Psychiatry - Theses
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ItemPsychopharmacological and psychophysiological studies in normal subjects and psychiatric patients(University of Melbourne, 1976)
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ItemThe neuropsychiatric disorders of focal epilepsy( 2017)Neuropsychiatric disorders commonly co-exist with focal epilepsy. Despite intense investigation there remains significant limitations to our current understanding of the aetiological relationship between these conditions, as well as the clinical and radiological factors that are associated with the development of mental illness in epileptic patients. To address these questions I assembled a large cohort of consecutive focal epilepsy patients reviewed at a large tertiary referral centre over an 11-year period, and analysed relevant clinical, radiological and demographic findings using both cross-sectional (baseline evaluation) and longitudinal (serial assessments) study designs. For cross-sectional analyses, psychiatric and epilepsy comorbidity were comprehensively identified and compared to baseline MRI-determined Deep Brain Structure (DSB) volumes. In the prospective study, standardised psychiatric and quality of life assessments were obtained in a subset of patients and the development of mental illness compared to interval changes in DSB volumes. I focus on depression and psychosis, as they represent the two most prevalent psychiatric disorders identified, and classify focal epilepsy patients according to the site of seizure origin and presence of a lesion. Contrary to the common medical belief, I found that the rates of neuropsychiatric disorders in temporal lobe epilepsy were equivalent to those in extratemporal lobe epilepsy. There were no differences between those with and without psychiatric disorder by age, gender, and laterality of seizure, epilepsy severity or duration. Patients with non-lesional epilepsy, both temporal and extratemporal, have double the rate of depression compared to those with lesional focal epilepsy. There were high rates of quality of life difficulties in people with epilepsy and comorbid psychiatric disorders but the pattern of subjective concerns does not match objective clinician ratings. The hippocampal and amygdalae volumes of epilepsy patients were reduced compared to normal controls. People with co-existing epilepsy and depression had a trend towards smaller reductions in temporal lobe structures, which may represent differential expressions of progression through inflammation, trauma or emotional processing needs with either relative sparing or volumetric increases. People with psychosis and epilepsy have bilaterally reduced hippocampi compared to those with epilepsy, where reductions are predominantly ipsilateral to seizure focus. There is less evidence for amygdala change in psychosis, but a small relative increased volume was observed compared to those with epilepsy alone. There was no evidence of progression over time at a population level over 3.9 years, although there was greater variability in size in all epilepsy subjects compared to normal controls. These results convincingly argue against assumptions about the primary role of temporal lobe foci in the pathogenesis of psychiatric comorbidities in patients with epilepsy, whilst allowing for the possibility that disruption to frontotemporal networks may be a component in the development of psychiatric disorders. Progression is not an inevitable part of the natural history, at least over a 4 year period but it is possible that individuals may exhibit marked changes. They highlight the as yet unexplored possibility that the absence of a lesion as an epileptic site may be associated with greater risks of neuropsychiatric illness and allow for speculation that this may be related to inhibitory surround impacts, more extensive underlying diffuse abnormalities and disruption to frontotemporal connectivity.
