A prevalência do transtorno de humor bipolar (THB) na populção mundial é em média 4%. Essa doença psiquiátrica está associada a elevadas taxas de mortalidade, principalmente devido a doenças cardiovasculares (DCVs). Pacientes com THB apresentam risco duas vezes maior de desenvolver doenças cardiovasculares em relação à população geral. Componentes importantes das DCVs incluem disfunção endotelial, ativação plaquetária, ativação imunológica e inflamação. Para este estudo foram avaliados biomarcadores associados com risco de doença cardiovascular em pacientes bipolares. Os níveis séricos de homocisteína, folato, vitamina B12, ferritina, creatina kinase e proteína C-reativa foram medidos em pacientes com THB em dois momentos: durante um episódio maníaco e após a remissão dos sintomas. A expressão do mRNA de MMP-2 e MMP-9, em sangue total, também foi analisada. Todos os parâmetros foram comparados com controles saudáveis. Pacientes e controles estavam aparentemente livres de doenças cardiovasculares. A expressão da MMP-2 mostrou uma relação negativa em relação ao IMC nos pacientes com THB nos estados maníaco e eutímico, enquanto que essa relação foi positiva nos indivíduos controles. Os níveis de ferritina se mostraram reduzidos apenas durante os episódios de mania. Não foram verificadas diferenças estatisticamente significantes nos demais biomarcadores estudados quando comparados os pacientes com THB e os controles. Exceto para a ferritina, todos os resultados obtidos durante o episódio de mania persistiram após a recuperação sintomática nos pacientes com THB. Nossa análise não valida a utilidade desses biomarcadores para diferenciar diferentes estados de humor quanto ao risco de DCV. É provável que a utilidade desses biomarcadores na caracterização de maior risco em indivíduos com doença cardiocascular estabelecida se justifique mais do que o seu uso como indicadores de risco de futuros eventos cardiovasculares. A possível relação da homocisteína com risco de doença cardiovascular no THB não foi obsevada após correção para o IMC. A diferença no padrão de expressão da MMP-2 no THB precisa ser investigada bem como, outros indicadores de remodelamento tecidual e inflamação. Os resultados mostram a importância da inclusão do IMC como uma covariável em estudos para investigar o risco cardiovascular no THB. Um adequado acompanhamento no que diz respeito ao desenvolvimento de comorbidades médicas em pacientes bipolares deve ser implantado. / The prevalence of BD is thought to be around 4% of the population. This psychiatric disorder is associated with increased mortality due to medical causes, most notably cardiovascular disease (CVD). Two-fold increased risk of cardiovascular disease has been found among adults with bipolar disorder versus general population. Important components of CVD include endothelial dysfunction, platelet and immune activation and inflammation. We evaluated biomarkers associated with increased risk of cardiovascular disease in bipolar patients. The serum levels of homocysteine, determinants of homocysteine metabolism such as folate and vitamin B12, ferritin, creatine kinase and C-reactive protein were measured in bipolar patients in two separate instances: during acute mania and after remission of manic symptoms. The mRNA expression of MMP-2 and MMP-9 in total blood was also evaluated. All parameters were compared with healthy controls. Patients and controls were free of clinically apparent cardiovascular disease. The mRNA levels for MMP2 were negatively associated with BMI in the BD and positively associated with BMI in controls. Ferritin levels were reduced only during mania. No statistically significant differences were found in the other markers comparing bipolar patients and controls. Except ferritin, the results persist across symptomatic recovery within the same bipolar patient. The biomarkers selected can not differentiate mood states as the cardiovascular risk. May be these biomarkers may be most usefull to characterize risk in individuals with an established CVD than using biomarkers as sole risk predictors of future CHD events. Our findings show the importance of assessing the BMI as a covariate in studies to investigate the cardiovascular risk in bipolar disorder. It is crutial to highlights the necessity of appropriate monitoring concerning development of medical comorbidities in bipolar patients.