Epigenetic Markers of Response to Psychotherapy in Obsessive-Compulsive Disorder

Abstract Background Cognitive-behavioral therapy (CBT) is a widely used treatment for mental disorders, yet the biological mechanisms underlying its effects, and the factors contributing to response, remain poorly understood. DNA methylation, an epigenetic mechanism shaped by both genetic and environmental factors, may offer insights into individual differences in psychotherapy outcomes. Methods Saliva samples were collected before treatment, after treatment, and three months post-treatment from individuals with OCD undergoing the Bergen 4-Day Treatment (n = 889). DNA methylation was measured using the Illumina EPIC v02 array, followed by epigenome-wide DNA methylation analyses of CBT response. Results We identified ten differentially methylated regions (DMRs) associated with treatment response at baseline, 23 DMRs showing consistent associations with response across multiple time points, and three DMRs displaying longitudinal methylation changes associated with response. These loci were annotated to genes with roles in neuroplasticity, stress response, immune function, mitochondrial processes, and gene regulation. Baseline and stable methylation signals were largely influenced by genetic variation, whereas all longitudinal associations appeared to be confounded by psychoactive medication use and psychiatric comorbidities. In addition, changes in monocyte and CD4+T cell proportions were associated with treatment response. Conclusions We identified DNA methylation markers associated with CBT response in OCD at baseline. Stable methylation patterns associated with treatment response are likely driven by genetic factors. Longitudinal methylation analyses should be interpreted cautiously, as medication and comorbidities can exert substantial effects - even when they remain unchanged over time. Baseline methylation profiles may ultimately help predict treatment outcomes, thereby advancing precision psychiatry.