A recent study by researchers at the Icahn School of Medicine at Mount Sinai has found that patients with major depressive disorder (MDD) share immune system abnormalities with those who have inflammatory skin diseases, particularly involving the Th2 immune pathway associated with atopic dermatitis. The findings, published in Molecular Psychiatry on February 11, suggest new therapeutic options for psychiatric illnesses.
The research team analyzed blood samples from patients with MDD and compared them to those from individuals with atopic dermatitis, psoriasis, and healthy controls. They discovered that people with MDD exhibit similar Th2 pathway activity and dysregulation of other immune-related proteins as those with atopic dermatitis.
James Murrough, MD, PhD, Director of the Dennis S. Charney, MD, Depression and Anxiety Discovery Center at Mount Sinai and co-senior author of the paper, explained the approach: “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.”
Using computer modeling for drug repurposing analysis, the team tested whether biologic drugs used in dermatology could affect the abnormal protein patterns seen in MDD patients. Their computational work highlighted dupilumab (Dupixent), an FDA-approved monoclonal antibody for moderate-to-severe atopic dermatitis that targets the IL-4 receptor α subunit (IL-4Rα) and inhibits Th2 signaling.
“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.”
The study also included animal experiments showing that blocking IL-4Rα prevented stress-induced social avoidance behavior—a depression-like symptom—in mice exposed to chronic social defeat stress.
Emma Guttman-Yassky, MD, Waldman Professor and System Chair of Dermatology at Mount Sinai and co-senior author of the study said: “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. 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 group recently received nearly $1 million from Wellcome to support a clinical trial testing whether dupilumab can reverse immune changes seen in MDD patients while improving their 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. He will lead this upcoming trial alongside Mina Rizk, MD.
In 2025, Icahn School of Medicine filed a provisional patent application based on these findings.
