This study explored how variations in pharmacodynamic genes influence prolactin elevation in pediatric and adolescent patients with autism spectrum disorder (ASD) receiving risperidone. Using a retrospective cohort of 124 patients treated with risperidone for at least three months, we analyzed multiple gene variants and devised a novel genetic risk scoring system for the dopamine D2 receptor (DRD2) to simplify haplotype interpretation.While single nucleotide polymorphisms (SNPs) alone did not show significant associations with prolactin levels, a specific diplotype combination (H1/H3: A2/A2-Cin/Cin-A/G) spanning DRD2 and ANKK1 Taq1A, DRD2 -141C indel, and DRD2 -141A>G—corresponding to a genetic risk score of 5.5—was linked to the highest median prolactin concentration (23 ng/ml). Patients with this diplotype also exhibited markedly higher prolactin levels in response to increasing plasma concentrations of risperidone, its active metabolite 9-OH-risperidone, and the total active moiety.Interestingly, lower prolactin levels were observed in patients who achieved favorable clinical responses, suggesting an inverse relationship between therapeutic efficacy and hyperprolactinemia. By providing a framework for scoring DRD2 haplotypes based on predicted protein expression, this study establishes a potential tool for guiding pharmacogenetic-informed dosing strategies. Incorporating such genetic information into clinical decision-making may help minimize prolactin-related adverse effects in pediatric ASD patients treated with risperidone.
