Bipolar disorder is a psychiatric illness characterized by recurrent fluctuations in mood and increased risk of suicide. Twin and family studies have identified the highly heritable nature of the disorder, but the limitations of the current DNA-centric paradigm underscore the need for a new perspective to gain a clearer understanding of its basis. This project investigates various facets of bipolar disorder from an epigenetic standpoint. We used mass spectrometry-based mapping of individual DNA modification differences of the brain-derived neurotrophic factor gene. Moreover, the epigenetic basis of suicidal behaviour in bipolar disorder was investigated using DNA methylation microarrays. We also used a newly-developed enrichment technique, mTAG, to interrogate chromosome-wide DNA modification profiles using tiling microarrays in post-mortem brains of bipolar disease patients and controls. Findings from these experiments highlight observable features of epigenomes of patients affected with mood disorders, and may further the understanding of the molecular origin of psychiatric diseases.

Intracellular calcium and oxidative stress dyshomeostasis, which can be highly interactive, occur in bipolar disorder (BD), but the pathogenesis of these disturbances is unknown. The transient receptor potential (TRP) melastatin subtype 2 (TRPM2) and canonical subtype 3 (TRPC3) calcium-permeable non-selective ion channels, already implicated in BD, are involved in calcium and oxidative stress signalling. Thus, I sought to determine whether the expression and function of these channels are modulated by oxidative stress exposure in rat cortical neurons, astrocytes, and in human B lymphoblast cell lines (BLCLs), a cell model that reports diagnostically relevant abnormalities in BD. This thesis work demonstrated that TRPC3 expression and function are decreased after chronic, but not acute oxidative stress exposure in both human and rat cell models. TRPM2 expression, on the other hand, was increased after both acute and chronic stressor treatments in rat cortical neurons. In BLCLs, TRPM2-mediated calcium entry was blunted although no difference in TRPM2 mRNA expression was detected. Moreover, BLCLs from BD-I patients exhibited greater susceptibility to cell death and a differential sensitivity of TRPM2-mediated calcium influx to acute oxidative stress compared with healthy subjects, further supporting reduced cellular resilience in the pathophysiology of BD-I. I also demonstrated that TRPC3 protein is expressed in human brain from 8 days to 83 years old supporting an ongoing role in the developing and adult human brain. These findings support an important role for TRPM2 and TRPC3 in sensing and responding to oxidative stress, and in transducing oxidative stress signalling to intracellular calcium homeostatic and cellular stress responses, which have been implicated in the pathophysiology of BD. Finally, this work has highlighted an inherent difference in TRPM2 channel functionality in BD type I subjects compared with controls, adding functional evidence to the genetic and differential expression findings implicating TRPM2 dysfunction in BD.

Intracellular calcium and oxidative stress dyshomeostasis, which can be highly interactive, occur in bipolar disorder (BD), but the pathogenesis of these disturbances is unknown. The transient receptor potential (TRP) melastatin subtype 2 (TRPM2) and canonical subtype 3 (TRPC3) calcium-permeable non-selective ion channels, already implicated in BD, are involved in calcium and oxidative stress signalling. Thus, I sought to determine whether the expression and function of these channels are modulated by oxidative stress exposure in rat cortical neurons, astrocytes, and in human B lymphoblast cell lines (BLCLs), a cell model that reports diagnostically relevant abnormalities in BD. This thesis work demonstrated that TRPC3 expression and function are decreased after chronic, but not acute oxidative stress exposure in both human and rat cell models. TRPM2 expression, on the other hand, was increased after both acute and chronic stressor treatments in rat cortical neurons. In BLCLs, TRPM2-mediated calcium entry was blunted although no difference in TRPM2 mRNA expression was detected. Moreover, BLCLs from BD-I patients exhibited greater susceptibility to cell death and a differential sensitivity of TRPM2-mediated calcium influx to acute oxidative stress compared with healthy subjects, further supporting reduced cellular resilience in the pathophysiology of BD-I. I also demonstrated that TRPC3 protein is expressed in human brain from 8 days to 83 years old supporting an ongoing role in the developing and adult human brain. These findings support an important role for TRPM2 and TRPC3 in sensing and responding to oxidative stress, and in transducing oxidative stress signalling to intracellular calcium homeostatic and cellular stress responses, which have been implicated in the pathophysiology of BD. Finally, this work has highlighted an inherent difference in TRPM2 channel functionality in BD type I subjects compared with controls, adding functional evidence to the genetic and differential expression findings implicating TRPM2 dysfunction in BD.

