Objective: To determine whether genetic variants in a pharmacokinetic gene (the number of
CYP2C19 reduced function alleles [RFAs]), and in pharmacodynamic genes (HTR2A, SLC6A4, and GRIK4) influence
sertraline tolerability and response in a cohort of pediatric patients with anxiety and
depressive disorders. Methods: A retrospective analysis was performed using the electronic medical record data of 352 patients <19 years of age being treated for anxiety and/or
depressive disorders with
sertraline and who underwent routine clinical
CYP2C19 genotyping. Additional genotyping and analysis of variants in HTR2A, SLC6A4, and GRIK4 were conducted for 249 patients. Multivariate regression models testing for associations with
CYP2C19 were adjusted for concomitant use of interacting medications. Combinatorial classification and regression tree (CART) analyses containing all pharmacokinetic and pharmacodynamic genes and clinical factors were performed. Results: The maximum
sertraline dose during the initial titration period of
sertraline was inversely associated with the number of
CYP2C19 RFAs and
sertraline dose at 60 (p = 0.025) and 90 days (p = 0.025). HTR2A rs6313 was associated with
sertraline dose (p = 0.011) and time to the average maximum
sertraline dose (p = 0.039). Regarding efficacy, the number of
CYP2C19 RFAs was not associated with the
sertraline dose at the time of response (p = 0.22), whereas for the pharmacodynamic genes, only HTR2A rs6313 was associated with response dose (p = 0.022). An association was observed between predicted expression levels of SLC6A4 and the duration on
sertraline (p = 0.025). Combinatorial CART and multivariate regression analyses implicated that pharmacodynamic genes and clinical factors influence the maximum
sertraline dose and response dose. The total number of side effects was not associated with any of the variants tested. Conclusion: Both pharmacokinetic and pharmacodynamic factors, in addition to clinical and demographic components, influence
sertraline dose, response, and tolerability, thereby necessitating further research to assess for the validity of these pharmacogenetic associations in children and adolescents.