Bipolar affective disorder and schizophrenia are highly heritable psychiatric illnesses and the leading causes of worldwide disability. The orbitofrontal cortex (OFC) is a region of the frontal lobe with wide spread connectivity with other brain areas involved in reward, motivation and emotion. Evidence from various neuroimaging, genetic, post-mortem and brain lesion studies suggest that orbitofrontal cortex may play a role in pathophysiology of mental illnesses. This thesis sought to investigate the pathogenesis of major psychiatric illnesses through the investigation of orbitofrontal morphology in schizophrenia and bipolar disorder and through its associations with brain structure and function. Orbitofrontal morphology and its structural and functional associations were examined in healthy controls, patients with schizophrenia or bipolar affective disorder, and those at high genetic risk using functional and structural MRI. In the first study we found that the orbitofrontal type III is more frequent and the orbitofrontal type I is less common in the right hemisphere in patients with schizophrenia while in patients with bipolar disorder type III appears more often in both left and right hemispheres. We then sought to examine the relationship of orbitofrontal morphology to disease risk in a study of 146 people at high risk of developing schizophrenia and 110 people at high risk of developing bipolar disorder. We discovered that in the unaffected high risk groups the orbitofrontal type III predicted the development of later psychiatric illnesses, when combined with anterior cingulate morphology. Finally we showed, in a further study, that OFC morphology was associated with measures of schizotypy, brain structure, brain function and cognition. In conclusion, orbitofrontal morphology is linked to major psychiatric disorder and has significant structural and functional associations. As orbitofrontal sulcogyral patterns are formed in early life a fuller awareness of their relevance to brain function holds out the prospect that we could use such measures as an indicator of vulnerability to the development of illness later in life. This work points to the potential for the foundation of a theory of predictive associations between morphological patterns and the development of psychosis.

Bipolar disorder is associated with significant social and occupational impairments, as well as increased risk for substance abuse and suicide. More research is needed to identify potential mechanisms associated with vulnerability to the disorder. Previous research has identified altered processing of emotional information in bipolar and bipolar-prone individuals, including attentional biases which appear to differ based on the current affective state of the individual. The current study applied a sensitive measure of attention (i.e., eye-tracking) to assess whether vulnerability to bipolar disorder, as indexed by hypomanic personality traits, would be correlated with biases in attention to emotional facial stimuli, independent of mood state. Hypomanic personality traits were hypothesized to be associated with greater attention to happy and angry faces, as indexed by faster initial orientation, more frequent gazes, and longer gaze duration for these stimuli. Participants completed self-report measures assessing current mood symptoms, positive and negative affect, and hypomanic personality traits. They then completed two tasks assessing attention for emotional faces. The first was an eye-tracking task, which measured latency to first fixation, total gaze duration and total number of gazes for each emotional face category. The second was a spatial cueing task which assessed both attentional engagement with emotional faces, and ability to disengage attention from this material. Hypomanic personality traits were significantly negatively correlated with latency to orient attention to happy faces. A trend toward decreased latency to orient to angry faces with higher hypomanic personality traits was also demonstrated. Hypomanic traits were not correlated with attention to sad faces. Furthermore, hypomanic traits were associated only with differences in initial orientation of attention, not with continued engagement or disengagement. The results of this study suggest that individuals with higher levels of hypomanic personality traits, who are hypothesized to be at greater risk of developing bipolar disorder, are characterized by differences in their initial orientation of attention to positive emotional stimuli, independent of their current mood state. This finding is indicative of biased information processing in individuals with vulnerability to bipolar disorder. Such a bias may have important clinical implications for individuals with a vulnerability to bipolar disorder, as it may represent a mechanism by which vulnerability leads to increased, and at times problematic, engagement with rewarding stimuli.

A dissertation submitted to the Faculty of Medicine in part fulfilment of the requirements for the Degree of Master of Medicine in Psychiatry at the University of the Witwatersrand. Johannesburg / This dissertation consists of a review of the literature, past and present, pertaining to the metal lithium. An overview is presented of its actions, its adverse effects, and its use in medicine particularly in psychiatry. As it is not irregular for many patients to receive two or more drugs concomitantly and often in a combination which has the potential to interact adversely, an overview of these interactions is also presented. / IT2018

