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Live Science spoke with the scientists behind an upcoming clinical trial testing an immune therapy for depression.
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In at least some people with depression, the immune system may contribute to the symptoms and severity of the condition, studies find.
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Explore An account already exists for this email address, please log in. Subscribe to our newsletter"I was completely surprised."
When psychiatrist Dr. James Murrough teamed up with dermatologist Dr. Emma Guttman-Yassky to investigate how the immune system might contribute to depression, he didn't expect to find a promising treatment.
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Seeing that this pathway was also ramped up in depression, the team then used computer modeling to predict which existing drugs might subdue that activity. They tested a few promising medicines in lab animals. Ultimately, they found that dupilumab — an antibody used to treat eczema and other inflammatory conditions — helped resolve the symptoms in a mouse model of depression.
Nicoletta Lanese: Prior to your new study, what was known about the role of the immune system in depression?
Sign up for the Live Science daily newsletter nowContact me with news and offers from other Future brandsReceive email from us on behalf of our trusted partners or sponsorsBy submitting your information you agree to the Terms & Conditions and Privacy Policy and are aged 16 or over.Dr. James Murrough: Going back a couple of decades, there started to accumulate evidence implicating the immune system in depression, or at least in some types of depression.
People that have some type of disorder of inflammation — whether it's rheumatoid arthritis or an inflammatory skin disease — have a higher incidence of co-occurring depression than you would predict based on the general background population. This is the epidemiologic evidence. So, there's some connection, but we don't know, "Does A cause B, or is there some underlying factor that's causing both?"
Stress of different types — psychological stress, stress from the environment, things like job losses, divorce, marriage, moving — can precipitate an episode of depression. When I was in medical school, we didn't really learn about it, but it turns out that the immune system is sensitive to stress. This has been shown in people and other animals, model systems, that psychological stress, social stress, isolation, bullying, trauma — you name it — it drives high the immune system.
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A classic finding that you do learn about in medical school is that hepatitis C used to be treated with things that are pro-inflammatory — cytokines, something called interferon alpha. No one really understood why, but a significant proportion of patients that had hepatitis C and got the treatment for it developed depression. This was well known, and people would put them on antidepressants beforehand.
And a lot of studies now have shown, if you look at common markers in the blood of inflammation … patients with depression reliably show small but statistically significant elevations in these pro-inflammatory factors.
NL: And what prompted your recent study, which also looked at inflammatory markers in the blood?
Dr. Emma Guttman-Yassky: James had an idea that maybe some inflammatory markers are involved in depression and came to me. Then together, we came up with an idea that it would be nice to compare patients with intractable depression to those patients with psoriasis and atopic dermatitis — and, of course, healthy controls — to understand where depression falls. That's when we understood that, in depression, the Th2 immune pathway likely plays a role, and we also associated it [its activity] with the severity of depression.
The magnitude of dysregulation is greater in patients with eczema — so patients with eczema have more systemic inflammation than patients with depression. But overall, the patients with depression still had significant elevations [of inflammatory markers] in their circulation compared to controls.
And then we did something actually quite novel: We took the [immune] signature of depression and the signature of what dupilumab does in atopic dermatitis patients, and we put the latter on top of the depression signature. We saw that actually, if we extrapolate, dupilumab is likely able to reverse the [immune] phenotype of depression.
That, plus the mouse model experiments, led us to think that probably the type 2 pathway, and maybe inflammation in general, likely play a role in depression. This led to this very novel trial designed by James that, if successful, I think could revolutionize, completely, the way we treat depression.
NL: With your mouse model of depression, were you surprised to see dupilumab have such a strong effect?
JM: I was very surprised. We hadn't used that technique before, the so-called in silico [computer] modeling technique. This study was also made possible with the recent development of being able to look at, in this case, close to 400 proteins in the blood. That probably led to uncovering some of these pathways that hadn't been previously reported in the literature. No one had really honed in on this particular IL-4 target, the Th2 pathway.
[Editor's note: IL-4 is a signaling protein that interacts with and is produced by Th2 cells, and it plays a central role in eczema. Dupilumab blocks receptors that respond to IL-4.]
We worked with Scott Russo, who's been a big part of this research and has contributed substantially to understanding the biology of the immune system in stress using animal models. His lab went back and did the validation studies. We identified the target in the human, went back to the mouse, and then were able to show that, if you gave a drug against the IL-4 receptor, you could block the depression-like behavior that develops in the context of stress, which is a common animal model.
NL: Could you explain what the role of type 2 immunity is in the body, usually?
EGY: When it's working well, it wards off parasites.
But in these patients, the type 2 immunity is misbehaving. In patients with eczema; asthma; allergy, including seasonal allergies; eosinophilic esophagitis; hives — they all have very high elevation of this pathway. But it's important to understand that, when you use drugs that target Th2, you do not increase the risk of infections, including those parasite infections.
