Background: Major depressive disorder (MDD) presents with both peripheral and central alterations, such that crosstalk between the periphery and the central nervous system could contribute to its aetio-pathophysiology. One putative mediating mechanism is circulating extracellular vesicles (EVs) and their microRNA (miRNA) cargo. In this study, we investigated differential expression of the serum EV miRNome in MDD patients versus controls with the aims of identifying potential EV miRNA biomarkers and downstream target gene pathways.

Methods: miRNA-Sequencing was performed on serum EVs isolated from MDD patients (n = 42) and matched healthy Controls (n = 18). Differential expression analysis was conducted, followed by diagnostic power analysis of dysregulated EV miRNAs, and pathway analysis of their target genes.

Results: Of 1800 serum EV miRNAs detected consistently, 33 were differentially expressed in MDD and Control subjects, 17 up-regulated and 16 down-regulated. Receiver-operating characteristic analysis identified an up-regulated and a down-regulated panel of EV miRNAs, each with additive diagnostic power as a differential biomarker for MDD. Predicted target gene-pathways were significantly enriched with respect to brain function, signal transduction and substance dependence ontology.

Conclusions: This study provides one of the first reports of dysregulation of the peripheral EV miRNome in MDD, including evidence for EV miRNAs as potential MDD biomarkers and identification of pathways via which they may contribute to MDD pathophysiology. Large-scale studies are required to confirm EV miRNome biomarker potential in MDD. Empirical evidence for involvement of the dysregulated EV miRNAs in the predicted target-gene pathways relevant to MDD pathophysiology is required.