Depression Could Be Linked to Your Immune System

Neuroimmunity

Source: Odelya Gertel Kraybill design

In 2019 I wrote about research suggesting anti-inflammatory medications might help some people with major depression. At the time, the idea that depression could have roots in the immune system felt almost radical. A new study published in Advanced Science (2025) takes this idea much further and what the researchers found might change how we think about certain types of depression.

What Makes This Study Different

Most depression research looks at one thing at a time: brain scans, blood tests, or questionnaires. This team did something unusual. They examined the same patients across three different biological systems, simultaneously.

They looked at blood proteins (what's floating around in your bloodstream), immune cells (specifically, what genes your white blood cells are turning on), and miniature brain models grown from the patients' own cells.

The patients were women with treatment-resistant major depressive disorder with atypical features and psychotic symptoms people who often don't get better with standard antidepressants.

What They Found: The Immune System Was the Missing Link

The results paint a picture of a body on high alert.

In the blood, patients showed elevated levels of several key proteins. One called DCLK3 is known to help neurons survive under stress. Another, C5, is part of your complement system, basically your immune system's early warning network. When C5 is elevated, it usually means inflammation is happening.

These protein levels correlated strongly with how much stress, trauma, anxiety, and depression the patients reported. The more severe the symptoms, the higher the inflammatory markers.

In the immune cells, researchers found that the patients' neutrophils and monocytes (immune cells that respond to threats) were highly activated. Meanwhile, their T cells and B cells (the "adaptive" immune system that handles specific threats) were depleted. In other words, their immune systems looked like they were constantly responding to some kind of ongoing threat, even when there wasn't an obvious physical illness. Their bodies were running in emergency mode.

Growing Mini-Brains

This is where things get interesting. The researchers took blood cells from one patient, reprogrammed them into stem cells, and grew tiny brain-like structures called organoids. Think of them as simplified models of developing brain tissue.

When they compared the patient's organoids to those from a healthy control, the differences were stark. The patient's mini-brains grew more slowly and ended up smaller. They had fewer neural progenitor cells (the cells that become neurons). They showed more cell death. And when exposed to stress hormones, they showed far more disruption in gene expression than the healthy organoids did.

The researchers exposed both sets of organoids to dexamethasone, a synthetic version of cortisol—the stress hormone your body releases when you're under pressure. The healthy organoids handled it reasonably well. The patient-derived organoids went haywire, with dozens of genes changing their activity levels.

This hints at something worth sitting with: the vulnerability to stress might be baked into the biology of these patients at a cellular level.

Your Depression Might Be a Neuroimmune Condition

If you've tried antidepressant after antidepressant without relief, this research offers validation.

Some forms of depression may operate through completely different biological pathways than the serotonin-based models most medications target.

Trauma leaves biological traces. The patients in this study had significantly higher trauma exposure than control group participants. We've known for decades that childhood adversity impacts all domains of health. This is an example of how it shapes the immune system and how those two systems interact.

Stress sensitivity might eventually be detectable. The fact that patient-derived brain organoids responded so dramatically to stress hormones suggests we might eventually be able to test who is most vulnerable and target treatments accordingly.

And inflammation-focused treatments might help some people. This connects directly to what I wrote about years ago. If inflammation is driving symptoms, then anti-inflammatory approaches whether medications, lifestyle changes, or other interventions might offer relief where traditional antidepressants haven't.

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This is a small study, but it reinforces something many trauma-informed practitioners already suspect: we need to look beyond the DSM checklist.

Factors like chronic inflammation, stress load, trauma history, and immune function might be just as relevant to treatment planning as symptom counts.

For people living with depression, especially treatment-resistant depression, this research offers hope that science is catching up to your experience.

This isn't about dismissing the role of neurotransmitters or therapy. It's about recognizing that depression, like most things in life, is more complex than any single story. We need to start looking at the role of the immune system in all cases of neuropsychiatric and psychiatric symptoms, and understand how these systems communicate with each other in ways we're only beginning to map.

As our understanding of neuroimmune conditions grows, it's becoming clear that clinicians working with treatment-resistant trauma-related symptoms need to become aware of the role the immune system plays in treatment intervention. This means paying attention not just to thoughts and emotions, but to what's happening beneath the surface in the blood, in the immune response, in the cellular machinery that shapes how we respond to stress.

The path forward isn't about choosing between psychological and biological approaches. It's about weaving them together into something more complete, something that finally reflects complete health in all its domains.