Thesis (MMed in Psychiatry) -- University of Limpopo, 2010 / Background: Bipolar disorder is a lifelong illness typically presenting with frequent relapses and/or recurrences. Bipolar disorder carries a high morbidity and mortality and can cause significant functional impairment. In understanding the relapsing course of the illness, chronicity may be reduced by preventing or delaying the occurrence of new episodes. Objectives: The objectives of this study were to establish the prevalence of new episodes in patients with bipolar I disorder and to determine predictors of new episodes. Methods: This was a retrospective, descriptive study based on the review of medical records of patients with bipolar I disorder seen at Dr. George Mukhari Hospital – psychiatry unit between the period of 1 June 2007 to 1 June 2008. Data concerning sociodemographic parameters of the patients and psychiatric information was collected using a data collection sheet. Results: Data was extracted and analysed from a total of 143 patient records. Ninety (63%) experienced new episodes and fifty-three patients (37%) did not have any new episodes. Seventy-nine patients (55%) had one or more manic episodes (mean=0.64) and nineteen (13.38 %) had one or more depressive episodes. (Mean=0.14). The maximum number of new episodes was 2 and the mean was 0.78. The most recent episode was manic in seventy-six patients (84%). The mean number of hospital admissions was 0.88. Of the patients that had new episodes, the age ranged from 18 to more than 55 years, the vast majority were black (94%) and of Christian faith (97%). More than half were female (58%) and single (49%), with 1-2 children (48%). The majority achieved high school education (60%), and were unemployed (70%). Only 47% were receiving a disability grant. New episodes were more prevalent in patients who experienced a younger age of onset of illness (41% in the 18-24 year age group) and who were ill for more than ten years (43%). Less than half had a positive family history of mental illness (43%), 39% had a history of substance use, the most common substance being alcohol (54%), and 39% suffered from one or more comorbid medical illnesses. 78% of the patients who had new episodes were on antipsychotics, 93% were on mood stabilisers, and 69% were on a xii combination of mood stabilisers and antipsychotics. The only factor that was significantly predictive of new episodes was poor compliance. Conclusion: There is a high prevalence of relapse in patients with bipolar I disorder, particularly to the manic pole. Compliance with medication remains a serious problem and is associated with the occurrence of new episodes. Improved treatments should include biopsychosocial strategies, identification of risk factors for relapse/recurrence and early and consistent intervention.

Thesis (M Med (Psychiatry))University of Limpopo (Medunsa Campus), 2010. / Background: Bipolar disorder is a lifelong illness typically presenting with frequent relapses and/or recurrences. Bipolar disorder carries a high morbidity and mortality and can cause significant functional impairment. In understanding the relapsing course of the illness, chronicity may be reduced by preventing or delaying the occurrence of new episodes. Objectives: The objectives of this study were to establish the prevalence of new episodes in patients with bipolar I disorder and to determine predictors of new episodes. Methods: This was a retrospective, descriptive study based on the review of medical records of patients with bipolar I disorder seen at Dr. George Mukhari Hospital – psychiatry unit between the period of 1 June 2007 to 1 June 2008. Data concerning sociodemographic parameters of the patients and psychiatric information was collected using a data collection sheet. Results: Data was extracted and analysed from a total of 143 patient records. Ninety (63%) experienced new episodes and fifty-three patients (37%) did not have any new episodes. Seventy-nine patients (55%) had one or more manic episodes (mean=0.64) and nineteen (13.38 %) had one or more depressive episodes. (Mean=0.14). The maximum number of new episodes was 2 and the mean was 0.78. The most recent episode was manic in seventy-six patients (84%). The mean number of hospital admissions was 0.88. Of the patients that had new episodes, the age ranged from 18 to more than 55 years, the vast majority were black (94%) and of Christian faith (97%). More than half were female (58%) and single (49%), with 1-2 children (48%). The majority achieved high school education (60%), and were unemployed (70%). Only 47% were receiving a disability grant. New episodes were more prevalent in patients who experienced a younger age of onset of illness (41% in the 18-24 year age group) and who were ill for more than ten years (43%). Less than half had a positive family history of mental illness (43%), 39% had a history of substance use, the most common substance being alcohol (54%), and 39% suffered from one or more comorbid medical illnesses. 78% of the patients who had new episodes were on antipsychotics, 93% were on mood stabilisers, and 69% were on a xii combination of mood stabilisers and antipsychotics. The only factor that was significantly predictive of new episodes was poor compliance. Conclusion: There is a high prevalence of relapse in patients with bipolar I disorder, particularly to the manic pole. Compliance with medication remains a serious problem and is associated with the occurrence of new episodes. Improved treatments should include biopsychosocial strategies, identification of risk factors for relapse/recurrence and early and consistent intervention.

Thesis (doctoral)--Universität Hamburg, 1978.

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.

