For complex traits, population genetic studies ask: to what extent do genetic variation and environmental variation influence, determine and predict phenotypic variation? More specifically, researchers ask two questions. First, how much of the phenotypic variation is genetic in origin? Second, if the genetic component of a trait has been ascertained, then by what mechanisms do the causal variants contribute to the genetic variation that impacts on the phenotype? Previous studies have indicated a polygenic structure for many complex traits, which means that the genetic variation in those traits is the result of the cumulative effect from hundreds or even thousands of genetic variants. To further decipher the polygenic genetic architecture of a complex trait, genetic studies aim to identify the number, the location in the genome, and the distribution of the effect sizes of causal variants, as well as their individual and interacting effects. Linkage analysis and genome-wide association studies (GWAS), either based on single variants or sets of variants categorized by functional annotations, can be applied to map the potentially causal variants in the genome. The identification of disease-associated loci, however, is only the starting point in identifying causal variants. Causal variants are usually difficult to distinguish from the large number of variants in linkage disequilibrium (LD) within the associated loci, and may be in incomplete LD with genotyped variants. Computational prediction integrated with multi-level ‘Omic’ data will help the prioritization of candidate causal variants, which then become important targets for experimental validation (Chapter 1). Major depressive disorder (MDD) is a complex trait, contributes the second most important burden to global disease. Both genetic and environmental components have been suggested for this disorder in previous studies, although a clear partitioning of the contribution of each component and the identification of major contributing components is yet to be achieved. In efforts to map causal genetic variants, genome-wide association studies of MDD have identified few significant associations so far. The polygenic architecture combined with the widespread clinical and genetic heterogeneity of MDD between populations may impede the identification of causal variants (Chapter 2). In this thesis, I will present three studies; the first study estimated the proportions of the phenotypic variation that are genetic or familial environmental in origin in two depression definitions(chapter 3), followed by two studies where distinct (non- GWAS) methods were used to identify candidate causal genetic variants for MDD (chapter 4,5). In detail, in chapter 3, a variance component analysis was applied to GS:SFHS (Generation Scotland: Scottish Family Health Study) to investigate the relative genetic and environmental contributions to diagnosed major depressive disorder (MDD) and self-declared depression (SDD). Models for MDD and SDD that simultaneously included genetic and environmental effects suggested that narrow-sense heritability could be inflated by the environments shared by nuclear family members. The most parsimonious models selected for both MDD and SDD included SNP and pedigree-associated genetic effects and the effect of the common environment of couples. In chapter 4, I integrated pathway analysis and multi-level regional heritability analyses in a pipeline designed to identify MDD-associated pathways. The pipeline was applied to two independent GWAS studies (GS:SFHS and PGC1-MDD). The NETRIN1 signalling pathway showed the most consistent association with MDD across the two samples. Polygenic risk scores (PRSs) from this pathway showed predictive accuracy better than whole-genome PRSs when using AUC statistics, logistic regression and the linear mixed model. In chapter 5, genome-wide Haplotype-block-based regional heritability mapping (HRHM) was applied to identify haplotype blocks significantly contributing to MDD. A haplotype block across a 24kb region within the TOX2 gene reached genotype-wide significance in GS:SFHS. Single-SNP and haplotype based association tests were used to localize the association signal within the region identified by HRHM, and demonstrated that five out of nine genotyped SNPs and two haplotypes were significantly associated with MDD. The results were replicated in the UK-Ireland group in PGC2-MDD. The brain expression of TOX2 and brain-specific LncRNA RP1-269M15.3 were also significantly regulated by MDD-associated SNPs within the identified haplotype block. The three studies highlight the value of the application of multiple population genetics and bioinformatics methods to multiple family-based and population-based cohorts in identification of risk factors for MDD.

