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Most life stress literature in bipolar disorder (BD) fails to account for the possibility of a changing relationship between psychosocial context and episode initiation across the course of the disorder. The kindling hypothesis states that over the longitudinal course of recurrent affective disorders, there is a weakening temporal relationship between major life stress and episode initiation (Post, 1992). This process could reflect either a progressive sensitization or a progressive autonomy (i.e., insensitivity) to life stress. The present study aimed to test the kindling model in BD by examining the effect of lifetime mood episodes on the relationship between proximal life events and prospectively assessed mood episodes. Polarity-specific tests of the model were conducted across the continuum of event severity, with respect to both impact and frequency of life events. Moreover, examination of the kindling hypothesis was embedded in the context of two emerging biopsychosocial theories of BD: the expanded Behavioral Approach System Dysregulation Model and the Circadian and Social Rhythm Theory. Data from 278 participants (146 bipolar spectrum participants and 132 normal control participants) were collected as part of the Temple-Wisconsin Longitudinal Investigation of Bipolar Spectrum Project. Hypotheses were polarity- and event-type specific and were in line with a stress sensitization model of bipolar spectrum disorders (BSD), rather than a stress autonomy model. Results partially supported a sensitization model: there was a decreased frequency and an increased impact of major events, and an increased frequency and impact of minor events. However, results for specific polarities and event types were not fully consistent with a stress sensitization model. Implications of these findings are addressed, followed by a discussion of study strengths, limitations, and promising directions for future research. / Psychology

In this study, I tested predictions of the Behavioral Approach System (BAS) model as applied to the course of bipolar spectrum disorders. In this model, when a vulnerable individual experiences a BAS activation-relevant event, the weak regulatory strength of the BAS interacts with pre-event BAS state and is likely to lead to hypomania/mania. In contrast, when a vulnerable individual experiences a BAS deactivation-relevant event, the weak regulatory strength of the BAS interacts with pre- event BAS state and is likely to lead to depression. A secondary goal of this study involved comparing the BAS model to the cognitive-vulnerability stress model of bipolar disorder. Toward this end, data from a sample of 217 individuals (112 individuals with a diagnosis in the bipolar spectrum and 105 demographically similar, normal controls) participating in the Longitudinal Investigation of Bipolar Spectrum Disorders (LIBS) Project, a two-site prospective examination of the role of BAS, cognitive styles, and life events in the course of bipolar disorders among college students, were analyzed. The results of this study suggest that there is some support for both the BAS model and the cognitive-vulnerability stress model. Specifically, BAS-relevant cognitive styles, in interaction with congruent positive life events, predicted hypomanic episodes. There was less support for either model in the prediction of depression. There was some support for BAS sensitivity and BAS-relevant events each predicting the course of bipolar disorder. However, there was no support for the interaction of BAS sensitivity and BAS-relevant events predicting the type and number of mood episodes. As such, this study found more support for a BAS-related cognitive vulnerability-stress model, as compared to the "pure" BAS model, as applied to bipolar spectrum disorders. Following a review of the results, strengths and limitations, as well as clinical implications and potential future research directions are discussed. / Psychology

