Bipolar disorder (BD) is a chronic, progressive illness characterized by fluctuations in mood. It is associated with psychosocial and cognitive impairment that can affect a person’s life at home, at work or school, and in interpersonal relationships. Children and adolescents diagnosed with BD experience similar functional impairments and risk for suicidal thoughts or actions compared to adults. Additionally, they are at an increased risk for poorer prognosis during adulthood given the negative outcomes associated with early illness onset, delayed treatment, misdiagnosis, and longer illness duration. The etiology and pathophysiology of bipolar disorder is incompletely understood. Peripheral blood biomarkers can provide insight into the mechanisms underlying the disease and can aid in identifying at-risk individuals, making an accurate diagnosis, monitoring illness activity and improving therapeutic intervention. A PubMed search was carried out and 12 studies were identified that assessed potential peripheral blood biomarkers in children and adolescents with bipolar disorder. These studies suggest that fatty acid biostatus, markers of lipid and protein oxidation, markers of inflammation and immune disturbance, neurotrophic factors and enzymes related to inflammation may serve as biomarkers of BD. These potential biomarkers of the disorder warrant further study in youth with BD. Current findings support a staging hypothesis of BD wherein cumulative episodes lead to disruptions of the pathways associated with the disorder and thus greater impairment in patients farther from their disease onset. However, these and other biomarkers will need to be evaluated in larger, longitudinal studies to validate their use and expand knowledge in the field.

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Huvudsyftet med denna uppsats är att analysera hur människor med bipolär sjukdom upplever att deras sjukdom påverkar deras livkvalitet. Vårt andra syfte är att analysera hur hur människor med bipolär sjukdom upplever insatserna de mottagit från socialtjänsten och Försäkringskassan. Uppsatsen har genomförts utifrån att vi analyserat tre olika självbiografier, Cecilia Asps bok Med mitt liv i mina händer - att leva med bipolär sjukdom, Carrå med Å´s bok Det stavas bipolär och kanske en gnutta borderline och Jenny Sandfors bok Bipolär fånge i min egna historia. Med hjälp av dessa självbiografier har vi insamlat material för att kunna besvara våra frågeställningar. De teorier vi valt att använda oss av i denna uppsats är Erving Goffmans teori avseende stigma, KASAM som är en sociologisk teori utformad av Aaron Antonovsky och empowerment. Goffmans teori går kortfattat ut på att stigma skapas ur situationer där individer upplever att de inte kan bemöta de krav och förväntningar som samhället har på dem. Antonovskys teori används i syftet att se vilka oordningar som författarna upplever samt vilka medel de funnit som kan användas som ett motstånd mot dem och på så sätt visa hur de hanterade livskriser som bipolär sjukdom kan ha gett författarna. Empowerment utgår från att delad makt inte minskar en annans makt och genom samverkan och samarbete så går det att dela kunskap och makt genom råd och stöd. Med utgångspunkt i empowerment undersöks hur författarna upplever mötet med myndigheter som socialtjänsten och Försäkringskassan. Med hjälp av teorierna kommer vi fram till att det finns likheter mellan Sandfors, Carrå med Å och Asps upplevelser av sin bipolära sjukdom, men också att det finns skiljaktigheter som visar på att sjukdomen påverkar människor på olika sätt. / The main purpose of this study was to analyze how people with bipolar disorder's quality of life is affected by the disorder. Our secondary purpose was to analyze how individuals with bipolar disorder experience the contributions of social workers and Försäkringskassan. The essay was carried out based on three different autobiographies that we analyzed; Cecilia Asps book "Med mitt liv i mina händer - att leva med bipolär sjukdom", Carrå med Å's book "Det stavas bipolär och kanske en gnutta borderline" and Jenny Sandfors book "Bipolär fånge i min egna historia", from which we collected material in order to be able to answer the question at hand. The theories of choice for the thesis has been; Erving Goffman's theory on stigma. KASAM a social theory authored by Aaron Antonovsky and empowerment. Goffman's theory covers the stigma that was created from situations where individuals feel that they cannot meet the demands and expectations society has of them. Antonovsky's theory was used for the purpose of studying which obstacles that the study participants experience and what means they have discovered to handle those obstacles. Empowerment assumes that shared power does not diminish individual power, and through collaboration and cooperation creates the possibility to share knowledge and power through advice and support. By using the aforementioned theories we found similarities between the three different authors of the autobiographies, but also differences in their personal experiences dealing with bipolar disorder.

