AsianScientist (Feb. 06, 2026) – For decades, depression has been viewed as a disorder of the mind, treated mainly by targeting chemical imbalances in the brain. Despite affecting millions worldwide, it still lacks objective biological markers, with diagnosis relying largely on symptoms that can vary widely between individuals. Researchers from Korea Advanced Institute of Science and Technology (KAIST) and Inha University have now identified that in certain types of depression, the immune system enters a state of hyperactivation that appears to interfere with brain development and stress responses.
The study, published in Advanced Science, focused on major depressive disorder with atypical features characterised by excessive sleeping and eating rather than the typical insomnia and loss of appetite. When accompanied by psychotic symptoms such as auditory hallucinations or distorted reality, this subtype becomes more difficult to diagnose and treat, even with conventional antidepressants. Atypical depression accounts for up to 40 percent of depression cases and is more common in young women.
To probe its biology, the team adopted a multi-omics approach. They examined seven female patients and ten healthy controls by analysing individual immune cells in the blood, measuring protein levels in plasma, and growing miniature brain models called organoids from patients’ own cells.
The researchers discovered that the patients’ immune systems were in a state of excessive activation. Single-cell RNA sequencing of white blood cells showed a spike in innate immune cells, such as neutrophils and monocytes, which drive inflammation, while adaptive immune cells like T-cells and B-cells were depleted.
In blood plasma, the researchers found higher levels of proteins involved in neural communication, including DCLK3 and CALY, alongside immune-related molecules such as complement protein C5, which amplifies immune responses. DCLK3 is known to help neurons survive stress and has been linked to schizophrenia and bipolar disorder, while CALY regulates dopamine signalling, a pathway central to mood and motivation. Together, these findings suggest that neural and immune systems may be unusually activated at the same time.
To see how these changes affect the brain directly, the team examined brain organoids by taking patients’ blood cells and reprogramming them into stem cells to form brain-like tissue. These patient-derived mini-brains grew more slowly than controls and showed disrupted patterns of neural development. When exposed to dexamethasone, a stress hormone used to mimic chronic stress conditions, patient organoids showed far more dramatic genetic changes, indicating increased vulnerability to stress at the cellular level.
While the study involved a small cohort, it offers a shift in perspective. With an imbalance in the “immune-neural axis” identified as the core mechanism driving the specific subtype of depression, this biological link challenges the traditional view of depression as solely a mental health issue. It implies that the body’s inflammatory response is directly related to neural health, creating a cycle of dysregulation.
“This achievement presents a new precision medicine model for psychiatric research,” said Jinju Han, assistant professor at KAIST. “We anticipate that this will actively lead to biomarker discovery and new drug development.”
The next critical step will be to test the protein candidates—DCLK3, CALY, and C5—across larger and more diverse patient populations, to determine whether these molecular signals are reproducible and clinically meaningful. If validated, they could serve as biomarkers to predict treatment response or establish the translational relevance for precision psychiatry.
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Source: Korea Advanced Institute of Science and Technology (KAIST); Image: Gumpanat/shutterstock
This article can be found at: Exploration of novel biomarkers through a precision medicine approach using multi‐omics and brain organoids in patients with atypical depression and psychotic symptoms
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