Selective Serotonin Reuptake Inhibitors and the Risk for Upper Gastrointestinal Bleeding

April 2015, Vol 3, No 4 - Inside Gastrointestinal Health
Nicole East, PharmD
Sandra J. Girgis, PharmD

According to a 2011 report from the National Center for Health Statistics, approximately 11% of Americans 12 years and older took an antidepressant between 2005 and 2008, with more than one-third of patients with current severe depressive symptoms taking antidepressants.1

Mechanism of Action

Selective serotonin re­uptake inhibitors (SSRIs) are a widely prescribed class of antidepressants. Currently, there are 6 SSRIs available in the United States: citalopram, escitalopram, fluoxetine, fluvoxamine, pa­roxetine, and sertraline.2 SSRIs work by inhibiting presynaptic serotonin reuptake via the serotonin transporters.3-8 There are varying levels of affinity for the serotonin transporters in this class of medication. SSRIs with lower dissociation constants indicate a higher affinity for the serotonin transporters (Tables 1 and 2).3-10

Table 1

Table 2

Indication and Side Effects

SSRIs have US Food and Drug Administration–labeled indications for the treatment of major depressive disorder, panic disorder, generalized anxiety disorder, posttraumatic stress disorder, premenstrual dysphoric disorder, and obsessive-compulsive disorder.3-8,11 Side effects associated with this class of medication include nausea, vomiting, diarrhea, insomnia, sexual dysfunction, headaches, and an increased risk for falls.2 Bleeding events have also been reported with SSRI use, including upper gastrointestinal bleeding (UGIB).12

Bleeding events associated with SSRIs are believed to occur as a result of impaired platelet activity.12 In particular, serotonin is stored within platelets and plays a role in the activation of platelet aggregation.11,13 By inhibiting platelet reuptake of serotonin, it is hypothesized that there may be a defect in platelet aggregation, resulting in a prolonged bleeding time.11,12 Studies have found that the serotonin concentration in platelets was reduced by 80% within 1 to 2 weeks of SSRI use.14-16 This adverse effect may be of great concern when SSRIs are coadministered with nonsteroidal anti-inflammatory drugs (NSAIDs), because they inhibit the platelet activator thromboxane A2. NSAIDs are also well known for producing gastrointestinal complications, including ulcers and bleeding.11

Upper Gastrointestinal Bleeding

Current data represent conflicting results on the risk for UGIB related to the use of SSRIs. In one study, Wang and colleagues showed that short-term SSRI use (28 days) was significantly associated with UGIB (adjusted odds ratio [aOR], 1.67; 95% confidence interval [CI], 1.34-2.08; P <.001).10 This association was only seen in patients taking an antidepressant with high or moderate affinity for the serotonin transporter. Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhi­bi­tors, and other antidepressants were not associated with an increased risk of UGIB. It should be noted that when calculating the risk associated with each specific SSRI, only fluoxetine (aOR, 1.68; 95% CI, 1.10-2.57) and sertraline (aOR, 1.87; 95% CI, 1.16-3.02) demonstrated an elevated risk of UGIB.10

In a systematic review and meta-analysis of 15 case-control studies and 4 cohort studies, Anglin and colleagues reported a modest increase in the risk for UGIB associated with SSRIs (odds ratio [OR], 1.66; 95% CI, 1.44-1.92) in the case-control studies and cohort studies (OR, 1.68; 95% CI, 1.13-2.50), as well as a further increased risk in the case-control studies when used in combination with NSAIDs (OR, 4.25; 95% CI, 2.82-6.42).12 In another study by Mort and colleagues, an elevated risk for UGIB was observed with the concurrent use of an SSRI and NSAID.11

Although these studies suggest an increased risk for UGIB with the use of an SSRI with or without an NSAID, conflicting data exist. Some studies included more than just the SSRI class and evaluated the bleeding risk with any type of serotonin reuptake inhibitor. In a multicenter case-control study assessing the risk of major UGIB associated with various groups of drugs (cases, 2783; controls, 7058), Vidal and colleagues did not find an increased risk for UGIB with the use of a serotonin inhibitor, or an interaction when coadministered with an NSAID.17 No significant risk was seen when analyzing individual SSRIs, regardless of the degree of affinity for serotonin transporters. In a population-based, matched, case-control analysis, Targownik and colleagues evaluated the role of proton pump inhibitors in chronic SSRI users. A modestly increased risk of UGIB was associated with SSRI use; however, this risk was significantly reduced with proton pump inhibitor cotherapy. In addition, they reported that SSRI use was not a major risk factor for NSAID-related UGIB.18 Data by Maschino and colleagues did not indicate an association between bleeding adverse reactions and exposure to a serotonin reuptake inhibitor in combination with antiplatelet agents compared with antiplatelets alone.19

Take-Away Message for Pharmacists and Clinicians

Because the absolute risk for UGIB associated with the use of an SSRI is unknown, pharmacists and clinicians should be aware of these concerns and identify patients who are at high risk for UGIB.

