Peripheral miRNA profiling identifies therapy-specific biological trajectories in the treatment of cognitive dysfunction in depression: an exploratory mechanistic study

Cognitive dysfunction in major depressive disorder (MDD) often persists despite standard treatment. Integral cognitive remediation (INCREM) shows clinical efficacy, yet its molecular drivers remain poorly understood compared to supportive interventions like psychoeducation (PSYCHOED). In this exploratory study, we investigated whether circulating microRNAs (miRNAs) reflect the distinct biological trajectories of these interventions. We conducted a longitudinal analysis of 38 candidate miRNAs (previously validated in postmortem brain tissue of MDD individuals) in plasma from 22 patients with MDD participating in a randomized clinical trial who were assigned to 12 weeks of INCREM or PSYCHOED. Using bioinformatic pathway analyses (KEGG/GO), we identified non-overlapping miRNA profiles associated with each treatment. The INCREM response was characterized by a specific seven-miRNA signature (let-7b-3p, miR-100-5p, miR-129-5p, miR-135a-5p, miR-151a-5p, miR-4516, and miR-451a) targeting gene networks regulated in neuroplasticity, axon guidance, and synaptic transmission. These molecular changes mirrored significant objective cognitive improvements. Conversely, PSYCHOED induced a distinct profile (miR-126-5p and miR-195-5p) related to systemic cellular homeostasis and Wnt signaling, without objective cognitive gains. Our findings suggest that psychological therapies act as specific biological stimuli with distinct molecular targets. These circulating miRNA signatures provide preliminary evidence of neuroplasticity-related pathways as key drivers of cognitive recovery, offering potential blood-based biomarkers for precision psychiatry in MDD.