SSRI Use Tied to Risk of Intracranial Hemorrhage

All drugs that affect serotonin reuptake were associated with some increased risk of ICH.
All drugs that affect serotonin reuptake were associated with some increased risk of ICH.

Risk of intracranial hemorrhage (ICH) associated with selective serotonin reuptake inhibitors (SSRIs) increases with the strength of the agent used (ICH), according to results from a large-scale population-based study published in JAMA Neurology.1

Depression has been linked to an increased risk for hemorrhagic stroke, independent of therapy type.Approximately two-thirds of SSRI prescriptions are for depression.3 Previous observational studies of the incidence of ICH with SSRI use have demonstrated conflicting results,4 which may have been due to a potential indication bias to the diagnosis of depression.

The current study was designed to specifically reduce this bias. “Separating the effect of depression from the effect of antidepressants on the risk of intracranial bleeding is difficult,” explained lead author Christel Renoux, MD, PhD, Assistant Professor of neurology and neurosurgery at McGill University in Montreal, Quebec, Canada and a researcher at the Lady Davis Research Institute. “This is why we chose to use a comparator group of patients also treated with antidepressants instead of a comparator group of patients not treated with antidepressants,” she told Neurology Advisor.

Dr Renoux and colleagues examined data from a population-based cohort of 1,363,990 people prescribed antidepressants. SSRIs are among the most commonly prescribed medictions.13,14 Among the participants, 773,364 (56.7%) were new users of SSRIs, compared with 534,587 (39.2%) new users of TCAs and 56,039 (4.1%) new users of other antidepressants. Mean age was 47.9 years, and gender distribution was 63.2% female to 36.8% male. The incidence rate for ICH over a mean follow-up period of 5.8 years was quite low at 3.8 (95% CI, 3.7-3.9) per 10,000, indicating a rare occurrence.

The investigators found that the use of all drugs that affect serotonin reuptake were associated with some increased risk of ICH compared to those using tricyclic antidepressants (relative risk (RR)= 1.17; 95% CI, 1.02-1.35), but these risks were increased by 25% among the participants taking the strongest SSRIs (RR= 1.25; 95% CI, 1.01-1.54) compared to those taking the weakest. Incremental increases between the strengths of different agents were associated with more modest increases in risk, which the authors noted accounted for the addition of relatively few new ICH events.

Concomitant use of oral anticoagulants among people taking SSRIs contributed to a significantly higher increased risk for ICH (RR=1.73; 95% CI, 0.89-3.39). The RR across all groups (high, medium, and low-strength SSRIs, with and without anticoagulants) was highest during the first 30 days of use, decreasing thereafter.

Although ICH was a relatively rare occurrence, the serious consequences of stroke warrant concern. The results of this large-scale study support a cautious approach to prescribing high-strength SSRIs, particularly in combination with anticoagulant therapies. “We showed that spontaneous ICH is slightly increased with antidepressants with strong serotonin reuptake inhibition properties. Although this event is quite rare, this potential risk must be kept in mind in patients at higher risk of intracranial bleeding,” Dr. Renoux said.


  1. Renoux C, Vahey S, Dell'Aniello S, et al. Association of selective serotonin reuptake inhibitors with risk for spontaneous intracranial hemorrhage. JAMA Neurol. 2016; doi:10.1001/jamaneurol.2016.5031.
  2. Daskalopoulou M, George J,Walters K, et al. Depression as a risk factor for the initial presentation of twelve cardiac, cerebrovascular, and peripheral arterial diseases: data linkage study of 1.9 million women and men. PLoS One. 2016;11(4):e0153838.
  3. Patten SB, Esposito E, Carter B. Reasons for antidepressant prescriptions in Canada. Pharmacoepidemiol Drug Saf. 2007;16:746-752.
  4. Bak S, Tsiropoulos I, Kjaersgaard JO, et al. Selective serotonin reuptake inhibitors and the risk of stroke: a population-based case-control study. Stroke. 2002;33:1465-1473.
  5. Chen Y, Guo JJ, Li H,Wulsin L, Patel NC. Risk of cerebrovascular events associated with antidepressant use in patients with depression: a population-based, nested case-control study. Ann Pharmacother. 2008;42:177-184.
  6. de Abajo FJ, Jick H, Derby L, Jick S, Schmitz S. Intracranial haemorrhage and use of selective serotonin reuptake inhibitors. Br J Clin Pharmacol. 2000;50:43-47.
  7. Douglas I, Smeeth L, Irvine D. The use of antidepressants and the risk of haemorrhagic stroke: a nested case control study. Br J Clin Pharmacol. 2011;71:116-120.
  8. Kharofa J, Sekar P, Haverbusch M, et al. Selective serotonin reuptake inhibitors and risk of hemorrhagic stroke. Stroke. 2007;38:3049-3051.
  9. Pan A, Okereke OI, Sun Q, et al. Depression and incident stroke in women. Stroke. 2011;42:2770-2775.
  10. Smoller JW, Allison M, Cochrane BB, et al. Antidepressant use and risk of incident cardiovascular morbidity and mortality among postmenopausal women in the Women's Health Initiative study. Arch Intern Med. 2009;169:2128-2139.
  11. Verdel BM, Souverein PC, Meenks SD, Heerdink ER, Leufkens HG, Egberts TC. Use of serotonergic drugs and the risk of bleeding. Clin Pharmacol Ther. 2011;89:89-96.
  12. Wu CS,Wang SC, Cheng YC, Gau SS. Association of cerebrovascular events with antidepressant use: a case-crossover study. Am J Psychiatry. 2011;168:511-521.
  13. Beck CA, Patten SB, Williams JV, et al. Antidepressant utilization in Canada. Soc Psychiatr Epidemiol. 2005;40:799-807.
  14. Mojtabai R. Increase in antidepressant medication in the US adult population between 1990 and 2003. Psychother Psychosom. 2008;77:83-92.
You must be a registered member of Neurology Advisor to post a comment.

Sign Up for Free e-newsletters