Pharmacogenetic Characterization of Cytochrome P450 Genes involved in Psychotropic Medication Metabolism in a Cohort of Patients with Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a rare multisystemic disorder characterized by obesity, endocrine dysfunctions, and psychiatric comorbidities, which imply frequent use of psychotropic medications. They account for atypical responses to standard dosages of psychiatric drugs. Pharmacogenetics could be part of the reason for this situation, potentially offering a valuable tool for individualized treatment. This study analyzed allelic and phenotypic frequency distributions of five of the main cytochrome P450 enzymes (CYP2D6, CYP2B6, CYP2C19, CYP2C9, CYP3A4) involved in psychiatric drug metabolism in 47 patients with genetically confirmed diagnosis of PWS and compared them to reference frequencies in the general European population. Allelic frequency comparisons between the European reference population and the overall PWS cohort revealed a significant global difference for CYP2B6, with CYP2C19 and CYP2D6 showing trends toward significance. Although no global allelic differences remained significant after false discovery rate correction, post-hoc analyses consistently identified an enrichment of reduced- or non-functional alleles CYP2B619 and CYP2D610 in patients with PWS. Predicted metabolizer phenotype analyses showed a significant shift toward intermediate metabolizers of CYP3A4 in the PWS cohort, with corresponding depletion of normal metabolizers. Subgroup analyses indicated that allelic differences were more pronounced in maternal uniparental disomy and non-deletion subtypes, particularly for CYP2B6, although no significant differences were observed between PWS genetic subtypes. Overall, results imply potential differences in metabolizing activity in PWS patients, and subsequent implications in drug efficacy and tolerability. These results support the idea that pharmacogenetic testing may improve therapeutic decision-making in PWS for psychiatric treatment. Larger studies are needed to confirm these preliminary results.