Alexander H. Glassman

CONTEXT: Major depressive disorder (MDD) occurs in 15% to 23% of patients with acute coronary syndromes and constitutes an independent risk factor for morbidity and mortality. However, no published evidence exists that antidepressant drugs are safe or efficacious in patients with unstable ischemic heart disease. OBJECTIVE: To evaluate the safety and efficacy of sertraline treatment of MDD in patients hospitalized for acute myocardial infarction (MI) or unstable angina and free of other life-threatening medical conditions. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial conducted in 40 outpatient cardiology centers and psychiatry clinics in the United States, Europe, Canada, and Australia. Enrollment began in April 1997 and follow-up ended in April 2001. PATIENTS: A total of 369 patients with MDD (64% male; mean age, 57.1 years; mean 17-item Hamilton Depression [HAM-D] score, 19.6; MI, 74%; unstable angina, 26%). INTERVENTION: After a 2-week single-blind placebo run-in, patients were randomly assigned to receive sertraline in flexible dosages of 50 to 200 mg/d (n = 186) or placebo (n = 183) for 24 weeks. MAIN OUTCOME MEASURES: The primary (safety) outcome measure was change from baseline in left ventricular ejection fraction (LVEF); secondary measures included surrogate cardiac measures and cardiovascular adverse events, as well as scores on the HAM-D scale and Clinical Global Impression Improvement scale (CGI-I) in the total randomized sample, in a group with any prior history of MDD, and in a more severe MDD subgroup defined a priori by a HAM-D score of at least 18 and history of 2 or more prior episodes of MDD. RESULTS: Sertraline had no significant effect on mean (SD) LVEF (sertraline: baseline, 54% [10%]; week 16, 54% [11%]; placebo: baseline, 52% [13%]; week 16, 53% [13%]), treatment-emergent increase in ventricular premature complex (VPC) runs (sertraline: 13.1%; placebo: 12.9%), QTc interval greater than 450 milliseconds at end point (sertraline: 12%; placebo: 13%), or other cardiac measures. All comparisons were statistically nonsignificant (P> or = .05). The incidence of severe cardiovascular adverse events was 14.5% with sertraline and 22.4% with placebo. In the total randomized sample, the CGI-I (P =.049), but not the HAM-D (P =.14), favored sertraline. The CGI-I responder rates for sertraline were significantly higher than for placebo in the total sample (67% vs 53%; P =.01), in the group with at least 1 prior episode of depression (72% vs 51%; P =.003), and in the more severe MDD group (78% vs 45%; P =.001). In the latter 2 groups, both CGI-I and HAM-D measures were significantly better in those assigned to sertraline. CONCLUSION: Our results suggest that sertraline is a safe and effective treatment for recurrent depression in patients with recent MI or unstable angina and without other life-threatening medical conditions.

A relationship between cigarette smoking and major depressive disorder was suggested in previous work involving nonrandomly selected samples. We conducted a test of this association, employing population-based data (n = 3213) collected between 1980 and 1983 in the St Louis Epidemiologic Catchment Area Survey of the National Institute of Mental Health. A history of regular smoking was observed more frequently among individuals who had experienced major depressive disorder at some time in their lives than among individuals who had never experienced major depression or among individuals with no psychiatric diagnosis. Smokers with major depression were also less successful at their attempts to quit than were either of the comparison groups. Gender differences in rates of smoking and of smoking cessation observed in the larger population were not evident among the depressed group. Furthermore, the association between cigarette smoking and major depression was not ubiquitous across all psychiatric diagnoses. Other data are cited indicating that when individuals with a history of depression stop smoking, depressive symptoms and, in some cases, serious major depression may ensue.

OBJECTIVE: The authors review the mechanisms and establish the risk of torsade de pointes and sudden death with antipsychotic drugs. METHOD: They present a review of original concepts, the distinction between familial and drug-induced cases of torsade de pointes, and the recognition of the role of noncardiac drugs in torsade de pointes and sudden death. They review the evidence linking QTc interval prolongation, potassium channels, and torsade de pointes from both the long QT syndrome and drugs. They examine the risk for torsade de pointes from antipsychotic drugs and estimate the frequency of sudden death on the basis of epidemiological data in normal and schizophrenic populations. RESULTS: All drugs that cause torsade de pointes prolong the QTc interval and bind to the potassium rectifier channel, but the relationships are not precise. Prediction of torsade de pointes and sudden death can be improved by examining dose dependency, the percent of QTc intervals higher than 500 msec, and the risk of drug-drug interactions. Although sudden unexpected death occurs almost twice as often in populations treated with antipsychotics as in normal populations, there are still only 10-15 such events in 10,000 person-years of observation. CONCLUSIONS: Although pimozide, sertindole, droperidol, and haloperidol have been documented to cause torsade de pointes and sudden death, the most marked risk is with thioridazine. There is no association with olanzapine, quetiapine, or risperidone. Ziprasidone does prolong the QT interval, but there is no evidence to suggest that this leads to torsade de pointes or sudden death. Only widespread use will prove if ziprasidone is entirely safe. To date, all antipsychotic drugs have the potential for serious adverse events. Balancing these risks with the positive effects of treatment poses a challenge for psychiatry.

Major depression has been associated with mortality from ischemic heart disease (IHD). In addition, a symptom of depression--hopelessness--has been suggested as a determinant of health status. We studied the relation of both depressed affect and hopelessness to IHD incidence using data from a cohort of 2,832 U.S. adults age 45-77 years who participated in the National Health Examination Follow-up Study (mean follow-up = 12.4 years) and had no history of IHD or serious illness at baseline. We used the depression subscale of the General Well-Being Schedule to define depressed affect and a single item from the scale to define hopelessness. At baseline, 11.1% of the cohort had depressed affect; 10.8% reported moderate hopelessness, and 2.9% reported severe hopelessness. Depressed affect and hopelessness were more common among women, blacks, and persons who were less educated, unmarried, smokers, or physically inactive. There were 189 cases of fatal IHD during the follow-up period. After we adjusted for demographic and risk factors, depressed affect was related to fatal IHD [relative risk = 1.5; 95% confidence interval (CI) = 1.0-2.3]; the relative risks of fatal IHD for moderate and severe levels of hopelessness were 1.6 (95% CI = 1.0-2.5) and 2.1 (95% CI = 1.1-3.9), respectively. Depressed affect and hopelessness were also associated with an increased risk of nonfatal IHD. These data indicate that depressed affect and hopelessness may play a causal role in the occurrence of both fatal and nonfatal IHD.