Peripheral miRNA profiling identifies therapy-specific biological trajectories in the treatment of cognitive dysfunction in depression: an exploratory mechanistic study
Year: 2026
Type: article
Abstract: 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.
Source: Scientific Reports
Authors: Lluis Miquel-Rio, Muriel Vicent-Gil, Judith Jericó-Escolar, Júlia Carrasco-Hernández, Miriam Jubero, Verónica Paz, Leonor Gawron, Esther Ruiz-Bronchal, Javi Vera, Caterina del Mar Bonnín, Dolors Puigdemont, Carlo Alemany, Narcís Cardoner, Javier de Diego-Adeliño, Analia Bortolozzi, Maria J. Portella
Institutions: Consejo Superior de Investigaciones Científicas, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, Institut d'Investigacions Biomèdiques de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat Autònoma de Barcelona, Hospital de Sant Pau, Institut de Recerca Sant Pau, Universitat de Barcelona, Hospital Clínic de Barcelona
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,690
Funders: Fundació la Marató de TV3, Ministerio de Ciencia, Innovación y Universidades, Generalitat de Catalunya, Centro de Investigación Biomédica en Red de Salud Mental, Agència de Gestió d'Ajuts Universitaris i de Recerca, Consejo Superior de Investigaciones Científicas, Instituto de Salud Carlos III, Agencia Estatal de Investigación
Awards: G1105844351, G1214581834, G1486922823, G1850208859, G2064873908, G2262748287, G2462415295, G2672435700, G288263039, G3005324705, G300979063, G3480869486, G3515179265, G4212894969, G425668148, G4336758381, G5080475149, Rehabilitación Integral cognitiva para DEpresión Mayor (RIDEM). Ensayo clínico multicéntrico, aleatorizado para investigar su eficacia., G5635532810, G5852091828, G5989551313, G6368058359, G7133451005, G7149725741, G7312825546, G7452833429, G7512896768, G7805626310, G7863371703, G8497050386, G8800679369, G8931010203
OpenAlex ID: W7162789709