Major Depressive Disorder is a prevalent and pervasive problem in the United States, and this mental disorder disproportionately affects adolescents of color. In particular, there is little research understanding how Hispanic/Latinx adolescents utilize and engage with mental health services, such as psychotherapy, to reduce their symptoms of depression, including factors that are positively and negatively related to engagement. As such, the aims of this study were to understand whether there were any relationships between presenting characteristics of adolescents seeking therapy for depression and their subsequent engagement with therapeutic services, with a focus on analyses examining trends in Hispanic/Latinx adolescents. To investigate these aims, we utilized data from a pilot study in which adolescents (n=42) received a mind-body intervention for depression called Mind-Body Skills Groups. We examined possible relationships between depression severity, age, Hispanic/Latinx background, and their interactions with engagement, as measured by attendance rates, self-reported motivation, and at-home skills practice. We hypothesized that high depression severity, high age, and being Hispanic/Latinx would all negatively influence engagement; we also hypothesized the depression-engagement and age-engagement relationships would be moderated by Hispanic/Latinx background. Results revealed initial relationships between lower age and being Hispanic/Latinx with higher attendance rates; depression severity was not related to attendance. When these relationships were further analyzed using hierarchical regression, no significant relationships between predictor and outcomes variables, as well as their interactions, were discovered. In an exploratory analysis investigating factors of adolescent depression using subscales, greater interpersonal problems predicted higher attendance rates. Results are interpreted relative to limitations of the small sample size and possible measurement concerns within this study, including a discussion of possible ways to improve related studies on Hispanic/Latinx youth in the future.

Carisbamate (CRS) and lamotrigine (LTG) are anticonvulsants which act mainly on neuronal voltage-gated sodium channels, that have been shown to have antidepressant-like effects in animal models of depression. In vivo electrophysiological recordings were carried out following 2 and 14 days of CRS or LTG administration. Overall firing activity in the dorsal raphe, locus coeruleus and ventral tegmental area were decreased with CRS. Similarly, a decrease in the dorsal raphe was also observed with LTG. Despite these presynaptic decreases in firing activity, both anticonvulsants exhibited significant enhancement of serotonergic transmission in the hippocampus as demonstrated by increased tonic activation of postsynaptic 5-HT1A receptors. This may be attributed to the observed desensitization of the terminal 5-HT1B autoreceptors. This study suggests that the enhanced serotonergic effect may be associated with an antiglutamatergic effect, and may contribute to the antidepressant-like effect of CRS in the forced swim test and the antidepressant properties of LTG.

This PhD investigated the efficacy of individual therapies for depression and went on to test metacognitive therapy (MCT) for major depressive disorder (MDD) in individual therapy and in transdiagnostic groups consisting of a range of disordersStudy 1 included a systematic review of meta-analyses comparing the effects of individual therapy for MDD across studies. The findings show small to moderate effect sizes between g=0.25 to d= 0.69 and recovery rates 34% to 47.9% for ITT analyses. However, studies are biased and lack objective definitions of recovery, remission and clinically meaningful change which makes comparisons across studies challenging. Study 2 aimed to test MCT in a single case study with four depressed Danes in an outpatient setting. Three out of four patients reached recovery levels (BDI-II smaller or equal to 8) in only five to eleven sessions and all four patients were recovered at 6-months follow-up. Study 3 involved a large randomised clinical trial (n= 153) in which the effect of MCT was compared to cognitive behaviour therapy (CBT) for MDD. Patients were allocated to up to 24 sessions of treatment and were assessed at pre, post and 6 months follow-up on primary and secondary measures. The mean number of sessions were significantly lower for MCT (5.5; SD = 2.4 versus 6.7; SD = 4.7) and MCT showed a higher completion rate (73.6% versus 65.4%). Both treatments were associated with significant improvements in depression measured with the HDRS and BDI-II. MCT was superior in its effects on the BDI-II and on secondary measures, showing a clear advantage of MCT. . Large ES were detected in both MCT and CBT. Using Jacobson and Truax (1991) criteria revealed that 76% reached recovery levels at post-treatment in MCT whereas 54% reached recovery in CBT. These findings were maintained for both conditions at 6-months follow-up. Study 4 evaluated the effect of MCT in a 6-week treatment protocol for mixed groups of diagnosis in an open trial (n= 131). Significant improvements were observed in outcomes and 85% of patients were reliably improved at post-treatment as measured on the HADS. These findings were maintained at follow- up and the treatment appeared effective in both anxious and depressed cases. In conclusion existing treatments for depression are effective but there is much room for increasing efficacy. MCT appeared more effective than a current treatment of choice; CBT in depression. MCT was also associated with significant improvement in anxiety and depression in patients in a transdiagnostic group setting. The results support the future study and implementation of MCT as an effective treatment option.

