Diss. (sammanfattning) Stockholm : Karol. Inst., 2002. / Härtill 6 uppsatser.

Introdução: Pacientes com Transtorno Bipolar (TB) e seus familiares apresentam níveis de estresse significativamente mais elevados que a população geral. Coping, utilizado para gerenciar situações estressantes, tem sido alvo de investigação e intervenções psicossociais em pacientes bipolares, auxiliando-os no manejo destes fatores e melhorando desfechos clínicos no tratamento. Objetivos: O presente estudo tem por objetivo primário comparar pacientes com TB, seus familiares de primeiro grau e um grupo de controles saudáveis quanto ao uso de estratégias de coping adaptativas e desadaptativas. Como objetivos secundários, serão feitas análises explorando diferenças de tipos específicos de coping utilizados pelos indivíduos dos diferentes grupos (pacientes, familiares e controles), através da escala Brief COPE. Outras correlações com variáveis clínicas serão exploradas, como fatores sociodemográficos e clínicos, buscando encontrar relações com as estratégias de coping na amostra de pacientes com TB. Método: Trata-se de um estudo transversal com amostragem por conveniência. O estudo incluiu 36 pacientes eutímicos com TB, 39 familiares de primeiro grau destes pacientes e 44 controles. As estratégias de coping foram avaliadas através da Escala Brief COPE. Resultados: Diferenças significativas foram encontradas quanto ao uso de estratégias adaptativas e desadaptativas entre pacientes, familiares e controles. Pacientes utilizam em menor grau estratégias adaptativas, quando comparados aos controles. Por outro lado, os familiares demonstram maior uso de estratégias desadaptativas, semelhante ao que é observado nos pacientes, diferindo do grupo controle. Limitações: O tamanho amostral é um importante limitador para as conclusões do estudo. Ainda, as conclusões foram baseadas em dados transversais. A utilização de avaliações psicológicas e clínicas em estudos longitudinais permitiriam um melhor mapeamento das mudanças ou manutenção nos padrões psicológicos dos participantes. Conclusões: O grupo de familiares encontra-se em um nível intermediário entre pacientes e controles, ou seja, familiares fazem uso de estratégias desadaptativas em níveis semelhantes ao grupo de pacientes, mas apresentam maior uso de estratégias adaptativas, assim como o grupo controle. Intervenções psicossociais com este grupo são justificadas, favorecendo o uso das estratégias adaptativas em detrimento das estratégias desadaptativas. / Background: Patients with Bipolar disorder (BD) and their relatives exhibit significantly higher stress levels than the general population. Coping strategies, used to manage stressful situations, have been the subject of research and have also been used in psychosocial interventions with bipolar patients in order to help them manage stress factors and improve the clinical outcome of treatment. Objectives: This study has the objective to compare BD patients, their first-degree relatives and a group of healthy controls on the use of adaptive strategies and maladaptive coping. The specific objectives, analyzes will be made by exploiting differences in specific types of coping used by individuals from different groups (patients, relatives and controls) through the Brief COPE scale. Other correlations with clinical variables will be explored, such as demographic and clinical factors, trying to find relations with coping strategies in the sample of patients with BD. Method: This was a cross-sectional study with sampling by convenience, enrolling 36 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 between use of adaptive and maladaptive strategies by patients, patients' relatives and controls. Patients used adaptive strategies less often than the patients' relatives and controls. In contrast, the patients' relatives reported greater use of maladaptive strategies than the controls and were similar to the patients in this respect. Limitations: The sample size is an important factor limiting the conclusions that can be drawn from this study. Furthermore, these conclusions are based on cross-sectional data. Conclusions: The group of patients' relatives were at an intermediate level between the patients and the healthy controls, i.e. family make use of maladaptive strategies at similar levels to the group of patients, but greater use of adaptive strategies, as well as the control group. This group merits psychosocial interventions to encourage use of adaptive strategies rather than maladaptive strategies.