"The first report describes a case of Major Depressive Disorder (MDD) in a pregnant women living in regional Australia. It begins with a discussion of issues of relevance to the treatment of a pregnant woman with MDD. It also describes the evidence based treatment provided and the results achieved for this client. The second report follows the same format to describe a case of PTSD in a married mother living in regional Australia following a suicide attempt. The third report describes a case of Bipolar I disorder in a separated mother living in regional Australia. Finally, fourth report explores the professional and ethical issues associated with the practice of clinical psychology [...]. This report explores professional issues which include self-care requirements and strategies, initial client contact, communication with colleagues and professional development and client records. Ethical issues covered include professional competency, termination of relationships and confidentiality." / Doctor of Psychology (Clinical)

"The first report describes a case of Major Depressive Disorder (MDD) in a pregnant women living in regional Australia. It begins with a discussion of issues of relevance to the treatment of a pregnant woman with MDD. It also describes the evidence based treatment provided and the results achieved for this client. The second report follows the same format to describe a case of PTSD in a married mother living in regional Australia following a suicide attempt. The third report describes a case of Bipolar I disorder in a separated mother living in regional Australia. Finally, fourth report explores the professional and ethical issues associated with the practice of clinical psychology [...]. This report explores professional issues which include self-care requirements and strategies, initial client contact, communication with colleagues and professional development and client records. Ethical issues covered include professional competency, termination of relationships and confidentiality." / Doctor of Psychology (Clinical)

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 7 uppsatser.

Bakgrund: Fysisk aktivitet har visat sig främja hälsa och minska risken för högt blodtryck, stroke, hjärt-kärlsjukdom, depression samt minska risken att insjukna, återinsjukna och förbättra återhämtningen från cytostatikabehandling vid bröst- eller coloncancer. Sambandet mellan psykisk sjukdom och fysisk aktivitet är mindre utforskat jämfört med sambandet mellan till exempel fysisk aktivitet och cancer.   Syfte: Syftet med denna litteraturstudie var att utforska hälsoeffekter av fysisk aktivitet hos människor med bipolärt syndrom.   Metod: Litteraturstudie baserad på nio inkluderade studier. Studier har sökts fram från databaserna PubMed och CINAHL.   Resultat: Fysisk aktivitet har goda hälsoeffekter som kan främja hälsan och parera sekundära effekter och sjukdomar som kan kopplas samman med bipolärt syndrom. Fysisk aktivitet bidra till en minskad stressnivå, minskad risk för diabetes typ 2 och hjärt-kärlsjukdomar. Fysisk aktivitet minskar också risken för samsjuklighet och lindrar bieffekter av psykofarmaka så som till exempel viktuppgång. Bipolärt syndrom kan medföra att träningsfrekvensen och träningsintensiteten variera beroende på sinnesstämning. Depressiva perioder karaktäriseras med minskad träningsfrekvens och intensitet medan maniska perioder kan ha ökad träningsfrekvens och intensitet.   Slutsats: Fysisk aktivitet och dess positiva hälsoeffekter kan på sikt minska risken för samsjuklighet och sekundära sjukdomstillstånd vid bipolärt syndrom. Motivering och implementering av fysisk aktivitet kan förbättra omvårdnaden och behandlingsalternativen hos personer med bipolärt syndrom. / Background: Physical activity has through modern research been shown to benefit the physical health for people and in turn reduce the risk for high blood pressure, reduce the risk to suffer from a stroke, cardiovascular disease and depression together with reducing the risk to be diagnosed with, reduce relapse risk and to improve the rate of recovery after chemotherapy from cancers such as breast or colon cancer. The relation between mental health and physical activity is less scientifically explored than similar areas of research such as the relation between physical activity and cancer.   Aim: The aim of this systematic review is to explore the beneficial effects physical activity might bring to people with bipolar disorder   Method: A systematic review including nine quantitative studies has been performed. The articles have been found through databases such as PubMed and CINAHL.   Results: Physical activity has been found to give health benefits for the conditions bipolar disorder might bring. Through physical activity the levels of stress are reduced, the risk for diabetes type 2 and cardiovascular disease are reduced. Physical activity also reduces the risk for comorbidity and will lessen the side effects psychotropic drugs bring such as weight gain. Bipolar disorder can reduce the ability to perform physical exercise depending on the current mood state. A depressive episode tends to cause in less physical activity, while a manic episode instead can cause increased physical activity and exercise intensity.   Conclusion: Physical activity and its positive health benefits can in the long run reduce the risk of comorbidity and secondary illnesses bipolar disorder might bring. With motivation and implementation of physical activity, the nursing care might improve and new alternative treatments for persons with bipolar disorder may arise.

