Contextual drug interaction decision support algorithm for warfarin - antidepressants



The high prevalence of depression is a major public concern due to its association with a significant reduction in quality of life.(1-3) Depression, anxiety, atrial fibrillation (AF), cardiovascular disease, and thromboembolic disorders often coexist.(1, 4-6) Studies found that when compared to people without depression, patients with depression have a greater risk of having coronary heart disease (1.7-fold)(7) and stroke(1.5-fold).(8) Also, patients with a prior myocardial infarction (MI) are at 5- and 7-times higher risk of anxiety and depression respectively, compared to people without prior MI.(9) In addition, a study suggested the risk of depression during the first 3 months after stroke is 8-fold higher than those without stroke.(10) Therefore, it is common for patients to receive concurrent anticoagulants and antidepressants.(1)

Warfarin is one of the most widely used anticoagulants(1) and is used to prevent thromboembolism for patients with non-valvular atrial fibrillation, as prophylaxis post-surgery, and in patients with a prior history of thromboembolism.(11) Antidepressant products on the market are typically grouped according to their mechanism of action. These include: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mirtazapine, and bupropion.(12) SSRIs are one of the most widely used antidepressants,(1) due to their low incidence of side-effects, ease of dosing, safety, tolerability and wide ranges of indications including anxiety disorders, major depression, obsessive-compulsive disorder, and posttraumatic stress disorder.(13-15) Both SSRIs and SNRIs are often prescribed in patients taking warfarin who also have other comorbidities such as major depression, anxiety, and other psychiatric disorders.(11) TCAs also have indications for major depressive disorder and peripheral neuropathies.(11)

Although there are concerns regarding bleeding risks associated with warfarin and antidepressants, only some antidepressants increase the risk of bleeding when given concurrently with warfarin. Thus, prescribers and pharmacists may see irrelevant warnings because of the lack of distinction across the antidepressants with respect to the risk of bleeding.  Also, clinicians need to be aware of other medications that can increase bleeding risk (e.g, NSAIDs, aldosterone antagonists, aspirin, glucocorticoid).(35-37) Other risk factors for GI bleeding include a history of peptic ulcer or GI bleeding and older age.(35) Factors that may increase the risk of brain hemorrhage include hypertension, severe renal disease, alcohol abuse, and cigarette smoking,(38) but the extent to which these factors increased the risk of brain hemorrhage in patients taking warfarin plus antidepressants is not known.


Warfarin is a vitamin K antagonist, which competitively inhibits a series of coagulation factors, as well as proteins C and S.(16) These factors are biologically activated by the addition of carboxyl groups depending on vitamin K.(16) Warfarin competitively inhibits this chemical reaction, thus depleting functional vitamin K reserves reducing the synthesis of active coagulation factors.(16)

Bleeding complications of serotonergic antidepressants (e.g, SSRIs, SNRIs, mirtazapine)serotonergic antidepressants (e.g, SSRIs, SNRIs, mirtazapine) treatment could be explained by an impairment of hemostatic response.(13) Serotonin receptors expressed on nerve cells and platelets.(17) Platelets store approximately 99% of the endogenous serotonin,(15)and release serotonin to promote vasoconstriction and platelet aggregation in response to vascular damage.(13) Platelets are not able to synthesize serotonin, therefore inhibiting the uptake of serotonin may lead to decrease serotonin level within the platelets. This can impair platelet secretory response and aggregation leading to increased bleeding.(13-15, 17-22)

Evidence in the literature regarding the association between bleeding and antidepressants is inconsistent, due to variation definitions of bleeding, lack of details concerning which antidepressants were included, and the lack of attention to confounding factors. For example, several case-control studies reported no association between the exposure of SSRIs or other antidepressants and the increased risk of intracerebral hemorrhage or intracranial hemorrhage.(13, 23) Another study reported that the use of SSRIs was associated with increased hemorrhagic and fatal stroke.(24) A systematic review and meta-analysis of 22 observational studies determined the odds for developing upper gastrointestinal bleed (UGIB) were 1.5 (95% CI: 1.35-1.78) times higher in patients taking SSRIs than those had not taken SSRIs.(25) Another meta-analysis of 42 observational studies also reported a 41% increase in the risk of severe bleeding, mainly gastrointestinal (GI), in patients taking SSRIs.(26) Similar findings were observed in a case-control study that showed an increase in the risk of UGIB (1.2-1.9-fold) among past, current, and recent users of SSRIs.(27) Evidence also suggested the bleeding risk may be correlated with potency of serotonin inhibition. High-potency antidepressants were associated with bleeding risk 2-3-fold higher than low-potency agents.(18, 28) Another study found high-potency agents were associated with only slightly increased risk of GI bleeding (RR=1.17, 1.02-1.34) compared to low-potency products.(29)

