Major depressive disorder (MDD), already suspected as being an inflammatory disease in at least some patients, might respond to the same highly targeted therapies that are effective for atopic dermatitis (AD) and other inflammatory skin diseases, according to a recently completed set of studies.

In a first step, using a proprietary proteomic assay to measure 353 serum proteins, the inflammatory profile of MDD was found to be most like that of those with AD, according to a multidisciplinary team of investigators led by Helen He, MD, assistant professor of dermatology, Icahn School of Medicine at Mount Sinai in New York City.

In a second step, performed with a medical simulation in vivo model, the interleukin (IL)-4 inhibitor dupilumab reversed the proteomic profile in MDD much like it does in AD, raising the possibility that specifically targeting the inflammatory profile common to AD could be beneficial in MDD. This profile, commonly known as a T helper type 2 (Th2) cell response to pathogens, is targetable with several anti-inflammatory therapies used in AD, including dupilumab.

“Overall, our data support the potential pathogenicity of the Th2 axis in MDD, warranting further exploration of specific immune targeting of Th2 as a novel, disease-modulating treatment strategy,” He and her coinvestigators stated in a summary of work published ahead of print in Molecular Psychiatry.

Targeted Therapy for MDD Called Revolutionary

The idea that MDD might be a disease mediated by inflammation is not new, according to several sets of evidence cited by the team of investigators. However, the concept that the inflammatory pathways might be shared with skin diseases and targetable with the same therapies is “revolutionary,” according to Emma Guttman-Yassky, MD, PhD, system chair of the Department of Dermatology, Icahn School of Medicine at Mount Sinai.

The evidence from this and other studies that the same immune dysregulation might drive different inflammatory diseases was “surprising,” Guttman-Yassky, who was one of two senior authors of this work, told Medscape Medical News. She credited He, the first author, with finding the proteomic similarities of inflammation expressed in dermatologic disorders and MDD, and pointed out that it is inconsistent with empiric observation.

“Depression in patients with eczema is common, and I had often wondered if these diseases might be linked,” she said. If additional studies support this early work, it would be “a game changer.” For one, the highly targeted anti-inflammatory therapies for AD are better tolerated in general than current MDD treatments, according to Guttman-Yassky. 

The work was based on a series of studies with the same goal. In the initial proteomic comparison, serum was drawn from 25 patients with MDD, 30 patients with AD, 21 patients with psoriasis, and 32 healthy control patients. Comparing the inflammatory signatures on the basis of expression of the 353 proteins measured, in-group correlations supported a Th2 inflammatory profile for both AD and MDD. The between-group differences only increased with pathway enrichment analyses. 

Experimental in silico analyses, meaning computational medical simulations, were then performed to test how the inflammatory profile was affected by anti-inflammatory therapies. Many agents, including cyclosporine, were associated with a downregulation of the inflammatory signature, but dupilumab, a biologic commonly employed in AD, had the greatest impact on the MDD signature of any of the drugs tested.

Animal Model Also Supports IL-4 Targeting in MDD

In this series of investigations, a validated chronic “social defeat” mouse model of mood disorders was also employed to test the effect of IL-4 inhibition. This showed that IL-4 inhibition modified behavioral changes linked to stress, according to James W. Murrough, MD, PhD, professor of psychiatry and neurology at the Icahn School of Medicine. 

Acknowledging that not much can be said about the actual antidepressant effect in a rodent, Murrough, who was another senior author of the study, said that this type of model “is fairly well validated” for studying change in mood status in the experimental setting. In the context of the earlier work tracking proteomic changes in markers of inflammation with dupilumab, this work is encouraging, he noted.

Across inflammatory diseases, “this is an example of translational research that is helping us understand the basic signaling and allow us to follow it to a new treatment,” Murrough told Medscape Medical News.

Based largely on these studies, Murrough recently received a grant to conduct a small pilot clinical study with dupilumab for the treatment of MDD. He cautioned against overinterpreting these data at this relatively early stage of investigation, but he thinks this area of science is close to clinical relevance.

