Medicine (RMH Academic Centre) - Research Publications

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    Ending our shame: call for a fundamental reconsideration of Australian refugee policy
    Bennett, EA ; Newman, L ; Burnside, JWK ; Phatarfod, B ; Thomas, RM ; Moodie, AR ; Moore, MJ (ELSEVIER SCIENCE INC, 2017-08-05)
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    A blood-based biomarker panel indicates IL-10 and IL-12/23p40 are jointly associated as predictors of β-amyloid load in an AD cohort
    Pedrini, S ; Gupta, VB ; Hone, E ; Doecke, J ; O'Bryant, S ; James, I ; Bush, AI ; Rowe, CC ; Villemagne, VL ; Ames, D ; Masters, CL ; Martins, RN (NATURE PORTFOLIO, 2017-10-25)
    Alzheimer's Disease (AD) is the most common form of dementia, characterised by extracellular amyloid deposition as plaques and intracellular neurofibrillary tangles of tau protein. As no current clinical test can diagnose individuals at risk of developing AD, the aim of this project is to evaluate a blood-based biomarker panel to identify individuals who carry this risk. We analysed the levels of 22 biomarkers in clinically classified healthy controls (HC), mild cognitive impairment (MCI) and Alzheimer's participants from the well characterised Australian Imaging, Biomarker and Lifestyle (AIBL) study of aging. High levels of IL-10 and IL-12/23p40 were significantly associated with amyloid deposition in HC, suggesting that these two biomarkers might be used to detect at risk individuals. Additionally, other biomarkers (Eotaxin-3, Leptin, PYY) exhibited altered levels in AD participants possessing the APOE ε4 allele. This suggests that the physiology of some potential biomarkers may be altered in AD due to the APOE ε4 allele, a major risk factor for AD. Taken together, these data highlight several potential biomarkers that can be used in a blood-based panel to allow earlier identification of individuals at risk of developing AD and/or early stage AD for which current therapies may be more beneficial.
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    Placement Instability Among Young People Removed from Their Original Family and the Likely Mental Health Implications.
    Rice, S ; Cotton, S ; Moeller-Saxone, K ; Mihalopoulos, C ; Magnus, A ; Harvey, C ; Humphreys, C ; Halperin, S ; Scheppokat, A ; McGorry, P ; Herrman, H ( 2017-04-25)
    BACKGROUND: Young people in out-of-home care are more likely to experience poorer mental and physical health outcomes related to their peers. Stable care environments are essential for ameliorating impacts of disruptive early childhood experiences, including exposure to psychological trauma, abuse and neglect. At present there are very few high quality data regarding the placement stability history of young people in out-of-home care in Australia or other countries. OBJECTIVES: To undertake the first systematic census of background, care type and placement stability characteristics of young people living in the out-of-home care sector in Australia. METHODS: Data was collected from four non-government child and adolescent community service organisations located across metropolitan Melbourne in 2014. The sample comprised 322 young people (females 52.8%), aged between 12 - 17 years (mean age=14.86 [SD=1.63] years). RESULTS: Most young people (64.3%) were in home-based care settings (i.e., foster care, therapeutic foster care, adolescent care program, kinship care, and lead tenant care), relative to residential care (35.7%). However, the proportion in residential care is very high in this age group when compared with all children in out-of-home care (5%). Mean age of first removal was 9 years (SD=4.54). No gender differences were observed for care type characteristics. Three quarters of the sample (76.9%) had a lifetime history of more than one placement in the out-of-home care system, with more than a third (36.5%) having experienced ≥5 lifetime placements. Relative to home-based care, young people in residential care experienced significantly greater placement instability (χ2=63.018, p<0.001). CONCLUSIONS: Placement instability is common in the out-of-home care sector. Given stable care environments are required to ameliorate psychological trauma and health impacts associated with childhood maltreatment, well-designed intervention-based research is required to enable greater placement stability, including strengthening the therapeutic capacities of out-of-home carers of young people.
