Psychiatry - Theses
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ItemThe development and evaluation of guidelines and an information website for adult caregivers of adults with bipolar disorder( 2012)Background and aim: Bipolar disorder is a challenging and usually chronic illness associated with occupational and social consequences that affect the lives of both the person and those who care for them. Family members and friends with a primary role in supporting an adult with bipolar disorder (caregivers) are at risk of caregiver burden, depression and health problems. However, there is little evidence-based information to guide caregivers in ways to provide helpful support and maintain their own wellbeing. Thus, the aim of this project was to develop an easily accessible resource with relevant and useful information and suggestions for caregivers. Methods: The project was divided into two phases. In the first phase a Delphi consensus study was conducted with expert clinician, caregiver and consumer panel members to establish what information and suggestions to include in guidelines for adult caregivers of adults with bipolar disorder (N=143). In the second phase of the project, a web-based version of the guidelines www.bipolarcaregivers.org was developed to make this information easily accessible over the Internet. A formative evaluation of the website was conducted to establish the relevance and usefulness of the information to caregivers and how it could be improved. This involved an initial online survey for visitors to the website (N=536) and a more detailed follow-up email feedback survey, sent to interested caregivers of adults with bipolar disorder a month later (N=121). Results: There was mostly high consensus about what to include in the guidelines between the different Delphi panels. Out of a total of 626 survey items rated by the Delphi panels over three survey rounds, 537 (86%) were included in the guidelines. In the evaluation study, the majority of caregiver visitors who completed the initial feedback survey (97%) reported thinking that the information on www.bipolarcaregivers.org was “very useful” or “useful”. Similarly, between 86.4%-97.4% of caregivers who responded to the follow-up survey rated the information they read as “very useful" or “useful”. Nearly 93% found the information relevant and all participants said it gave them the impression that others were going through similar experiences. Over two thirds reported using the sections on providing support and working with the person to manage the illness and gave concrete examples of how they implemented the guidelines. Nevertheless, despite the overall positive results, qualitative feedback suggested practical ways the website could be further refined. Discussion: This project resulted in a publicly accessible information resource www.bipolarcaregivers.org that was reported to be relevant and useful by most of the users in the evaluation study. The website includes brief information summaries and a PDF of the guidelines that can easily be printed. The guidelines have been translated into booklets in Portugal and Brazil. According to Google Analytics, traffic to the website continues to increase. Www.bipolarcaregivers.org may form an initial step in providing basic information to caregivers caring for an adult with bipolar disorder. Those who care for people with more severe and complex illness presentations might benefit from additional support and training to cope with their caregiving role. Similarly, more detailed or tailored information and support may be suitable for caregivers who are already very experienced or well informed. A strength of this project is its consideration of the views of stakeholders and careful comparison and integration with the research literature. Future studies could combine stakeholder involvement with more rigorous evaluation of www.bipolarcaregivers.org and its long-term effect on caregiver and consumer outcomes. If funds become available, the website could be made more interactive to enhance learning of information and skills, and offer more tangible and tailored support. Background and aim: Bipolar disorder is a challenging and usually chronic illness associated with occupational and social consequences that affect the lives of both the person and those who care for them. Family members and friends with a primary role in supporting an adult with bipolar disorder (caregivers) are at risk of caregiver burden, depression and health problems. However, there is little evidence-based information to guide caregivers in ways to provide helpful support and maintain their own wellbeing. Thus, the aim of this project was to develop an easily accessible resource with relevant and useful information and suggestions for caregivers. Methods: The project was divided into two phases. In the first phase a Delphi consensus study was conducted with expert clinician, caregiver and consumer panel members to establish what information and suggestions to include in guidelines for adult caregivers of adults with bipolar disorder (N=143). In the second phase of the project, a web-based version of the guidelines www.bipolarcaregivers.org was developed to make this information easily