Psychiatry - Theses
Permanent URI for this collection
Search Results
1 - 5 of 5
-
ItemMoodSwings: an online self-guided intervention for bipolar disorder( 2016)Bipolar disorder is a chronic illness characterised by extreme mood swings. The efficacy limitations of medication alone have flagged a role for adjunctive psychosocial treatments. Despite strong evidence for these interventions, accessing such specialised programs is problematic. Online psychosocial interventions have been found to be effective for a range of mental illness, and some burgeoning work that has evaluated online bipolar programs is encouraging. This current study seeks to further contribute to this embryonic work. Two studies are described within this thesis. Study one, aimed to test the efficacy of a self-guided online intervention (MoodSwings) for bipolar disorder. In a head to head trial of an international sample, 156 participants with bipolar disorder were randomised to receive either a psychoeducation (PE) based program, or the same PE program plus additional interactive Cognitive Behavioural Therapy elements. A mixed model repeated measure (MMRM) analysis found a significant (p = 0.02) difference between the two groups at 12 months on mania scores. Both groups also demonstrated significant within group differences. An exploratory analysis based on effect sizes >.8 found the following potential factors suggestive of having an impact on outcomes: demographic factors associated with functionality, time on site, locus of control and medication adherence. Study two utilised the same participant sample and reports on the use of MoodSwingssmall group discussion boards. It aimed to explore their role in enhancing social support and identifying the types of supportive exchanges. Contrary to the hypotheses, no significant differences (p = .271) were found on social support levels between high and low posting groups. In addition, those on higher posting boards did not demonstrate greater program engagement (p = .298). There was a significantly higher number of posts by those in the PE condition in comparison to the CBT group (p <.000). Qualitatively the posts contained many supportive comments, the most frequent demonstrated emotional support. This current study was limited by only using self-report assessments, a moderate sample size, and a high attrition rate in the completion of follow up assessments. The head-to-head study design did not allow for a determination of whether MoodSwings was superior to a control condition or treatment as usual. Further studies could explore this using an attention control condition. A guided intervention model would also provide an interesting contrast to the current studies self-guided approach in terms of additional costs and benefits. There is also a great opportunity to further explore the use of online discussion boards both as a tool of engagement and as having its own therapeutic elements. MoodSwings is one of the first online programs for BD. Its findings are encouraging and pave the way for future studies to build on this work.
-
ItemFunctional in vitro modelling of the nervous system using human pluripotent stem cells; a platform to study brain disorders( 2016)Human pluripotent stem cells (hPSC) constitute a valuable resource for establishing in vitro models of nervous system development, function and dysfunction. This is particularly needed for complex developmental brain disorders whereby animal models and access to postmortem human brain tissue may be limited. A major prerequisite step to developing suitable in vitro models of the human nervous system is to establish hPSC induction protocols to derive regionally specific neuronal populations. The first major aim of this thesis was to characterize the phenotype and maturation stage of neural progenitor cell types derived from the following induction protocols: the dual SMAD inhibition protocol (DS), sonic hedgehog pathway agonist protocol (SAG), and SMAD/GSK3b inhibition protocol (CHIR). Our studies show that the dual SMAD inhibition protocol results predominantly in cortical progenitors representative of deep and intermediate cortical layer neurons, while combined early treatment of sonic hedgehog agonist during neural induction give rise to progenitors of ventral cortical identity. Using an induction protocol involving inhibition of the SMAD and GSK3b pathways, followed by later exposure to BMP2/4, hPSC are directed towards neural crest lineages, which upon further differentiation give rise to peripheral sensory neurons. Another essential component for in vitro modelling of the human nervous system using hPSC is to demonstrate neuronal activity and connectivity as measures of functionality. Whilst intercellular activity and characteristics of hPSC-derived neurons are well documented, reports on their potential to form functional network is scarce. This feature is critical for using hPSC to model psychiatric disorders such as Autism spectrum disorder (ASD) in which abnormal connectivity is one of the major characteristics of the disease. Using microelectrode arrays (MEA), the second major