Psychiatry - Research Publications

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    Genetic and Epigenetic Regulation in Lingo-1: Effects on Cognitive Function and White Matter Microstructure in a Case-Control Study for Schizophrenia
    Andrews, JL ; Zalesky, A ; Nair, S ; Sullivan, RP ; Green, MJ ; Pantelis, C ; Newell, KA ; Fernandez, F (MDPI, 2023-11)
    Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) plays a vital role in a large number of neuronal processes underlying learning and memory, which are known to be disrupted in schizophrenia. However, Lingo-1 has never been examined in the context of schizophrenia. The genetic association of a single-nucleotide polymorphism (SNP, rs3144) and methylation (CpG sites) in the Lingo-1 3'-UTR region was examined, with the testing of cognitive dysfunction and white matter (WM) integrity in a schizophrenia case-control cohort (n = 268/group). A large subset of subjects (97 control and 161 schizophrenia subjects) underwent structural magnetic resonance imaging (MRI) brain scans to assess WM integrity. Frequency of the rs3144 minor allele was overrepresented in the schizophrenia population (p = 0.03), with an odds ratio of 1.39 (95% CI 1.016-1.901). CpG sites surrounding rs3144 were hypermethylated in the control population (p = 0.032) compared to the schizophrenia group. rs3144 genotype was predictive of membership to a subclass of schizophrenia subjects with generalized cognitive deficits (p < 0.05), in addition to having associations with WM integrity (p = 0.018). This is the first study reporting a potential implication of genetic and epigenetic risk factors in Lingo-1 in schizophrenia. Both of these genetic and epigenetic alterations may also have associations with cognitive dysfunction and WM integrity in the context of the schizophrenia pathophysiology.
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    Investigation of Brain Iron in Niemann-Pick Type C: A 7T Quantitative Susceptibility Mapping Study
    Ravanfar, P ; Syeda, WT ; Rushmore, RJ ; Moffat, B ; Lyall, AE ; Merritt, AH ; Devenyi, GA ; Chakravarty, MM ; Desmond, P ; Cropley, VL ; Makris, N ; Shenton, ME ; Bush, AI ; Velakoulis, D ; Pantelis, C ; Walterfang, M (AMER SOC NEURORADIOLOGY, 2023-06-22)
    BACKGROUND AND PURPOSE: While brain iron dysregulation has been observed in several neurodegenerative disorders, its association with the progressive neurodegeneration in Niemann-Pick type C is unknown. Systemic iron abnormalities have been reported in patients with Niemann-Pick type C and in animal models of Niemann-Pick type C. In this study, we examined brain iron using quantitative susceptibility mapping MR imaging in individuals with Niemann-Pick type C compared with healthy controls. MATERIALS AND METHODS: A cohort of 10 patients with adolescent- and adult-onset Niemann-Pick type C and 14 age- and sex-matched healthy controls underwent 7T brain MR imaging with T1 and quantitative susceptibility mapping acquisitions. A probing whole-brain voxelwise comparison of quantitative susceptibility mapping between groups was conducted. Mean quantitative susceptibility mapping in the ROIs (thalamus, hippocampus, putamen, caudate nucleus, and globus pallidus) was further compared. The correlations between regional volume, quantitative susceptibility mapping values, and clinical features, which included disease severity on the Iturriaga scale, cognitive function, and the Social and Occupational Functioning Assessment Scale, were explored as secondary analyses. RESULTS: We observed lower volume in the thalamus and voxel clusters of higher quantitative susceptibility mapping in the pulvinar nuclei bilaterally in patients with Niemann-Pick type C compared with the control group. In patients with Niemann-Pick type C, higher quantitative susceptibility mapping in the pulvinar nucleus clusters correlated with lower volume of the thalamus on both sides. Moreover, higher quantitative susceptibility mapping in the right pulvinar cluster was associated with greater disease severity. CONCLUSIONS: Our findings suggest iron deposition in the pulvinar nucleus in Niemann-Pick type C disease, which is associated with thalamic atrophy and disease severity. This preliminary evidence supports the link between iron and neurodegeneration in Niemann-Pick type C, in line with existing literature on other neurodegenerative disorders.