accessible over the Internet. A formative evaluation of the website was conducted to establish the relevance and usefulness of the information to caregivers and how it could be improved. This involved an initial online survey for visitors to the website (N=536) and a more detailed follow-up email feedback survey, sent to interested caregivers of adults with bipolar disorder a month later (N=121). Results: There was mostly high consensus about what to include in the guidelines between the different Delphi panels. Out of a total of 626 survey items rated by the Delphi panels over three survey rounds, 537 (86%) were included in the guidelines. In the evaluation study, the majority of caregiver visitors who completed the initial feedback survey (97%) reported thinking that the information on www.bipolarcaregivers.org was “very useful” or “useful”. Similarly, between 86.4%-97.4% of caregivers who responded to the follow-up survey rated the information they read as “very useful" or “useful”. Nearly 93% found the information relevant and all participants said it gave them the impression that others were going through similar experiences. Over two thirds reported using the sections on providing support and working with the person to manage the illness and gave concrete examples of how they implemented the guidelines. Nevertheless, despite the overall positive results, qualitative feedback suggested practical ways the website could be further refined. Discussion: This project resulted in a publicly accessible information resource www.bipolarcaregivers.org that was reported to be relevant and useful by most of the users in the evaluation study. The website includes brief information summaries and a PDF of the guidelines that can easily be printed. The guidelines have been translated into booklets in Portugal and Brazil. According to Google Analytics, traffic to the website continues to increase. Www.bipolarcaregivers.org may form an initial step in providing basic information to caregivers caring for an adult with bipolar disorder. Those who care for people with more severe and complex illness presentations might benefit from additional support and training to cope with their caregiving role. Similarly, more detailed or tailored information and support may be suitable for caregivers who are already very experienced or well informed. A strength of this project is its consideration of the views of stakeholders and careful comparison and integration with the research literature. Future studies could combine stakeholder involvement with more rigorous evaluation of www.bipolarcaregivers.org and its long-term effect on caregiver and consumer outcomes. If funds become available, the website could be made more interactive to enhance learning of information and skills, and offer more tangible and tailored support.
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ItemProfessional sexual misconduct as a breach of trustworthiness: a moral typology of doctors who have engaged in professional sexual misconduct( 2012)The importance of trustworthiness in the medical profession seems obvious and beyond question. Despite the importance of trustworthiness for the medical profession, there is no established understanding of what the standards of trustworthiness must be in the context of the doctor – patient relationship. If the medical profession does not hold a shared understanding of the expectations of trustworthiness and its standards, the community it serves certainly cannot. An established understanding of trustworthiness is necessary as both a normative standard, and as a basis for understanding the ways in which professional misconduct deviates from the standards expected of the medical profession. I consider philosophical examinations of trustworthiness, and conclude that it is only those versions of trustworthiness which require regard for the preferences of the truster, and an ability to communicate the limits of their own trustworthiness in the trustee that are appropriate for the medical profession. I accordingly define standards of trustworthiness as they must be considered for the medical profession. Professional sexual misconduct and the ways that professional sexual misconduct is understood as a failure of professional conduct are examined. I argue that existing moral frameworks, which are based upon an understanding of professional sexual misconduct as a failure of informed consent, are problematic. I argue that professional sexual misconduct is readily understood as a breach of trustworthiness, and examine the ways that professional sexual misconduct breaches standards of trustworthiness. I therefore propose the Framework for Trustworthiness in Doctors, which demonstrates potential moral implications of different forms of professional sexual misconduct. Finally, I demonstrate application of the Framework for Trustworthiness in Doctors to four cases of professional sexual misconduct. I argue that application of this Framework has utility in considering such cases, and reflects the mandate of the Medical Board of Australia as well as reasonable community expectations. I conclude by proposing other potential uses for the Framework, and the research necessary to justify these applications.
