2026 ECNP Congress

PS03-3094

Analysis of plasma extracellular vesicle microRNAs in major depressive disorder and treatment-resistant depression

Claudia Pisanu — F. Mazzarotto, A. Meloni, D. Congiu, A. Magistrali, B. Palazzi, M. Bortolomasi, G. Severino, C. Chillotti, R. Ardau, P. Paribello, U. Isayeva, F. Pinna, M. Gennarelli, M. Manchia, A. Squassina, A. Minelli · University of Cagliari, Department of Biomedical Sciences, Monserrato, Italy

2026 ECNP Congress

Background

Major depressive disorder is a prevalent and recurrent mental disorder amongst the leading causes of disease burden worldwide. There is wide interindividual variability in treatment response and about one third of patients have treatment-resistant depression (TRD). To date, little is known about the molecular determinants of response to psychotropic medication, and no reliable biomarker has been identified and validated. The characterization of the molecular cargo of extracellular vesicles (EV), which are vesicles secreted by different cells that carry bioactive molecules to adjacent or distant cells, thus regulating intercellular communication and signal transmission, might increase our knowledge on MDD and TRD and provide relevant biomarkers. EVs are enriched in microRNAs (miRNAs), a class of small non-coding RNAs that play a crucial role in regulation of gene expression. Notably, miRNA content in EVs can be altered by physiological or pathological processes, including those associated with disease states. Aim of this study was to characterize the miRNA content of plasma EVs from patients with MDD characterized for response to antidepressants as well as controls, to evaluate the role of EV miRNAs as biomarkers of MDD and TRD.

Methods

The study included 30 patients with a diagnosis of MDD (15 with TRD and 15 responders to antidepressants), in accordance with DSM 5 criteria, and 15 non-psychiatric controls, recruited at the Unit of Psychiatry and the Unit of Clinical Pharmacology of the University of Cagliari. For each patient, a peripheral blood sample was collected to isolate plasma EVs. Morphology, size and concentration of EVs were characterized with Tunable Resistive Pulse Sensing (TRPS) and transmission electron microscopy (TEM). EVs were isolated with size exclusion chromatography (SEC) columns (IZON). After quality control, the RNA extracted from EVs was used for library preparation and sequencing of miRNAs on a NextSeq 2000 platform (Illumina). Raw data were preprocessed and aligned to the reference genome (hg38) with bowtie. miRNA counts were quantified with miRDeep2, normalized with the TMM method and analyzed to identify differentially expressed miRNAs based on diagnosis or response using the edgeR package in R.

Results

Five miRNAs were differentially expressed in patients with MDD compared with controls. Of these, two were overexpressed (hsa-miR-486-5p, log fold-change [FC]: 1.59, p = 1.6E-06, FDR = 0.0002; hsa-miR-451a, logFC: 2.15, p = 9.7E-05, p = 0.004) and three underexpressed (hsa-miR-335-5p, logFC: -1.17, p = 2.4E-05, p = 0.002; hsa-miR-151a-5p, logFC: -0.81, p = 0.0004, FDR = 0.01; hsa-miR-191-5p, logFC = -0.80, p = 0.001. FDR = 0.03) in patients with MDD compared with controls. Enrichment and functional analyses of targets of mRNAs predicted to be regulated by miRNAs differentially expressed in patients with MDD compared with controls are currently ongoing. Conversely, we found no miRNA to be significantly differentially expressed in patients with TRD compared with responders to antidepressants. Preliminary results from the present study support a potential role of plasma EV microRNAs in MDD.

Acknowledgements

The study was funded by European Union - Next Generation EU, Missione 4 Componente 1 CUP F53D23006570006 under the PRIN 2022 call (Project ID: 20228974E8).

References

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