Evaluation of the relationship between methylphenidate treatment and CES1 and SLC6A2 gene polymorphisms in attention-deficit/hyperactivity disorder

Objectives: This study investigated the association between polymorphisms in the CES1 and SLC6A2 genes and methylphenidate treatment response and side effects in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). This is the first study to co-analyze these genes using next-generation sequencing in the Turkish population. Materials and Methods: The study included 48 children and adolescents with ADHD diagnosed according to the DSM-5-TR criteria. Clinical response and side effects were evaluated before and in the second month of treatment using the Conner's Parent Rating Scale (CPRS), Turgay Disruptive Behavior Disorders Screening and Rating Scale (T-DBDSRS), Weiss Functional Impairment Rating Scale–Parent Form (WFIRS-P), and Barkley Stimulant Side Effect Rating Scale (BSSERS). DNA isolated from blood samples was analyzed using targeted next-generation sequencing (tNGS) to examine the exons and exon-intron boundaries of the CES1 and SLC6A2 genes. The genotypes were then compared with the clinical outcome data. Results: Variants rs112236246, rs2307229, and rs3217164 in CES1 were significantly associated with methylphenidate treatment response. In the SLC6A2 gene, variants rs15534, rs5568, and rs1800887 were associated with drug-related side effects. Furthermore, the 'CTCTC' haplotype involving both genes was more frequent in the responder group, approaching statistical significance (p=0.05). Conclusion: Our findings suggest that CES1 variants could be potential biomarkers for predicting methylphenidate response, while SLC6A2 variants could predict the side effect profile. This study highlights the importance of transitioning to pharmacogenetic-based personalized medicine for the treatment of ADHD. Keywords: CES1, SLC6A2, Attention-Deficit/Hyperactivity Disorder, Methylphenidate, Pharmacogenetics