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    Investigation of brain iron in anorexia nervosa, a quantitative susceptibility mapping study
    Ravanfar, P ; Rushmore, RJ ; Lyall, AEE ; Cropley, V ; Makris, N ; Desmond, P ; Velakoulis, D ; Shenton, MEE ; Bush, AII ; Rossell, SLL ; Pantelis, C ; Syeda, WTT ; Phillipou, A (BMC, 2023-08-21)
    BACKGROUND: Anorexia nervosa (AN) is a potentially fatal psychiatric condition, associated with structural brain changes such as gray matter volume loss. The pathophysiological mechanisms for these changes are not yet fully understood. Iron is a crucial element in the development and function of the brain. Considering the systemic alterations in iron homeostasis in AN, we hypothesized that brain iron would be altered as a possible factor associated with structural brain changes in AN. METHODS: In this study, we used quantitative susceptibility mapping (QSM) magnetic resonance imaging to investigate brain iron in current AN (c-AN) and weight-restored AN compared with healthy individuals. Whole-brain voxel wise comparison was used to probe areas with possible group differences. Further, the thalamus, caudate nucleus, putamen, nucleus accumbens, hippocampus, and amygdala were selected as the regions of interest (ROIs) for ROI-based comparison of mean QSM values. RESULTS: Whole-brain voxel-wise and ROI-based comparison of QSM did not reveal any differences between groups. Exploratory analyses revealed a correlation between higher regional QSM (higher iron) and lower body mass index, higher illness severity, longer illness duration, and younger age at onset in the c-AN group. CONCLUSIONS: This study did not find evidence of altered brain iron in AN compared to healthy individuals. However, the correlations between clinical variables and QSM suggest a link between brain iron and weight status or biological processes in AN, which warrants further investigation.
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    Genetic variation in glutamatergic genes moderates the effects of childhood adversity on brain volume and IQ in treatment-resistant schizophrenia.
    Mohamed Saini, S ; Bousman, CA ; Mancuso, SG ; Cropley, V ; Van Rheenen, TE ; Lenroot, RK ; Bruggemann, J ; Weickert, CS ; Weickert, TW ; Sundram, S ; Everall, IP ; Pantelis, C (Springer Science and Business Media LLC, 2023-09-14)
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    Effects of risperidone/paliperidone versus placebo on cognitive functioning over the first 6 months of treatment for psychotic disorder: secondary analysis of a triple-blind randomised clinical trial
    Allott, K ; Yuen, HP ; Baldwin, L ; O'Donoghue, B ; Fornito, A ; Chopra, S ; Nelson, B ; Graham, J ; Kerr, MJJ ; Proffitt, T-M ; Ratheesh, A ; Alvarez-Jimenez, M ; Harrigan, S ; Brown, E ; Thompson, ADD ; Pantelis, C ; Berk, M ; McGorry, PDD ; Francey, SMM ; Wood, SJJ (SPRINGERNATURE, 2023-06-10)
    The drivers of cognitive change following first-episode psychosis remain poorly understood. Evidence regarding the role of antipsychotic medication is primarily based on naturalistic studies or clinical trials without a placebo arm, making it difficult to disentangle illness from medication effects. A secondary analysis of a randomised, triple-blind, placebo-controlled trial, where antipsychotic-naive patients with first-episode psychotic disorder were allocated to receive risperidone/paliperidone or matched placebo plus intensive psychosocial therapy for 6 months was conducted. A healthy control group was also recruited. A cognitive battery was administered at baseline and 6 months. Intention-to-treat analysis involved 76 patients (antipsychotic medication group: 37; 18.6Mage [2.9] years; 21 women; placebo group: 39; 18.3Mage [2.7]; 22 women); and 42 healthy controls (19.2Mage [3.0] years; 28 women). Cognitive performance predominantly remained stable (working memory, verbal fluency) or improved (attention, processing speed, cognitive control), with no group-by-time interaction evident. However, a significant group-by-time interaction was observed for immediate recall (p = 0.023), verbal learning (p = 0.024) and delayed recall (p = 0.005). The medication group declined whereas the placebo group improved on each measure (immediate recall: p = 0.024; ηp2 = 0.062; verbal learning: p = 0.015; ηp2 = 0.072 both medium effects; delayed recall: p = 0.001; ηp2 = 0.123 large effect). The rate of change for the placebo and healthy control groups was similar. Per protocol analysis (placebo n = 16, medication n = 11) produced similar findings. Risperidone/paliperidone may worsen verbal learning and memory in the early months of psychosis treatment. Replication of this finding and examination of various antipsychotic agents are needed in confirmatory trials. Antipsychotic effects should be considered in longitudinal studies of cognition in psychosis.Trial registration: Australian New Zealand Clinical Trials Registry ( http://www.anzctr.org.au/ ; ACTRN12607000608460).
