Novel strategies for pharmacogenetic and metabolomic analysis of antidepressant treatment response in depression

Introduction Major Depressive Disorder (MDD) is a global burden whose treatment with antidepressant drugs (ATDs) is modestly effective. Predictors of ATD response may help improve therapeutic outcomes. Hundreds of biological associations are observed at both the genetic and metabolomic level, but novel methods, tools, and strategies continue to evolve, opening new avenues of analysis. The objective of this thesis is to leverage novel strategies to explore the association of genetic variation within candidate genes with clinical outcomes and metabolite concentrations following ATD treatment. Methods This work is based on the analysis of data from METADAP, a prospective, multicentric, and naturalistic cohort of 624 patients between 18 and 65 years of age suffering from a major depressive episode (MDE) in the context of MDD and requiring a new ATD treatment. Patients underwent clinical and biological evaluation at inclusion and 1, 3, and 6 months after beginning ATD treatment. Analyzed data included clinical measures, genetic data from a high-throughput sequencing gene panel or TaqMan genotyping, and serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations. Results 1) the ERICH3 rs11580409(A>C) genetic polymorphism was associated with clinical improvement, but not 5-HT levels, following ATD treatment in depressed patients; 2) the A allele of the MAOA rs979605(A>G) genetic polymorphism was associated with worse clinical improvement in females compared to males, while the MAOB rs1799836(T>C) genetic polymorphism was associated with the plasma 5-HIAA/5-HT ratio; 3) rare ARRB1 genetic variation accumulation and two ARRB1 genetic polymorphisms with potential functional consequences, rs553664(G>A) and rs536852(A>G), were associated with worse clinical outcomes; 4) across a candidate gene panel, SLC1A1 genetic variation was most associated with clinical measures; the C allele of the SLC1A1 rs301435(T>C) genetic polymorphism was associated with worse clinical improvement. Conclusion This work leveraged novel strategies to reveal several associations between candidate genetic variation and clinical outcomes following ATD treatment. Several context-dependent associations are suggested by these findings. However, most remain associations requiring independent replication and functional validation in the context of ATD treatment for MDD.