Psychiatry - Research Publications

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    Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives
    Eratne, D ; Janelidze, S ; Malpas, CB ; Loi, S ; Walterfane, M ; Merritt, A ; Diouf, I ; Blennow, K ; Zetterberg, H ; Cilia, B ; Warman, C ; Bousman, C ; Everall, I ; Zalesky, A ; Jayaram, M ; Thomas, N ; Berkovic, SF ; Hansson, O ; Velakoulis, D ; Pantelis, C ; Santillo, A (SAGE PUBLICATIONS LTD, 2022-10)
    OBJECTIVE: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. METHODS: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine (n = 82), compared to first-degree relatives (an at-risk group, n = 37), people with schizophrenia not treated with clozapine (n = 13), and age- and sex-matched controls (n = 59). RESULTS: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's r = 0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia (r = 0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight (r = -0.305, 95% confidence interval: [-0.504, -0.076]). CONCLUSION: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.
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    Relationships between global functioning and neuropsychological predictors in subjects at high risk of psychosis or with a recent onset of depression
    Squarcina, L ; Kambeitz-Ilankovic, L ; Bonivento, C ; Prunas, C ; Oldani, L ; Wenzel, J ; Ruef, A ; Dwyer, D ; Ferro, A ; Borgwardt, S ; Kambeitz, J ; Lichtenstein, TK ; Meisenzahl, E ; Pantelis, C ; Rosen, M ; Upthegrove, R ; Antonucci, LA ; Bertolino, A ; Lencer, R ; Ruhrmann, S ; Salokangas, RRK ; Schultze-Lutter, F ; Chisholm, K ; Stainton, A ; Wood, SJ ; Koutsouleris, N ; Brambilla, P (TAYLOR & FRANCIS LTD, 2022-09-14)
    OBJECTIVE: Psychotic disorders are frequently associated with decline in functioning and cognitive difficulties are observed in subjects at clinical high risk (CHR) for psychosis. In this work, we applied automatic approaches to neurocognitive and functioning measures, with the aim of investigating the link between global, social and occupational functioning, and cognition. METHODS: 102 CHR subjects and 110 patients with recent onset depression (ROD) were recruited. Global assessment of functioning (GAF) related to symptoms (GAF-S) and disability (GAF-D). and global functioning social (GF-S) and role (GF-R), at baseline and of the previous month and year, and a set of neurocognitive measures, were used for classification and regression. RESULTS: Neurocognitive measures related to GF-R at baseline (r = 0.20, p = 0.004), GF-S at present (r = 0.14, p = 0.042) and of the past year (r = 0.19, p = 0.005), for GAF-F of the past month (r = 0.24, p < 0.001) and GAF-D of the past year (r = 0.28, p = 0.002). Classification reached values of balanced accuracy of 61% for GF-R and GAF-D. CONCLUSION: We found that neurocognition was related to psychosocial functioning. More specifically, a deficit in executive functions was associated to poor social and occupational functioning.
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    Whole-genome sequencing analysis of clozapine-induced myocarditis
    Narang, A ; Lacaze, P ; Ronaldson, KJ ; McNeil, JJ ; Jayaram, M ; Thomas, N ; Sellmer, R ; Crockford, D ; Stowe, R ; Greenway, SC ; Pantelis, C ; Bousman, CA (SPRINGERNATURE, 2022-05)
    One of the concerns limiting the use of clozapine in schizophrenia treatment is the risk of rare but potentially fatal myocarditis. Our previous genome-wide association study and human leucocyte antigen analyses identified putative loci associated with clozapine-induced myocarditis. However, the contribution of DNA variation in cytochrome P450 genes, copy number variants and rare deleterious variants have not been investigated. We explored these unexplored classes of DNA variation using whole-genome sequencing data from 25 cases with clozapine-induced myocarditis and 25 demographically-matched clozapine-tolerant control subjects. We identified 15 genes based on rare variant gene-burden analysis (MLLT6, CADPS, TACC2, L3MBTL4, NPY, SLC25A21, PARVB, GPR179, ACAD9, NOL8, C5orf33, FAM127A, AFDN, SLC6A11, PXDN) nominally associated (p < 0.05) with clozapine-induced myocarditis. Of these genes, 13 were expressed in human myocardial tissue. Although independent replication of these findings is required, our study provides preliminary insights into the potential role of rare genetic variants in susceptibility to clozapine-induced myocarditis.
