Biomarcadores periféricos no primeiro episódio psicótico
Arquivos
Data
2022-10-21
Autores
Noto, Mariane Vargas Nunes 
Orientadores
Bressan, Rodrigo Affonseca
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
INTRODUÇÃO: Transtornos psicóticos são uma experiência extremamente perturbadora para o indivíduo e seus familiares, em que ocorre uma distorção da realidade evidenciada por sintomas como delírios, alucinações e desorganização do comportamento. Estima-se que o principal transtorno psicótico, a esquizofrenia, seja a 11a causa de incapacidade em todo o mundo. O estudo em pacientes em primeiro episódio psicótico (PEP), livres de medicação e de muitas variáveis confundidoras presentes em amostras de pacientes crônicos pode contribuir para o avanço do conhecimento da neurobiologia e etiologia da psicose, além de fatores relacionados à resposta ao tratamento com antipsicóticos. Apesar de nos anos recentes o primeiro episódio psicótico ter sido amplamente estudado, até o presente momento não se conhece exatamente a sua fisiopatologia. Diversos estudos apontam para o envolvimento do sistema imune na etiologia das psicoses. Uma resposta inflamatória aumentada e níveis reduzidos de fator neurotrófico derivado do cérebro (BDNF) foram encontrados já nas fases iniciais dos transtornos psicóticos, o que pode acarretar a efeitos prejudiciais no cérebro, levando a anormalidades duradouras nos circuitos cerebrais. No entanto, há uma variabilidade nos resultados dos biomarcadores inflamatórios na literatura, o que pode ser explicado devido ao uso da medicação, fase ativa dos sintomas ou estadiamento da doença. A maioria dos estudos também utiliza estudos transversais e é restrita a análise de poucos marcadores inflamatórios.
OBJETIVOS : Nesta tese foram avaliados biomarcadores relacionados à resposta imune e níveis plasmáticos de BDNF em pacientes no Primeiro Episódio Psicótico virgens de antipsicóticos antes e depois do uso de risperidona. O objetivo é avaliar alterações nos níveis de biomarcadores e possíveis relações com sintomas e com a resposta ao tratamento.
MÉTODOS: Foram incluídos 31 pacientes, com diagnóstico realizado pela Entrevista Clínica Estruturada para DSM-IV (SCID-I), e 22 controles saudáveis. A sintomatologia foi avaliada usando a The Positive and Negative Syndrome Scale (PANSS). Amostras de sangue (10 mL) foram coletadas de todos os pacientes na admissão, antes da primeira dose de risperidona, e após 10 semanas de tratamento e de todos os controles saudáveis.
RESULTADOS: Os pacientes no PEP mostraram uma resposta inflamatória maior (especialmente fator estimulador de colônias de granulócitos e macrófagos (GM-CSF), interleucina (IL)-6 e IL -12) em comparação com a resposta anti-inflamatória. Marcadores inflamatórios, especialmente IL-6 e IL-8, foram significativamente correlacionados com dimensões dos sintomas negativos, psicóticos, afetivos e de excitação. O tratamento com risperidona suprimiu significativamente os componentes inflamatórios e anti-inflamatórios. Os níveis basais de biomarcadores anti-inflamatórios, especialmente o receptor de fator de necrose tumoral solúvel-1 e IL-10, foram preditores de melhora clínica após o tratamento.
Os pacientes em PEP virgens de antipsicóticos também apresentaram níveis diminuídos de BDNF, que foram normalizados após o tratamento com risperidona. Os níveis de BDNF foram inversamente associados à ativação do sistema de resposta inflamatório. Os resultados apoiam a hipótese de que o aumento da inflamação está ligado à uma diminuição do BDNF, que portanto, pode estar envolvida no desenvolvimento de psicose e na progressão da doença.
CONCLUSÃO: Os resultados indicam que existe uma resposta inflamatória exacerbada no PEP, e que os pacientes estão propensos aos efeitos prejudiciais das citocinas inflamatórias e dos menores níveis de BDNF nesta fase da doença.
