Antidepressant Use Linked to Increased Brain Bleed Risk

Nancy A. Melville

January 12, 2016

Use of antidepressants is linked to an increased risk for the development of first-time cerebral microbleeds, results of a longitudinal study show.

"In this population-based study, we found that antidepressant use was associated with an increased risk of incident first-ever microbleeds after 4 years of follow-up," the authors, led by Bruno H. Stricker, MMed, PhD, Erasmus University Medical Center, in Rotterdam, the Netherlands, write.

"Associations were similar for different categories of antidepressants users, and persisted after adjusting for depressive symptoms and cardiovascular risk," they add.

The study was published online December 15 in Stroke.

Reverse Causality?

In previous research, the same investigators found no association between use of antidepressants that have high serotonin affinity and subclinical microbleeds. However, the authors concluded that the study was limited by its cross-sectional design.

The new research took a longitudinal approach, evaluating 2550 participants aged 45 years or older who were without a history of microbleeds at baseline in the population-based Rotterdam study. The median age of the participants was 58.7 years, and 54.8% were women.

On the basis of brain MRI taken at baseline and at a mean interval of 3.9 years between 2005 and 2013, the overall incidence of cerebral microbleeds was determined to be 3.7%.

The use of antidepressants was found to be associated with a higher odds ratio (OR) of having a cerebral microbleed than not using antidepressants (OR, 2.22; 95% confidence interval [CI], 1.31 - 3.76). Use of selective serotonin reuptake inhibitors (SSRIs) was associated with an increased risk that was similar to that for patients who did not receive SSRIs (OR, 2.27, 2.28, respectively).

In categorizing antidepressants according to affinity for the serotonin transporter, use of antidepressants that had intermediate serotonin affinity was associated with the highest risk for microbleeds (OR, 3.07; 95% CI, 1.53 - 6.17). Results regarding high serotonin affinity did not reach statistical significance (OR, 2.18; 95% CI, 0.90 - 5.29).

The results remained consistent after adjusting for cardiovascular risk factors. Nonsignificant differences were seen after adjusting for duration and dose of antidepressant treatment.

"These findings are in line with previous cross-sectional results from other studies, although our study is the first to describe a temporal association between antidepressants and subclinical cerebral hemorrhages," the authors note.

The increased risk for microbleeds with SSRIs is speculated to be linked to a mechanism similar to that of antiplatelet drugs, in which SSRIs "block the reuptake of serotonin by platelets and decrease serotonin platelet concentration, which may lead to impaired aggregation and prolonged bleeding times," the authors add.

However, the finding that the risk for microbleeds is similar with SSRIs and non-SSRIs suggests that the affinity of the serotonin transporter may not play a role, and another unidentified mechanism may explain the effect.

The authors add that an important consideration is the possibility of a "reverse causality," in which the microbleed itself leads to antidepressant use.

"Biologically it has been hypothesized that microbleeds may contribute to the progression of depression," they write.

The findings nevertheless suggest that caution be exercised in the treatment of depression in patients who might be at risk for microbleeds, Dr Stricker told Medscape Medical News.

"[Clinicians should] be careful with prescribing antidepressants, especially to frail elderly," he said.

Longitudinal Look

Commenting on the findings for Medscape Medical News, Daniel G. Hackam, MD, Division of Clinical Pharmacology, Department of Medicine, Western University, London, Ontario, Canada, who wrote a previous meta-analysis on the role of SSRIs in brain hemorrhage, described the study's longitudinal look at a community sample as "unique."

"This is the first prospective, longitudinal, associative study linking antidepressant exposure to microbleeds. Therefore, the results are eagerly anticipated," Dr Hackam said.

The study’s finding of no significant differences in risk between antidepressant categories was especially notable, he said.

"This is quite surprising and a little troubling. One would have expected to see a much stronger risk for SSRIs than for non-SSRIs, given the putative mechanism underlying the association between antidepressants and bleeding.

"The fact that both SSRIs and non-SSRI antidepressants were associated with bleeding suggests that we either have the mechanism wrong or there is confounding at play," Dr Hackam said.

Weigh Risk/Benefit

Richard Morriss, MD, professor of psychiatry and community mental health at the University of Nottingham, United Kingdom, who has also published several studies on the role of antidepressants in intracranial bleeds, agreed that the new study leaves open the question of whether the increased risk for microbleeds is linked to the antidepressant use or the depression itself, as has been suggested in some studies.

He added, "There is also no certainty that a prescription of an antidepressant meant that people actually took the drug.

"My overall take on this is that elderly people may already have a number of risk factors for hemorrhagic stroke, such as other medical conditions that they may or may not be aware of or medications that increase the risk of cerebral bleeding," Dr Morriss told Medscape Medical News.

"In such patients, the additional risk of cerebral bleeding with antidepressants with serotonergic activity may precipitate symptomatic cerebral bleeding, such as transient ischemic attacks or strokes."

With such concerns in mind, clinicians should weigh the benefits of antidepressant treatment with the possible risks, Dr Morriss added.

"In my view, caution needs to be exercised in the use of antidepressants with serotonergic activity for managing depression if people have multiple risk factors for cerebral bleeds. Antidepressants with relatively low serotonergic activity, such as desipramine or psychological treatment, might be used instead."

The study received funding from the Netherlands Organization for Health Research and Development (ZonMW) Priority Medicines Elderly program and from a ZonMW clinical fellowship. The authors, Dr Hackam, and Dr Morriss had disclosed no relevant financial relationships.

Stroke. Published online December 10, 2015. Abstract


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