Pharmacogenetics of the efficacy and side effects of antidepressant drugs

Abstract

Both major depressive disorder (MDD) and antidepressant drug efficacy show an established evidence of being significantly affected by genetic polymorphisms. Thus, the pharmacogenetics of antidepressants has developed since the 1990s as a promising tool to produce tailored treatments of MDD. Candidate gene studies were focused on a limited number of genes that were suggested to be involved in antidepressant mechanisms of action by preclinical evidence. Particularly, candidate studies provided quite replicated findings for the serotonin transporter gene (SLC6A4), brain-derived neurotrophic factor (BDNF), some subtypes of serotonin receptors (e.g., HTR2A), and genes involved in antidepressant metabolism and transport (e.g., ABCB1). Genome-wide association studies (GWAS) overcame the need of any a priori hypothesis and allowed the study of hundreds of thousands of polymorphisms throughout the whole genome. GWAS provided interesting signals in some individual genes (e.g., IL-11, NRG1, and RORA), but they also allowed to carry out more comprehensive analysis (e.g., pathway analysis), opening new perspectives. Some pilot studies recently supported the clinical applicability of genotyping to tailor antidepressant treatments. A combinatorial categorization approach based on polymorphisms in cytochrome P450 genes (CYP2D6, CYP2C19, CYP2C9, and CYP1A2), SLC6A4 and HTR2A genes, was demonstrated to predict healthcare utilization and disability claims in patients treated with antidepressant drugs. Confirmations and further improvements of this tool are expected to receive recommendation for application in clinical practice according to specific guidelines.