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Risk of Upper Gastrointestinal Bleeding With Selective Serotonin Reuptake Inhibitors With or Without Concurrent NonSteroidal Anti-Inflammatory Use: A Systematic Review and Meta-Analysis

The American Journal of Gastroenterology volume 109, pages 811819 (2014) | Download Citation



There is emerging concern that selective serotonin reuptake inhibitors (SSRIs) may be associated with an increased risk of upper gastrointestinal (GI) bleeding, and that this risk may be further increased by concurrent use of nonsteroidal anti-inflammatory (NSAID) medications. Previous reviews of a relatively small number of studies have reported a substantial risk of upper GI bleeding with SSRIs; however, more recent studies have produced variable results. The objective of this study was to obtain a more precise estimate of the risk of upper GI bleeding with SSRIs, with or without concurrent NSAID use.


MEDLINE, EMBASE, PsycINFO, the Cochrane central register of controlled trials (through April 2013), and US and European conference proceedings were searched. Controlled trials, cohort, case–control, and cross-sectional studies that reported the incidence of upper GI bleeding in adults on SSRIs with or without concurrent NSAID use, compared with placebo or no treatment were included. Data were extracted independently by two authors. Dichotomous data were pooled to obtain odds ratio (OR) of the risk of upper GI bleeding with SSRIs +/− NSAID, with a 95% confidence interval (CI). The main outcome and measure of the study was the risk of upper GI bleeding with SSRIs compared with placebo or no treatment.


Fifteen case–control studies (including 393,268 participants) and four cohort studies were included in the analysis. There was an increased risk of upper GI bleeding with SSRI medications in the case–control studies (OR=1.66, 95% CI=1.44,1.92) and cohort studies (OR=1.68, 95% CI=1.13,2.50). The number needed to harm for upper GI bleeding with SSRI treatment in a low-risk population was 3,177, and in a high-risk population it was 881. The risk of upper GI bleeding was further increased with the use of both SSRI and NSAID medications (OR=4.25, 95% CI=2.82,6.42).


SSRI medications are associated with a modest increase in the risk of upper GI bleeding, which is lower than has previously been estimated. This risk is significantly elevated when SSRI medications are used in combination with NSAIDs, and physicians prescribing these medications together should exercise caution and discuss this risk with patients.

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  1. 1.

    , , . Increased use of antidepressants in Canada: 1981–2000. Ann Pharmacother 2002;36:1375–1379.

  2. 2.

    , , et al. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis. BMJ 2003;326:1014.

  3. 3.

    . Selective serotonin reuptake inhibitors and increased bleeding risk: are we missing something? Am J Med 2006;119:113–116.

  4. 4.

    , , . Meta-analysis: gastrointestinal bleeding due to interaction between selective serotonin uptake inhibitors and non-steroidal anti-inflammatory drugs. Alim Pharmacol Ther 2008;27:31–40.

  5. 5.

    , . Influence of antidepressants on hemostasis. Dialogues Clin Neurosci 2007;9:47–59.

  6. 6.

    , , et al. Effects of serotonin on platelet activation in whole blood. Blood Coagul Fibrinolysis 1997;8:517–523.

  7. 7.

    , , et al. Serotonin reuptake inhibitor antidepressants and abnormal bleeding: a review for clinicians and a reconsideration of mechanisms. J Clin Psychiatry 2010;71:1565–1575.

  8. 8.

    . Fluoxetine and sertraline stimulate gastric acid secretion via a vagal pathway in anaesthetised rats. Pharmacol Res 2004;50:309–316.

  9. 9.

    , , et al. Selective serotonin reuptake inhibitors and gastrointestinal bleeding: a case-control study. PloS One 2011;6:e19819.

  10. 10.

    , , et al. An association between selective serotonin reuptake inhibitor use and serious upper gastrointestinal bleeding. Clin Gastroenterol Hepatol 2009;7:1314–1321.

  11. 11.

    , . Risk of upper gastrointestinal tract bleeding associated with selective serotonin reuptake inhibitors and venlafaxine therapy: interaction with nonsteroidal anti-inflammatory drugs and effect of acid-suppressing agents. Arch Gen Psychiatry 2008;65:795–803.

  12. 12.

    , , . Acid suppressants reduce risk of gastrointestinal bleeding in patients on antithrombotic or anti-inflammatory therapy. Gastroenterology 2011;141:71–79.

  13. 13.

    , , . Gastro-intestinal haemorrhage risks of selective serotonin receptor antagonist therapy: a new look. Br J Clin Pharmacol 2008;66:76–81.

  14. 14.

    , , et al. Risk factors for peptic ulcer bleeding. Tidsskr Nor Laegeforen 2010;130:1135–1139.

  15. 15.

    , , 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.

  16. 16.

    , , et al. Risk of upper gastrointestinal bleeding and the degree of serotonin reuptake inhibition by antidepressants: a case-control study. Drug Saf 2008;31:159–168.

  17. 17.

    , , et al. Upper gastrointestinal bleeding associated with NSAIDs, other drugs and interactions: a nested case-control study in a new general practice database. Eur J Clin Pharmacol 2013;69:691–701.

