SSRIs and Risk of Abnormal Bleeding

**Admin** Sat Jul 23, 2011 2:13 pm

Association of Risk of Abnormal Bleeding With Degree of Serotonin Reuptake Inhibition by Antidepressants

Welmoed E. E. Meijer, PhD; Eibert R. Heerdink, PhD; Willem A. Nolen, MD, PhD; Ron M. C. Herings, PhD; Hubert G. M. Leufkens, PharmD; Antoine C. G. Egberts, PharmD
Arch Intern Med. 2004;164:2367-2370.

Serotonin plays a role in platelet aggregation. Because antidepressants influence blood serotonin levels, their use may be associated with an increased risk of abnormal bleeding.

This study found a significant association between degree of serotonin reuptake inhibition by antidepressants and risk of hospital admission for abnormal bleeding as the primary diagnosis.
Antidepressants with a high degree of inhibition of serotonin reuptake were associated with a 2.6-fold increased risk of bleeding events compared with antidepressants with a low
degree of serotonin reuptake inhibition.

Read the full article at: Archives of Internal Medicine

SSRIs and Risk of Abnormal Bleeding Ssris10

SSRIs and Risk of Abnormal Bleeding Ssris10

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**Admin** Sun Jul 24, 2011 11:25 am

Mechanism underlying these adverse effects:

SSRIs limit uptake of blood serotonin by platelets. Since platelets are unable to synthesize serotonin, this leads to a lower concentration of
serotonin within the platelets, and because one of the functions of serotonin within the platelets is to promote platelet
aggregation, a decreased amount of serotonin in the platelets may increase the risk of abnormal bleeding.

Statistical Analysis

Statistical analysis was adjusted for potential confounding in the regression model by including:
- Current and prior use of other medications (Aspirin, other NSAIDs, Anticoagulants, Glucocorticoids, Estrogens,
Progestagens, Histamine2 blockers, Proton pump inhibitors, and Antidiabetic agents) and
- History of hospitalization for bleeding.

Primary Admission Diagnosis of Patients Hospitalized With Abnormal Bleeding

1. Uterus bleeding (metorrhagia, menorrhagia, postmenopausal bleeding)- 47.4%
2. Upper gastrointestinal tract bleeding (all bleeding ulcers, hematemesis, melena, gastrointestinal bleeding NOS)- 15.8%
3. Cerebral bleeding (subarachnoidal bleeding, intracerebral bleeding, subdural bleeding, intracranial bleeding NOS)- 10.7%
4. Blood abnormalities (thrombocytopenia, anemia due to blood loss)- 3.1%
5. Other bleeding abnormalities (hematuria, epistaxis, hemoptosys, hemarthorsis, hematoma, excessive bleeding following a surgical procedure, bleeding NOS)- 23.0%

**Admin** Sun Jul 24, 2011 12:50 pm

Evidence from other articles on same topic

1. In a large case control study, de Abajo et al (1999) found that the risk of upper GI bleeding was thrice as high in patients prescribed SSRIs, but was not significantly elevated in those receiving tricyclic antidepressant (TCA) drugs.
Article: http://www.bmj.com/content/319/7217/1106.1.full.pdf

2. In a large pharmacoepidemiologic study in the elderly, Van Walraven et al (2001) found that drugs with stronger inhibition of serotonin reuptake were more likely to be associated with GI bleeds than drugs with weaker inhibition of serotonin reuptake; the risk was most apparent in older subjects and in those with a previous history of GI bleeding, but did not vary significantly with gender, presence of diabetes, and the use of steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or anticoagulants.
Article: http://www.bmj.com/content/323/7314/655.full.pdf?sid=d3d1b0d6-adfc-463e-a233-7a3776d97611

3. In another pharmacoepidemiologic study, Dalton et al (2003) compared the incidence of bleeding in subjects who did (n=26,005) and those who did not use antidepressant drugs. They found that the use of an SSRI more than trebled the risk of hospitalization for upper GI bleeding; that the risk was increased when low dose aspirin or an NSAID was concurrently used; that the risk persisted for only as long as the SSRI was taken; that other antidepressant drugs which (less potently) inhibit serotonin reuptake also increased the risk; and, finally, that antidepressants without effect on serotonin reuptake did not increase the risk.
Article: http://archinte.ama-assn.org/cgi/reprint/163/1/59

4. In a nested case-control study of a cohort of 64,647 new antidepressant users followed up for an average of 229 days, Meijer et al (2004) found that, after controlling for other risk factors for abnormal bleeding, the risk of hospitalization for abnormal bleeding in 196 cases as compared with 972 controls was significantly greater for antidepressants with intermediate (OR, 1.9; 95% CI, 1.1-3.5) and high degrees of serotonin reuptake inhibition (OR, 2.6; 95% CI, 1.4-4.8 )
Article: http://archinte.ama-assn.org/cgi/reprint/164/21/2367

5. de Abajo et al (2008) described a nested case-control study of 1321 patients with upper GI bleeding and 10,000 control subjects matched for age, sex, and calendar year of the bleed. Significantly more cases than controls were currently using SSRIs (5.3% vs 3.0%; OR, 1.6; 95% CI, 1.2-2.1) or venlafaxine (1.1% vs 0.3%; OR, 2.9; 95% CI, 1.5-5.6).
Article: http://archpsyc.ama-assn.org/cgi/reprint/65/7/795

6. Opatrny et al (2008) described a population-based case control study of 4,028 patients with GI haemorrhage and 40,171 controls. SSRIs (OR, 1.3; 95% CI, 1.1-1.6) and venlafaxine (OR, 1.9; 95% CI, 1.3-2.6) but not TCA (OR, 1.0; 95% CI, 0.8-1.3) were associated with the risk of bleeding.
Article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2485264/pdf/bcp0066-0076.pdf

7. In a population-based case-control study of data from the Manitoba Population Health Research Data Repository, Targownik et al (2009) matched hospitalized patients with upper GI bleeding with nonbleeding controls. SSRI use was associated with a 43% increased risk of bleeds (OR, 1.43; 95% CI, 1.09-1.89).
Article: http://www.nature.com/ajg/journal/v104/n6/abs/ajg2009128a.html

**Admin** Sun Jul 24, 2011 1:01 pm

Conclusions:

1. Antidepressant drugs which do not inhibit the reuptake of serotonin are likely to be safe in patients at risk of abnormal bleeding. These drugs include mirtazapine, bupropion, moclobemide, reboxetine, and others.

2. The risk of upper gastrointestinal bleeds with SSRIs is small and could be in the region of 3-5 per 1000 treatment years. The risk should nevertheless be taken seriously because abnormal bleeding is potentially life-threatening.

3. NSAIDs are themselves associated with an increased risk of upper GI bleeds. Does the combined use of SSRIs and NSAIDs magnify the risk?
Some but not all studies suggest that the combined use of an SSRI and an NSAID increases the risk of upper gastrointestinal bleeding beyond that associated with either drug alone.

4. The risk of upper gastrointestinal bleeding with SSRIs is reduced in patients who are receiving treatments for gastric acidity. Therefore, patients with a current or past history of acid-peptic disease should avoid SSRI medication, or should receive these drugs only under cover of a proton pump inhibitor.

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