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. 2025 Oct:129:359-372.
doi: 10.1016/j.bbi.2025.06.004. Epub 2025 Jun 10.

Disease severity across psychiatric disorders is linked to pro-inflammatory cytokines

Pierre Solomon  1 , Monika Budde  2 , Mojtaba Oraki Kohshour  3 , Kristina Adorjan  4 , Maria Heilbronner  2 , Alba Navarro-Flores  5 , Sergi Papiol  6 , Daniela Reich-Erkelenz  2 , Eva C Schulte  7 , Fanny Senner  8 , Thomas Vogl  2 , Lalit Kaurani  9 , Dennis M Krüger  9 , Farahnaz Sananbenesi  10 , Tonatiuh Pena  9 , Susanne Burkhardt  9 , Anna-Lena Schütz  10 , Ion-George Anghelescu  11 , Volker Arolt  12 , Bernhardt T Baune  13 , Udo Dannlowski  12 , Detlef E Dietrich  14 , Andreas J Fallgatter  15 , Christian Figge  16 , Georg Juckel  17 , Carsten Konrad  18 , Fabian U Lang  19 , Jens Reimer  20 , Eva Z Reininghaus  21 , Max Schmauß  22 , Carsten Spitzer  23 , Jens Wiltfang  24 , Jörg Zimmermann  25 , André Fischer  26 , Peter Falkai  27 , Thomas G Schulze  28 , Urs Heilbronner  29 , Jeremie Poschmann  30
Affiliations
Free article

Disease severity across psychiatric disorders is linked to pro-inflammatory cytokines

Pierre Solomon et al. Brain Behav Immun. 2025 Oct.
Free article

Abstract

Importance: Numerous studies indicate that the traditional categorical classification of severe mental disorders (SMD), such as schizophrenia, bipolar disorders, and major depressive disorders, does not align with the underlying biology of those disorders as they frequently overlap in terms of symptoms and risk factors.

Objective: This study aimed to identify transdiagnostic patient clusters based on disease severity and explore the underlying biological mechanisms independently of the traditional categorical classification.

Design: We utilized data from 443 participants diagnosed with SMD of the PsyCourse Study, a longitudinal study with deep phenotyping across up to four visits. We performed longitudinal clustering to group patients based on symptom trajectories and cognitive performance. The resulting clusters were compared on cross-sectional variables, including independent measures of severity as well as polygenic risk scores, serum protein quantification, miRNA expression, and DNA methylation.

Results: We identified two distinct clusters of patients that exhibited marked differences in illness severity but did not differ significantly in age, sex, or diagnostic proportions. We found 19 serum proteins significantly dysregulated between the two clusters. Functional enrichment pointed to a convergence of immune system dysregulation and neurodevelopmental processes.

Conclusion: The observed differences in serum protein expression suggest that disease severity is associated with the convergence of immune system dysregulation and neurodevelopmental alterations, particularly involving pathways related to inflammation and brain plasticity. The identification of pro-inflammatory proteins among the differentially expressed markers underscores the potential role of systemic inflammation in the pathophysiology of SMD. These results highlight the importance of considering illness severity as a core dimension in psychiatric research and clinical practice and suggest that targeting immune-related mechanisms may offer promising new therapeutic avenues for patients with SMD.

Keywords: Cognitive dysfunction; Disease severity; Inflammation; Multi-omics analysis; PLAUR; Proteomics; Severe mental disorders; Transdiagnostic clustering.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Volker Arolt has been working as a counselor for Sanofi-Aventis Germany and Springer-Nature Verlag, Germany. Ion-George Anghelescu has served as a counselor, advisor or CME speaker for the following entities: Aristo Pharma, Janssen Pharmaceutica, Merck, Dr. Willmar Schwabe, Recordati Pharma. Jens Wiltfang acted as a consultant for Immungenetics, Noselab, Roboscreen, served on a scientific advisory board for Abbott, Biogen, Boehringer Ingelheim, Lilly, Immungenetics, MSD Sharp-Dohme, Noselab, Roboscreen, Roche, and received honoraria for presentations by Beeijing Yibai Science and Technology Ltd, Eisai, Gloryren, Janssen, Pfizer, Med Update GmbH, Roche, Lilly. Carsten Konrad has been working as advisor for Janssen Pharmaceuticals and received speakers honorary from Janssen, Lundbeck, Neuraxpharm, and Servier. Peter Falkai is currently president of the WFSBP. Peter Falkai has been EPA president in 2022 and is a co-editor of the German (DGPPN) schizophrenia treatment guidelines and a co-author of the WFSBP schizophrenia treatment guidelines. Peter Falkai received speaking fees from Boehringer-Ingelheim, Janssen, Otsuka, Lundbeck, Recordati, and Richter and was a member of the advisory boards of these companies and Rovi. Jörg Zimmermann served as an advisor for Biogen concerning Aducanumab (Alzheimer’s Disease). All other authors report no biomedical financial interests or potential conflicts of interest.