Bipolar disorder is characterised by intense fluctuations in mood, including the experience of severe episodes of depression, mania and hypomania. The experience of bipolar disorder can also be associated with biases in various cognitive processes, including rumination in response to positive and negative mood states and tendencies to make dysfunctional self-appraisals. Preliminary research has also suggested that bipolar disorder may be associated with deficits in the recall of specifically detailed autobiographical memories. The lack of specificity in the recall of autobiographical memories, known as the 'overgeneral' recall bias, refers to tendencies to generate generalised memory representations as the memory recall process is terminated prior to the activation of specifically detailed memories. This overgeneral recall of autobiographical memories can also contribute to ruminative thought patterns, impair the generation of effective solutions to problems, and is associated with poor illness outcomes. The overgeneral bias has been extensively researched within major depressive disorder and suicidality, but has been comparatively under-researched in bipolar disorder and in vulnerable individuals. A series of eight studies were designed to: (i) investigate the cross-sectional associations across measures of positive and negative rumination and self-appraisal with the vulnerability to hypomania, and investigate the associations of these cognitive styles with prospective mood symptoms in an at-risk sample; (ii) investigate the cognitive vulnerability to hypomania in relation to rumination, problem-solving and autobiographical memory specificity; (iii) conduct a preliminary investigation into the associations between goal-related memory processes and extreme goal-pursuit in relation to hypomania vulnerability; (iv) investigate whether the vulnerability to hypomania and future bipolar disorders is associated with similar patterns of overgeneral memory recall on a standardised cue memory task; and (v) investigate the patterns of autobiographical memory specificity within a remitted bipolar sample. The heightened vulnerability to future bipolar disorders was associated with tendencies to engage in both positive and negative forms of ruminative thought processes, and with poorer psychosocial problem-solving, however, this relationship with problem-solving was not independent of current mood symptoms. The results of two studies indicated that the heightened vulnerability to hypomania was associated with an overgeneral memory bias across two different assessments of memory specificity, in direct contrast to previous research. Individuals diagnosed with bipolar disorder also reported more extreme overgenerality during memory recall than a sample of age and gender-matched healthy controls, but were able to recall some specifically detailed negative memories in short response latencies compared to non-bipolar control participants. The research presented within this thesis supports the notion of a continuum of increasing overgenerality in the bipolar disorder spectrum, inclusive of at-risk individuals to people formally diagnosed with bipolar disorder. Although bipolar disorder appears to be associated with a trait-based overgeneral memory bias, bipolar individuals appear to have ready access to some specific negative memories even during remission from symptoms. The clinical implications of this research, methodological considerations in the assessment of memory specificity, and directions for further investigations into the nature of autobiographical memory recall in bipolar spectrum disorders are discussed.

This thesis investigated the experiences of children who have a parent with a mental illness, using qualitative methods. It is divided into three separate sections, the first two written as standalone journal papers. Paper 1 is a systematic review and synthesis of qualitative studies exploring children's experiences of having a parent with a mental illness. The review used specific databases, a search of qualitative journals and a general internet search to identify relevant studies, and the subsequent application of inclusion/exclusion criteria and a quality appraisal assessment. 14 studies meeting inclusion and quality criteria were identified exploring the experiences of 163 children and young people aged between 5 and 22 years, from a range of countries, with a variety of parental mental health diagnoses. The review then involved synthesising the findings of these studies to generate five overarching themes which were found to influence children's experiences. Children who had some knowledge and understanding of their parent's mental illness were more likely to use effective coping strategies, have a more positive relationship with their parent, and experience fewer negative effects on them as a child. Paper 2 is an original research study which explored the experiences of children who have a parent with bipolar disorder, to see how this might impact on the child's emotional wellbeing. This qualitative study used 'In My Shoes', a computer assisted interview tool, to explore the experiences of ten children from England aged between 4 and 10 years. Subsequent comparison with their parent's accounts enabled greater insight into family life. Child and parent interview data was analysed using thematic and content analyses. The four main themes that emerged from the child interviews were: knowledge and awareness of bipolar disorder; perception of parents; managing family life with a 'bipolar' parent; and living in a family with bipolar disorder. The study concluded that further research was needed to understand children's perspectives, which should be taken into account when developing appropriate services and interventions to support children and parents with mental illness, including bipolar disorder. Finally the third section of the thesis was a critical appraisal of the literature review, research study and research process as a whole, including methodological reflections, implications for future research and clinical practice, and the researcher's personal reflections in undertaking the research. The findings were deemed vitally important for the future of families in which a parent has bipolar disorder.

