Abstract Objective: To evaluate relative expression of genes with the potential to translate environmental stimuli into long-term alterations in the brain, namely early growth response (EGR)1, EGR3, and cryptochrome circadian regulator (CRY)2 genes, in peripheral blood from patients with bipolar disorder (BD), schizophrenia (SZ), and major depressive disorder (MDD) and from healthy controls (HC). Methods: Thirty individuals ranging from 18 to 60 years old were recruited for each group (BD, SZ, MDD, or HC) from a Brazilian public hospital. These individuals’ peripheral blood was collected and EGR1, EGR3, and CRY2 gene expression analyzed by real-time polymerase chain reaction (qPCR). Results: EGR1 mRNA levels were significantly lower in psychiatric patients when compared to HC, but there were no differences for EGR3 or CRY2. Exploring the findings for each diagnosis separately, there were only significant differences between each of the diagnostic groups and controls for EGR1, which was lower in BD, MDD, and SZ compared to HC. No significant correlations were found between gene expression and clinical features. Conclusion: EGR1 is downregulated in psychiatric patients, regardless of diagnosis, and may be a potential common target in major psychiatric disorders. As a transcription factor, EGR1 modulates many other genes and participates in crucial neuronal and synaptic processes, such as plasticity, neurotransmitter metabolism, vesicular transport, and signaling pathways. The study of EGR1 and its upstream regulators might lead to potential new therapeutic targets in psychiatry. Objective longterm long term brain EGR 1, 1 (EGR)1 CRY 2 (CRY) BD , (BD) (SZ) MDD (MDD HC . (HC) Methods 6 (BD hospital realtime real time qPCR. qPCR (qPCR) Results separately features Conclusion disorders factor processes plasticity metabolism transport pathways psychiatry (EGR) (CRY (SZ (HC (qPCR (EGR

Resumo Introdução: O objetivo deste estudo foi comparar os pacientes com transtorno bipolar (TB), seus familiares de primeiro grau e um grupo de controles saudáveis em termos de uso de estratégias adaptativas e não adaptativas, explorando diferenças entre tipos específicos de estratégias e suas correlações com variáveis clínicas. Métodos: Estudo transversal, envolvendo 36 pacientes com TB eutímicos, 39 familiares de primeiro grau e 44 controles. As estratégias de enfrentamento foram avaliadas usando a escala Brief COPE. Resultados: Foram detectadas diferenças significativas no uso de estratégias adaptativas e não adaptativas por pacientes, seus familiares e controles. Os pacientes usaram estratégias adaptativas com menos frequência do que os familiares (p<0,001) e controles (p=0,003). Não houve diferença significativa entre familiares dos pacientes e controles (p=0,707). Por outro lado, os pacientes (p<0,001) e seus familiares (p=0,004) exibiram pontuações mais elevadas para coping não adaptativo em relação aos controles. Não houve diferença significativa quando os pacientes foram comparados com seus familiares (p=0,517). Conclusões: Familiares de primeiro grau estavam em um nível intermediário entre pacientes com TB e controles no que diz respeito ao uso de habilidades de enfrentamento. Esta descoberta apoia o desenvolvimento de intervenções psicossociais para incentivar o uso de estratégias adaptativas em vez de estratégias inadequadas nessa população.

Abstract Introduction: The objective of this study was to compare patients with bipolar disorder (BD), their first-degree relatives and a group of healthy controls in terms of use of adaptive and maladaptive coping strategies, exploring differences between specific types of strategies and their correlations with clinical variables. Methods: This was a cross-sectional study enrolling 36 euthymic patients with BD, 39 of their first-degree relatives and 44 controls. Coping strategies were assessed using the Brief COPE scale. Results: Significant differences were detected in the use of adaptive and maladaptive strategies by patients, their first-degree relatives and controls. Patients used adaptive strategies less often than the patients’ relatives (p<0.001) and controls (p = 0.003). There was no significant difference between first-degree relatives and controls (p=0.707). In contrast, patients (p<0.001) and their relatives (p=0.004) both exhibited higher scores for maladaptive coping than controls. There was no significant difference regarding the use of maladaptive strategies between patients and their relatives (p=0.517). Conclusions: First-degree relatives were at an intermediate level between patients with BD and controls regarding the use of coping skills. This finding supports the development of psychosocial interventions to encourage use of adaptive strategies rather than maladaptive strategies in this population.

