Introduction

About one in five patients with acute coronary syndromes (myocardial infraction or MI, unstable angina pectoris) suffer subsequently from a major depression. And post-MI depression is associated with a 3-fold increase in morbidity and mortality. Moreover, this depression is usually untreated, as classical antidepressant drugs have been shown to be cardiotoxic. Now, a study reported in JAMA shows that successful treatment of post-MI depression is possible, without running the risk of doing more harm than good.

Method

The study, called SADHART (Sertraline Antidepressant Heart Attack Randomization Trial), was conducted in 40 outpatient cardiology and psychiatric clinics in North America, Europe, and Australia. Depressed patients who had been hospitalized for MI or unstable angina were randomized to receive 24 weeks of sertraline (a selective serotonin reuptake inhibitor, or SSRI) or placebo, given in a double-blind fashion. Potential patients were identified by screening patient charts and preliminary depression-diagnosis interviews.

Strict inclusion criteria were used for diagnoses - patients were required to have been hospitalized within the previous 30 days with an acute MI or unstable angina, and to be experiencing an episode of major depressive disorder, as defined in the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth edition). Cardiological complications or other medical conditions, and incompatible concomitant medications, formed the main exclusion criteria.

During a 2-week assessment period patients were given single-blind placebo medication. Just before randomization, a further psychiatric test (the Diagnostic Interview Schedule, or DIS) was done to verify that the patient met the depression diagnosis.

A total of 369 patients were randomized to receive sertraline in flexible escalating dosages of 50 to 200 mg/day, or placebo, for 24 weeks. No concomitant psychotropic drugs were allowed, except chloral hydrate for sleep problems. After 24 weeks, patients were tapered off medication.

The primary safety outcome measure was change in left ventricular ejection fraction (LVEF) from baseline. Also measured were ventricular premature complex (VPC) runs, and widened QTc intervals. Changes in depression were measured by Hamilton Depression Scale (HAM-D) and Clinical Global Impression-Improvement (CGI-I) scores. These measures were made at different intervals throughout the study. A patient was considered a 'responder' if a CGI-I score of 1 or 2 was achieved by the end of the study.

Results

The mean age of the 369 patients was 57 years. Most of them were men (63%), with at least two cardiovascular risk factors, 40% of them had experienced a previous MI, and 50% had at least one previous major depression.

There were no statistically significant differences between the sertraline-treated and placebo patients with respect to LVEF, VPC, QTc, or other cardiac parameters. There were severe cardiovascular events in 14.5% of the sertraline and 22.4% of the placebo patients.

Sertraline was significantly more effective than placebo with regard to changes in the CGI-I depression scale; however, there were no significant differences in the HAM-D scores, except in subsets of patients who had a previous depression and those with more severe depression (HAM-D >/=18), where sertraline was significantly superior to placebo.

Comments

An accompanying editorial in JAMA¹ describes this study as 'truly an important trial' and 'a major step forward'. It shows that an SSRI drug can be used safely and effectively soon after an MI or unstable angina episode. It must be noted, however, that severely medically ill patients were excluded in this study. Also, treatment was only started, on average, 30 days after the incident cardiac event, because of the need for safety assessments imposed by the trial design; earlier use of SSRIs might produce different effects.

It should be remembered that up to a third of post-MI depressions resolve spontaneously. It is now important to know what are the characteristics that differentiate those patients likely to improve on their own, and those that will benefit most from an apparently safe, effective medication. And 'effectiveness' here means not only an improvement in depressive symptomatology, but also likely improvement in cardiovascular outcomes.