Psychiatry - Research Publications

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    A multivariate cognitive approach to predict social functioning in recent onset psychosis in response to computerized cognitive training
    Walter, N ; Wenzel, J ; Haas, SS ; Squarcina, L ; Bonivento, C ; Ruef, A ; Dwyer, D ; Lichtenstein, T ; Bastruek, O ; Stainton, A ; Antonucci, LA ; Brambilla, P ; Wood, SJ ; Upthegrove, R ; Borgwardt, S ; Lencer, R ; Meisenzahl, E ; Salokangas, RKR ; Pantelis, C ; Bertolino, A ; Koutsouleris, N ; Kambeitz, J ; Kambeitz-Ilankovic, L (PERGAMON-ELSEVIER SCIENCE LTD, 2024-01-10)
    Clinical and neuroimaging data has been increasingly used in recent years to disentangle heterogeneity of treatment response to cognitive training (CT) and predict which individuals may achieve the highest benefits. CT has small to medium effects on improving cognitive and social functioning in recent onset psychosis (ROP) patients, who show the most profound cognitive and social functioning deficits among psychiatric patients. We employed multivariate pattern analysis (MVPA) to investigate the potential of cognitive data to predict social functioning improvement in response to 10 h of CT in patients with ROP. A support vector machine (SVM) classifier was trained on the naturalistic data of the Personalized Prognostic Tools for Early Psychosis Management (PRONIA) study sample to predict functioning in an independent sample of 70 ROP patients using baseline cognitive data. PRONIA is a part of a FP7 EU grant program that involved 7 sites across 5 European countries, designed and conducted with the main aim of identifying (bio)markers associated with an enhanced risk of developing psychosis in order to improve early detection and prognosis. Social functioning was predicted with a balanced accuracy (BAC) of 66.4% (Sensitivity 78.8%; Specificity 54.1%; PPV 60.5%; NPV 74.1%; AUC 0.64; P = 0.01). The most frequently selected cognitive features (mean feature weights > ± 0.2) included the (1) correct number of symbol matchings within the Digit Symbol Substitution Test, (2) the number of distracting stimuli leading to an error within 300 and 200 trials in the Continuous Performance Test and (3) the dynamics of verbal fluency between 15 and 30 s within the Verbal Fluency Test, phonetic part. Next, the SVM classifier generated on the PRONIA sample was applied to the intervention sample, that obtained 54 ROP patients who were randomly assigned to a social cognitive training (SCT) or treatment as usual (TAU) group and dichotomized into good (GF-S ≥ 7) and poor (GF-S < 7) functioning patients based on their level of Global Functioning-Social (GF-S) score at follow-up (FU). By applying the initial PRONIA classifier, using out-of-sample cross-validation (OOCV) to the sample of ROP patients who have undergone the CT intervention, a BAC of 59.3% (Sensitivity 70.4%; Specificity 48.1%; PPV 57.6%; NPV 61.9%; AUC 0.63) was achieved at T0 and a BAC of 64.8% (Sensitivity 66.7%; Specificity 63.0%; PPV 64.3%; NPV 65.4%; AUC 0.66) at FU. After SCT intervention, a significant improvement in predicted social functioning values was observed in the SCT compared to TAU group (P ≤0.05; ES[Cohens' d] = 0.18). Due to a small sample size and modest variance of social functioning of the intervention sample it was not feasible to predict individual response to SCT in the current study. Our findings suggest that the use of baseline cognitive data could provide a robust individual estimate of future social functioning, while prediction of individual response to SCT using cognitive data that can be generated in the routine patient care remains to be addressed in large-scale cognitive training trials.
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    Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders
    Eratne, D ; Kang, M ; Malpas, C ; Simpson-Yap, S ; Lewis, C ; Dang, C ; Grewal, J ; Coe, A ; Dobson, H ; Keem, M ; Chiu, W-H ; Kalincik, T ; Ooi, S ; Darby, D ; Brodtmann, A ; Hansson, O ; Janelidze, S ; Blennow, K ; Zetterberg, H ; Walker, A ; Dean, O ; Berk, M ; Wannan, C ; Pantelis, C ; Loi, SM ; Walterfang, M ; Berkovic, SF ; Santillo, AF ; Velakoulis, D (SAGE PUBLICATIONS LTD, 2024-01)
    OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.
