Antidepressant use and the risk of myocardial infarction.

Depressive symptoms increase the risk of cardiovascular events in both community samples (1– 4) and in patients with coronary disease (5– 7). Therefore, we need to develop treatments that reduce that risk while alleviating the symptoms of depression. It has been known for some time that tricyclic antidepressants increase the risk of myocardial infarction in patients with ischemic heart disease and should not be routinely used in these patients (8); selective serotonin reuptake inhibitors (SSRIs) should be used instead. The article by Cohen et al (9) in the current issue, if confirmed in other studies, has a far-reaching implication: it may be prudent to extend this practice to other patients. They observed more than a twofold increased risk of myocardial infarction in health plan members who received prescriptions for tricyclic agents compared with those with no antidepressant use. There was no such elevated risk for those using SSRI antidepressants. The elevated risk associated with tricyclic use does not necessarily imply that those drugs are cardiotoxic in patients without coronary disease. The greater risk is just as likely a result of the presence of depression in those who use tricyclic agents. This conclusion was shared by Pratt et al (4), who found that there was little effect of psychotropic medications on the risk of coronary disease after adjusting for depression. When viewed in this light, the message of the current study may be that SSRIs counteract the elevated risk resulting from depression, and tricyclic agents do not. Confidence in these findings is bolstered by their biological plausibility. For example, chronic stress could, over time, contribute to the initiation and progression of atherosclerosis by means of increased cardiac sympathetic input (10). The anticholinergic effects of tricyclic agents (11) could reduce the buffering by the parasympathetic nervous system of such stress-induced effects. Although the results of the study by Cohen et al are provocative, a number of caveats are necessary when interpreting them. As they note, the findings do not agree with those from several previous studies, perhaps because of limited follow-up and small sample sizes in prior studies. The study also has several limitations that result from the use of prescription records as the primary source of data. First, there was no way to know how many people taking antidepressant medications were initially free of heart disease. The authors did stratify by the use of heart medications and found a slightly smaller effect of medication among those who were not taking drugs for heart disease. This is a helpful analysis but not a completely satisfactory solution to the problem. Another issue has to do with the definition of antidepressant medication use, which was defined as ever having a prescription for antidepressants. This ignores the amount and duration of antidepressant usage, which would be necessary to establish a dose–response effect. Finally, there are no data on depression itself. Medication use may be a mediocre proxy for depression: a substantial proportion of people with depressive disorders do not seek professional help (12) and therefore do not take antidepressants. This limitation prevented the authors from estimating the independent effects of medication and underlying depression. Despite these problems, the results of this study call for intensified investigation of the cardiovascular risk associated with antidepressant use in community samples. Most important, they offer hope that treatment with SSRIs may mitigate the cardiovascular risk associated with depressive symptoms.