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ItemThe expectations and experience of a diagnosis of dementia: lessons from patients and families( 2012)Objectives: To explore the expectations of the patient and family in attending a memory clinic. In particular, do the patient and family expect, in all instances, to be told of the diagnosis? To ascertain what information is understood by the patient and carer at the feedback session, pinpointing aspects of the feedback session that were of value, locate areas of the presentation that could be improved and perhaps identify information that is not provided but could be of value. Sample: The sample was drawn from attendees at two Melbourne Memory Clinics and private patients of two associates of the National Ageing Research Institute (NARI). Methodology: The study consisted of a series of four studies. Phase I consisted of two questionnaires, one for the patient and one for the next-of-kin to complete, asking about their wants and expectations of their appointment at the memory clinic. Phase II consisted of an interview with the patient and next-of-kin at the treatment review visit. Questions related to their recall of the ‘feedback’ session, their understanding of a diagnosis of dementia and the best way to impart the diagnosis. Phase III consisted of a second interview which commenced with a recap of the first. Patient and next of kin were asked if they had changed their minds about anything they had said the first time and if they had anything to add. For Phase IV, a focus group of specialists in the diagnosis of memory disorders was conducted. Pertinent results from phases I and II were presented for discussion. Results: Phase I demonstrated that 84% of patients expected to be told of their diagnosis and 90 % wanted to be told. Their reasons for this were: to make plans/put affairs in order, to receive treatment, to get help/learn strategies to cope, “It’s my right to know/I want to know the truth”. Seventy per cent of patients thought the best way to present a diagnosis of dementia was to use a direct/straight forward approach, 11% thought a straight forward but sensitive approach was required. Seventy five per cent of next of kin thought the diagnosis should be presented in a straight forward fashion. Following a recap of this interview in Phase III, none of the respondents wanted to alter anything they had said. Psychological adjustment theory (PAT) was identified as a useful theory to explain the approach used by patients and their families in adapting to the diagnosis. During the Phase IV specialist focus group, discussion was concerned with current practice and retention of information from the feedback session. Techniques were suggested to improve patient and carer recall of the feedback session. Conclusions: The patient and their next of kin seek accurate information in order to plan their futures and manage their affairs and lifestyle even before a definitive diagnosis has been made. Gathering information, finding solutions for problems, planning and looking for support from the community are healthy strategies used by the individual to maintain self-esteem during the process of adaptation to a chronic illness. These strategies are also the building blocks of successful adaptation to a chronic illness or injury, as described by PAT.
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ItemSupporting the adolescent mother-infant relationship: trial of a peri-natal attachment intervention( 2012)This thesis tested whether a new, brief, peri-natal, attachment intervention, provided to pregnant adolescents in addition to their routine maternity care, would improve the quality of the relationship they were able to form with their infant. The ‘AMPLE’ intervention aimed to prevent some of the significant attachment relationship difficulties and adverse developmental consequences observed among infants of adolescent mothers, by helping pregnant adolescents see their baby as a person during the transition to motherhood. A pre-test, post-test, control group study design was used to test the intervention in a convenience sample of pregnant adolescents recruited from a specialized, multi-cultural service for young women at a large, tertiary, maternity hospital in Melbourne (N = 97). The acceptability of the study was high, with a study participation rate of 82.9% and a completion rate of 75.3%. Among the study completers (n = 73), 35 participants received the intervention in addition to routine care (intervention group) and 38 received care as usual (control group). Receipt of the intervention was associated with significantly better mother-infant interaction, videoed at home at infant age 4 months and coded using the Emotional Availability Scales 4th Edition. Coding of 20-minutes of free play (n = 73) revealed significantly reduced negative maternal behaviours known to adversely affect infant attachment (hostility and intrusiveness) in the intervention group compared with the control group. Coding of 20 minutes of free play followed by a five minute separation-reunion episode (n = 55) revealed significantly increased maternal sensitivity, known to positively influence infant attachment, in addition to reduced maternal hostility and intrusiveness, in the intervention group. The effect sizes were medium to large. The ‘AMPLE’ intervention therefore appears to be an acceptable,affordable and effective means for maternity services to support the adolescent mother-infant relationship. Further research is warranted and should include a cluster randomized controlled trial to confirm the findings and establish causality. The implication of the findings for clinical practice is that the AMPLE intervention could be manualised and offered as part of routine maternity care, with the potential to positively influence the developmental trajectory of young mothers and their babies from the beginning.
