Sex and the Estrous-Cycle Phase Influence the Expression of G Protein-Coupled Estrogen Receptor 1 (GPER) in Schizophrenia: Translational Evidence for a New Target.

Schizophrenia is a mental disorder with sex bias in disease onset and symptom severity. Recently, it was observed that females present more severe symptoms in the perimenstrual phase of the menstrual cycle. The administration of estrogen also alleviates schizophrenia symptoms. Despite this, little is known about symptom fluctuation over the menstrual cycle and the underlying mechanisms. To address this issue, we worked with the two-hit schizophrenia animal model induced by neonatal exposure to a virus-like particle, Poly I:C, associated with peripubertal unpredictable stress exposure. Prepulse inhibition of the startle reflex (PPI) in male and female mice was considered analogous to human schizophrenia-like behavior. Female mice were studied in the proestrus (high-estrogen estrous cycle phase) and diestrus (low-estrogen phase). Additionally, we evaluated the hippocampal mRNA expression of estrogen synthesis proteins; TSPO and aromatase; and estrogen receptors ERα, ERß, and GPER. We also collected peripheral blood mononuclear cells (PBMCs) from male and female patients with schizophrenia and converted them to induced microglia-like cells (iMGs) to evaluate the expression of GPER. We observed raised hippocampal expression of GPER in two-hit female mice at the proestrus phase without PPI deficits and higher levels of proteins related to estrogen synthesis, TSPO, and aromatase. In contrast, two-hit adult males with PPI deficits presented lower hippocampal mRNA expression of TSPO, aromatase, and GPER. iMGs from male and female patients with schizophrenia showed lower mRNA expression of GPER than controls. Therefore, our results suggest that GPER alterations constitute an underlying mechanism for sex influence in schizophrenia.

Validation of the Brazilian version of the Hinting Task and Facial Emotion Recognition Test (FERT-100) in patients with schizophrenia / Validação da versão brasileira do Hinting Task e do Teste de Reconhecimento de Emoções Faciais (FERT-100) em pacientes com esquizofrenia

ABSTRACT Social cognition is an especially relevant domain in schizophrenia due to its association with functional impairment. However, we still do not have studies that have validated instruments with internationally established psychometric qualities for the Brazilian population. Objectives: This study aimed to present psychometric qualities and contribute to the validation of the Brazilian version of the Hinting Task and Facial Emotion Recognition Test (FERT-100). Methods: A total of 104 stabilized patients living in the community diagnosed with schizophrenia and 89 controls were evaluated. We assess the psychometric properties of Hinting Task and FERT-100 for discriminant construct validity, divergent construct validity, convergent construct validity, concurrent criterion validity, and reliability. Results: There is a statistically significant difference between patients and controls regarding social cognition (Hinting Task: Z=6.85, p<0.001; FERT-100: t=4.88, p<0.001). The main predictors of variation in social cognition were the neurocognitive domains. The associations between social cognition tests and other studied variables are similar to what is found in the literature. Social cognition maintains correlation with functional capacity even when neurocognition is taken into account. Conclusions: The validity of the Brazilian version of Hinting Task and FERT-100 can be determined, since the relationship of these tests with other clinical variables is similar to that observed in the literature.