The purpose of the current study was to examine neuropsychological functioning in patients with bipolar disorder (BD) with psychotic features. Data from a large, epidemiological study of patients with first-episode psychosis was used to examine verbal learning and working memory 10 years after onset of psychosis in patients with BD relative to patients with schizophrenia (SZ) and patients with psychotic major depressive disorder (MDD). Cross-sectional comparisons of verbal learning and working memory at the 10-year follow-up mirrored findings of relative performance at the 2-year follow-up (Mojtabai, 2000), as patients with SZ performed significantly worse than patients with psychotic affective disorders. When FEP patients' cognitive performance was examined longitudinally, all groups showed non-significant decline over time, with no significant diagnostic group differences after accounting for current symptoms. More frequent hospitalizations and longer treatment with antipsychotics were associated with poorer performance on cognitive testing 10 years after illness onset, but these associations disappeared when controlling baseline cognitive performance. Within the BD sample, current positive and negative psychotic symptoms were associated with poorer performance on cognitive testing. After controlling for baseline cognitive performance, markers of clinical course were unrelated to cognitive performance, consistent with existing literature on longitudinal cognitive functioning in patients with BD. The current findings support a neurodevelopmental model of verbal learning and working memory deficits in patients with bipolar disorder.

There is generally a lack of studies examining prevalence and phenomenology of bipolar disorder in Africa. In literature, a unipolar manic course of illness in particular is reported to be rare. The purpose of this study was to investigate and describe the course of illness and clinical features in a cross-section of patients diagnosed with bipolar disorder attending public hospitals in Limpopo Province, South Africa and to determine the rate of a unipolar manic course in this sample of patients. This was a descriptive, cross-sectional study of patients presenting with a history of mania between October 2009 and April 2010, to three hospitals in Limpopo Province. A purposeful sample of 103 patients was recruited and interviewed using the Affective Disorders Evaluation. This study confirms that a unipolar manic course is indeed much more common than rates suggested in present day literature with57% of the study sample only ever experiencing manic episodes. The study also confirms the debilitating nature of bipolar disorder with more than two-thirds being unemployed in spite of a quarter of the study subjects having a tertiary education. The high rates of attempted suicide, history of violence and history of drug abuse all furthermore points to the devastating effects bipolar disorder has on individuals and their families. Treatment choice appeared to be a combination of a mood-stabilising agent in combination with an anti-psychotic. It was found that two-thirds of study subjects had consulted with faith- or traditional healers. Significant gender differences appeared in that females were more likely to suffer from comorbid anxiety disorders, have a history of sexual trauma, and be HIV positive whilst men were more likely to have a forensic- and substance-abuse history, experience hallucinations and receive clozapine. Patients presenting with a unipolar manic course of illness, as described in this thesis, may contribute to the search for an etiologically homogeneous sub-group which presents unique phenotype for genetic research and the search for genetic markers in mental illness. A unipolar manic course therefore needs to be considered as a specifier in diagnostic systems in order to heighten the awareness of such a course of illness in bipolar disorder, with a view to future research. / Thesis (MD)--University of Pretoria, 2012. / Psychiatry / unrestricted

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TOPIC. Advances in the psychopharmacologic treatment of bipolar affective disorders (BPAD). PURPOSE. To increase advanced practice nurses' ability to match prescribing practices with known etiological factors and the neurobiology of this complex set of disorders. SOURCES. Published literature. CONCLUSIONS. A wide array of pharmacological agents exist that can be useful to manage BPAD symptoms. APRNs play a critical role in helping patients and their families to use these drugs effectively.

