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Large-scale transcriptomic studies are among of the most comprehensive accounts we have of the biological processes underlying human brain development and ageing. However, many analyses and descriptive models applied to gene expression data implicitly assume that developmental change is continuous and uninterrupted. Perhaps this bias is often overlooked because the emphasis is on what is changing during development rather than how development itself is changing. Indeed, despite the richness of transcriptomic data and its capacity to recapitulate higher-order functions, few have used it to understand the dynamics of brain development. Gene expression is determined by complex, high-dimensional interactions of the gene regulatory network. Dynamic systems theory states that the interactions of components in any complex systems will converge on certain stable patterns, also known as attractor states. To approximate these stable states, the current study leveraged robust and sparse k-means clustering to identify tissue samples with similar patterns of gene expression across the transcriptome. Sample ages were then used to visualize when in developmental time these stable patterns are present. The resulting model describes the developmental dynamics of the brain transcriptome as a series of non-linear, overlapping states that progress across the lifespan. / Thesis / Master of Science (MSc)

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: 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.

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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Bipolar disorder (BD) is a chronic, progressive illness characterized by fluctuations in mood. It is associated with psychosocial and cognitive impairment that can affect a person’s life at home, at work or school, and in interpersonal relationships. Children and adolescents diagnosed with BD experience similar functional impairments and risk for suicidal thoughts or actions compared to adults. Additionally, they are at an increased risk for poorer prognosis during adulthood given the negative outcomes associated with early illness onset, delayed treatment, misdiagnosis, and longer illness duration. The etiology and pathophysiology of bipolar disorder is incompletely understood. Peripheral blood biomarkers can provide insight into the mechanisms underlying the disease and can aid in identifying at-risk individuals, making an accurate diagnosis, monitoring illness activity and improving therapeutic intervention. A PubMed search was carried out and 12 studies were identified that assessed potential peripheral blood biomarkers in children and adolescents with bipolar disorder. These studies suggest that fatty acid biostatus, markers of lipid and protein oxidation, markers of inflammation and immune disturbance, neurotrophic factors and enzymes related to inflammation may serve as biomarkers of BD. These potential biomarkers of the disorder warrant further study in youth with BD. Current findings support a staging hypothesis of BD wherein cumulative episodes lead to disruptions of the pathways associated with the disorder and thus greater impairment in patients farther from their disease onset. However, these and other biomarkers will need to be evaluated in larger, longitudinal studies to validate their use and expand knowledge in the field.