Abstract
BACKGROUND: Direct Oral Anticoagulants (DOACs) and antidepressants are often co-administered, but their combined effect on bleeding risk in real-world settings is poorly quantified. This study aimed to evaluate this risk using pharmacovigilance data. METHODS: Data spanning quarter 3 (Q3) 2010 to quarter 1 (Q1) 2025 were analyzed from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, comparing bleeding adverse events reported for DOACs monotherapy versus DOACs combined with antidepressants. Bleeding signals were assessed using the Reporting Odds Ratio (ROR). RESULTS: The proportion of bleeding events was 31.00% (64,165/207,000) in the DOACs monotherapy group versus 57.92% (307/530) in the DOACs-antidepressant combination therapy group. Concomitant use of DOACs with antidepressants was associated with a significant increase in overall bleeding risk (reporting odds ratio [ROR] = 1.45, 95% confidence interval [CI]: 1.29-1.63). Selective serotonin reuptake inhibitors (SSRIs) presented the highest class risk (ROR 1.78, 95% CI 1.54-2.04), with apixaban plus paroxetine showing the strongest signal (ROR 14.12, 95% CI 7.62-26.15). Nervous system bleeding was also elevated (ROR 1.86, 95% CI 1.44-2.40). Notably, mirtazapine significantly increased nervous system bleeding risk (ROR 9.83, 95% CI 4.92-19.67) despite its non-SSRI mechanism. CONCLUSION: Co-administration of antidepressants and DOACs significantly elevates bleeding risk, especially for the nervous system. Clinicians must exercise heightened caution, particularly with SSRIs and when using mirtazapine, and further validation studies are needed.