Major Depressive Disorder Shares Immune Abnormalities and Potential Therapeutic Targets With Inflammatory Skin Diseases, According to New Study
Findings provide rationale for targeted strategy in psychiatry that may lead to new personalized treatments for major depressive disorder and other conditions
(L to R): Emma Guttman-Yassky, MD, the Waldman Professor and System Chair of the Kimberly and Eric J. Waldman Department of Dermatology; James Murrough, MD, PhD, Director of the Dennis S. Charney, MD, Depression and Anxiety Discovery Center at the Icahn School of Medicine at Mount Sinai. Photo credit: Mount Sinai Health System
A team of leading clinical research scientists from the Departments of Psychiatry and Dermatology at the Icahn School of Medicine at Mount Sinai has found that the serum of patients with major depressive disorder shares immune abnormalities with inflammatory skin diseases, most notably the common Th2 immune pathway that is implicated in atopic dermatitis. Because these skin diseases are treatable, the findings suggest new therapeutic possibilities for psychiatric illness as well.
The study findings, published February 11 in Molecular Psychiatry, underscore the potential role of the Th2 axis in major depressive disorder and highlight the potential of targeting this specific immune pathway that involves interleukin-4 receptor alpha, a cell receptor known to play a key role in regulating inflammation, as a disease-modifying treatment for this psychiatric disorder. Furthermore, the back-translational drug repurposing strategy employed in this study may offer a new approach to identifying immunomodulatory drugs in psychiatry.
Major depressive disorder is a neuropsychiatric disorder that affects millions of people and often does not respond to current treatments. There is increasing evidence of a close interaction between the brain and immune system that contributes to the pathophysiology of stress-related disorders, including major depressive disorder.
A large number of studies have described immune changes related to depression, but few clinical studies have tested the efficacy of anti-inflammatory drugs in reducing symptoms of it. In contrast, targeted immunomodulatory drugs have revolutionized the treatment of inflammatory skin disorders like atopic dermatitis and psoriasis. Most prominently, dupilumab (Dupixent), which targets the IL-4 receptor α subunit (IL-4R α) and thus inhibits the Th2 pathway, was the first monoclonal antibody approved by the U.S. Food and Drug Administration as a long-term therapy for the treatment of moderate-to-severe atopic dermatitis.
“Given the successful translational approach in dermatology, where disease immunophenotyping led to advances in understanding pathogenesis and expansion of the therapeutic pipeline, we put together a cross-disciplinary team of leading researchers from psychiatry, dermatology, and neuroscience to assess the viability of a targeted treatment approach in major depressive disorder,” said James Murrough, MD, PhD, Director of the Dennis S. Charney, MD, Depression and Anxiety Discovery Center at the Icahn School of Medicine at Mount Sinai, and corresponding co-senior author of the paper.
First, the team compared the blood proteomic profiles of patients with major depressive disorder to those of patients with atopic dermatitis, psoriasis, and healthy controls. They demonstrated that the proteomic profiles of patients with major depressive disorder share Th2 pathway skewing and dysregulation of other immune/neurovascular-related proteins with those who have atopic dermatitis. Next, they performed an in silico (computer modeling) drug repurposing analysis to test whether common biologics used in dermatology could also affect the dysregulated proteomic signature observed in major depressive disorder patients.
“This computational approach identified dupilumab, which targets the IL-4 receptor α subunit and thus inhibits the Th2 axis, as significantly affecting the major depressive disorder signature by reversing the dysregulation of several inflammatory proteins related to Th2 signaling,” said Dr. Murrough. “Stemming directly from our findings, our team will soon launch a new clinical trial to investigate whether targeting the Th2 pathway with dupilumab can improve depressive symptoms for patients with major depressive disorder.”
Finally, the team found that neutralization of IL-4Rα with a monoclonal antibody prevented stress-induced social avoidance behavior in stress-susceptible mice following chronic social defeat stress, a commonly used and effective mouse model of depression.
“We are thrilled that the successful translational approach in dermatology, where disease immunophenotyping led to advances in understanding pathogenesis and expansion of the therapeutic pipeline that has revolutionized the treatment paradigm in inflammatory skin diseases may also be an effective strategy for patients who face major depressive disorder and other psychiatric conditions,” said Emma Guttman-Yassky, MD, the Waldman Professor and System Chair of the Kimberly and Eric J. Waldman Department of Dermatology and co-senior author of the study. “These study findings provide a strong foundation and justification for human studies and clinical trials that directly address this new drug target, and we are eager to move this line of research forward, combining our collective expertise.”
The Mount Sinai research team recently received a nearly $1 million grant from Wellcome to investigate whether dupilumab can reverse the immune changes that are seen in patients with major depressive disorder and thereby improve their depressive symptoms.
“This study is exciting because it opens the possibility of a completely new way to treat depression by targeting the immune system, as opposed to more traditional antidepressants that target neurotransmitters in the brain,” said Dr. Murrough, who will lead the new trial together with Mina Rizk, MD, Assistant Professor of Psychiatry at Mount Sinai.
The Icahn School of Medicine at Mount Sinai filed a provisional patent application in 2025 based on the findings reported in this paper.
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