Depression is not just a state of mind, but an extremely complex biochemical game going on throughout the body.The latest research by a Polish-Austrian team of scientists, initiated by Dr. Lukasz Zadek of Wroclaw Medical University, shows how microscopic “letter carriers” – extracellular vesicles – can not only indicate the presence of disease, but also predict the effectiveness of treatment.
The invisible language of our cells
Imagine that cells are sending tiny packages to each other. Inside them are proteins, RNAs, enzymes, anything that can affect the function of the recipient cell. These extracellular vesicles can go almost anywhere, even crossing the blood-brain barrier. Their presence in the blood is like access to the body’s private mail.
Thanks to a study initiated by Dr. Lukasz Zadka of Wroclaw Medical University, with the participation of a team from Vienna, it was possible to visualize what this biological communication system looks like in the context of depression.
– Our study evaluated tissue material taken from patients diagnosed with a depressive episode, as well as from healthy individuals who were a control group, explains Dr. Zadka. – The term ‘depression’ itself can have many meanings. Depressive and anxiety symptoms often co-occur and are also present in somatic diseases, such as cancer or endocrine disorders. Therefore, it is difficult to talk about the specificity of depression as such.
However, different states of depression may manifest a distinct profile of EVs, which could support personalized diagnosis and treatment in the future.
Serotonin code
The researchers looked at blood samples from 34 depressed patients and 57 healthy individuals. With the help of digital holographic tomography and electron microscopy, they analyzed tens of thousands of extracellular vesicles, measuring their size, shape, and content. In patients with depression, the vesicles were smaller, more homogeneous, and their chemical composition differed from that of those in healthy individuals. A trend toward an increase in their number in plasma was also observed. It was as if the body was trying to send more messages, but in simpler language.
The most considerable stir, however, was the discovery of a serotonin transporter inside these microscopic packets. Furthermore, different isoforms of this protein were identified, which correlated with the distribution of its image in the brain as measured by PET-MRI imaging.
– For the first time, we have identified a serotonin transporter in plasma-derived extracellular vesicles, and even different isoforms of it, which at the level of the vesicular protein correlate with the distribution of the transporter on PET-MRI, says Dr. Zadka. – In my opinion, this is a significant discovery with the potential to open new doors in modern psychiatry.
Biomarker of the future
The researchers also noted that people with higher levels of small vesicles and higher expression of the CD9 marker responded less well to treatment. Their presence in the blood may signal less effective therapy.
– However, the results of our project suggest some distinctiveness of the vesicles found in depression, which underscores their potential importance in the diagnosis of depressive episodes, as well as, more importantly, points to the possibility of using EVs in the category of a predictive marker of response to implemented antidepressant treatment – and this should be emphasized in the project completed by our team, Dr. Zadka points out. The vesicles turn out to be carriers of complex information, from RNA fragments to membrane proteins, making them a unique source of biological data.
Technological challenges and potential
Although extracellular vesicles have great diagnostic potential, their routine clinical use is not yet feasible.
– I would mention specificity first. It should be emphasized that the population of vesicles present in the plasma fraction is itself extremely diverse, Dr. Zadka stresses. – In the maze of different vesicles, one would have to select the appropriate subpopulation of them that is unique to a given group of psychiatric disorders. An additional barrier is cost; procedures for isolating and analyzing EVs are still too expensive for widespread use.
Nevertheless, technological advances offer hope. – In terms of the ability to visualize and phenotype EVs, we have more and more modern techniques, Dr. Zadka adds. – I wouldn’t worry about technical capabilities, but about cost and availability of funding.
A revolution in psychiatry?
This question still awaits a complete answer. At this point, the discovery of the importance of EVs in depression and in response to implemented pharmacotherapy remains a huge success. Does depression have its biological code? Perhaps the answer to this question hides precisely in the microscopic vesicles that course through our circulation every day, and which, little by little, we are beginning to learn about.
This material is based on an article:
Phenotyping extracellular vesicles and their serotonin transporter cargo in major depressive disorder.
Journal of Affective Disorders 2025 Authors: Łukasz Zadka, Benjamin Eggerstorfer, Igor Buzalewicz , Chrysoula Vraka, Agnieszka Rusak, Godber M. Godbersen, Agnieszka Opalinska , Jakob Unterholzner , Agnieszka Ulatowska-Jarża, Cécile Philippe, Katarzyna Haczkiewicz-Leśniak, Leo Silberbauer, Matej Murgaš, Lukas Nics , Andreas Hahn, Marcus Hacker, Agnieszka Gomułkiewicz, Dan Rujescu, Marzenna Podhorska-Okołów, Rupert Lanzenberger, Gregor Gryglewski.
https://doi.org/10.1016/j.jad.2025.119740