Avaliação de retrotransposons em pacientes com esquizofrenia resistente ao tratamento

Abstract

Schizophrenia is a mental disorder triggered by genetic, environmental, and epigenetic factors. Recently, the expression of Human Endogenous Retroviruses (HERVs), such as HERV-W and Long Interspersed Nuclear Element 1 (LINE-1), has been associated with schizophrenia, suggesting a possible role for inflammatory mechanisms in symptom severity. Identifying biomarkers related to these elements is essential for early diagnosis and improved treatment. This study primarily aimed to evaluate the expression of the HERV-W ENV and LINE-1 genes and LINE-1 methylation in patients with treatment-responsive and treatment-resistant schizophrenia compared with healthy individuals. Participants were recruited to form four groups: Healthy (control n=16), Responders to conventional antipsychotic treatment, excluding clozapine (n=15), Patients with Antipsychotic Treatment-Resistant Schizophrenia (TRS) and Responders to clozapine (n=14), and Patients with Ultra-Treatment-Resistant Schizophrenia (UTRS n=14). The study was submitted for review and approved by the UFC Research Ethics Committee (CEP/UFC/PROPESQ). Participants with schizophrenia underwent clinical evaluation with the Brief Psychiatric Rating Scale (BPRS) to estimate the total and positive symptom scores. Participants also underwent neuropsychological tests such as the Abbreviated Scale of Intelligence (WASI) and the Feinstein Attention Test (FDT), as well as the Social Skills Inventory (SSI) to assess cognitive and social deficits. The expression of the inflammatory/oxidative gene RELA, which encodes the NFkB protein, and the retrotransposons HERV-W, HERV-W GAG, HERV-W ENV, and LINE-1 was determined in peripheral blood buffy coat samples by qRT-PCR. LINE-1 methylation was also performed. The t-test was performed to analyze discrete variables and the ANOVA test for continuous variables. The significance level was set at *P ≤ 0.05. Neuropsychological tests and the SSI revealed cognitive and social deficits in most patients. The BPRS score was significantly higher in the UTRS group. ENV gene expression was significantly higher in the Treatment Responding group. However, LINE-1 expression was higher in the UTRS group, correlating with greater disease severity. The UTRS group also showed a hypomethylated LINE-1 pattern, corroborating the finding of its expression and again demonstrating its relationship with disease severity. The results indicate that LINE-1 may be a relevant biomarker for schizophrenia severity, while HERV-W ENV gene expression does not appear to be directly associated with severity in the groups tested. Therefore, by identifying biomarkers such as LINE-1 and exploring its epigenetic regulation, this study opens new avenues for personalized diagnostic and therapeutic strategies, particularly for patients with treatment-resistant schizophrenia, since, in the TRS group, clozapine is the medication of choice, but it presents important side effects such as metabolic syndrome and agranulocytosis, in addition to which, in this group, only 40% respond to treatment with clozapine, characterizing UTRS.