Dynamic Epigenetic Changes During Antidepressant Pharmacotherapy in Major Depressive Disorder

Although antidepressants remain the main pharmacological treatment for major depressive disorder (MDD), therapeutic response varies, highlighting the need for molecular markers that predict treatment response, as well as insights into the biological processes underlying antidepressant efficacy. Candidate-gene and cross-sectional epigenome-wide association studies (EWAS) have reported DNA methylation signatures associated with antidepressant response; however, findings remain inconsistent. To date, no longitudinal EWAS has examined methylation trajectories across multiple time points during antidepressant treatment in MDD. 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. Patients were assessed at four times across eight-weeks of standardized antidepressant treatment, while controls were assessed twice. Differentially methylated positions (DMPs) and regions (DMRs) were identified using longitudinal EWAS models and the comb-p algorithm. Baseline methylation levels were associated with depressive symptom severity at day 28 and day 56 through two and six DMRs, respectively (e.g., TNRC6C , CAT ), whereas no single DMP reached significance. Longitudinal analyses identified one DMP associated with improvement in depressive symptoms ( YLMP1 ) and three DMRs showing methylation changes over time (e.g., GPR126, PM20D1) . Combined patient-control analyses revealed additional DMPs and DMRs associated with diagnosis and temporal effects. This study provides first longitudinal evidence of regionally coordinated DNA methylation changes during antidepressant pharmacotherapy, revealing alterations in genes involved in neuroplasticity and inflammatory processes that are associated with clinical response. Replication and functional validation will be essential to determine their relevance for personalized antidepressant treatment.