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People with major depressive disorder or schizophrenia have been found to have lower levels of the synaptic protein “SNAP-25” in their cerebrospinal fluid. These were the findings of a study by University Medicine Halle that included more than 200 participants. Even though SNAP-25 cannot yet be used to make reliable diagnoses, the findings suggest that protein biomarkers could one day play an important role in the diagnosis and monitoring of psychiatric disorders. The findings were published in the journal BMJ Mental Health.
Biomarkers have long been a standard tool for diagnosing a wide variety of diseases. Current developments in biomarker research for neurodegenerative diseases underscore their enormous medical potential. However, they have yet to be used in diagnosing psychiatric disorders.
Research on major depressive disorder is currently focusing on impaired nerve cell function and various molecular factors. “We wanted to understand if and how the levels of synaptic proteins in cerebrospinal fluid change in patients with major depressive disorder, schizophrenia and bipolar disorder,” explains Professor Markus Otto, last author of the study and director of the University Clinic and Outpatient Clinic for Neurology at University Medicine Halle.
In their study the researchers focused on the protein “SNAP-25” (synaptosome-associated protein 25), which is involved in the transmission of messenger substances between nerve cells. It belongs to a larger protein complex that ensures that small molecular transport packages, known as vesicles, are able to fuse with the synapses, allowing the nerve cells to absorb the messenger substances.
SNAP-25 significantly lower for depression and schizophrenia, but not for bipolar disorder
The study team analyzed samples of cerebrospinal fluid from 202 individuals aged between 18 and 67. All had undergone standardized clinical-psychiatric and clinical-neurological examinations. Of the participants, 99 suffered from major depressive disorder, 50 from schizophrenia and 24 from bipolar disorder. The remaining 29 made up the healthy control group.
An analysis of the cerebrospinal fluid revealed significantly lower levels of SNAP-25 in patients with major depressive disorder compared to those of the healthy control subjects. These findings were independent of antidepressant medication and the severity of the depression. SNAP-25 levels were also significantly lower in patients with schizophrenia. However, in people with bipolar disorder, the values were similar to those of the healthy control subjects.
Currently only limited applications
In order to ensure a reliable diagnosis, a biomarker test must be able to correctly identify, with a high probability, ill and healthy individuals. “We are only just beginning to learn how synaptic proteins behave in these diseases. In this case, the test still lacks a sufficient level of specificity and sensitivity to be considered truly effective. Therefore, according to the current state of research, SNAP-25 can only be used as a diagnostic tool for major depressive disorder and schizophrenia,” explains Professor Petra Steinacker, lead author of the study and head of the neurology lab at University Medicine Halle.
Further large multicentre studies are required to improve the understanding of its clinical significance. “Next, we would like to examine whether the decrease in SNAP-25 is due to downregulation – that is, whether the production of this protein is specifically reduced. Unlike neurodegenerative diseases, in which nerve cells undergo restructuring processes, this mechanism could potentially be reversible. SNAP-25 could allow for a subtyping that would make it possible to differentiate between patients with and without synaptic downregulation. This could then be used to provide a more specific form of therapy,” concludes Professor Steinacker.
Development of a blood test and possible link to neurodegenerative diseases
The analysis of cerebrospinal fluid requires that samples be taken through a lumbar puncture in the lower back. This invasive procedure is only performed if there is a clear medical indication. “A lumbar puncture would not be performed in the case of a suspected psychiatric disorder, nor would it be performed solely to monitor patients who are otherwise well. Developing a minimally invasive blood test would make more sense. This is something we are currently working on as part of a new EU-funded project,” says Professor Otto, looking ahead.
Further findings of the study show correlations between synaptic markers and markers typical for Alzheimer’s disease. If and how these diseases are interrelated is currently the subject of neurological research being done in close collaboration with the University Clinic and Outpatient Clinic for Psychiatry, Psychotherapy and Psychosomatics at University Medicine Halle.
The study was supported by the European Research Area Network for Neuroscience Research (ERA-NET NEURON) and the Horizon Europe program.
University Medicine Halle
University Clinic and Outpatient Clinic for Neurology
Professor Markus Otto, Director
neurologie@uk-halle.de
Steinacker P, […], Otto M. Evidence for reduced synaptic protein SNAP-25 in cerebrospinal fluid in major depressive disorder and schizophrenia. BMJ Ment Health. 2025 Aug 21;28(1):e301752. https://doi.org/10.1136/bmjment-2025-301752
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