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

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.