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    Heritability of specific cognitive functions and associations with schizophrenia spectrum disorders using CANTAB: a nation-wide twin study
    Lemvigh, CK ; Brouwer, RM ; Pantelis, C ; Jensen, MH ; Hilker, RW ; Legind, CS ; Anhoj, SJ ; Robbins, TW ; Sahakian, BJ ; Glenthoj, BY ; Fagerlund, B (CAMBRIDGE UNIV PRESS, 2022-04)
    BACKGROUND: Many cognitive functions are under strong genetic control and twin studies have demonstrated genetic overlap between some aspects of cognition and schizophrenia. How the genetic relationship between specific cognitive functions and schizophrenia is influenced by IQ is currently unknown. METHODS: We applied selected tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) to examine the heritability of specific cognitive functions and associations with schizophrenia liability. Verbal and performance IQ were estimated using The Wechsler Adult Intelligence Scale-III and the Danish Adult Reading Test. In total, 214 twins including monozygotic (MZ = 32) and dizygotic (DZ = 22) pairs concordant or discordant for a schizophrenia spectrum disorder, and healthy control pairs (MZ = 29, DZ = 20) were recruited through the Danish national registers. Additionally, eight twins from affected pairs participated without their sibling. RESULTS: Significant heritability was observed for planning/spatial span (h2 = 25%), self-ordered spatial working memory (h2 = 64%), sustained attention (h2 = 56%), and movement time (h2 = 47%), whereas only unique environmental factors contributed to set-shifting, reflection impulsivity, and thinking time. Schizophrenia liability was associated with planning/spatial span (rph = -0.34), self-ordered spatial working memory (rph = -0.24), sustained attention (rph = -0.23), and set-shifting (rph = -0.21). The association with planning/spatial span was not driven by either performance or verbal IQ. The remaining associations were shared with performance, but not verbal IQ. CONCLUSIONS: This study provides further evidence that some cognitive functions are heritable and associated with schizophrenia, suggesting a partially shared genetic etiology. These functions may constitute endophenotypes for the disorder and provide a basis to explore genes common to cognition and schizophrenia.
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    Empathy and resting-state functional connectivity in children
    Bray, KO ; Pozzi, E ; Vijayakumar, N ; Richmond, S ; Seal, M ; Pantelis, C ; Anderson, V ; Whittle, S (Elsevier BV, 2022-12-01)
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    Intelligence trajectories in individuals at ultra-high risk for psychosis: An 8-year longitudinal analysis
    Cheng, N ; Lin, A ; Bowden, S ; Gao, C ; Yung, AR ; Nelson, B ; Thompson, A ; Yuen, HP ; Brewer, WJ ; Cagliarini, D ; Bruxner, A ; Simmons, M ; Broussard, C ; Pantelis, C ; McGorry, PD ; Allott, K ; Wood, SJ (ELSEVIER, 2022-10)
    Cognitive impairment is a well-documented predictor of transition to a full-threshold psychotic disorder amongst individuals at ultra-high risk (UHR) for psychosis. However, less is known about whether change in cognitive functioning differs between those who do and do not transition. Studies to date have not examined trajectories in intelligence constructs (e.g., acquired knowledge and fluid intelligence), which have demonstrated marked impairments in individuals with schizophrenia. This study aimed to examine intelligence trajectories using longitudinal data spanning an average of eight years, where some participants completed assessments over three time-points. Participants (N = 139) at UHR for psychosis completed the Wechsler Abbreviated Scale of Intelligence (WASI) at each follow-up. Linear mixed-effects models mapped changes in WASI Full-Scale IQ (FSIQ) and T-scores on Vocabulary, Similarities, Block Design, and Matrix Reasoning subtests. The sample showed stable and improving trajectories for FSIQ and all subtests. There were no significant differences in trajectories between those who did and did not transition to psychosis and between individuals with good and poor functional outcomes. However, although not significant, the trajectories of the acquired knowledge subtests diverged between transitioned and non-transitioned individuals (β = -0.12, 95 % CI [-0.29, 0.05] for Vocabulary and β = -0.14, 95 % CI [-0.33, 0.05] for Similarities). Overall, there was no evidence for long-term deterioration in intelligence trajectories in this UHR sample. Future studies with a larger sample of transitioned participants may be needed to explore potential differences in intelligence trajectories between UHR transition groups and other non-psychosis outcomes.