Systematic review Background: Bipolar disorder is associated with a higher rate of physical health problems and lower levels of physical activity than other clinical and general populations. Despite the potential benefits of physical activity to people with bipolar disorder, little research has been published around this and no recent review of this topic is available. Due to the clinical utility of summarising the available research evidence on this topic, this review aimed to answer the question “Is physical activity associated with manic and depressive symptoms in people with bipolar disorder?”. Methods: Seven electronic databases were searched using a range of search terms to reflect physical activity and bipolar disorder variables. Results: Ten studies were identified that reported associations between physical activity and mood symptoms of bipolar disorder. There were inconsistent findings on the relationship between physical activity and mood, in particular with relation to manic symptoms, with reports of physical activity being both helpful and harmful to manic symptoms. Findings were more consistent with regards to the association between physical activity and depressive symptoms, with most showing that higher levels of physical activity are associated with lower depressive symptoms. Limitations: Many studies had small sample sizes and very few manipulated physical activity and included a control group. Measures and diagnosis method were heterogeneous. Four studies lacked a direct measure of manic symptoms. Conclusions: Results showed inconsistent findings with regards to the relationship between physical activity and mood symptoms and further research is needed to inform any guidelines developed for this client group. Empirical paper: Background: Despite the published evidence for the benefits of physical activity on mood in the general population and in people with mental illness, there is a lack of research into the associations between physical activity and mood in people with bipolar disorder. The current study therefore aimed to investigate the relationship between symptoms of mania and depression and different intensities, regularity, and total duration of physical activity per day and across the week. Methods: People with a diagnosis of bipolar disorder (N = 29) completed daily diaries on physical activity and manic and depressive symptoms over 14 days. Analysis included multilevel modelling, t-tests and correlation analysis. Results: No association was found between manic symptoms and physical activity, either at the within- or the between-person level. An association was found at the within-person level between higher duration of physical activity and lower depression symptoms, however no association was found at the between-person level. Limitations: The small sample size was adequate only to detect large-sized effects for between-person hypotheses. Participants were highly active and may not be representative of the wider BD population. Physical activity levels were assessed via self-report. Conclusions: The relationship between physical activity and manic symptoms in BD remains inconclusive, but a significant within-person association indicates that physical activity may reduce depressive symptoms in the short term. Given previous research on physical activity and manic symptoms, people with BD and professionals working with them may need to remain cautious, modifying any PA engagement depending on mood state.

OBJECTIVES. It has been illustrated in numerous studies that children with Bipolar Disorder (BD) consistently show deficits in declarative memory. There are a number of regions within the brain that have been inferred to correspond to these deficits. Currently, there are a limited number of studies that have analyzed the direct relationship between neuropsychological tests and anatomical brain regions. The purpose of this study was to establish a relationship between structural neuroanatomical measurements and cognitive tasks measurements in Pediatric Bipolar Patients. METHODS. We administered the California Verbal Learning Test-II (CVLT-II) to 46 children and adolescents with BD and compared their scores 35 age-matched healthy controls. A MANCOVA between PBD and Healthy was performed and Long-Delay Free Recall (LDFR) and Long-Delay Cued Recall (LDQR) were significantly different. A multiple linear regression between LDFR and LDQC cognitive variables and anatomical volume and cortical thickness was performed in SPM and FreeSurfer libraries. RESULTS. There was overall significance in CVLT-II Trial 1 (p=0.042), Long Delay Free Recall (LDFR) (p=0.047), and Long Delay Cued Recall (LDQC) scores (0.038), amongst the diagnostic groups (BD-I, BD-II, BD-NOS, Other, Healthy). Within Bipolar subjects, LDFR scores were positive correlated to the gray matter volume of the cingulate gyrus, Brodmann's area 6, parrahippocampal gyrus and the thickness of the lateralorbitofrontal region. LDQC scores were positive correlated to the gray matter volume of the cingulate gyrus, Brodmann's area 7 and middle temporal gyrus. LDQC was also correlated to the volume of the superior frontal, pars triangularis, insula and the thickness of the rostral middle frontal region. CONCLUSION. These results reaffirm previous reports of the cognitive deficits present in children with bipolar disorder. This study also revealed a positive correlation between gray matter density of structures within the limbic system and performance on cognitive variables of the California Verbal Learning Test-II Children's version.