aim of this thesis was to assess the functional maturation rate and neuronal network activities of hPSC-derived cortical and peripheral sensory neuronal populations. Our data demonstrate that functional maturation of hPSC-derived cortical neurons occurs at a slower rate relative to hPSC-derived sensory neurons with no evidence of network activities detected over 8 weeks of differentiation. In contrast, hPSC-derived sensory neurons show faster maturation and form functional networks in vitro by week 6-7 post differentiation. Further functional characterization on MEA reveals the capability of sensory neuronal subtypes to respond to appropriate stimuli including heat, capsaicin and hypoosmotic induced stretch. The final major objective of the thesis was to employ our in vitro model of corticogenesis to interrogate neurodevelopmental disorders, specifically microcephaly and ASD. Accordingly, one aim was to investigate the function of WD Repeat Domain 62 (WDR62) in neurogenesis, a major candidate gene of autosomal recessive primary microcephaly. Studies of WDR62 utilizing human based in vitro models are lacking. Our studies show that WDR62 expression coincides with SOX2 and PAX6 expression during hPSC neural induction, the prime period of neurogenesis. Furthermore, knockdown of WDR62 expression in hPSC impacted on neurogenic and gliogenic differentiation, as shown by a reduction in TBR2 (EOMES) and S100b+ progenitor populations, respectively. The final aim was to characterize idiopathic ASD induced pluripotent stem cell (iPSC)-derived cortical neurons, focusing on the expression of genes associated with corticogenesis, glia specification, synaptic function, cell proliferation and cell death. Our data suggests higher expression of TBR1 and lower expression of MAP2AB, GFAP and GRM5 in ASD neurons compared to controls. These results implicate processes related to deep cortical layer neuronal differentiation, dendritic formation, glial differentiation and synaptic function in ASD core pathophysiology, paving the way for future studies utilizing these ASD iPSC lines. In summary, these studies provide key information for utilizing hPSC to model neural circuitry systems and demonstrate hPSC robustness as a complementary in vitro model system to investigate developmental brain disorders.
-
ItemRedox biology and autism( 2016)Background: Evidence suggests that oxidative stress may be related to the aetiology of autism. This is supported by studies showing deficiencies in glutathione and other antioxidants, mitochondrial dysfunction and genetic links between autism and abnormalities in redox biology. Glutathione, an important cellular antioxidant, is therefore proposed as a potential treatment target in autism. N-acetyl cysteine (NAC), a glutathione precursor, may be an effective method of supplementing glutathione levels, and thus improving behavioural symptoms and functioning, in children with autism. Method: This study was a mixed-methods, double-blind, randomised, placebo-controlled clinical trial of 500 mg daily NAC, in addition to treatment as usual, for 6 months in children with autistic disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, revised. The primary outcomes were the core symptoms of autistic disorder: social interaction, as measured by the Social Responsiveness Scale; communication, as measured by the Children’s Communication Checklist – Second Edition; and restricted and repetitive behaviours and interests, as measured by the Repetitive Behavior Scale – Revised. Secondary outcomes were problem behaviours, as measured by the Developmental Behaviour Checklist – Primary Carer Version; adaptive functioning, as measured by the Vineland Adaptive Behavior Scales – Second Edition; and parent and clinician global impression scales. In addition, qualitative analysis of parent/guardian reports and clinicians’ observations was carried out to supplement the main efficacy study. Results: A total of 98 children (79 male, 19 female; age range = 3.1-10.1 years) were enrolled into the study, of whom 48 were randomised to receive NAC and 50 were randomised to receive placebo. The NAC and placebo groups did not differ on any demographic or baseline symptom severity measure. Seventy-one participants (34 from NAC group, 37 from placebo group) completed the 6-month trial. NAC did not differ from placebo on safety and tolerability. There were no differences between the NAC and placebo groups on any primary or secondary outcome measures. In contrast, the qualitative analysis found that NAC was associated with more frequent reports of improved calmness and verbal communication than placebo. Conclusions: This study found that NAC was not effective in improving core symptoms or functioning in children with autism, as assessed by a range of comprehensive quantitative measures. However, this study did demonstrate the potential utility of mixed-methods approaches in autism treatment trials. Overall, this study does not support the widespread use of NAC for autism, although questions remain regarding dosage, and effects on specific symptoms within the broader clinical picture.
