Stroke patients randomized to receive a low daily dose of the antidepressant escitalopram (Lexapro) for one year were significantly less likely to become depressed than those randomized to receive either a placebo or psychosocial therapy, according to a study published in the May 28 Journal of the American Medical Association.
Studies have shown that depression occurs in more than one-third of patients within a year after a stroke. The new findings, if replicated, suggest that escitalopram could be prescribed prophylactically post-stroke, in the same way that statins are prescribed by cardiologists after a heart attack, said the first author of the study, Robert Robinson MD, professor and chair of psychiatry at the University of Iowa.
George Bartzokis, MD, professor of neurology at the University of California, Los Angeles, who was not involved with the study, said: “I tend to be conservative in my therapeutic approach. But if there are one or two more studies like this, I would be very much in favor of it. The safety of these drugs is remarkable.”
For now, Dr. Bartzokis and others said, neurologists should be more diligent in assessing for the disorder in their stroke patients and offering treatment when appropriate.
“The results of this study are fairly dramatic,” said Eric E. Smith, MD, associate director of acute stroke services at Massachusetts General Hospital and assistant professor of neurology at Harvard Medical School. “Of course, it's only one study; it would be nice to have confirmatory studies. But in my practice, I'm going to be a little more careful in screening people who might be at high risk and would tend to treat them with a drug such as escitalopram with a lower threshold than before.”
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
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• Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science
• US Preventive Services Task Force. Screening for depression: Recommendations and rationale. Ann Int Med