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Selective Serotonin Reuptake Inhibitor Exposure Is Associated with Greater Risk of Recurrent Hemorrhagic Stroke

Article In Brief

Selective serotonin reuptake inhibitor use following intracerebral hemorrhage was associated with fewer depressive symptoms and an increased risk of recurrent hemorrhagic stroke.

Patients treated with selective serotonin reuptake inhibitors (SSRIs) for post-stroke depression following intracerebral hemorrhage (ICH) had fewer depressive symptoms but also have an increased risk of recurrent hemorrhagic stroke, according to a longitudinal cohort study published online on August 31 in JAMA Neurology.

SSRIs are generally considered first-line therapies for depression after stroke, the study authors noted, but they are also known to be associated with first-ever ICH risk. A dearth of research is available, however, on the associated risk of SSRIs and recurrent ICH risk. Consequently, clinicians have limited insight into the potential risks and benefits of SSRI use after ICH.

To study the problem, investigators at the Massachusetts General Hospital analyzed data from ICH survivors involved in the single center study between January 2006 and December 2017. A review of the data and medical records revealed that SSRIs were associated with a decrease in both post-ICH depression as indicated by a subhazard ratio (SHR) of 1.53 (95% CI 1.12-2.09) and ICH recurrence as indicated by an SHR of 1.31 (95% CI 1.08-1.59).

Other data showed that among patients at high risk for recurrent ICH, SSRIs were associated with increased risk of 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).

Notably, the incidence of depression after ICH was high, said the senior study author Alessandro Biffi, MD, the director of the Aging & Brain Health Research Group and assistant professor of neurology at Massachusetts General Hospital and Harvard Medical School in Boston.

“We may have suspected that based on how disabling of an event it is, but this is also one of the largest dedicated studies of depression after ICH and really paints a very stark picture of the risk of developing depression and also how resistant the treatment of depression after ICH appears to be.”

The study authors assessed the associations between SSRI exposure and study outcomes among ICH survivors at low and high risk of recurrent hemorrhagic stroke, they noted. The association between SSRI use and ICH recurrence had a larger effect size among certain groups at higher risk for recurrent hemorrhagic stroke—patients with lobar ICH, carriers of the APOE e2/e4 alleles, minority participants, and those with prior ICH, they added.

“SSRIs are generally well-tolerated in post-stroke patients. They've been used safely in a number of studies and by the clinical community, so I would not subscribe to the idea that SSRIs shouldn't be used in post-stroke patients.”

—DR. GARY ABRAMS

“I think that the most direct clinical implication is that there is a certain group of ICH survivors that do not benefit more from SSRI and have an increased risk for ICH recurrence. Compared to everyone else, for them, the negative effects of SSRIs are more substantial, and in particular, these are patients who had multiple prior hemorrhages before as well as other patients with high-risk features,” Dr. Biffi said.

“So, where possible, it may be reasonable clinically for providers to think about different agents for the treatment of depression in these patients because they may be at higher risk for recurrent hemorrhage, not increased benefits in terms of depression control. So, the overall benefit to risk balance may not be favorable,” Dr. Biffi told Neurology Today.

Study Findings, Results

The researchers reviewed data on 1,279 patients who survived the primary ICH; of that group, 281 participants survivors were prescribed SSRIs—including fluoxetine, sertraline, paroxetine, escitalopram, fluvoxamine, citalopram, volazodone, and vortioxetine—following an ICH.

The researchers contacted the participants and/or their surrogates at three and six months after the index ICH and every six months after that. They also administered various scales to measure post-stroke disability, activities of daily living, depression and reviewed their electronic medical records.

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“It may be reasonable clinically for providers to think about different agents for the treatment of depression in these patients because they may be at higher risk for recurrent hemorrhage, not increased benefits in terms of depression control. So, the overall benefit to risk balance may not be favorable.”—DR. ALESSANDRO BIFFI

The research team excluded participants presenting with secondary ICH as a result of a demyelinating lesion, infection, intracranial tumor, transformation of ischemic infarct, ruptured aneurysm, trauma, or other vascular abnormalities.

