With their ability to cross the blood-brain barrier, transport and regulate the release of various signaling molecules, extracellular vesicles (EVs) constitute a novel avenue to study intercellular communication in various pathologies, including psychiatric disorders. We studied 34 major depressive disorder (MDD) patients and 57 healthy controls and characterized EVs isolated from plasma using digital holographic tomography (DHT) and nanoparticle tracking analysis (NTA). EVs detected in DHT were markedly smaller and less variable in size in MDD patients. Furthermore, a lower variance of refractive indices related to the dry mass density of EVs was observed in patients. Meanwhile, NTA revealed a trend for elevated concentration of EVs in MDD. In DHT, EV dimensions correlated with plasma mRNA expression of exosomal markers CD63 and CD9, with corresponding alterations in MDD. Levels of EV concentration and CD9 were both negatively correlated with antidepressant treatment response. Utilizing electron microscopy and immunoblots we confirmed the presence of serotonin transporters (SERT) as EV cargo. SERT levels in EVs correlated with cerebral SERT binding potential in the amygdala measured using positron emission tomography. Next to the implication of altered EV communication in mood disorders, the pronounced differences in plasma EV characteristics and exosomal markers in MDD might inform the development of assays with diagnostic or prognostic value for clinical practice.

RL received investigator-initiated research funding from Siemens Healthcare regarding clinical research using PET/MR and travel grants and/or conference speaker honoraria from Bruker BioSpin, Shire, AstraZeneca, Lundbeck A/S, Dr. Willmar Schwabe GmbH, Orphan Pharmaceuticals AG, Janssen-Cilag Pharma GmbH, Heel and Roche Austria GmbH. in the years before 2020. He is a shareholder of the start-up company BM Health GmbH, Austria since 2019. DR served as consultant for Janssen, received honoraria from Boehringer-Ingelheim, Gerot Lannacher, Janssen and Pharmagenetix, received travel support from Angelini, Janssen and Schwabe, and served on advisory boards of AC Immune, Boehringer-Ingelheim, Roche and Rovi. The remaining authors declare no potential conflict of interest with respect to the research, authorship, and/ or publication of this article.

NCT02711215

This research was funded in whole, or in part, by the Austrian Science Fund (FWF) [grant DOIs: 10.55776/DOC33, 10.55776/KLI516, 10.55776/KLI1006; PI: R. Lanzenberger], by the Else Kroener-Fresenius-Stiftung (2014_A192, PI: R. Lanzenberger), and the Vienna Science and Technology Fund (WWTF) [grant DOI: 10.47379/CS18039, Co-PI: R. Lanzenberger]. This study was further financial supported by Foundation of the Wroclaw Medical University. DHT analysis was funded by the Wroclaw University of Science and Technology. The commercially available reagents used for the isolation procedure of extracellular vesicles, the primary antibodies against exosomal tetraspanins, the colloidal gold particles and the grids for TEM imaging were purchased from funding received from the National Science Centre (NCN, Poland); the PRELUDIUM Program; grant no. UMO-2017/27/N/NZ5/02020; granted to Ł. Zadka. G. Gryglewski, LR. Silberbauer and M. Murgas were recipients of DOC Fellowships of the Austrian Academy of Sciences at the Department of Psychiatry and Psychotherapy, Medical University of Vienna. Further, this study was supported partly through a research agreement between the Medical University of Vienna and the Siemens Healthcare GmbH. For open access purposes, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission.

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