MicroRNAs expression changes associated with trauma-focused psychotherapy efficacy in treatment-resistant depression: An exploratory study

This study employed a miRNomic approach to investigate plasma miRNA changes associated with trauma-focused psychotherapy, including EMDR therapy, in treatment-resistant depression (TRD) patients with a history of early life stress.

Article Abstract

“Early life stress (ELS) increases vulnerability to major depressive disorder (MDD) and treatment-resistant depression (TRD) through lasting neurobiological and epigenetic alterations. MicroRNAs (miRNAs), key post-transcriptional regulators of gene expression, are emerging as potential biomarkers linking environmental stressors and depression pathophysiology. This study employed a miRNomic approach to investigate plasma miRNA changes associated with trauma-focused psychotherapy in TRD patients with a history of ELS. Twenty-four patients received either trauma-focused cognitive behavioural therapy (TF-CBT) or eye movement desensitization and reprocessing (EMDR) over eight weeks, with depressive symptoms assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline (T0) and post-treatment (T8). Plasma levels of 188 miRNAs were quantified using qRT-PCR. Of these, 148 passed quality control and were included in the analysis. Twenty-two miRNAs were nominally significantly downregulated after psychotherapy, with miR-132-3p remaining significant after correction for multiple testing, and four (let-7f-5p, miR-195-5p, miR-29c-3p, miR-32-5p) showing trends toward significance. Pathway enrichment analyses identified 120 pathways involved in inflammation, neuroplasticity, and stress response, including Hippo, TGF-β, TNF, Wnt, PI3K-Akt, Neurotrophin, glutamatergic synapse, and dopaminergic signaling. Subgroup analyses identified nominal downregulation of miRNAs following EMDR (miR-132-3p and let-7f-5p) and TF-CBT (miR-32-5p and let-7f-5p), with none remaining significant after correction. Correlational analyses between miRNAs changes and treatment outcomes showed, in the whole sample, that miR-139-5p downregulation was nominally associated with greater improvements in overall depressive symptoms, as well as cognitive and neurovegetative symptom domains. Subgroup correlational analyses identified significant nominal associations between miR-125b-5p downregulation and improvements in overall depressive symptoms, mood, and neurovegetative domains following TF-CBT, and between miR-139-5p downregulation and overall depressive symptoms (trend significant) and neurovegetative symptom improvement following EMDR; however, none of these associations survived multiple-testing correction. These findings suggest that trauma-focused psychotherapies may induce peripheral miRNA modulation linked to clinical response, with miR-132-3p, miR-125b-5p, and miR-139-5p emerging as potential biomarkers of treatment response. The results support a role for miRNA-mediated neuroplastic and inflammatory mechanisms in the molecular underpinnings of psychotherapy efficacy in TRD patients exposed to ELS.

Highlights:

• Longitudinal omics analyses show miRNA changes after trauma-focused psychotherapy.
• Trauma-focused psychotherapy downregulated 22 miRNAs in TRD patients.
• MiR-139-5p decrease correlated with symptom improvement following EMDR.
• MiR-125b-5p downregulation correlated with symptom improvement after TF-CBT.
• MiR-132-3p and miR-139-5p emerge as potential biomarkers of treatment response.”

—Description from publisher

Article Access

Open Access

Buson, L., Carvalho Silva, R., Galbiati, C., Bortolomasi, M., Scaglia, M., Perusi, G., Abate, M., Maffioletti, E., Gennarelli, M., Lorenzon, N., & Dierssen, M. (2026). MicroRNAs expression changes associated with trauma-focused psychotherapy efficacy in treatment-resistant depression: An exploratory study. Neuroscience Applied, 5(6), 107020. https://doi.org/10.1016/j.nsa.2026.107020