‘It could completely revolutionize the treatment of depression’: Researchers explore promising immunotherapy to treat psychiatric symptoms

I was really surprised.

When psychiatrist Dr. James Murrow teamed up with dermatologist Dr. Emma Gutman-Yaskey to investigate how the immune system contributes to depression, he didn’t expect to find a promising treatment.

In a study published in February in the journal Molecular Psychiatry, Murrow, Guttmann-Yassky and colleagues uncovered similarities in the immune systems of patients with depression and those with eczema (the most common form of which is called atopic dermatitis). These similarities emerged in the “type 2 pathway,” an immune response that involves immune cells called helper 2 (Th2) cells. When type 2 immunity is working properly, it protects against parasites. However, in inflammatory conditions such as allergies, asthma, and eczema, the activity of this pathway is disrupted in the absence of parasitic infection.

you may like

Confirming that this pathway was also increased in depression, the team used computer modeling to predict which existing drugs might inhibit its activity. They tested several promising drugs on laboratory animals. Ultimately, they found that dupilumab, an antibody used to treat eczema and other inflammatory conditions, helped resolve symptoms in mouse models of depression.

Live Science spoke with Murrow, director of the Center for the Detection and Treatment of Depression and Anxiety at the Icahn School of Medicine at Mount Sinai, and Gutman Jaskey, director of the health system for dermatology at Mount Sinai. Their team is now preparing to begin a small trial of dupilumab in patients with treatment-resistant depression whose symptoms have not improved with other treatments. Information about this exam will be available soon on the Mount Sinai website.

The scientists spoke with us about their recent research, upcoming trials, and their long-term hopes for this research.

Nicoletta Lanese: Before your new study, what was known about the role of the immune system in depression?

Dr. James Murrow: Going back several decades, evidence began to accumulate that the immune system was involved in depression, or at least some types of depression.

People with any kind of inflammatory disease, whether it’s rheumatoid arthritis or an inflammatory skin disease, are more likely to develop depression than would be expected based on their general background population. This is epidemiological evidence. In other words, although there is some connection, we don’t know “Does A cause B, or is there an underlying factor that causes both?”

Many types of stress can trigger depressive episodes, including psychological stress, environmental stress, job loss, divorce, marriage, and moving. Although I didn’t know much about it when I was in medical school, we know that the immune system is sensitive to stress. This has been shown in humans, other animals, and model systems, showing that a variety of factors boost the immune system, including psychological stress, social stress, isolation, bullying, and trauma.

What to read next

The classic discovery you learn in medical school is that hepatitis C was treated with something that promotes inflammation, a cytokine called interferon alpha. Although no one understood exactly why, a significant proportion of patients who contracted and were treated for hepatitis C developed depression. This was so well known that people were pre-medicated with antidepressants.

And now, a number of studies have shown that when we look at common markers of inflammation in the blood, patients with depression do have small but statistically significant increases in these pro-inflammatory factors.

NL: So what prompted your recent study that also looked at inflammatory markers in the blood?

Dr. Emma Guttmann-Yaskey: James came to me thinking that perhaps some inflammatory markers are involved in depression. So together we came up with the idea that it would be nice to compare patients with refractory depression to patients with psoriasis and atopic dermatitis and, of course, to healthy controls to understand how their depression is faring. At that time, we realized that the Th2 immune pathway likely plays a role in depression, and we also showed that there is a connection between it and the Th2 immune pathway. [its activity] With severity of depression.

Because the degree of dysregulation is greater in eczema patients, eczema patients have more systemic inflammation than depression patients. But overall, depressed patients still showed a significant increase. [of inflammatory markers] in their circulation compared to controls.

And we actually did something very novel. [immune] We compared the features of depression and the features of dupilumab’s effect on patients with atopic dermatitis, placing the latter on top of the features of depression. In fact, by extrapolation, we found that dupilumab could probably reverse this condition. [immune] Depression phenotype.

This and experiments in mouse models have led us to believe that the type 2 pathway, and perhaps inflammation in general, is likely involved in depression. This led to this very novel trial that James designed that, if successful, I think could completely revolutionize the way depression is treated.

NL: Were you surprised that dupilumab had such a strong effect in your mouse model of depression?