Some studies suggest that concurrent use of SSRIs and warfarin is not associated with a significant increase in the risk of hospitalization for UGIB,(30) while other studies suggest that the bleeding effects of SSRIs or SNRIs and warfarin could be additive, and duel usage of warfarin and SSRIs or SNRIs was an independent predictor of mortality among patients with primary intracerebral hemorrhage.(20) Several observational studies compared warfarin monotherapy to the dual-use of SSRIs or SNRIs and warfarin. The combined use is associated with a higher risk of various bleeding events including hemorrhage (1.4-fold)(31), GI bleeding (up to 1.7-fold (32), any bleeding event during the 6-month period (2.6-fold)(11), and hospital admission due to bleeding (3.5-fold)(33).

Not all antidepressants have been associated with increased bleeding risk.(11) Evidence suggests that tricyclic antidepressants are unlikely to increase the bleeding risk in patients taking warfarin.(31, 34) Although mirtazapine does effect circulating serotonin, it is not a serotonin reuptake inhibitor.(12) Thus, mirtazapine is not expected to interact with warfarin.(32) Despite one study finding an increase the risk of GI bleeding when combined with warfarin,(32) additional studies are needed to confirm this finding. In addition, bupropion only inhibits the reuptake of dopamine and norepinephrine, not serotonin.(12) Thus, it does not appear to be serotonergic, and would not be expected to increase the bleeding risk by affecting platelets

Creation Date

Artifact Creation and Usage


Richard Boyce (rdb20@pitt.edu), Daniel Malone, Philip Hansten, John Horn, Andrew Romero, Sheila Gephart,  Eric Chou

IP Attestation The author asserts that this artifact has been developed in compliance with the intellectual property rights attributed to the source material.

This potential drug-drug interaction knowledge artifact is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License (CC BY-NC-SA 3.0). For more details on this license: https://creativecommons.org/licenses/by-nc-sa/3.0/

MeSH Topics
Implementation Details
Engineering Details

Data from a urban tertiary care facility was used to identify high-priority DDIs for contextualized alerting. A panel of DDI experts developed algorithms to incorporate drug and patient characteristics that affect the relevance of such warnings. The algorithms were then applied to both synthetic and real-world EHR data. See the Implementation Guide document for further details.

Repository Information
Knowledge Level

Structured code that is interpretable by a computer (includes data elements, value sets, logic)