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ItemFunctional brain networks in schizophrenia: mapping connectivity and topology at early and late psychotic illness stages( 2017)Schizophrenia is a severe mental disorder that is characterised by symptoms including hallucinations, delusions and disorganized thought. The cause of schizophrenia remains unknown; however, it is thought that a combination of genetics, environment and altered neurobiology play a role in the emergence and perpetuation of the disorder. Accumulating evidence suggests that disrupted brain network connectivity may in part underlie the pathophysiology of psychosis, and that network connectivity is to some extent genetically determined and heritable. However, there is still much to be learned surrounding the nature of network abnormalities and how they differ in early versus late psychosis. Exploring the underlying neurobiology at discrete clinical stages of psychotic illness creates a framework to evaluate the biological factors that may be contributing to the progression from early psychosis, to more advanced chronic stages of the disorder. This thesis used resting-state functional magnetic resonance imaging (fMRI) to characterise network functional connectivity and topology in early and late psychosis, as well as in a group of unaffected family members (UFM) of individuals with schizophrenia. Resting-state fMRI is a well validated and sensitive tool for probing the intrinsic functional integrity of the brain. Specifically, this thesis used a data-driven approach to map the temporal coherence of fMRI time series (functional connectivity) across the whole brain. To complement the resting-state functional connectivity (rs-FC) analysis, this thesis used graph theory to explore functional network topology. Network topology describes that brains ability to maintain a balance between local processing speed and global integration of information. These methodological approaches were used to investigate network abnormalities in three groups relative to healthy controls; a first-episode psychosis (FEP) group, a treatment-resistant schizophrenia (TRS) group and a group of UFM. This thesis aimed to investigate 1) whether rs-FC and network topology was abnormal in the early FEP stage of schizophrenia relative to healthy controls at two time-points (baseline and at 12-months follow-up); 2) whether rs-FC and network topology was impaired in a chronic TRS group relative to healthy controls; 3) whether abnormal rs-FC and network topology was evident in a group of UFM, and whether any network measure could be characterised as a marker of risk or resilience to psychosis in UFM. Firstly, results showed no evidence of abnormal rs-FC or topology in FEP individuals relative to healthy controls at baseline, or at the 12-months follow-up. Further, longitudinal changes in network properties over a 12-month period did not significantly differ between FEP individuals and healthy controls. Secondly, this thesis found widespread reductions in rs-FC in the TRS group that predominantly involved temporal, occipital and frontal brain regions. The TRS group also showed reduced global network efficiency and increased local efficiency relative to controls. Thirdly, TRS and UFM shared frontal and occipital rs-FC deficits, representing a ‘risk’ endophenotype. Additional reductions in frontal and temporal rs-FC appeared to be associated with risk that precipitates psychosis in vulnerable individuals, or may be due to other illness-related effects, such as medication. Functional brain networks were more topologically resilient in UFM compared to TRS, which may protect UFM from psychosis onset despite familial liability. Together, the body of work presented in this thesis provides a number of novel and unique findings that serve to advance the current state of knowledge regarding the pathophysiology and heritability of psychosis. Specifically, the work demonstrated that the latest most severe stage of psychosis, TRS, is associated with widespread reduced rs-FC, and that milder, yet similar patterns of dysconnectivity were observed in UFM, implying a genetic root to some, but not all of the observed network abnormalities. Network topology differed relative to healthy controls in both UFM and TRS patients, suggesting that functional network architecture is also disturbed in late psychosis, and again, results suggest a genetic/shared environmental basis for this characteristic. Our finding of no significant difference in rs-FC or network topology in our FEP sample suggests that there is a differentiation between biological processes occurring in early and late psychosis with a subgroup of individuals’ rs-FC potentially being unaffected in the FEP stage.
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ItemExploration of the NRG-ErbB genetic pathway for biomarkers of Clozapine mediated symptom remission and symptom severity in treatment-resistant schizophrenia( 2017)Schizophrenia is a disabling mental health disorder that is characterized by positive symptoms (delusions, hallucinations etc.), negative symptoms (apathy, social withdrawal, emotional blunting etc.) and cognitive deficits (impaired memory, lack of attention etc.). Current pharmacological treatment includes typical and atypical antipsychotics but 20-30% of patients do not adequately respond to these treatments and are thus defined as treatment-resistant. Clozapine is indicated for the treatment of treatment-resistant schizophrenia (TRS). However, biomarkers of clozapine mediated symptom remission and symptom severity