  18. 18.

    , , et al. Upper gastrointestinal bleeding: incidence, etiology and outcomes in a population-based setting. Scand J Gastroenterol 2013;48:439–447.

  19. 19.

    , , et al. Lower gastrointestinal bleeding: incidence, etiology, and outcomes in a population-based setting. Eur J Gastroenterol Hepatol 2013;25:37–43.

  20. 20.

    , , et al. Moderate and high affinity serotonin reuptake inhibitors increase the risk of upper gastrointestinal toxicity. Pharmacoepidemiol Drug Saf 2008;17:328–335.

  21. 21.

    , , et al. Antidepressant drug prescription and risk of abnormal bleeding: a case-control study. J Clin Psychopharmacol 2009;29:33–38.

  22. 22.

    , , et al. Use of serotonergic drugs and the risk of bleeding. Clin Pharmacol Ther 2011;89:89–96.

  23. 23.

    , , et al. Risk factors for gastrointestinal bleeding: a hospital-based case-control study. Swiss Med Wkly 2007;137:705–710.

  24. 24.

    , , et al. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ 2011;343:d4551.

  25. 25.

    , , . Risk of upper gastrointestinal hemorrhage in elderly selective serotonin/norepinephrine reuptake inhibitor users. In: AAGP Annual Meeting 2009; March 2009; Honolulu, HI; 2009, A94.

  26. 26.

    , , . Selective serotonin reuptake inhibitors and risk of gatrointestinal bleeding in two prospective, population-based cohorts. In: Digestive Disease Week, May 2011; Chicago, IL, USA; 2011 S-137.

  27. 27.

    , . The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. (cited 1 February 2011) Available from: .

  28. 28.

    , , et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–560.

  29. 29.

    , , et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 2011;343:d4002.

  30. 30.

    , , et al. Acute upper GI bleeding: did anything change? Time trend analysis of incidence and outcome of acute upper GI bleeding between 1993/1994 and 2000. Am J Gastroenterol 2003;98:1494–1499.

  31. 31.

    , , et al. Hospitalization and mortality rates from peptic ulcer disease and GI bleeding in the 1990s: relationship to sales of nonsteroidal anti-inflammatory drugs and acid suppression medications. Am J Gastroenterol 2002;97:2540–2549.

  32. 32.

    , , . Use and misuse of population attributable fractions. Am J Public Health 1998;88:15–19.

  33. 33.

    , , et al. Incidence and determinants of long-term use of antidepressants. Eur J Clin Pharmacol 2004;60:57–61.

  34. 34.

    , , et al. Trends in psychotropic medication use among US adults. Pharmacoepidemiol Drug Saf 2007;16:560–570.

  35. 35.

    , , et al. Calculating measures of biological interaction. Eur J Epidemiol 2005;20:575–579.

  36. 36.

    , , . Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999;319:1106–1109.

  37. 37.

    , , et al. Does concurrent prescription of selective serotonin reuptake inhibitors and non-steroidal anti-inflammatory drugs substantially increase the risk of upper gastrointestinal bleeding? Alim Pharmacol Ther 2005;22:175–181.

  38. 38.

    , , et al. COX-2-selective inhibitors and the risk of upper gastrointestinal bleeding in high-risk patients with previous gastrointestinal diseases: a population-based case-control study. Alim Pharmacol Ther 2004;19:817–825.

  39. 39.

    , , et al. Increased use of selective serotonin reuptake inhibitors in patients admitted with gastrointestinal haemorrhage: a multicentre retrospective analysis. Alim Pharmacol Ther 2006;23:937–944.

  40. 40.

    , , et al. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Int Med 2003;163:59–64.

  41. 41.

    , , et al. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut 2009;58:367–378.

  42. 42.

    , , et al. Evidence of prescription of antidepressants for non-psychiatric conditions in primary care: an analysis of guidelines and systematic reviews. BMC Fam Pract 2013;14:55.

  43. 43.

    , , et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2002;4:CD002296.

  44. 44.

    , , . Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: benefits versus risks. Alim Pharmacol Ther 2009;29:481–496.

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We appreciate the additional information provided by the following authors: Coupland et al. (24) and Huang et al. (26).

Author information


  1. Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada

    • Rebecca Anglin
  2. Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada

    • Rebecca Anglin
    • , Yuhong Yuan
    • , Paul Moayyedi
    • , Frances Tse
    • , David Armstrong
    •  & Grigorios I Leontiadis


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Competing interests

Guarantor of the article: Rebecca Anglin, MD, PhD.

Specific author contributions: Conceived and drafted the study: Rebecca Anglin, David Armstrong, Yuhong Yuan, Paul Moayyedi, Grigorios I. Leontiadis, and Frances Tse; collected all data: Rebecca Anglin and Yuhong Yuan; analyzed and interpreted data: Rebeca Anglin, Yuhong Yuan, Grigorios I. Leontiadis, and Paul Moayyedi; drafted the manuscript: Rebecca Anglin. All authors commented on the drafts of the paper and approved the final draft of the manuscript.

Financial support: None.

Potential competing interests: None.

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Correspondence to Rebecca Anglin.

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