Altered intracellular calcium homeostasis and oxidative stress are involved in the pathophysiology of bipolar disorder (BD)-I. To explore the genes contributing to these abnormalities, we examined the association with BD of the iPLA2β (PLA2G6), a signaling enzyme that mobilizes the arachidonic acid signaling cascade and activates oxidative stress, and assessed whether it interacts genetically with type 2 transient receptor potential channel gene (TRPM2), an oxidative stress-responsive calcium channel implicated both functionally and genetically in BD-I. Two tag single nucleotide polymorphisms rs4375 and rs3788533 in iPLA2β were genotyped in 446 White case-control individuals and 296 BD families using a 5′-nuclease TaqMan assay. The results were analyzed using χ-test and transmission disequilibrium tests, and Haploview. In a secondary analysis, we tested gene-gene interactions between TRPM2 and iPLA2β on BD vulnerability by logistic regression using a case-only design in PLINK. iPLA2β-rs3788533 showed a borderline association with BD-I in patients with a history of psychosis in both case-control and family designs. Association with BD as a whole was observed in the family study (significant over transmissions of rs3788533-allele C, P=0.015, PBonferroni=0.03, TDTPHASE). A borderline interaction was found between rs749909 within TRPM2 and rs4375 within iPLA2β (Puncorrected=0.009), on the basis of the case-only design analyzed with PLINK. A significant association of iPLA2β variants with BD-I and a trend gene-gene interaction between iPLA2β and TRPM2 provides additional support for the notion that genetic variation in these two functionally implicated candidates contributes toward the risk and pathophysiology of this illness.

Background: Previous reports have suggested that there may be gene×gender interaction for bipolar disorder (BD)-associated genes/loci at 22q11-13. This study aimed to investigate the associations of SEZ6L genetic variants with bipolar disorder I (BD-I) and to examine gender-specific genetic associations. Methods: 605 BD-I Caucasian cases and 1034 controls were selected from the publicly available data of the Whole Genome Association Study of BD. To increase power, an additional 362 Caucasian controls were added to this study from the Genome-Wide Association Study of Schizophrenia. In total, 605 BD-I cases and 1396 controls (934 males and 1067 females) were available for genetic association analysis of 118 SNPs within the SEZ6L gene using PLINK software. Results: 16 SNPs showed significant gene x gender interactions influencing BD-I (P<0.01). In addition, significant differences in the distribution of the alleles for these 16 SNPs were observed between the female BD-I patients and healthy controls (P<0.015) but no significant associations were found for the male sample (P>0.05). The SNP rs4822691 showed the strongest association with BD-I in the female sample (P=2.18×10-4) and the strongest gene×gender interaction in influencing BD-I (P=9.16×10 -5). Limitations: The findings of this study need to be replicated in independent samples. Conclusions: This is the first demonstration that genetic variants in the SEZ6L gene are associated with BD-I in female patients and provides additional compelling evidence for genetic variation at 22q11-13 that influences BD-I risk. The present findings highlight the gene x gender interactions modifying BD-I susceptibility.

Altered intracellular calcium homeostasis and oxidative stress are involved in the pathophysiology of bipolar disorder (BD)-I. To explore the genes contributing to these abnormalities, we examined the association with BD of the iPLA2β (PLA2G6), a signaling enzyme that mobilizes the arachidonic acid signaling cascade and activates oxidative stress, and assessed whether it interacts genetically with type 2 transient receptor potential channel gene (TRPM2), an oxidative stress-responsive calcium channel implicated both functionally and genetically in BD-I. Two tag single nucleotide polymorphisms rs4375 and rs3788533 in iPLA2β were genotyped in 446 White case-control individuals and 296 BD families using a 5′-nuclease TaqMan assay. The results were analyzed using χ-test and transmission disequilibrium tests, and Haploview. In a secondary analysis, we tested gene-gene interactions between TRPM2 and iPLA2β on BD vulnerability by logistic regression using a case-only design in PLINK. iPLA2β-rs3788533 showed a borderline association with BD-I in patients with a history of psychosis in both case-control and family designs. Association with BD as a whole was observed in the family study (significant over transmissions of rs3788533-allele C, P=0.015, PBonferroni=0.03, TDTPHASE). A borderline interaction was found between rs749909 within TRPM2 and rs4375 within iPLA2β (Puncorrected=0.009), on the basis of the case-only design analyzed with PLINK. A significant association of iPLA2β variants with BD-I and a trend gene-gene interaction between iPLA2β and TRPM2 provides additional support for the notion that genetic variation in these two functionally implicated candidates contributes toward the risk and pathophysiology of this illness.