in TRS have yet to be identified. One promising biomarker is neuregulin 1 (NRG1), a growth factors that activates ErbB receptor tyrosine kinases and initiates the NRG-ErbB signalling pathway, which plays a key role in neurodevelopment. Genomic, transcriptomic, and proteomic abnormalities in NRG-ErbB pathway have been linked to schizophrenia and clozapine has been shown to modulate NRG1 gene and protein expression. Thus, NRG-ErbB pathway gene and protein expression profiles, as well as genetic variation, may serve as biomarkers for clozapine mediated symptom remission and symptom severity. In this thesis, we will present our investigation of the peripheral gene and protein expression levels of NRG-ErbB pathway genes in TRS patients and healthy controls and how they relate to clozapine mediated symptom remission as well as symptom severity. In addition, we will discuss the role genetic polymorphisms in NRG1 play in regulating its gene and protein expression. Finally, we will present results from healthy peripheral blood mononuclear cells exposed in vitro to clozapine for 24 hours and seven days and discuss the effects of clozapine on NRG-ErbB pathway gene and protein expression. Chapter 1 contains systematic review of scientific literatures and justifies the main 3 goals of the thesis. Chapter 2 of this thesis aimed at investigation of the candidate SNPs and microsatellites within the NRG1 gene among 16,720 patients, 20,449 controls, and 2,157 family trios via a meta-analytic procedure. We found significant association for three polymorphisms at the 5’ end (rs62510682, rs35753505, and 478B14-848) and two (rs2954041 and rs10503929) at the 3’ end of the NRG1 with schizophrenia. We could not find association for haplotypes. Chapter 3 aimed to assess the peripheral expression pattern of major NRG1 mRNA isoforms in whole blood and NRG1-β1 protein in serum in patients with TRS to find clinically useful biomarkers of clozapine mediated symptom severity and symptom remission. Using RT-qPCR we found upregulation of three NRG1 mRNA isoforms (NRG1 EGFα, NRG1 EGFβ, NRG1 typeI(Ig2)) in whole blood in TRS patients. However, protein assay via ELISA showed lower level of serum NRG1-β1 in TRS patients but it was confounded by smoking. Expression of NRG1 EGFα, NRG1 EGFβ was also negatively correlated with age of illness onset. In Chapter 4, we continued to examine the peripheral mRNA expression pattern of the major NRG-ErbB pathway downstream signaling genes in TRS patients and controls to see if increased expression in ligands leads to overexpression of receptors and subsequent upregulation of the full pathway in treatment-resistant schizophrenia. We found that five mRNA transcripts (ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1) were upregulated in TRS patients, although only one (P70S6K) survived after correction for multiple comparisons. Moreover, investigation of the clinical factors revealed that expression of ErbB2, PIK3CD, PIK3R3, AKT1, mTOR, and P70S6K were negatively correlated with duration of illness. Chapter 5 summarises the main findings of the thesis, its relevance to previous literature, advancement of knowledge, implications and future steps in investigation of the NRG-ErbB genetic pathway for suitable biomarkers in schizophrenia, more specifically treatment-resistant schizophrenia.
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ItemStriatal morphology, frontostriatal circuits and functional correlates in neurodegenerative disease( 2017)This thesis comprises five major sections, based on research work that I have led via an international network of collaborators that I established. The studies in this thesis are targeted at characterising quantitative measures of the structural integrity of recurrent fronto-striato-pallido-thalamo-cortical neural circuits and the relationship of such measures to clinical manifestations of neurodegenerative disease. Section 1 presents the foundational basis of my conceptualisation of quantitative measurement of human brain neuroanatomical structures (shape and volume – morphology), specifically, the striatum, as a means of developing in vivo biomarkers that correlate to clinical intermediate phenotypic manifestations (endophenotypes) of neurodegenerative disease. I describe here the international collaborative research network I established to conduct the research program embodied in this thesis. Section 2 involves the results of studies of the in vivo morphology of the striatum in neurodegenerative diseases in which neuropathology of the striatum has been implicated, comparing relative differences in striatal morphology between disease groups. In Section 3, I extend the work in Section 2 by examining whether quantitative morphology (morphometry) of the striatum correlates to endophenotypic cognitive, emotional, behavioural and motoric manifestations of the specific neurodegenerative diseases. In Section 4, the theoretical underpinning of the conceptualisation of the thalamus as another target for quantitative morphology and correlation to endophenotype, as well as the development of an innovative quantitative manual measurement method for the thalamus, is described. Through the works in Sections 1-4, I had come to conceptualise a subcortical connectome (Section 5): a quantitative mapping of the hubs and spokes of recurrent neuroanatomical circuits, as well as potentially the spaces between the structures underlying and connecting to the cortex. In Section 5, I also describe the development of a further vision for my collaborative research program. Section 1: The first