New Data on Antidepressants and Stroke Risk

Damian McNamara

August 12, 2019

Use of antidepressants that strongly inhibit serotonin is associated with a somewhat lower risk for ischemic stroke compared to agents that weakly inhibit the neurotransmitter, results of a large, population-based study suggest.

Investigators found a 12% reduced risk for ischemic stroke among study participants who were currently taking a stronger selective serotonin-reuptake inhibitor (SSRI) or third-generation antidepressant compared to those taking a weaker inhibitor of serotonin.

"Use of strong inhibitors of serotonin reuptake may be associated with a small decreased risk of ischemic stroke without affecting the risk of myocardial infarction [MI]," study investigator Christel Renoux, MD, PhD, assistant professor in the Department of Neurology and Neurosurgery at McGill University and the Jewish General Hospital – Lady Davis Research Institute in Montreal, Canada, told Medscape Medical News.

The study was published online August 7 in Neurology.

CV Safety an Ongoing Concern

In the general population, depression and cardiovascular disease are often comorbid. This comorbidity means antidepressants are commonly prescribed to patients who are at increased risk for ischemia. The investigators also point out that "the cardiovascular safety of these drugs has been an ongoing concern."

Evaluating antidepressants beyond drug class may make sense in the assessment of cardiovascular effects, specifically, the affinity of individual agents for the serotonin-reuptake transporter.

Inhibition of serotonin transport into thrombocytes can interfere with their function, the researchers explain, "and antidepressants strongly inhibiting serotonin reuptake have been associated with an increased risk of major bleeding such as gastrointestinal bleeding and intracranial hemorrhage.

"Thus, it has also been hypothesized that strong inhibitors may conversely reduce the risk of arterial ischemic events," they note.

Although this is not the first study to assess a link between antidepressants and stroke/MI risk, most previous work featured "several methodologic limitations such as choice of inappropriate study design, absence of an active comparator, important residual confounding, or selection bias," the investigators write.

In search of a more definitive answer, the investigators conducted a retrospective cohort study with matched case controls. They identified 868,755 adults who had been newly prescribed an SSRI and another 69,633 who were taking a third-generation antidepressant between January 1, 1995, and June 30, 2014. Of the total cohort, 64% were women.

Using the UK Clinical Practice Research Datalink database, Renoux and colleagues evaluated outcomes according to use of antidepressants by degree of their inhibition of serotonin-reuptake inhibition.

Duloxetine, fluoxetine, paroxetine, and sertraline were strong inhibitors; citalopram, escitalopram, fluvoxamine, and venlafaxine were classified as intermediate inhibitors; and mianserin, mirtazapine, nefazodone, reboxetine, agomelatine, and viloxazine were weak inhibitors.

During a mean 5.7 years of follow-up, 15,860 individuals were diagnosed with ischemic stroke or a transient ischemic attack (TIA). This translated to a crude incidence rate of 31.1 per 10,000 persons per year (95% confidence interval [CI], 30.6 – 31.6).

Unexpected Finding

Current use of one of the strong inhibitors of serotonin reuptake was associated with a decreased rate of ischemic stroke/TIA (relative risk [RR], 0.88; 95% CI, 0.80 – 0.97) compared to weak inhibitors of serotonin reuptake.

In addition, the decrease was more prominent when the duration of use was between 61 and 180 days (RR, 0.84; 95% CI, 0.72 – 0.97).

The associations held when researchers adjusted for potential confounders in a multivariable analysis. They controlled for obesity, smoking status, alcohol abuse, arterial hypertension, atrial fibrillation, congestive heart failure, and other factors.

However, there was a caveat. The effect size was small in some sensitivity analyses, and the results should not guide therapy decisions at this point, Renoux said.

"The choice of a particular antidepressant treatment should be based primarily on the expected benefits and adverse events, rather than the risk of arterial ischemic events," she said.

During follow-up, 8626 patients had an MI, yielding a crude incidence rate of 16.7 per 10,000 persons per year (95% CI, 16.3 – 17.0). Unlike stroke risk, however, the rates of MI between strong and weak inhibitors of serotonin were similar (RR; 1.00, 95% CI, 0.87 – 1.15).

"We were expecting no increased risk of stroke or myocardial infarction with antidepressants that are strong serotonin reuptake inhibitors, or a small decreased risk, compared with weak inhibitors," Renoux said. "However, we were a bit surprised that our results suggest a small decreased risk for stroke — but not for myocardial infarction."

In a second analysis, the researchers compared only the SSRI antidepressants. Because no SSRIs weakly inhibit serotonin, it became a comparison between strong and intermediate inhibitors.

They found the ischemic stroke/TIA rates were similar between strong and intermediate SSRIs (hazard ratio, 0.98; 95% CI 0.92 – 1.04) overall or by duration of use.

In contrast, the same comparison revealed a "borderline increased rate" of MI associated with strong SSRIs compared to intermediate SSRIs (RR, 1.09; 95% CI 1.00 – 1.18). Again, the effect was more apparent when the duration of use was between 61 and 180 days (RR 1.17; 95% CI, 1.02 – 1.34).

Perhaps not surprisingly, the risk was further elevated among patients who had a history of cardiovascular disease (RR, 1.46, 95% CI, 1.01 – 2.11).

Antiplatelet Effect

"The modestly decreased rate of ischemic stroke is in line with our study hypothesis and congruent with the proposed antiplatelet effects of serotonin reuptake inhibition," the researchers note.

"Of note, the modest effect size in the primary analysis seems pharmacologically plausible given that acetylsalicylic acid, the antiplatelet agent currently recommended as first-line treatment for the prevention of ischemic stroke, has been shown to reduce the risk by no more than 30%," they write.

This is one of the few studies to classify antidepressant stroke risk according to inhibition of serotonin. The population-based design make the results "highly generalizable," the researchers note.

Another strength was the large cohort size, which allowed for a more precise estimation of stroke risk. The study was observational, so residual confounding was a potential limitation. In addition, the database only includes antidepressants prescribed by general practitioners.

The investigators propose expanding on this line of research.

"We plan to continue working on the impact of the degree of serotonin inhibition of antidepressants on vascular outcomes when these drugs are taken in combination with other drugs with antiplatelet effects," Renoux said.

Influence on Antidepressant Choice

Commenting on the findings for Medscape Medical News, Sarah Song, MD, MPH, vascular neurologist at Rush University Medical Center, assistant professor of neurology at Rush University in Chicago, and a fellow of the American Academy of Neurology, said that overall, the study was well done.

"They used appropriate statistical techniques to account for, among other things, the large cohort and the duration of follow-up. However, it's important to note that this study was observational, and even though they did attempt to adjust the model in a variety of ways, bias exists," she said.

Another potential limitation is use of "unspecific codes" to identify stroke. This could have affected the results, she added.

Song said that although the findings provide some guidance as to antidepressant choice, the study "is not as helpful as it might be, just because the effect size was modest."

Clinicians are more likely to choose a specific antidepressant on the basis of efficacy and side effects rather than the study results, she said.

"However," she added, "this does provide additional information about the intersection of these medications and ischemic stroke, which, with other existing data, could assist practitioners in making clinical decisions alongside their patients," Song added.

The study was supported by a grant from the Canadian Institutes of Health Research. The authors and Song have disclosed no relevant financial relationships.

Neurology. Published online August 7, 2019. Abstract

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