“This is part of something that is much larger,” Murrough said, referring to both MDD and other pathologies now being recognized as inflammation driven. He said it is now clear that the “immune system does much more than we thought 20 years ago.”

In this regard, he believes that the term immune system might be a “misnomer” when it refers only to its function as a defense against disease. Rather, he considers the up- and downregulated proteins of inflammation “a highly complex multifaceted communication system that links the body to the brain.”

In dermatology, the advent of anti-inflammatory biologics and highly targeted small-molecule inhibitors has been transformative. Many skin diseases are now nearly or completely controlled with these agents. According to Guttman-Yassky, this has been an important attribute in dermatology and would likely apply to other pathologies.

“In psychiatry and depression in particular, the current therapies have a lot of side effects because they are not targeted,” she observed. “The drugs we now have in dermatology are way safer.”

Andrew H. Miller, MD, vice-chair for research in the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine in Atlanta, has also been working on the relationship between inflammation and MDD. Author of a 2025 review article published in the American Journal of Psychiatry, he is pursuing the hypothesis that multiple types of immune dysregulation are involved.

Based on his own work and that of others, there appear to be “at least two pathways involved,” he told Medscape Medical News. One involves lymphocytes, which he said can be either T or B cells, and the other involves myeloid cells such as neutrophils and monocytes.

Inflammatory Therapy Might Be Individualized for MDD

This implies that the targets of anti-inflammatory therapies might not be the same for all patients, Miller said.

“These data are consistent with the notion that the effects of the immune system in depression may be more nuanced and require targeting of select immune pathways in specific individuals based on immune biomarkers,” he explained.

Yet, he is optimistic that inflammatory subtypes of MDD will be defined, which, in turn, will pave the way for “precision medicine” in this disease and perhaps other psychiatric disorders.

Past studies have suggested that only 20%-30% of patients with MDD have evidence of systemically elevated inflammation when evaluated for elevated C-reactive protein or other inflammatory biomarkers, but the 25 patients recruited for the proteomic analysis in this series of studies by the Mount Sinai researchers were screened only to confirm MDD and not for evidence of an inflammatory subtype, Murrough said.

This suggests “that targeting inflammation in MDD might be more generalizable” than the limited subgroups previously hypothesized to be candidates, he explained. One reason that the role of inflammation might not have been appreciated previously is that the expression of inflammatory proteins in MDD is much more subtle than that associated with AD or psoriasis, according to the initial proteomic analyses comparing these three diseases to healthy control groups.

According to Murrough, immune dysregulation might not be an etiologic factor in all patients with MDD. In addition, even when MDD is driven by inflammation, different inflammatory pathways or even more than one pathway might be involved. Consistent with comments made by Miller, he believes the research might be heading toward biomarkers that would help subtype inflammation-related MDD to guide specific therapies.

If further studies confirm that at least some forms of MDD can be treated with targeted anti-inflammatory therapies, including those now employed for inflammatory skin diseases, it will further the evidence that the same inflammatory pathways drive different types of pathology, Guttman-Yassky said.

While the efficacy of biologics targeting TNF in psoriasis, inflammatory bowel disease, and rheumatologic disorders already shows this is true, the link between skin diseases and mood disorders, if proven, will be new, she said.

“We will see if dupilumab or other targeted drugs we use in dermatology can be employed as monotherapies or adjunctive treatments, but this is a very exciting direction of research,” Guttman-Yassky said.

He reported a financial relationship with Clinique. Murrough reported financial relationships with Autobahn, Biohaven, ClinicLabs, Clexio Biosciences, Compass, Pathfinder, Dr Jay, Frontier Pharma, Janssen, LivaNova, Merck, Otsuka, WCG Clinical, and Xenon. Guttman-Yassky reported financial relationships with more than 50 pharmaceutical companies, including Sanofi, which makes dupilumab, and other companies that make anti-inflammatory therapies. Miller reported financial relationships with Cerevel and Sirtsei.