The gain-of-function variant in the NLRP3 gene predicts the effectiveness of brief psychotherapy but not the risk of major depression

Major depressive disorder (MDD) is a highly prevalent psychiatric condition whose pathophysiology has been linked to neuroinflammatory processes involving the NLRP3 inflammasome. To address this point, the study investigated the association of the NLRP3 rs10754558 polymorphism with MDD diagnosis in a young adults population based study and the effectiveness of brief psychotherapies in a randomized clinical trial. A cross-sectional, population-based study was conducted with 1100 individuals aged 18-35 years, including 615 controls and 485 patients with MDD. Diagnosis was determined using the Mini International Neuropsychiatric Interview (M.I.N.I.) based on DSM-IV criteria. Our clinical trial included 227 participants with MDD aged 18-60 years from a randomized clinical trial evaluating the effectiveness of two brief psychotherapies for MDD. Depressive and anxiety symptoms were assessed at baseline, post-treatment (16-18 weeks), and 6-month follow-up using the Beck Depression Inventory-II (BDI-II) and the Beck Anxiety Inventory (BAI). Statistical analyses included logistic regression and generalized estimating equation (GEE) model adjusted for demographic and clinical variables. The results showed no significant association between rs10754558 genotypes and MDD diagnosis. However, when evaluating the efficacy of brief psychotherapies, the GG genotype was associated with poorer treatment outcomes for both depressive and anxiety symptoms compared to the GC/CC genotypes (p < 0.05). Longitudinal analysis revealed significant differences over time, with GG individuals demonstrating less symptom improvement (BDI-II: baseline 36.61 to follow-up 21.75; BAI: baseline 26.32 to follow-up 19.55) compared to GC/CC genotypes (BDI-II: baseline 32.05 to follow-up 20.29; BAI: baseline 22.05 to follow-up 17.96). These findings suggest that the GG genotype, previously characterized as a gain-of-function variant, may contribute to genetic heterogeneity influencing psychotherapy outcomes. This highlights the potential for genetic markers, such as rs10754558, to inform personalized psychiatric treatments and improve therapeutic strategies.