RESUMO A cognição social é um domínio especialmente relevante na esquizofrenia devido à sua associação com o comprometimento funcional. No entanto, ainda não temos estudos que validaram instrumentos com qualidades psicométricas internacionalmente estabelecidas para a população brasileira. Objetivos: Apresentar as qualidades psicométricas e contribuir para a validação da versão brasileira do Hinting Task e do Teste de Reconhecimento de Emoções Faciais (FERT-100). Métodos: Foram avaliados 104 pacientes estabilizados residentes na comunidade com diagnóstico de esquizofrenia e 89 controles. Avaliou-se as propriedades psicométricas do Hinting Task e FERT-100 para validade de construto discriminante, validade de construto divergente, validade de construto convergente, validade de critério concorrente e confiabilidade. Resultados: Houve uma diferença estatisticamente significativa entre pacientes e controles quanto à cognição social (Hinting Task: Z=6,85; p<0,001. FERT-100: t=4,88; p<0,001). Os principais preditores da variação na cognição social foram os domínios neurocognitivos. As associações entre os testes de cognição social e outras variáveis estudadas são semelhantes às encontradas na literatura. A cognição social mantém correlação com a capacidade funcional mesmo quando a neurocognição é levada em consideração. Conclusões: A validade da versão brasileira do Hinting Task e do FERT-100 pode ser determinada, pois a relação desses testes com outras variáveis clínicas é semelhante à observada na literatura.

Validation of the Brazilian version of the Hinting Task and Facial Emotion Recognition Test (FERT-100) in patients with schizophrenia.

Social cognition is an especially relevant domain in schizophrenia due to its association with functional impairment. However, we still do not have studies that have validated instruments with internationally established psychometric qualities for the Brazilian population. Objectives: This study aimed to present psychometric qualities and contribute to the validation of the Brazilian version of the Hinting Task and Facial Emotion Recognition Test (FERT-100). Methods: A total of 104 stabilized patients living in the community diagnosed with schizophrenia and 89 controls were evaluated. We assess the psychometric properties of Hinting Task and FERT-100 for discriminant construct validity, divergent construct validity, convergent construct validity, concurrent criterion validity, and reliability. Results: There is a statistically significant difference between patients and controls regarding social cognition (Hinting Task: Z=6.85, p<0.001; FERT-100: t=4.88, p<0.001). The main predictors of variation in social cognition were the neurocognitive domains. The associations between social cognition tests and other studied variables are similar to what is found in the literature. Social cognition maintains correlation with functional capacity even when neurocognition is taken into account. Conclusions: The validity of the Brazilian version of Hinting Task and FERT-100 can be determined, since the relationship of these tests with other clinical variables is similar to that observed in the literature.

A cognição social é um domínio especialmente relevante na esquizofrenia devido à sua associação com o comprometimento funcional. No entanto, ainda não temos estudos que validaram instrumentos com qualidades psicométricas internacionalmente estabelecidas para a população brasileira. Objetivos: Apresentar as qualidades psicométricas e contribuir para a validação da versão brasileira do Hinting Task e do Teste de Reconhecimento de Emoções Faciais (FERT-100). Métodos: Foram avaliados 104 pacientes estabilizados residentes na comunidade com diagnóstico de esquizofrenia e 89 controles. Avaliou-se as propriedades psicométricas do Hinting Task e FERT-100 para validade de construto discriminante, validade de construto divergente, validade de construto convergente, validade de critério concorrente e confiabilidade. Resultados: Houve uma diferença estatisticamente significativa entre pacientes e controles quanto à cognição social (Hinting Task: Z=6,85; p<0,001. FERT-100: t=4,88; p<0,001). Os principais preditores da variação na cognição social foram os domínios neurocognitivos. As associações entre os testes de cognição social e outras variáveis estudadas são semelhantes às encontradas na literatura. A cognição social mantém correlação com a capacidade funcional mesmo quando a neurocognição é levada em consideração. Conclusões: A validade da versão brasileira do Hinting Task e do FERT-100 pode ser determinada, pois a relação desses testes com outras variáveis clínicas é semelhante à observada na literatura.

Adiponectin and Stnfr2 peripheral levels are associated with cardiovascular risk in patients with schizophrenia.