two chapters describe the theory and hypotheses underpinning my research on the quantitative morphometry (measurement of shape and volume) of fronto-striato-pallido-thalamo-cortical (frontostriatal) circuit hubs in neurodegenerative disease. Chapter 1 describes the conceptual background for the study of striatal morphology, a key hub of frontostriatal circuits, as a potential biomarker in neurodegenerative disease. Chapter 2 extends the striatal morphology biomarker model to the frontotemporal dementias towards establishing potential intermediate phenotypes (endophenotypes). Chapter 3 describes the Australian, US, Scandinavian Imaging Exchange (AUSSIE) research network I established to conduct the research program and to expand our knowledge of the role of the subcortical connectome as a potential biomarker in neurodegenerative disease. Section 2: Chapters 4-7 describe the application of the theory and methods outlined in section 1, initially in differentiating between neurodegenerative disease groups that have striatal morphologic change implicated as part of disease progression. Chapters 3 and 4 describe cross-sectional studies of differential striatal morphometry in frontotemporal dementia subtypes and Alzheimer’s disease (AD). Chapter 5 describes the application of striatal morphometry to progressive supranuclear palsy (PSP), whilst Chapter 6 describes cross-sectional studies of differential striatal morphometry in Huntington’s disease (HD), frontotemporal dementia (FTD) and Alzheimer’s disease. Section 3: Chapters 8-10 describe the extension of the striatal morphometric work to investigate functional correlations of morphology with clinical manifestations of the cognitive, emotional and motor circuits subserved by frontostriatal circuits, i.e. towards establishing an endophenotype. Chapters 7 and 8 describe correlations of striatal morphometry with executive dysfunction and gait disturbance in a cohort of persons with age-related white matter change respectively. Chapter 9 describes correlations of striatal morphometry with measures of behavioural change in frontotemporal dementia. Section 4: Chapters 11-12 describe development of methods for further research into another hub in fronto-striatal circuits (Chapter 10). Chapter 10 describes the characterisation of another crucial hub in frontostriatal circuits, the thalamus, and the rationale for further investigation. Chapter 11 describes the development of a method for manual neuroanatomical measurement of the thalamus for quantification of its shape and volume, i.e. morphology, in neurodegenerative disease. Section 5: Chapter 13 describes the conceptualisation of the overarching concept of the subcortical connectome to direct further research extending to other key subcortical structures and spaces in neurodegenerative disease. This thesis describes the development of quantitative measures of the shape and volume of crucial brain neurocircuit hubs (quantified morphology = morphometry) in human neurodegenerative disease that correlate to clinical cognitive, emotional, behavioural and motoric manifestations of disease aimed towards developing endophenotypes.
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ItemInvestigating complex PTSD for understanding the consequences of trauma in a homeless sample( 2017)Background: The International Classification of Diseases (ICD)-11 that is due for release in 2018 will introduce revised Posttraumatic Stress Disorder (PTSD) criteria as well as a new diagnosis of Complex PTSD. Criteria for this diagnosis of Complex PTSD has been under development, with considerable debate and revision of proposed criteria to this point. This study aimed to test the proposed ICD-11 criteria for PTSD and Complex PTSD in a sample of people who have experienced homelessness. Objective: This study investigated the fit of the ICD-11 Complex PTSD construct with mental health symptoms as reported by a sample of people who have experienced homelessness. This population was chosen to investigate the construct based on previous literature and clinical experience, suggesting that the experience of homelessness is largely synonymous with significant histories of trauma and associated mental health difficulties. Method: Two studies were conducted. First, a pilot study of semi-structured interviews were completed with individuals (N = 20) known to have a history of homelessness and trauma exposure. Findings were used to inform the second study: a cross-sectional empirical investigation of trauma exposure, related symptoms and comorbid mental disorders. Participants (N = 206) were service users who attended homeless support agencies in Melbourne, Australia. Latent Class Analysis (LCA) was used to investigate ICD-11 diagnostic groups in the sample. Results: The sample experienced very high levels of trauma exposure with the majority experiencing childhood abuse and neglect. Four distinct classes of participants emerged in relation to the potential to meet the proposed diagnosis: Class 1, ‘LCA Complex PTSD’ (n=119, 58%), Class 2, ‘LCA no diagnosis’ (n= 34, 16%); Class 3, ‘LCA PTSD’ (n=23, 11%) and finally Class 4, ‘LCA affect, social and self difficulties’ (n= 28, 14%). While those with an ICD-11 Complex PTSD diagnoses fell into the LCA Complex PTSD class, so also did those with an ICD-11 PTSD diagnosis. Conclusions: Our findings provide support for the proposed distinction between Complex PTSD and PTSD. The sample used in this study, of people experiencing homelessness, may have impacted on our findings given they were a highly exposed trauma sample.