Schizophrenia is a complex mental disorder characterised by positive symptoms such as hallucinations and psychosis, negative symptoms such as avolition and anhedonia, and cognitive defects. Schizophrenia risk has a genetic component, and it is likely that this is caused by interaction between numerous genes with individually small effects. Environment also plays a role; factors associated with schizophrenia include drug use, prenatal stressors and living environment. Candidate genes linked to schizophrenia have been identified through recent GWAS of human populations with the disorder, including ANK3, TCF4 and CACNA1C. GWAS associations alone are not sufficient to identify these as definitive risk genes for the disease. In order to validate these findings, animal models (in particular the mouse) can be used to study the effect of mutations in these genes of interest. Knockouts of these genes in the mouse are lethal, so we have used the ENU mutagenesis DNA archive at MRC Harwell to screen for additional allelic variants expressing more subtle and varied behavioural phenotypes. Endophenotypes associated with schizophrenia and bipolar disorder, such as anxiety, cognitive deficits and sensorimotor gating deficits, can be characterised in these mutants and, together with molecular characterisation, this can validate these genes as risk factors. While mutations in Ank3 and Tcf4 proved to be non-functional, two mutations in Cacna1c have been associated with anxiety phenotypes and differences in EEG power spectra, as well as causing a cardiac phenotype.

Bipolar disorder (BD) is one of the leading causes of disability worldwide and has a detrimental impact on health-related quality of life (HRQoL), and personal and social functioning. Despite this, there is insufficient knowledge of the costs, HRQoL implications relevant to BD, and the cost-effectiveness of current treatments for BD in the UK. This thesis aims to inform decisions about local and national service provision by applying a variety of health economic tools to build an economic case for BD. First, economic evaluations of BD management strategies are systematically reviewed. A cost-of-illness study is then conducted to estimate the societal burden of BD in the UK and explore the factors that drive variations in these costs. The appropriateness of applying the EQ-5D-3L outcome measure in BD is assessed, and the feasibility of mapping disease-specific measures to the EQ-5D-3L is explored. Finally, a cost-utility analysis (CUA) is conducted to bring together evidence on the costs and outcomes associated with alternative psychological interventions in BD management. This thesis makes critical contributions to multiple research domains, informing the allocation of scarce healthcare resources in this context. There is a sheer dearth of evidence on cost-effectiveness strategies for the long-term management of BD in the UK, especially the evidence for psychological therapies is limited. The annual societal costs associated with BD in the UK are estimated to be £5.14 billion, demonstrating the significant economic burden associated with this disease. The EQ-5D-3L instrument is found to be useful in measuring HRQoL in BD patients who predominantly experience depressive symptoms but is not sensitive enough to detect changes in individuals with mania. More psychometric evidence is therefore required before this instrument can be widely applied in economic evaluations of BD-related interventions. Finally, the CUA indicates that a novel structured psychoeducation intervention in individuals on remote mood monitoring in the UK is not cost-effective.