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / O transtorno afetivo bipolar (TAB) à um transtorno psiquiÃtrico multifatorial, progressivo, que se caracteriza por uma oscilaÃÃo entre episÃdios manÃacos ou hipomanÃacos e depressivos. Estima-se que o transtorno afete cerca de 1 â 2 % da populaÃÃo mundial. O diagnÃstico definitivo e o tratamento adequado podem demorar 10 anos para se concretizar. Leva a grande prejuÃzo à qualidade de vida dos pacientes, gerando altas taxas de incapacidade funcional, comorbidades clÃnicas, como hipertensÃo e alta prevalÃncia de suicÃdio. A fisiopatologia do transtorno ainda permanece obscura, porÃm muitos esforÃos sÃo empregados em pesquisas para tentar elucidar os possÃveis mecanismos envolvidos no TAB, bem como para melhorar seu tratamento. As hipÃteses para explicar a fisiopatologia do TAB incluem: desregulaÃÃo da dopamina, alteraÃÃes mitocondriais, aumento do estresse oxidativo, reduÃÃo dos nÃveis de neurotrofinas, dentre outras. Diante deste cenÃrio, buscou-se investigar os possÃveis efeitos antimanÃacos do carvedilol (CVD), um beta-bloqueador nÃo seletivo usado amplamente no tratamento da hipertensÃo arterial com comprovada aÃÃo antioxidante e neuroprotetora. Para tanto, se utilizou um modelo animal de mania induzido por dimesilado de lisdexanfetamina (LDX), recentemente validado por nosso grupo de pesquisa. O LDX à um prÃ-fÃrmaco que se converte a D-anfetamina, a qual possui efeito psicoestimulante. O CVD foi avaliado em dois protocolos de tratamento, prevenÃÃo (simulando a fase de manutenÃÃo do TAB) e reversÃo (simulando a fase de crise do TAB), em ambos o valproato (VAL) foi utilizado como estabilizante do humor padrÃo. Foram avaliadas no presente estudo alteraÃÃes comportamentais e de estresse oxidativo. Os animais submetidos aos protocolos de prevenÃÃo (animais prÃ-tratados durante 7 dias com CVD, VAL e Salina e por mais 7 dias com LDX 10 mg/kg) e reversÃo (prÃ-tratados durante 7 dias com LDX e posteriormente tratados com CVD, VAL e Salina) tiveram os nÃveis de glutationa reduzida (GSH) e de peroxidaÃÃo lipÃdica (TBARS) determinados nas Ãreas cerebrais do cÃrtex prÃ-frontal (PFC) e corpo estriado (CE) e o fator neurotrÃfico derivado do cÃrebro (BDNF) no hipocampo (HC). Os resultados indicaram que o CVD preveniu e reverteu a hiperlocomoÃÃo e comprometimento da interaÃÃo social induzidas por LDX. Na avaliaÃÃo neuroquÃmica o CVD foi capaz de aumentar prevenir e reverter as alteraÃÃes nos nÃveis de GSH, BDNF e peroxidaÃÃo lipÃdica dos animais submetidos ao modelo de mania com resultados comparÃveis aos dos animais tratados com VAL e controles. Em conclusÃo, os resultados deste estudo revelaram que o CVD à um fÃrmaco em potencial para o tratamento da mania, sendo indicados, portanto, estudos clÃnicos que comprovem a aÃÃo deste fÃrmaco. / Bipolar disorder (BD) is a psychiatric disorder with multifactorial development and neuroprogressive characterized by oscillation between periods of manic and depressive episodes. It is estimated that the disease affects about 1 - 2% of the worldwide population and it takes about 10 years to a definitive diagnosis and appropriate treatment. BD brings many impairment of quality of life of patients, generating high rates of functional disability, comorbidities such as hypertension during the clinical course of the disease and presenting a high prevalence of suicide. The pathophysiology of the disease remains unclear, but many efforts are employed in research to try to elucidate the possible mechanisms involved in BD. The pathways hypothesized to take part of BD pathophysiology includes: dopamine deregulation, increased oxidative