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ItemAstrocyte neuropathology in autism: role of neuroinflammation & glutamatergic signalling( 2017)Alterations in excitatory glutamatergic signalling together with increased astrocytic activation and neuroinflammation have been observed in the brain of individuals with autism. Astrocytes play important roles in developmental corticogenesis and neurogenesis, as well as regulating glutamate receptor signalling and intercellular glutamate levels at the glutamatergic tripartite synapse. The overall aim of my PhD was to investigate astrocytic neuropathology in autism and its potential interaction with disruptions in mGluR5 signalling. I conducted a post-mortem stereological investigation within the white matter of the dorsolateral prefrontal cortex (DLPFC) to assess density of astrocyte and other glia utilising the optical fractionator. In addition, astrocytic somal size was assessed via the nucleator and total astrocyte process length estimated utilising the spaceballs probe. Using an in-vitro approach I then explored the effect of Poly I:C mediated astrocyte activation on mGluR5 glutamatergic signalling. This included assessing levels of the pro-inflammatory markers IL-6 and Rantes using ELISA, gene expression of astrocytic and glutamatergic genes via qPCR, as well as mGluR5 activity using a radioligand binding assay. Finally, I characterised the gene and protein expression of astrocyte markers of human pluriporent stem cells (hPSC) derived astrocytes using qPCR and immunohistochemistry, as well as cytokines levels using ELISA. The current study revealed no change in astrocyte density or activation morphology within the white matter of the DLPFC in autism versus age matched controls. There was also no alteration in astrocyte cell somal size and total process length. In-vitro Poly I:C induced astrocyte activation demonstrated reduced mGluR5 binding and mRNA expression, with disruption to other astrocytic glutamatergic elements. A novel protocol for differentiating. human pluripotent stem cells into astrocytes was developed, with hPSC-derived astrocytes displaying morphology similar to that of primary human foetal astrocytes and expressing mature astrocyte markers at the gene and protein level, as well as having the ability to be activated upon exposure to Poly I:C. My findings suggest that astrocyte activation within the brain in autism may be less severe than previously appreciated, with the absence of severe astrocytic hypertrophy and increased proliferation not observed. Results from the mechanistic in-vitro studies suggest that mGluR5 and glutamatergic signalling dysregulation can occur as a result of astrocyte activation, and that modulation of mGluR5 through positive allosteric modulation may have potential benefits in reversing some of these astrocyte activation mediated glutamatergic disruptions. Finally, our improved protocol for hPSC astrocyte differentiation provides a simple and efficient method to derive mature and functional astrocytes as an in-vitro model for autism and other neurological disorders.
