SSRIs Risky After Intracerebral Hemorrhage

Megan Brooks

September 02, 2020

Selective serotonin reuptake inhibitors (SSRIs) effectively treat depression following intracerebral hemorrhage (ICH) but also increase risk for recurrent hemorrhagic stroke, particularly in patients at high risk for repeat ICH, new research indicates.

"Clinicians must exercise judgement when weighing the use of SSRIs for ICH survivors in the high risk category — especially those with multiple ICH events," study investigator Alessandro Biffi, MD, director, Aging and Brain Health Research (ABHR) Group, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, told Medscape Medical News.

The study was published online August 31 in JAMA Neurology.

Risks and Benefits

Depression is common following stroke. SSRIs are generally considered first-line treatment for post-stroke depression but are associated with increased risk for first ICH, most likely owing to their antithrombotic effects. Less is known about SSRI use and recurrent ICH risk.

To investigate, Biffi and colleagues followed 1279 adults (mean age, 71.3 years) for a median of 53.2 months (4.5 years) following primary ICH; 602 were women, 1049 were White, 89 Black, 77 Hispanic, and 64 were other race/ethnicity. 

During follow-up, 128 adults suffered recurrent ICH (annual rate, 4.2%) and 766 (60%) were diagnosed with depression.

In multivariable analyses, SSRIs were associated with an increased likelihood of post-ICH depression remission (subhazard ratio [SHR], 1.53; 95% CI, 1.12 - 2.09; P = .009).

However, SSRI use was also an independent risk factor for recurrent ICH (SHR, 1.31; 95% CI, 1.08 - 1.59; P = .006).

High SSRI dose was associated with higher ICH recurrence risk (SHR, 1.61; 95% CI, 1.15 - 2.25), with a larger effect size (comparison P = .02) than low SSRI dose (SHR, 1.25; 95% CI, 1.01 - 1.55), but there was no difference in depression remission comparing low vs high SSRI dose.

Among individuals at high risk for recurrent ICH, SSRI use was associated with further increased risk for ICH recurrence (SHR, 1.79; 95% CI, 1.22 - 2.64) compared with all other survivors of ICH (SHR, 1.20; 95% CI, 1.01 - 1.42; P = .008 for comparison of effect sizes). 

These higher-risk subgroups included carriers of the APOE ε2/ε4 alleles, patients with lobar ICH, patients with prior ICH, and minority participants.

"Our analyses identified patients for whom the risks are higher, and therefore additional thought is warranted. This approach may in the future lead to personalized/precision medicine approaches to determining whether these patients should receive SSRIs or not," said Biffi.

Experts Weigh In

Commenting on the research for Medscape Medical News, Daniel G. Hackam, MD, Division of Clinical Pharmacology, Western University, London, Ontario, Canada, said the study is "an important contribution to the literature, as there are to date no data on the risk of ICH in prior ICH survivors in relation to SSRI exposure."

"The bottom line is that I would be very cautious about initiating SSRIs in patients with a history of ICH," said Hackam, who was not involved with the study.

"There are other nonserotonergic antidepressants that could be used instead, which do not inhibit platelet function. There was still a risk even in the lower-risk ICH survivors. ICH is a highly recurrent disease. We already avoid antiplatelets, anticoagulants, and high dose statins in these patients. I would add SSRI's to that list, based on this study," said Hackam.

Also weighing in, Amytis Towfighi, MD, associate professor of neurology, Keck School of Medicine, University of Southern California, Los Angeles, said this study addresses a "common clinical dilemma: how to manage depression among individuals with ICH, given the high risk of recurrent ICH among ICH survivors and potential for SSRIs to increase that risk. This scenario is common, and a source of debate for practicing clinicians."

"The authors conducted an elegant study," said Towfighi, by considering sociodemographic, historical, imaging, and genetic factors.

"One must interpret this study with caution as it is a single-center cohort study. However, it provides the most rigorous information to date regarding the associations between SSRI use and recurrent ICH," she told Medscape Medical News.

The study was supported by the National Institutes of Health. Biffi, Hackam, and Towfighi have disclosed no relevant financial relationships.

JAMA Neurology. Published August 31, 2020. Abstract

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