Objective: In the present study, we aimed to examine the effects of repeated D-amphetamine (AMPH) exposure, a well-accepted animal model of acute mania in bipolar disorder (BD), and histone deacetylase (HDAC) inhibitors on locomotor behavior and HDAC activity in the prefrontal cortex (PFC) and peripheral blood mononuclear cells (PBMCs) of rats. Moreover, we aimed to assess brain-derived neurotrophic factor (BDNF) protein and mRNA levels in these samples. Methods: We treated adult male Wistar rats with 2 mg/kg AMPH or saline intraperitoneally for 14 days. Between the 8th and 14th days, rats also received 47.5 mg/kg lithium (Li), 200 mg/kg sodium valproate (VPT), 2 mg/kg sodium butyrate (SB), or saline. We evaluated locomotor activity in the open-field task and assessed HDAC activity in the PFC and PBMCs, and BDNF levels in the PFC and plasma. Results: AMPH significantly increased locomotor activity, which was reversed by all drugs. This hyperactivity was associated with increased HDAC activity in the PFC, which was partially reversed by Li, VPT, and SB. No differences were found in BDNF levels. Conclusion: Repeated AMPH administration increases HDAC activity in the PFC without altering BDNF levels. The partial reversal of HDAC increase by Li, VPT, and SB may account for their ability to reverse AMPH-induced hyperactivity.

Objective: Bipolar disorder (BD) is associated with significant morbidity and mortality due to comorbid general medical conditions, particularly cardiovascular disease. This study is the first report of the Brazilian Research Network in Bipolar Disorder (BRN-BD) that aims to evaluate the prevalence and clinical correlates of cardiovascular risk factors among Brazilian patients with BD. Methods: A cross-sectional study of 159 patients with DSM-IV BD, 18 years or older, consecutively recruited from the Bipolar Research Program (PROMAN) in São Paulo and the Bipolar Disorder Program (PROTAHBI) in Porto Alegre. Clinical, demographic, anthropometric, and metabolic variables were systematically assessed. Results: High rates of smoking (27%), physical inactivity (64.9%), alcohol use disorders (20.8%), elevated fasting glucose (26.4%), diabetes (13.2%), hypertension (38.4%), hypertriglyceridemia (25.8%), low HDL-cholesterol (27.7%), general (38.4%) and abdominal obesity (59.1%) were found in the sample. Male patients were more likely to have alcohol use disorders, diabetes, and hypertriglyceridemia, whereas female patients showed higher prevalence of abdominal obesity. Variables such as medication use pattern, alcohol use disorder, and physical activity were associated with selected cardiovascular risk factors in the multivariable analysis. Conclusion: This report of the BRN-BD provides new data regarding prevalence rates and associated cardiovascular risk factors in Brazilian outpatients with BD. There is a need for increasing both awareness and recognition about metabolic and cardiovascular diseases in this patient population.