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ItemInvestigating the association between regular cannabis use and human brain structure( 2012)Regular cannabis exposure is related to significant adverse mental health outcomes that constitute a major burden on addiction treatment services. Converging evidence suggests that these adverse outcomes are persistent in nature and are mediated by persistent neurobiological alterations occurring in brain regions that are high in cannabinoid receptors (CB1). These brain regions are involved in mediating psychopathology and impaired neurocognition, both of which are observed in regular cannabis users (CB). Structural brain imaging techniques have proven useful in providing preliminary evidence for persistent brain alterations in regular CB users. However, the literature to date is limited by numerous methodological factors that prevent characterisation of structural brain abnormalities in CB users, including small sample sizes, limited investigation on the role of sex on the obtained findings, psychiatric and substance use comorbidity, poor sample characterisation and lack of analyses exploring the impacts of differing cannabis use patterns and psychopathology/neurocognitive measures on brain regional volumes in CB users. This thesis aimed to overcome the methodological limitations of the structural imaging literature to date, to provide an improved characterisation of the association between regular cannabis exposure and human brain morphology. To this end, high-resolution structural Magnetic Resonance Imaging (sMRI) was utilised to cross-sectionally compare regular CB users to age and sex-matched non-cannabis using controls (HC) in the largest sample examined to date. Regular CB users with a high inter-individual variability in levels of cannabis exposure with respect to dosage, frequency and duration of cannabis use were recruited. All participants were screened for significant psychopathology and exposure to substances other than cannabis, and were comprehensively characterised with respect to cannabis use patterns, psychopathology symptoms and neurocognitive measures. Key cannabis use patterns and measures of psychopathology, neurocognitive performance and global functioning were ascertained. The association between these variables and regional brain volumes was then examined in brain structures high in CB1 receptors and involved in mediating psychopathology and altered neurocognition observed in regular CB users. These regions included: - The hippocampus, which is involved in mediating memory and learning, psychopathology symptoms, stress regulation and reward processing; - The amygdala, which mediates emotional and reward processes, and is involved in the neurobiology of a range of psychiatric disorders and in the regulation of the stress response; - The pituitary gland that, being a core part of the stress regulation system, is involved in the neurobiology of a variety of psychiatric disorders and in cannabis-related craving and withdrawal states. These regions were manually delineated via application of previously validated manual tracing protocols to high-resolution sMRI images. This rigorous approach enabled sensitivity to identify potentially subtle effects of regular cannabis exposure on regional brain volumes using highly reliable and anatomically valid segmentation techniques. The analyses conducted in this work aimed to achieve a number of objectives, which included examining whether: 1. Regular cannabis exposure is associated with structural alteration of brain regions high in CB1 receptors and involved in mediating psychopathology and altered neurocognition in regular CB users; 2. Cannabis use patterns mediate the association between regular cannabis exposure and brain structural alterations, and which cannabis use patterns best predict structural brain alterations in regular CB users; 3. ‘Clinical’ variables including psychopathology symptoms, key neurocognitive measures and global functioning are associated with regional brain volumes in regular CB users independently from the impact of cannabis use patterns. The findings emerging from this thesis lead to three key results in relation to the presented research objectives. First, the association between regular cannabis exposure and brain morphology brain was regionally dependent, with CB users showing volumetric reductions in the hippocampus and the amygdala, but not the pituitary gland, with more marked alterations being observed in hippocampal, as opposed to amygdala, volumes. Second, the association between cannabis use patterns and brain volumes was also regionally dependent, being apparent for hippocampal volumes, subtle for on amygdala volumes, and not observable for pituitary volumes. The key cannabis use patterns that affected brain volumes in CB users were age of onset of regular cannabis use and cannabis dosage, affecting hippocampal and amygdala volumes, respectively. Sex, laterality and recency of cannabis use also played a key role in these associations. Third, ‘clinical’ variables did not exert a confounding influence on the association between cannabis use patterns and regional brain volumes, and there was preliminary evidence for positive psychotic symptoms to be associated with the volumes of the pituitary gland, but not those of the hippocampus and the amygdala, and in male, as opposed to female, CB users. The results emerging from this dissertation support the notion that the association between cannabis exposure, cannabis use patterns, psychopathology symptoms and brain volumes occur in a region-dependent manner. A number of factors including laterality, sex and recency of cannabis use also mediate the nature of structural brain alterations in regular CB users. These results demonstrate that the association between regular cannabis exposure and regional brain volumes is mediated by complex factors and provide useful insight for future studies investigating structural brain measures in regular CB users. Nevertheless, a number of limitations prevent from drawing firm conclusions regarding the nature of the observed structural brain alterations. The role of confounding factors associated with regular cannabis use, including comorbid substance use and heightened psychiatric symptoms, needs to be carefully accounted for in future studies. Further, longitudinal investigations are warranted to determine whether regional brain alterations pre-exist cannabis use onset and recover after prolonged abstinence.