Some risk factors for UGIB include alcohol consumption, advanced age, smoking, history of an UGIB, and concomitant use of other blood-thinning medications.10,11 Patients should also be aware of the potential risk, and counseled on the signs and symptoms of UGIB, such as dark, tarry stools, hematemesis (vomiting blood), and abdominal cramps.20

Pharmacists and clinicians should also note that a discussion on the choice of over-the-counter analgesics may be warranted based on an individual’s bleeding risk. One population-based, case-control analysis found that proton pump inhibitors reduced the risk of SSRI-related UGIB by approximately 61%.21 Proton pump inhibitors may be used with SSRIs to reduce the risk for recurrence in patients who have a history of UGIB.


  1. Pratt L, Brody D, Gu Q; Centers for Disease Control and Prevention. Antidepressant use in persons aged 12 and over: United States, 2005-2008. Updated October 19, 2011. Accessed February 5, 2015.
  2. American Psychiatric Association. Major depressive disorder: practice guideline (November 2010). Published October 2010. Accessed February 12, 2015.
  3. Prozac [package insert]. Indianapolis, IN: Eli Lilly & Co; 2014.
  4. Paxil [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2013.
  5. Zoloft [package insert]. New York, NY: Pfizer; 2014.
  6. Celexa [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc; 2014.
  7. Lexapro [package insert]. St. Louis, MO: Forest Pharmaceuticals, Inc; 2014.
  8. Luvox [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc; 2008.
  9. Tatsumi M, Groshan K, Blakely RD, et al. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997;340:249-258.
  10. Wang Y, Chen Y, Tsai C, et al. Short-term use of serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding. Am J Psychiatry. 2014;171:54-61.
  11. Mort J, Aparasu R, Baer R. Interaction between selective serotonin reuptake inhibitors and nonsteroidal antiinflammatory drugs: review of literature. Pharmacotherapy. 2006;26:1307-1313.
  12. Anglin R, Yuan Y, Moayyedi P, et al. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol. 2014;109:811-819.
  13. Smyth SS, Whiteheart S, Italiano JE Jr, et al. Chapter 114. Platelet Morphology, Biochemistry, and Function. In: Williams Hematology, 8th ed. New York, NY: McGraw-Hill; 2010.
  14. Hergovich N, Aigner M, Eichler HG, Entlicher J, Drucker C, Jilma B. Paroxetine decreases platelet serotonin storage and platelet function in human beings. Clin Pharmacol Ther. 2000;68:435-442.
  15. Kotzailias N, Marker M, Jilma B. Early effects of paroxetine on serotonin storage, plasma levels, and urinary excretion: a randomized, double-blind, placebo-controlled trial. J Clin Psychopharmacol. 2004;24:536-539.
  16. de Abajo FJ. Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes, and implications for use in elderly patients. Drugs Aging. 2011;28:345-367.
  17. Vidal X, Ibáñez L, Vendrell L, et al; Spanish-Italian Collaborative Group for the Epidemiology of Gastrointestinal Bleeding. Risk of upper gastrointestinal bleeding and the degree of serotonin reuptake inhibition by antidepressants: a case-control study. Drug Saf. 2008;31:159-168.
  18. Targownik LE, Bolton JM, Metge CJ, et al. Selective serotonin reuptake inhibitors are associated with a modest increase in the risk of upper gastrointestinal bleeding. Am J Gastroenterol. 2009;104:1475-1482.
  19. Maschino F, Hurault-Delarue C, Chebbane L, et al. Bleeding adverse drug reactions (ADRs) in patients exposed to antiplatelet plus serotonin reuptake inhibitor drugs: analysis of the French Spontaneous Reporting Database for a controversial ADR. Eur J Clin Pharmacol. 2012;68:1557-1560.
  20. National Institute of Diabetes and Digestive and Kidney Diseases. Bleeding in the digestive tract. ing-in-the-digestive-tract/Pages/facts.aspx#sec4. Updated September 17, 2014. Accessed February 5, 2015.
  21. Dall M, dePont Christiansen R, Schaffalitzky de Muckadell OB, et al. Re-prescribing of causative drugs in persons discharged after serious drug-induced upper gastrointestinal bleeding. Aliment Pharmacol Ther. 2012;35:948-954.
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