The relationship between decreased depressive symptoms and SSRI were comparable between patients at high risk for recurrent ICH and all ICH survivors, they added. No individual SSRI had significantly different effects for the association with either ICH recurrence or post-ICH depression emission. But high-dose SSRIs were associated with higher ICH risk, with a larger effect size (p=0.02) than low-dose SSRIs.

“I was not necessarily expecting higher risk features like clinical imaging and genetic information, to have so much potential in identifying a high-risk individual. I was thinking they would make a small difference that may not be relevant clinically. However, they actually do seem to be something that we may be able to formally leverage in the future to predict risk for individuals if they are exposed to SSRIs,” said Dr. Biffi.

Expert Commentary

The 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, said Amytis Towfighi, MD, chief of neurology and associate medical director of neurological services at the University of Southern California Medical Center.

“This scenario is common, and a source of debate for practicing clinicians,” she said.

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“Cognitive-behavioral therapy and counseling are therapy options besides medication, so I think counseling is a very big part of the treatment. It should not just be solely medication.”—DR. ALEJANDRO VARGAS

“Patients with ICH are prone to developing depression, with as many as 50 percent developing depression at some point after their stroke. Yet SSRIs—the most commonly used class of medications for depression—have been associated with risk of intracerebral hemorrhage in those without a history of ICH,” Dr. Towfighi added.

These findings suggest “clinicians should be cautious about high dose SSRIs, particularly when treating individuals with high-risk ICH,” Dr. Towfighi told Neurology Today.

“One must interpret this study with caution as it is a single-center observational cohort study and not a randomized controlled trial; however, it provides the most rigorous information to date regarding the associations between SSRI use and recurrent ICH,” Dr. Towfighi added.

There has been a lot of suspicion that SSRIs might increase the risk of ICH, noted Gary Abrams, MD, a professor of neurology at the University of California, San Francisco.

“There's been some debate that's gone on over the years. I think some people think it raises the risk, but the risk is not necessarily significant that would preclude someone from using SSRIs and just any person who happens to need an SSRI for treatment of depression,” Dr. Abrams said.

“In situations where there may be an elevated risk of hemorrhage, I think there's some reasonable concerns about using SSRIs given what we know about them and their effect on ICH. I think this particular paper adds to that concern.”

Using SSRIs might be a little risky for the types of cases outlined in this paper, even though they may have an important role in treating post-stroke depression, noted Dr. Abrams.

“SSRIs are generally well-tolerated in post-stroke patients. They've been used safely in a number of studies and by the clinical community, so I would not subscribe to the idea that SSRIs shouldn't be used in post-stroke patients,” Dr. Abrams continued.

But medication is only one treatment option for depression, said Alejandro Vargas, MD, MS, an assistant professor in the department of neurological sciences at Rush University Medical Center in Chicago, IL. “Cognitive-behavioral therapy and counseling are therapy options besides medication, so I think counseling is a very big part of the treatment. It should not just be solely medication.”

Figure

“One must interpret this study with caution as it is a single-center observational cohort study and not a randomized controlled trial; however, it provides the most rigorous information to date regarding the associations between SSRI use and recurrent ICH.”—DR. AMYTIS TOWFIGHI

“SSRIs, in a way, are double-edged. We do know that they do increase this bleeding risk, and they could be not just the medication alone, but a combination of other factors. But [in this study], it helped resolve a lot of depressive symptoms in their patient population. So, I do think the dual nature of some benefit with increased risk of some complications is surprising,” Dr. Vargas added.

Disclosures

Dr. Biffi disclosed that he received grants from the National Institutes of Health while doing the investigation. Drs. Vargas, Towfighi, and Abrams did not report any disclosures.

Link Up for More Information

• Kubiszewski P, Sugita L, Kourkouli C, et al. Association of selective serotonin reuptake inhibitor use after intracerebral hemorrhage with hemorrhage recurrence and depression severity https://jamanetwork.com/journals/jamaneurology/article-abstract/2770031. JAMA Neurol 2020; Epub 2020 Aug 31.