Serotonergic Antidepressant Initiation is Associated with Increased Platelet Inhibition Variability After Lower Extremity Revascularization.

Abstract

Depression affects 20% to 37% of patients with peripheral artery disease, frequently requiring serotonergic antidepressants while receiving antiplatelet therapy concomitantly after vascular intervention. Because platelets depend entirely on the serotonin transporter for serotonin uptake, serotonergic agents may alter platelet function in this setting. Hence, we aimed to determine whether serotonergic antidepressant exposure is associated with longitudinal instability in adenosine diphosphate (ADP)-mediated platelet inhibition. In this retrospective cohort study of prospectively enrolled patients with PAD undergoing lower extremity revascularization (December 2020-December 2025) at a single US tertiary care center, serial thromboelastography with platelet mapping (TEG-PM) data (December 2020-December 2025) were used to construct consecutive-visit pairs. The primary outcome was visit-to-visit variability in ADP-mediated platelet inhibition, defined as log-transformed absolute change between consecutive measurements, capturing larger visit-to-visit change regardless of direction. Serotonergic antidepressant exposure (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, or trazodone) was evaluated both as active exposure at the current assessment within each consecutive measurement pair and as a 4-level transition variable: stable non-exposure ((0→0), reference), initiation(0→1, exposure onset between two sequential assessments), discontinuation (1→0), and stable exposure (1→1). Associations were estimated using adjusted linear mixed-effects model. Prespecified exploratory analyses were performed in the chronic limb threatening ischemia (CLTI) subgroup. Among 514 enrolled cases, 330 contributing 896 consecutive-visit pairs were included; 307 patients contributed 838 consecutive-visit pairs in the complete case adjusted analysis. Active serotonergic exposure was not independently associated with greater longitudinal variability in platelet inhibition (β=0.135; 95% CI, -0.901 to 0.360; p=0.240). However, serotonergic initiation was associated with increased variability compared with stable non-exposure (β=0.571, 95% CI, 0.144 to 0.998; p=0.009), persisting after adjustment for psychiatric diagnosis burden. Discontinuation showed a borderline association (β=0.405, p=.05); stable exposure was not associated with greater variability (β=0.105, p=.40). Ticagrelor use was independently associated with lower variability in primary adjusted models (β= -0.521, 95% CI, -0.901 to -0.141; p=0.008). In exploratory chronic climb-threatening ischemia (CLTI) analyses, initiation was associated with a 19.7 percentage point mean upward shift in ADP-mediated platelet inhibition (95% CI, 3.9-35.6, p=0.015) and higher odds of entering a high-inhibition range previously linked to bleeding risk (OR 7.61, 95% CI 1.32-43.96, p=0.023). Serotonergic antidepressant initiation, rather than stable ongoing therapy, was associated with increased instability in ADP-mediated platelet inhibition after lower extremity revascularization. These findings identify the peri-initiation window with implications for medication reconciliation in vascular surgery patients and raise the hypothesis that background P2Y12 regimen consistency may modulate the magnitude of serotonergic medication-induced platelet instability.