OBJETIVO: Avanços no conhecimento da genética dos transtornos mentais (TM) contribuíram para um melhor entendimento de suas bases fisiopatológicas. No entanto, dúvidas e questões ainda persistem. Estudos recentes têm se concentrado nas influências do ambiente no desenvolvimento de TM, e o advento de metodologias neurocientíficas oferece novas perspectivas. Eventos precoces de vida, como estresse na infância, podem ser capazes de alterar o neurodesenvolvimento através de mecanismos como interação gene-ambiente e regulação epigenética, resultando em patologias na idade adulta. O objetivo deste artigo é revisar as evidências referentes ao papel do ambiente, em especial o estresse na infância, na fisiopatologia de TM. METODOLOGIA: Revisamos artigos que avaliam as influências ambientais, com um foco especial no trauma na infância, na morfologia cerebral, nas funções cognitivas e no desenvolvimento de psicopatologias e TM. RESULTADOS E CONCLUSÃO: Estudos com ressonância magnética demonstram que a exposição a traumas em uma idade precoce pode levar a diversas alterações neuroestruturais, como a diminuição do hipocampo e do corpo caloso. O desempenho e o funcionamento cognitivo também são alterados nessa população. Por fim, o estresse na infância está ligado a um maior risco de desenvolver TM como depressão, transtorno bipolar, esquizofrenia e abuso de substâncias. Concluímos que existem evidências sólidas quanto à importância do ambiente, especificamente das experiências adversas na infância, em diversos aspectos dos TM.

OBJECTIVE: Advances in our knowledge of mental disorder (MD) genetics have contributed to a better understanding of their pathophysiology. Nonetheless, several questions and doubts persist. Recent studies have focused on environmental influences in the development of MDs, and the advent of neuroscientific methodologies has provided new perspectives. Early life events, such as childhood stress, may affect neurodevelopment through mechanisms such as gene-environment interactions and epigenetic regulation, thus leading to diseases in adulthood. The aim of this paper is to review the evidence regarding the role of the environment, particularly childhood stress, in the pathophysiology of MD. METHODOLOGY: We reviewed articles that evaluated environmental influences, with a particular focus on childhood trauma, brain morphology, cognitive functions, and the development of psychopathology and MD. RESULTS AND CONCLUSION: MRI studies have shown that exposure to trauma at an early age can result in several neurostructural changes, such as the reduction of the hippocampus and corpus callosum. Cognitive performance and functioning are also altered in this population. Finally, childhood stress is related to an increased risk of developing MD such as depression, bipolar disorder, schizophrenia and substance abuse. We conclude that there is robust evidence of the role of the environment, specifically adverse childhood experiences, in various aspects of MD.

OBJETIVO: Pesquisas sugerem as citocinas como potenciais mediadores da interação entre os sistemas imune e neuroendócrino, e que existe um estado pró-inflamatório associado com transtorno bipolar e esquizofrenia. O objetivo deste estudo é comparar os níveis de citocinas entre os dois distúrbios. MÉTODO: Vinte pacientes com transtorno bipolar eutímicos, 53 pacientes com esquizofrenia cronicamente estabilizados e 80 controles saudáveis foram recrutados. Todos os indivíduos são não-fumantes e não-obesos. As citocinas TNF-α, IL-6 e IL-10 foram examinadas por ELISA sanduíche. RESULTADOS: A IL-6 estava aumentada nos pacientes com esquizofrenia quando comparados aos controles (p < 0,0001) e aos pacientes bipolares eutímicos (p < 0,0001). Os níveis de IL-6 não foram diferentes nos controles em comparação com pacientes com transtorno bipolar eutímicos (p = 0,357). Os níveis de IL-10 foram menores nos controles quando comparados aos esquizofrenia (p = 0,001) ou aos bipolares (p = 0,004). Não houve diferença significativa nos níveis séricos de TNF-α entre os grupos (p = 0,284). A separação por sexo não mostrou diferenças significativas e não houve correlação entre a dose de antipsicóticos e os níveis de citocinas em pacientes com esquizofrenia. DISCUSSÃO: Estes resultados evidenciam uma ativação imune crônica na esquizofrenia. O transtorno bipolar parece apresentar um aumento da atividade inflamatória relacionado ao episódio de humor. Níveis maiores de IL-10 no transtorno bipolar e esquizofrenia sugerem diferentes padrões de equilíbrio inflamatório entre esses dois transtornos. Resultados fornecem apoio adicional para a investigação de citocinas como possíveis biomarcadores para a atividade da doença ou resposta ao tratamento.

