Mediadores inflamatórios e estresse oxidativo/nitrosativo como marcadores de resposta à Clozapina na esquizofrenia: o papel da inflamação na resistência ao tratamento

Abstract

Schizophrenia is a serious and persistent mental disorder, commonly marked by functional losses, which is one of the biggest challenges for psychiatry, as a third of its patients do not respond to common antipsychotic medications, requiring the use of the antipsychotic Clozapine. Furthermore, males are more prone to more severe symptoms manifestations (resistant to treatment) and to the earlier onset of the disease. Clozapine, although superior in efficacy, induces the appearance of many side effects, such as metabolic syndrome (especially in males), and other more rare and potentially fatal effects, such as agranulocytosis. Although its superiority is unquestionable, its mechanism of action is still not completely clear. In this work, changes in inflammatory mediators (IL1β, IL4, IL6, IL17, IL23, IL33, MMP3, S100B, TLR4, IFNγ e IFNβ) were evaluated and oxidative/nitrosative stress (GSH, nitrite, TBARS) in patients of both sexes who respond to standard treatment (n=18); responders to Clozapine (TRS) (n=19); resistant to Clozapine (UTRS) (n=16); and healthy controls (n=23), in search of markers for response and resistance to Clozapine. An increase in the expression of TLR4, IL6 and S100B in the TRS and UTRS was found in the patients' serum compared to common responders and controls, accompanied by a reduction in lipopolysaccharide (LPS) in the same TRS and UTRS, in other words, in Clozapine users, in relation to responders, and an increase in GSH only in the UTRS group in relation to the others, indicating that the immunological pathway of response to bacterial endotoxins appears to be involved in the pathophysiology of resistance to schizophrenia treatment, at least in some individuals, and that there is an activity compensatory in an attempt to control the inflammatory response. When performing the Principal Component Analysis with inflammatory mediators as variables, the first component that accounts for 23.7% of the variance is formed, in order of magnitude, mainly by IFNγ, IL4, IL33, IL1β, MMP3 and IL23, which points to the involvement of different immune response pathways such as T-helper(Th)1, Th2 and Th17, while the second component accounts for 21.7% of the total variance, and is mainly composed of TLR4, IL17, IFNβ and IL6, which are related to the TLR4 and Th17 pathways, with relevant vector overlap between TLR4 and IL17, and demonstrating a gap between treatment-resistant groups compared to responders and control group. The UTRS group stands out from the others, including the TRS, in terms of the second component, pointing to the probable involvement of the inflammatory mechanism activated by TLR4 in resistance to Clozapine. The need to understand treatment resistance in schizophrenia finds immunological response patterns an important path, and the present findings can help in the development of other treatments that intervene in these pathways, as well as in the early recognition and personalized targeting of existing treatments. As is typical of science, many new studies are needed, but the present results can contribute to the search of these biosignatures.