NL: Does that suggest that the drugs bring the pathway into a "normal" range, rather than completely suppressing it?
EGY: Yes, you stole my thought. I explain to my patients that the old treatments [for eczema] — like cyclosporine, methotrexate, oral prednisone — these were really immune suppressants. Now we are dealing, I think, with immune "correction" rather than immune suppression.
The higher the inflammation in the blood, the greater their reaction in the amygdala, even though at the same time, it's reduced in the reward center.
Dr. James Murrough, Icahn School of Medicine at Mount Sinai
NL: In depression, why might that kind of immune modulation be helpful?
JM: Inflammation has been shown to suppress the brain's response to reward. So that's a hint as to why being inflamed might make you feel depressed. That's been worked out also in stress models in animals, and we can use technology like functional brain imaging to look at markers of that in the brain. We're also going to be doing that [in our upcoming trial].
We think that the suppression of the reward system is a key factor, but we know there are other effects. For example, we did some prior studies in people with depression and looked at their inflammation, and we were able to show that the higher their inflammatory markers in the blood, the less responsive their brain was during a standard reward-activation task. That's in a part of the brain called the nucleus accumbens, [within] the ventral striatum.
One way we think of depression is you have this group of symptoms related to lack of effort, lack of motivation, lack of response to pleasure. There are brain systems that we feel pretty confident are connected to that, but why they're suppressed, often, we don't know. Maybe the immune system is a piece of that.
But then you have other parts of the brain, like the amygdala, which is more attuned to threat. People with depression have been shown to have abnormally reactive amygdala responses, specifically to negative information or threats — sad faces, fearful faces, things like that. So, there's evidence for blunted positive responses, but then also, abnormally reactive responses to negative information in the world. We did a study that showed that the higher the inflammation in the blood, the greater their reaction in the amygdala, even though at the same time, it's reduced in the reward center.
NL: To clarify, as we're thinking about using immune modulation as a depression treatment, would it likely be helpful to all patients, or only a subset?
JM: We don't know. It's likely that only a subset — only some patients that carry a diagnosis of major depression will have an abnormality in their immune system, at least one that's relevant for treating.
EGY: We hypothesize now, starting with the study soon, that treating with an immune-based treatment that targets this pathway may be able to reverse part of the phenotype of depression and ameliorate [symptoms in] these patients.
I think time will tell what will be the improvement and what is the right patient, and so on.
JM: As our knowledge evolves, some people are starting to talk about an immune subtype of depression. It doesn't currently exist; it's not recognized in the textbooks yet. It's not in our "bible of psychiatric illnesses," the DSM [Diagnostic and Statistical Manual of Mental Disorders]. But there are proposals, and folks are gearing up to write the next DSM. It's on the table; it's gaining some traction. The challenge is, how should it be defined?
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We hope that one day a patient [with depression] will get a blood test that can say, "OK, you have a blood marker that indicates dysfunction in your immune system — or even better, a specific component of your immune system. Now, we're going to give you a medicine that targets that." We'd like to be able to personalize our treatment based on known, underlying biology. So, instead of just saying a patient has depression, we'd like to be able to say, "You have this type of depression, and therefore, you need that treatment."
There's a lot of detail trying to be worked out, but there is clearly a link between what's going on in the body and these brain systems that support our emotions, our emotional health. I think psychiatry is advancing to the point where we're going to start to understand our illnesses in terms of specific pathways and brain systems, which, of course, is not always how it's been understood.
We're right at that cusp of, hopefully, a lot of fundamental biology and neuroscience knowledge starting to spill into how we actually practice the treatment of psychiatry. We're trying to move towards that in the next few years.
Editor's note: This interview has been edited for length and clarity.
DisclaimerThis article is for informational purposes only and is not meant to offer medical advice.
Article SourcesHe, H., Cathomas, F., Parise, L. F., David, E., Rizk, M., Hawkins, K., Karpman, E., Russo, S. J., Guttman, E., & Murrough, J. W. (2026). Major depressive disorder shares systemic immune signatures and potential therapeutic targets with inflammatory skin diseases. Molecular Psychiatry. https://doi.org/10.1038/s41380-025-03383-5
Nicoletta LaneseSocial Links NavigationChannel Editor, HealthNicoletta Lanese is the health channel editor at Live Science and was previously a news editor and staff writer at the site. She holds a graduate certificate in science communication from UC Santa Cruz and degrees in neuroscience and dance from the University of Florida. Her work has appeared in The Scientist, Science News, the Mercury News, Mongabay and Stanford Medicine Magazine, among other outlets. Based in NYC, she also remains heavily involved in dance and performs in local choreographers' work.
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