Bipolar affective disorder is a severe mood disorder, which is characterised by episodes of mania and depression. The aetiology of bipolar disorder remains elusive, with little known about the underlying biological, anatomical, or biochemical effects. However, family, twin and adoption studies provide evidence for a strong genetic component to the disorder. Due to the high heritability, familial clustering, and common population prevalence of the illness, molecular genetic studies can be implemented to identify bipolar disorder susceptibility genes. This thesis investigated the candidate gene serotonin 2A receptor (HTR2A), which lay within a region on chromosome 13q14 previously identified by bipolar disorder genome-wide linkage scans. Significant association was found with bipolar disorder and a SNP within intron 2 of HTR2A in an Australian case-control cohort. Haplotype association analysis identified a 5-SNP protective haplotype within HTR2A. Conducting a new genome-wide linkage scan on 35 Australian bipolar disorder pedigrees found significant evidence for linkage on chromosome 15q25-26. Subsequent fine-mapping of the region verified the linkage peak with a significant maximum multipoint LOD score of 4.58. Haplotype analysis, based on pedigree-specific, identical-by-descent allele sharing, supported the location of a bipolar susceptibility gene within a 6.2Mb confidence interval. The candidate gene sialyltransferase 8B (ST8SIA2), which had previously shown association with SNPs within the gene’s promoter region and schizophrenia in two independent Asian cohorts, lies within the chromosome 15q25-26 locus. Failing to replicate the association found with these specific SNPs, and without finding association with two additional SNPs in an upstream conserved putative regulatory region, a fine-mapping association study was conducted across the entire 6.2Mb interval. The strongest association signals were observed at SNPs 16kb upstream from and within the fourth intron of ST8SIA2. A specific bipolar disorder risk haplotype was identified for ST8SIA2, and this was also observed to be over-represented in a cohort of Australian schizophrenia cases. This finding suggests that the ST8SIA2 gene, for which strong developmental regulation was observed, may be a shared susceptibility gene for both bipolar disorder and schizophrenia. In summary, this thesis has provided evidence identifying both HTR2A and ST8SIA2 as bipolar disorder susceptibility genes.

Background: Time Perspective is an individual difference variable that is believed to underpin ‘virtually all aspects of human functioning’ (Boniwell & Zimbardo, 2010). Indeed, it has so far predicted a large variety of outcome variables in previous research, including behaviours, attitudes, values, habits and decision-making. However, it has never been tested as a predictor of mood, or in psychiatric disorders. Time perspective theory posits that a balanced time perspective is necessary for healthy functioning. Time Perspective biases, on the other hand, are believed to lead to maladaptive functioning. This thesis investigates whether time perspective does also underpin and predict the most extreme ends of the mood spectrum in bipolar disorder. Participants: Three online studies were conducted with two samples of adults with bipolar disorders and one sample of adults with no mental health diagnosis. Setting: All samples were collected online, from across the world. Objectives: A series of studies investigated various aspects of time perspective theory to establish the relationship between mood and time perspective. Ten research questions were designed to answer questions on time perspective’s ability to differentiate and predict mood, and to find out whether or not it functions differently in normal and abnormal mood. It was also established whether time perspective predicts mood states differentially. Methodology: Regression analyses, MANOVAs, ANOVA and t-tests were performed to answer the research questions. Results: Our time perspective profile does indeed appear to underpin bipolar mood states. All five time perspectives were able to differentiate between four bipolar mood states. When considered separately, the five time perspectives did appear to predict mood states differentially, i.e. different time perspectives were predictors for separate bipolar mood states. Moreover, time perspective does appear to function significantly different in adults with no mental health diagnosis. Conclusions: The results of this series of studies suggests that time perspective indeed also underpins mood and can differentiate between normal and abnormal bipolar mood states. Compared to impulsiveness and BIS/BAS sensitivity, time perspective was able to explain more variance in these samples when used as a predictor.

