2026 ECNP Congress

PS03-3045

Upregulation of inflammatory proteins as a systemic immune activation in major depressive disorder

Maria J. Portella — X. Bai, A. Cervantes-González, J. de Diego-Adelino, C. Alemany, J. Carrasco, D. Alcolea, J. Fortea, N. Cardoner, J. Trujols, O. Belbin, M. Vicent-Gil · IR Sant Pau, Mental Health Research Group. Department of Psychiatry, Barcelona, Spain

2026 ECNP Congress

Background

Major depressive disorder (MDD) is a leading cause of disability worldwide, characterized by substantial heterogeneity. Increasing evidence implicates low‑grade systemic inflammation in the pathophysiology of MDD, with peripheral immune activity influencing central nervous system function [1]. Although cytokines have been extensively studied, their biological variability limits their utility as stable clinical biomarkers. In contrast, downstream inflammatory‑related plasma proteins provide a more robust index of chronic immune activation and may better capture broad inflammatory phenotypes [2]. Meta‑analytic evidence supports modest elevations of such markers in MDD, though findings remain heterogeneous and influenced by demographic factors such as age and sex. Moreover, it is unclear whether inflammatory alterations persist beyond acute depressive episodes. The aim of this study was to comprehensively characterize plasma inflammatory protein profiles in individuals with MDD compared with healthy controls, accounting for age and sex, and to explore whether inflammatory alterations persist in remitted patients.

Methods

This cross‑sectional study included adults with MDD (DSM‑5‑TR criteria) and healthy controls. Patients ranged from partial or full remission to moderate–severe depression. Healthy controls were recruited from a community‑based cohort without psychiatric or neurological disorders. Plasma samples were collected and stored following standardized protocols and analyzed using the NULISAseq™ Inflammation Panel (250 proteins), with samples randomized across assay runs. Group differences in inflammatory protein levels were assessed using linear regression models adjusted for age, sex, and technical factors, with false discovery rate (FDR) correction. Secondary analyses examined a subsample of patients in partial or full remission.

Results

The final sample comprised 149 patients with MDD and 25 healthy controls, with no group differences in mean age or sex distribution. Plasma inflammatory protein profiling revealed significant differences between patients with MDD and controls. In unadjusted analyses, 49 inflammatory proteins were increased, and 2 proteins (GDF15 and TNFSF9) were decreased in MDD (FDR < 0.05). These findings remained largely unchanged after adjustment for age, sex, and technical covariates. A similar pattern of inflammatory protein upregulation was observed in the subsample of remitted patients (n = 88), with nine additional proteins showing increased levels. Age was significantly associated with multiple inflammatory proteins, with older age linked to higher levels of several immune‑ and metabolism‑related proteins.

Conclusions

This study demonstrates a broad upregulation of plasma inflammatory‑related proteins in MDD that is largely independent of age, sex, and technical factors, supporting the presence of a stable low‑grade inflammatory phenotype, even in patients in partial or full remission, suggesting that inflammatory dysregulation may persist beyond the acute symptomatic state and reflect trait‑like biological vulnerability. The use of a multiplex proteomic approach extends previous findings based on single or limited markers and highlights the complexity of immune alterations in depression. While the relatively small control sample may have limited power for some comparisons, stringent matching enhanced group comparability. Overall, these findings support the relevance of downstream inflammatory proteins as candidate biomarkers for biologically informed stratification in MDD and underscore the importance of accounting for demographic modifiers in immunopsychiatric research.

References

  1. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016 Jan;16(1):22-34. doi: 10.1038/nri.2015.5. PMID: 26711676; PMCID: PMC5542678.
  2. Stanke F, Janciauskiene S and Olejnicka B (2023) Editorial: Acute phase proteins as biomarkers and therapeutics in acute and chronic inflammatory conditions. Front. Pharmacol. 14:1145990. doi: 10.3389/fphar.2023.1145990