stress, decreased levels of neurotrophins such as BDNF, mitochondrial dysfunction among others. Based on the described above we sought to investigate the effects of carvedilol, (CVD), a nonseletive beta-blocker widely used in the treatment of hypertension with antioxidant properties, in a model of mania induced by dimesilate of lisdexamfetamine (LDX) a prodrug metabolized to D-amphetamine, in rats. The experimental design of the study consisted evaluation of CVD against behavioral changes and oxidative stress alterations in two protocols of treatment, prevention and reversal using valproate (VAL) a humor stabilizer as standard drug to assess the effectiveness of CVD. In the prevention protocol the animals were pre-treated for 7 days with CVD, saline or VAL). In the reversal protocol the animals were pre-treated for 7 days with LDX and for further 7 days received CVD, saline or VAL plus LDX. The behavioral determinations of locomotor activity and social interaction were conducted 2 h after the last administration of LDX. Reduced glutathione (GSH) and lipid peroxidation (TBARS) levels were determined in brain areas of the prefrontal cortex (PFC) and striatum (EC) and brain-derived neurotrophic factor (BDNF) in the hippocampus (HC) rats. The results indicated that CVD prevented and reversed the hyperlocomotion and deficit in social contacts induced by LDX. In the neurochemical determinations CVD significantly prevented and reversed the alterations in BDNF, GSH and MDA levels induced by LDX presenting results comparable to those of saline and VAL groups. Therefore, the results of the present study indicates that CVD prevents reverts the behavioral and neurochemical alterations induced by LDX used as an animal model of mania being, thus, a potential drug for the treatment of BD.

A prevalência do transtorno de humor bipolar (THB) na populção mundial é em média 4%. Essa doença psiquiátrica está associada a elevadas taxas de mortalidade, principalmente devido a doenças cardiovasculares (DCVs). Pacientes com THB apresentam risco duas vezes maior de desenvolver doenças cardiovasculares em relação à população geral. Componentes importantes das DCVs incluem disfunção endotelial, ativação plaquetária, ativação imunológica e inflamação. Para este estudo foram avaliados biomarcadores associados com risco de doença cardiovascular em pacientes bipolares. Os níveis séricos de homocisteína, folato, vitamina B12, ferritina, creatina kinase e proteína C-reativa foram medidos em pacientes com THB em dois momentos: durante um episódio maníaco e após a remissão dos sintomas. A expressão do mRNA de MMP-2 e MMP-9, em sangue total, também foi analisada. Todos os parâmetros foram comparados com controles saudáveis. Pacientes e controles estavam aparentemente livres de doenças cardiovasculares. A expressão da MMP-2 mostrou uma relação negativa em relação ao IMC nos pacientes com THB nos estados maníaco e eutímico, enquanto que essa relação foi positiva nos indivíduos controles. Os níveis de ferritina se mostraram reduzidos apenas durante os episódios de mania. Não foram verificadas diferenças estatisticamente significantes nos demais biomarcadores estudados quando comparados os pacientes com THB e os controles. Exceto para a ferritina, todos os resultados obtidos durante o episódio de mania persistiram após a recuperação sintomática nos pacientes com THB. Nossa análise não valida a utilidade desses biomarcadores para diferenciar diferentes estados de humor quanto ao risco de DCV. É provável que a utilidade desses biomarcadores na caracterização de maior risco em indivíduos com doença cardiocascular estabelecida se justifique mais do que o seu uso como indicadores de risco de futuros eventos cardiovasculares. A possível relação da homocisteína com risco de doença cardiovascular no THB não foi obsevada após correção para o IMC. A diferença no padrão de expressão da MMP-2 no THB precisa ser investigada bem como, outros indicadores de remodelamento tecidual e inflamação. Os resultados mostram a importância