OBJECTIVE: Previous reports suggest that cytokines act as potential mediators of the interaction between the immune and neuroendocrine systems, and that a proinflammatory state may be associated with bipolar disorder and schizophrenia. The aim is to compare cytokine levels in both disorders. METHOD: Twenty euthymic bipolar disorder patients, 53 chronic stabilized schizophrenia patients and 80 healthy controls were recruited. Subjects were all non-smokers and non-obese. Cytokines TNF-α, IL-6, and IL-10 were examined by sandwich ELISA. RESULTS: IL-6 levels were increased in schizophrenia patients when compared to controls (p < 0.0001) and euthymic bipolar disorder patients (p < 0.0001). IL-6 levels were no different in controls compared to euthymic bipolar disorder patients (p = 0.357). IL-10 was lower in controls compared to schizophrenia patients (p = 0.001) or to bipolar disorder patients (p = 0.004). There was no significant difference in TNF-α serum levels among the groups (p = 0.284). Gender-based classification did not significantly alter these findings, and no correlation was found between the antipsychotic dose administered and cytokine levels in patients with schizophrenia. DISCUSSION: These findings evidence a chronic immune activation in schizophrenia. Bipolar disorder seems to present an episode-related inflammatory syndrome. Increased anti-inflammatory factor IL-10 in bipolar disorder and schizophrenia suggests different patterns of inflammatory balance between these two disorders. Results further support the need to investigate cytokines as possible biomarkers of disease activity or treatment response.

OBJETIVO E MÉTODO: Existem crescentes evidências indicando que alterações no fator neurotrófico derivado do cérebro e aumento do estresse oxidativo podem estar envolvidos na fisiopatologia do transtorno bipolar. Considerando os achados recentes de que os níveis de fator neurotrófico derivado do cérebro estão diminuídos em situações de aumento de estresse oxidativo, nós testamos a correlação entre os níveis séricos de substâncias reativas do ácido tiobarbitúrico, um índice de peroxidação lipídica, e os níveis séricos de fator neurotrófico derivado do cérebro em pacientes portadores de transtorno bipolar durante mania aguda e em controles saudáveis. RESULTADOS: Os níveis séricos de substâncias reativas do ácido tiobarbitúrico e fator neurotrófico derivado do cérebro apresentaram uma correlação negativa em pacientes bipolares (r = -0,56; p = 0,001), enquanto não houve correlação significativa no grupo controle. CONCLUSÃO: Estes resultados sugerem que alterações de estresse oxidativo podem ser mecanisticamente associadas com níveis reduzidos de BDNF observados em indivíduos com transtorno bipolar.

OBJECTIVE AND METHOD: There is a growing amount of data indicating that alterations in brain-derived neurotrophic factor and increased oxidative stress may play a role in the pathophysiology of bipolar disorder. In light of recent evidence demonstrating that brain-derived neurotrophic factor levels are decreased in situations of increased oxidative stress, we have examined the correlation between serum thiobarbituric acid reactive substances, a measure of lipid peroxidation, and serum brain-derived neurotrophic factor levels in bipolar disorder patients during acute mania and in healthy controls. RESULTS: Serum thiobarbituric acid reactive substances and brain-derived neurotrophic factor levels were negatively correlated in bipolar disorder patients (r = -0.56; p = 0.001), whereas no significant correlation was observed in the control group.. CONCLUSION: These results suggest that alterations in oxidative status may be mechanistically associated with abnormal low levels of brain-derived neurotrophic factor observed in individuals with bipolar disorder.

