KAIST

<(From Left) Ph.D candidate Insook Ahn from KAIST, Professor Jinju Han from KAIST, (Upper Left) Yangsik Kim from Inhan University School of Medicine, Ph.D candidate Soyeon Chang(psychiatrist)>

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.

KAIST announced on the November 20^th that Professor Jinju Han's research team from the Graduate School of Medical Science and Engineering (GSMSE) at KAIST, in collaboration with Professor Yangsik Kim's research team (Ph.D., KAIST GSMSE) from Inha University School of Medicine, performed a multi-omics analysis combining plasma proteomic analysis, WBC single-cell analysis, and patient-derived brain organoids (mini-brains). This study focused on female patients with MDD who exhibited 'Atypical Features' (such as hypersomnia and overeating) and 'Psychotic Symptoms'(such as auditory hallucinations and idea of reference), which are different from typical depression symptoms, and who also had impaired reality judgment.

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■ "Immune Cells and Brain Function are Altered Together" A New Biological Clue for Depression

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.

■ World's First Integration of "Leukocyte Single-Cell Analysis + Brain Organoid" 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 inter-neuronal 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.

■ "Immune-Neural Axis Imbalance is the 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.

<Integration of clinical symptoms, blood analysis, and patient-derived brain organoid analysis in women with major depressive disorder>

Professor Jinju Han stated, "This achievement presents a new precision medicine model for psychiatric research," adding, "We anticipate that this will actively lead to biomarker discovery and new drug development."

This accomplishment was published online in the world-renowned international scientific journal, Advanced Science, on October 31st.

※ Paper Title: Exploration of Novel Biomarkers through a Precision Medicine Approach Using Multi-omics and Brain Organoids in Patients with Atypical Depression and Psychotic Symptoms DOI: https://doi.org/10.1002/advs.202508383

※ Author Information: Soyeon Chang (Inha University, Co-First Author), Seok-Ho Choi, Jiyoung Lee, Yangsik Kim (Inha University, Corresponding Author), Insook Ahn (KAIST, Co-First Author), and Jinju Han (KAIST, Corresponding Author)

This research was supported by the National Research Foundation of Korea and the Korea Health Industry Development Institute.