OBJECTIVES: To investigate the association between cytokine peripheral levels and the risk of cardiovascular disease in patients with schizophrenia and controls. METHODS: A sample of 40 patients and 40 control subjects participated in the study. Psychiatric diagnosis was established following structured clinical assessment. The Framingham Score was used to assess cardiovascular risk (CVR). Serum levels of the cytokines IL-1ß, IL-6, IL-8, IL-10, IL-12p70 and TNF-α were determined by cytometric bead array (CBA) technique, and the serum levels of IL-33, sST2, sTNFR1, sTNFR2, Leptin and Adiponectin by Enzyme-Linked Immunosorbent assay (ELISA). RESULTS: Patients with schizophrenia showed greater frequency of moderate CVR when compared with controls (p = 0.14). In addition, patients showed higher levels of sTNFR2 and Adiponectin compared to controls (p = 0.007 and p < 0.001, respectively). Adiponectin and sTNFR2 were associated with CVR only in patients (p = 0.0002 and p = 0.033, respectively). In multivariate analysis controlling for socio-demographic and clinical confounders, illness duration (r = 0.492; p < 0.002) and sTNFR2 (r = 0.665; p < 0.004) were independent predictors of CVR. CONCLUSION: Our results reinforce the concept that patients with schizophrenia are at greater risk to develop cardiovascular diseases, and suggest that the associated chronic low-grade inflammation might play a role in this process.

Investigating potential associations between neurocognition/social cognition and oxidative stress in schizophrenia.

INTRODUCTION: Deficits in neurocognition and social cognition play a critical role in the functional impairment of patients with schizophrenia. Increased oxidative stress has been evidenced in schizophrenia. Increased oxidative stress can affect neuronal function and lead to impairments in neurocognitive functions (especially working memory) and social cognition. OBJECTIVE: To investigate deficits in neurocognition and social cognition and their potential association with oxidative stress biomarkers in schizophrenia. MATERIAL AND METHODS: Eight-five clinically stable patients with schizophrenia and 75 controls were enrolled in this study. Neurocognition was evaluated through the Brief Assessment of Cognition in Schizophrenia (BACS). Social cognition was assessed through the Hinting Task - a test of theory of mind - and an emotion processing test, Facial Emotion Recognition Test (FERT-100). Oxidative stress was assessed by measuring serum levels of glutathione (GSH) and thiobarbituric acid reactive substances (TBARS). RESULTS: Patients had decreased serum levels of GSH (Z=3.56; p<0.001) and increased TBARS (Z=5.51; P<0.001) when compared with controls. TBARS levels are higher in patients using first generation antipsychotics. Higher serum levels of TBARS in patients were associated with poor performance in working memory test (r=-0.39; p=0.002), even when controlling for age and negative symptoms (Standard Beta: -0.36; CI= -2.52 a -13.71). DISCUSSION: The association between greater lipid peroxidation, as assessed by TBARS, and worse performance in working memory corroborates theoretical models of greater vulnerability of schizophrenia to oxidative stress.

Psychoeducation in bipolar disorder: A systematic review.

BACKGROUND: Bipolar disorder (BD) is a severe psychiatric disorder characterized by mood swings. Psychosocial interventions, such as psychoeducation, play an essential role in promoting social rehabilitation and improving pharmacological treatment. AIM: To investigate the role of psychoeducation in BD. METHODS: A systematic review of original studies regarding psychoeducation interventions in patients with BD and their relatives was developed. A systematic literature search was performed using the Medline, Scopus, and Lilacs databases. No review articles or qualitative studies were included in the analysis. There were no date restriction criteria, and studies published up to April 2021 were included. RESULTS: A total of forty-seven studies were selected for this review. Thirty-eight studies included patients, and nine included family members. Psychoeducation of patients and family members was associated with a lower number of new mood episodes and a reduction in number and length of stay of hospitalizations. Psychoeducational interventions with patients are associated with improved adherence to drug treatment. The strategies studied in patients and family members do not interfere with the severity of symptoms of mania or depression or with the patient's quality of life or functionality. Psychoeducational interventions with family members do not alter patients' adherence to pharmacotherapy. CONCLUSION: Psychoeducation as an adjunct strategy to pharmacotherapy in the treatment of BD leads to a reduction in the frequency of new mood episodes, length of hospital stay and adherence to drug therapy.