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

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.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O Transtorno Afetivo Bipolar (TAB) à uma doenÃa crÃnica, altamente incapacitante e associada a custo excessivo aos sistemas de saÃde. Atualmente, reconhece-se o papel importante da Angiotensina II em transtornos de ansiedade e humor. A desregulaÃÃo do Sistema renina-angiotensina (SRA) cerebral pela ativaÃÃo de receptores da angiotensina II subtipo 1 (AT1Rs) està associada à formaÃÃo de espÃcies reativas de oxigÃnio, ativaÃÃo de vias prÃ-inflamatÃrias, reduÃÃo da neuroplasticidade e disfunÃÃo mitocondrial, estando esses eventos relacionados com a fisiopatologia do TAB. Assim, objetivou-se avaliar a aÃÃo da candesartana (CDS) em um modelo animal de mania induzido por d-anfetamina (AMPH). Utilizou-se camundongos Swiss machos (peso: 20-25g) submetidos a dois protocolos de tratamento. No protocolo de prevenÃÃo (PP), os animais receberam CDS (0,1; 0,3; 1 ou 3 mg/Kg/dia), lÃtio (47,5 mg/Kg/dia) ou veÃculo por 14 dias e entre o 8 e o 14 dia receberam AMPH (2 mg/Kg/dia i.p) ou salina. No protocolo de reversÃo (PR), administrou-se AMPH ou salina por 14 dias e entre o 8 e o 14 dia os animais foram tratados com CDS, lÃtio ou veÃculo. No 14 dia, os animais foram submetidos aos testes comportamentais, campo aberto e Y Maze. Foram realizadas anÃlises neuroquÃmicos para avaliar o estresse oxidativo (TBARS e GSH) no vÃrmis cerebelar (VC), cÃrtex prÃ-frontal (PF), hipocampo (HPC) e corpo estriado (CE). AlÃm disso, foram avaliados os nÃveis de BDNF, TNF-α e fosfo-Ser9-GSK-3β para as doses de 0,3 e 1 mg/Kg de CDS. Os nÃveis de fosfo-Ser9-GSK-3β e BDNF foram avaliados apenas no HPC e os nÃveis de TNF-α no HPC e VC. Em ambos os protocolos de tratamento, observou-se aumento da atividade locomotora nos grupos que receberam apenas AMPH, que foi prevenida e revertida pela CDS. Os resultados obtidos nos animais tratados com CDS + AMPH foram semelhantes aos do grupo controle e dos animais que receberam LÃtio + AMPH. No teste de Y maze, a CDS conseguiu prevenir e reverter o prejuÃzo cognitivo causado pela AMPH e apenas as doses de CDS 0,1 no PP e 0,3 no PR nÃo tiveram efeito, assim como o tratamento com lÃtio em ambos os protocolos. A CDS aumentou os nÃveis de GSH no HPC e VC no PP e no PF, HPC e CE no PR. Os nÃveis de TBARS foram reduzidos pela CDS no PF, HPC e VC no PP e no PF, HPC e CE no PR. Em ambos os protocolos de tratamento, a AMPH reduziu os nÃveis hipocampais de BDNF e o lÃtio e ambas as doses de CDS avaliadas restauraram os nÃveis dessa neurotrofina. No PP, a AMPH e ambas as doses de CDS reduziram o nÃvel de fosfo-Ser9-GSK-3β que foi expressivamente aumentado pelo lÃtio. Os nÃveis de TNF-α foram aumentados pela AMPH e reduzidos pelo lÃtio no HPC e VC. Ambas as doses de CDS avaliadas tiveram efeito na prevenÃÃo do aumento de TNF-α no HPC e preveniram e reverteram esse aumento no VC. Juntos, os dados mostraram que a CDS, semelhante ao Li, à efetiva na prevenÃÃo e reversÃo de alteraÃÃes comportamentais e neuroquÃmicas induzidas pela AMPH, com exceÃÃo da fosfo-Ser9-GSK-3β, sugerindo que estudos sejam desenvolvidos para avaliaÃÃo da atividade antimanÃaca desse fÃrmaco em pacientes bipolares, porÃm mais estudos prÃ-clÃnicos sÃo necessÃrios. / The Bipolar Disorder (BD) is a highly prevalent and chronic psychiatric disorder, associated with functional disability and excessive cost to the health system. The pharmacological therapy of BD displays low efficacy due the complex and poorly understood etiology, which makes it imperative to find new therapeutic targets for this disorder. The renin-angiotensin system (RAS) has been studied concerning neurological diseases, and is currently recognized important role of angiotensin II in anxiety and mood disorders. The deregulation of SRA brain is associated with the formation of reactive oxygen species, activation of proinflammatory pathways, reduced neuroplasticity and mitochondrial dysfunction. It is noteworthy that all these events are related to the pathophysiology of BD. Thus, this study aimed to evaluate the effect of candesartan (CDS) in an animal model of mania induced by d-amphetamine (AMPH). The animals were submitted to two treatment protocols. In prevention protocol, animals received CDS (0.1; 0.3; 1 or 3 mg/kg/day), lithium (47.5 mg/kg/day) or vehicle for 14 days and between the 8th and 14th day received AMPH (2 mg/kg/day ip) or saline. In reversal protocol, was administered AMPH or saline for 14 days and between the 8th and 14th day the animals were treated with CDS, lithium or vehicle. The effect of CDS was evaluated on 14th day by exploratory behavior of animals in the open field test used for pre-clinical study of antimanic drugs. The working memory was also evaluated by Y Maze test. Neurochemical analisis of oxidative stress (TBARS and GSH), was assessed in cerebellar vÃrmix (CV), prefrontal cortex (PF), hippocampus (HPC) and striatum (ST). For evaluate the levels of BDNF, TNF-α e fosfo-Ser9-GSK-3β,we used CDS 0,3 and CDS 1. BDNF and fosfo-Ser9-GSK-3β was assessed only in HPC and TNF-α in HPC and CV. In both treatment protocols, there was an increase in locomotor activity in the animals that received only AMPH, which was prevented and reversed by CDS, whose results were similar to the control group and the animals that received AMPH and lithium. In the memory test, the CDS prevented and reversed the cognitive impairment caused by AMPH and only the CDS doses of 0.1 in prevention protocol and 0.3 in reversal protocol were not successful. Lithium treatment neither prevented nor reversed the cognitive impairment. The CDS increased GSH levels in HPC and CV in the prevention protocol and in PF, HPC and ST in the reversal protocol. The TBARS levels were reduced by CDS in PF, HPC and CV in the prevention protocol and in PF, HPC and ST in the reversal protocol. However, MDA level was increased by higher dose of CDS in ST in prevention protocol and by the two lower doses of CDS in CV in reversal protocol. In both treatment protocols, AMPH reduced BDNF and lithium and both doses of CDS restored the levels of this neurotrophin. In the prevention protocol, AMPH and both doses of CDS reduced the level of phospho-Ser9-GSK-3β that was significantly increased by lithium. The levels of TNF-α were increased by AMPH and reduced by lithium in HPC and VC. CDS prevented the increase of TNF-α in HPC and prevented and reversed this increase in CV. Our findings showed that CDS, similarly to Li, is effective in reversing and preventing AMPH-induced behavioral and neurochemical alterations, providing a rationale for evaluating CDS as a novel antimanic agent, however new pre-clinical studies are necessary.

