A growing body of evidence has suggested that the immune system is dysregulated in some patients with major depressive disorder (MDD). Past studies, in fact, have shown that 20% to 30% of patients have low-grade systemic inflammation. Now, newly published research co-led by BBRF grantees shows one way in which links between the immune system and depression may be exploited to develop new therapeutics to reduce depression symptoms.
Two of the co-first authors of the paper reporting the new research in Molecular Psychiatry, Flurin Cathomas, M.D., and Lyonna Parise, Ph.D., and two of its senior authors, Scott J. Russo Ph.D., and James W. Murrough, M.D., were involved in a study published in 2024 that explained how a protein called MMP8, released during chronic social stress by circulating immune cells, can invade the brain and induce changes that in animal models correlate with behavioral changes such as social avoidance that are seen in depression and other mood disorders.
The new research explores the concept of whether drugs like those approved for use in inflammatory skin conditions such as atopic dermatitis (AD) and psoriasis might potentially benefit major depression patients. Before clinical tests of this concept can be contemplated, a good deal of basic research needs to be conducted, to explore, among other things, whether dysregulated inflammatory processes implicated in those skin conditions may also be affecting that subset of depressed patients with elevated inflammation.
Drs. Russo and Murrough are members of BBRF’s Scientific Council. Dr. Russo received BBRF Young Investigator grants in 2008 and 2006; Dr. Murrough was a 2009 BBRF Young Investigator. Drs. Cathomas and Parise, respectively, received BBRF Young Investigator grants in 2020 and 2022. Dr. Helen He was also a co-first author of the new paper, and Dr. Emma Guttman was also a co-team leader. All are at the Icahn School of Medicine at Mount Sinai. Mina Rizk, M.D., another team member, is a 2019 BBRF Young Investigator.
“Despite the large number of studies describing immune changes in MDD, few clinical studies have tested the efficacy of anti-inflammatory drugs in reducing depression symptoms,” the team noted. This, they said, “stands in stark contrast to primary immune-inflammatory disorders like AD and psoriasis.” AD is the most common inflammatory skin disorder, affecting up to 10% of adults; psoriasis affects another 3%. Dysregulation of T-helper cells plays a key role in both conditions.
T-helper cells (also called CD4+ lymphocytes) are key players in the adaptive immune system. They activate other immune cells, including B cells, macrophages, and cytotoxic T cells, to combat infections. They recognize specific pathogens and differentiate into specialized subtypes to tailor immune responses against intracellular bacteria, parasites, or viruses.
Pathways involving one of the subtypes of T-helper cells, called Th2 (T-helper 2), are inhibited by a drug called dupilumab (Dupixent) that has been approved for long-term treatment of moderate-to-severe AD. Delivered via injection, this monoclonal antibody therapeutic targets a site on a receptor called IL-4, a cellular regulator of the immune response. A drug with relatively few side effects, it can be administered to patients as young as 6 months of age.
A first step taken by the team in exploring the possibility of using a drug like dupilumab in depression was to compare the immune signature of MDD patients with those of people with AD and psoriasis. Were there similarities? They analyzed blood samples from 25 people with MDD, 30 with AD, 21 with psoriasis, and 32 healthy controls who were neither depressed nor suffered from any inflammatory conditions. Levels of 353 proteins in the blood were assessed.
This revealed that MDD shares certain aspects of the inflammatory signature seen in AD, specifically elevated Th2 pathway activation as well as several other immune and neurovascular abnormalities. In MDD patients, the Th1 pathway also showed elevated activation, although less prominently than the Th2 pathway. In AD, Th2 “skewing” results in activation of particular T-helper cells and up-regulation of certain proteins whose levels correspond with activation of specific immune cell types. As noted by the researchers, the exact relationship between Th1 and Th2 activation and depression causation remains uncertain.
A computer-driven analysis of the effects of approved drugs suggested to the team that dupilumab, which, in targeting the IL-4 receptor, inhibits the Th2 pathway, might help to reverse the immune signature seen in the MDD patients. To test this possibility, they used mice and a behavioral paradigm called social-defeat stress. Animals dominated by aggressive cagemates develop behaviors analogous to those seen in depression. In stress-naïve animals, they used a drug to inhibit the portion of the IL-4 receptor (the IL-4-alpha subunit) targeted by dupilumab. The animals were then subjected to social-defeat stress, but did not develop social-avoidance behavior that is the usual result.
The study demonstrated that the serum of patients with MDD (blood with clotting factors removed) “contains unique up-regulation of neuroinflammatory and vascular inflammation or cardiovascular risk proteins, but also shares immune abnormalities with inflammatory skin diseases, most notably the Th2 skewing in AD.” These abnormalities appear to be modifiable by inhibiting IL-4 receptors. Before a drug like dupilumab would be tested in human patients, human studies and clinical trials are needed, the researchers said, to determine the precise role of the Th2 pathway in major depression—for example, how it affects gene activation and protein levels in cells involved in the immune response and in brain function.
The researchers said that it would be important to look for differences among patients with major depression, for example in levels of inflammatory markers that might be involved. They also noted the current study doesn’t indicate any overlap in pathology between MDD and AD or psoriasis, or that the immune markers they share actually drive pathologies. What the results do indicate, however, is that systemic inflammation is common to all three disorders “and generally hastens disease progression.” The hope, they said, is that in MDD, as in AD, therapeutic targeting of proinflammatory pathways that all three disorders share would result in a significant reduction in depression symptoms and reduction of the chance of disease progression via inflammatory pathways.
