Background: The objective of this thesis was to measure oxidative stress (OS) in women with Bipolar Disorder (BD) who used combined oral contraceptives (OCU). Based on our literature review, it was predicted that OCU would increase OS levels relative to non-contraceptive users (NCU) in women. Methods: Thirty-five participants (BD n=25; Control n=10) were recruited from an ongoing study based in British Columbia ‘The Systematic Treatment Optimization Program in Early Mania.’ Participants were administered psychological screening tools (Young Mania Rating Scale (YMRS), Montgomery-Åsberg Depression Rating Scale, Mini International Neuropsychiatric Interview and Hamilton Depression Rating Scale) and provided a blood sample for the assays (Lipid Hydroperoxide (LPH), Protein Carbonylation, 4-Hydroxynonenal, 3-Nitrotyrosine (3-NT) and 17-Beta Estradiol). Results: In our primary analysis we did not find differences in OS between BD and controls relative to OCU. Within our remaining analyses, only BD women (n=17) and who gave smoking status were included. We found 3-NT to be increased in OCU compared to NCU (F (1, 12) = 5.639, p = 0.035). With respect to mood stabilizer use, 3-NT was increased in OCU relative to NCU (F (1, 10) = 6.33, p=0.031). As for atypical antipsychotics, 3-NT was heightened in OCU adjunctive users compared to NCU who did not use atypical antipsychotics (F (3, 10) = 4.822, p = 0.025). As for our correlation analyses, YRMS correlated with 3-NT and LPH in OCU BD women (r(11)= 0.711, p=0.014 and r(11) = 0.676, p=0.022, respectively) and 17-Beta Estradiol correlated with LPH (r(17) = 0.598, p = 0.001). Our results are preliminary and are limited by our small sample size and various other factors (i.e. controls). Conclusion: The association between hormones and oxidative stress still remains controversial. Here we showed, after controlling for smoking, BMI and age the use of a COC significantly increased 3-NT in women with BD. Moreover, hormones may influence the relationship between OS and mood episodes. / Thesis / Master of Science (MSc)

Introduction: Bipolar disorder is associated with cortical abnormalities, including deficits in intracortical myelination. Intracortical myelin follows an inverted-U trajectory over the lifetime, but this trajectory is blunted in individuals with bipolar disorder. Little is understood about which genetic factors contribute to these deficits. Neuregulin-1, a cell-signalling protein, has been shown to contribute to cortical abnormalities and increase susceptibility to related disorders. Assessing the prevalence of neuregulin-1 polymorphisms, notably rs6994992, in bipolar disorder may elucidate the genetic contributors of intracortical myelin deficits and increase our understanding of factors causing susceptibility to bipolar disorder. Methods: 67 participants with bipolar disorder type I and 75 healthy control participants were included. T1-weighted MRI images were collected and processed to create R1 cortical maps, a proxy measure of intracortical myelin. Participant blood samples were genotyped at the rs6994992 locus. Linear models were used to test whether intracortical myelin can be predicted by age, bipolar diagnosis and NRG1 genotype. Results: Intracortical myelin is significantly predicted by age, diagnosis and genotype together in the motor cortex (left: R2 = 0.09, p < 0.01, right: R2 = 0.06, p < 0.05), the right premotor cortex (R2 = 0.095, p < 0.001), and the right inferior frontal cortex (R2 = 0.098, p < 0.001). Age is a significant individual predictor of intracortical myelin in the right dorsal anterior cingulate cortex, the bilateral motor cortex, the right premotor cortex, and the right inferior frontal cortex. Conclusions and Future Directions: Our study suggests that the right premotor, bilateral primary motor, and right inferior frontal cortices are regions of interest for understanding how intracortical myelin changes throughout the lifetime, especially in bipolar disorder. Future work should examine the impact of polygenic risk scores of bipolar disorder on intracortical myelin. / Thesis / Master of Science (MSc) / Bipolar disorder is associated with neurobiological changes, including cortical abnormalities, contributing to a greater disorder burden. Cortical myelination changes throughout the lifetime and larger deficits are found in individuals with bipolar disorder. However, the role of genetics in these intracortical myelin deficits is largely unknown. This thesis investigates how intracortical myelin content in various regions of the cortex is impacted by age, bipolar disorder diagnosis, and neuregulin gene variants. The goal of this research is to contribute to a better understanding of how genetics and age impact intracortical myelin in bipolar disorder to better understand the neurobiological changes of the disorder.