No description available.

Bipolar Disorder (BD) is a debilitating mental illness that presents as mood alterations between manic and depressive states. There remain large gaps in the knowledge surrounding the disease, due to three main issues in understanding the illness. First is a lack of an appropriate animal model that mimics both manic and depressive symptoms. Second is a lack of knowledge on the biological cause of the disease. Finally, a lack of knowledge on the precise mechanism of action of lithium (Li), the main treatment for BD prevents more progressive research into the disease. Inflammation and a subsequent disruption of the blood-brain barrier (BBB) have recently been demonstrated in other psychiatric conditions, such as Alzheimer’s Disease (AD) and Schizophrenia (SZ). This mechanism remains to be fully investigated in BD. This thesis presents an inflammatory model of BBB disruption in rodents. A study examining gene expression in discordant sibling pairs with SZ or BD discovered that the Max gene was elevated two-fold in bipolar patients as compared to their non-BD siblings. We aim to elucidate on these findings and examine the effect of common BD treatments on Max gene expression. The first study utilized lipopolysaccharides (LPS) to induce an inflammatory response in the BBB, and sodium fluoroscein (NaF) to measure the levels of resulting disruption. It was shown that Li is unable to attenuate disruption of the BBB, and an LPS administration with Li pretreatment causes higher disruption than either substance alone in several brain regions. The second study examined Max gene expression levels in naïve rats as a result of Li or valproate (VPA) treatment. VPA was shown to significantly downregulate the expression of Max in a rodent model. These studies may provide insight into understanding the pathophysiology of BD, leading to better, more accurate animal models and more targeted therapies for the disorder. / Thesis / Master of Science (MSc)

Bipolar disorder (BD) is a chronic and often progressive illness that has a significant impact on quality of life and functioning. Pharmacological treatments are not effective for all patients, emphasizing the need to better understand the pathophysiology of the disorder. It is well known that patients with BD present with increased levels of inflammatory markers during mood episodes and often exhibit chronic low grade inflammation, implicating the immune system in the etiology of the disorder. Furthermore, patients with BD show deficits in neurotrophic factors suggesting that alterations in neurogenesis may precipitate clinical features. Recent evidence indicates that accelerated aging processes may underlie the pathophysiological changes observed in BD, implicating biomarkers related to aging. The chemokine C-C motif chemokine 11 (CCL11) and the cytokine growth differentiation factor 11 (GDF11) have been identified as proteins that increase and decrease with age, respectively. As such, this thesis presents research examining serum levels of these proteins in drug-naive young adults with BD and a matched healthy control group. We analyzed serum levels of CCL11 and GDF11 using enzyme linked immunosorbent assay (ELISA). Our results indicate that serum levels of CCL11 and GDF11 do not differ between the BD group and the healthy control group, however CCL11 levels were elevated in males and in individuals with tobacco abuse/dependence when considering the entire sample. Our results suggest that serum levels of these proteins do not differ between drug-naive young adults with BD and healthy controls, but that alterations may be due to demographic and lifestyle factors. Small sample size and low power should be considered when interpreting these results. / Thesis / Master of Science (MSc)