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    Staging in bipolar disorder: from theoretical framework to clinical utility
    Berk, M ; Post, R ; Ratheesh, A ; Gliddon, E ; Singh, A ; Vieta, E ; Carvalho, AF ; Ashton, MM ; Berk, L ; Cotton, SM ; McGorry, PD ; Fernandes, BS ; Yatham, LN ; Dodd, S (WILEY, 2017-10)
    Illness staging is widely utilized in several medical disciplines to help predict course or prognosis, and optimize treatment. Staging models in psychiatry in general, and bipolar disorder in particular, depend on the premise that psychopathology moves along a predictable path: an at-risk or latency stage, a prodrome progressing to a first clinical threshold episode, and one or more recurrences with the potential to revert or progress to late or end-stage manifestations. The utility and validity of a staging model for bipolar disorder depend on its linking to clinical outcome, treatment response and neurobiological measures. These include progressive biochemical, neuroimaging and cognitive changes, and potentially stage-specific differences in response to pharmacological and psychosocial treatments. Mechanistically, staging models imply the presence of an active disease process that, if not remediated, can lead to neuroprogression, a more malignant disease course and functional deterioration. Biological elements thought to be operative in bipolar disorder include a genetic diathesis, physical and psychic trauma, epigenetic changes, altered neurogenesis and apoptosis, mitochondrial dysfunction, inflammation, and oxidative stress. Many available agents, such as lithium, have effects on these targets. Staging models also suggest the utility of stage-specific treatment approaches that may not only target symptom reduction, but also impede illness neuroprogression. These treatment approaches range from prevention for at-risk individuals, to early intervention strategies for prodromal and newly diagnosed individuals, complex combination therapy for rapidly recurrent illness, and palliative-type approaches for those at chronic, late stages of illness. There is hope that prompt initiation of potentially disease modifying therapies may preclude or attenuate the cognitive and structural changes seen in the later stages of bipolar disorder. The aims of this paper are to: a) explore the current level of evidence supporting the descriptive staging of the syndromal pattern of bipolar disorder; b) describe preliminary attempts at validation; c) make recommendations for the direction of further studies; and d) provide a distillation of the potential clinical implications of staging in bipolar disorder within a broader transdiagnostic framework.
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    Getting RID of the blues: Formulating a Risk Index for Depression (RID) using structural equation modeling
    Dipnall, JF ; Pasco, JA ; Berk, M ; Williams, LJ ; Dodd, S ; Jacka, FN ; Meyer, D (SAGE PUBLICATIONS LTD, 2017-11)
    OBJECTIVE: While risk factors for depression are increasingly known, there is no widely utilised depression risk index. Our objective was to develop a method for a flexible, modular, Risk Index for Depression using structural equation models of key determinants identified from previous published research that blended machine-learning with traditional statistical techniques. METHODS: Demographic, clinical and laboratory variables from the National Health and Nutrition Examination Study (2009-2010, N = 5546) were utilised. Data were split 50:50 into training:validation datasets. Generalised structural equation models, using logistic regression, were developed with a binary outcome depression measure (Patient Health Questionnaire-9 score ⩾ 10) and previously identified determinants of depression: demographics, lifestyle-environs, diet, biomarkers and somatic symptoms. Indicative goodness-of-fit statistics and Areas Under the Receiver Operator Characteristic Curves were calculated and probit regression checked model consistency. RESULTS: The generalised structural equation model was built from a systematic process. Relative importance of the depression determinants were diet (odds ratio: 4.09; 95% confidence interval: [2.01, 8.35]), lifestyle-environs (odds ratio: 2.15; 95% CI: [1.57, 2.94]), somatic symptoms (odds ratio: 2.10; 95% CI: [1.58, 2.80]), demographics (odds ratio:1.46; 95% CI: [0.72, 2.95]) and biomarkers (odds ratio:1.39; 95% CI: [1.00, 1.93]). The relationships between demographics and lifestyle-environs and depression indicated a potential indirect path via somatic symptoms and biomarkers. The path from diet was direct to depression. The Areas under the Receiver Operator Characteristic Curves were good (logistic:training = 0.850, validation = 0.813; probit:training = 0.849, validation = 0.809). CONCLUSION: The novel Risk Index for Depression modular methodology developed has the flexibility to add/remove direct/indirect risk determinants paths to depression using a structural equation model on datasets that take account of a wide range of known risks. Risk Index for Depression shows promise for future clinical use by providing indications of main determinant(s) associated with a patient's predisposition to depression and has the ability to be translated for the development of risk indices for other affective disorders.
