Immune and Long Interspersed Nuclear Element-1 Dysregulation in Schizophrenia: An Exploratory Case–Control Study in a Brazilian Cohort with Ultra-Treatment Resistance
Year: 2025
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Ultra-treatment-resistant schizophrenia (UTRS) is a severe phenotype with unclear biology. Immune dysfunction is increasingly implicated, but the role of retroelements such as long interspersed nuclear element-1 (LINE-1) remains unexplored. We investigated a Brazilian cohort to test whether retrotransposon dysregulation, alongside immune-inflammatory changes, may underlie UTRS. STUDY DESIGN: We evaluated immune-inflammatory and retrotransposon-related biomarkers across schizophrenia subtypes: treatment-sensitive schizophrenia (TSS, n = 18), treatment-resistant schizophrenia (TRS, n = 19), and ultra-treatment-resistant schizophrenia (UTRS, n = 16), compared to healthy controls (n = 23). Participants were recruited from psychiatric outpatient services in Fortaleza, Brazil, and stratified by clinical response to antipsychotic treatment. Biomarkers included cytokines, toll-like receptor 4 (TLR4), and LINE-1 methylation and expression. Data were analyzed using principal component analysis (PCA) and random forest classification. STUDY RESULTS: TLR4 distinguished TRS from TSS and UTRS from non-UTRS (TSS + TRS). Interferon (IFN) gamma and interleukin (IL)-33 differentiated TRS from TSS, while IFN-β emerged as a key marker for UTRS. PCA and random forest identified three biomarker clusters: (1) proinflammatory (IL-1β, IL-6, IL-17, IL-23, IL-33, and MMP-3); (2) treatment-related (TLR4, clozapine exposure, and age at onset); and (3) immunoregulatory (IFN-β and IL-4). Top predictors of UTRS included IFN-β, TLR4, IL-4, IL-17, and MMP-3. LINE-1 analysis revealed increased expression and hypomethylation in UTRS, consistent with epigenetic instability. CONCLUSIONS: These findings reveal a distinct immune-epigenetic signature associated with treatment resistance in schizophrenia. Immune activation, Th17 signaling, and LINE-1 dysregulation may underlie the UTRS phenotype. Given the limited sample size and post hoc power analysis, the results should be regarded as exploratory and hypothesis-generating, warranting replication in larger cohorts.
Source: Schizophrenia Bulletin
Authors: Carolina Saraiva Nunes de Pinho, Joel Porfirio Pinto, Paulo Levi Bezerra Martins, Natália Gindri Fiorenza, Dino Cesar da Silva Clemente, Hoanna Izabely Rêgo Castro, Marylane da Silva Viana, Camilla Beatriz Marinho Teles, Manoela de Oliveira Rebouças, Maria Francilene Souza Silva, Débora Ferreira de Assis, Raylha Farias Tavares, Bruno Riccelli dos Santos Silva, Caio Andrade de Oliveira, David Nunes de Lima Júnior, João Alexandre Lobo Marques, Saulo Giovanni Castor Albuquerque, Jaime Eduardo Cecilio Hallak, Clarissa Severino Gama, David Freitas de Lucena, Eugênio de Moura Campos, Lia Lira O Sanders, Danielle S Macedo
Language: English
Subfield: Biological Psychiatry
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Award: G5531250551
OpenAlex ID: W4416891934