Dynamic Epigenetic Changes During Antidepressant Pharmacotherapy in Major Depressive Disorder

Background: Although antidepressants remain the main pharmacological treatment for major depressive disorder (MDD), therapeutic response is highly variable, highlighting the need for reliable markers that predict and mechanistically explain treatment outcomes. Previous candidate-gene and cross-sectional epigenome-wide association studies (EWASs) have suggested DNA methylation signatures associated with antidepressant response; however, findings are inconsistent. To date, no longitudinal EWAS has systematically examined dynamic methylation changes across multiple time points during antidepressant treatment to identify early epigenetic markers of response. Methods: Within the Early Medication Change trial, DNA methylation data was generated for 162 patients with MDD (81 responders, 81 non-responders) and 48 matched healthy controls. Patient samples were collected at four time points during eight weeks of standardized antidepressant treatment, and controls were assessed twice. Longitudinal EWASs were performed to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) were identified using the comb-p algorithm. Results: Baseline methylation was associated with treatment outcome at day 56 through six DMRs (e.g., TNRC6C, CAT, CCNY), whereas no DMP reached significance. Longitudinal analyses identified one DMP linked to clinical improvement (YLMP1) and three DMRs with time effects (GPR126, C20orf54, PM20D1). Combined patient-control analyses revealed additional DMPs and DMRs associated with diagnosis and temporal changes. Conclusions: This study provides the first longitudinal evidence of dynamic, regionally coordinated methylation changes during antidepressant pharmacotherapy in MDD. These alterations occur in genes involved in neuroplasticity and inflammation and are linked to clinical response. Defining such methylation signatures as predictive or mechanistic markers could advance personalized treatment strategies for MDD, though replication and functional validation in larger cohorts remain essential.