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    The relative and interactive impact of multiple risk factors in schizophrenia spectrum disorders: a combined register-based and clinical twin study
    Lemvigh, C ; Brouwer, R ; Hilker, R ; Anhoj, S ; Baandrup, L ; Pantelis, C ; Glenthoj, B ; Fagerlund, B (CAMBRIDGE UNIV PRESS, 2021-08-05)
    BACKGROUND: Research has yielded evidence for genetic and environmental factors influencing the risk of schizophrenia. Numerous environmental factors have been identified; however, the individual effects are small. The additive and interactive effects of multiple risk factors are not well elucidated. Twin pairs discordant for schizophrenia offer a unique opportunity to identify factors that differ between patients and unaffected co-twins, who are perfectly matched for age, sex and genetic background. METHODS: Register data were combined with clinical data for 216 twins including monozygotic (MZ) and dizygotic (DZ) proband pairs (one or both twins having a schizophrenia spectrum diagnosis) and MZ/DZ healthy control (HC) pairs. Logistic regression models were applied to predict (1) illness vulnerability (being a proband v. HC pair) and (2) illness status (being the patient v. unaffected co-twin). Risk factors included: A polygenic risk score (PRS) for schizophrenia, birth complications, birth weight, Apgar scores, paternal age, maternal smoking, season of birth, parental socioeconomic status, urbanicity, childhood trauma, estimated premorbid intelligence and cannabis. RESULTS: The PRS [odds ratio (OR) 1.6 (1.1-2.3)], childhood trauma [OR 4.5 (2.3-8.8)], and regular cannabis use [OR 8.3 (2.1-32.7)] independently predicted illness vulnerability as did an interaction between childhood trauma and cannabis use [OR 0.17 (0.03-0.9)]. Only regular cannabis use predicted having a schizophrenia spectrum diagnosis between patients and unaffected co-twins [OR 3.3 (1.1-10.4)]. CONCLUSION: The findings suggest that several risk factors contribute to increasing schizophrenia spectrum vulnerability. Moreover, cannabis, a potentially completely avoidable environmental risk factor, seems to play a substantial role in schizophrenia pathology.
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    The relationship between subjective sleep disturbance and attenuated psychotic symptoms after accounting for anxiety and depressive symptoms.