Bipolar disorder is a psychiatric disorder with alarming rates of morbidity and mortality. Since the pathophysiology of the disease is not well understood, it is difficult to develop treatments or even explain why the current treatments are successful. An increasingly popular hypothesis is that mitochondrial dysfunction plays a role. This paper examines the relationship between mitochondrial dysfunction and bipolar disorder by examining the following: (i) mitochondrial complex I dysfunction and oxidative damage, (ii) mitochondrial complex I dysfunction, epigenetic modifications, and treatment with lithium, (iii) post-mortem brain studies, (iv) the mtDNA common deletion, (v) calcium, (vi) comorbidity with mitochondrial disorders, (vii) lactate and intracellular pH levels, (viii) phosphocreatine, (ix) apoptosis, and (x) inositol. These studies point to a definitive correlation between the bipolar disorder and mitochondrial dysfunction, but it is too soon to determine causation. Further research is needed.

Biomarcadores tem se tornado uma parte essencial da pesquisa clínica. Na psiquiatria, diversos biomarcadores séricos têm sido estudados. No Transtorno Bipolar, considerável atenção tem sido dada a marcadores inflamatórios e entre esses destacam-se as citocinas. No entanto, o entendimento dos diferentes padrões de envolvimento desses marcadores ainda não foi suficientemente estudado. Também, até o momento, poucos foram os estudos que avaliaram seu papel como marcadores de atividade ou preditores de curso de doença. A presente tese é composta por dois estudos: 1) uma comparação de citocinas inflamatórias entre pacientes eutímicos com um diagnóstico de Transtorno Bipolar em relação a pacientes com Esquizofrenia e controles saudáveis. 2) um estudo prospectivo de pacientes com Transtorno Bipolar avaliando medidas de citocinas no baseline em relação a variáveis clínicas de um ano de seguimento. Como um todo, os resultados apresentados corroboram o involvimento de citocinas inflamatórias no Transtorno Bipolar e na Esquizofrenia, no entanto evidenciando um padrão diferenciado de envolvimento nos dois transtornos. Também a IL-6 mostrou-se alterada em pacientes eutímicos que viriam a apresentar um ou mais episódios depressivos durante um ano de seguimento e seu aumento correlacionou-se com o numero de dias com sintomas depressivos. Esses achados fornecem apoio adicional para a investigação de citocinas como possíveis biomarcadores para a atividade da doença ou preditores de recorrência. / Biomarkers are becoming an essential part of clinical research. In Psychiatry, several serum biomarkers are currently being studied. In Bipolar Disorder, increasing attetion has been given to inflammatory markers and among these cytokines has received special attention. However, the understanding of the different patterns of inflammation has not yet been fully clarified. Few studies have focused on its properties as markers of disease activity and predictors of outcome. This thesis contains two different studies: 1) a comparison of cytokine levels in patients with Bipolar Disorder, Schizophrenia and healthy controls. 2) a prospective study of euthymic patients with Bipolar Disorder assessing baseline cytokines and theis association with clinical variables during follow-up. These studies reinforce the idea of an inflammatory response in both Bipolar Disorder and Schizophrenia; however, the pattern of reponse seems to be different between the two disorders. Also, increased levels of IL-6 were observed in euthymic patients that would later present a depressive episode during follow-up and this increase was correlated with the numbers of days depressed. These findings five further support for the investigation of cytokines as possible biomarkers of disease activity and predictors of recurrence.

O vínculo parental e apego precoce tem um importante papel no desenvolvimento psicossocial das crianças, e vínculos disfuncionais têm sido associados a um maior risco para disfunção neurobiológica, incluindo risco para psicopatologia como Esquizofrenia (ESQ) e Transtorno Bipolar (TB). Biomarcadores periféricos de neuroplasticidade, inflamação e estresse oxidativo também têm sido associados a ambos transtornos. Nesta tese, examinamos pacientes com TB e ESQ comparados com controles saudáveis quanto às diferenças no estilo do vinculo parental, e se essas diferenças estariam correlacionadas com marcadores neurobiológicos. No primeiro artigo, descrevemos diferenças significativas na percepção do apego pelos pacientes com ESQ e TB nos primeiros 16 anos de vida. Os vínculos parentais dos pacientes com TB em relação aos com ESQ foram caracterizados pelo menor afeto (i.e., formulários mãe e pai, escores de “cuidado”) e maior controle (i.e., formulários mãe e pai, escores de superproteção), e nos pacientes ESQ maior exigência afetiva tanto da mãe como do pai, em relação aos pacientes com TB e CTR (i.e. formulários mãe e pai, escores de cuidado, afeto). No segundo artigo, avaliamos a correlação entre escala de vínculo parental e biomarcadores periféricos. Houve uma correlação positiva entre os níveis de IL6 e escores de cuidado do pai na ESQ e entre escores de cuidado materno no TB, ao mesmo tempo em que uma correlação negativa entre IL6 e superproteção paterna tanto na ESQ quanto no TB. Esses resultados sugerem que o estilo parental de vínculo pode ser uma ferramenta útil para detectar sinais precoces de ESQ e TB, o que pode ser correlacionado com gravidade dos sintomas ou com outros fatores que necessitam esclarecimento futuro, os quais podem estar associados às alterações na neurobiologia. O significado clínico dessas alterações biológicas ainda necessita investigação, envolvendo desenhos longitudinais. / Parent-child bonds and early attachment seem to have an important role in children’s psychosocial development, and disturbances in this relationship have been associated with increased risk for neurobiological dysfunctions, including mental disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD). Peripheral biomarkers of neuroplasticity, inflammation and oxidative stress have also been implicated in the pathophysiology of both disorders. In this work, we examined patients with BD and SCZ compared with healthy controls regarding differences in parental bonding style, and if these differences would correlate with neurobiological markers. In the first report, we describe that there were significant differences in the perception of attachment by patients during the first 16 years between SCZ and BD. The parental bonds of BD patients when compared to patients with SCZ were characterized by lower care (i.e., mother and father forms - care scores) and higher control (i.e., mother and father forms – overprotection scores) and in patients with SCZ higher care by parents compared to patients with BD and CTR (i.e., mother and father forms - care scores). In the second article, we conducted a correlation between the Parental Bonding Index and peripheral biomarkers. We found that IL-6 positively correlated with PBI father care in SCZ and PBI mother care in BD, and negatively correlated with PBI father overprotection in both disorders. These findings suggest that parental bonding style may be an useful tool to detect early signs of SCZ and BD and may be correlated to severity of symptoms or other factors that warrant further investigation, which are associated with changes in neurobiology. The clinical meaning of these changes remains to be examined in future longitudinal studies.

Introdução: Pacientes com Transtorno Bipolar (TB) e seus familiares apresentam níveis de estresse significativamente mais elevados que a população geral. Coping, utilizado para gerenciar situações estressantes, tem sido alvo de investigação e intervenções psicossociais em pacientes bipolares, auxiliando-os no manejo destes fatores e melhorando desfechos clínicos no tratamento. Objetivos: O presente estudo tem por objetivo primário comparar pacientes com TB, seus familiares de primeiro grau e um grupo de controles saudáveis quanto ao uso de estratégias de coping adaptativas e desadaptativas. Como objetivos secundários, serão feitas análises explorando diferenças de tipos específicos de coping utilizados pelos indivíduos dos diferentes grupos (pacientes, familiares e controles), através da escala Brief COPE. Outras correlações com variáveis clínicas serão exploradas, como fatores sociodemográficos e clínicos, buscando encontrar relações com as estratégias de coping na amostra de pacientes com TB. Método: Trata-se de um estudo transversal com amostragem por conveniência. O estudo incluiu 36 pacientes eutímicos com TB, 39 familiares de