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ItemUnderstanding the role of frontotemporal brain structures in schizophrenia through magnetic resonance imaging and neuropathological studies( 2012)Section 1: The first two chapters describe my initial hippocampal volumetric work in patients with first-episode psychosis and chronic schizophrenia that identified hippocampal changes early in the course of psychosis. Chapter 3 explores in detail the theoretical basis for hippocampal involvement in schizophrenia and introduces for the first time the concept that the hippocampal volume changes observed in patients with first episode psychosis and chronic schizophrenia may not be present in patients at high risk of psychosis. Chapters 4 to 6 describe a series of cross sectional studies showing that hippocampal volumes are normal in high risk patients who later develop psychosis (Chapter 4 and 6), normal in patients with schizophreniform psychosis (Chapter 6), reduced on the left side in patients with first-episode schizophrenia (Chapter 6) and bilaterally reduced in patients with chronic schizophrenia (Chapter 6). These findings suggest that right hippocampal volume reduction occurs with increased illness duration, a finding supported by a voxel based morphometry study of patients with chronic schizophrenia (Chapter 5). Finally in contrast to our original findings (Chapter 1) that hippocampal volumes were equally reduced in patients with first-episode schizophrenic and non schizophrenic psychoses, our study of a much larger first-episode cohort (Chapter 6) showed that hippocampal volume reduction was specific to schizophrenic psychoses while amygdala enlargement was specific to non schizophrenic first-episode psychoses. These findings suggested either that (i) patients who make the transition from high-risk to first-episode or first-episode to chronic schizophrenia already have hippocampal changes and/or (ii) that hippocampal volume changes occurred progressively over the course of the illness. Section 2: Chapters 7 and 8 describe follow-up longitudinal imaging studies in a first-episode cohort and a high-risk cohort respectively. We did not identify hippocampal volume change over a two-year period (Chapter 7) but observed whole brain changes over time in first-episode and chronic schizophrenia cohorts. We hypothesised that structural changes may have occurred prior to or over the transition to active psychotic illness. Chapter 8 describes parahippocampal and frontal changes in high-risk patients who developed a psychotic illness and not in those who did not develop a psychotic illness. These findings provided support for the concept that some patients with a psychotic illness exhibit progressive structural brain changes. Section 3: Chapters 1 to 8 describe evidence for the presence of structural brain changes in the hippocampi of patients with schizophrenia. Structural MRI cannot determine the neurobiological correlates of such brain changes i.e what is causing the changes or which elements of brain tissue are involved. The neurobiology of diseases that mimic schizophrenia (‘secondary schizophrenias’) has provided insights into schizophrenia. Chapter 9 describes a previously unrecognised association between young onset frontotemporal dementia and schizophrenia-like psychosis and specific hippocampal pathology in these cases. Chapter 10 describes similar pathological abnormalities in the hippocampus of patients with schizophrenia and bipolar disorder, who had never been suspected of having dementia earlier in life. The identification of clinical and neuropathological associations between FTD and schizophrenia / bipolar disorder is of significant clinical relevance and provide new avenues for research into the underlying neurobiology of major mental disorders. Section 4: The concluding section discusses how the work in this thesis can be understood within the context of neuroimaging work that has emanated from this large dataset and the current schizophrenia literature. The association between schizophrenia and FTD identified in Chapters 9 and 10 is explored further in this final section with reference to the literature and some illustrative case reports.
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ItemThe effects of catecholamine depletion and acute psychosocial stress on neurocognition( 2012)Extensive research has clearly established that neurocognition is negatively impacted by various stressors. While the extant research has focused on the effects of cortisol on declarative memory, little attention has been given to the role of the catecholamines in the deterioration of neurocognitive performance following psychosocial stress. Forty healthy male (n = 21) and female (n = 19) volunteers aged between 18-47 years who had been screened for eligibility participated in the study. Heart rate, blood pressure and salivary cortisol were measured at baseline, pre-stress, post stress (immediate) and after one hour of rest (post stress recovery). Neurocognitive assessment included immediate and delayed verbal recall, spatial learning and strategy, attention and working memory (spatial and non-spatial) at the same four phases. Participants randomly received an L-tyrosine and L-phenylalanine depleted (DEP) or a nutritionally balanced (BAL) amino acid drink in a randomised, double blind, placebo-controlled parallel group design 5 hrs before exposure to the Trier Social Stress Test (TSST). The ratio of L-tyrosine and L-phenylalanine to the sum of other large neutral amino acids (ΣLNAAs) in plasma were both significantly reduced by -80% at the post-ingestion period (5 h) compared to baseline. Exposure to the TSST for both ATPD and balanced-treated participants resulted in the robust stimulation of the sympathomedullary (SAM) and hypothalamic-pituitary adrenocortical (HPA) axes. This was demonstrated by significant increases in heart rate and blood pressure immediately after stress exposure compared to baseline in both ATPD and balanced conditions. Salivary cortisol levels significantly increased immediately after the completion of the TSST compared to pre-stress levels. There were a limited number of effects of the TSST combined with ATPD on measures of neuropsychological performance. These outcomes suggest that neurocognition is not severely impacted by acute social stress under conditions of catecholamine depletion.
