Abnormal Bleeding Risk with SSRIs

Abstract & Commentary

Synopsis: Increased hospitalizations for abnormal bleeding were found in new users of selective serotonin reuptake inhibitor (SSRI) antidepressants, with more risk associated with SSRIs containing greater degrees of serotonin reuptake inhibition.

Source: Meijer W, et al. Arch Int Med. 2004;164:2367-2370.

Using a prescription database of 69,000 new adult antidepressant users over 8 years in the Netherlands, researchers identified all hospitalizations with a primary diagnosis of abnormal bleeding and linked them to use of antidepressants classified as high, intermediate or low serotonin reuptake inhibition activity. This classification was based on the drug’s biochemical affinity for the serotonin transporter which is thought to cause higher inhibition of serotonin reuptake.1

Matched case-controls for age and sex were used, and 6.7% were excluded because they received only 1 prescription without refills. Mean age was 58 years. Follow-up ended when a refill gap of more than 30 days or a hospitalization for bleeding occurred; average follow-up was 229 days. Conditional logistic regression was used on the matched sets, with adjustments for the use of other medications.

In the users of the drugs with highest reuptake activity (fluoxetine, sertraline, clomipramine, paroxetine), there was a 2.6-fold increased risk of hospitalization for bleeding compared to users of drugs with lowest activity (trazadone, nortriptyline, doxepin, etc). For intermediate activity (amitriptyline, imipramine, citalopram, etc), there was a 1.9-fold increase.

Total hospitalizations for bleeding were 196 out of 64,647 in the study, giving an incidence of 4.9 per 1000 person-years. Forty-seven percent (47%) were for uterine bleeding (including menorrhagia and post-menopausal bleeding), 16% upper GI bleeding, and 11% cerebral bleeding. Most participants (73.5%) were women.

Comment by Mary Elina Ferris, MD

Serotonin in platelets promotes aggregation and blood clotting, and it makes logical sense that SSRIs with the most inhibition of serotonin uptake would lead to more bleeding risk. This study from the Netherlands is intriguing because it differentiates between the numerous SSRIs on the basis of their presumed degree of reuptake inhibition activity and does find an association of more bleeding hospitalizations with more inhibition. This could lead to new research to help clinicians understand the differences among our myriad antidepressant choices.

Case reports and case-control studies have been published showing an association between SSRI use and various kinds of abnormal bleeding (upper GI bleeding, purpura, epistaxis, intracranial hemorrhage, vaginal bleeding, bleeding during surgery), with further increased risks shown when SSRIs are taken along with aspirin or NSAIDs.2 Abnormal bleeding and altered platelet function are listed as potential side effects in the product literature for many SSRIs.

However, this association does not prove a cause-and-effect relationship, and actual platelet aggregation/coagulation studies have not shown measurable impaired hemostasis.3 Unfortunately, there does not appear to be a benefit of SSRI use to prevent the development of first-time acute MI,4 but that study did not differentiate SSRI’s by level of activity. In the meantime, it would seem prudent to be cautious when using SSRIs with the highest reuptake activity in those patients with pre-existing bleeding risks.

Dr. Ferris, Clinical Associate Professor, University of Southern California, is Associate Editor of Internal Medicine Alert.


1. van Walraven C, et al. BMJ. 1999; 319:1106-1109.

2. Dalton S, et al. Arch Int Med. 2003;163:59-64.

3. Alderman C, et al. Ann Pharmacother. 1996;30: 1232-1234.

4. Meier C, et al. Br J Pharmacol. 2001;52:179-184.