Depression significantly elevates mortality risk, yet the long-term survival impact of antidepressant medications (ADMs) remains uncertain. This study examines ADMs utilization trends (2005-2018) and quantifies their role in depression-related mortality within a nationally representative cohort

Data from seven NHANES cycles (2005–2018; n  = 11,569 adults) were analyzed. Depression was defined by patient health Questionnaire-9 ≥ 10. ADMs exposure was pharmacy-verified and classified (SSRIs, SNRIs, TCAs, others). Mortality linkage extended through 2019. Weighted logistic regression assessed depression-mortality associations with sequential adjustment for sociodemographics, cardiometabolic comorbidities, and lifestyle. Mediation analyses quantified ADMs' pathway effects, while stratified models examined class-specific hazard ratios (HRs)

Depression independently increased all-cause mortality risk by 61 % (fully adjusted OR = 1.61, 95 %CI:1.24–2.08). ADMs usage mediated 27.3 % of depression's mortality burden ( P   <  0.001). Prescribing trends showed SSRIs dominating utilization ( > 75 %; 12.7 % → 20.1 %), SNRIs exhibiting rapid growth (3.4 % → 6.1 %), and TCAs declining (2.5 % → 1.8 %). Crucially, ADM classes showed differential mortality effects: SNRIs were associated with reduced mortality risk (HR = 0.72), SSRIs neutral (HR = 0.93), while TCAs increased risk (HR = 1.19)

While depression imposes substantial mortality independent of comorbidities, ADMs selection modifies this risk. Though residual antidepressant selection bias effects cannot be ruled out, SNRIs demonstrate protective survival benefits, supporting their preferential use in high-risk populations versus TCAs. These findings underscore ADMs class as a critical effect modifier in depression management and highlight the need to integrate pharmacoepidemiologic evidence into clinical practice