Serum levels of interleukin-33 and its soluble form receptor (sST2) are associated with cognitive performance in patients with schizophrenia.

OBJECTIVE: Changes in immune system have been reported in schizophrenia. This study aimed to evaluate the involvement of IL-33, a member of the IL-1 cytokine family, in schizophrenia and its association with cognitive performance in these patients. METHODS: Forty patients with chronic schizophrenia and 40 healthy subjects participated in the study. Serum levels of IL-33 and sST2 (soluble form of the IL-33 receptor) were measured using enzyme-linked immunosorbent assay (ELISA). Patients were evaluated with the Brief Assessment of Cognition in Schizophrenia (BACS) and the Schizophrenia Cognition Rating Scale (SCoRS). RESULTS: Patients with schizophrenia and controls presented similar serum levels of IL-33 and sST2. Levels of both markers were positively correlated with cognitive performance in patients with schizophrenia. CONCLUSION: We found a significant correlation between IL-33 and sST2 levels and cognition in schizophrenia. Our results might help in the understanding of how immune markers are associated with cognitive impairment in schizophrenia. It remains to be determined whether the association between IL-33/sST2 and cognition is restricted to patients with schizophrenia.

How specific are negative symptoms and cognitive impairment in schizophrenia? An analysis of PANSS and SCoRS.

INTRODUCTION: Interview-based scales can be used as coprimary measures to complement the assessment of cognitive impairment in schizophrenia. One major question that arises from the use of such tools is how specific they are in relation to other psychopathological domains. We analyse the specificity of the Positive and Negative Syndrome Scale (PANSS) negative subscale and the Schizophrenia Cognition Rating Scale (SCoRS). METHODS: We performed a principal component analysis (PCA) of PANSS negative subscale, rated by the interviewer, and SCoRS ratings from three different sources (patient, informant, and interviewer) in 101 patients with schizophrenia. Additionally, we correlated mean SCoRS ratings to PANSS negative subscale items to determine whether any PANSS item is particularly related to cognition. RESULTS: The PCA showed that the two first components, which explained approximately 40% of the total variance of the scales, represent the SCoRS ratings and the PANSS negative subscale ratings, respectively. The mean interviewer SCoRS was significantly correlated with the PANSS negative Item 5 (difficulty in abstract thinking) and with the mean PANSS negative subscale. The latter correlation was no longer significant when "difficulty in abstract thinking" was eliminated from PANSS negative subscale. CONCLUSIONS: In general, SCoRS and PANSS negative subscale scores address different constructs; however, the PANSS negative item "difficulty in abstract thinking" seems to address a cognitive dimension.

Associações entre déficits cognitivos e qualidade de vida na esquizofrenia: [revisão] / Associations between cognitive impairment and quality of life in schizophrenia: [review]

CONTEXTO: A Qualidade de Vida (QV) constitui valiosa forma de avaliação do impacto de doenças na vida diária e favorece intervenções mais efetivas sob uma perspectiva biopsicossocial. OBJETIVOS: Este artigo procura analisar criticamente os dados disponíveis sobre as relações entre QV e cognição na esquizofrenia. MÉTODOS: Foi realizada uma pesquisa na base de dados PubMed e Lilacs com os descritores de assunto "schizophrenia" e "cognition disorder" ou "cognition" e "quality of life" ou "outcome assessment". RESULTADOS: Dos 27 artigos selecionados que estudavam a relação entre cognição e QV medida por meio de escalas, 20 mostraram associações. Essas foram mais importantes nos estudos que utilizaram escalas de QV administrada por pesquisador, em comparação com escalas de autoavaliação. CONCLUSÃO: A associação entre cognição e QV é mais evidente nos estudos que utilizaram medidas de QV feitas por pesquisadores do que naqueles que utilizaram autoavaliações. A avaliação cognitiva é importante não somente como parâmetro determinante de QV dos pacientes, mas também auxilia na interpretação das escalas de QV, sendo as autoavaliações mais adequadas em pacientes com menor prejuízo cognitivo.

