Pharmacogenetics of antidepressant response: a focused review on CYP2C19, CYP2D6, SLC6A4, and HTR2A polymorphisms

Abstract

Pharmacogenetics has redefined the understanding of antidepressant response by demonstrating that genetic variability profoundly influences both drug efficacy and safety. This review synthesizes current evidence on the impact of pharmacokinetic and pharmacodynamic polymorphisms in guiding antidepressant therapy, focusing on the cytochrome P450 enzymes CYP2C19 and CYP2D6, as well as the serotonergic genes SLC6A4 and HTR2A. A comprehensive literature search in NCBI and Google Scholar (2017–2024) identified recent meta-analyses and clinical studies evaluating genotype–phenotype associations in patients treated with selective serotonin reuptake inhibitors (SSRIs). Findings indicate that CYP2C19 and CYP2D6 polymorphisms markedly affect plasma concentrations, therapeutic outcomes, and adverse-event risk—where poor metabolizers exhibit increased efficacy but greater toxicity, while ultrarapid metabolizers show reduced therapeutic response. Likewise, functional variants such as SLC6A4 (5-HTTLPR) and HTR2A modulate serotonin transporter availability and receptor sensitivity, influencing clinical improvement and tolerability, especially in interaction with environmental stressors. The integration of these genetic markers into conceptual clinical frameworks enables more rational antidepressant selection, personalized dosing, and minimization of adverse reactions, demonstrating that both pharmacokinetic and pharmacodynamic polymorphisms jointly contribute to antidepressant efficacy within a stepwise precision-medicine approach.