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ItemA population-based study of alcohol use in elderly men: associations with physical and mental health( 2012)Considerable attention has been paid to the prevalence and outcomes of alcohol use disorders in both in population-based and clinical samples, and also to the harms associated with alcohol intake in young adults. However less attention has been paid to alcohol consumption in elderly men. The aims of this population-based study were to investigate the patterns of alcohol consumption and the associations between different levels of alcohol intake and demographic, lifestyle, physical and mental health outcomes in a representative sample of elderly men. Five hundred and fifty five participants aged at least 65 years and enrolled in the Geelong Osteoporosis Study reported their usual alcohol consumption for the prior 12-months, had their BMD measured and completed a comprehensive range of medical and lifestyle assessments. Alcohol consumption was common, the majority (48.7%) consumed alcohol moderately (≤2 drinks/day), with a further 19.7% consuming 3-4 drinks and 13.5% consuming ≥5 drinks/day. Almost one in five elderly men in this sample were a non-drinker at the time of assessment. The alcohol consumption groups were compared on demographic and lifestyle variables, and also on key physical and mental health outcomes. The median alcohol consumption increased with increasing socio-economic status. The heaviest alcohol consumption groups were more likely to report current or past cigarette smoking and were also more likely to have low leisure-time physical activity levels in age adjusted models (OR=1.74 95% CI 1.01-3.00), and more likely to have impaired mobility as measured by the Timed Up & Go test (OR=3.01 95% CI 1.41-6.43) when compared to moderate alcohol consumers. Current non-drinkers were more likely to have low leisure-time physical activity levels (OR=1.75 95% CI 1.05-2.91) and were less likely to be current participant in sport (OR=0.52 95% CI 0.29-0.94) than moderate alcohol consumers, independently of age, cigarette smoking and current use of five or more medications. In comparison to non-drinkers, consumers of ≥5 drinks/day had mean differences in adiposity of +4.8% (BMI), +20.1% (FMI), +5.0% (waist circumference), +15.2% (%body fat), +5.3% (% trunk fat) and had a mean difference in lean tissue mass of -5.0%. Furthermore, they had a 2.8-fold increased risk of being classified as obese according to BMI (≥30 kg/m2) and a 3.4-fold increased risk of having a waist circumference of at least 102 cm. While the groups differed in total energy intake, they did not differ in energy intake obtained from food suggesting unregulated supplementation of energy intake from alcohol. Aside from a difference at the mid-forearm site BMD was not associated with alcohol consumption, however bone quality as measured by quantitative ultrasound at the heel decreased with increasing alcohol consumption. Overall, 14.8% of this sample met criteria for a lifetime history of a mental illness, and 3.1% were identified as having a current psychiatric illness, most commonly major depressive disorder. Non-drinkers (OR=2.58 95% CI 1.20-5.56) and consumers of ≥3 drinks/day (OR=1.73 95% CI 0.85-3.51) were more likely to have a lifetime history of any psychiatric illness than moderate alcohol consumers after adjustment for age and mobility. There was a low prevalence of alcohol use disorders in this sample, 2.6% for a lifetime history and 0.8% for a current disorder. One third of elderly men currently drink at a level in excess of the Australian government recommendations for safe alcohol consumption, which in combination with medical comorbidities and high levels of medication use places this group at increased risk of harm. Furthermore, both heavy alcohol consumption and current non-drinking was associated with negative physical and mental health outcomes, this highlights the importance of routinely screening for alcohol consumption within the elderly, and extending the investigation into other important correlates when indicated. Although causality cannot be inferred, these findings provide an insight into the association between alcohol intake, lifestyle and physical and mental health.
