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A research report submitted to the Faculty of Medicine, University of the Witwatersrand Medical School, in partial fulfilment of the requirements for the Degree Masters of Medicine in the branch of Psychiatry, Johannesburg, August, 2015 / Introduction Pharmacotherapy is a key component in the management of bipolar disorder. Whilst one might aim for fewer agents, not all patients with bipolar disorder can be stabilized with monotherapy and combination treatment (polypharmacy) is increasingly used to manage patients in clinical practice. Mood stabilizers have traditionally been prescribed as monotherapy, however the use of atypical antipsychotic agents is seen in clinical practice with various such agents approved for such usage. Combination treatment with an antipsychotic, preferably an atypical antipsychotic together with a standard mood stabilizer is also noted in clinical practice as well as recommended by guidelines. Bipolar patients managed in a specialist psychiatric setting have a greater chance of being managed with polypharmacy than in a general practice setting. The use of polypharmacy may also be attributed to receiving treatment in an academic environment. This current study was based on the application of diagnostic criteria and principles of the Diagnostic and Statistical Manual of Mental Disorders version IV TR (DSM IV TR), published by the American Psychiatric Association and The International Classification of Diseases version 10 (ICD 10), published by the World Health Organisation. Aims The study aims to describe the range and frequency of medications used in the management of bipolar bisorder in a specific setting as well as describe the nature and frequency of monotherapy versus polypharmacy use. Hypothesis The study hypothesized that the majority of patients attending the specialist / academic psychiatric outpatient clinic at Tara Hospital would be prescribed polypharmacy and that antipsychotics (typical or atypical) would be prescribed in combination with standard mood stabilizers in the majority of cases. Method The study took the form of a retrospective patient file review. The clinical files were for patients attending the Tara Hospital psychiatric outpatient clinic. The files of every patient who attended the clinic at least once in 2009 were screened and included in the study where the recorded ICD 10 code corresponded with a bipolar disorder subtype or a single manic or hypomanic episode. Where the recording of the ICD 10 code was missing or incomplete further scrutiny of the clinical notes enabled the researcher to establish a diagnosis of bipolar disorder using the ICD 10 and/ or DSM IV TR diagnostic criteria and therefore include the patient file in the study. Other necessary information was obtained by reviewing clinical notes as well as the prescription written on the last patient visit for 2009. Results The study found that the majority of patients (93.8%) were prescribed polypharmacy, with 3.2 the mean number of psychotropic medications prescribed per patient. Lithium was prescribed in 34.3% of patients. Sodium valproate was prescribed in 37.1% of patients. Eighty three point eight percent (83.8%) of the patients were prescribed at least one standard mood stabilizer. The atypical antipsychotics (46.6%) were prescribed more frequently than the typical antipsychotics (16.5%). Lamotrigine (31.8%) was the preferred novel anticonvulsant and the selective serotonin reuptake inhibitors (SSRI’s) were the most commonly prescribed antidepressant (28.9%). Clonazepam (26.8%) was the most frequently prescribed benzodiazepine add-on. The use of combination treatment to manage bipolar disorder was the rule rather than the exception. There was however much variety in the combinations used with no particular combination being prescribed in the majority of patients. Forty seven percent (47%) of the combinations used included a standard mood stabilizer and a typical or atypical antipsychotic. Conclusion The current study provides preliminary data on the prescribing patterns in bipolar disorder in a specialist psychiatric clinic within an academic complex in South Africa. The findings are in keeping with international studies and highlights that polypharmacy and combination treatment in the management of bipolar disorder is the norm in such settings. There is a large variation in clinician practices and much variety seen in the combinations of medications used to treat bipolar disorder despite the availability and use of treatment guidelines. This is perhaps because bipolar disorder is such a complex disorder and that most of the treatment recommendations are based on limited data. Treatment guidelines have emerged in order to attempt to standardize treatment and provide clinicians with algorithms to utilize and apply research findings in daily clinical practice. Further study into the effective prescribing principles for bipolar disorder is necessary.

