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 role of cholinergic muscarinic receptor 2 and 3 in mood disorders( 2014)Variation in cholinergic muscarinic receptor (CHRM) levels is thought to be involved in the pathophysiology of bipolar disorder (BPD) and major depressive disorder (MDD). Lower levels of CHRM2/CHRM4 protein in the human dorsolateral frontal cortex (Brodmann’s area (BA) 46) from subjects with BPD and MDD, and CHRM3 in the human orbitofrontal cortex (BA 10) from subjects with BPD have previously been reported by my laboratory. I sought to confirm those findings in BA 10 and 46 in a larger cohort from subjects with BPD (n = 15), MDD (n = 15) and controls (n = 20) as well as see whether these changes occur in other cortical regions by examining BA 17, 24 and 47, which are also thought to be affected in mood disorders. I investigated whether the binding densities of the CHRM selective radioligands [3H]4-DAMP, [3H]pirenzepine and [3H]AF-DX 384 are altered in mood disorders. Findings from the binding data were confirmed using Western blot and quantitative Real-Time PCR (qPCR), and oxotremorine M stimulated-[35S]GTPγS binding was used to see whether changes in protein levels affected the receptor activity. I also investigated whether muscarinic receptor levels, using [3H]AF-DX 384 and [3H]pirenzepine binding, are altered in the rat brain regions 24 hours after the last acute or chronic treatment with mood stabilisers or antidepressant drugs (n = 20 per group) as part of potential confounding factors. Previous protocols used to measure [3H]4-DAMP binding measured both CHRM3 and CHRM1. I adapted this protocol to make the [3H]4-DAMP binding assay more selective to CHRM3. Contrasting previous findings, there was no difference in levels of CHRM3 protein in any cortical region from subjects with BPD and MDD compared to controls. [3H]pirenzepine binding was lower in the outer layer of BA 17 and BA 24 in BPD and MDD, and in BA 47 from subjects with MDD, but not BPD. [3H]AF-DX 384 binding was lower in the outer layer of BA 17 and BA 24 from subjects with BPD and MDD, and in the inner layer of BA 17 and BA 46 from subjects with BPD, but not MDD, compared to controls. I subsequently examined levels of CHRM2 and CHRM3 protein using Western blotting. Two CHRM2-specific immunogenic bands were detected on the western blots. CHRM2 protein levels were significantly lower in the upper band (71 kDa), but not the lower band (67 kDa), in BA 24 in BPD only compared to controls. By contrast, there was no change in BA 46 from subjects with BPD and MDD. Moreover, levels of CHRM3 protein were not changed in BA 10 from subjects with BPD and MDD compared to control subjects. Similarly, the levels of CHRM3 mRNA using qPCR in BA 10 were also not altered. Levels of specific [35S]GTPγS binding stimulated by oxotremorine M were significantly lower in BA 24 from subjects with BPD, but not MDD, compared to controls. However, there was no change in oxotremorine M stimulated-[35S]GTPγS binding in BA 46. In neuropsychopharmacological studies, there were widespread regions-specific increases in levels of [3H]AF-DX 384 and [3H]pirenzepine binding in rats following chronic treatment lithium and sodium valproate. Chronic lithium administration resulted in a significant increase in the densities of [3H]AF-DX 384 binding in the cingulate, parietal cortices, caudate putamen, nucleus accumbens and olfactory tubercle, but not the frontal cortex. Interestingly, there were significantly higher levels of [3H]pirenzepine binding in all rat brain regions examined after treatment with lithium. Moreover, treatment with sodium valproate for 28 days caused an increase in levels of [3H]AF-DX 384 binding in the caudate putamen, nucleus accumbens and olfactory tubercle of rats and an increase in [3H]pirenzepine binding densities in the cingulate cortex, caudate putamen and nucleus accumbens. By contrast, acute and chronic antidepressant drugs, fluoxetine and imipramine, administration resulted in no change in the levels of [3H]AF-DX 384 binding in any brain region of rats. No change in [3H]pirenzepine binding was found in any rat brain region following acute and chronic administration of antidepressant drugs. These findings suggest that regionally specific decreases in the level of cortical muscarinic receptors are involved in the pathophysiology of mood disorders.