da inclusão do IMC como uma covariável em estudos para investigar o risco cardiovascular no THB. Um adequado acompanhamento no que diz respeito ao desenvolvimento de comorbidades médicas em pacientes bipolares deve ser implantado. / The prevalence of BD is thought to be around 4% of the population. This psychiatric disorder is associated with increased mortality due to medical causes, most notably cardiovascular disease (CVD). Two-fold increased risk of cardiovascular disease has been found among adults with bipolar disorder versus general population. Important components of CVD include endothelial dysfunction, platelet and immune activation and inflammation. We evaluated biomarkers associated with increased risk of cardiovascular disease in bipolar patients. The serum levels of homocysteine, determinants of homocysteine metabolism such as folate and vitamin B12, ferritin, creatine kinase and C-reactive protein were measured in bipolar patients in two separate instances: during acute mania and after remission of manic symptoms. The mRNA expression of MMP-2 and MMP-9 in total blood was also evaluated. All parameters were compared with healthy controls. Patients and controls were free of clinically apparent cardiovascular disease. The mRNA levels for MMP2 were negatively associated with BMI in the BD and positively associated with BMI in controls. Ferritin levels were reduced only during mania. No statistically significant differences were found in the other markers comparing bipolar patients and controls. Except ferritin, the results persist across symptomatic recovery within the same bipolar patient. The biomarkers selected can not differentiate mood states as the cardiovascular risk. May be these biomarkers may be most usefull to characterize risk in individuals with an established CVD than using biomarkers as sole risk predictors of future CHD events. Our findings show the importance of assessing the BMI as a covariate in studies to investigate the cardiovascular risk in bipolar disorder. It is crutial to highlights the necessity of appropriate monitoring concerning development of medical comorbidities in bipolar patients.

No description available.

Bipolar disorder (BD), previously known as manic depressive disorder, is associated with recurring episodes of depression and mania/hypomania. Currently, no definitive biological mechanisms have been pinpointed with regards to the origin and progression of BD, however, inflammation and oxidative stress have been shown to present in the brains of individuals with BD. Notably, other neurodegenerative disorders which also contain an inflammatory component including Alzheimer’s disease and Multiple Sclerosis display with disruption of the brain blood barrier (BBB). We thus propose a model of BD wherein BBB disruption facilitates inflammation and oxidative stress induced neural damage. This study looked to utilize amphetamine (AMPH) induced mania model and lipopolysaccharide (LPS) induced inflammatory model to represent BD like conditions in rats and to assess BBB permeability. We observed elevated locomotor data in response to AMPH administration and a trend of increased BBB permeability across regions following low dose chronic AMPH injections. In the LPS induced BBB permeability model, we did not detect any elevated serum C-reactive protein (CRP) or tumour necrosis factor alpha (TNF-α) levels but did see significantly elevated BBB permeability in the LPS group and lithium pre-treatment providing some protection against BBB permeability in one of our cohorts. These trends were further corroborated by a follow-up study and thus warrant further investigation into the mechanistic nature of BBB breakdown in this model. This may provide a breakthrough in understanding the pathophysiology of BD and the underlying mechanistic effects of lithium, paving the way for new more target therapeutic remedies to combat this debilitating disorder. / Thesis / Master of Science (MSc)

No description available.

No description available.