Daily rhythms of physiology and behaviour in mammals are orchestrated by a hierarchical network of cellular oscillators. The master pacemaker that defines local and systemic timing across the brain and body are the suprachiasmatic nuclei of the hypothalamus (SCN). Disruption to the timing of sleep and daily behavioural activity can manifest in a range of pathologies including neuropsychiatric disorders. Bipolar disorder (BPD) is once such neurological condition that exhibits profound associations with altered circadian rhythm generation and whose toolkit of pharmacological interventions impact upon circadian rhythm generation. Currently it is unclear exactly how changes to rhythmic physiology contribute to the aetiology and pathology of BPD. In recent years, rodent models possessing lesions within genes that make up the basic cellular oscillator are widely reported to exhibit concomitant changes in affective behaviours, namely mania-like phenotypes. Recently a mouse model possessing a mutation within the neuron-specific Na+/K+-ATPase (NKA) alpha3 subunit, known as Myshkin, was described as a model of the manic phase of BPD. The NKA alpha3 is not reported as a critical element of the circadian oscillator and we used this opportunity to characterise the behavioural and physiological circadian system of these animals. Under wheel-running paradigms Myk/+ animals exhibited a broad array of behavioural deficits including lengthened, low amplitude and labile free-running rhythms, altered phase re-setting and elevated metabolic activity. Physiological characterisation of the SCN revealed deficits in amplitude of electrical output and changes to post-synaptic signalling although the ex vivo molecular pacemaking of the SCN remained intact. Myshkin animals therefore represent a novel model in which changes to central output arise independently of changes to basic molecular pacemaking. Despite this seemingly distinct mechanism Myshkin animals share many mood and circadian phenotypes with other clock gene models of affective behaviours highlighting that changes to pacemaking output of the SCN may be a critical factor across animal models exhibiting circadian and mood deficits. In addition, the impact of the mood stabiliser lithium, commonly prescribed in BPD, on cellular pathways within the SCN was investigated. Lithium consistently lengthens the period of cellular and behavioural rhythms in mammals although the mechanism of this action is yet undefined. Glycogen synthase kinase 3β (GSK3β) and inositol monophosphatase (IMPase) are the major biochemical targets of lithium at therapeutic concentrations. GSK3β is known to shorten rhythms and this study targeted IMPase and inositol phosphate turnover in the period lengthening effects of lithium. We reveal that although inhibition of IMPase dampens SCN molecular rhythms, the period of oscillations remains unchanged and therefore lithium acts upon distinct cellular pathways within the SCN to exert effects on period.

Bipolar disorder is a serious mental disorder, affecting anywhere from 2 to 4 percent of Americans. Though research has indicated that this disorder can be devastating for patients, less is known about how the disorder impacts family members. There is no research that has considered impacts on family members adjusting to college. The purpose of the current study was to determine the extent to which having a family member with bipolar disorder impacts adjustment to college, as well as factors that might account for worse functioning. Two groups were recruited: students with a bipolar family member (n = 25) and students with no family history of the disorder (n = 50). Participants were interviewed regarding their own histories of a mood disorder, as well as mood disorder histories in their immediate families. They then completed surveys assessing adjustment to college, functioning, caregiving burden, parental relationship, and attachment style. Students with a family history of bipolar disorder had significantly lower social adjustment scores, lower personal-emotional adjustment scores, and lower financial functioning scores than students without this history. Lower scores were found even after controlling for psychopathology. Avoidant attachment behaviors, anxious attachment behaviors, and aspects of the paternal relationship were identified as potential mediators. Caregiving burden was identified as a partial mediator. Implications for families and educational institutions are discussed.

Objective: Phenomenological and treatment differences between children and adolescents with bipolar I disorder in a public mental health system were examined. Method: A systematic medical record review was performed on a sample of 83 patients, focusing on documented DSM IV symptoms of mania or depression, attention deficit hyperactivity disorder, conduct disorder, schizophrenia, and post-traumatic stress disorder. Cross-tabulation and logistic regression analyses were performed comparing the presence/absence of symptoms for each disorder and treatments provided for children and adolescents. Results: Prepubertal patients were significantly more likely to be male, easily distracted, inattentive, detached from others, hyper-vigilant, prescribed stimulant medication, and to meet the diagnostic criteria for attention-deficit/hyperactivity disorder or Conduct Disorder than adolescents. Conclusions: Consistent with the published literature, phenomenological differences between children and adolescents are present and being recognized for differential diagnosis and treatment by community practitioners. More attention to documenting some cardinal symptoms of mania, the persistence of bipolar symptoms, and the nature of cycling for those with mixed states is needed.

Individuals who experience bipolar disorder may have difficulty acquiring and maintaining relationships due to the stigma associated with mental illness. The purpose of this generic qualitative study was to examine the attitudes and perceptions of African American men and women regarding their experiences of dating and relationships with individuals who suffer from bipolar disorder. The theory used in this study was equity theory. The research question for this study explored how African American adults experience relationship acquisition and maintenance with a partner who has been diagnosed with bipolar disorder. For this generic qualitative study, there were 12 respondents. Participants were African American adults who had dated or been in a relationship with an individual diagnosed with bipolar disorder. Themes that emerged from this study were sense of relief, sense of fear, unmodified affection, benefits of the relationship, resolution of unfair situations, reluctance to participate in a relationship with an individual diagnosed with bipolar disorder again, and race intensified the relationship. The participants associated acquisition, or the early stages of the relationship, with challenges, especially if they were unaware of the diagnosis in the beginning and could not explain certain behaviors. The results of this study can be used to promote understanding about bipolar disorder and the impact of mental illness on relationships.

No description available.