Introduction: Major depressive disorder (MDD), generalized anxiety disorder (GAD), and bipolar disorder (BD) are mental illnesses associated with socio-cognitive functional impairments, reduced quality of life, and increased risk of medical and psychiatric comorbidities. These disorders are also associated with unhealthy patterns in several fundamental lifestyle areas according to the current notions of lifestyle psychiatry, such as diet, physical activity, substance use, sleep, stress management, and social relationships. With the rising prevalence rates of poor mental well-being following the onset of the COVID-19 pandemic, it is essential to understand the relationship between a multifactorial lifestyle and the presence of psychiatric symptoms. Thus, the aim of this thesis was to assess the association between a multidimensional lifestyle and symptoms of MDD and GAD during the COVID-19 pandemic, and lifestyle patterns among symptomatic individuals with BD. We additionally reviewed the literature on lifestyle interventions for improvement of outcomes related to BD. Results: Unhealthy lifestyle behaviours were associated with symptoms of MDD and GAD during the COVID-19 pandemic in Spain, Brazil, and Canada. Machine learning analyses revealed strong predictive power for detecting the presence of these symptoms through lifestyle behaviours and perceptions. Individuals with BD engage in more unhealthy lifestyles than healthy individuals across all the core areas of lifestyle psychiatry, regardless of the polarity of the mood episode. Furthermore, to date, traditional lifestyle domains such as diet, physical activity, and sleep have been the most frequently targeted domains for interventions to improve mood symptoms and functional outcomes of BD, while domains such as substance use, stress management and social relationships have been more neglected. In addition, multidimensional lifestyle interventions have demonstrated a higher efficacy rate of improving outcomes of BD than single-domain interventions, however, there has been a lack of interventions for BD targeting majority of the core lifestyle domains. Conclusion: The findings suggest that multidimensional unhealthy lifestyles are associated with symptoms of MDD, GAD, and BD. These results support the current notions of lifestyle psychiatry, indicating that a multidimensional assessment of lifestyle behaviours and perceptions can be a beneficial approach towards understanding the cumulative impact of various lifestyle patterns on psychiatric symptoms. This work highlights the importance of imposing a holistic approach towards studying the association between lifestyle factors and psychiatric disorders in order to implement effective, personalized preventive and treatment strategies for mental health disorders. / Thesis / Doctor of Philosophy (PhD) / People experiencing symptoms of psychiatric disorders may also engage in more unhealthy routines and behaviours in everyday life. Lifestyle is a construct characterized by behaviours and perceptions in multiple areas of life which are fundamental for the overall well-being of a person. The aim of this thesis was to investigate the relationship between multidimensional lifestyle characteristics and symptoms of depression, anxiety, and bipolar disorder (BD). We examined the association between multidimensional lifestyle and symptoms of depression and anxiety in the general populations of Spain, Brazil, and Canada during the COVID-19 pandemic. We also assessed the relationship between unhealthy behaviours and symptomatic individuals with BD in comparison to healthy individuals, and the importance of lifestyle interventions for improvement of outcomes related to BD. The findings indicated an association between multidimensional unhealthy lifestyles and symptoms of depression and anxiety during COVID-19. Unhealthy lifestyles across all domains were also seen in people with BD currently experiencing a mood episode, while lifestyle interventions for BD have shown promising results so far. A multidimensional approach to evaluating quality of lifestyle can be beneficial for developing preventive and treatment lifestyle strategies for common psychiatric disorders.

Emotion processing and regulatory deficits have been well established in individuals diagnosed with bipolar disorder (BD). Both structural and functional neural deficits have been associated with the presence of psychiatric symptoms in BD. In Chapter 2, we reviewed cortical thickness deficits found in patients with BD. It is unclear however, how early these deficits appear; whether they contribute to risk, or whether these deficits develop as a consequence of the onset of symptoms. To address this, many researchers have turned to high-risk offspring populations. These high-risk offspring are at much greater risk of developing BD by virtue of having a parent diagnosed with BD. Moreover, the presence of anxiety, depression or ADHD related symptoms in this population suggest these children are at even greater risk to develop BD. By comparing high-risk offspring with and without the symptoms can help to elicudate neural correlates associated with risk and resilience for BD. It was the aim of this thesis research to investigate the behavioural, structural and functional correlates of risk. Specifically, presented in this thesis, we compared the gray matter integrity, through volume (Chapter 3) and cortical thickness (Chapter 4) techniques, in symptomatic and asymptomatic high-risk offspring to healthy children of healthy parents. We also compared the ability of these offspring to perform an emotion-labelling task (Chapter 5) and engage in emotional conflict monitoring and conflict adaptation during an fMRI scan (Chapter 6). Altogether, our results provide evidence for the presence of gray matter volume, emotion labelling, and conflict monitoring and conflict adaptation functional deficits in high-risk offspring compared to healthy children of healthy parents. With the exception of cortical thickness, we found that the deficits between symptomatic and asymptomatic high-risk offspring were comparable. This suggests that behavioural, structural and functional deficits may reflect neural correlates of risk and are not associated with the presence of symptoms. / Thesis / Doctor of Philosophy (PhD)