O transtorno bipolar (TB) é uma das doenças psiquiátricas mais comuns e com altas taxas de morbimortalidade. Existe uma busca de um modelo neurofisiológico que poderia fornecer medidas objetivas para o diagnóstico desta doença, bem como fornecer parâmetros fisiológicos para monitorar a progressão, quantificar o dano causado pela mesma e prever a resposta ao tratamento na tentativa de direcionar a terapêutica adequada a cada estágio e evitar sua progressão. Kapczinski et al (2014) propôs um modelo de estadiamento do TB baseado em sintomas interepisódio, biomarcadores (inflamatórios e neuroplásticos) e dano cognitivo. Na última década, técnicas de neuroimagem e de genética proliferaram e vem se tornando promissoras ferramentas para se estabelecer a base de modelos neurofisiológicos do TB. Embora o prejuízo cognitivo já esteja bem descrito na literatura, o conhecimento sobre as alterações de conectividade em estudos de neuroimagem associadas a esta condição ainda é escasso. A atual pesquisa se propos a investigar os mecanismos fisiopatológicos do transtorno do humor bipolar com enfoque na substância branca (SB) cerebral. Primeiramente foi feita uma revisão sistemática da literatura internacional de estudos que correlacionaram o TB e estudo de tensor de difusão (DTI) por ressonância magnética (RM). Foram incluidos 18 trabalhos que fechavam com os critérios da pesquisa. Os trabalhos mostraram nas análises de DTI alterações na integridade da SB entre o os pacientes com TB em comparação com os controles normais. Essas alterações foram encontradas especialmente nos tratos de SB implicados em conectar uma ampla gama de redes neurais, incluindo as regiões estriatais ventrais e fronto-temporais. A maioria dos estudos mostrou valores de anisotropia fracionada (FA) reduzidos em tratos comissurais inter-hemisféricos e de associação frontolímbicos, com destaque para o corpo caloso que foi a estrutura mais acometida nos diferentes estudos. Estes achados são concordantes com a "síndrome de desconexão" que é encontrada em pacientes com TB. O segundo propósito desta tese foi fazer uma comparação dos volumes de substância branca total, do volume do corpo caloso e do volume total de substância cinzenta entre pacientes com TB em estagio inicial e avançado em relação aos seus respectivos controles normais pareados para sexo, idade, hemisfério dominante e nível de escolaridade. A análise de volumetria das estruturas corticais e subcorticais foi feita por meio de método de segmentação automatizada pelo software Freesurfer. Foram avaliados 55 sujeitos, sendo 29 pacientes com TB e 26 controles normais. A análise volumétrica encontrou redução da SB total e do volume do corpo caloso tanto em pacientes com TB no estagio inicial quanto tardio da doença. O volume de susbtância cinzenta (SC) total estava reduzido somente nos pacientes com TB em estágio tardio. Estes achados são inéditos na literatura e podem explicar a síndrome desconectiva dos pacientes com TB desde os estágios iniciais e o declínio cognitivo acentuado dos pacientes em estágios mais avançados da doença. Podem propor uma pista para achados de biomarcadores em populações em risco para desenvolver TB. / Bipolar disorder (BD) is one of the most common psychiatric disorders and with high morbidity and mortality rates. There is a search for a neurophysiological model that could provide objective measurements for diagnosis of this disease, as well as providing physiological parameters to monitor the progression, quantify the damage caused by it and predict response to treatment in an attempt to direct the appropriate therapy for each stage and prevent its progression. Kapczinski et al. (2014) proposed a staging BD model based on interepisode symptoms, biomarkers (inflammatory and neuroplastic) and cognitive impairment. In the last decade, techniques of neuroimaging and genetic proliferated and are becoming promising tools to settle the basis of neurophysiological models of BD. Although cognitive impairment is already well described in the literature, knowledge of the connectivity changes in neuroimaging studies associated with this condition is still scarce. Current research is proposed to investigate the pathophysiological mechanisms of bipolar disorder focusing on white matter (WM) brain. It was first made a systematic review of the literature studies that correlated the BD and diffusion tensor imaging (DTI). We found 18 published DTI studies that identified WM changes in subjects with bipolar disorder. The studies showed changes in the integrity of DTI WM between BD patients compared with normal controls. These changes were found especially in the treatment of WM connecting implicated in a wide range of neural networks, including ventral striatal regions and frontotemporal. Most studies showed reduced FA values in commissural inter-hemispheric and fronto-limbic association tracts, especially the corpus callosum which was the most affected structure in different studies. These findings are consistent with the "disconnection syndrome" which is found in patients with TB. The second purpose of this thesis was to compare the total white matter volume, the corpus callosum volume and total volume of gray matter in patients with BD in early and advanced stage in relation to their normal controls matched for sex, age, dominant hemisphere and education level. The volumetric analysis of cortical and subcortical structures was performed by automated segmentation method by FreeSurfer software. We evaluated 55 subjects, 29 BD patients and 26 normal controls. Volumetric analysis found reduced total WM and the corpus callosum volume both in BD patients at the early stage and late disease. The volume of total gray matter (GM) was reduced only in patients with late-stage BD. These findings are unprecedented in the literature and may explain the disconnection syndrome that is present in patients from the early stages and the marked cognitive decline of patients in more advanced stages of the disease. These findings may offer a clue to biomarker findings in populations at risk to develop BD.