other hypothesized mechanisms of depression that adversely affect cardiac diseases (platelet aggregation, inflammatory biomarkers, etc). Stay tuned for the results in the near future.