Genetic variants in serotonergic pathways and their association with AD resistance in major psychiatric disorders

Introduction: Treatment-resistant depression (TRD) affects approximately one-third of patients with major depressive disorder (MDD) and represents a significant clinical and public health challenge. Genetic factors, particularly within serotonergic pathways, may contribute to individual differences in response to antidepressants (ADs). Methods: We conducted a genetic association study on 107 MDD patients, stratified into low and high AD resistance groups based on failure to respond to at least two adequate AD trials. Genotyping was performed for four serotonergic polymorphisms: 5-HTTLPR (SLC6A4), rs6311, rs6314, and rs7997012 (HTR2A). Group comparisons were analyzed using logistic regression models adjusted for age, sex, and total number of previous ADs. Results: The distribution of specific alleles and genotypes differed between resistance groups, particularly for the HTR2A variants. In fact, the HTR2A rs6311 variant was associated with higher resistance, while rs6314, rs7997012, and 5-HTTLPR showed no significant effects. No significant differences were found in demographic or clinical variables. Haplotype analysis revealed suggestive associations between specific genetic profiles and higher resistance levels. Discussion: These findings support the role of serotonergic gene variants in influencing the outcomes of AD treatment. Pharmacogenomic screening may help identify individuals at risk for TRD and guide personalized treatment strategies. Incorporating genetic testing into clinical workflows may optimize care and reduce the societal burden associated with ineffective AD therapy. Conclusion: These findings support a contributory role of serotonergic genetic variability in AD resistance. In particular, HTR2A-related variants and combined haplotypic effects may influence treatment outcomes. Integrating pharmacogenomic markers into clinical assessment could facilitate personalized therapeutic strategies and improve management of TRD.