BACKGROUND: The Quality of Life (QoL) is a valuable way of assessing the impact of diseases in daily life and favors more effective interventions under a biopsychosocial perspective. OBJECTIVES: This article aimed to critically analyze the available data on the relationship between QoL and cognitive function in schizophrenia. METHODS: We performed a search in PubMed and Lilacs databases with the terms "schizophrenia" and "cognition disorder" or "cognition" and "quality of life" or "outcome assessment". RESULTS: From the 27 selected articles that studied the relationship between cognition and QoL measured by scales, 20 articles showed associations. The association was more robust in studies using scales administered by a researcher, compared to self-report scales. DISCUSSION: The cognitive assessment is important not only as a parameter for determining QoL of patients, but also as a factor to be taken into account when analyzing the data obtained by self-report QoL scales.

Sensitivity and applicability of the Brazilian version of the Brief Assessment of Cognition in Schizophrenia (BACS).

Cognitive assessment in schizophrenia has traditionally used batteries that are long and complex or differ widely in their content. The Brief Assessment of Cognition in Schizophrenia (BACS) has been developed to cover the main cognitive deficits of schizophrenia as well as to be easily and briefly administered, portable, sensitive and reliable. OBJECTIVES: To investigate the applicability and sensitivity of the Brazilian Version of the BACS (Brazilian-BACS). METHODS: Performance of 20 stable patients with schizophrenia on the Brazilian-BACS was compared to 20 matched healthy controls. RESULTS: Applying the Brazilian-BACS required 43.4±8.4minutes for patients and 40.5±5.7 minutes for controls (p=0.17). All tests demonstrated significant differences between controls and patients (P<0.01). Pearson's correlation analysis and Cronbach's a evidenced a high internal consistency for patient performance. The cognitive deficit in the patients was approximately 1.5 standard deviations below controls. These results were consistent with those reported in the validation of the original version and in meta-analyses of similar studies. CONCLUSIONS: The Brazilian-BACS displayed good applicability and sensitivity in assessing the major cognitive constructs that are impaired in schizophrenia. Thus, the Brazilian-BACS seems to be a promising tool for assessing cognition in patients with schizophrenia in Brazil.

A avaliação cognitiva na esquizofrenia tem utilizado tradicionalmente baterias longas e complexas ou que variam significativamente em seu conteúdo. A "Brief Assessment of Cognition in Schizophrenia" (BACS) foi desenvolvida para cobrir os principais déficits cognitivos na esquizofrenia, para ser de fácil e breve aplicação, assim como portátil, sensível e confiável. OBJETIVOS: Investigar a aplicabilidade e a sensibilidade da versão brasileira da BACS (Brazilian-BACS). MÉTODOS: O desempenho de 20 pacientes estáveis com esquizofrenia na Brazilian-BACS foi comparado ao de 20 controles saudáveis pareados. RESULTADOS: A aplicação da Brazilian-BACS exigiu 43.4±8.4minutos nos pacientes e 40.5±5.7 minutos nos controles (p=0.17). Todos os testes foram significativamente diferentes entre pacientes e controles (P<0.01). A correlação de Pearson e o alfa de Cronbach evidenciaram alto grau de consistência interna no desempenho dos pacientes. O déficit cognitivo nos pacientes foi cerca de 1,5 desvio-padrão menor do que nos controles. Esses resultados são consistentes com os relatados na validação da versão original e em meta-análises de estudos similares. CONCLUSÕES: A Brazilian-BACS mostrou boas aplicabilidade e sensibilidade na investigação dos principais domínios cognitivos comprometidos na esquizofrenia. Portanto, a Brazilian-BACS mostra-se um instrumento promissor no estudo da cognição de pacientes com esquizofrenia no Brasil.