Circulating miRNA signatures following cognitive remediation in depressive disorder: Insights from plasma and neuron-derived extracellular vesicles

Major depressive disorder (MDD) is a leading cause of global disability, characterised by mood alterations and persistent cognitive impairments that frequently remain unresponsive to standard pharmacotherapy. Although integral cognitive remediation (INCREM) shows clinical efficacy, its underlying molecular drivers remain poorly understood. MicroRNAs (miRNAs) have been identified as master regulators of gene expression, modulating neurobiological functions such as synaptic remodelling and cellular stress resilience. Given their ability to cross the blood-brain barrier, circulating miRNAs emerge as potential peripheral biomarkers of treatment-induced molecular changes. Crucially, while total plasma miRNA analysis captures broad systemic adaptations, profiling the miRNA cargo within neuron-derived extracellular vesicles (NDEVs) provides a specific, non-invasive window into brain signalling dynamics. This study aimed to investigate whether total plasma miRNAs reflect the specific neurobiological trajectories elicited by distinct therapeutic interventions, and to evaluate the brain origin of top-candidate miRNAs by profiling the NDEV compartment.

In this exploratory longitudinal study, 22 MDD outpatients in partial remission with persistent cognitive deficits were randomised to 12 weeks of INCREM (n=15) or PSYCHOED (n=7). Peripheral plasma samples were collected at baseline and post-intervention, and the expression of 38 brain-validated candidate miRNAs was quantified using RT-qPCR. Functional enrichment (KEGG/GO) was performed to identify mechanistic pathways. Furthermore, plasma-derived extracellular vesicles (EVs) were isolated by ultracentrifugation and characterised using nanoparticle tracking analysis (NTA), electron microscopy (EM), and western blotting (WB) for EV markers (e.g., Alix, CD81). NDEVs were enriched using double immunomagnetic separation (L1CAM, SNAP25). Finally, the expression of the three top-candidate miRNAs (miR-129-5p, miR-135a-5p, miR-4516) was analysed within the NDEV fraction.

MiRNA analyses revealed distinct, non-overlapping miRNA profiles for each intervention. The INCREM response was characterised by a 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 related to neuroplasticity, axon guidance, and synaptic transmission. Clinically, these molecular alterations mirrored rapid and sustained improvements in objective cognitive performance (SCIP) and subjective cognitive deficits (PDQ), alongside early recovery in psychosocial functioning (FAST). Conversely, PSYCHOED induced a distinct profile (miR-126-5p and miR-195-5p) related to systemic cellular homeostasis and Wnt signalling. Clinically, this intervention only evidenced delayed functional benefits at six months, without objective cognitive gains. To validate the central origin of the miRNA profiles identified in total plasma, NDEV enrichment was technically verified through the presence of canonical vesicle morphology and high neuronal marker expression. Crucially, the expression of key neuroplasticity-associated miRNAs (miR-129-5p, miR-135a-5p, miR-4516) in the NDEV fraction mirrored the changes observed in total plasma, supporting their potential brain origin.

Our findings suggest that specific psychological interventions function as targeted biological stimuli for specific molecular networks. The identified circulating miRNA profiles provide preliminary evidence that neuroplasticity-related pathways drive cognitive recovery in MDD. The alignment between total plasma and NDEV fractions highlights the potential of NDEVs as a specific liquid biopsy platform for advancing precision psychiatry.

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