Bipolar disorder (BD) is a chronic mood disorder affecting ~1-2% of the global population, characterized by cycling moods of mania and depression. The exact pathogenesis of BD is unknown; however, it has been established that endoplasmic reticulum (ER) stress plays an important role. It is known that BD patients have abnormal activity and expression of ER stress proteins in several brain regions. There exists a need for a definitive diagnostic test for the early detection of BD as it is often misdiagnosed for other conditions including unipolar depression and schizophrenia. Understanding the underlying mechanisms and therapeutic targets being used by BD treatments will be helpful in establishing a diagnostic test. The current gold standard for BD treatment includes Lithium (LiCl) prescription, along with other mood stabilizers such as Valproic acid (VPA) and antipsychotics such as Olanzapine. Current therapies only relieve symptoms and are unable to stop disease progression. Neurotrophic factors (NTFs) are naturally occurring proteins that are responsible for the maintenance, differentiation, and survival of neurons. Cerebral dopamine NTF (CDNF) and Mesencephalic astrocyte-derived NTF (MANF) belong to a novel class of NTFs specific to dopaminergic neurons. This study investigated the role of CDNF and MANF as therapeutic targets for bipolar disorder in SH-SY5Y cells and Sprague Dawley rats, as well as determining the endogenous mRNA levels of CDNF and MANF in BD patients. We demonstrated that common BD mood stabilizers – LiCl and VPA – significantly increased the mRNA expression of MANF and CDNF in vitro. Additionally, we also established that these mood stabilizers alter the NTFs expression in different rat brain regions including pre-frontal cortex (PFC) and cortex. These findings suggest that BD drug treatments potentially act via NTFs in order to relieve symptoms. Thus it highlights the importance of further investigating the interaction between neurotrophic factors and bipolar disorder. / Thesis / Master of Science (MSc)

Introduction: Women with bipolar disorder (BD) have higher rates of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). The primary goal of this thesis was to examine the neural correlates of bipolar disorder and comorbid PMDD and identify changes in brain structure or function that may mediate emotional and cognitive dysregulation in the late luteal phase. Results: In healthy women with no history of PMDD, absolute levels of estradiol, progesterone, allopregnanolone and dehydroepiandrosterone sulfate (DHEAS) were correlated with patterns of functional coupling in multiple regions associated with emotional and cognitive processes, in the mid-follicular and late luteal menstrual phases. A systematic review of the literature on resting state functional connectivity (Rs-FC) in BD during euthymia highlighted consistent patterns of resting state functional connectivity (Rs-FC) using ICA and SBA; including stability of the default mode network (DMN), salience network (SN) and fronto-parietal network (FPN) relative to controls. Available literature largely failed to control for sex, menstrual cycle phase or menstrual cycle disorders. Thus, we conducted the first fMRI studies to control for menstrual cycle phase in BD. During the mid-follicular phase, we found increased Rs-FC between critical nodes of the default mode and frontoparietal networks in BD compared to controls and increased functional connectivity between the somatosensory cortex and the insular cortex, inferior prefrontal gyrus and frontal orbital cortex in BD compared to controls. Voxel based morphometry analysis showed decreased gray matter in the somatosensory cortex in the same population compared to controls. Finally, women with BD and co-morbid PMDD displayed different patterns of Rs-FC using the right and left hippocampi as seed regions than women with BD without comorbid PMDD and controls with PMDD. Differences in cortical thickness between controls with and without PMDD and with and without BD were also found in regions central to emotional regulation and cognitive processing. Conclusions: Results highlight the influence of sex hormones on Rs-FC and support the need to control for menstrual phase and PMDD diagnosis. Differences in structural and functional connectivity, and the clinical profile of women with BD and those with BD and co-morbid PMDD highlights the impact of PMDD on BD and the need for future research in this area. / Thesis / Doctor of Philosophy (PhD)

This thesis presents research investigating objectively and subjectively examined cognitive impairment in Bipolar Disorder (BD) in comparison to disorders with similar cognitive symptomatologies. First, a systematic review and meta-analyses compared the cognitive performance between BD and Mild Cognitive Impairment (MCI) or dementia. Studies included in this review and meta-analyses assessed cognitive performances using multiple objective cognitive assessments. Results from these meta-analyses found greater impairment in BD relative to MCI on motor initiative abilities. Additionally, there were similarities in cognitive deficits on delayed memory recall and visuoconstructional abilities between BD and MCI. For the comparison between BD and dementia, we analyzed the findings of studies comparing BD across different mood states with different types of dementia, where BD in acute mood episode demonstrated greater deficits in attention, working memory, verbal memory, and executive function than behavioral variant frontotemporal dementia (bvFTD). In contrast, overall cognitive functioning and verbal fluency was more impaired in Alzheimer’s disease (AD) in comparison to BD during euthymia. Next, we shifted the focus on examining subjective cognitive complaints in BD relative to Major Depressive Disorder (MDD). Our study is unique from previous literature with the same aim considering that it only involved patients recently diagnosed with BD, and subjective complaints were assessed with the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA), an instrument specific to cognitive complaints detected in BD. The findings demonstrate higher subjective cognitive complaints in euthymic BD in comparison to euthymic MDD, suggesting greater self-perceived difficulties in BD, even in the beginning of the illness. Taken together, findings from the studies presented in this thesis highlight the importance of early detection and intervention of cognitive impairments in BD, with the aim of enhancing cognitive abilities, and prevention of further cognitive degradation with the progression of the disorder / Thesis / Master of Science (MSc)

