The Impact of Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants on the Risk of Gastrointestinal Bleeding : A Systematic Review of Randomized Controlled Trials and Controlled Observational Studies

Introduction: Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressants worldwide. Chronic SSRI use depletes intraplatelet serotonin via serotonin transporter (SERT) blockade, impairing platelet aggregation. This pharmacodynamic effect, compounded by increased gastric acid secretion and cytochrome P450 interactions, provides a biological rationale for elevated gastrointestinal (GI) bleeding risk. Methods: The study strictly adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines. Eligible studies included RCTs or controlled observational studies enrolling adults exposed to SSRIs, reporting GI bleeding with adjusted effect estimates. Two reviewers independently screened records, extracted data, and appraised quality using RoB 2 and Newcastle-Ottawa Scale. Fourteen outcome domains were pre-specified; narrative synthesis with GRADE certainty assessment was performed. Results: Twenty-three studies (3 RCTs, 20 observational) encompassing >2 million individuals were included. SSRI exposure was consistently associated with upper GI bleeding (adjusted estimates 1.22–3.00; representative: OR 1.67, 95% CI 1.46–1.92; HR 1.97, 95% CI 1.67–2.31). Lower GI bleeding was also increased (HR 2.96, 95% CI 2.46–3.57). Risk was markedly amplified by concurrent NSAIDs (pooled OR 4.25, 95% CI 2.82–6.42) and triple therapy with NSAID plus aspirin (OR 28, 95% CI 7.6–103). Oral anticoagulant co-exposure increased major bleeding by one-third (IRR 1.33, 95% CI 1.24–1.42), peaking in the first 30 days (IRR 1.74, 95% CI 1.37–2.22). Proton pump inhibitor co-therapy attenuated risk (OR 0.39, 95% CI 0.16–0.94). A SERT-affinity gradient was demonstrated (RR 1.17, 95% CI 1.02–1.34). Risk emerged within 7–14 days and declined with prolonged exposure. Absolute excess risk rose from 2.0 to 7.9 per 1000 person-years across declining renal function strata. Once bleeding occurred, SSRI use did not increase refractory bleeding, rebleeding, or 30-day mortality. Discussion: The association is consistent across diverse designs, including self-controlled studies eliminating time-invariant confounding. The SERT-affinity gradient, short latency, and multiplicative interactions support causality. However, absolute risk remains very low in young, healthy patients; the clinically actionable finding is risk stratification and mitigation rather than SSRI avoidance. Conclusion: SSRIs are associated with a modest (~40–70%) relative increase in GI bleeding risk, which rises substantially with NSAID, aspirin, or anticoagulant co-prescription. Absolute risk is low in low-risk populations. Routine SSRI avoidance is not warranted; systematic bleeding-risk stratification, preferential use of low-SERT-affinity agents in high-risk patients, and proton pump inhibitor co-prescription constitute the appropriate clinical response.