The global burden of mental health disorders is rising with the world health organization recently having recognized major depressive disorder as the leading cause of disability worldwide. Nearly one in five Canadians are now estimated to struggle with a mental health disorder and Generalized Aanxiety Ddisorder (GAD) Mmajor Ddepressive Ddisorder (MDD) and Bbipolar Ddisorder are three of the most prevalent. Despite significant research into the disorders’ cause, the pathophysiology and underlying etiology of these diseases remains largely undiscovered. Recent research has highlighted the potential role of the gut microbiota in mental health, in particular in connection with anxiety. Our research aims to investigate this link in a cohort of GAD, MDD and bipolar patients recruited through the Anxiety Treatment and Research Centre at St. Joseph’s Healthcare in Hamilton, as well as through the University Health Nnetwork in Toronto. 71 GAD, 18 MDD, 17 euthymic MDD and 23 Bipolar patients provided fecal samples from which DNA was extracted, following which the V3 region of the 16S rRNA gene was amplified and sequenced using the Illumina Miseq platform. Sequencing data was analyzed through an in-house pipeline to construct community profiles of patients and age and sex matched healthy controls. My work involved analyzing the data to identify signature organisms that might identify putative disease associated microbial communities for further hypothesis generation about possible roles in disease. Furthermore, an extensive culturing effort was undertaken to identify and characterize some of the Bacteroides strains which were enriched in the GAD patient population. This study presents novel insights into some of the organisms that may be markers for a number of different diseases as well developing a better understanding of the Bacteroides that were correlated with anxiety. / Thesis / Master of Science (MSc) / Mental hHealth disorders including Ggeneralized Aanxiety Ddisorder (GAD), Mmajor Ddepressive Ddisorder (MDD) and Bbipolar Ddisorder (BD) affect somewhere between five and ten percent of Canadians, with the Wworld Hhealth Oorganization recently labeling MDD the leading cause of disability worldwide. Despite decades of research, on these disorders we still have a poor understanding of what factors may contribute to causing these disorders their underlying mechanisms of actionetiology. Another hallmark of many mental health conditions are increased rates of gastrointestinal symptomsor digestive distress relative to the healthy populatioindividualsn. Recently, there has been a great deal of research about how the trillions of bacteria that live in the digestive tract play a role in neuronal brain development and behaviour. This study aimed to better understand which the organisms reside iinn the digestive tract of mental health patients in hopes of better understanding how some of these organisms could be contributing to patients’ poor mental health. Additionally, through better understanding the nature of these communities, recommendations could potentially be made about therapeutic interventions to restore a healthy community.

Thesis--Auburn University, 2009. / Abstract. Vita. Includes bibliographic references (p.64-66).

O presente estudo avaliou um grupo de pacientes com transtorno do humor bipolar (THB), episódio depressivo, através de uma bateria de testes neuropsicológicos – Dígitos da Escala Wechsler de Inteligência para Adultos, 3ª edição (WAIS-III) e Wisconsin Card Sorting Test (WCST) –, escala de funcionalidade – Functioning Assessment Short Test (FAST) – e escala de sintomas depressivos – Montgomery-Asberg Depression Rating Scale (MADRS) – e o comparou com um grupo de controles saudáveis. Obtiveram-se como resultados déficits cognitivos significativos no grupo dos pacientes com THB, no que se refere à memória imediata e de trabalho e funções executivas, quando comparados aos controles saudáveis. Também se encontrou uma correlação entre funcionalidade, sintomatologia depressiva e déficits na memória de trabalho e funcionamento executivo. Estes achados levantam a hipótese de que as dificuldades cognitivas e sintomas depressivos interferem significativamente no funcionamento laboral, afetivo e social dos pacientes com THB. / The present study evaluated a group of patients with Bipolar Disorder (BD), major depressive episode, through a battery of neuropsychological tests - Digits of the Wechsler Intelligence Scale for Adults, 3rd edition (WAIS-III) and Wisconsin Card Sorting Test (WCST) - scale functionality - Functioning Assessment Short Test (FAST) - and scale of depressive symptoms - Montgomery-Asberg Depression Rating scale (MADRS) - and compared with a group of healthy controls. Results were obtained as significant cognitive deficits in the patients with BD, with regard to the immediate and working memory and executive functions compared to healthy controls. We also found a correlation between functionality, depressive symptoms and deficits in working memory and executive functioning. These findings raise the hypothesis that the cognitive and depressive symptoms significantly interfere with work functioning, affective and social development of BD patients.