-
ItemPersonality and care-related factors and their associations with depressive symptoms in older carers( 2016)With the rapidly ageing global population, there will be increased demand on informal older carers, who provide important roles in supporting older adults to live longer in their own homes. Depression in older carers is a well-known adverse outcome, however there is lack of consistent knowledge concerning factors associated with this outcome. The research reported in this thesis therefore investigated factors associated with depressive symptoms in a sample of older carers living at home with the older adults with whom they were caring for (the care-recipient, CR). This study differs from previous work in that a variety of different, but clinically relevant factors have been investigated. A convenience sample of 202 older carers were assessed cross-sectionally on their demographic characteristics, health measures, depressive symptoms, personality, attitudes to ageing, and CR factors (CR diagnosis and the hours spent caring). The cut-off score on the Geriatric Depression Scale (GDS-15) of ≥5 was used to delineate “depressed” and “non-depressed” carers, and a comparison of these characteristics was made between the 87 depressed, and 115 non-depressed carers. Female gender, but no other demographic factors were associated with a higher number of depressive symptoms. The CR diagnosis was not an independent factor associated with depressive symptoms. Higher levels of Neuroticism and more negative attitudes to ageing in the carers were associated with depressive symptoms. Depressed carers had worse physical health, participated in increased amounts of domestic physical activity (PA), but similar amounts of leisure-PA, compared to non-depressed carers. The regression analyses demonstrated that higher levels of Neuroticism, increased hours spent caring, and possibly increased amounts of domestic-PA, were independent factors associated with depressive symptoms. The findings of this study highlight the importance of carer-related factors when identifying risk factors for depressive symptoms in older carers. The clinical implications of this study, particularly that increased hours of care are a risk factor for depressive symptoms, suggest that in order to potentially reduce the risk of developing depression, older carers should be encouraged to “share the care” – that is the support of the CR should be preferably spread among more than one person, whether this be among other family members, and/or formal care services. Thus, being able to access support services such as “Home Help”, and respite is important. This approach may not be supported by the principles behind the current Victorian Active Services Model, which encourages self-reliance and enablement. Clinicians have an important role to encourage older carers to accept help, but this needs to be individually tailored, taking into account the carers’ personality structure.
-
ItemInvestigating potential subgroups within the schizophrenias: a study of cholinergic muscarinic receptor density and energy metabolism( 2016)Background. A crucial step towards understanding the aetiology of schizophrenia (SCZ), and developing more effective diagnostic methods and treatments is to identify and characterise potential subgroups within the diagnosis. There is growing evidence to support the existence of biologically discrete subgroups; one such demonstration is a subgroup denoted muscarinic receptor deficient schizophrenia (MRDS). Making up 25% of the SCZ population, these subjects are separated due to their marked loss (75%) in [3H] pirenzepine binding (cholinergic muscarinic M1 receptor preferring ligand), measured in the dorsolateral prefrontal cortex (DLPFC) in post-mortem brain tissue. Having established the SCZMRDS subgroup in our laboratory, we have the ability to investigate the pathophysiology that presents within this discrete subgroup. Study 1. Previous reports suggest lower [3H] pirenzepine and [3H] AF-DX 384 (muscarinic M2/ M4 receptor preferring ligand) binding in the caudate putamen (C.Pu) in SCZ subjects. However, it is not known if SCZMRDS subjects drive this