The multisite trial randomly assigned patients within three months of acute ischemic or hemorrhagic stroke to either a double-blind placebo-controlled comparison of escitalopram (n=59), with placebo (n=58), or a non-blinded problem-solving therapy group (n=59).
After 12 months, 22.4 percent of patients who received placebo developed a major or minor depression, compared to 11.9 percent of those who received problem-solving therapy (psychotherapy) (p<0.001) and 8.5 percent of those who received escitalopram (p<0.001). Those results were adjusted to include a history of mood disorders and remained significant after considering age, sex, treatment site, and severity of impairment.
After also controlling for history of mood disorders, escitalopram was superior to placebo (23.1 percent vs. 34.5 percent; p=0.007), while problem-solving therapy was no longer significantly better than placebo (30.5 percent vs. 34.5 percent; p=0.51). Adverse events, including all-cause hospitalizations, and sexual or other side effects previously associated with escitalopram did not significantly differ between the three groups.
A LINK TO MORTALITY?
A 1993 paper by Dr. Robinson and colleagues in the American Journal of Psychiatry found that after controlling for confounding variables, patients who had acute-onset depression after a stroke were at significantly increased risk of death in the following ten years (p=0.03). Another paper, published in 2001 in Stroke, found that the two-year risk of death was approximately doubled in patients who showed signs of depression (p=0.009).
Although the current paper reported no effects of treatment on mortality, a 2003 report by Dr. Robinson concluded that, whether or not a patient was depressed, those given fluoxetine (Prozac) or nortriptyline (Pamelor, Aventyl) for 12 weeks in the first six months after a stroke had about half the risk of dying within nine years of the stroke than those given placebo (35.7 percent compared to 67.9 percent), a significant difference even after controlling for confounding variables.
“We think these patients are dying because of the effect of depression on the heart — heart rate variability decreases when you're depressed and makes it more likely you'll have an arrhythmia,” Dr. Robinson said.
Antidepressants have also been hypothesized, in a 2003 paper in Science, to play a role in neuronal plasticity. But, according to Dr. Bartzokis, increasing brain levels of serotonin, dopamine and acetylcholine might also exert benefits beyond those on neurons alone. “The non-neuronal effects of these neurotransmitters may actually be beneficial to the repair process,” said Dr. Bartzokis. “More than half of serotonin and dopamine and more than 90 percent of acetylcholine are not released at classical synapses but are released at varicosities into extracellular space and no clear post-synaptic structures. They likely have secondary targets in the brain, in oligodendrocytes and astrocytes.”
Dr. Robinson cited a report by the US Preventive Services Task Force, published in the Annals of Internal Medicine in 2002, that found that physicians need only ask two questions to make an accurate diagnosis for depression poststroke: 1) Over the past two weeks, have you ever felt down, depressed, or hopeless? 2) Over the past two weeks, have you felt little interest or pleasure in doing things? These and longer sets of question can identify depression, he said.
“If the patient says, ‘No I'm not depressed, I'm sleeping all right, my appetite is okay,’ the likelihood they're having a depression is pretty low,” Dr. Robinson said.
Other randomized trials failed to show a preventive benefit in prescribing either mianserin (Tolvon) or sertraline (Zoloft) to post-stroke patients. Dr. Robinson speculated that the new trial's benefits may be attributed to the relatively young age of the patients (median age, 62), the larger sample size than in previous studies, the risk-benefit profile of escitalopram over that of other antidepressants, or the low doses used (10 mg per day in those aged 65 or older, and 20 mg in younger patients).
“These relatively low doses of escitalopram may have been particularly well-suited for this patient population,” the paper noted.
ARTICLE IN BRIEF
A new study suggests that a low-dose antidepressant escitalopram may prevent depression in patients who have had a stroke.
• Robinson RG, Jorge RE, Moser DJ, et al. Escitalopram and problem-solving therapy for prevention of poststroke depression: A randomized controlled trial. JAMA
• Astro M, Adolfsson R, Asplund K. Major depression in stroke patients: a 3-year longitudinal study. Stroke
• Berg A, Psych L, Palomaki H, et al. Poststroke depression — an 18-month follow-up. Stroke
• Morris PLP, Robinson RG, Price TR, et al. Association of depression with 10-year post-stroke mortality. Am J Psychiatry
• House A, Knapp P, Vail A, et al. Mortality at 12 and 24 months after stroke may be associated with depressive symptoms at 1 month. Stroke
• Jorge RE, Robinson RG, Starkstein SE, et al. Mortality and post-stroke depression: a placebo controlled trial of antidepressants. Am J Psychiatry
• Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science
©2008 American Academy of Neurology
• US Preventive Services Task Force. Screening for depression: Recommendations and rationale. Ann Int Med
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