<p>Mutations in the gene SHANK2, which encodes a synaptic scaffolding protein, have been shown to cause a spectrum of neuropsychiatric disorders including: intellectual disability, autism spectrum disorders (ASDs), bipolar disorder (BD), and schizophrenia. However, many aspects of SHANK2 including the array of isoforms expressed, the expression pattern of the protein, biochemical and regulatory mechanisms, and in vivo protein function remain elusive. This body of work aims to uncover the function of the SHANK2 gene and its role in neuropsychiatric disorders using in vitro and in vivo experimental systems.</p> <p>Using a molecular genetics approach, I revealed the transcript architecture of the mouse Shank2 gene including characterization of promoters, isoforms and protein domains. I then outlined the temporal and spatial pattern of the Shank2 isoform expression throughout development. To further explore the protein’s function, we sought to identify novel SHANK2 interacting proteins using a yeast-2-hybrid screen and characterized the interacting proteins. Lastly, in order to understand how Shank2 deficiencies alter brain function we generated and characterized both Shank2 conventional (∆e24) and conditional mutant mice (e24floxed) by deleting or floxing exon 24 that encodes the Homer binding site and has nonsense mutations in human patients with neuropsychiatric disorders.</p> <p>Collectively, these studies 1) provide insight into the transcriptional regulation of Shank2 during brain development; 2) support the value of using Shank2 to further dissect the pathophysiology and circuitry mechanism underlying manic and autism like behaviors; 3) offers a novel mechanistic link between ubiquitination-mediated protein modification and SHANK2 function that may elucidate the molecular basis underlying SHANK2-related neuropsychiatric disorders. Ultimately, these findings may lead to the development of new therapeutic interventions for SHANK2-related neuropsychiatric disorders.</p> / Dissertation

The basic helix-loop-helix PAS domain transcription factor gene NPAS3 is a risk factor for psychiatric disorders. A knockout mouse model also exhibits behavioural and adult neurogenesis deficits consistent with human illness. To define the location and mechanism of NPAS3 aetiopathology immunofluorescent and transcriptomic approaches were used. Npas3 was co-localised with Dcx, but not other neurogenesis markers, in the hippocampal subgranular zone - the site of adult neurogenesis. This implied that NPAS3 might be involved in maturing, rather than proliferating, neuronal precursor cells. Microarray analysis revealed that the transcriptional activities of NPAS3 and its truncated form (C-terminal deletion) in the HEK293 cell line are sensitive to circadian rhythm context. The most highly up-regulated NPAS3 target gene, VGF, encodes secretory peptides with established roles in neurogenesis, depression and schizophrenia. VGF was one of many NPAS3 target genes also shown to be regulated by the SOX family of transcription factors, suggesting an overlap in neurodevelopmental pathways. The transcriptional repression of multiple glycolytic genes indicated that NPAS3 has a second role in metabolic regulation. This finding was also confirmed by collaboration with a metabolomics research group at the University of Strathclyde. SOX11, a transcription factor known to play a role in neuronal and glial cell differentiation, was shown to be down-regulated by NPAS3. The set of genes targeted by SOX11 and their ontologies were deduced by a microarray analysis in a SOX11 overexpressing HEK293 cell line. Regulated genes include a previously established SOX11 target, known markers of neurogenesis as well as genes implicated in neuropsychiatric disorders. Multiple histone and zinc finger genes are regulated by SOX11, many of which were located in two clusters on chromosomes 6 and 19. The chromosome 6 cluster lies within a region of the genome showing the strongest genetic association with schizophrenia. SOX11 may alter localised expression competence and its targets induce a complex programme of chromatin remodelling and downstream gene expression changes to achieve the mature neuronal phenotype. This thesis details how transcription factors are involved in biological processes linked to psychiatric illness. The dual neurodevelopmental and metabolic aspects of NPAS3 activity described here increase our understanding of aspects of neurogenesis relevant to mental illness and may explain the innate and medication-induced susceptibility to diabetes reported in psychiatric patients.

