Intracranial Hemorrhage Risk Increased with Selective Serotonin Reuptake Inhibitors

Intracranial Hemorrhage SSRI Risk
Intracranial Hemorrhage SSRI Risk
Relative to tricyclic antidepressants, SSRIs were associated with an increased risk for intracranial hemorrhage.

Selective serotonin reuptake inhibitors (SSRIs) were associated with an increased risk for intracranial hemorrhage (ICH) in first-time antidepressant users, according to research published in JAMA Neurology.

Christel Renoux, MD, PhD, of Lady Davis Research Institute at the Jewish General Hospital in Montreal, Canada, and colleagues conducted a retrospective cohort study using data derived from the United Kingdom’s Clinical Practice Research Datalink (CPRD). They selected patients who were considered “new users” of antidepressants between 1995 and 2014. Those with less than 1 year of data in the CPRD were excluded, as were patients who had been given any antidepressant prior to study entry. Patients with a history of stroke or transient ischemic attack were also excluded.

A total of 1,363,900 individuals (mean age: 47.9; 63.2% female) were included in the cohort. More than 56% were new users of SSRIs, nearly 40% were new users of tricyclic antidepressants (TCAs), and 4% were new users of other antidepressants. Each first ICH case was matched with as many as 30 control cases for age, sex, calendar time, and follow-up duration (mean follow-up: 5.8 years).  

During follow-up, 3036 patients were diagnosed with ICH and matched to 89,702 controls (incidence rate: 3.8 per 10,000 patients; 95% confidence interval [CI], 3.7-3.9). Relative to TCAs, SSRIs were associated with an increased risk for ICH (incidence rate ratio: 1.17; 95% CI, 1.02-1.35). This translated to an absolute adjusted rate difference of 6.7 (95% CI, 0.2-13.2) per 100,000 persons per year. The highest risk was observed during the first 30 days of SSRI use (incidence rate ratio: 1.44; 95% CI, 1.04-1.99).

Strong inhibitors of serotonin reuptake were associated with a 25% increased risk of ICH compared with weak inhibitors (incidence rate ratio: 1.25; 95% CI, 1.01-1.54), for an absolute adjusted rate difference of 9.5 (95% CI, -0.5 to 19.6) per 100,000 persons per year. This risk was also highest during the first 30 days of SSRI use (incidence rate ratio: 1.68; 95% CI, 0.90-3.12).

In addition, the researchers discovered that concomitant anticoagulant use substantially increased ICH risk (incidence rate ratio: 1.73; 95% CI, 0.89-3.39). Specifically, there was a 3-fold increased risk of ICH with concomitant use of anticoagulants and SSRIs compared with concomitant anticoagulants and TCAs, although this did not reach statistical significance. Concomitant use of antiplatelet agents and SSRIs, however, did not increase the risk of ICH.

“Antidepressants with strong serotonin reuptake inhibition properties increase the risk for [ICH], and caution must be exerted with concomitant use of anticoagulants,” the researchers concluded.

Study Limitations

  • Observational nature of the study.
  • Possibility of residual confounding.
  • The definition of antidepressant exposure was based only on prescriptions issued, not filled or taken by patients, which could result in misclassification. This would most likely be nondifferential between cases and control, potentially biasing results toward the null. 

Related Articles


Renoux C, Vahey S, Dell’Aniello S, Boivin J-F. Association of selective serotonin reuptake inhibitors with the risk for spontaneous intracranial hemorrhage [published online December 5, 2016]. JAMA Neurol. doi:10.1001/jamaneurol.2016.4529.