Psychiatry - Theses
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ItemA prospective longitudinal study of child development following in-utero exposure to antidepressant medication( 2014)Background: The recognition of the importance of treatment for depression in pregnancy to optimise both maternal and child outcomes parallels the increasing use of antidepressants in pregnancy across many countries in the world. However, there is also research to suggest that women are often reluctant to commence treatment or they abruptly cease antidepressant treatment on becoming pregnant due to concerns about long term safety of exposure for their unborn child. This thesis examines child developmental outcomes following in utero exposure to antidepressant medication using two data sets. These two data sets are distinct in methodology allowing a comparison of both methods and results when examining child outcomes following exposure in pregnancy. Methods: The first study is the Victorian Psychotropic Registry (VPR), a purpose designed, prospective, longitudinal study established by the candidate and where children have been followed from in utero to 5 years of age. The second study is the Longitudinal Study of Australian Children (LSAC), a large, normative, population based cohort across early childhood established by the Commonwealth Government of Australia. Both studies had an antidepressant exposed group of children and a control group and both studies had measures of maternal depression in pregnancy, postpartum and into childhood as well as measures of other exposures in pregnancy, such as alcohol and smoking. The VPR collected all data prospectively whereas the pregnancy measures for LSAC were retrospectively collected in the postpartum. The three areas of child development of focus in this thesis are: cognitive development, motor development and child adjustment and emotional development. Where possible, measures were chosen in LSAC, which closely matched those in age and domain to the VPR. Children were assessed at 4-7 years of age across the two studies. Results: This thesis found that in both data sets there was no evidence of an effect on cognitive development from antidepressant exposure in pregnancy. The results for both motor development and emotional development were more complex. For motor development there was a trend to lower scores in the VPR study on a specific neuropsychological measure of motor development: Movement ABC, without reaching a statistically significant difference but small effect sizes. There was no observational or task measures of motor development in LSAC. Both the VPR study and LSAC found a difference on a screening measure, Peds QL Physical Health Score, with exposed children having a lower score. However, when this was adjusted for the covariate of maternal depression this was no longer significant. Child adjustment and emotional development was examined in two areas. The first was internalizing and externalizing scores, within the VPR on the CBCL and within LSAC on SDQ, the second area was parenting and parent-child relational stress measured in VPR with PSI total stress score and within LSAC with the Parenting Efficacy Scale. VPR found there was no statistically significant difference on either measure for exposed children. Whereas, LSAC found both internalizing and externalizing scores and Parenting Efficacy Scale scores did show statistically significant differences, with higher externalizing and internalizing scores and lower Parenting Efficacy scores in exposed children. However, again when adjusted for the covariate of maternal depression these differences became non significant. Conclusions: Using two independent samples to examine antidepressant exposure in pregnancy on child developmental outcomes, no statistically significant difference was found between children exposed and controls on a range of cognitive, motor, child emotional and adjust outcomes at 4-6 years of age. There was also no difference in mothers who took antidepressants in pregnancy on parenting stress and efficacy at 4-6 years postpartum. However, the secondary findings within LSAC study was that maternal depression in the postpartum, as measured by the K6, was associated with poorer cognitive, language, emotional and parenting outcomes This suggests the very important role of maternal depression in examining longitudinal child outcomes. This thesis has contributed both original data to the limited information available on child developmental outcomes following antidepressant exposure across two distinct studies. By using two studies this thesis has also allowed a comparison of findings using different methodologies. This thesis has also been able to contribute data on the effects of maternal depression on child development. These findings support clinical recommendations and practices, which highlight the importance of detection and appropriate treatment of maternal depression in pregnancy.
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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.