This study explores the effectiveness of “In-Sight”, a holistic recovery-based group training for people with bipolar disorder. Drawn from professional therapies and lived experience of the user-researcher who is diagnosed with having the illness, the training was delivered over 12 weekly sessions. Within a case study approach, an experimental design incorporated pilot (eight participants), main study (five) and control groups (six). Participants with a wide range of DSM-IV bipolar disorders were sought. Three non-bipolar participants experiencing severe mood swings were maintained in the pilot. One bipolar pilot participant later trained as the main study group co-facilitator in delivering the training. Self-report scales measured mood, coping, empowerment and quality of life pre-, post- and six months post-training. Semi-structured interviews noted individual change within the same time frame. Mental health professional interviews, medical note analysis and user-researcher observations also informed the study. Findings from self-report questionnaires indicated promising evidence that participants experienced improved mood stability, symptom severity, coping and quality of life and greater empowerment. A model has emerged to illustrate the various course components that appeared to benefit participants (user-led approach, self-help iii group format, illness management techniques, interpersonal skills development, healthy lifestyle, structure and planning, and intellectual change of perspective). The model illustrates how these components appeared to impact upon coping strategies, in turn leading to greater mood stability, maintaining wellness and personal development resulting in greater empowerment, improved outlook on self and the future and improved quality of life over time. The three non-bipolar pilot participants also appeared to benefit from the training compared to controls albeit to a lesser degree than the bipolar participants. The co-facilitator showed evidence of the greatest improvement. Four controls indicated evidence of continued use of poor coping and risk of further deterioration in illness, of whom two experienced major episodes with psychosis. Two controls indicated slight improvements. The “In-Sight” training is proposed as a step towards a more comprehensive approach for recovery from bipolar disorder informing the development of a new Expert Patients Programme in the UK.

Background: The Behavioural Activation System dysregulation theory of Bipolar Disorder (BD) proposes that (hypo)manic episodes represent prolonged periods of elevated approach-motivation and high-activation positive affect (PA). Excessive goal-setting behaviour and increased engagement in stimulating activities have been found amongst people with BD and may interact with elevated approach-motivation, contributing to an “upward spiral”. Hypotheses were: both i) approach-related behaviours in response to PA; and ii) high-activation PA, will be more common in individuals with BD than those without; iii) individuals with BD will be more likely to respond to high-activation PA than to low-activation PA with approach-related behaviours, compared to individuals without BD. Method: Individuals with BD and a non-clinical control group were tested. Participants completed measures of current hypomanic/depressive symptoms, trait PA, and two versions of two measures of response to PA, asking about low-activation and high-activation PA. Results: The BD group used more approach-related responses to PA, particularly within high-activation mood states, compared to controls. The groups differed in their experience of different types of PA, due to the control group experiencing more low-activation PA. Limitations: It is unclear whether the findings are specific to BD or affective disorders in general, due to a lack of a clinical control group. The groups may also differ in their expectations of PA due to medication use and previous experience of mania. Conclusions: It may be therapeutically beneficial to help individuals with BD use non-approach-related strategies in response to high-activation PA. Further research would identify which strategies are most useful.

The purpose of this study proposal is to examine the potential relationship between linguistic creativity and mood disorders, specifically depression and bipolar disorder. Participants will be approximately 67 adults who have either bipolar disorder, major depressive disorder, or serve as a healthy control group. Participants will complete prompts in order to measure linguistic creativity and then fill out several questionnaires relating to depressed mood, mania, general creativity, and rumination levels. It is predicted that bipolar disorder will have higher levels of certain types of linguistic creativity, such as lexical and semantic creativity, whereas depression will have more syntactic creativity. Furthermore, it is anticipated that higher rumination levels in the depressed group will be associated with higher levels of linguistic creativity, as opposed to participants in the depressed group with lower levels of rumination. Lastly, it is predicted that the type of writing prompt will influence the amount of creativity exhibited by each participant group. The proposed study has implications for therapeutic benefits, the emergence of a new area of research in two separate fields, and a new way of analyzing shifts in speech patterns of those with mood disorders.