    Formica, MJC ; Fuller-Tyszkiewicz, M ; Hickie, I ; Olive, L ; Wood, SJ ; Purcell, R ; Yung, AR ; Phillips, LJ ; Nelson, B ; Pantelis, C ; McGorry, PD ; Hartmann, JA (Elsevier BV, 2023-08)
    BACKGROUND AND HYPOTHESES: Sleep disturbances are increasingly recognized as cooccurring with psychotic symptoms. The potential importance of this relationship is complicated when considering the effects of anxiety and depressive symptoms which commonly present in early-stage illness states. This study aimed to investigate the relationship between self-reported sleep disturbance on the development of attenuated psychotic symptoms (APS) cross-sectionally and longitudinally while adjusting for roles of anxiety and depressive symptoms. DESIGN: Eight-hundred and two help-seeking young people aged 12 to 25 years who engaged with our Australian early intervention services were included in the study (the "Transitions" cohort). Cross sectional mediation and cross-lagged longitudinal (12-month) mediation models were developed with outcomes being different APS domains. RESULTS: Only baseline excessive daytime sleepiness predicted later APS when accounting for previous APS, anxiety and depressive symptomatology. Cross sectionally, self-reported sleep disturbance showed both direct and indirect predictive relationships with all APS domains. Partial mediation through anxiety and depression was shown for unusual thought content, perceptual abnormalities, and disorganised speech, while full mediation through depression was shown for non-bizarre ideas. CONCLUSIONS: The specificity of the relationship between self-reported sleep disturbance on APS highlights the potential for different roles in mechanistic models of psychotic symptom expression. This further indicates the need for further experimental research to illuminate potential causal pathways. Future research should continue to use continuous, symptom level approaches across a range of timeframes to more accurately model the complex dynamics present in the sleep-psychosis relationship.
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    Structural and Functional Brain Patterns Predict Formal Thought Disorder's Severity and Its Persistence in Recent-Onset Psychosis: Results From the PRONIA Study.
    Buciuman, M-O ; Oeztuerk, OF ; Popovic, D ; Enrico, P ; Ruef, A ; Bieler, N ; Sarisik, E ; Weiske, J ; Dong, MS ; Dwyer, DB ; Kambeitz-Ilankovic, L ; Haas, SS ; Stainton, A ; Ruhrmann, S ; Chisholm, K ; Kambeitz, J ; Riecher-Rössler, A ; Upthegrove, R ; Schultze-Lutter, F ; Salokangas, RKR ; Hietala, J ; Pantelis, C ; Lencer, R ; Meisenzahl, E ; Wood, SJ ; Brambilla, P ; Borgwardt, S ; Falkai, P ; Antonucci, LA ; Bertolino, A ; Liddle, P ; Koutsouleris, N ; PRONIA Consortium, (Elsevier BV, 2023-06-19)
    BACKGROUND: Formal thought disorder (FThD) is a core feature of psychosis, and its severity and long-term persistence relates to poor clinical outcomes. However, advances in developing early recognition and management tools for FThD are hindered by a lack of insight into the brain-level predictors of FThD states and progression at the individual level. METHODS: Two hundred thirty-three individuals with recent-onset psychosis were drawn from the multisite European Prognostic Tools for Early Psychosis Management study. Support vector machine classifiers were trained within a cross-validation framework to separate two FThD symptom-based subgroups (high vs. low FThD severity), using cross-sectional whole-brain multiband fractional amplitude of low frequency fluctuations, gray matter volume and white matter volume data. Moreover, we trained machine learning models on these neuroimaging readouts to predict the persistence of high FThD subgroup membership from baseline to 1-year follow-up. RESULTS: Cross-sectionally, multivariate patterns of gray matter volume within the salience, dorsal attention, visual, and ventral attention networks separated the FThD severity subgroups (balanced accuracy [BAC] = 60.8%). Longitudinally, distributed activations/deactivations within all fractional amplitude of low frequency fluctuation sub-bands (BACslow-5 = 73.2%, BACslow-4 = 72.9%, BACslow-3 = 68.0%), gray matter volume patterns overlapping with the cross-sectional ones (BAC = 62.7%), and smaller frontal white matter volume (BAC = 73.1%) predicted the persistence of high FThD severity from baseline to follow-up, with a combined multimodal balanced accuracy of BAC = 77%. CONCLUSIONS: We report the first evidence of brain structural and functional patterns predictive of FThD severity and persistence in early psychosis. These findings open up avenues for the development of neuroimaging-based diagnostic, prognostic, and treatment options for the early recognition and management of FThD and associated poor outcomes.