JM: I was very surprised. We had never used that technique before, so-called in silico. [computer] modeling technology. This research was also made possible by recent developments that have made it possible to look at nearly 400 different proteins in the blood. It probably led to uncovering some of these pathways that were not previously reported in the literature. No one had really focused 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 collaborated with Scott Russo, who contributed significantly to this research and to our understanding of the biology of the immune system during stress using animal models. His lab went back and conducted validation studies. We identified the human target and were able to go back to mice and show that administering a drug directed against the IL-4 receptor can block depression-like behavior that develops in situations of stress, a common animal model.

NL: Can you explain what role type 2 immunity typically plays in the body?

EGY: When it’s working well, it wards off parasites.

However, in these patients, type 2 immunity is malfunctioning. For patients with eczema. Asthma; Allergies, including seasonal allergies. Eosinophilic esophagitis. Hives – They are all located at very high elevations on this route. However, it is important to understand that using Th2-targeted drugs does not increase the risk of infections, including parasitic infections.

NL: Does that suggest that the drug returns the pathway to a “normal” range rather than completely suppressing it?

EGY: Yes, you stole my idea. I explain old treatments to my patients. [for eczema] Cyclosporine, methotrexate, oral prednisone, these were just immunosuppressants. I think we are now working on immune “correction” rather than immunosuppression.

As inflammation increases in the blood, the response in the amygdala also increases, but at the same time, the response in the reward center decreases.

NL: Why might such immune modulation be helpful in depression?

JM: We know that inflammation suppresses the brain’s response to reward. This gives you a hint as to why inflammation can make you feel depressed. This has also been demonstrated in animal stress models, where techniques such as functional brain imaging can be used to examine markers of stress in the brain. we’re going to do that too [in our upcoming trial].

We believe that suppression of the reward system is an important factor, but we also know that there are other influences. For example, we’ve done some previous research in people with depression and looked at their inflammation. As a result, they were able to show that higher levels of inflammatory markers in the blood led to lower brain responses during standard reward activation tasks. It is located in a part of the brain called the nucleus accumbens. [within] Ventral striatum.

One way we think about depression is that there is a set of symptoms associated with a lack of effort, a lack of motivation, and a lack of response to pleasure. There are brain systems that we believe are involved, but in many cases we don’t know why they are being suppressed. Maybe the immune system is part of it.

But there are other parts of the brain that are more sensitive to threat, such as the amygdala. People with depression have been shown to have an abnormal response in the amygdala, especially to negative information or threats, such as sad or fearful faces. In other words, not only is there evidence that positive reactions are becoming slower in the world, but there is also evidence that people are reacting abnormally to negative information. In our research, we found that the higher the level of inflammation in the blood, the greater the response in the amygdala, but at the same time the response in the reward center decreases.

NL: Just to be clear, we’re thinking about using immunomodulation as a treatment for depression, but is that likely to help all patients or only some patients?

JM: I don’t know. Only some patients diagnosed with major depression are likely to have at least treatment-related immune system abnormalities.

EGY: We hypothesize, with research beginning soon, that treatment with immune-based therapies that target this pathway may reverse and reverse some of the depression phenotypes. [symptoms in] These patients.

I think only time will tell what will improve and which patients are appropriate.

JM: As our knowledge evolves, some people are starting to talk about immune subtypes of depression. Does not currently exist. It is not yet recognized in textbooks. It’s not in the DSM, our “bible of mental illness.” [Diagnostic and Statistical Manual of Mental Disorders]. But the proposals are out there, and people are getting ready to write the next DSM. It’s on the table. It’s gaining some traction. The challenge is how to define it.

We hope that someday the patient will [with depression] If you take a blood test, you can say, “Hey, we found a blood marker that indicates a malfunction in your immune system. And by extension, it points to a specific component of your immune system. Now, we’re going to give you a drug that targets that.” We want to be able to personalize treatment based on the basic biology that we know. So instead of just saying a patient has depression, we want to be able to say, “You have this type of depression and you need that treatment.”

Although many details are still being worked out, there is clearly a link between what is happening inside our bodies and the brain systems that support our emotional and mental health. I think psychiatry has advanced to the point where we can understand diseases in terms of specific pathways and brain systems. Of course, it is not always understood that way.

We’re really at the cusp of that, and hopefully a lot of the basic biology and neuroscience knowledge is starting to be funneled into the way we actually practice psychiatric treatment. We are trying to move towards that in the next few years.

Editor’s note: This interview has been edited for length and clarity.