Epigenetic profiles of response to transcranial magnetic stimulation in treatment resistant depression

Background Transcranial magnetic stimulation (TMS) is an established treatment for major depressive disorder (MDD), yet response rates remain suboptimal and biomarkers predictive of treatment outcomes are currently lacking. Recently, DNA methylation (DNAm) has shown promise as an epigenetic predictor of antidepressant and electroconvulsive therapy treatment outcomes but no study to our knowledge has characterized DNAm profiles of treatment outcomes in the context of TMS. Here, we present the first genome-scale DNAm analysis of TMS outcomes in patients with treatment-resistant depression (TRD). Methods Peripheral blood samples from 60 TRD patients were collected prior to a standard 36-session TMS course. DNAm was profiled using the Illumina EPIC array and filtered to retain only the top 5% most variable probes for subsequent analysis in relation to three treatment outcomes in an analytic sample of 46 patients: treatment response (> 50% PHQ-9 reduction), symptom trajectory (ΔPHQ-9), and remission (PHQ-9 < 5). Results Methylated CpG Set Enrichment Analysis ( mCSEA ) identified 67, 23, and 163 differentially methylated regions (DMRs) associated with treatment response, symptom trajectory, and remission, respectively (FDR < 0.05). Sixteen DMRs were common across all outcomes, implicating genes involved in neurodevelopment ( HOXA4 , HOXA5 ), immune signaling ( RUNX1 , OTUD5 ), and synaptic function ( EFNB1 , RAP2C). Targeted analysis of 84 CpGs in the BDNF promoter revealed 10 nominally significant CpGs that differentiated responders from non-responders. Several DMRs showed strong blood–brain methylation concordance (r > 0.5), supporting their potential relevance to central nervous system mechanisms. Conclusions Despite the limited sample size, these findings suggest distinct epigenetic signatures prior to treatment that are associated with TMS outcomes, supporting the potential utility of DNAm as a biomarker for response stratification in TRD.