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    Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers
    Boen, R ; Kaufmann, T ; van der Meer, D ; Frei, O ; Agartz, I ; Ames, D ; Andersson, M ; Armstrong, NJ ; Artiges, E ; Atkins, JR ; Bauer, J ; Benedetti, F ; Boomsma, DI ; Brodaty, H ; Brosch, K ; Buckner, RL ; Cairns, MJ ; Calhoun, V ; Caspers, S ; Cichon, S ; Corvin, AP ; Crespo-Facorro, B ; Dannlowski, U ; David, FS ; de Geus, EJC ; de Zubicaray, GI ; Desrivieres, S ; Doherty, JL ; Donohoe, G ; Ehrlich, S ; Eising, E ; Espeseth, T ; Fisher, SE ; Forstner, AJ ; Fortaner-Uya, L ; Frouin, V ; Fukunaga, M ; Ge, T ; Glahn, DC ; Goltermann, J ; Grabe, HJ ; Green, MJ ; Groenewold, NA ; Grotegerd, D ; Grontvedt, GR ; Hahn, T ; Hashimoto, R ; Hehir-Kwa, JY ; Henskens, FA ; Holmes, AJ ; Haberg, AK ; Haavik, J ; Jacquemont, S ; Jansen, A ; Jockwitz, C ; Joensson, EG ; Kikuchi, M ; Kircher, T ; Kumar, K ; Le Hellard, S ; Leu, C ; Linden, DE ; Liu, J ; Loughnan, R ; Mather, KA ; Mcmahon, KL ; Mcrae, AF ; Medland, SE ; Meinert, S ; Moreau, CA ; Morris, DW ; Mowry, BJ ; Muehleisen, TW ; Nenadic, I ; Noethen, MM ; Nyberg, L ; Ophoff, RA ; Owen, MJ ; Pantelis, C ; Paolini, M ; Paus, T ; Pausova, Z ; Persson, K ; Quide, Y ; Marques, TR ; Sachdev, PS ; Sando, SB ; Schall, U ; Scott, RJ ; Selbaek, G ; Shumskaya, E ; Silva, AI ; Sisodiya, SM ; Stein, F ; Stein, DJ ; Straube, B ; Streit, F ; Strike, LT ; Teumer, A ; Teutenberg, L ; Thalamuthu, A ; Tooney, PA ; Tordesillas-Gutierrez, D ; Trollor, JN ; Van't Ent, D ; van den Bree, MBM ; van Haren, NEM ; Vazquez-Bourgon, J ; Voelzke, H ; Wen, W ; Wittfeld, K ; Ching, CRK ; Westlye, LT ; Thompson, PM ; Bearden, CE ; Selmer, KK ; Alnaes, D ; Andreassen, OA ; Sonderby, IE (ELSEVIER SCIENCE INC, 2024-01-15)
    BACKGROUND: Carriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure. METHODS: Magnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual's regional difference and global difference, were used to test for regional differences that diverge from the global difference. RESULTS: For the 1q21.1 distal deletion carriers, cortical surface area for regions in the medial visual cortex, posterior cingulate, and temporal pole differed less and regions in the prefrontal and superior temporal cortex differed more than the global difference in cortical surface area. For the 15q11.2 BP1-BP2 deletion carriers, cortical thickness in regions in the medial visual cortex, auditory cortex, and temporal pole differed less and the prefrontal and somatosensory cortex differed more than the global difference in cortical thickness. CONCLUSIONS: We find evidence for regional effects beyond differences in global brain measures in 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants. The results provide new insight into brain profiling of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants, with the potential to increase understanding of the mechanisms involved in altered neurodevelopment.
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    Combining Clinical With Cognitive or Magnetic Resonance Imaging Data for Predicting Transition to Psychosis in Ultra High-Risk Patients: Data From the PACE 400 Cohort.
    Hartmann, S ; Cearns, M ; Pantelis, C ; Dwyer, D ; Cavve, B ; Byrne, E ; Scott, I ; Yuen, HP ; Gao, C ; Allott, K ; Lin, A ; Wood, SJ ; Wigman, JTW ; Amminger, GP ; McGorry, PD ; Yung, AR ; Nelson, B ; Clark, SR (Elsevier BV, 2023-12-03)
    BACKGROUND: Multimodal modeling that combines biological and clinical data shows promise in predicting transition to psychosis in individuals who are at ultra-high risk. Individuals who transition to psychosis are known to have deficits at baseline in cognitive function and reductions in gray matter volume in multiple brain regions identified by magnetic resonance imaging. METHODS: In this study, we used Cox proportional hazards regression models to assess the additive predictive value of each modality-cognition, cortical structure information, and the neuroanatomical measure of brain age gap-to a previously developed clinical model using functioning and duration of symptoms prior to service entry as predictors in the Personal Assessment and Crisis Evaluation (PACE) 400 cohort. The PACE 400 study is a well-characterized cohort of Australian youths who were identified as ultra-high risk of transitioning to psychosis using the Comprehensive Assessment of At Risk Mental States (CAARMS) and followed for up to 18 years; it contains clinical data (from N = 416 participants), cognitive data (n = 213), and magnetic resonance imaging cortical parameters extracted using FreeSurfer (n = 231). RESULTS: The results showed that neuroimaging, brain age gap, and cognition added marginal predictive information to the previously developed clinical model (fraction of new information: neuroimaging 0%-12%, brain age gap 7%, cognition 0%-16%). CONCLUSIONS: In summary, adding a second modality to a clinical risk model predicting the onset of a psychotic disorder in the PACE 400 cohort showed little improvement in the fit of the model for long-term prediction of transition to psychosis.
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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, 2023-03)
    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.