Role of inflammatory genes in antidepressant-induced sexual dysfunction

Sexual dysfunction (SD) is a frequent adverse effect of antidepressants, affecting 20%-70% of patients. Although some studies have examined serotonergic, dopaminergic, and glutamatergic gene variants, results remain inconclusive. Given the role of inflammatory cytokines in antidepressant response, their genetic variants may also influence SD. The aim of this study is to investigate associations between inflammatory cytokine gene variants and antidepressant-induced SD.

A total of 99 Caucasian patients (51 women, 48 men) in remission or with mild depressive or anxiety symptoms and receiving stable SSRI or SNRI monotherapy were recruited. Participants completed a semistructured interview, clinical assessments, and the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ-SALSEX). DNA samples were genotyped for 61 single nucleotide polymorphisms (SNPs) in 9 cytokine-related genes (IL-1β, IL-2, IL-6, IL-6R, IL-8, IL-10, IL-18, TNF-α, IFN-γ). Analyses included linear and logistic regression, adjusting for age, sex, antidepressant type, dose, and treatment duration. Primary endpoints included the presence and severity of SD, with secondary outcomes focusing on associations between specific SNPs and SD subdomains.

SD was reported by 78.8% of participants, and 57.6% experienced moderate-to-severe impairment; 60.8% did not report symptoms spontaneously. Significant associations were found between SD and polymorphisms in TNF-α, IL-2, IL-1β, IL-6, and IL-18. The TNF-α rs1799724-T allele was associated with a lower risk of SD, particularly delayed orgasm and absence of orgasm, whereas rs1799964-C was associated with an increased risk. The rs361525-A variant showed a protective effect against decreased libido. A TNF-α haplotype (rs1799724-T, rs1799964-T, rs1800629-G, rs3093664-A, rs361525-G) was inversely related to SD scores. IL-2 rs3136534-G increased SD risk, whereas rs1479923-A was protective. IL-1β haplotypes were associated with reduced sexual desire and dysfunction.

This study provides novel evidence linking inflammatory cytokine gene variants, especially TNF-α, to antidepressant-induced SD. These findings support further research into immune-genetic mechanisms underlying antidepressant-associated sexual adverse effects.