Antidepressants May Be Linked to Increased Stroke Risk

Underlying Mechanisms Unclear, Researchers Say

Fran Lowry

March 16, 2011

March 16, 2011 — Antidepressant use may be associated with an increased risk for stroke, according to new research published online March 15 in the American Journal of Psychiatry.

Senior author Susan Shur-Fen Gau, MD, PhD, professor and chairperson of the department of psychiatry at National Taiwan University, Taiwan, said the results "lend evidence to support our hypothesis that acute exposure to antidepressants, particularly those with high inhibition of the serotonin transporter, increases the stroke risk," Dr. Gau told Medscape Medical News.

Depression is known to be an independent risk factor for stroke, but whether treating depression with antidepressants reverses this risk is not known, the study authors, led by Chi-Shin Wu, MD, from Far Eastern Memorial Hospital, Taipei, Taiwan, write.

Concerns about the cerebrovascular effects of antidepressants have increased since a growing body of evidence has shown that antidepressants — particularly selective serotonin reuptake inhibitors — may induce bleeding complications and vasoconstriction of the large cerebral arteries, the study authors note.

To shed more light on whether the risk for cerebrovascular events was associated with the use of antidepressant medications, Dr. Wu and coauthors conducted a case-crossover study of 24,214 patients with stroke who were enrolled in the National Health Insurance Research Database in Taiwan from 1998 to 2007.

"The case-crossover design is one method for examining the effect of transient exposures on acute outcomes. In this study design, each patient serves as his or her own control," they write.

The researchers compared rates of antidepressant use during case and control time windows of 7, 14, and 28 days.

The analysis showed that the mean age at stroke onset was 68.6 years (SD, 12.0). Nearly half (48.3%) of the study subjects were women, 36.3% had mood disorders, and 75.9% had ischemic strokes.

Fewer Prescriptions, Greater Risk

Antidepressant use in the 2 weeks before the stroke was associated with a 48% higher risk for stroke (95% confidence interval, 1.37 – 1.59). However, there was no association with the number of antidepressant prescriptions in the previous year, the study authors note.

In addition, there was no statistical association between antidepressant use in the 2 weeks before the stroke and stroke risk for patients with 3 to 5 prescriptions in the previous year.

However, patients who had more than 6 antidepressant prescriptions had a lower stroke risk and those who had 1 or 2 prescriptions had the greater stroke risk, the study authors report.

Use of antidepressants with high inhibition of the serotonin transporter was associated with a greater risk for stroke than use of other types of antidepressants.

"Our findings are compatible with those of studies showing that a high inhibition of the serotonin transporter has a more potent antiplatelet effect and is associated with a higher risk of abnormal bleeding in other organ systems," the investigators write.

They add that a surprising finding was that high-potency serotonin inhibitors were associated with a greater risk for ischemic stroke. They suggest "antidepressant-induced vasoconstriction" as a possible mechanism.

Paradoxical Finding?

Still, they point out, the use of low-potency inhibitors of the serotonin transporter is associated with an excess risk for any stroke type.

"Thus, other underlying mechanisms for stroke risk in relation to antidepressant use warrant further investigation," the study authors write.

They also found that long-term users of antidepressants may actually be protected against stroke, adding that the interpretation of such a finding is "not clear."

The investigators also note that the case-crossover design of the study means that the frequency of exposure to antidepressant medication changes over time and also that their results may have been influenced by the confounding factors of acute indications, such as abrupt emotional distress.

In addition, there are several limitations inherent in using claims databases, including an inability to accurately measure adherence.

Despite these limitations, the study authors conclude that their results have major clinical and public health implications.

They recommend starting antidepressants at low doses and monitoring for adverse effects, particularly in individuals at risk for cerebrovascular events, because the stroke risk appears to be dose related and noted in the first few prescriptions.

Contradictory Findings?

Commenting briefly on this study for Medscape Medical News, Lee H. Schwamm, MD, professor of neurology at Harvard Medical School, Boston, Massachusetts, and a spokesman for the American Academy of Neurology, said the study design was very complex and that certain aspects of the study appeared to be contradictory.

"They write that the use of an antithrombotic increased risk of stroke 2.6-fold but that multiple prescriptions for antidepressants decrease the risk. I also worry about unmeasured confounders," he said.

Dr. Gau reiterated the recommendation for close monitoring of patients newly started on antidepressant medication.

"We recommend starting antidepressants at low dosages and closely monitoring the side effects for initial prescriptions, particularly for individuals at risk for cerebrovascular events. These high-risk patients are advised to use other antidepressants than antidepressants with a high affinity for the serotonin transporter to treat their depression," she said.

Dr. Wu reports financial relationships with Eli Lilly and Astellas. Dr. Schwamm has disclosed no relevant financial relationships.

Am J Psychiatry. Published online March 15, 2011.

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