Integrating Genetic Variants and Expression Profiles of Pharmacogenes in Treatment- Resistant Depression

Background. Treatment-resistant depression (TRD) is a major clinical challenge in the management of major depressive disorder (MDD). While pharmacogenetics has been suggested to have some clinical utility in guiding antidepressant treatment, only few studies have explored if and how pharmacogenes can be involved in TRD pathophysiology and its clinical outcomes. In this study we explored the role of differences in metabolizer phenotypes, gene expression levels, and microRNAs of three key pharmacogenes (CYP2D6, CYP2C19, and CYP2B6) in TRD pathophysiology and antidepressant response in a cohort of 300 patients with MDD from the PROMPT consortium. Results. CYP2D6 phenotype distribution did not differ significantly between TRD and non-TRD groups, but mRNA expression was significantly upregulated in TRD patients (log fold change [logFC] = 0.35, adj p = 0.0002). Additionally, hsa-miR-26b-5p, a microRNA predicted to regulate CYP2D6, was significantly downregulated in TRD (logFC = -0.62, adj p = 2.5E-05). For CYP2C19, intermediate metabolizers (IM) were underrepresented in TRD compared to non-TRD individuals (IM vs normal metabolizers (NM): χ2 = 6.07, p = 0.019). microRNA hsa-let-7d-5p and hsa-miR-27a-3p, predicted to regulate CYP2C19, were significantly downregulated in TRD (logFC = -0.31, adj p = 0.002; logFC = -0.38, adj p = 0.0008). No significant differences were found for CYP2B6. In the analysis of remission to the last antidepressant trial, only nominally significant differences were reported, which did not survive multiple testing corrections. Conclusions. By investigating high levels of evidence pharmacogenes, this study contributes valuable insights to the PROMPT project on how pharmacokinetic gene variants, their expression and regulatory mechanisms may influence antidepressant response and resistance in MDD.