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    Complement proteins are elevated in blood serum but not CSF in clinical high-risk and antipsychotic-naive first-episode psychosis
    Cropley, VL ; Kittel, M ; Heurich, M ; Focking, M ; Leweke, FM ; Pantelis, C (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2023-10)
    Alterations in the complement system have been reported in some people with psychotic disorder, including in pre-psychotic individuals, suggesting that complement pathway dysregulation may be a feature of the early psychosis phenotype. Measurement of complement protein expression in psychosis has been largely restricted to the blood from patients with established illness who were taking antipsychotic medication. The present study examined a range of complement proteins in blood and cerebrospinal fluid (CSF) derived from individuals at clinical high-risk for psychosis (CHR), antipsychotic-naïve first-episode psychosis (FEP) and healthy controls. A panel of complement proteins (C1q, C3, C3b/iC3b, C4, factor B and factor H) were quantified in serum and matched CSF in 72 participants [n = 23 individuals at CHR, n = 24 antipsychotic-naïve FEP, n = 25 healthy controls] using a multiplex immunoassay. Analysis of covariance was used to assess between-group differences in complement protein levels in serum and CSF. Pearson's correlation was used to assess the relationship between serum and CSF proteins, and between complement proteins and symptom severity. In serum, all proteins, except for C3, were significantly higher in FEP and CHR. While a trend was observed, protein levels in CSF did not statistically differ between groups and appeared to be impacted by BMI and sample storage time. Across the whole sample, serum and CSF protein levels were not correlated. In FEP, higher levels of serum classical and alternative grouped pathway components were correlated with symptom severity. Our exploratory study provides evidence for increased activity of the peripheral complement system in the psychosis spectrum, with such elevations varying with clinical severity. Further study of complement in CSF is warranted. Longitudinal investigations are required to elucidate whether complement proteins change peripherally and/or centrally with progression of psychotic illness.
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    Inflammatory subgroups of schizophrenia and their association with brain structure: A semi-supervised machine learning examination of heterogeneity
    Lalousis, PA ; Schmaal, L ; Wood, SJ ; Reniers, RLEP ; Cropley, VL ; Watson, A ; Pantelis, C ; Suckling, J ; Barnes, NM ; Pariante, C ; Jones, PB ; Joyce, E ; Barnes, TRE ; Lawrie, SM ; Husain, N ; Dazzan, P ; Deakin, B ; Weickert, CS ; Upthegrove, R (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2023-10)
    OBJECTIVE: Immune system dysfunction is hypothesised to contribute to structural brain changes through aberrant synaptic pruning in schizophrenia. However, evidence is mixed and there is a lack of evidence of inflammation and its effect on grey matter volume (GMV) in patients. We hypothesised that inflammatory subgroups can be identified and that the subgroups will show distinct neuroanatomical and neurocognitive profiles. METHODS: The total sample consisted of 1067 participants (chronic patients with schizophrenia n = 467 and healthy controls (HCs) n = 600) from the Australia Schizophrenia Research Bank (ASRB) dataset, together with 218 recent-onset patients with schizophrenia from the external Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin) dataset. HYDRA (HeterogeneitY through DiscRiminant Analysis) was used to separate schizophrenia from HC and define disease-related subgroups based on inflammatory markers. Voxel-based morphometry and inferential statistics were used to explore GMV alterations and neurocognitive deficits in these subgroups. RESULTS: An optimal clustering solution revealed five main schizophrenia groups separable from HC: Low Inflammation, Elevated CRP, Elevated IL-6/IL-8, Elevated IFN-γ, and Elevated IL-10 with an adjusted Rand index of 0.573. When compared with the healthy controls, the IL-6/IL-8 cluster showed the most widespread, including the anterior cingulate, GMV reduction. The IFN-γ inflammation cluster showed the least GMV reduction and impairment of cognitive performance. The CRP and the Low Inflammation clusters dominated in the younger external dataset. CONCLUSIONS: Inflammation in schizophrenia may not be merely a case of low vs high, but rather there are pluripotent, heterogeneous mechanisms at play which could be reliably identified based on accessible, peripheral measures. This could inform the successful development of targeted interventions.