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ItemHope and recovery in a family treatment for schizophrenia: a program evaluation of a family psychoeducational intervention( 2014)A focus on recovery is increasingly widespread in practice and policy in services for people with schizophrenia and their families. Recovery principles suggest that hope is integral to recovery, which can occur (and implicitly hope can improve) independent of the symptomatic severity of mental illness. However, there is little research on this or recovery-focused services in general. This is a concern for services wishing to evaluate the provision of recovery-focused practices. Unless the relationship between hope and recovery is investigated broadly, the understanding and evaluation of recovery is compromised. Over 50 RCTs demonstrate the effectiveness of family psychoeducation (FPE) in reducing relapse in consumers and burden in carers. Although not studied previously, FPE appears well suited to improve hope and recovery because it develops purpose and support within families. This study investigated (1) the trajectory of hope, recovery and symptoms across an FPE program; and (2) the usefulness of a hope model which defined hope as the positive expectancy of achieving goals through optimism and self-efficacy. Emergent hope, in contrast, emphasises the beginning of hope as the “tiny fragile spark” in the midst of adversity. Method: The study used a mixed-methods, quasi-experimental design with consumers and relatives selected for FPE suitability, compared to TAU, conducted in community mental health centres in disadvantaged suburbs. Assessments conducted before and after 10 months of FPE or TAU included: hope, consumer functioning and symptoms; and carer distress and burden. Treatment satisfaction was assessed in participants from the treatment cohort. Results: 62 consumers and 63 carers were recruited across treatment and TAU cohorts; most consumers had persistent symptomology and fifty percent had co-morbidities. Average hope in consumers and carers was significantly below community norms. Higher symptoms were correlated with reduced hope. There were no changes over time in outcomes and no significant differences between FPE and TAU groups. Carers expressed some hopes in terms of positive expectancy and self-efficacy, but also discussed hopes without optimism for their attainment. Consumers did not express their hopes in terms of goals, motivation and planning. However, in the absence of objective changes, participants reported high levels of satisfaction with FPE. Conclusion: These results emphasise the lack of hope in consumers with severe and enduring mental illnesses and the need for new ways to address this important problem. The lack of treatment effect for FPE could not be attributed to low statistical power; the findings suggest there are considerable challenges in restoring hope and achieving recovery for this group of consumers. The study demonstrates the difficulties in translating evidence from successful efficacy trials into effective recovery-based programs. Hope was not independent of symptoms, consistent with other research, but not the recovery paradigm. A nuanced reading of recovery narratives suggests that while recovery can occur despite the persistence of symptoms, it is not a given. In the early stages of recovery and low levels of hope, symptoms can dominate positive expectancies. As a mix of optimism and efficacy, expectancy hope showed limited relevance, as it could not account for carer hopes expressed in the face of considerable adversity. Lower hope levels might be better assessed using emergent models of hope. These findings encourage closer attention to the successful implementation of FPE in routine practice, more research into the relationship between hope and recovery, and the need for suitable models and measures of hope to evaluate recovery-focused services.
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ItemQuality of life in people with cognitive impairment: nursing homes versus home care( 2014)The evaluation of quality of life (QoL) among older adults has become increasingly important in health and social science as it provides evidence which may have influential implications for ageing policies. Although this has been studied in developed countries, there are also issues for emerging countries, which have ageing populations. Living arrangements play a pivotal role in determining the QoL of people with cognitive impairment. Although informal care (home-based) is favoured, transition to formal care (residential care) often becomes necessary, especially in the later stages of cognitive impairment. The primary objective of the thesis was to compare the QoL of people with cognitive impairment in the community and nursing homes. In addition, factors that differentiate the QoL of people with cognitive impairment in these two settings were identified. A cross sectional observational study of people with cognitive impairment from government hospitals (home care) and nursing homes was carried out. This study involved interviews with older adults aged between 60 to 89 years old. Participants completed the QoL measurements (the EUROPE Health Interview Survey-Quality of Life and the Assessment of Quality of Life) as well as other measurements that assess factors contributing to QoL (e.g. the Short Mini Mental State Examination, the Barthel Index, the Cornell Scale for Depression in Dementia, the Camberwell Assessment of Needs for Elderly and the Friendship Scale). All measurements were examined for their psychometric properties (reliability, validity and structure). In a pilot study, 49 older adults with cognitive impairment were recruited and completed the questionnaires. Results showed significant differences in QoL and social connectedness among people with cognitive impairment in home care and those in nursing home. No significant differences were found by socio-demographic factors, cognitive severity and depression between the study cohorts. In a primary study, 219 people with cognitive impairment were recruited. The main study finding on the QoL of people with cognitive impairment demonstrated that those receiving home care experienced significantly better QoL. Other findings were that home care recipients had better cognitive function, were less depressed, had fewer unmet needs and reported higher social connectedness compared to nursing home participants. No significant differences were observed with regards to health condition, co morbidities and physical functions between study cohorts. This suggests that the findings were not due to health differences between the two study cohorts. It was also observed that all scales achieved the reliability and validity criteria set for this study. Thus, suggesting that the scales used in this study were reliable and valid for this study sample. In conclusion, older adults with cognitive impairment living at home experienced higher QoL, had better cognitive function, were less depressed, had fewer unmet needs and reported higher social connectedness compared to those living in institutional care. Therefore, support should be provided enabling home care and empowering caregivers to provide better care for people with cognitive impairment. As this is the first Malaysian study on this topic, this study may provide valuable and useful information for the patients, care givers, government and policy makers with regards to cognitive impairment and dementia care in Malaysia. Strong collaboration between government and NGO’s is needed in promoting ageing in community, by developing infrastructure to facilitate mobility and also encourage social interaction and intergenerational relationships.