What concurrent medications taken with Selective Serotonin Reuptake Inhibitors (SSRIs) can increase the risk of gastrointestinal (GI) bleeding?

Medications That Increase Risk of GI Bleeding When Taken With SSRIs

NSAIDs, anticoagulants, corticosteroids, and antiplatelet agents significantly increase the risk of gastrointestinal bleeding when taken concurrently with SSRIs. 1, 2

High-Risk Medication Combinations with SSRIs

NSAIDs

• Concurrent use of NSAIDs and SSRIs substantially increases the risk of GI bleeding compared to either medication alone 1, 2
• The FDA drug label for naproxen specifically warns about increased risk of GI bleeding when NSAIDs are combined with SSRIs 1
• Recent network meta-analysis (2023) found that combined SSRI/NSAID use increased bleeding risk compared to SSRI alone (OR 2.14,95% CI 1.52-3.02) and NSAID alone (OR 1.49,95% CI 1.20-1.84) 2

Anticoagulants

• Warfarin combined with SSRIs significantly increases GI bleeding risk 3
• The excess risk of GI bleeding with concomitant use of NSAIDs and anticoagulants was 2.4, while the excess risk with low-dose aspirin and anticoagulants was 1.9 3
• Direct oral anticoagulants (DOACs) like dabigatran and rivaroxaban already carry increased risk of GI bleeding, particularly in older adults, and this risk may be further elevated when combined with SSRIs 4

Corticosteroids

• Concurrent use of corticosteroids with SSRIs increases the risk of GI bleeding 4
• Patients aged ≥75 years taking aspirin and either corticosteroids or SSRIs should be treated concomitantly with a proton pump inhibitor (PPI) or misoprostol 4

Antiplatelet Agents

• Aspirin combined with SSRIs increases GI bleeding risk 4
• European Society of Cardiology guidelines specifically caution against combining antiplatelets with SSRIs due to increased bleeding risk 4
• The combination of low-dose aspirin with SSRIs showed an excess risk of 0.5 for GI bleeding 3

Mechanism of Increased Bleeding Risk

• SSRIs deplete serotonin from platelets, potentially impairing platelet aggregation 5
• NSAIDs cause GI mucosal damage and inhibit platelet function through COX inhibition 6
• When combined, these medications have synergistic effects on bleeding risk through different mechanisms affecting hemostasis 3, 5

Risk Stratification and Mitigation

High-Risk Patients

• Elderly patients (≥75 years) 4
• History of GI bleeding or peptic ulcer disease 4, 5
• Concurrent use of multiple medications that increase bleeding risk 4, 5
• Estimated excess GI bleedings attributable to SSRI use: 3.1 per 1000 treatment years in general population, 4.1 per 1000 treatment years in octogenarians, and 11.7 per 1000 treatment years in those with prior GI bleeding 5

Protective Strategies

• Consider PPI co-prescription for patients requiring both SSRI and NSAID/antiplatelet therapy 4
• The European Society of Cardiology recommends PPI use in patients at increased risk for GI bleeding who are taking antiplatelets 4
• For patients requiring antiplatelet therapy who are at high risk of GI bleeding (≥75 years, history of GI bleeding, concurrent use of anticoagulants, antiplatelets, SSRIs or glucocorticoids), concomitant treatment with misoprostol or a PPI is recommended 4

Common Pitfalls and Caveats

• Not recognizing that the risk of GI bleeding with SSRIs alone is modest but significantly increases when combined with other medications 6, 2
• Failing to consider protective strategies (like PPI co-prescription) for high-risk patients 4
• Not accounting for patient-specific risk factors that may further increase bleeding risk 5
• The magnitude of risk varies between studies, but the most recent and comprehensive meta-analyses consistently show increased risk with combined therapy 6, 2