Carisbamate (CRS) and lamotrigine (LTG) are anticonvulsants which act mainly on neuronal voltage-gated sodium channels, that have been shown to have antidepressant-like effects in animal models of depression. In vivo electrophysiological recordings were carried out following 2 and 14 days of CRS or LTG administration. Overall firing activity in the dorsal raphe, locus coeruleus and ventral tegmental area were decreased with CRS. Similarly, a decrease in the dorsal raphe was also observed with LTG. Despite these presynaptic decreases in firing activity, both anticonvulsants exhibited significant enhancement of serotonergic transmission in the hippocampus as demonstrated by increased tonic activation of postsynaptic 5-HT1A receptors. This may be attributed to the observed desensitization of the terminal 5-HT1B autoreceptors. This study suggests that the enhanced serotonergic effect may be associated with an antiglutamatergic effect, and may contribute to the antidepressant-like effect of CRS in the forced swim test and the antidepressant properties of LTG.

Carisbamate (CRS) and lamotrigine (LTG) are anticonvulsants which act mainly on neuronal voltage-gated sodium channels, that have been shown to have antidepressant-like effects in animal models of depression. In vivo electrophysiological recordings were carried out following 2 and 14 days of CRS or LTG administration. Overall firing activity in the dorsal raphe, locus coeruleus and ventral tegmental area were decreased with CRS. Similarly, a decrease in the dorsal raphe was also observed with LTG. Despite these presynaptic decreases in firing activity, both anticonvulsants exhibited significant enhancement of serotonergic transmission in the hippocampus as demonstrated by increased tonic activation of postsynaptic 5-HT1A receptors. This may be attributed to the observed desensitization of the terminal 5-HT1B autoreceptors. This study suggests that the enhanced serotonergic effect may be associated with an antiglutamatergic effect, and may contribute to the antidepressant-like effect of CRS in the forced swim test and the antidepressant properties of LTG.

Social defeat is an ethologically relevant stressor that utilizes the natural establishment of social rank in male rodents and has been shown to be relevant to major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). In the present study, we wished to establish a social defeat stress model in combination with the chronic unpredictable stress model, which is considered a mild stressor to the rodent. In this way, we create a “double hit” model that may more accurately mimic severe stress that is common in both MDD and PTSD. In the present study, residents established dominance over the intruder for 10 consecutive days. In addition, social defeat stress was followed by another stressor given at random times during each day, i.e. chronic unpredictable stress. These unpredictable stressors included 30 min restraint, 1 h shaking/crowding, a cold water swim, a warm water swim or a tipped cage for 24 h. In one cohort of animals, brain tissue was taken 24 h after the last stressor for DNA. In a second cohort, animals were tested on a sucrose preference test in which two bottles containing 0.8% sucrose was placed on their cages for 3 consecutive days (days 8-10 of social defeat stress), and the total amount of sucrose was calculated relative to total volume consumed. Brain tissue analyses revealed significantly elevated DNA oxidation in white matter comparing stressed animals to non-stressed controls, consistent with what has been found in post-mortem white matter from MDD subjects. Further, animals given the social defeat + chronic unpredictable stress demonstrated a deficit in sucrose preference, a natural reward, revealing that these animals were anhedonic as compared to controls. Stressed animals also demonstrated fear of the intruder in a social interaction test performed one day after the social defeat/chronic unpredictable stress was complete. Therefore, it appears that social defeat plus chronic unpredictable stress produces a phenotype relevant to clinical data in humans.

