Your Immune System Might Be Causing Your Depression
September 11, 2026
Think about the last time you were really sick. You didn't want to eat, you stayed in bed, you lost interest in everything. That's your immune system talking to your brain. For roughly one in four people with depression, that circuit never fully turns off.
Dr. Naoise Mac Giollabhui, Director of Research on Inflammatory Depression at Harvard Medical School and Mass General, joins Neural Compass to explain what chronic inflammation is doing to the brain — and why treating it could change psychiatry.
Option B — Failed trials/science problem as a hook:
For decades, researchers ran large trials giving anti-inflammatory drugs to depressed patients. Most of them failed. The problem wasn't the treatment — it was that only about one in four depressed people actually have the inflammatory subtype those drugs could help.
Dr. Naoise Mac Giollabhui joins Mark to explain how psychiatry is finally learning to ask the right question: not just "is this person depressed?" but "why?"
Inflammatory depression research and precision psychiatry biomarkers like C-reactive protein (CRP) are the focus of this neurobiology episode. Dr. Naoise Mac Giollabhui, Director of Research on Inflammatory Depression at Harvard Medical School and Mass General, joins host Mark Jacobstein on Neural Compass by Jimini Health.
This discussion explores the heterogeneous nature of depressive disorders and why moving toward a precision medicine model is necessary for effective clinical treatment. Dr. Mac Giollabhui explains how sickness behavior acts as an evolutionarily conserved mechanism where the immune system communicates with the brain to reduce energy expenditure and limit social interactions during infection.
The conversation details the use of CRP as a clinical biomarker to identify individuals with systemic inflammation who may endorse symptoms such as fatigue and anhedonia. Drawing parallels to successful models in oncology, the guests explore how targeting specific biological phenotypes can improve psychiatric trial outcomes.
They also examine the blood-brain barrier as a selective filter that allows peripheral cytokines and immune cells to influence central nervous system function. Finally, the episode highlights future research into regulatory T-cell promotion and PET imaging to monitor neuroinflammation and resolve chronic immune activation.
What You’ll Learn:
- The definition and specific phenotype of inflammatory depression.
- How evolutionary theory explains "sickness behavior" as a survival mechanism.
- The role of C-reactive protein (CRP) as a dose-response biomarker for systemic inflammation.
- Lessons from oncology applied to precision medicine in mental health.
- The future of regulatory T-cell promotion to resolve chronic inflammation.
- Why the blood-brain barrier functions more as a selective filter than a solid wall.
About the Guest:
Dr. Naoise Mac Giollabhui is a Clinical Psychologist and Professor at Harvard Medical School and Mass General, where he serves as the Director of research on inflammatory depression. His research focuses on the intersection of the immune system and neurobiology to understand how inflammation contributes to depressive disorders.
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Episode Highlights:
[00:03:06] How Inflammation Can Produce Depressive Symptoms
Dr. Mac Giollabhui explains how immune activation can trigger fatigue, disrupted sleep and appetite, reduced social interaction, and anhedonia. In short-term illness, those responses may help the body conserve energy, but chronic immune activation could keep the same circuitry switched on for much longer.
Dr. Mac Giollabhui explains how immune activation can trigger fatigue, disrupted sleep and appetite, reduced social interaction, and anhedonia. In short-term illness, those responses may help the body conserve energy, but chronic immune activation could keep the same circuitry switched on for much longer.
[00:08:09] Why CRP Matters In Inflammatory Depression
C-reactive protein gives researchers a practical way to measure systemic inflammation. Dr. Mac Giollabhui explains that people with depression can show chronically elevated CRP even when they are not acutely ill, making it a useful starting point for identifying patients whose depression may have an inflammatory component.
C-reactive protein gives researchers a practical way to measure systemic inflammation. Dr. Mac Giollabhui explains that people with depression can show chronically elevated CRP even when they are not acutely ill, making it a useful starting point for identifying patients whose depression may have an inflammatory component.
[00:13:15] Why The Right Patients Matter In Clinical Trials
Dr. Mac Giollabhui says roughly one in four people with depression may have CRP levels consistent with chronic low-grade inflammation. That helps explain why earlier anti-inflammatory trials often failed: researchers were treating broad groups of depressed patients rather than selecting the subgroup most likely to benefit.
Dr. Mac Giollabhui says roughly one in four people with depression may have CRP levels consistent with chronic low-grade inflammation. That helps explain why earlier anti-inflammatory trials often failed: researchers were treating broad groups of depressed patients rather than selecting the subgroup most likely to benefit.
[00:15:15] The Case For Precision Psychiatry
When researchers focused specifically on depressed patients with elevated inflammation, they saw improvement in overall depressive symptoms and an even stronger effect on anhedonia. Dr. Mac Giollabhui sees this as a signal that psychiatry may benefit from the same biomarker-driven precision approach that transformed areas like oncology.
When researchers focused specifically on depressed patients with elevated inflammation, they saw improvement in overall depressive symptoms and an even stronger effect on anhedonia. Dr. Mac Giollabhui sees this as a signal that psychiatry may benefit from the same biomarker-driven precision approach that transformed areas like oncology.
[00:27:15] How The Immune System Communicates With The Brain
The conversation explores the growing evidence that the brain is not as isolated from the immune system as once believed. Dr. Mac Giollabhui describes how cytokines, immune cells, and regions of the blood-brain barrier can transmit inflammatory signals into the central nervous system, opening up new questions about both mechanism and treatment.
The conversation explores the growing evidence that the brain is not as isolated from the immune system as once believed. Dr. Mac Giollabhui describes how cytokines, immune cells, and regions of the blood-brain barrier can transmit inflammatory signals into the central nervous system, opening up new questions about both mechanism and treatment.