O transtorno bipolar é um transtorno grave, geralmente associado a elevadas taxas de inatividade física e comorbidades clínicas relacionadas a essa condição. Os benefícios da prática regular de exercício físico para pessoas com transtorno bipolar são bem documentados. Tal prática é capaz de prevenir e auxiliar no tratamento dessas comorbidades, além afetar desfechos críticos para tais pacientes, como a adesão ao tratamento, funcionamento e qualidade de vida. Contudo, apesar dessas evidências, pessoas com transtorno bipolar tendem a ser mais sedentárias que a população em geral e pouco tem se investigado, do ponto de vista do paciente, sobretudo na população brasileira, quais são as barreiras e os facilitadores percebidos para tal prática. O objetivo deste estudo foi conhecer quais são as barreiras e os facilitadores percebidos por pessoas com transtorno bipolar para praticar exercício físico, a partir de uma abordagem qualitativa. Foram selecionados para este estudo, de forma intencional, indivíduos com diagnóstico de transtorno bipolar em atendimento no Programa de Transtorno Bipolar (PROTAHBI) e na unidade de internação psiquiátrica do Hospital de Clínicas de Porto Alegre que estivessem em condições de consentir com a pesquisa. Esses indivíduos participaram de uma entrevista em profundidade com questões abertas relacionadas à prática de exercício físico e os cuidados com saúde. A análise dos conteúdos emergidos nas entrevistas foi realizada a partir da Grounded Theory de Corbin e Strauss, e gerou quatro principais áreas de interesse: prática e trajetória de exercício, cuidados com a saúde, barreiras e facilitadores para a prática. Apesar dos potenciais benefícios da prática regular de exercício físico, constatamos que a maioria da nossa amostra não pratica regularmente. Isso indica que devemos conhecer as barreiras bem como os facilitadores percebidos por estas pessoas para praticar exercício físico a fim de viabilizar ofertas de atividades onde estes sujeitos possam participar e se beneficiar de maneira eficaz. / Bipolar disorder is a serious disorder, generally associated with levels of physical inactivity and rates of clinical comorbidities. The benefits of regular exercise practice for people with bipolar disorder are well documented. This practice is potentially capable of preventing and helping in the treatment of these comorbidities. Besides to affect relevant outcomes for patients, such as adherence to treatment, functioning and quality of life. However, in spite of this evidence, people with bipolar disorder tend to be more sedentary than the general population and little has been investigated from the viewpoint of the patients, especially in the Brazilian population, about the barriers and facilitators to such a practice. The aim of this study was to know what are the barriers and facilitators perceived for people with bipolar disorder to practice exercise, employing a qualitative approach. Individuals with diagnosis of bipolar disorder currently treated at the Bipolar Disorders Program (PROTAHBI) and at the psychiatric hospitalization unit of the Hospital de Clínicas de Porto Alegre, with conditions to provide consent for the study were purposefully selected. These individuals participated in an in-depth interview with open questions related to physical activity and health care. The interviews were recorded and transcribed. The analysis of the contents that emerged in interviews was analyzed using Corbin Strauss and Strauss’s Grounded Theory. The analysis pointed to 4 main areas of interest: practice and trajectory of exercise, health care, barriers and facilitators to practice. Despite the benefits of regular physical exercise, we noticed that most of our sample does not practice it regularly. This indicates the benefits of knowing the barriers and facilitators perceived by these people to practice exercise in order to facilitate the provision of activities where they can participate and benefit effectively.

Study one is a meta-analysis of the relationship between childhood adversity and bipolar disorder. The results suggest that individuals with bipolar disorder are 2.63 times more likely to experience childhood adversity than non-clinical controls. This effect remained significant even when controlling for bias and when considering epidemiological and case control studies separately. Levels of adversity in bipolar disorder were comparable to those observed in samples diagnosed with unipolar depression and schizophrenia. In adversity subtype analysis, emotional abuse conveyed the greatest risk of bipolar disorder with an odds ratio of 4.04. The results suggest that childhood adversity, particularly emotional abuse, may play an important role in the development of bipolar disorder. This challenges the notion that bipolar disorder is solely the result of a genetic predisposition. Study two is cross-sectional research investigating the association between childhood adversity and social functioning across the continuum of psychosis, and possible mediators of this relationship (i.e. attachment style, theory of mind ability, clinical symptoms). Fifty-four clinical and 120 non-clinical participants completed self-report questionnaires, interviews and tasks of theory of mind ability. The author used multiple group structural equation modelling to fit mediation models, whilst allowing for differential relationships across the samples. In the final model, only depression mediated the relationship between childhood adversity and social functioning. Childhood adversity did not significantly predict theory of mind ability in this data. The results suggest that psychosocial interventions for improving social functioning should also target low mood, particularly in individuals with a history of childhood adversity. Taken together this thesis suggests that childhood adversity can have long-reaching and negative effects on individuals' mental well-being. The author explores the wider clinical, academic and theoretical implications, and potential limitations, of the research in paper three. This section also contains the author's reflections on the research process and a justification of key methodological and analytical decisions.

