Genetic and epigenetic determinants of cytochrome P450 activity in psychopharmacology: from pharmacogenetics to functional pharmacogenomics.

Classical pharmacogenetics has explained interindividual variability in psychotropic drug response primarily through inherited polymorphisms in cytochrome P450 enzymes. This framework successfully identified extreme metabolizer phenotypes and informed genotype-guided dosing recommendations. However, genotype-based predictions frequently correlate more strongly with pharmacokinetic parameters than with clinical outcomes. Patients sharing similar CYP genotypes often exhibit divergent therapeutic trajectories, while metabolic phenotypes may change during treatment without corresponding alterations in DNA sequence. These observations suggest the existence of a genotype-phenotype gap mediated by regulatory processes not captured by genotyping alone. Evidence from epigenetic regulation, environmental modulation of pharmacogene expression, and phenoconversion indicates that metabolic capacity is better understood as a dynamic functional state rather than a fixed inherited trait. This review examines the role of these mechanisms in psychiatric pharmacotherapy and explores the implications of shifting the predictive focus of precision medicine from static genotype to functional state.