Concurrent Antidepressant Use and Metastasis Risk Among Women Receiving Tamoxifen for Breast Cancer: A Real‐World Cohort Study

ABSTRACT Objective Concurrent use of antidepressants, particularly cytochrome P450 2D6 (CYP2D6) inhibitors, may reduce tamoxifen bioactivation and effectiveness. However, the clinical significance of this potential interaction remains inconclusive. This study examined whether concurrent antidepressant use is associated with increased metastasis risk among women receiving tamoxifen for nonmetastatic breast cancer. Methods We conducted a cohort study using the Merative MarketScan Database. Eligible women with nonmetastatic breast cancer were followed from tamoxifen initiation until metastasis, disenrollment, or study end, whichever occurred first. Patients were classified as concurrent users (tamoxifen with overlapping antidepressant prescriptions) or nonusers (tamoxifen only). Time‐dependent Cox models estimated metastasis risk. Analyses were stratified by concurrent exposure duration and CYP2D6 inhibition degree and adjusted for relevant covariates. Results Among 14,771 women (mean age: 51 ± 10 years), 4780 (32.4%) used tamoxifen concurrently with an antidepressant, most commonly moderate inhibitors ( n = 1815) and least commonly strong inhibitors ( n = 427). Median overlap duration was 8 months (IQR: 3–20). During follow‐up, 443 patients (3.0%) developed metastasis: 161 of 4780 concurrent users (3.4%) versus 282 of 9991 nonusers (2.8%). Concurrent antidepressant use was not significantly associated with metastasis risk (HR = 0.99; 95% CI: 0.81–1.21). Exposure duration was also not significantly associated with metastasis. Use of mixed‐inhibitor regimens was associated with higher risk in partially adjusted models (HR = 1.39; 95% CI: 1.04–1.87), though full adjustment attenuated the association. Conclusions Concurrent antidepressant use was not significantly associated with increased metastasis risk among women receiving tamoxifen for nonmetastatic breast cancer. Individualized and coordinated decisions regarding antidepressant selection may help balance cancer control goals with the psychological and symptomatic management needs in this population.