FORT MYERS, FLA—Successful treatment of poststroke depression may partially reverse the cognitive impairment often seen in stroke patients and may even delay or prevent poststroke dementia, according to a series of new studies. The findings, reported in part at the 11th Annual Meeting of the American Neuropsychiatric Association (ANPA), not only lend new urgency to the importance of treating poststroke depression but may help resolve a crucial question: Does cognitive impairment lead to depression in stroke survivors, or does depression cause the cognitive impairment?

"This is the first time somebody has been able to show in a controlled trial that treatment of poststroke depression has a significant impact on cognitive function," said Robert G. Robinson, MD, who coauthored the studies. "There are very few things we know to do to improve on the natural course of recovery from stroke and the usual process of rehabilitation therapy. Thus, the recognition and treatment of depression could really [improve] the recovery of patients with stroke, and that is quite an advance."

WHICH COMES FIRST?

Numerous studies have shown that depression and cognitive difficulties are common in the months following stroke. A report published in the March 14 issue of Neurology,for example, found that 26% of ischemic stroke patients met criteria for dementia three months after their stroke. Meanwhile, two separate studies reported in February at the American Stroke Association's 25th International Stroke Conference found that depression occurred in approximately 40% of patients with ischemic stroke or subarachnoid hemorrhage.

Although researchers have long known that cognitive impairment and depression are associated in the elderly, a corresponding relationship in stroke patients was only identified in 1986. But the issue of causality has remained controversial.

"One of the questions I've always had is whether the depression and cognitive impairment are parallel," said Dr. Robinson, who is professor and chairman of the Department of Psychiatry at the University of Iowa. "Intuitively, it seems that the pathophysiologic mechanism that would lead to cognitive impairment should be different from the mechanism that leads to depression."

Nonetheless, some researchers have argued that poststroke depression is the cause of the cognitive impairment. Other experts, noting that several clinical trials have failed to show that antidepressants improve cognitive function in stroke patients, have endorsed the view that cognitive impairment precipitates poststroke depression.

IMPROVED COGNITION—BUT ONLY IN RESPONDERS

The new studies, plus a third report presented at the ANPA meeting, may finally resolve the issue. In one study, led by Nippon Medical School neuropsychiatrist Mahito Kimura, MD, in collaboration with Dr. Robinson, researchers combined and reanalyzed data from two earlier trials in which patients with hemorrhagic or thromboembolic stroke were randomized to either nortriptyline or placebo. In one trial, patients were treated for six weeks with a regimen in which the nortriptyline dose was gradually increased from 20 to 100 mg/d; in the second trial, nortriptyline recipients received similar doses over 12 weeks. All subjects underwent extensive neurologic and psychiatric examinations; depression and cognitive impairment were assessed using the Hamilton Rating Scale for Depression (HAM-D) and the Mini-Mental State Examination (MMSE), respectively. The final study population included 47 patients with major (n = 33) or minor (n = 14) depression.

Depression levels were assessed at two- or three-week intervals. Patients in the nortriptyline group improved more rapidly than did placebo recipients; response rates were 76% and 31%, respectively, by the end of the trials. However, there was no difference in cognitive improvement between the two groups—a finding that seemed to mirror the failure of prior treatment trials.

The results were very different, though, when the researchers assessed the data according to whether patients responded to treatment. Planned comparisons revealed that the 24 responders (16 nortriptyline, 8 placebo) had significantly less cognitive impairment at the end of the trial than did the 23 patients (5 nortriptyline, 18 placebo) who were still depressed. The key factor, in other words, was not whether subjects received the drug but whether their depression improved. Even within the placebo group, patients whose depression improved had higher MMSE scores.

While the study only examined a single medication, "any treatment method that improves mood should improve cognitive function," Dr. Kimura and colleagues speculated in the paper, which is currently in peer review. "Treatment of depression may constitute one of the major methods of improving cognitive recovery in victims of stroke."

WHAT ABOUT DEMENTIA?