decreased binding in the C.Pu, as they do in cortical regions. Therefore, to better understand the changes in muscarinic receptors in the C.Pu from SCZ subjects, and to delineate whether the SCZMRDS subgroup was identifiable in subcortical regions, we measured [3H] pirenzepine and [3H] AF-DX 384, and [3H] 4’DAMP binding in C.Pu from 40 SCZ subjects, 20 of which were SCZMRDS, 20 that were MRDSNON-MRDS, and 20 non-psychiatric controls (CTRL). These measures gave good estimation of muscarinic M1 receptor (CHRM1), CHRM2/4, and CHRM3 receptor levels, respectively. The level of [3H] pirenzepine binding was significantly lower in the C.Pu from subjects with SCZ when compared to CTRL (p < 0.0007). This was driven by the SCZMRDS group (p < 0.0001 relative to CTRL). The levels of [3H] AF-DX 384 binding was significantly lower in the C.Pu from SCZ subjects compared to CTRL (p < 0.0001); this was demonstrated more strongly in SCZMRDS subjects (p < 0.0001) than SCZNON-MRDS subjects (p < 0.001) when compared to CTRL subjects. No significant differences in [3H] 4’DAMP measures were shown. Collectively, the results demonstrated that the SCZMRDS subgroup had significantly different CHRM density profiles within the striatum, when compared to SCZNON-MRDS and CTRLS. These results reinforce the idea that SCZMRDS and SCZNON-MRDS cohorts are biochemically distinct with regards to CHRM biology. Within the cortex, reductions in CHRM density were observed predominately within the SCZMRDS cohort for all binding densities measured. Within the striatum however, reductions of [3H] AF-DX 384 binding were observed in both SCZMRDS and SCZNONMRDS subjects compared to CTRLS. This suggests that in terms of CHRM density, the striatum is more complicated compared to the cortex. As CHRM1/4 agonist therapy represents a promising approach for treatment of both the positive and cognitive symptoms in people with schizophrenia, these results characterising discrete subgroups with regards to CHRM density are extremely relevant to CHRM drug therapy discussions. Study 2. A recent microarray study by our group showed a significant decrease in the expression of Pyruvate dehydrogenase beta subunit (PDHß) in the dorsolateral prefrontal cortex (BA 9) from SCZMRDS subjects compared to SCZNON-MRDS subjects and controls. PDHß is the catalytic component of pyruvate dehydrogenase (PDH) that plays an essential role in its ability to convert pyruvate to acetyl-CoA, a rate-limiting step in the production of energy from glucose. Changes in levels of PDHß within the CNS could therefore have profound effects on energy utilisation in people with SCZ. The potential importance of such changes in PDHß led us to validate the microarray data. Quantitative PCR was used to measure levels of PDHß mRNA whilst Western blotting was used to measure levels of PDHß protein in BA 9 and the caudate in 40 SCZ subjects, 20 of which were SCZMRDS, and 20 non-psychiatric controls. Metabolite levels influenced by the rate of PDH activity were also measured in the caudate (pyruvate and lactate) in the same subjects. PDHß levels were not significantly different between SCZNON-MRDS or SCZMRDS and CTRL in BA9 at the levels of mRNA (p = 0.38), nor protein (p= 0.38). Within the caudate, protein levels were significantly different between the three groups (p < 0.05), where SCZNON-MRDS subjects demonstrated reduced levels compared to SCZMRDS and CTRLS. At the level of the metabolites, both pyruvate and lactate were increased in SCZNON-MRDS subjects compared to SCZMRDS and CTRL (p < 0.05, p < 0.01, respectively). Collectively, these results support the hypothesis that discrete biological subgroups in schizophrenia exist, segregating patients by the presence or absence of energy metabolism dysfunction, specifically PDH protein levels and the concentration of pyruvate and lactate within the caudate. Careful dissection of schizophrenia subgroups is an important step in understanding the aetiology of the syndrome. My data contributes to our understanding of biological subgroups and may ultimately help establish necessary biological markers and appropriate treatments for the diverse patients living with schizophrenia.