Treatment of Depression Following Acute Myocardial Infarction

Depression is a risk factor for mortality after acute myocardial infarction (MI), and it predicts a slow recovery and a poor quality of life.^{1 - 4} Nevertheless, only a minority of patients who are depressed after an MI receive treatment for their depression. In the past, the only available antidepressants had cardiotoxic effects and were contraindicated for many patients with heart disease, particularly older patients at risk for orthostatic hypotension and patients with left bundle branch block.⁵ Some of the older antidepressants also have proarrhythmic effects.⁶

The newer selective serotonin reuptake inhibitor (SSRI) antidepressants are free of cardiotoxic effects in relatively healthy depressed patients.⁷ However, because heart disease has remained a standard exclusion criterion in clinical trials of antidepressants, very little is actually known about the safety and efficacy of antidepressants for depressed patients with heart disease. Psychotherapy is a safe and effective alternative to antidepressants, but the 2 types of psychotherapy that have been proven effective in treating depression (cognitive behavioral therapy and interpersonal psychotherapy) are not available in every community, and insurance coverage for psychotherapy is either limited or not available in many managed care plans. Thus, cardiologists and general practitioners find themselves between the proverbial "rock and a hard place" when faced with a decision about whether to do nothing about a patient's depression and hope that it remits without treatment, or to prescribe an antidepressant that might be neither safe nor effective. Fortunately, the results from the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART), published in this issue of THE JOURNAL,⁸ have made the hard place a little softer.

Although not without flaws, the SADHART study is truly an important trial. It provides the first real evidence that at least one of the SSRI antidepressants, sertraline, is safe for use soon after an acute MI or an episode of unstable angina, and that it is an efficacious treatment, at least for relatively severe, recurrent depression. This is a major step forward in the care of depressed patients with coronary heart disease. There is now an alternative to ignoring a comorbid psychiatric disorder that often has devastating consequences for these patients.

The SADHART study has several important limitations. First, severely medically ill patients were excluded, as were patients for whom SSRIs were contraindicated. Thus, the results cannot be generalized to the general population of post-MI patients. Second, as noted by the investigators, although 369 patients were randomized to double-blind treatment with sertraline or placebo, the study was too small to identify less common drug-drug interactions or adverse events. Third, the patients did not receive the study drug until after an average of 1 month following the acute MI. Thus, safety of the drug in the early post-MI period is unclear. Fourth, sertraline was the only antidepressant agent tested in this trial. Whether the results are informative only with respect to sertraline or whether they apply to the general class of SSRIs is not yet determined.

Similar questions have surrounded trials involving β-blockers and angiotensin-converting enzyme inhibitors.^{9 - 10} Certainly, generalization of the results of SADHART to the "dual action" antidepressant drugs that affect both serotonergic and adrenergic systems is not warranted. Furthermore, although the antidepressant benefit of sertraline may well be a class effect of SSRIs, these agents are metabolized by the P450 liver enzyme system, as are many cardiac drugs. The specific enzymes that are involved, and thus the potential for drug-drug interactions, vary from one SSRI to the next. Nevertheless, despite these qualifiers and caveats, clinicians now have reason for cautious optimism when deciding whether it is safe to treat depression in patients with a recent MI or unstable angina.

A clinically important issue raised by this study, and also by the recent Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial,¹¹ is that a high proportion of cases of depression in patients recovering from an acute MI spontaneously remit without specific treatment. The rate may even be higher than that reported in the SADHART study since 34% of potential study enrollees were excluded from the trial during the prerandomization placebo phase, in many cases because their symptoms of depression remitted. Thus, one of the important directions for future research is to identify characteristics that differentiate patients whose depression will remit spontaneously from patients who need treatment.

Left ventricular ejection fraction, the study's primary indicator of the safety of the drug, did not differ between the drug and placebo groups. In contrast, about 20% fewer serious cardiovascular events, including death and nonfatal MI, occurred in the sertraline group than in the placebo group. This difference was not statistically significant, but it is encouraging. Whether treatment of depression can improve cardiovascular functioning is an important question. The investigators appropriately call for another clinical trial, informed by the SADHART results and designed with adequate statistical power, to determine whether successful treatment of depression improves survival following MI. This is particularly important in light of the preliminary findings of the ENRICHD trial,¹¹ in which psychotherapy for depression and inadequate social support failed to increase survival in post-MI patients. Based on what has been learned from SADHART and ENRICHD, future trials of treatment for depression in the context of acute coronary syndromes should attempt to recruit only patients who have depression that is unlikely to remit without treatment. A careful analysis of these data should provide some information about the characteristics of such patients.

Whether the risk of cardiac mortality and morbidity can be reduced by treating depression is an open question. However, depression is associated with significant psychological, social, and functional impairment.¹² There is evidence that treating depression improves the quality of life and overall functioning of depressed patients seen in primary care settings.¹³ We hope that the results of this important study will encourage physicians to recognize and appropriately treat depression in patients with heart disease.