Introduction: Sleep and biological rhythms have not been investigated in women with comorbid Bipolar and Premenstrual Dysphoric Disorder in the context of the menstrual cycle. We explored whether menstrual cycle phase causes increased disturbances in sleep, biological rhythms and mood symptoms. Additionally, we explored whether these women have worse illness outcome than women diagnosed with either Bipolar or Premenstrual Dysphoric Disorder, and healthy women. Methods: In this post-hoc analysis, participants were split into four groups: those with a Bipolar and comorbid Premenstrual Dysphoric Disorder diagnosis (n = 17, BDPMDD), those with a Bipolar Disorder diagnosis (n = 16, BD), those with a Premenstrual Dysphoric Disorder diagnosis (n = 19, PMDD), and women with no history of psychiatric diagnosis (n = 25, HC). The primary outcome variable was biological rhythm disruption as measured by the Biological Rhythms Interview and Assessment in Neuropsychiatry (BRIAN). The secondary outcome variables were depressive symptoms (Montgomery-Asberg Depression Scale, MADRS; Hamilton Depression Rating Scale, HAMD), manic symptoms (Young Mania Rating Scale, YMRS), and sleep quality (Pittsburgh Sleep Quality Index, PSQI). All variables were collected at both mid-follicular and late-luteal stages of the menstrual cycle. Results: The BDPMDD group did not have significantly higher disruptions in biological rhythms than the BD or PMDD groups at the luteal phase; however, there were significant disruptions and mood symptoms in comparison to the HC group, especially at the follicular stage, which point to markedly higher disruptions in these areas that seem to persist beyond the symptomatic luteal phase. Conclusion and Future Directions: Women diagnosed with a BD and PMDD comorbidity experience a higher illness burden then women diagnosed with either BD or PMDD. A relatively small sample size, not excluding for participants who were taking medications that affect sleep and relying solely on subjective measures of biological rhythms may explain some of the null results. Future studies should employ objective measures of sleep such as actigraphy to complement subjective measures like the BRIAN, as well as recruit a larger sample of participants. More importantly, more studies surrounding this topic must be done in order to create a robust body of evidence that can be used to compare results across studies and identify specific biological rhythms domains that can be targets for treatment. / Thesis / Master of Science (MSc) / Sleep disruptions are common in women diagnosed with Bipolar Disorder and in those diagnosed with Premenstrual Dysphoric Disorder. Illness burden has been shown to be greater in women diagnosed with a comorbidity of the above disorders in terms of clinical variables such as number of comorbidities, episode relapse, rapid cycling and mixed mood states. This thesis aims to investigate whether women diagnosed with Bipolar and comorbid Premenstrual Dysphoric Disorder have greater biological rhythms disruptions than women diagnosed with either disorder. Biological rhythms will be evaluated at both the follicular and late-luteal stages. The overall goal of this work is to add to the currently scant literature on the clinical presentation of a Bipolar and Premenstrual Dysphoric Disorder comorbidity.

