Depression Shares Immune Signature with Atopic Dermatitis, Study Finds
Researchers at Icahn School of Medicine at Mount Sinai found that major depressive disorder shares key immune abnormalities with atopic dermatitis, particularly Th2 pathway activation. The team plans to test dupilumab in a clinical trial for depression.
Investigators at the Icahn School of Medicine at Mount Sinai identified overlap between the blood immune profiles of patients with depression and inflammatory skin diseases, highlighting the Th2 axis as a potential treatment target. In findings published in Molecular Psychiatry, researchers report that the serum proteomic profile of patients with major depressive disorder (MDD) shares key immune abnormalities with inflammatory skin diseases—most notably activation of the T helper 2 (Th2) immune axis implicated in atopic dermatitis.
The work adds to a growing body of literature suggesting that depression, long conceptualized primarily as a disorder of neurotransmission, may also involve clinically meaningful immune dysregulation. For practicing clinicians, the study is noteworthy not only for its mechanistic implications but also for its therapeutic ambition: the team is preparing to test whether dupilumab, an FDA-approved biologic for atopic dermatitis that targets interleukin-4 receptor alpha (IL-4Rα), can improve depressive symptoms in patients with MDD.
Major depressive disorder affects millions of individuals worldwide and remains refractory to treatment in a substantial proportion of patients. Although monoaminergic antidepressants remain first-line therapy, increasing evidence supports bidirectional communication between the immune system and the central nervous system in stress-related disorders. Elevated inflammatory markers, altered cytokine profiles, and immune cell shifts have all been described in subsets of patients with MDD. However, translating these findings into targeted, disease-modifying interventions has proven difficult.
In contrast, dermatology has seen rapid progress over the past decade. Disease immunophenotyping in conditions such as psoriasis and atopic dermatitis has led to targeted biologic therapies that substantially alter disease trajectory. Dupilumab (Dupixent; Sanofi and Regeneron), a monoclonal antibody directed against the IL-4Rα subunit, inhibits signaling of IL-4 and IL-13—key drivers of the Th2 pathway—and was the first FDA-approved long-term biologic for moderate to severe atopic dermatitis.
Seeking to apply a similar translational model to psychiatry, the Mount Sinai team assembled experts from psychiatry, dermatology, and neuroscience. The investigators first compared blood proteomic profiles from patients with MDD to those from patients with atopic dermatitis, psoriasis, and healthy controls. They found that patients with MDD exhibited Th2 pathway skewing and dysregulation of immune and neurovascular-related proteins similar to patterns seen in atopic dermatitis.
This overlap suggested a potentially actionable pathway. To explore therapeutic implications, the team conducted an in silico drug repurposing analysis. Using computational modeling, they examined whether biologic agents commonly used in dermatology might reverse the dysregulated proteomic signature observed in MDD.
This computational approach identified dupilumab as significantly affecting the major depressive disorder signature by reversing the dysregulation of several inflammatory proteins related to Th2 signaling. Stemming directly from these findings, the 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.
To complement the proteomic and computational data, the investigators turned to a well-established mouse model of depression: chronic social defeat stress.