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ItemIs epidermal growth factor system dysfunction associated with schizophrenia subtypes?( 2017)Schizophrenia is a severe neuropsychiatric disorder characterised by positive symptoms such as delusions and hallucinations, negative symptoms such as amotivation and asociality and cognitive symptoms such as working memory and processing speed deficits. It is also accompanied by consequential clinical features and paradigms such as suicidality and treatment resistance. Clozapine, an atypical antipsychotic medication, mitigates suicidality and is efficacious in treatment resistance. The unique actions of clozapine may be due to its ability, but not other anti-psychotic medications, to recruit the Epidermal Growth Factor (EGF)/EGF Receptor (EGFR) signalling system. In this thesis, we used post mortem brain samples from the dorsolateral prefrontal cortex (DLPFC) of 37 individuals with schizophrenia and 37 without the disorder, who were a matched cohort. We utilized quantitative PCR to examine the EGF receptor. Then, to establish the distribution and localisation of EGFR in schizophrenia, we supplemented our quantitative studies with protein assays for the EGFR protein and in situ hybridization followed by autoradiography for EGFR mRNA. In order to then examine the relationship of cognitive functioning in schizophrenia and the EGF/EGFR signalling molecules, we examined the cognitive profile of 449 persons with schizophrenia and 637 control participants from the Australian Schizophrenia Research Bank database. We also examined if the cognitive performance in schizophrenia cluster to inform disorder sub typing and subsequently explored the relationship of cognition in schizophrenia to EGF/EGFR genomic signals by way of a candidate gene approach. In our studies, we found that EGFR protein levels are significantly increased in the DLPFC of persons with schizophrenia, although, there were no mRNA expression differences. The older neopallidal layers of the cortex showed that participants who had died of non-suicide had lower EGFR mRNA expression. Similarly, those without a history of suicide attempts showed a decreased mRNA expression more widely in the neopallidal layers. We also showed layer specific changes in relation to a number of clinical features in schizophrenia. In comparison to all other previous studies, we showed a case control difference without the need for stratification that persons who carry the AA genotype of the EGF A61G single nucleotide polymorphism (SNP), are more likely to have schizophrenia. We also showed that there are three clusters of cognitive performance within schizophrenia and treatment resistance and 2 NRG1 SNPs associate with various cluster memberships significantly. Our results show evidence to support the role of EGF/EGFR signalling in mediating and moderating several clinical parameters in schizophrenia such as treatment resistance, suicidality and cognitive functioning. We also have identified a relationship between EGF/EGFR signalling system hypofunction and schizophrenia and propose that clozapine may augment this signalling thereby mitigating this hypofunctional state. Together, these results may offer further insights into the relationship between the EGF signalling system, cognition and clinical features of schizophrenia and allow for development of novel biomarker strategies to identify early at-risk patients.
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ItemGathering longitudinal outcomes in wellbeing after burns (GLOW) study( 2017)Objective: Burn injuries are common and debilitating traumatic injuries that are associated with a range of post-injury maladjustments. Burn patients experience high rates of psychiatric morbidity, have low rates of return to work and experience reductions in quality of life in the months and years after discharge. Despite this, very limited longitudinal research has evaluated these outcomes in less severe burns, and has examined what early psychosocial risk factors may contribute to these outcomes. Further, common limitations across burns psychological research include variation in sample characteristics, limited reporting of findings, simplistic methodologies and small sample sizes. Aims: In light of the limitations in the burns literature, this research study aimed to investigate what pre-burn, acute and 3-month early psychosocial risk factors contribute to psychopathology, quality of life and return to work outcomes 6-months after burn injury. Method: Consecutive admissions to the burns unit in Melbourne, Victoria with a Total Burned Surface Area of 20% or less were recruited for the study. 109 burn patients provided consent to participate, and 74 completed the 3 and 6-month follow-up assessments. Participants completed structured clinical interviews to measure psychiatric history and post-trauma symptomatology, and a battery of self-report questionnaires assessing factors such as pain, sleep quality, appearance dissatisfaction, anger and social support. Bayesian Structural Equation Modeling was conducted for each outcome (psychopathology, quality of life, return to work) to identify early psychosocial contributors to these outcomes. Results: At 6-months, 28.4% of participants met criteria for an Axis I psychiatric disorder, and while only 3.0% met criteria for PTSD, 7.5% met criteria for subsyndromal PTSD. Quality of life was most affected in relation to taking care of the burn and skin sensitivity. 14% reported not having returned to work at 6-months as a result of the burn, and many participants reported at least moderate difficulty with performing work tasks. Symptoms of PTSD at 6-months were predicted by 3-month mental health symptoms, higher 3-month pain and social support. Symptoms of depression were predicted by higher age and more mental health symptoms at 3-months. Symptoms of anxiety were predicted by 3-month mental health symptoms only. Quality of life, as indicated by the domains of Affect and Relations, Skin Involvement and Functioning, were significantly predicted by various earlier risk factors, but they differed by domain outcome. Specifically, Affect and Relations, meaning problems related to affect, interpersonal relationships and sexuality, was predicted by 3-month mental health symptoms and higher pain. Skin involvement, meaning problems related to skin sensitivity and taking care of the burn, was predicted by burn severity (TBSA) and 3-month mental health symptoms. Functioning at 6-months was only significantly predicted by higher age. Problems returning to work at 6-months was significantly predicted by 3-month greater pain and more mental health symptoms. Conclusions: The findings from this study suggest that even in minor burn injuries, maladjustment is common in the months following the burn. Specifically, these burns experience elevated rates of psychiatric disorders, reduced quality of life and problems returning to work. While these outcomes are related, the findings further demonstrate that different risk factors are important to predicting each of these outcomes. Overall this study highlights the need for early, although not acute, psychosocial screening of even minor burns in order to improve psychosocial services available to minor burns.