Nas últimas décadas as pesquisas tem evidenciado o papel do sistema imune na fisiopatologia dos transtornos mentais. No Transtorno de Humor Bipolar (THB) os marcadores inflamatórios, destacando-se citocinas e neurotrofinas, tem recebido especial atenção. Citocinas pró-inflamatórias, anti-inflamatórias e BDNF (brain derived neurotrophic fator) encontram-se alterados em episódios agudos de humor, principalmente na mania. O balanço destas biomarcadores parece estar diretamente relacionado com a neuroprogressão da doença. Entretanto os estudos até o momento são predominantemente em adultos e, na maioria, com doença crônica. A investigação de biomarcadores em crianças e adolescentes com Transtorno Bipolar pode contribuir para o entendimento da fisiopatologia da doença. Objetivo: investigar o comportamento dos biomarcadores (IL-6, IL-10 e BDNF) em crianças e adolescentes com Transtorno Bipolar. Método: citocinas séricas e BDNF de 30 pacientes do Programa de Crianças e Adolescentes Bipolares (ProCAB) foram dosadas no momento do ingresso no programa e comparados com um grupo controle de crianças e adolescentes sem doenças psiquiátricas. Resultados: Não houve diferença significativa entre pacientes bipolares e controles em relação a IL-6, IL-10 e BDNF. As variáveis clínicas e metabólicas também não foram correlacionadas aos biomarcadores estudados. Conclusão: Diferentemente do que já está bem estabelecido na população adulta com THB, nosso estudo sugere que em crianças e adolescentes o THB não está associado a disfunção do sistema imune e alterações de neurotrofinas. A ausência de literatura nesta população torna importante mais estudos que possam auxiliar para o melhor entendimento da fisiopatologia do THB na população pediátrica. / Over the last decades, research has highlighted the role of the immune system in the pathophyisiology of mental disorders. In Bipolar Disorders the inflammatory biomarkers, highlighting the cytokines and neurotrophins, have received special attention. Proinflammatory, anti inflammatory cytokines and BDNF are altered in acute episodes of humor, mainly in mania. The balance among them seems to be directly related to the neuroprogression of the disease. Nonetheless the researches up to this moment are predominantly in adults and, in majority, with chronic disease. The investigation of this biomarkers in children and adolescents with Bipolar Disorder may contribute to the understanding of the pathophysiology of the disorder. Objective: to look through the biomarkers behavior (IL-6, IL-10 and BDNF) in children and adolescents diagnosed with Bipolar Disorder. Method: Serum cytokines and BDNF of 30 patients from ProCAB (Programa de Crianças e Adolescentes Bipolares) were dosed when the patients iniciated the program, and compared with a healthy control group. Results: There were no meaningful differences between bipolar patients and controls in relation to IL-6, IL-10 and BDNF. The clinical and metabolic variables have also been correlated to the biomarkers. Conclusion: Apart from what has already been established in the Bipolar Disorder adult population, our results suggest that in children and adolescents the disease is not associated to a disfunction of the imune system and neurotrophins alterarion. The lack of literature in this population makes it important for more studies to better undertand the pathophysiology of Bipolar Disorder in pediatric population.

Bipolar plates used in a PEM fuel cell must have high electric conductivity, good mechanical and chemical stability, low gas permeability, and low cost. For portable applications, lightweight and low volume should also be considered. Our laboratory has developed a new heterogeneous composite bipolar plate. Which has many advantages, such as low contact resistance, good chemical stability, low cost, lightweight and high performance. Since automation is the key to low cost, this research is to develop the automatic fabrication process of the new plate. The process involves mainly the making of carbon fiber bunches by sticking the central portion of the carbon fiber together with glue but leaving both ends free. Secondly, use injection molding to form the plastic main body with all the carbon fiber bunches. In order to shorten the developing time, we divide the process into four parts: (1) the unfolding of carbon fiber (2) the automation of gluing (3) harden and cutting to sizes (4) Injection molding of bipolar plates. This thesis has completed the study of the first three parts of the manufacturing processes. We have compared the contact resistances between our product and the previously handmade ones and found that the results are satisfactory.