The aetiology of bipolar disorder remains unclear and investigation to date has focussed largely on bipolar patients. Whilst ultimately of huge value, such studies may also be confounded by current mood or experience of repeated illness episodes or current or past medication; using at-risk samples may bypass some of these problems. The current research therefore assessed the efficacy of the Mood Disorder Questionnaire (MDQ) as a screening tool for vulnerability to bipolar disorder. The MDQ was used with two sets of criteria to identify two sub-groups of medication-naïve young bipolar phenotype subjects who were at risk for bipolar disorder by virtue of experience of mood elevation. Analysis of data from the Student Stress Survey was carried out to characterise the bipolar phenotype. Compared to a control group with no experience of mood elevation, the two bipolar phenotype sub-groups showed a gradient of prevalence of bipolar diagnosis and associated co-morbidity. Behavioural and functional magnetic resonance imaging (fMRI) techniques were employed to investigate emotional processing, decision-making, and sleep and circadian rhythmicity in bipolar phenotype students. Analyses revealed that positive emotional processing biases, disrupted decision-making, and increased activity during sleep were associated with the bipolar phenotype and, therefore, may represent vulnerability markers for bipolar disorder. Finally, a psychopharmacological investigation of quetiapine, which stabilises mood, was carried out in healthy volunteers. One-week quetiapine administration resulted in biases away from both positive and negative emotional stimuli (i.e. a mood-stabilising effect), reduced discrimination between different magnitudes of gains and losses during risky decision-making (consistent with an antidepressant effect), and increased sleep duration. In sum, this research has developed our understanding of vulnerability markers associated with the bipolar phenotype and provided a first step towards uncovering the psychological mechanisms through which quetiapine’s clinical effects may be mediated.

Objectives: To elucidate the relationship between the course of bipolar disorder (BD) and structural brain changes across the life span, we conducted a systematic review of longitudinal imaging studies in adolescent and adult BD patients.- Methods: Eleven studies with 329 BD patients and 277 controls met our PICOS criteria (participants, intervention, comparison, outcome and study design): BD diagnosis based on DSM criteria, natural course of disease, comparison of grey matter changes in BD individuals over ≥1-year interval between scans. - Results: The selected studies yielded heterogeneous findings, partly due to varying patient characteristics, data acquisition and statistical models. Mood episodes were associated with greater grey matter loss in frontal brain regions over time. Brain volume decreased or remained stable in adolescent patients, whereas it increased in healthy adolescents. Adult BD patients showed increased cortical thinning and brain structural decline. In particular, disease onset in adolescence was associated with amygdala volume reduction, which was not reported in adult BD. - Conclusions: The evidence collected suggests that the progression of BD impairs adolescent brain development and accelerates structural brain decline across the lifespan. Age-specific changes in amygdala volume in adolescent BD suggest that reduced amygdala volume is a correlate of early onset BD. Clarifying the role of BD in brain development across the lifespan promises a deeper understanding of the progression of BD patients through different developmental episodes.

Text in English / Literature notes an increase in the number of children and adolescents diagnosed with bipolar disorder. Several challenges faced by clinicians who diagnose and treat early-onset bipolar disorder have been discussed with particular emphasis being placed on its pharmacological management. The contributions made by psychologists including psychosocial interventions, have been explored in this regard; however, there still exists a paucity of voices in the field of psychology that discuss the experiences surrounding the management of this disorder. Most studies on early-onset bipolar disorder do not distinguish between childhood and adolescent presentations. Adolescence has been recognized herein, as a distinct developmental and transitional phase and thus, it forms the basis of this inquiry. This qualitative study thus explores clinical psychologists’ experiences ofmanaging adolescents diagnosed with bipolar disorder and will be approached from a social constructionist perspective which was selected as a means of exploring the meanings that individuals attribute to their experiences as they engage with others in their environment. A literature review evaluated the current available literature on juvenile bipolar disorder. Clinical psychologists in private practices were interviewed using semi-structured interviews. The participants were selected using purposive sampling. Two pilot studies were used to pre-test the study. One participant took part in pilot study 1 and one in pilot study 2. Thereafter, four semi-structured interviews were held with four participants who took part in the main study. Themes were drawn from the data and were explored using thematic content analysis. An analysis of the themes revealed several shared experiences in clinical psychologists’ management of juvenile bipolar disorder which were similar to what is reflected in the current available literature on early-onset bipolar disorder. / Psychology / M.A. (Clinical Psychology)