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    Configural and Featural Face Processing Influences on Emotion Recognition in Schizophrenia and Bipolar Disorder
    Van Rheenen, TE ; Joshua, N ; Castle, DJ ; Rossell, SL (CAMBRIDGE UNIV PRESS, 2017-03)
    OBJECTIVES: Emotion recognition impairments have been demonstrated in schizophrenia (Sz), but are less consistent and lesser in magnitude in bipolar disorder (BD). This may be related to the extent to which different face processing strategies are engaged during emotion recognition in each of these disorders. We recently showed that Sz patients had impairments in the use of both featural and configural face processing strategies, whereas BD patients were impaired only in the use of the latter. Here we examine the influence that these impairments have on facial emotion recognition in these cohorts. METHODS: Twenty-eight individuals with Sz, 28 individuals with BD, and 28 healthy controls completed a facial emotion labeling task with two conditions designed to separate the use of featural and configural face processing strategies; part-based and whole-face emotion recognition. RESULTS: Sz patients performed worse than controls on both conditions, and worse than BD patients on the whole-face condition. BD patients performed worse than controls on the whole-face condition only. CONCLUSIONS: Configural processing deficits appear to influence the recognition of facial emotions in BD, whereas both configural and featural processing abnormalities impair emotion recognition in Sz. This may explain discrepancies in the profiles of emotion recognition between the disorders. (JINS, 2017, 23, 287-291).
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    Deterioration of visuospatial associative memory following a first psychotic episode: a long-term follow-up study
    Wannan, CMJ ; Bartholomeusz, CF ; Cropley, VL ; Van Rheenen, TE ; Panayiotou, A ; Brewer, WJ ; Proffitt, TM ; Henry, L ; Harris, MG ; Velakoulis, D ; McGorry, P ; Pantelis, C ; Wood, SJ (CAMBRIDGE UNIV PRESS, 2018-01)
    BACKGROUND: Cognitive deficits are a core feature of schizophrenia, and impairments in most domains are thought to be stable over the course of the illness. However, cross-sectional evidence indicates that some areas of cognition, such as visuospatial associative memory, may be preserved in the early stages of psychosis, but become impaired in later established illness stages. This longitudinal study investigated change in visuospatial and verbal associative memory following psychosis onset. METHODS: In total 95 first-episode psychosis (FEP) patients and 63 healthy controls (HC) were assessed on neuropsychological tests at baseline, with 38 FEP and 22 HCs returning for follow-up assessment at 5-11 years. Visuospatial associative memory was assessed using the Cambridge Neuropsychological Test Automated Battery Visuospatial Paired-Associate Learning task, and verbal associative memory was assessed using Verbal Paired Associates subtest of the Wechsler Memory Scale - Revised. RESULTS: Visuospatial and verbal associative memory at baseline did not differ significantly between FEP patients and HCs. However, over follow-up, visuospatial associative memory deteriorated significantly for the FEP group, relative to healthy individuals. Conversely, verbal associative memory improved to a similar degree observed in HCs. In the FEP cohort, visuospatial (but not verbal) associative memory ability at baseline was associated with functional outcome at follow-up. CONCLUSIONS: Areas of cognition that develop prior to psychosis onset, such as visuospatial and verbal associative memory, may be preserved early in the illness. Later deterioration in visuospatial memory ability may relate to progressive structural and functional brain abnormalities that occurs following psychosis onset.
