Background: Childhood trauma is associated with increased risk of depression and epigenetic alterations in stress-related pathways. Preclinical studies suggest that methyl donors may facilitate DNA methylation changes. This first-in-human trial of epigenetic treatment investigated methyl donor S-adenosylmethionine (SAMe) as add-on to trauma-focused therapy for depression.
Methods: In this randomized, double-blind, placebo-controlled trial with 6-month follow-up, 31 adults with trauma-related depression were enrolled. Participants received 1200 mg SAMe or placebo alongside 12-weeks trauma-focused therapy. Depression symptoms were assessed using the Hamilton Rating Scale of Depression (HAM-D). Plasma SAMe levels and genome-wide DNA methylation were measured pre- and post-treatment, including epigenome-wide association analyses, differentially methylated region analyses, and epigenetic clock measures.
Results: Twenty-eight participants completed the study. Depression symptoms decreased significantly during treatment and remained improved at follow-up, reflecting the effect of psychotherapy, without clinical benefit of SAMe. SAMe supplementation did not alter plasma SAMe levels. However, SAMe treatment was associated with differential methylation across 66 regions. Epigenetic clock analyses showed no consistent treatment-related changes.
Conclusions: This first-in-human epigenetic intervention study in psychiatry demonstrates the feasibility of combining trauma-focused psychotherapy with targeted epigenetic analyses. While SAMe showed no additive clinical effects, the results provide important leads for future trials.
Clinical trial identifier (eudract): 2017-002097-38.
Keywords: Epigenomics; S-adenosylmethionine; adverse childhood experiences; clinical trial; depressive disorder.
Depression is common and can be especially difficult to treat in people who experienced traumatic events during childhood. Early life stress may leave long-lasting biological “marks”: small changes to DNA that influence how genes work, in a process called “DNA methylation.” Trauma induces DNA methylation changes around genes related to the stress response, which can affect how the body responds to stress.In this study, we tested whether a natural substance called S-adenosylmethionine (SAMe) could help improve depression symptoms by influencing these biological traces. We investigated whether using SAMe alongside trauma-focused psychotherapy could help facilitate treatment-induced changes in DNA methylation linked to stress.Twenty-eight adults with depression and a history of childhood trauma participated in this clinical trial. Half received SAMe and the other half received a placebo. All participants received trauma-focused psychotherapy. We measured depression symptoms and DNA methylation patterns before and after treatment. Depression symptoms were improved after psychotherapy in both groups, but SAMe did not lead to additional improvement in symptoms. We also did not observe clear changes in DNA methylation. However, some small, regional differences were detected, that can inform future research directions.Although SAMe did not show clear added benefit in this study, the trial provides important insights into the challenging translation of biological treatments from laboratory research into clinical practice. It also offers guidance for designing future studies that aim to target biological processes involved in trauma-related depression.