Objective: We synthesized the epidemiologic evidence concerning selective serotonin reuptake inhibitor (SSRI) exposure and the risk of CNS hemorrhage.

Methods: We searched for controlled observational studies comparing SSRI therapy with a control group not receiving SSRIs. We used DerSimonian and Laird fixed effect models to compute summary risk associations.

Results: Intracranial hemorrhage was related to SSRI exposure in both unadjusted (rate ratio [RR] 1.48, 95% confidence interval [CI] 1.22–1.78) and adjusted analyses (RR 1.51, 95% CI 1.26–1.81). Intracerebral hemorrhage was also associated with SSRI exposure in both unadjusted (RR 1.68, 95% CI 1.46–1.91) and adjusted (RR 1.42, 95% CI 1.23–1.65) analyses. In a subset of 5 studies (3 of intracranial hemorrhage and 1 each reporting hemorrhagic stroke and intracerebral hemorrhage), SSRI exposure in combination with oral anticoagulants was associated with an increased risk of bleeding compared with oral anticoagulants alone (RR 1.56, 95% CI 1.33–1.83). When all studies were analyzed together, increased risk was seen across cohort studies (1.61, 95% CI 1.04–2.51), case-control studies (odds ratio [OR] 1.34, 95% CI 1.20–1.49), and case-crossover studies (OR 4.24, 95% CI 1.95–9.24).

Conclusions: SSRI exposure is associated with an increased risk of intracerebral and intracranial hemorrhage, yet given the rarity of this event, absolute risks are likely to be very low.