Affective stratification of peripheral inflammatory markers in first-episode psychosis

Introduction

First-episode psychosis (FEP) is biologically and clinically heterogeneous [1], and peripheral inflammatory findings in early psychosis remain inconsistent because of diagnostic differences, antipsychotic exposure [2], metabolic status [3], recent infection and variable outcome definitions. Affective symptom burden may define a clinically meaningful subgroup with partially distinct immune-inflammatory mechanisms [4]. We therefore designed a cross-sectional clinical-biological study to compare a peripheral immunoinflammatory profile in FEP with and without clinically significant affective symptoms and in healthy controls.

Methods

This observational case-control study will be conducted at a psychiatry clinic in Cluj-Napoca, Romania, and it will include adults aged 18-65 years with FEP and healthy controls. The FEP sample will be stratified into participants with clinically significant affective symptoms, defined by a Hamilton Depression Rating Scale score of at least 17 and/or a Young Mania Rating Scale score of at least 20 at baseline, or by an ICD diagnosis of an affective episode with psychotic symptoms, and participants without significant affective symptoms. Healthy controls will have no history of psychotic disorder or major affective disorder and no acute infection or active inflammatory illness. Key exclusions are acute clinical or biological infection within two weeks, active autoimmune disease, recent systemic immunosuppressive or clinically relevant anti-inflammatory treatment, pregnancy or breastfeeding, major active neurological illness explaining psychosis, and inability to complete sampling or the minimum clinical assessment. Obesity, smoking, diabetes, hypertension, substance use and other common comorbidities will be documented and modelled as covariates rather than automatic exclusions. Primary biomarkers are interleukin-6, C-reactive protein and blood-based derived biomarkers (such as neutrophil-to-lymphocyte ratio); secondary biomarkers include tumor necrosis factor-alpha and monocyte chemoattractant protein-1. Psychopathology and functioning will be assessed with the Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, Young Mania Rating Scale and either the Global Assessment of Functioning or the World Health Organization Disability Assessment Schedule 2.0. Primary analyses will compare interleukin-6, C-reactive protein and neutrophil-to-lymphocyte ratio across the three groups with adjustment for age, sex, body mass index, smoking and antipsychotic exposure. Secondary analyses will examine symptom correlations, false discovery rate correction, exploratory clustering only if clearly labelled, and prespecified handling of values below the limit of detection.

Expected Results and Conclusions

We expect a graded increase in inflammatory markers, with the highest levels in FEP with non-affective symptoms, intermediate levels in affective FEP, and lowest in controls. Interleukin-6 and C-reactive protein will likely remain significantly elevated in the non-affective subgroup after covariate adjustment, while neutrophil-to-lymphocyte ratio may show similar but weaker effects. Secondary markers may follow the same direction with smaller effect sizes. Inflammatory markers are expected to correlate modestly with non-affective, but core psychotic, symptoms. These findings would support an inflammation-associated FEP subgroup characterized by non-affective burden, suggesting partially distinct pathophysiology. This reinforces stratified models of early psychosis and a potential role for targeted immunomodulatory approaches. However, causal inference is limited, and residual confounding and cross-sectional design necessitate longitudinal validation.

References

1. Koutsouleris N, Dwyer DB, Degenhardt F, Maj C, Urquijo-Castro MF, Sanfelici R, et al. Multimodal machine learning workflows for prediction of psychosis in patients with clinical high-risk syndromes and recent-onset depression. JAMA Psychiatry. 2021;78(2):195–209
2. Fillman SG, Sinclair D, Fung SJ, Webster MJ, Shannon Weickert C. Markers of inflammation and stress distinguish subsets of individuals with schizophrenia. Transl Psychiatry. 2014;4(2):e365
3. Noto MN, Noto C, Caribé AC, Miranda-Scippa Â, Nunes SO, Chaves AC, et al. The effect of excess weight on circulating inflammatory cytokines in drug-naïve first-episode psychosis individuals. Psychiatry Res. 2019;271:525–31
4. Laskaris LE, Cropley VL, Bruggemann J, Forster S, Maller JJ, Weickert CS, et al. Evidence of innate immune dysfunction in first-episode psychosis patients with accompanying mood disorder. J Neuroinflammation. 2022;19(1):287