Objective: Primarily, to determine if affective Theory of Mind (ToM) decoding differs between patients with bipolar disorder who are experiencing mania, euthymia, or depression. Secondarily, to determine if a bias in ToM in patients experiencing different affective episodes is related to a positive, negative, or neutral valence of the target. Finally, to determine if mental state decoding is related to the severity of depressive, manic, or anxious symptoms Methods: A prospective, cross-sectional, study of ToM in patients with bipolar disorder experiencing mania (n = 14), depression (n = 25), or euthymia (n = 20), using the “Reading the Mind in the Eyes Task” (Eyes Task) and the Animal Task developed to control for nonsocial response demands of the Eyes Task. Measures of depressive and anxious symptoms were taken using self-report scales. Interview measures of depressive and manic symptoms were also conducted. A review of patient records was conducted to collect information regarding medications, and course of illness variables. Results: Patients experiencing mania were significantly impaired in mental state decoding compared to euthymic and depressed patients with bipolar disorder. No significant difference was observed between the depressed and euthymic groups. These relationships were maintained when controlling for age of illness onset and Animal Task accuracy. No effect of valence was found. Manic symptom severity was negatively correlated to Animal Task accuracy but no other relationships between Eyes and Animal Tasks and the severity of manic, depressive, or anxious symptoms were found. Group differences in Eyes Task performance were not due to differences in demographics, axis I comorbidities, history of psychosis, or course of illness measures. Limitations: The sample was too small to assess differences between acutely and chronically ill patients. There was no assessment of neurocognition or intelligence using tasks previously validated with manic patients. Conclusions: Patients with bipolar disorder experiencing mania were significantly impaired in mental state decoding compared to patients who were depressed or euthymic. The deficit in ToM decoding in manic patients independent of indicators of illness severity may be indicative of qualitative differences in interpersonal dysfunction between mania, depression, and euthymia in patients with bipolar disorder. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2011-02-10 13:18:17.667

Objective: To primarily determine the effect of ziprasidone augmentation therapy on sleep architecture, specifically slow wave sleep (SWS) and rapid eye movement sleep (REM), in the treatment of bipolar depression. Secondarily, to determine the effect of ziprasidone augmentation treatment on clinical measures of subjective sleep quality and illness severity. Finally, to examine the correlation between change in sleep architecture and change in clinical measures. Methods: This was a prospective, double-blind, randomized, placebo-controlled study. 14 patients with bipolar disorder currently experiencing a major depressive episode were included. Patients were on a stable medication regime for 4 weeks prior to study enrollment and throughout the study. Sleep architecture was measured by overnight, ambulatory polysomnography. Subjective sleep quality was assessed using the self-reported Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and a visual analogue scale. Illness severity was determined using the 17 item Hamilton Depression Rating Scale (HAMD-17), the Montgomery Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAMA) and the Clinical Global Impression-Severity scale (CGI-S). Polysomnographs and clinical measures were administered at baseline, after 2-5 days and after 28-31 days of treatment. Results: There was no significant difference between ziprasidone and placebo treated groups on age, gender, diagnosis, education level, employment or marital status and number of children. Duration of SWS, latency to REM, duration of stage 2 sleep, total sleep time, onset to sleep latency, sleep efficiency and number of awakenings significantly improved in ziprasidone treated participants over placebo, whereas duration of REM sleep did not. CGI-S and HAMA scores were significantly improved with ziprasidone treatment. No significant difference between treatment groups was seen on the HAMD-17 and MADRS or in self-reported sleep quality. Change in REM sleep significantly correlated to change in subjective sleep quality in the ziprasidone group. Conclusion: Ziprasidone augmentation treatment in bipolar depression improves SWS duration, REM latency, and sleep continuity while also having a beneficial effect on overall illness severity and anxiety symptoms. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2011-08-02 17:39:05.883

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Almost all neuropsychological studies of adult bipolar disorder (BP) have failed to control for the established cognitive effects of attention deficit hyperactivity disorder (ADHD), and often other covariates. ADHD comorbidity in BP is common, and has already been shown to significantly worsen the clinical presentation of BP. This study of young adults (16 - 34 years) aimed to establish whether ADHD and BP with childhood ADHD groups had more impaired cognitive profiles (after controlling for numerous covariates) relative to BP without childhood ADHD and control groups. Using recognised structured and semi-structured clinical interviews and symptom rating scales, BP with (n = 18) or without (n = 66) childhood ADHD groups were recruited from a therapy study, and ADHD (n = 27) and control (n = 26) groups were recruited from the community. Participants completed tests (some from the Cambridge Neuropsychological Test Automated Battery) of executive functioning, memory, attention and psychomotor speed. MANCOVA results for cognitive performance indicated that the BP with childhood ADHD group did not differ significantly from the other three groups (except on a test of visual object memory, where it outperformed the ADHD group). The ADHD group was impaired relative to the BP without childhood ADHD and control groups on measures of verbal and visual memory. It was also more impaired than controls on a measure of attention. The BP without childhood ADHD group had visual memory and attention difficulties relative to controls. Compared to BP (controlling for ADHD), ADHD is associated with a more diverse range of cognitive impairment. Nevertheless, individuals with BP may independently demonstrate memory and attention difficulties which have the potential to interfere with treatment and day-to-day functioning.