Cerebrovascular Effects of Selective Serotonin Reuptake Inhibitors: A Systematic Review

Rajamannar Ramasubbu, M.D., F.R.C.P.C.

Objectives: An understanding of cerebrovascular effects of selective serotonin reuptake inhibitors (SSRIs) is essential, since SSRIs are a widely used antidepressant, serotonin is a vasoactive and thrombostatic amine, and there is a bidirectional relationship between depression and cerebrovascular disease.

Data Sources: A MEDLINE search was performed to identify published reports over the period of 1966 through 2003, using the terms SSRIs and antidepressants matched with the terms platelets, coagulation, anticoagulation, bleeding, fibrinolysis, thrombosis, embolism, cerebral ischemia, stroke, cerebrovascular accident, acute and chronic cerebrovascular disease, intracranial hemorrhage, cerebrovascular disorder, and cerebral circulation. Adverse event reports collected from the World Health Organization (WHO), manufacturers, and the Physicians' Desk Reference (PDR) were also examined.

Data Synthesis: Two case-control studies failed to show an association between SSRI use and intracranial hemorrhage, and of these, 1 showed no association with ischemic stroke. Sixteen studies of SSRI treatment in poststroke patients found no significant cerebrovascular adverse reactions. The WHO data have shown several hundred cases of SSRI-associated cerebrovascular disease, but definitive causal relationships remain undetermined. Four cases of vasoconstrictive stroke related to drug interactions between SSRIs and other serotonergic drugs have been reported. PDR and manufacturer reference sources categorized cerebrovascular reaction as an infrequent or rare adverse event related to SSRI use.

Conclusions: Available evidence suggests that SSRI treatment has a very low rate of cerebrovascular adverse reaction. Pharmacovigilance is required in the use of SSRIs in high-risk populations for bleeding and vasoconstrictive stroke. More research is warranted to examine the variability of pharmacologic and genetic factors, depressive illness, and stroke on the antiplatelet and vasospastic effects of SSRIs and their significance to cerebrovascular protection or adverse reactions.

(J Clin Psychiatry 2004;65:1642-1653)

Received Nov. 7, 2003; accepted May 24, 2004. From the Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.

Dr. Ramasubbu reports no financial affiliation or other relationship relevant to the subject matter in this article.

The author thanks Somnath Chatterjee, M.D., for his assistance in obtaining WHO data.

Corresponding author and reprints: Rajamannar Ramasubbu, M.D., Department of Psychiatry, University of Calgary, Foothills Medical Centre, Room AW258A, 1403-29th Street N.W., Calgary, Alberta, Canada, T2N 2T9 (e-mail: rramasub@ucalgary.ca).