Depression can occur due to a malfunction between the immune system and the brain

A team of researchers studied women with severe forms of depression who have atypical symptoms — increased drowsiness, overeating, an increased stress response, as well as psychotic signs: hallucinations, guilt, lack of criticality to what is happening. Such cases are especially difficult because they often do not respond to standard antidepressants, and the risk of misdiagnosis — for example, mixing depression with bipolar disorder — is quite high.

To understand what is happening in the body of such patients, the team applied an integrated approach: blood analysis, examination of individual immune cells, as well as “brain organoids” — miniature models of the brain grown from the cells of the patients themselves. This allowed us to see the picture on several levels at once.

It turned out that the patients simultaneously altered the functioning of the immune system and disrupted the activity of proteins responsible for the transmission of signals between neurons. Elevated levels of C5 protein, one of the key enhancers of inflammatory reactions, were detected in the blood. In the mini-brains created from the patients’ cells, slow growth and impaired normal development of neural networks were observed. This indicates that inflammatory processes and immune failures do not affect the brain indirectly, but directly.

Additionally, the researchers found elevated levels of two important proteins, DCLK3 and CALY, which play a key role in the functioning of neurons. Their unusually high activity suggests that the brain is literally overloaded with signals, whether they are related to stress, anxiety, or impaired emotion regulation.

All these data add up to a single picture: some people develop depression not as a purely psychological phenomenon, but as a result of a general immune imbalance that affects the functioning of the nervous system. This approach changes the usual perception of the disease and explains why some patients do not respond to standard treatments.

The authors of the study believe that their work paves the way for the creation of new biomarkers that will help objectively diagnose depression, rather than relying solely on symptoms. In addition, understanding the role of the immune system may lead to the emergence of new drugs that focus not only on neurotransmitters, but also on immune mechanisms.