Individualized pharmacogenomics for depressive episodes: A narrative review.

Abstract

Major depressive disorder (MDD) and bipolar disorder (BD) are highly prevalent psychiatric conditions, both characterized by depressive episodes and associated with substantial disability, marked clinical heterogeneity, and variable responses to pharmacological treatment. Despite the widespread use of antidepressants and antipsychotics, a significant proportion of patients experience delayed therapeutic response, adverse drug reactions, or treatment resistance, due to interindividual biological variability. In this context, pharmacogenomics has emerged as a key strategy to address this challenge by integrating genetic variability with pharmacokinetic and pharmacodynamic mechanisms to inform personalized treatment decisions. This narrative review aims to: (i) summarize key pharmacogenes and genetic variants implicated in the pharmacological treatment of MDD; (ii) differentiate genes with established clinical actionability from those requiring further evidence; and (iii) evaluate their current and future roles in precision psychiatry. Evidence was synthesized from curated pharmacogenomic guideline resources, including the Clinical Pharmacogenetics Implementation Consortium (CPIC), the Pharmacogenomics Knowledge Base (PharmGKB), and the Dutch Pharmacogenetics Working Group (DPWG). Robust and replicated evidence supports the clinical employ of the pharmacokinetic genes CYP2D6 and CYP2C19, for which genotype-informed prescribing recommendations are available and have demonstrated benefits in optimizing drug exposure, reducing adverse effects, and improving treatment outcomes, particularly for selective serotonin reuptake inhibitors (SSRIs). CYP3A4 and CYP1A2 contribute substantially to the metabolism of many psychotropic drugs and influence dosing through both genetic and environmental modifiers (e.g., enzyme inducers/inhibitors and smoking), although formal guideline-level recommendations remain limited for a small subset of substrates. In contrast, pharmacodynamic and regulatory genes, including COMT, FKBP5, HTR2A, SLC6A4, and MTHFR, represent promising avenues for future clinical implementation. Polygenic risk scores for antidepressant response (PRS-AD) capture the highly polygenic architecture of treatment outcomes but, at present, lack the predictive performance required for routine clinical use, particularly across non-European ancestries. Randomised trials and meta-analyses (GUIDED, PRIME Care, IGNITE-network and others) provide moderate evidence that pharmacogenomic-guided prescribing modestly improves remission, response, and side-effect burden; however, the magnitude and durability of benefit remain under active debate. Pharmacogenomic testing therefore represents a clinically informative - though not curative - adjunct to psychiatric care; its full potential will be achieved by combining routine guideline-based testing of validated pharmacogenes with ongoing translational research on emerging candidates and polygenic models.