Those conclusions were bolstered by a second double-blind treatment trial, reported at the ANPA meeting by University of Iowa psychiatrist Ricardo Jorge, MD, in which dementia and depression were assessed in 55 stroke patients who had completed a 12-week course of nortriptyline, fluoxetine, or placebo. All patients underwent comprehensive examinations upon entry; in addition to measures of stroke severity and functional impairment, the evaluation included a semistructured psychiatric interview, the HAM-D, and the Hamilton Anxiety Rating Scale. Follow-up neuropsychologic evaluations were conducted three months later; dementia was diagnosed according to DSM-IV criteria.

At follow-up, 15 patients (27%) met criteria for dementia; the diagnosis was especially common among subjects with severe strokes or low socioeconomic status. Depression was significantly more common in patients with dementia, a finding consistent with the cognitive impairment trial.

The most striking finding, however, was that 12 of the 30 placebo recipients (40%) but only three of the 25 patients receiving antidepressants (12%) had dementia at follow-up. The difference remained significant after the researchers controlled for stroke severity, education, and socioeconomic status.

Prior studies of cognitive impairment in poststroke depression have used such terms as pseudodementia to describe patients' deficits. The new study, Dr. Robinson said, "suggests there are in fact dementias associated with depressive disorders and that they improve with improvement of mood."

THE EVIDENCE BUILDS…

The question of whether poststroke depression leads to cognitive impairment, rather than vice versa, was the focus of a third report from Dr. Robinson's group. In this study, led by Yuichi Murata, MD, the researchers examined cognitive recovery in patients with (n = 41) or without (n = 135) poststroke depression at baseline. Because the study was observational, patients did not receive therapy, although approximately 20% sought treatment elsewhere. Subjects were classified as having improved mood if their HAM-D scores had decreased by at least 50% after three to six months; cognitive impairment was measured using the MMSE.

The findings, reported at the ANPA meeting and scheduled for publication in the American Journal of Geriatric Psychiatry,revealed that among patients who were depressed at baseline, those whose mood had improved at follow-up "had significantly greater recovery in cognitive function than patients whose mood did not improve," the researchers reported. If cognitive impairment were the cause of poststroke depression, reducing depressive symptoms would not be expected to improve cognitive impairment because the lesions causing those deficits would remain. "These findings suggest that cognitive impairment is not a major cause of depression," Dr. Murata and colleagues concluded.

HOW SHOULD POSTSTROKE DEPRESSION BE TREATED?

While the new findings strongly support the aggressive treatment of poststroke depression, it remains unclear which therapies are best suited for this population. Prior to the new studies, only a few trials had assessed treatment of poststroke depression; evidence suggests that nortriptyline, trazodone, and citalopram may have efficacy.

However, in a recent study that was the first to compare the relative benefits of a tricyclic antidepressant and a selective serotonin reuptake inhibitor in poststroke depression, Dr. Robinson found substantial differences between the two drugs. Treatment with nortriptyline for 12 weeks yielded benefits in 63% to 77% of subjects, depending on the type of analysis used; response rates for fluoxetine, however, were no better than for placebo. "Treatment response to fluoxetine may have been more marked in a more severely depressed patient group," Dr. Robinson suggested, noting that most patients had only mild to moderate depression. The study was published in the March issue of the American Journal of Psychiatry.

Prior studies have reported improvements in poststroke depression using other modalities, such as electroconvulsive and psychologic therapy; but these studies were not controlled. Dr. Robinson's group is currently testing the efficacy of transcranial magnetic stimulation. While there is no reason to suspect that the technique will not prove effective in this setting, "we wouldn't have suspected that fluoxetine wouldn't work," Dr. Robinson noted.

—Peter Doskoch

Suggested Reading
1. Murata Y, Kimura M, Robinson RG. Does cognitive impairment cause poststroke depression? Am J Geriatr Psychiatry.In press.
2. Robinson RG, Schultz SK, Castillo C, et al. Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study. Am J Psychiatry.2000;157:351-359.

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