The global burden of mental health disorders is rising with the world health organization recently having recognized major depressive disorder as the leading cause of disability worldwide. Nearly one in five Canadians are now estimated to struggle with a mental health disorder and Generalized Aanxiety Ddisorder (GAD) Mmajor Ddepressive Ddisorder (MDD) and Bbipolar Ddisorder are three of the most prevalent. Despite significant research into the disorders’ cause, the pathophysiology and underlying etiology of these diseases remains largely undiscovered. Recent research has highlighted the potential role of the gut microbiota in mental health, in particular in connection with anxiety. Our research aims to investigate this link in a cohort of GAD, MDD and bipolar patients recruited through the Anxiety Treatment and Research Centre at St. Joseph’s Healthcare in Hamilton, as well as through the University Health Nnetwork in Toronto. 71 GAD, 18 MDD, 17 euthymic MDD and 23 Bipolar patients provided fecal samples from which DNA was extracted, following which the V3 region of the 16S rRNA gene was amplified and sequenced using the Illumina Miseq platform. Sequencing data was analyzed through an in-house pipeline to construct community profiles of patients and age and sex matched healthy controls. My work involved analyzing the data to identify signature organisms that might identify putative disease associated microbial communities for further hypothesis generation about possible roles in disease. Furthermore, an extensive culturing effort was undertaken to identify and characterize some of the Bacteroides strains which were enriched in the GAD patient population. This study presents novel insights into some of the organisms that may be markers for a number of different diseases as well developing a better understanding of the Bacteroides that were correlated with anxiety. / Thesis / Master of Science (MSc) / Mental hHealth disorders including Ggeneralized Aanxiety Ddisorder (GAD), Mmajor Ddepressive Ddisorder (MDD) and Bbipolar Ddisorder (BD) affect somewhere between five and ten percent of Canadians, with the Wworld Hhealth Oorganization recently labeling MDD the leading cause of disability worldwide. Despite decades of research, on these disorders we still have a poor understanding of what factors may contribute to causing these disorders their underlying mechanisms of actionetiology. Another hallmark of many mental health conditions are increased rates of gastrointestinal symptomsor digestive distress relative to the healthy populatioindividualsn. Recently, there has been a great deal of research about how the trillions of bacteria that live in the digestive tract play a role in neuronal brain development and behaviour. This study aimed to better understand which the organisms reside iinn the digestive tract of mental health patients in hopes of better understanding how some of these organisms could be contributing to patients’ poor mental health. Additionally, through better understanding the nature of these communities, recommendations could potentially be made about therapeutic interventions to restore a healthy community.

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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

Although most research on bipolar I disorder has focused on biological models, recent investigation has elucidated the importance of psychosocial predictors of the course of illness. Theories of the Behavioral Activation System?s role in affect have helped unify biological and environmental explanations of the disorder. Along these lines, researchers have proposed that goal striving and attainment predict manic symptoms. In the current study, experience-sampling methodology was used to assess the relationship between fluctuations in goal striving and affect among 12 persons with bipolar I disorder and 12 without a history of mood disorder (control group). Participants completed measures of goal striving and affect three times each day for a period of three weeks. It was hypothesized that moving more quickly than expected toward a given goal would result in decreased subsequent effort toward that goal (coasting) for the control group, and increased subsequent effort (anti-coasting) for those with bipolar I disorder, with positive affect mediating the relationship in both cases. Results indicated that those in the bipolar I disorder group were significantly more likely to anti-coast than those in the control group. This finding, however, was explained primarily by gender, as men in the bipolar I disorder group showed no evidence of anti-coasting. In addition, there was no evidence of the mediating role of positive affect in these phenomena. Implications of the findings, limitations, and future directions are discussed.

Psychologists face challenges on a daily basis. Among the challenges they face are making diagnostic decisions. Recently, bipolar disorder has shown an increase in diagnosis in children and adolescents. Once felt to be an adult disorder, journals are describing the use of the diagnosis with children and adolescents. While the diagnosis has been considered as relevant, no psychological measures have been developed to make an accurate diagnosis. Developing a new psychological measure for bipolar disorder in children is critical. Due to the lack of data on what constitutes normal behavior as well as the absence of an accurate measurement of early-onset bipolar disorder, it is necessary to develop such a measure. The purpose of this study was to evaluate a newly developed measure based on the literature on bipolar disorder in children. The measure was developed through a review of the current literature, DSMIV-TR criteria for bipolar disorder, and ideas developed within a bipolar disorder research team at Texas A&M University. Because of the item content, the new measure is entitled the Mania Assessment Scale for Children (MASC). The first steps in understanding a new measure for early-onset bipolar disorder is to determine the factor structure of the scale as well as the reliability and validity. Results indicated that the MASC is best understood as a measure with a single score, or factor. Once the underlying structure of the MASC was determined, the study evaluated which behaviors of typically developing children may be misconstrued as indicative of bipolar disorder. Group differences on the measure are also evaluated. Results from statistical analysis showed that there were significant group differences between age groups, but not gender and ethnic groups. In addition, there was a statistically significant difference between clinical and non-clinical groups. To conclude, a discussion of the findings and recommendations for future research is presented. Overall, it is hoped that the study will help psychologists better understand the complexity of behaviors associated with the diagnosis of bipolar disorder in children and adolescents.

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.