A severe form of depression accompanied by atypical symptoms and psychotic episodes may be linked to a systemic disorder that connects immune system function with neural tissue development. This conclusion was reached by South Korean scientists. The study was published in Advanced Science.

Depressive disorder remains one of the most common and serious mental health conditions. Diagnosis is based on patient complaints and clinical observation—objective biological tests still do not exist. Atypical depression with psychotic symptoms is particularly difficult to diagnose and treat: patients may experience hallucinations or delusional ideas. This form responds poorly to standard antidepressants and is associated with a high risk of harmful behavior.

Researchers sought to identify biological traces of this disorder. The study involved young women with a severe form of atypical depression; the control group consisted of healthy volunteers. Even in standard blood tests, researchers found elevated levels of leukocytes—a nonspecific sign of inflammation. A more detailed proteomic analysis of plasma revealed the presence of proteins typically found in neural tissue, which is extremely unusual.

Among these were DCLK3, involved in the formation of neuronal connections, and CALY, which affects dopamine signaling. Their presence in the bloodstream may indicate either a breakdown of the barriers between the brain and the bloodstream or a systemic malfunction affecting both neurons and the immune system. At the same time, patients showed elevated levels of complement component C5, one of the key regulators of inflammatory responses. These findings support the hypothesis that hyperactive immunity plays a central role in the development of severe psychiatric disorders.

To understand how these systemic changes affect the brain, the scientists went further and created miniature brain analogues—organoids. They reprogrammed patients’ blood cells into stem cells and directed their development toward neural tissue. Even at early stages, noticeable differences appeared: organoids from patients grew more slowly and remained smaller. When exposed to a synthetic stress hormone, these structures responded far worse than organoids from healthy participants—genes associated with cell damage were activated, and normal neuron maturation processes were disrupted.

According to the authors, the results offer hope for the creation of objective biomarkers for depression. In the future, the presence of DCLK3, CALY, and C5 proteins in the blood may serve as the basis for a diagnostic test that would not only allow for more accurate diagnosis but also help tailor treatment to the patient’s specific immunological profile.