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ItemNegative mood and depressive symptoms from mid-life to late life: results of the women’s healthy ageing project( 2017)A substantial body of research has been conducted examining depressive symptom prevalence in the early stages of reproductive ageing, yet few studies have examined prevalence into the early and late postmenopause. Much of what is known about the relationship between mood and reproductive ageing is drawn from longitudinal, epidemiological studies of varying durations. This thesis aims to extend this research by utilising data from an Australian longitudinal study, the Women’s Healthy Ageing Project (WHAP), which is of adequate duration to assess mood changes from the late reproductive stage through to late postmenopause. The Women’s Healthy Ageing Project is an ongoing longitudinal, epidemiological study examining factors that contribute to women’s healthy ageing in a sample of community dwelling Australian women. At baseline, in 1992, women were aged between 45 and 55 years, with a mean age of 50 years. In 2012, the last assessment point utilised in this work, women were aged between 65 and 75 years. This project utilises data drawn from the first twenty years of the study, providing an assessment of mood factors spanning two decades. Measures used included the Negative Mood scale from the Affectometer 2 , the Centre for Epidemiological Studies Depression Scale – Short Form (CESD-SF) administered between 2002 and 2012, and the Geriatric Depression Scale – Short Form (GDS-SF) administered in 2012. The thesis is comprised of two main studies, each with two sub-studies. Study 1 explored prevalence rates of negative mood and depressive symptoms in regards to chronological ageing (Study 1.1). In the second sub-study negative mood scores (Affectometer-2) and depressive symptoms (CESD-SF) were examined in relation to the stages of reproductive ageing (Study 1.2). Within this thesis particular emphasis was placed on examining mood scores in the context of early postmenopause and late postmenopause, based on the STRAW+10 criteria, rather than the broader category of ‘postmenopause’ employed by numerous studies. The findings from Study 1 demonstrated that both negative mood and depressive symptoms decreased significantly as women transitioned from mid-life to late life. Scores of negative mood and depressive symptoms were significantly higher in the early postmenopause than the late postmenopause, suggesting the need to distinguish between these two stages in any future research relating to mood and reproductive ageing. While there were significant reductions for both mood measures between the stages of reproductive ageing, age was found to have a stronger association with score. In exploring mood and reproductive ageing, chronological ageing should always be considered. The second part of the thesis, Study 2, determined the extent to which the prevalence of depressive symptoms was consistent between the WHAP cohort and an age matched cross-cultural sample, in this case a sample of community dwelling Japanese women. With the increasing number of women migrating to Western populations, the effects of cross-cultural influence on item selection and score on depressive symptom measures needs to be evaluated to test the generalisability of findings. The first sub-study, Study 2.1, compared the prevalence rates of depressive symptoms in the WHAP cohort and an age matched sample of Japanese women from the Kumamoto prefecture in Southern Japan. Of the Japanese cohort 33% scored within the mild/moderate range on the GDS-SF, compared to 9% of the Australian women. This prompted an examination of cultural influences on item selection and possible inflation of scores to determine if the depressive symptom prevalence reported was a true phenomenon or impacted by the type of measure being used to assess the depressive symptoms (Study 2.2.). Culture specific profiles of item endorsement were found, and it was determined that the GDS-SF was a good fit for assessing the Australian cohort but not for the Japanese cohort. These findings suggest that the GDS picks up on distinctive aspects of depressive symptomatology in different cultural samples, despite the measure being well established to assess symptoms across populations. Any cross-cultural examination of depressive symptoms should use caution when interpreting results and further work in this area is needed to examine culture specific presentations of symptoms.