Major depressive disorder (MDD) is characterized by a lowered mood and loss of interest, contributing not only to difficulties in academic and professional life but also as a major cause of suicide in South Korea. However, there are currently no objective biological markers that can be used for diagnosis or treatment.
Amidst this, a research team from KAIST has revealed that depression is not merely a problem of the mind or brain, but is deeply connected to abnormalities in the body’s overall immune response.
They found that this immune abnormality affects brain function, and the “Immune Neural Axis” imbalance is the core mechanism of depression, opening up the possibility for the discovery of new biomarkers and the development of new drugs for depression treatment.
Professor Jinju Han’s research team from the Graduate School of Medical Science and Engineering at KAIST, in collaboration with Professor Yangsik Kim’s research team from Inha University School of Medicine, performed a multi-omics analysis combining blood analysis, single-cell analysis, and patient-derived brain organoids (mini-brains).
The study is published in Advanced Science.
The study focused on female patients with MDD who exhibited atypical features (such as hypersomnia and overeating) and psychotic symptoms (such as auditory hallucinations, excessive guilt, and self-blame), which are contrary to typical depression symptoms, and who also had impaired reality judgment.
Immune cells and brain function are altered together
The research team simultaneously examined genetic changes in immune cells in the blood and changes in nervous-system-related proteins. The results confirmed a breakdown in the balance of immune-neural interaction in patients with depression.
MDD, especially in young women, often presents with atypical symptoms (hypersomnia, overeating, mood reactivity, etc.), which increases the risk of a later diagnosis of bipolar disorder. Furthermore, about 40% of patients are classified as treatment-resistant depression, showing no response to various antidepressants.
Consequently, there has been a continuous call for the development of new therapeutic strategies and the discovery of biomarkers based on immunity and metabolism, moving beyond the traditional drug-centric approach.
A new paradigm for psychiatric research
The research team presented the world’s first precision medicine approach by integrating plasma proteomics, leukocyte single-cell transcriptome analysis, and analysis of brain organoids created from patient-derived induced pluripotent stem cells (iPSCs).
The results showed that patients with atypical depression exhibited high levels of stress, anxiety, and depression. Furthermore, proteins crucial for interneuronal signaling (DCLK3 and CALY) were significantly elevated compared to normal levels, and Complement Protein C5, which strongly enhances the body’s immune response, was also increased. This indicates that both ‘brain function’ and ‘immune function’ are excessively activated and out of balance within the body.
This finding confirms a clue that depression is not merely a mood issue but is connected to biological changes occurring throughout the entire body. Upon examining the immune cells of depression patients, genetic changes were found that make inflammatory responses in the body occur more easily and strongly than usual.
This implies that the entire bodily immune system is in a state of excessive activation, and this immune/inflammatory abnormality may influence the development of depression.
The patient-derived brain organoids showed accompanying growth retardation and abnormal neural development, supporting the possibility that immune abnormalities interact with changes in brain function to exacerbate the disease.
A core mechanism of atypical depression
This study integrated clinical data, single-cell omics, proteomics, and brain organoids to demonstrate that the “Imbalance of the Immune-Neural Axis” is the core mechanism of MDD accompanied by atypical and psychotic symptoms.
Professor Jinju Han stated, “This achievement presents a new precision medicine model for psychiatric research. We anticipate that this will actively lead to biomarker discovery and new drug development.”
More information:
Insook Ahn et al, Exploration of Novel Biomarkers Through a Precision Medicine Approach Using Multi?Omics and Brain Organoids in Patients With Atypical Depression and Psychotic Symptoms, Advanced Science (2025). DOI: 10.1002/advs.202508383
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