A Nested Case-Control Study

Selective Serotonin Reuptake Inhibitors and Risk of Noncardioembolic Ischemic Stroke: A Nested Case-control Study

Rasha Alqdwah-Fattouh, MPH; Sara Rodríguez-Martín, PhD; Diana Barreira-Hernández, PharmD; Laura Izquierdo-Esteban, MD; Miguel Gil, PhD; Diana González-Bermejo, PhD; Encarnación Fernández-Antón, PharmD; Antonio Rodríguez-Miguel, PhD; Alberto García-Lledó, PhD; Francisco Bolúmar, PhD; Francisco J. de Abajo, PhD


Stroke. 2022;53(5):1560-1569. 

In This Article

Abstract and Introduction


Background: Multiple studies have reported that the use of selective serotonin reuptake inhibitors (SSRIs) is associated with an increased risk of ischemic stroke; however, this finding may be the result of a confounding by indication. We examined the association using different approaches to minimize such potential bias.

Methods: A nested case-control study was carried out in a Spanish primary health-care database over the study period 2001 to 2015. Cases were patients sustaining an ischemic stroke with no sign of cardioembolic or unusual cause. For each case, up to 5 matched controls (for exact age, sex, and index date) were randomly selected. Antidepressants were divided in 6 pharmacological subgroups according to their mechanism of action. The current use of SSRIs (use within a 30-day window before index date) was compared with nonuse, past use (beyond 365 days) and current use of other antidepressants through a conditional logistic regression model to obtain adjusted odds ratios and 95% CI. Only initiators of SSRIs and other antidepressants were considered.

Results: A total of 8296 cases and 37 272 matched controls were included. Of them, 255 (3.07%) were current users of SSRIs among cases and 834 (2.24%) among controls, yielding an adjusted odds ratio of 1.14 (95% CI, 0.97–1.34) as compared with nonusers, 0.94 (95% CI, 0.77–1.13) as compared with past-users and 0.74 (95% CI, 0.58–0.93) as compared with current users of other antidepressants. No relevant differences were found by duration (≤1, >1 year), sex, age (<70, ≥70 years old) and background vascular risk.

Conclusions: The use of SSRIs was not associated with an increased risk of noncardioembolic ischemic stroke. On the contrary, as compared with other antidepressants, SSRIs appeared to be protective.


The relationship between the use of selective serotonin reuptake inhibitors (SSRIs), the most widely prescribed antidepressants, and ischemic stroke has been a matter of controversy for the last 2 decades, with many studies suggesting an increased risk,[1–5] while a few showing a decreased risk[6,7] or a neutral effect.[8] These findings seem to be a pharmacological paradox as SSRIs have a recognized antiplatelet effect[9] and one should expect a risk reduction, similar to the one found for acute myocardial infarction.[10–19] Such discrepancies can be attributed to several factors: (1) depression itself has been reported to be a risk factor for stroke,[20,21] and this may result in a confounding by indication when users of antidepressants are compared with nonusers, as most studies did; (2) some studies pooled SSRIs with other antidepressants, as if they all had the same pharmacological profile;[22] (3) none of the studies distinguished between the 2 main pathophysiological types of ischemic stroke: cardioembolic versus noncardioembolic, when it may not be reasonable to expect the same effect of SSRIs on both types; and (4) the inclusion of prevalent users in the analysis.[23]

In the present study, we aimed to assess the association of SSRIs and 5 other antidepressant subgroups with ischemic stroke of probable noncardioembolic origin, trying to overcome the aforementioned problems by using different methodological approaches.