primeiro grau destes pacientes e 44 controles. As estratégias de coping foram avaliadas através da Escala Brief COPE. Resultados: Diferenças significativas foram encontradas quanto ao uso de estratégias adaptativas e desadaptativas entre pacientes, familiares e controles. Pacientes utilizam em menor grau estratégias adaptativas, quando comparados aos controles. Por outro lado, os familiares demonstram maior uso de estratégias desadaptativas, semelhante ao que é observado nos pacientes, diferindo do grupo controle. Limitações: O tamanho amostral é um importante limitador para as conclusões do estudo. Ainda, as conclusões foram baseadas em dados transversais. A utilização de avaliações psicológicas e clínicas em estudos longitudinais permitiriam um melhor mapeamento das mudanças ou manutenção nos padrões psicológicos dos participantes. Conclusões: O grupo de familiares encontra-se em um nível intermediário entre pacientes e controles, ou seja, familiares fazem uso de estratégias desadaptativas em níveis semelhantes ao grupo de pacientes, mas apresentam maior uso de estratégias adaptativas, assim como o grupo controle. Intervenções psicossociais com este grupo são justificadas, favorecendo o uso das estratégias adaptativas em detrimento das estratégias desadaptativas. / Background: Patients with Bipolar disorder (BD) and their relatives exhibit significantly higher stress levels than the general population. Coping strategies, used to manage stressful situations, have been the subject of research and have also been used in psychosocial interventions with bipolar patients in order to help them manage stress factors and improve the clinical outcome of treatment. Objectives: This study has the objective to compare BD patients, their first-degree relatives and a group of healthy controls on the use of adaptive strategies and maladaptive coping. The specific objectives, analyzes will be made by exploiting differences in specific types of coping used by individuals from different groups (patients, relatives and controls) through the Brief COPE scale. Other correlations with clinical variables will be explored, such as demographic and clinical factors, trying to find relations with coping strategies in the sample of patients with BD. Method: This was a cross-sectional study with sampling by convenience, enrolling 36 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 between use of adaptive and maladaptive strategies by patients, patients' relatives and controls. Patients used adaptive strategies less often than the patients' relatives and controls. In contrast, the patients' relatives reported greater use of maladaptive strategies than the controls and were similar to the patients in this respect. Limitations: The sample size is an important factor limiting the conclusions that can be drawn from this study. Furthermore, these conclusions are based on cross-sectional data. Conclusions: The group of patients' relatives were at an intermediate level between the patients and the healthy controls, i.e. family make use of maladaptive strategies at similar levels to the group of patients, but greater use of adaptive strategies, as well as the control group. This group merits psychosocial interventions to encourage use of adaptive strategies rather than maladaptive strategies.

O Transtorno Bipolar (TB) é uma doença psiquiátrica grave, altamente incapacitante que está associada com diversas comorbidades médicas e altas taxas de suicídio. Embora sua fisiopatologia não esteja completamente elucidada, inúmeros estudos têm mostrado alterações no sistema imune de indivíduos com TB. A resposta crônica destes indivíduos ao estresse parece gerar um aumento da inflamação sistêmica bem como da neuroinflamação. A micróglia ativada devido aos estímulos inflamatórios contínuos deve ocasionar diferentes prejuízos tanto bioquímicos quanto funcionas. Os macrófagos, primeira linha de defesa, são células de característica plástica de extrema importância do sistema imune e podem ser estimulados a polarizar para diferentes formas com liberação de fatores pró e antiinflamatórios, estimulando ou mantendo a homeostase no ambiente agredido de alguma forma. Desta forma, nosso trabalho buscou investigar a resposta fenotípica dos macrófagos contra o meio ambiente pró-inflamatório sistêmico observado no plasma de pacientes bipolares eutímicos, maníacos e depressivos em comparação aos controles. A amostra incluiu 5 controles saudáveis, 8 pacientes bipolares remetidos, 5 pacientes maníacos e 5 pacientes depressivos. As citocinas e quimiocinas de RNAm em células U937 tratadas com plasma mostraram um padrão de expressão diferente relativo entre controles saudáveis e pacientes com TB. As citoquinas inflamatórias tais como IL-1β e TNF-α, em pacientes bipolares maníacos e depressivos demonstram maiores quantidades de IL-1β mRNA do que os pacientes