2026 ECNP Congress

PS01-1046

Plasma levels of inflammatory, endothelial, metabolic and glial markers in first-episode psychosis: A cross-sectional study

Igor Horrillo — M. Recio-Barbero, O. Mentxaka, R. Romero-Jimenez, L.F. Callado, L. Uriguen, P. Unzueta-Larrinaga, E. Collado-Gonzalez, J. Cabezas-Garduño, R. Segarra · University of the Basque Country- EHU, Dept. of Pharmacology, Leioa- Bizkaia, Spain

2026 ECNP Congress

Background

First-episode psychosis (FEP) represents a critical window for understanding the biological underpinnings of psychotic disorders, as patients are often early in the disease course and have had limited lifetime exposure to antipsychotic medications. Accumulating evidence implicates immune dysregulation, blood-brain barrier (BBB) dysfunction, metabolic abnormalities, and glial pathology in chronic schizophrenia [1], but whether they are present at illness onset is unclear.

Aims

Simultaneously assess inflammatory cytokines, kynurenine pathway enzymes, endothelial adhesion molecules, adipokines, and glial injury markers in FEP to identify early peripheral biological signatures before chronicity and long-term treatment obscure the underlying pathophysiology.

Methods

This study included patients diagnosed with FEP (n=30) and healthy controls (n=27). Plasma samples were analyzed for the following biomarkers: pro-inflammatory IL-6, antiinflammatory IL-10, indoleamine 2,3-dioxygenase (IDO), endothelial adhesion molecules ICAM-1 and VCAM-1, adipokine leptin and astroglial injury marker S100B. Quantification was performed using Multiplex ELLA array system and standard ELISA assays.

Results

Patients with FEP showed significantly elevated plasma concentration of IL-6 (2.36 ± 0.30 vs 1.61 ± 0.18 pg/mL; p=0.030), indicating a pro-inflammatory state, while IL-10 was also higher (2.29 ± 0.18 vs 1.11 ± 0.11 pg/mL; p=0.018), suggesting a concurrent compensatory anti-inflammatory response. IDO plasmatic concentration was upregulated (0.71 ± 0.14 vs 0.39 ± 0.06 pg/mL; p=0.041), pointing to enhanced tryptophan catabolism along the kynurenine pathway potentially leading to neurotoxic metabolites. ICAM-1 and VCAM-1 levels were both significantly elevated (ICAM-1: 324.3 ± 15.9 vs 263.1 ± 10.7 ng/mL; p=0.002; VCAM-1: 508.2 ± 42.8 vs 366.9 ± 53.5 ng/mL; p=0.043), consistent with endothelial activation and possible BBB compromise. Leptin concentrations were higher in patients (28.6 ± 4.6 vs 16.4 ± 2.3 ng/mL; p=0.021), indicative of hyperleptinemia and potential leptin resistance. S100B levels were increased (13.4 ± 1.5 vs 8.9 ± 1.3 pg/mL; p=0.032), suggesting ongoing astroglial injury. Correlation analyses revealed two notable findings. First, a strong positive correlation was observed between ICAM-1 and VCAM-1 (r = 0.86, p < 0.001), indicating coordinated endothelial activation in FEP patients. Second, despite both being elevated, a negative correlation was found between leptin and IDO within the patient group (r=-0.40; p<0.029). This unexpected inverse relationship suggests that metabolic dysregulation (hyperleptinemia) and immune-driven tryptophan catabolism may operate as partially independent or counter-regulatory processes in FEP.

Conclusions

Patients with FEP exhibit a distinctive plasma biomarker profile characterized by elevated IL-6, IL-10, IDO, ICAM-1, VCAM-1, leptin, and S100B. This pattern reflects concurrent inflammation, kynurenine pathway activation, endothelial dysfunction, metabolic dysregulation, and glial injury already present at the early stages of psychotic illness, prior to long-term medication exposure or chronicity. The positive ICAM-1/VCAM-1 correlation supports coordinated endothelial activation, while the negative leptin-IDO correlation highlights that elevated group means can mask complex, dissociated relationships at the individual level. These findings support the notion that FEP is associated with a multi-system peripheral alteration rather than isolated mono-pathway defects, and underscore the potential for biomarker-based subtyping early in the disease course [2]. Future longitudinal studies should investigate whether this biomarker signature predicts clinical progression to chronic schizophrenia, treatment response, or the development of metabolic comorbidities.

References

  1. Pillinger T, D’Ambrosio E, McCutcheon R, Howes OD. Is psychosis a multisystem disorder? A meta-review of central nervous system, immune, cardiometabolic, and endocrine alterations in first-episode psychosis and perspective on potential models. Mol Psychiatry. 2019 Jun;24(6):776-794. doi: 10.1038/s41380-018-0058-9. Epub 2018 May 9. Erratum in: Mol Psychiatry. 2019 Jun;24(6):928. 2. Enrico P, Delvecchio G, Turtulici N, Aronica R, Pigoni A, Squarcina L, Villa FM, Perlini C, Rossetti MG, Bellani M, Lasalvia A, Bonetto C, Scocco P, D’Agostino A, Torresani S, Imbesi M, Bellini F, Veronese A, Bocchio-Chiavetto L, Gennarelli M, Balestrieri M, Colombo GI, Finardi A, Ruggeri M, Furlan R, Brambilla P; GET UP Group. A machine learning approach on whole blood immunomarkers to identify an inflammation-associated psychosis onset subgroup. Mol Psychiatry. 2023 Mar;28(3):1190-1200.