INTRODUCTION: Psychotic disorders are an extremely disturbing experience for the individual and his family members, in which there is a distortion of reality evidenced by symptoms such as delusions, hallucinations and disorganization of behavior. The main psychotic disorder, schizophrenia, is estimated to be the 11th cause of disability worldwide. Studying patients with first-episode psychosis (FEP), free of medication and of many confounding variables present in samples of chronic patients, may contribute to the knowledge advance on the neurobiology and etiology of psychosis, in addition to the factors related to the response to antipsychotic treatment. Although in recent years the first psychotic episode has been comprehensively studied, to date its pathophysiology is not exactly known. Several studies point to the involvement of the immune system in the etiology of psychosis. An increased inflammatory response and reduced levels of brainderived neurotrophic factor (BDNF) have been found already in the early stages of psychotic disorders, which can lead to detrimental effects on the brain, leading to longlasting abnormalities in brain circuitry. However, there is variability in the results of inflammatory biomarkers in the literature, which can be explained by the use of medication, active phase of symptoms or disease staging. Most studies also use crosssectional studies and are restricted to the analysis of few inflammatory markers. OBJECTIVES: In this thesis, biomarkers related to the immune response and plasma levels of BDNF in patients in the First Psychotic Episode (FEP) naïve to antipsychotics before and after the use of risperidone were analyzed. The aim is to assess changes in biomarker levels and possible relationships with symptoms and response to treatment. METHODS: Thirty-one patients, diagnosed by the Structured Clinical Interview for DSM-IV (SCID-I), and 22 healthy controls were included. The sintomatology was assessed using The Positive and Negative Syndrome Scale (PANSS). Blood samples (10 mL) were collected from all patients on admission, before the first dose of risperidone, and after 10 weeks of treatment and from all healthy controls. RESULTS: Patients on FEP showed a greater inflammatory response (especially granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6 and IL12) compared to the anti-inflammatory response. Inflammatory markers, especially IL-6 and IL-8, were significantly correlated with dimensions of negative, psychotic, affective and arousal symptoms. Risperidone treatment significantly suppressed inflammatory and anti-inflammatory components. Baseline levels of anti-inflammatory biomarkers, especially soluble tumor necrosis factor receptor-1 and IL-10, were predictors of clinical improvement after treatment. Patients on antipsychotic-naive FEP also had decreased levels of BDNF, which normalized after treatment with risperidone. BDNF levels were inversely associated with activation of the inflammatory response system. The results support the hypothesis that increased inflammation is linked to a decrease in BDNF, which therefore may be involved in the development of psychosis and disease progression. CONCLUSION: The results indicate that there is an exacerbated inflammatory response in FEP, and that patients are prone to the harmful effects of inflammatory cytokines and lower BDNF levels at this stage of the disease.
INTRODUCTION: Psychotic disorders are an extremely disturbing experience for the individual and his family members, in which there is a distortion of reality evidenced by symptoms such as delusions, hallucinations and disorganization of behavior. The main psychotic disorder, schizophrenia, is estimated to be the 11th cause of disability worldwide. Studying patients with first-episode psychosis (FEP), free of medication and of many confounding variables present in samples of chronic patients, may contribute to the knowledge advance on the neurobiology and etiology of psychosis, in addition to the factors related to the response to antipsychotic treatment. Although in recent years the first psychotic episode has been comprehensively studied, to date its pathophysiology is not exactly known. Several studies point to the involvement of the immune system in the etiology of psychosis. An increased inflammatory response and reduced levels of brainderived neurotrophic factor (BDNF) have been found already in the early stages of psychotic disorders, which can lead to detrimental effects on the brain, leading to longlasting abnormalities in brain circuitry. However, there is variability in the results of inflammatory biomarkers in the literature, which can be explained by the use of medication, active phase of symptoms or disease staging. Most studies also use crosssectional studies and are restricted to the analysis of few inflammatory markers. OBJECTIVES: In this thesis, biomarkers related to the immune response and plasma levels of BDNF in patients in the First Psychotic Episode (FEP) naïve to antipsychotics before and after the use of risperidone were analyzed. The aim is to assess changes in biomarker levels and possible relationships with symptoms and response to treatment. METHODS: Thirty-one patients, diagnosed by the Structured Clinical Interview for DSM-IV (SCID-I), and 22 healthy controls were included. The sintomatology was assessed using The Positive and Negative Syndrome Scale (PANSS). Blood samples (10 mL) were collected from all patients on admission, before the first dose of risperidone, and after 10 weeks of treatment and from all healthy controls. RESULTS: Patients on FEP showed a greater inflammatory response (especially granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6 and IL12) compared to the anti-inflammatory response. Inflammatory markers, especially IL-6 and IL-8, were significantly correlated with dimensions of negative, psychotic, affective and arousal symptoms. Risperidone treatment significantly suppressed inflammatory and anti-inflammatory components. Baseline levels of anti-inflammatory biomarkers, especially soluble tumor necrosis factor receptor-1 and IL-10, were predictors of clinical improvement after treatment. Patients on antipsychotic-naive FEP also had decreased levels of BDNF, which normalized after treatment with risperidone. BDNF levels were inversely associated with activation of the inflammatory response system. The results support the hypothesis that increased inflammation is linked to a decrease in BDNF, which therefore may be involved in the development of psychosis and disease progression. CONCLUSION: The results indicate that there is an exacerbated inflammatory response in FEP, and that patients are prone to the harmful effects of inflammatory cytokines and lower BDNF levels at this stage of the disease.