Antidepressant Use and Circulating Lipoprotein(a) Levels: A UK Biobank Analysis Including LPA Variant Carriers

Experimental studies suggest that serotonergic antidepressants may enhance hepatic uptake of lipoprotein(a) [Lp(a)] through serotonin-dependent endocytic pathways, but whether antidepressant use is associated with circulating Lp(a) concentrations in humans remains unknown. We evaluated the cross-sectional association between antidepressant use and circulating Lp(a) and apolipoprotein(a) [apo(a)] levels in a large population-based cohort. We analyzed UK Biobank data including serum Lp(a) measured by immunoturbidimetry (n=365,459) and plasma apo(a) quantified by Olink proteomics (n=38,937). Antidepressant use and Lp(a)/apo(a) measurements were ascertained at the same baseline assessment. Multivariable linear regression models assessed associations of three selective serotonin reuptake inhibitors (SSRIs; citalopram, sertraline, paroxetine), two tricyclic antidepressants (TCAs; imipramine, amitriptyline), and combined exposure groups with rank-based inverse normal transformed Lp(a) and apo(a) levels. Analyses were performed in the full cohort, restricted to European ancestry, and among carriers of the LPA variants rs3798220 and rs10455872. Across 112 prespecified models, no antidepressant was significantly associated with Lp(a) or apo(a) levels after Bonferroni correction (P < 4.5 × 10-4). Regression coefficients were uniformly small with no consistent pattern in magnitude or direction. Results were consistent across Lp(a) and apo(a) assays and ancestry strata; carrier-restricted analyses were generally concordant but less precise because of smaller sample sizes. In this large cross-sectional population-based study, SSRI and TCA use were not associated with circulating Lp(a) or apo(a) levels. Small, dose-dependent, duration-dependent, or within-person treatment effects cannot be excluded. Further mechanistic and longitudinal studies are warranted to clarify serotonergic influences on Lp(a) metabolism.