eutímicos e pacientes depressivos induziram maiores quantidades de RNAm de TNF-α do que os pacientes eutímicos em células U937. Já a expressão das quimiocinas CXCL9 e CXCL10 no plasma de pacientes com TB depressivos, demostraram ser de menor expressão significativa no grupo de pacientes maníacos quando comparados a controles e pacientes bipolares eutímicos. Nossos resultados sugerem que as citocinas periféticas devem modular a polarização M1 ou M2 de macrófagos no TB. / Bipolar Disorder (BD) is a severe and highly incapacitating psychiatric disorder which is associated with the presence of medical comorbidities. The progression of BD is related to an important cognitive deficit and also to biological and clinical manifestations that lead to treatment resistance and worse prognosis. Immune disturbances have been widely observed and investigated in BD patients. Chronic inflammatory responses induce neuroinflammation, mainly by pro-inflammatory microglial activation, and result in biochemical and functional impairment. Macrophages are the first line of defense of the immune system and exhibit cell plasticity. As well, microglia represents the resident macrophage of the central nervous system been responsible for its protection. Both cells can be stimulated to polarize into two different phenotypes, mainly pro- and anti-inflammatory, maintaining the homeostasis under physiologic and pathologic conditions. Therefore, we aimed to investigate macrophages phenotypical response when submitted to BD patients plasma in different episodes, which is considered a pro-inflammatory environment, and healthy controls plasma. Subjects included healthy controls (n=5), remitted BD patients (n=8), manic patients (n=5) and depressive patients (n=5). The mRNA expression of chemokynes and cytokines from U937 cells treated with BD patients plasma were different from those submitted to healthy controls plasma. Higher mRNA expression of IL-1β was observed in those cells submitted to manic and depressive BD patients plasma when compared to euthymic patients. Also, depressive BD patients plasma induced higher expression of TNF-α compared to euthymic patients. However, chemokynes expression, such as CXCL9 and CXCL10, were reduced in depressive BD patients. However, chemokynes expression, such as CXCL9 and CXCL10, were reduced in depressive BD patients. Inflammatory cytokines such as IL-1β and TNF-α in bipolar manic and depressive patients demonstrate higher amounts of IL-1β mRNA that euthymic patients and depressive patients induced higher amounts of TNF-α mRNA levels than the patients in euthymic U937. Since the expression of CXCL9 and CXCL10 chemokines in plasma from patients with depressive TB, proved less significant expression in the group of manic patients when compared to controls and euthymic bipolar patients.

Objetivo: Esta dissertação tem por objetivo avaliar as relações entre marcadores inflamatórios e o transtorno bipolar (TB), avaliando de forma prospectiva os níveis séricos de diversas citocinas de uma mesma amostra de pacientes com transtorno de humor bipolar em mania e após seu tratamento. Métodos: Para a avaliação dos níveis séricos de citocinas em diferentes fases do TB, foi acompanhado um grupo de vinte e três pacientes antes e após o tratamento de um episódio de mania. O diagnóstico foi definido conforme critérios da Entrevista Clínica Estruturada para DSM-IV, SCID-I. A análise das variáveis foi realizada através do teste de Wilcoxon para amostras pareadas. Resultados: Não foram observadas diferenças nos níveis de citocinas antes e após o tratamento dos pacientes em episódio maníaco. Conclusões: Estes achados devem ser interpretados com cautela. Devido ao pequeno tamanho amostral não é possível controlar possíveis fatores de confusão, como, por exemplo, índice de massa corpórea e fármacos utilizados para o episódio maníaco. Estudos maiores poderiam elucidar se o tratamento do episódio maníaco não está associado a alterações nos níveis de citocinas. / Objectives: This report aims to evaluate the relation between inflammatory markers and bipolar disorder, assessing prospectively cytokines serum levels of a group of bipolar patients in acute mania and after treatment. Methods: In order to assess changes in cytokines serum levels of BD patients during acute mania and after treatment, twenty three bipolar patients were prospectively compared during and after treatment of a manic episode. Diagnoses were made using the Structured Clinical Interview for DSM-IV, SCID-I. Analysis were made using paired samples Wilcoxon signed rank test. Results: No differences were found in cytokine serum levels before and after treatment for acute mania Conclusion: These findings should be interpreted with caution. Due to small sample size, it was not possible to control possible bias, such as body mass index and prescribed medications.