Bipolar disorder and borderline personality disorder are common psychiatric diagnoses. One is a mood disorder with a strong genetic basis while the other is a disorder of personality commonly related to abusive experiences in childhood. Despite contrasting aetiologies they can be difficult to differentiate because of overlapping clinical presentations and symptoms. Diagnostic accuracy is important because of their polarised treatment approaches: long term treatment with mood stabilizers for bipolar disorder and psychotherapy for borderline personality disorder. A qualitative study of psychiatrists revealed comprehensive knowledge of the diagnostic criteria however, many expressed the view that diagnostic criteria did not assist diagnostic differentiation. These findings were validated in a large electronic survey of UK psychiatrists. A detailed study of actual diagnostic processes revealed that this scepticism appeared to influence actual practice. Clinicians largely ignored diagnostic criteria but continued to give diagnoses. Age and IQ matched women with bipolar disorder, borderline personality disorder and a healthy control group were compared in a series of cognitive tasks. Borderline personality disorder was associated with a failure to establish and maintain reciprocal cooperation in a game theoretic measure of social exchange. This behavioural change was not seen in euthymic bipolar disorder. Borderline personality disorder was also associated with an insensitivity to reward and losses in a risky decision-making task. Using a simple two-choice reaction task post error slowing was significantly amplified in the borderline group despite overall reaction times and error rates being similar in all three groups. Clinical diagnostic practice as revealed in this study is not adequate to reliably differentiate between bipolar disorder and borderline personality disorder. Laboratory measures of social exchange, decision making and post-error slowing highlight fundamental difficulties in borderline personality disorder not seen in euthymic bipolar disorder. These findings support the differentiation of bipolar disorder from borderline personality disorder and offer translational models for developing and evaluating new treatments for borderline personality disorder.

Alteração da fosfolipase A2 tem sido descrita em diversas doenças neuropsiquiátricas. Esta enzima é responsável pelo metabolismo dos fosfolípides de membrana e parece estar envolvida na fisiopatologia do transtorno bipolar. Neste estudo, foram analisados os três principais subtipos da PLA2 (sPLA2, cPLA2 e iPLA2) em plaquetas de pacientes e indivíduos controles. A atividade de subtipos de PLA2 foi determinada em 20 pacientes TB sem tratamento com estabilizadores de humor e após seis semanas de tratamento com lítio; 72 pacientes medicados e 65 controles (16 pareados com os pacientes sem tratamento e 49 com os pacientes previamente medicados), pelo método radioenzimático. Os pacientes foram diagnosticados e classificados de acordo com os critérios estabelecidos no DSM-IV-TR. Foi verificado que Os pacientes no estágio inicial da doença apresentaram menor atividade de iPLA2, sPLA2 e cPLA2 quando comparadas ao grupo controle. Seis semanas de tratamento com o lítio não foram suficientes para observar alterações nos resultados obtidos. No entanto, o lítio diminuiu a sintomatologia maníaca e a depressiva, avaliadas pelas escalas de Hamilton e Young, respectivamente (p < 0,01 para as duas comparações). Os pacientes medicados não diferiram do grupo controle para os três subtipos de PLA2 avaliados. Estes resultados sugerem que no estágio inicial do TB há uma diminuição da atividade das PLA2, e que a ação de um ou mais medicamentos que são incluídos na terapêutica para este transtorno podem reverter essa diminuição. Sugere-se ainda que a diminuição da atividade da iPLA2 no estágio inicial do transtorno bipolar, além de alterar o remodelamento da membrana, possa ser um fator de risco para o desenvolvimento de demência nestes pacientes. / Changes in phospholipase A2 have been reported in several psychiatric disorders. This enzyme is responsible for the metabolism of membrane phospholipids and has been suggested to play a role in bipolar disorder physiopathology. In this study, the activity of the three main subtypes of phospholipase A2 (PLA2) were analyzed (sPLA2, cPLA2 and iPLA2) in platelets of BD patients and health subjects. Subjects enrolled were: 20 drug-naïve and drug free BD patients, who were treated with lithium for six weeks; 72 BD long-term treatment patients and 65 controls (16 for the drug-naïve and drug free and 49 for the long term group). PLA2 subtype activities were determined by the radio enzymatic method. Patients\' diagnostic and classification were made according to DSM-IV-TR criteria. Patients at the early stage of the disease presented lower iPLA2, sPLA2 and cPLA2 activity than the control group. Six weeks treatment with lithium did not change these activities. However, lithium reduced the maniac and depressive symptoms, evaluated with Hamilton and Young scales, respectively (p < 0.01, for both comparisons). Long-term treated patients presented similar PLA2 activities to control group. The results suggest that at the early stage of BD iPLA2 activity is decreased and that the adequate treatment of BD could reverse this reduction. We suggest that a reduction of iPLA2 activity at the early stage of BD can modify the membrane metabolism, and could be a risk for the development of dementia in BD patients.