This thesis comprises research investigating explicit EM biases in MDD during acute depression and euthymia (i.e., clinical remission). First, a systematic review was conducted to investigate whether acutely depressed and euthymic MDD participants display an explicit EM bias. An ‘explicit EM bias’ was operationally defined to denote enhanced memory for negative or positive stimuli compared to matched healthy controls (HCs). Studies that were included in this systematic review investigated explicit EM using free recall and recognition memory paradigms. The main finding from this investigation was that acutely depressed MDD participants do not display an explicit EM bias. An unintended consequence of this investigation was the identification that research on explicit EM in MDD during euthymia is surprisingly sparse. Next, building upon the findings from our systematic review, we conducted an empirical investigation of explicit EM within a sample of well-characterized euthymic MDD participants compared to age/sex/gender/IQ-matched HCs. In this study, participants performed incidental encoding (i.e., emotional reactivity) and recognition memory tasks (separated by one week). These tasks employed emotionally-valent picture stimuli obtained from the International Affective Picture System. Results from this study revealed that, compared to matched HCs, euthymic MDD participants do not display an emotional reactivity or explicit EM bias. Taken together, the findings from this thesis suggest that explicit EM represents a sub-domain of cognition that may be unaffected in individuals with MDD. Our findings have important implications for the unified model of depression and may represent a basis upon which future research can build in an attempt to understand the nuanced cognitive phenotypes associated with MDD. / Thesis / Master of Science (MSc) / Major depressive disorder (MDD) is one of the most common mental disorders worldwide. It is estimated that over 10% of Canadians will experience MDD at some point in their lifetime. The symptoms of MDD include, among other things: depressed mood, loss of interest in regular daily activities, and impairments in cognition (e.g., attention, emotion, memory, etc.). Clinicians and researchers have argued for years that MDD is associated with negative cognitive biases, including increased attention to, and more accurate memory for, negative information; however, attention, emotion and memory are general forms of cognition, and the existence of cognitive biases for specific sub-domains of cognition in MDD are largely unknown. Given that MDD has a negative effect on emotion and memory, one potentially important sub-domain of cognition is explicit emotional memory (EM; i.e., conscious memory for emotionally-stimulating information). The purpose of the current thesis was to investigate whether MDD, during both the active (i.e., acute) and euthymic (i.e., clinically-remitted) stages, is associated with explicit EM biases compared to healthy volunteers. This thesis discusses how patterns of explicit EM may be important for our understanding of the development of MDD.

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)

There is still a great deal that is unknown about various depressive conditions, though it is a very common affliction and cause of disability throughout the world. Not only do the underlying mechanisms of various types of depression remain uncertain, but the mystery of how different treatment options work and who will respond to them also persists. The aim of this study was to identify potential non-invasive biomarkers, to predict responsiveness to electroconvulsive therapy. Two hypotheses were investigated in this study. The first was that patient improvement from baseline on the neurocognitive, computer based pattern separation task prior to the third ECT treatment will correlate with a clinical antidepressant response. The second was that increased prefrontal slowing relative to baseline will correlate with a decrease in depressive symptoms. As a first step to validate this approach, a healthy control group performed both the pattern separation and EEG tasks once per week over the course of three weeks. Patient participants completed both tasks before their first ECT treatment, prior to their third treatment, and prior to their last treatment. A spectral analysis of EEG data was then conducted. Results indicated good test-retest reliability for the pattern separation task and EEG measurements across all three trials in the healthy control group. Results from patient data are inconclusive, but indicates that there is a change from baseline to subsequent trials for at least the EEG measurements. However, a larger sample size is needed to determine this. The limited results from this small patient sample suggest that these measurements may have clinical value in refining ECT treatment, and merit further study.