A circulating miRNA profile is associated with response to cognitive remediation in major depressive disorder

Cognitive symptoms are a core and debilitating feature of major depressive disorder (MDD), often persisting and poorly addressed by current treatments, underscoring the need for objective biomarkers to guide therapeutic interventions. This study investigated whether circulating microRNAs (miRNAs) are associated with cognitive response to two distinct psychological interventions: integral cognitive remediation (INCREM) and psychoeducation (PSYCHOED). A panel of 38 miRNAs was analyzed in plasma from MDD patients before and after interventions. Our results reveal two distinct, non-overlapping miRNA patterns associated with therapeutic response. Specifically, a seven-miRNA profile ‒let-7b-3p, miR-100-5p, miR-129-5p, miR-135a-5p, miR-151a-5p, miR-4516, and miR-451a‒ was associated with response to INCREM. Bioinformatic analysis of their predicted target genes showed significant enrichment in molecular pathways crucial for neuroplasticity, synaptic function, and cognition, which correlated with objective improvements in cognitive performance. Conversely, a distinct two-miRNA profile involving miR-126-5p and miR-195-5p was associated with response to PSYCHOED. The targets of these miRNAs converge on pathways related to systemic cellular processes such as cell structure and intercellular communication, including Wnt signaling, cellular senescence, and the cell cycle. These findings provide novel mechanistic insights, suggesting that INCREM directly modulates gene networks related to neuroplasticity, whereas PSYCHOED affects more general cellular pathways. These circulating miRNA profiles are promising, minimally invasive biomarkers that could be used to personalize treatment strategies for cognitive dysfunction in MDD.