Obesity is a common medical illness that is known to confer risk for a large number of medical illnesses, such as Type II Diabetes, hypertension, cancer, and late-life dementia. More recently, the relation between obesity and decline in cognitive performance, independent of other comorbid medical conditions, has begun to be examined. Individuals with mood disorders (Bipolar Disorder [BD] or Major Depressive Disorder [MDD]) display an increased prevalence of both obesity and risk factors for cardiovascular disease. Moreover, BD and MDD are associated with impairment in cognitive functioning across multiple domains. The contribution of obesity to cognitive decline in this population has not been explored. This thesis begins with a systematic review of the literature examining the impact of obesity on cognition, providing a thorough background of this relation. The following chapter introduces a prospective cohort study designed to comprehensively explore the relation between obesity and cognition in individuals both with, or without, a mood disorder. The first of set of results from this study are presented in the remaining chapters. The neuropsychological study findings indicate that MDD and obesity may have an additive effect on cognition, resulting in significant cognitive decline in obese adults with MDD. Moreover, we show that different neural activation patterns are seen during a cognitive magnetic resonance imaging (MRI) task in obese versus obese MDD patients. Collectively, this provides strong evidence that populations already at risk for cognitive impairment, such as mood disorder populations, are susceptible to further cognitive changes due to increased weight. / Thesis / Doctor of Philosophy (PhD)

Antipsychotic medications are highly effective in the treatment of patients experiencing first-episode psychosis. However, some patients do not respond to the first antipsychotic medication they are given, and may require trials of several drugs before an effective treatment is found. While antipsychotics may take months to achieve their full effect, recent evidence suggests that it is possible to predict whether a patient will respond to a particular drug by assessing early response after as little as 2 weeks of treatment. Assessing early antipsychotic response has the potential to improve treatment strategies for psychotic patients, but there is still a great deal of uncertainty about what early response can and cannot predict, and how the predictive value of early response differs among drugs and patient populations. The work presented in this thesis addresses some of the most pressing questions about early antipsychotic response in several samples of antipsychotic-naive patients with first-episode psychosis. This work demonstrates that: (1) the appropriate time point at which to assess early response differs between antipsychotic drugs; (2) early improvement in depressive and manic symptoms predicts treatment outcome, while early improvement in anxiety symptoms may not; (3) strong early response is associated with decreased rates of extrapyramidal side-effects; (4) early antipsychotic response can predict long-term treatment outcome at least 2 years after treatment initiation; (5) the appropriate time point at which to assess early response differs in patients who receive antidepressant treatment in addition to antipsychotic treatment; (6) patients with a poor early response may benefit from being switched to another antipsychotic, particularly one with a distinct receptor binding profile. These results highlight several weaknesses of the current literature, suggesting that early antipsychotic response should be assessed differently depending on the psychiatric symptom profile of each patient and the specific medications that are being used. However, the data presented here also emphasize the potential therapeutic value of assessing early response. The ability of early response to predict treatment outcome appears to be even greater than previously thought, and understanding how to appropriately use this important assessment to guide treatment strategies may improve the efficiency and efficacy of treatment for psychotic patients. / Thesis / Doctor of Philosophy (PhD)

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Pediatric bipolar disorder (PBD) is a growing public health problem in the United States, especially among adolescent children. Despite awareness of the diagnosis and the effects that it has on the child, little attention has been given to the effects that PBD has on the guardian. The purpose of this qualitative phenomenological study was to explore the factors influencing guardians' experiences related to PBD. Penchansky and Thomas' Theory of Access and Family Systems Theory were used in this study to explore guardians lived experiences of PBD, its effects on the entire family system, and mental health service treatment. This approach was composed through interviewing 6 guardians caring for adolescents diagnosed with PBD. Interviews were conducted, transcribed and coded using NVivo12 software. The findings revealed the emergent themes as follows: disbelief of initial diagnosis, coping mechanisms, advice, barriers, burdens, stressors, and challenges. The themes described the experiences of guardians that led to feelings of denial, frustration, embarrassment, and resentment. Damaged relationships, medical problems, and financial hardships are only some of the challenges that guardians expressed during the interview. The issues that the guardians experienced provide evidence to fill the gap in the literature regarding effects on guardians. Further research into mental health services and guardians' perceptions on PBD is needed. This study promotes social change by informing mental health providers of the feelings and stressors of the guardians of PBD patients, which may lead to improved care for the family unit.