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ItemThe specificity of morphological changes of the corpus callosum in schizophrenia and related major mental disorders( 2010)Schizophrenia is a disabling major mental illness associated with marked impairments in reality testing, organization of speech and behaviour and cognition. Significant evidence points to functional dysconnectivity between cortical and subcortical regions as the major pathophysiological underpinning of the symptoms and disability associated with schizophrenia. Modern neuroimaging techniques have suggested that this dysconnectivity is driven, at least partially, by neuroanatomical changes to connectivity in the brain at the level of white matter tracts, the main connecting “organs” in the brain. This thesis describes the analysis of the structure of the corpus callosum, the brain’s largest white matter fibre tract, with the aim of determining if changes to anatomical connectivity in schizophrenia are associated with a unique callosal shape “signature”. This was undertaken by using a shape analysis methodology that examined regional callosal thickness, using a non-parametric permutation method to determine between-group differences and the relationship between illness variables and callosal shape. This methodology was applied to multiple illness stages: established illness, first-episode psychosis and pre-psychotic patients. It was then applied to other major mental disorders, including multiple cohorts of patients with bipolar disorder and patients with major depression, to determine if any changes seen in schizophrenia patients were specific to schizophrenia-spectrum illness or were more general markers of major mental illness. The results suggest that patients with schizophrenia-illness show specific thickness reductions at the level of the anterior callosum, connecting frontal cortical regions, that are present during the pre-psychotic phase and with first-episode illness. Furthermore, with established illness, these changes are accompanied by additional changes in the callosum connecting cingulate, temporal and parietal regions. Changes seen in healthy individuals as part of the normal ageing process appeared to be disrupted in schizophrenia patients. In bipolar patients, a very different pattern of results emerged, with more global thickness reductions and disproportionate thinning at the level of the posterior callosum. Depressed patients, by contrast, showed state-specific posterior expansions, which bore some homology to changes seen in patients with depressed first-episode psychotic patients and patients with schizoaffective disorder. Furthermore, in the schizophrenia-spectrum group, changes at the level of the genu were strongly predictive of transition to psychosis in those individuals at high-risk for psychosis, and in first-episode individuals were highly predictive of long-term outcome of their psychotic illness. These changes suggest that there are schizophrenia-specific changes at the level of the callosum, marking a unique callosal “signature” for schizophrenia-spectrum illness. These changes show predictive validity for outcome at the earliest stages of illness, and are distinct from changes seen in major affective disorders. These findings suggest that shape changes to white matter structures may be a useful marker to aid diagnosis, in the identification of individuals who may develop a psychotic illness, and in defining the nature of their future illness course.
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ItemEstrogen and neuropsychiatric disorders in later life( 2010)Experimental evidence suggests that estrogen can have both psycho- and neuro-protective effects; however this has not been consistently supported by certain clinical trials and epidemiological studies. This thesis aimed to provide a detailed investigation of the role of estrogen in later-life depression and cognitive functioning by examining serum estrogen levels, estrogen exposure across the lifetime, characteristics of hormone treatment (HT) and the role of estrogen receptor polymorphisms. Data was obtained from two longitudinal population-based studies, the 13-year Melbourne Women’s Midlife Health Project of 438 middle-aged postmenopausal women in Australia, and the seven-year Three City/ESPRIT study of 5644 older French women. Multivariate adjusted regression models showed that endogenous and exogenous hormonal characteristics late in the reproductive life can decrease the risk of late-life depression and a decline in serum estradiol levels increased the risk for recently postmenopausal women. Discontinuing HT increased the risk of depression for older women, as did the use of progestin-containing HT. Estrogen receptor polymorphisms were associated with late-life depression and can interact with HT to modify the risk of depression and mortality. Endogenous reproductive factors linked to higher lifetime estrogen exposure and high levels of estradiol in the early postmenopause were associated with better performance on certain cognitive tasks. Cognitive function also varied according to the characteristics of HT and HT reduced the risk of dementia in genetically susceptible women carrying the apolioprotein ε4 allele. This work brings some important new findings to this field of research, suggesting that the modulation of estrogen levels may be used as a possible therapeutic tool to reduce neuropsychiatric disorders and that certain subgroups of women may be genetically more susceptible to hormone modifications or to the effects of HT.