Purpose and Usage
Supporting Evidence


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  11. Cochran KA, Cavallari LH, Shapiro NL, Bishop JR. Bleeding incidence with concomitant use of antidepressants and warfarin. Ther Drug Monit. 2011;33(4):433-8. PMID: 21743381
  12. Sansone RA, Sansone LA. Warfarin and Antidepressants: Happiness without Hemorrhaging. Psychiatry (Edgmont). 2009;6(7):24-9. PMID: 19724766
  13. Bak S, Tsiropoulos I, Kjaersgaard J, Andersen M, Mellerup E, Hallas J. Selective serotonin reuptake inhibitors and the risk of stroke: a population-based case-control study. Stroke. 2002;33:1465-73. PMID: 12052976
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  16. Fawzy AM, Lip GYH. Pharmacokinetics and pharmacodynamics of oral anticoagulants used in atrial fibrillation. Expert Opin Drug Metab Toxicol. 2019;15(5):381-98. PMID: 330951640
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  20. Lopponen P, Tetri S, Juvela S, Huhtakangas J, Saloheimo P, Bode MK, et al. Association between warfarin combined with serotonin-modulating antidepressants and increased case fatality in primary intracerebral hemorrhage: a population-based study. J Neurosurg. 2014;120(6):1358-63. PMID: 24506245
  21. Abdelmalik N, Ruhe HG, Barwari K, van den Dool EJ, Meijers JC, Middeldorp S, et al. Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism. J Thromb Haemost. 2008;6(12):2168-74. PMID: 18983505
  22. Dalton SO, Johansen C, Mellemkjaer L, Norgard B, Sorensen HT, Olsen JH. Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med. 2003;163(1):59-64. PMID: 12523917
  23. de Abajo F, Jick H, Derby L, Jick S, Schmitz S. Intracranial haemorrhage and use of selective serotonin reuptake inhibitors. Br J Clin Pharmacol. 2000;50:43-7. PMID: 10886117
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  27. Dall M, Schaffalitzky de Muckadell OB, Lassen AT, Hansen JM, Hallas J. An association between selective serotonin reuptake inhibitor use and serious upper gastrointestinal bleeding. Clin Gastroenterol Hepatol. 2009;7(12):1314-21. PMID: 19716436
  28. Lewis JD, Strom BL, Localio AR, Metz DC, Farrar JT, Weinrieb RM, et al. Moderate and high affinity serotonin reuptake inhibitors increase the risk of upper gastrointestinal toxicity. Pharmacoepidemiol Drug Saf. 2008;17(4):328-35. PMID: 18188866
  29. Castro VM, Gallagher PJ, Clements CC, Murphy SN, Gainer VS, Fava M, et al. Incident user cohort study of risk for gastrointestinal bleed and stroke in individuals with major depressive disorder treated with antidepressants. BMJ Open. 2012;2(2):e000544. PMID: 22466034
  30. Kurdyak PA, Juurlink DN, Kopp A, Herrmann N, Mamdani MM. Antidepressants, warfarin, and the risk of hemorrhage. J Clin Psychopharmacol. 2005;25(6):561-4. PMID: 16282838
  31. Quinn GR, Singer DE, Chang Y, Go AS, Borowsky LH, Udaltsova N, et al. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol. 2014;114(4):583-6. PMID: 25001151
  32. Schelleman H, Brensinger CM, Bilker WB, Hennessy S. Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. PLoS One. 2011;6(6):e21447. PMID: 21731754
  33. Wallerstedt SM, Gleerup H, Sundstrom A, Stigendal L, Ny L. Risk of clinically relevant bleeding in warfarin-treated patients–influence of SSRI treatment. Pharmacoepidemiol Drug Saf. 2009;18(5):412-6. PMID: 19301238
  34. Opatrny L, Delaney JA, Suissa S. Gastro-intestinal haemorrhage risks of selective serotonin receptor antagonist therapy: a new look. Br J Clin Pharmacol. 2008;66(1):76-81. PMID: 18460039
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Artifact Representation

Concomitant exposure to warfarin and an antidepressant

Interventions and Actions

The algorithm first identifies basic concomitant exposures of warfarin and antidepressants. Among these concomitant exposures, the algorithm identifies whether the type of antidepressant is an SSRI or SNRI. If so, the algorithm then determines whether the patient has one or more risk factors for major bleeding based on other pertinent medical history and ongoing drug exposures. Patients with one or more risk factors for major bleeding yield a Class 1 (Red) alert, while those without additional risk factors result in a Class 2/3 (Yellow) alert. For antidepressants that are not SSRIs or SNRIs, if the type of antidepressant is a mirtazapine, a Class 2/3 (Yellow) alert is fired. Otherwise, if the antidepressant is a tricyclic or bupropion, a Class 4 (Green) alert is fired.

Drug factors involved:

  • Warfarin
  • SSRIs and SNRIs
  • Mirtazapine
  • Tricyclics
  • Bupropion

Risk factors considered for major bleeding:

  • History of Gastrointestinal Bleeds
  • Older than 64 years of age
  • NSAIDs
  • Aspirin
  • Systemic corticosteroids
  • Aldosterone antagonists
  • Anti-platelet medications

Alert Classifications:

  • Class 4: Green: No Special Precautions
  • Class 2/3: Yellow: Usually Avoid Combination or Minimize Risk
    •  For Warfarin – NSAIDS rule:
      • Recommendation: Assess risk and take action if necessary
      • Rationale: Possible increased risk of bleeding
  • Class 1: Red: Avoid Combination
    • For Warfarin – NSAIDS rule:
      • Recommendation: Use only if benefit outweighs risk
      • Rationale: Increased bleeding risk likely
Testing Experience
Pilot Experience

The algorithm has been validated using synthetic data but it has not yet been piloted in a clinical setting.