Scientists link inflammation to neural vulnerability in psychotic depression

New research suggests that a severe and specific form of depression involves a systemic disruption linking the immune system to brain development. Published in Advanced Science, the findings identify potential biological markers in the blood that correspond to structural changes in brain tissue. This offers a new perspective on how physical inflammation might act as a driving force behind severe mental illness.

Major depressive disorder affects hundreds of millions of people globally and is a leading cause of disability. Despite its prevalence, psychiatrists lack objective biological tests for diagnosis or treatment planning. Doctors currently rely on symptom checklists and patient self-reports. This lack of physical evidence makes it difficult to predict which patients will respond to standard medications.

The biological mechanisms underlying depression remain largely opaque. This is particularly true for a subtype known as major depressive disorder with atypical features and psychotic symptoms. Patients with this condition experience reversed physical symptoms, such as overeating and sleeping too much, rather than the insomnia and loss of appetite seen in typical depression. They also suffer from a break with reality, experiencing hallucinations or delusions.

This subtype is associated with significant social impairment and a higher risk of suicide. It is frequently resistant to conventional antidepressant treatments. Previous scientific work has hinted at a connection between this disorder and the immune system. Elevated inflammation is a common trait in many psychiatric conditions. However, the exact relationship between circulating immune markers and the actual function of brain cells has been difficult to map in living patients.

A team of researchers from Inha University and KAIST in South Korea sought to bridge this gap. The team was led by Soyeon Chang, Seok-Ho Choi, Jiyoung Lee, Yangsik Kim, Insook Ahn, and Jinju Han. They aimed to find measurable biological signs, or biomarkers, that could explain the severity of this specific condition. They utilized a precision medicine approach that combined clinical data with advanced laboratory techniques.

The researchers recruited young female patients diagnosed with atypical depression and psychotic symptoms. They compared these participants to a group of healthy female controls. The study focused on women because this depression subtype is more common in females and often presents with distinct biological patterns.

The team began by assessing the clinical history of the participants. They found that the patients had experienced significantly higher levels of lifetime trauma and perceived stress. Psychological evaluations confirmed severe levels of anxiety and depression. Initial standard blood tests revealed that the patients had higher white blood cell counts, a nonspecific sign of bodily inflammation.

To understand the molecular landscape, the researchers analyzed proteins floating in the blood plasma. They utilized a technique called proteomics to screen for hundreds of proteins simultaneously. This analysis uncovered specific alterations in the patient group. The patients exhibited elevated levels of proteins that are typically associated with the nervous system rather than the blood.

One of these proteins is Doublecortin-Like Kinase 3, or DCLK3. This protein usually plays a role in the survival of neurons and the formation of synapses in the brain. Another elevated protein was Calcyon, or CALY, which is involved in dopamine signaling and vesicle trafficking within nerve cells. The presence of these brain-linked proteins in the blood suggests a potential disruption in the barrier between the brain and the circulatory system or a systemic dysregulation affecting both areas.

The researchers also found elevated levels of Complement Component 5, or C5. This protein is a central part of the immune system’s inflammatory response. Its upregulation supports the theory that an overactive immune system is a key feature of this psychiatric condition.

The investigation moved from proteins to the genetic activity within individual immune cells. The team performed single-cell RNA sequencing on white blood cells. This technology allows scientists to see which genes are turned on or off in every single cell in a sample.

The results showed a clear imbalance in the immune systems of the patients. The cells responsible for innate immunity were overactive. These cells, such as neutrophils and monocytes, act as the body’s first responders to infection or injury. Their genetic activity pointed toward a state of chronic inflammation.

Conversely, the cells responsible for adaptive immunity were less active. These are the B cells and T cells that remember specific pathogens. This shift suggests the patients’ bodies were stuck in a persistent state of general alert.

The most innovative aspect of the study involved the creation of brain organoids. Studying the living human brain at the cellular level is impossible. To overcome this, the scientists took blood cells from the patients and reprogrammed them into induced pluripotent stem cells. These stem cells have the ability to turn into any tissue in the body.

The researchers coaxed these stem cells to develop into three-dimensional brain tissue. These “mini-brains” allow scientists to observe how a patient’s own genetic code directs brain development in a dish. The observations revealed significant differences. The brain organoids derived from the patients grew more slowly than those derived from healthy controls. By day sixty of development, the patient organoids were noticeably smaller.

The team then exposed these organoids to a synthetic stress hormone called dexamethasone. This chemical mimics the effects of cortisol, the body’s primary stress hormone. This step was designed to replicate the biological reality of the patients, who reported high levels of life stress.

The patient-derived tissues struggled to cope with this chemical pressure. The healthy organoids managed the stress relatively well. However, the patient organoids showed distinct patterns of gene expression that indicated a failure to adapt. They exhibited increased rates of apoptosis, or programmed cell death. This suggests that the neural cells of these patients possess an inherent genetic vulnerability to stress. This vulnerability leads to impaired growth and survival of neurons.

The study proposes a connection known as the immune-neural axis. The findings suggest that the elevated inflammation seen in the blood is not just a side effect. It appears to be biologically linked to the developmental issues seen in the brain tissue. The same signaling pathways that drive the immune overreaction may be contributing to the synaptic dysfunction and stunted neural growth.

There are limitations to this research that require consideration. The sample size was small, involving only a handful of patients and controls. This is common in studies using expensive and labor-intensive technologies like organoids and single-cell sequencing. However, it means the results must be interpreted with caution until they are replicated in larger groups.

The study included only female participants. This was a deliberate choice to reduce biological variability, but it means the findings might not apply to men. Additionally, the brain organoid experiments relied on cells from a single patient donor compared to controls. While the researchers used multiple replicates to ensure technical accuracy, individual genetic differences could influence the results.

The brain organoids also lack a complete immune system. They do not contain microglia, the resident immune cells of the brain. The researchers had to infer the interaction between the peripheral immune system and the brain based on separate analyses. Future models that incorporate immune cells into the brain tissue could provide a clearer picture of this interaction.

The researchers highlight the potential for these findings to lead to new diagnostic tools. The proteins DCLK3, CALY, and C5 could potentially serve as biomarkers. If validated, a blood test could one day help psychiatrists identify this severe subtype of depression. This would allow for more targeted treatment strategies that address both the mental and immunological aspects of the disorder.

This study represents a step toward precision psychiatry. It moves beyond subjective symptom descriptions to uncover the hard biology of mental illness. By linking clinical trauma, blood inflammation, and neural development, the work underscores that depression is a systemic disease affecting the whole body.

The study, “Exploration of Novel Biomarkers Through a Precision Medicine Approach Using Multi-Omics and Brain Organoids in Patients With Atypical Depression and Psychotic Symptoms,” was authored by Insook Ahn, Soyeon Chang, Jiyoung Lee, Seok-Ho Choi, Jinju Han, and Yangsik Kim.