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 the Graduate School of Medical Science and Engineering (GSMSE) at Korea Advanced Institute of Science and Technology (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.
Scientists performed a multi-omics analysis combining blood analysis, 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, excessive guilt and self-blame), which are contrary to typical depression symptoms, and who also had impaired reality judgment. 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. As a revolution, 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) and Complement Protein C5, which strongly enhances the body’s immune response, were increased. Given its enrichment in stress-sensitive regions and involvement in major psychiatric disorders, altered DCLK3 expression may reflect adaptive mechanisms to immune-neural disruption and elevated allostatic load in MDD. CALY, a neuron-enriched transmembrane protein involved in clathrin-mediated endocytosis and dopaminergic signaling, regulates AMPA receptor internalization, axonal trafficking and D1 receptor dynamics.
Dysregulation of CALY has been implicated in neuropsychiatric conditions such as ADHD and schizophrenia. In this investigation, CALY was upregulated in plasma but downregulated in patient-derived brain organoids, suggesting compartment-specific alterations in synaptic and dopaminergic signaling. These opposing patterns between peripheral and central compartments may reflect distinct regulatory mechanisms or compensatory responses relevant to MDD pathophysiology. C5 has been implicated in neuronal injury, glutamatergic dysfunction and cognitive impairment, with elevated levels reported in the cerebrospinal fluid of patients with schizophrenia and MDD.
In this study, C5 was elevated in plasma, supporting immune activation as a potential contributor to MDD pathophysiology, particularly through mechanisms involving cortical thinning and synaptic dysregulation. Overall, the experimental data indicate 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. 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.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific rerferences
Ahn E et al. Advanced Sci 2025 Oct; advs.202508383.
Bayes A et al. Psychoneuroendocrinol. 2024; 159:106418.
Refisch A et al. Neuropharmacology 2023; 235:109568.
