Association of 5-HTTLPR/rs25531 polymorphism with escitalopram induced adverse effects in Pakistani patients of Major Depressive Disorder

Inter-individual variability in adverse effects to Selective Serotonin Reuptake Inhibitors (SSRIs) remains a major challenge in the treatment of Major Depressive Disorder (MDD). Functional genetic variation in the serotonin transporter gene (SLC6A4), particularly 5-HTTLPR and rs25531 polymorphisms, may contribute to differences in treatment tolerability. This study investigated the association of 5-HTTLPR/rs25531 variants with the occurrence and severity of escitalopram-related adverse effects in patients with MDD. This prospective observational analytical study included 430 adults with newly diagnosed MDD who received escitalopram and were followed for 12 weeks. Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HAMD-17). Adverse effects were evaluated using the Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale at baseline and at weeks 4, 8, and 12. To capture adverse effects occurring at any stage of treatment, the maximum UKU score recorded during the 12-week follow-up was used for the primary tolerability analysis. The 5-HTTLPR polymorphism was genotyped using PCR, followed by agarose gel electrophoresis to identify SS, SL, and LL genotypes. The rs25531 variant was determined using restriction fragment length polymorphism (RFLP) analysis. Genetic associations were assessed according to biallelic genotypes, 5-HTTLPR/rs25531 diplotypes, and functional groups (0L, 1L, and 2L). Clinically significant adverse effects were observed in 253 of 430 participants (58.8%). The occurrence and severity of adverse effects differed significantly across 5-HTTLPR genotypes, 5-HTTLPR/rs25531 diplotypes, and functional groups. Participants carrying the S allele and those classified in the 0 L functional group (SS, SLG, LGLG) experienced a greater adverse-effect burden, whereas LALA carriers or 2 L functional group, had comparatively lower UKU scores. These associations remained statistically significant. Functional genetic variation in SLC6A4 was associated with differences in the occurrence and severity of escitalopram-related adverse effects in patients with MDD. These findings suggest that 5-HTTLPR/rs25531 variation may contribute to inter-individual differences in escitalopram tolerability. Further prospective studies in independent populations are required to establish the reproducibility and potential clinical relevance of these associations. • In this prospective observational study of Pakistani patients with major depressive disorder treated with escitalopram, variation in the serotonin transporter gene (5-HTTLPR/rs25531) was associated with both the occurrence and severity of treatment-emergent adverse effects. • Individuals carrying S and LG alleles (0 L functional group), experienced a greater burden of adverse effects and highly likelihood of clinically significant side effects compared with LALA carriers (2 L functional group). • The findings suggest that genetic differences in serotonin transporter expression may contribute to inter-individual variability in escitalopram tolerability and warrants further investigations as a potential pharmacogenetic marker. • Given the observational design, causal inferences regarding relationship between genetic variations and adverse outcomes cannot be established. • The analysis was limited to escitalopram and a selected SLC6A4 gene variations, and did not account for other pharmacogenetic (including CYP2C19 variations) or environmental factors that may influence antidepressant tolerability. • Adverse effects were assessed over a 12-week follow-up period, and longer-term tolerability outcomes or delayed adverse effects beyond this timeframe were not evaluated.