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    Characterizing cognitive heterogeneity on the schizophrenia-bipolar disorder spectrum
    Van Rheenen, TE ; Lewandowski, KE ; Tan, EJ ; Ospina, LH ; Ongur, D ; Neill, E ; Gurvich, C ; Pantelis, C ; Malhotra, AK ; Rossell, SL ; Burdick, KE (CAMBRIDGE UNIV PRESS, 2017-07)
    BACKGROUND: Current group-average analysis suggests quantitative but not qualitative cognitive differences between schizophrenia (SZ) and bipolar disorder (BD). There is increasing recognition that cognitive within-group heterogeneity exists in both disorders, but it remains unclear as to whether between-group comparisons of performance in cognitive subgroups emerging from within each of these nosological categories uphold group-average findings. We addressed this by identifying cognitive subgroups in large samples of SZ and BD patients independently, and comparing their cognitive profiles. The utility of a cross-diagnostic clustering approach to understanding cognitive heterogeneity in these patients was also explored. METHOD: Hierarchical clustering analyses were conducted using cognitive data from 1541 participants (SZ n = 564, BD n = 402, healthy control n = 575). RESULTS: Three qualitatively and quantitatively similar clusters emerged within each clinical group: a severely impaired cluster, a mild-moderately impaired cluster and a relatively intact cognitive cluster. A cross-diagnostic clustering solution also resulted in three subgroups and was superior in reducing cognitive heterogeneity compared with disorder clustering independently. CONCLUSIONS: Quantitative SZ-BD cognitive differences commonly seen using group averages did not hold when cognitive heterogeneity was factored into our sample. Members of each corresponding subgroup, irrespective of diagnosis, might be manifesting the outcome of differences in shared cognitive risk factors.
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    Widespread Volumetric Reductions in Schizophrenia and Schizoaffective Patients Displaying Compromised Cognitive Abilities
    Van Rheenen, TE ; Cropley, V ; Zalesky, A ; Bousman, C ; Wells, R ; Bruggemann, J ; Sundram, S ; Weinberg, D ; Lenroot, RK ; Pereira, A ; Weickert, CS ; Weickert, TW ; Pantelis, C (OXFORD UNIV PRESS, 2018-05)
    OBJECTIVE: Progress toward understanding brain mechanisms in psychosis is hampered by failures to account for within-group heterogeneity that exists across neuropsychological domains. We recently identified distinct cognitive subgroups that might assist in identifying more biologically meaningful subtypes of psychosis. In the present study, we examined whether underlying structural brain abnormalities differentiate these cognitively derived subgroups. METHOD: 1.5T T1 weighted structural scans were acquired for 168 healthy controls and 220 patients with schizophrenia/schizoaffective disorder. Based on previous work, 47 patients were categorized as being cognitively compromised (impaired premorbid and current IQ), 100 as cognitively deteriorated (normal premorbid IQ, impaired current IQ), and 73 as putatively cognitively preserved (premorbid and current IQ within 1 SD of controls). Global, subcortical and cortical volume, thickness, and surface area measures were compared among groups. RESULTS: Whole cortex, subcortical, and regional volume and thickness reductions were evident in all subgroups compared to controls, with the largest effect sizes in the compromised group. This subgroup also showed abnormalities in regions not seen in the other patient groups, including smaller left superior and middle frontal areas, left anterior and inferior temporal areas and right lateral medial and inferior frontal, occipital lobe and superior temporal areas. CONCLUSIONS: This pattern of more prominent brain structural abnormalities in the group with the most marked cognitive impairments-both currently and putatively prior to illness onset, is consistent with the concept of schizophrenia as a progressive neurodevelopmental disorder. In this group, neurodevelopmental and neurodegenerative factors may be important for cognitive function.