Antidepressant treatment for patients who have had a stroke, regardless of whether they are depressed, appears to increase their chances of living longer. Researchers found that treatment with fluoxetine or nortriptyline for 12 weeks during the first six months after a stroke significantly increased the survival of both depressed and nondepressed patients.

“This finding suggests that the pathophysiological processes determining the increased mortality risk associated with poststroke depression last longer than the depression itself and can be modified by antidepressants,” reported Ricardo E. Jorge, MD, Assistant Professor of Psychiatry at the University of Iowa, and colleagues. Their study appeared in the October issue of the American Journal of Psychiatry.

Previous research has shown that patients with poststroke depression were 3.5 times more likely to die during 10 years of follow-up than were patients without depression. In addition, approximately one in five people who have a stroke will develop major depression, while another one in five survivors will have less severe depression. “Given the relationship between poststroke depression and mortality, one would obviously question whether adequate antidepressant treatment would reduce long-term mortality,” Dr. Jorge told NEUROLOGY REVIEWS. “Our present findings suggest that patients who receive antidepressant medication after an index stroke would have significantly better long-term survival than would patients who do not receive antidepressants. In addition, preventing the development of depression, which occurred in 49% of [initially] nondepressed patients over two years, through the use of antidepressants may have such a profoundly significant effect on patient outcome that it justifies the administration of antidepressants even among the nondepressed.”

STROKE, ANTIDEPRESSANTS, AND MORTALITY

The study involved 104 patients who were randomly assigned to receive nortriptyline, fluoxetine, or placebo early in the recovery period after a stroke. Mortality data were obtained for all patients nine years after the study began. Demographic and clinical measurements were collected at three, six, nine, 12, 18, and 24 months after the stroke. By the end of the nine-year follow-up, 50 patients (48%) had died. About half the patients (27 of 53) who received antidepressants were depressed at the start of the study, and 13 of 28 patients (46%) who received placebo were depressed at baseline. Twenty-three patients did not complete their initial assignment to take either one of the antidepressants or the placebo for 12 weeks.

Dr. Jorge and colleagues found that 36 of 53 patients (68%) who received all 12 weeks of antidepressant treatment were alive after nine years, compared with 10 of 28 patients (36%) who received 12 weeks of placebo. Analysis of the causes of death revealed that patients who received antidepressants were less likely to die from cardiovascular problems than were patients who did not receive antidepressants. Thirty percent of the patients, depressed or not, who received antidepressants and died within nine years died from cardiovascular causes. In comparison, nearly 55% of patients who did not receive adequate antidepressant therapy and died during the same period died from cardiovascular causes.

Dr. Jorge theorized that antidepressants may provide protective effects in several ways, both behaviorally and physiologically. For one, he said, depressed patients may not comply with treatments. For example, a person who is depressed after a stroke and has diabetes may poorly control the diabetes by failing to eat properly and not taking his or her medications. Meanwhile, a nondepressed person with diabetes may be more attentive to these important self-care measures. Depression also may be associated with changes in platelet function, and there is evidence that depression can affect blood pressure and heart rate, making depressed patients prone to heart attacks. “Antidepressants may modify the way a person reacts to stress and, thus, reduce the frequency of these complications,” he said.

TARGETING POSTSTROKE DEPRESSION

Dr. Jorge emphasized that patients who develop poststroke depression need to be identified and treated to improve their cognitive and functional outcome. “The evidence supporting antidepressant use among nondepressed patients is certainly preliminary and needs to be replicated in large-scale studies,” he said. “Meanwhile, I would suggest that stroke patients without depression should be carefully assessed and given antidepressants if they are at high risk for developing depressive disorders, such as family or personal history of mood disorders, poor social support network, prefrontal lesions, etc.” One limitation of the study, he pointed out, is that the participants were primarily white, which may mean that the findings are not applicable to other groups of patients who have a stroke.

Before considering prophylactic treatment with antidepressant medication for a prolonged period, physicians must address the risk/benefit relationship of this therapeutic strategy, according to Dr. Jorge. “Are we exposing these patients to an increased risk of medical complications?” he asked. “If so, is this increased risk substantially minor when compared with the benefits derived from prevention of the occurrence of depressive disorders?”

The investigators have examined the available evidence on the administration of both tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) among patients with stroke and their relationship to medical complications or significant side effects during treatment. “As one might expect,” said Dr. Jorge, “the complication rate with tricyclic antidepressants was more than two times the rate with SSRIs. But the rate of complications was not significantly higher in the patients treated with tricyclics or other newer antidepressants compared with patients treated with placebo. Pharmacogenetic studies—for example, analyzing CYP2D6 polymorphisms—would be extremely important to identify those patients who are at greater risk of developing side effects.”

Dr. Jorge noted that the incidence of stroke in Western societies has been relatively stable for the past few years because of the prevention and control of conditions such as hypertension and other cardiovascular risk factors. However, he asserted that as the population in the United States ages, the total number of strokes will eventually increase, requiring a renewed effort in implementing primary and secondary prevention strategies.

Currently, Robert G. Robinson, MD, Head of the Department of Psychiatry at the University of Iowa, and Dr. Jorge are conducting a randomized, parallel-group, double-blind study of the efficacy of S-citalopram versus placebo to prevent the onset of depression in patients who have had a stroke.

—Colby Stong

Suggested Reading
Jorge RE, Robinson RG, Arndt S, Starkstein S. Mortality and poststroke depression: a placebo-controlled trial of antidepressants. Am J Psychiatry. 2003;160:1823-1829.
Morris PL, Robinson RG, Andrzejewski P, et al. Association of depression with 10-year poststroke mortality. Am J Psychiatry. 1993;150:124-129.

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