2026 ECNP Congress

EP02-2035

Association of CES1/SLC6A2 gene polymorphisms with clinical outcomes of methylphenidate treatment in attention-deficit/hyperactivity disorder in a Turkish paediatric cohort

Melik Yiğit Bayindir — K.C. Pekkoc-Uyanik, M.F. Akdemir, A. Aydin-Okuyan, B. Yildiz-Bayindir, B. Mercan, M.C. Tarakcioglu, B. Dogangun, S. Ozyazgan, Z.G. Todurga-Seven · Istanbul University-Cerrahpasa Cerrahpasa Medical Faculty, Department of Medical Pharmacology, Istanbul, Türkiye

2026 ECNP Congress

Background

Methylphenidate (MPH) is a first-line treatment for attention-deficit/hyperactivity disorder (ADHD), yet efficacy and tolerability vary considerably across paediatric patients [1]. Because MPH exposure is largely shaped by carboxylesterase 1–mediated metabolism, genetic variation in the carboxylesterase 1 (CES1; MPH metabolism) gene may contribute to interindividual variability in MPH pharmacokinetics [2]. In parallel, variation in noradrenergic pathway genes, including solute carrier family 6 member 2 (SLC6A2; norepinephrine transporter), may influence MPH-related clinical response [3]. Evidence remains limited regarding the simultaneous assessment of CES1 and SLC6A2in non-European paediatric cohorts, particularly in studies evaluating both treatment response and tolerability [4]. A genotype-informed evaluation may therefore inform safer, more individualised prescribing [5].

Aims

To examine the contribution of CES1(pharmacokinetic) and SLC6A2(pharmacodynamic) gene variations to interindividual differences in MPH treatment response and tolerability in Turkish children and adolescents with ADHD, using a targeted next-generation sequencing approach.

Methods

The study protocol was approved by the Clinical Research Ethics Committee of Istanbul University–Cerrahpaşa, Cerrahpaşa Faculty of Medicine on 11 June 2024 (decision no. 1014531). Written informed consent was obtained from the parents of all participating children. Forty eight children and adolescents with ADHD were prospectively treated with MPH for 2 months. Response was assessed by improvement on the Conners Parent Rating Scale (CPRS) and the Turgay DSM-based Disruptive Behavior Disorders Rating Scale (T-DBDRS); treatment-related adverse effects were rated using the Barkley Stimulant Side Effect Rating Scale (BSSERS). CES1 and SLC6A2 were genotyped from genomic DNA using targeted next-generation sequencing. Variant associations were tested under genotypic, dominant, and allelic models using chi-square or Fisher’s exact tests, as appropriate; combined CES1and SLC6A2effects were explored by haplotype analysis.

Results

Six variants were analysed; CES1(rs112236246, rs2307229, rs3217164) and SLC6A2(rs15534, rs5568, rs1800887). According to CPRS, CES1rs112236246 was associated with response under genotypic, dominant, and allelic models (p = 0.019, p = 0.032, p = 0.010, respectively). Additional associations were observed for rs2307229 under two genotypic (p = 0.002 and p = 0.034) and one dominant model (p = 0.002), and for rs3217164 under genotypic, dominant, and allelic models (p = 0.035,p = 0.013, p = 0.009, respectively). rs112236246 was also significant under the genotypic model using T-DBDRS (p = 0.025). BSSERS analysis showed associations for rs15534 (allelic p = 0.041), rs5568 (genotypic and dominant; p = 0.049, p = 0.041, respectively), and rs1800887 (genotypic, dominant, and allelic; p = 0.049, p = 0.043, p = 0.015, respectively). The CES1 and SLC6A2 genes“CTCTC” haplotype was showed a trend toward higher frequency in responders (16.0% vs. 3.4%, p = 0.053).

Conclusions

This study suggests that variability in MPH efficacy and tolerability in youth with ADHD may be associated with CES1and SLC6A2gene variations. These findings support a clinically relevant pharmacokinetic / pharmacodynamic framework for future individualised MPH treatment strategies in routine paediatric clinical care. Replication in larger, independent, and more diverse cohorts is warranted to validate these results and further clarify the contribution of less frequent variants to treatment response.

Keywords: ADHD, Methylphenidate, CES1, SLC6A2, Next-generation sequencing.

References

  1. Cortese S. Pharmacologic Treatment of Attention Deficit-Hyperactivity Disorder. N Engl J Med. 2020;383(11):1050-1056.
  2. Sun Z, Murry DJ, Sanghani SP, et al. Methylphenidate is stereoselectively hydrolyzed by human carboxylesterase CES1A1. J Pharmacol Exp Ther. 2004;310(2):469-476.
  3. Yuan D, Zhang M, Huang Y, Wang X, Jiao J, Huang Y. Noradrenergic genes polymorphisms and response to methylphenidate in children with ADHD: A systematic review and meta-analysis. Medicine (Baltimore). 2021;100(46):e27858.
  4. Myer NM, Boland JR, Faraone SV. Pharmacogenetics predictors of methylphenidate efficacy in childhood ADHD. Mol Psychiatry. 2018;23(9):1929-1936.
  5. Brown JT, Beery N, Taran A, et al. Associations between CES1 variants and dosing and adverse effects in children taking methylphenidate. Front Pediatr. 2023;10:958622.