Immune and Long Interspersed Nuclear Element-1 Dysregulation in Schizophrenia: An Exploratory Case–Control Study in a Brazilian Cohort with Ultra-Treatment Resistance

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.