OBJETIVO: O objetivo deste estudo é o de comparar a qualidade de vida entre pacientes com transtorno bipolar que estão atualmente deprimidos, com depressão subsindrômica e com remissão de sintomas, e avaliar se o nível de depressão tem correlação com os escores de qualidade de vida em pacientes com transtorno bipolar. MÉTODO: Sessenta pacientes bipolares tratados ambulatorialmente, diagnosticados pela Entrevista Clínica Estruturada do DSM-IV, que preencheram critérios diagnósticos de transtorno bipolar tipo I, tipo II ou sem outra especificação (TB-SOE), e que não estavam atualmente em um episódio maníaco ou misto foram incluídos. As principais variáveis de interesse foram qualidade de vida, avaliada utilizando-se o instrumento de 26 questões de qualidade de vida da Organização Mundial de Saúde (WHOQOL-BREF) e depressão avaliada utilizando a Escala de 17 itens de Hamilton. RESULTADOS: O teste de tendência linear mostrou uma associação dose-reposta entre o estado de humor atual do paciente e todos os domínios da qualidade de vida. Escores maiores de qualidade de vida foram encontrados entre pacientes com remissão completa dos sintomas, seguidos pelos pacientes com sintomas subsindrômicos. Os pacientes deprimidos apresentaram escores de qualidade de vida mais baixos que os demais, exceto no domínio social. Os quatro domínios da escala WHOQOL tiveram uma correlação negativa com a Escala de 17 itens de Hamilton para avaliação de depressão. CONCLUSÕES: Nossos achados sugerem que a depressão bipolar e os sintomas residuais de depressão estão negativamente correlacionados com qualidade de vida em pacientes com transtorno bipolar.

OBJECTIVE: The aim of the present study is to compare quality of life among currently depressed, subsyndromal and remitted patients with bipolar disorder (BD) and to assess whether the level of depression correlates with the scores of quality of life in BD patients. METHOD: Sixty bipolar outpatients diagnosed using the Structured Clinical Interview for DSM-IV who met criteria for diagnosis of BD type I, II or not otherwise specified (BD-NOS), and who were not currently on a manic or mixed episode were included. The main variables of interest were quality of life (QOL) assessed using the 26-item World Health Organization QOL instrument (WHOQOL-BREF) and depression assessed using the 17-item Hamilton Depression Rating Scale (HDRS). RESULTS: A linear trend test showed a dose response association between patients' current mood state and all domains of quality of life. Higher quality of life scores were found among remitted patients, followed by subsyndromal patients; depressed patients presented lower scores of quality of life, except for the social domain. The four domains of the WHOQOL scale correlated negatively with the HDRS. CONCLUSIONS: Our findings suggest that bipolar depression and residual symptoms of depression are negatively correlated with QOL in BD patients.

O presente artigo é uma síntese das evidências provenientes de ensaios clínicos randomizados sobre o tratamento do transtorno bipolar. A metodologia para a busca do material disponível é descrita, e os resultados são apresentados. Com o melhor nível de evidência disponível, ou seja, revisões sistemáticas de mais de um ensaio clínico randomizado ou pelo menos um ensaio clínico randomizado, temos as seguintes recomendações: 1) a mania aguda pode ser tratada com Lítio, Valproato, Carbamazepina, e antipsicóticos; 2) a depressão bipolar pode ser tratada com antidepressivos (com risco aumentado de virada para mania), com lamotrigina e a associação fluoxetina/olanzapina e 3) a manutenção do transtorno bipolar pode ser realizada com o lítio, valproato, carbamazepina, olanzapina e lamotrigina (quando o objetivo for a profilaxia da depressão bipolar). A não existência de ensaios clínicos publicados não significa que determinadas intervenções não sejam úteis.

The present article is a synthesis of the published clinical trials about the treatment of Bipolar disorder (BD). The methodology used to search the literature is described and results are presented. Using the best available evidence (systematic reviews of clinical trials or at lest one randomized clinical trial) the following is recommended: 1) acute mania can be treated with lithium, carbamazepine, valrpoate and antipsychotics; 2) acute depression can be treated with lamotrigine, olanzapine/fluoxetine combination and with antidepressants (with an increased risk of switch into mania); 3) maintenance can be performed using lithium, valproate, olanzapine and lamotrigine (when the aim is prophylaxis of bipolar depression). The absence of published results about certain interventions does not mean that such interventions are not useful.