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    Pineal morphology of the clinical high-risk state for psychosis and different psychotic disorders
    Takahashi, T ; Wood, SJ ; Yung, AR ; Nelson, B ; Lin, A ; Yuen, HP ; Phillips, LJ ; Suzuki, M ; McGorry, PD ; Velakoulis, D ; Pantelis, C (ELSEVIER, 2022-06)
    BACKGROUND: Pineal volume reductions have been reported in schizophrenia and clinical high-risk states for the development of psychosis, supporting the role of melatonin dysregulation in the pathophysiology of psychosis. However, it remains unclear whether pineal volume is associated with the later onset of psychosis in individuals at clinical high-risk (CHR) of psychosis or if pineal atrophy is specific to schizophrenia among different psychotic disorders. METHODS: This magnetic resonance imaging study examined the volume of and cyst prevalence in the pineal gland in 135 individuals at CHR of psychosis [52 (38.5%) subsequently developed psychosis], 162 with first-episode psychosis (FEP), 89 with chronic schizophrenia, and 87 healthy controls. The potential contribution of the pineal morphology to clinical characteristics was also examined in the CHR and FEP groups. RESULTS: Pineal volumes did not differ significantly between the CHR, FEP, and chronic schizophrenia groups, but were significantly smaller than that in healthy controls. However, pineal volumes were not associated with the later onset of psychosis in the CHR group or FEP sub-diagnosis (i.e., schizophrenia, schizophreniform disorder, affective psychosis, and other psychoses). No significant differences were observed in the prevalence of pineal cysts between the groups, and it also did not correlate with clinical characteristics in the CHR and FEP groups. CONCLUSION: These results suggest that pineal atrophy is a general vulnerability marker of psychosis, while pineal cysts do not appear to contribute to the pathophysiology of psychosis.
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    Virtual Ontogeny of Cortical Growth Preceding Mental Illness
    Patel, Y ; Shin, J ; Abe, C ; Agartz, I ; Alloza, C ; Alnaes, D ; Ambrogi, S ; Antonucci, LA ; Arango, C ; Arolt, V ; Auzias, G ; Ayesa-Arriola, R ; Banaj, N ; Banaschewski, T ; Bandeira, C ; Basgoze, Z ; Cupertino, RB ; Bau, CHD ; Bauer, J ; Baumeister, S ; Bernardoni, F ; Bertolino, A ; del Mar Bonnin, C ; Brandeis, D ; Brem, S ; Bruggemann, J ; Bulow, R ; Bustillo, JR ; Calderoni, S ; Calvo, R ; Canales-Rodriguez, EJ ; Cannon, DM ; Carmona, S ; Carr, VJ ; Catts, SV ; Chenji, S ; Chew, QH ; Coghill, D ; Connolly, CG ; Conzelmann, A ; Craven, AR ; Crespo-Facorro, B ; Cullen, K ; Dahl, A ; Dannlowski, U ; Davey, CG ; Deruelle, C ; Diaz-Caneja, CM ; Dohm, K ; Ehrlich, S ; Epstein, J ; Erwin-Grabner, T ; Eyler, LT ; Fedor, J ; Fitzgerald, J ; Foran, W ; Ford, JM ; Fortea, L ; Fuentes-Claramonte, P ; Fullerton, J ; Furlong, L ; Gallagher, L ; Gao, B ; Gao, S ; Goikolea, JM ; Gotlib, I ; Goya-Maldonado, R ; Grabe, HJ ; Green, M ; Grevet, EH ; Groenewold, NA ; Grotegerd, D ; Gruber, O ; Haavik, J ; Hahn, T ; Harrison, BJ ; Heindel, W ; Henskens, F ; Heslenfeld, DJ ; Hilland, E ; Hoekstra, PJ ; Hohmann, S ; Holz, N ; Howells, FM ; Ipser, JC ; Jahanshad, N ; Jakobi, B ; Jansen, A ; Janssen, J ; Jonassen, R ; Kaiser, A ; Kaleda, V ; Karantonis, J ; King, JA ; Kircher, T ; Kochunov, P ; Koopowitz, S-M ; Landen, M ; Landro, NI ; Lawrie, S ; Lebedeva, I ; Luna, B ; Lundervold, AJ ; MacMaster, FP ; Maglanoc, LA ; Mathalon, DH ; McDonald, C ; McIntosh, A ; Meinert, S ; Michie, PT ; Mitchell, P ; Moreno-Alcazar, A ; Mowry, B ; Muratori, F ; Nabulsi, L ; Nenadic, I ; Tuura, RO ; Oosterlaan, J ; Overs, B ; Pantelis, C ; Parellada, M ; Pariente, JC ; Pauli, P ; Pergola, G ; Piarulli, FM ; Picon, F ; Piras, F ; Pomarol-Clotet, E ; Pretus, C ; Quide, Y ; Radua, J ; Ramos-Quiroga, JA ; Rasser, PE ; Reif, A ; Retico, A ; Roberts, G ; Rossell, S ; Rovaris, DL ; Rubia, K ; Sacchet, M ; Salavert, J ; Salvador, R ; Sarro, S ; Sawa, A ; Schall, U ; Scott, R ; Selvaggi, P ; Silk, T ; Sim, K ; Skoch, A ; Spalletta, G ; Spaniel, F ; Stein, DJ ; Steinstrater, O ; Stolicyn, A ; Takayanagi, Y ; Tamm, L ; Tavares, M ; Teumer, A ; Thiel, K ; Thomopoulos, SI ; Tomecek, D ; Tomyshev, AS ; Tordesillas-Gutierrez, D ; Tosetti, M ; Uhlmann, A ; Van Rheenen, T ; Vazquez-Bourgon, J ; Vernooij, MW ; Vieta, E ; Vilarroya, O ; Weickert, C ; Weickert, T ; Westlye, LT ; Whalley, H ; Willinger, D ; Winter, A ; Wittfeld, K ; Yang, TT ; Yoncheva, Y ; Zijlmans, JL ; Hoogman, M ; Franke, B ; van Rooij, D ; Buitelaar, J ; Ching, CRK ; Andreassen, OA ; Pozzi, E ; Veltman, D ; Schmaal, L ; van Erp, TGM ; Turner, J ; Castellanos, FX ; Pausova, Z ; Thompson, P ; Paus, T (ELSEVIER SCIENCE INC, 2022-08-15)
    BACKGROUND: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life. METHODS: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. RESULTS: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. CONCLUSIONS: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.
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    Disruptions in white matter microstructure associated with impaired visual associative memory in schizophrenia-spectrum illness
    Wannan, CMJ ; Bartholomeusz, CF ; Pantelis, C ; Di Biase, MA ; Syeda, WT ; Chakravarty, MM ; Bousman, CA ; Everall, IP ; McGorry, PD ; Zalesky, A ; Cropley, VL (SPRINGER HEIDELBERG, 2022-09-01)
    Episodic memory ability relies on hippocampal-prefrontal connectivity. However, few studies have examined relationships between memory performance and white matter (WM) microstructure in hippocampal-prefrontal pathways in schizophrenia-spectrum disorder (SSDs). Here, we investigated these relationships in individuals with first-episode psychosis (FEP) and chronic schizophrenia-spectrum disorders (SSDs) using tractography analysis designed to interrogate the microstructure of WM tracts in the hippocampal-prefrontal pathway. Measures of WM microstructure (fractional anisotropy [FA], radial diffusivity [RD], and axial diffusivity [AD]) were obtained for 47 individuals with chronic SSDs, 28 FEP individuals, 52 older healthy controls, and 27 younger healthy controls. Tractography analysis was performed between the hippocampus and three targets involved in hippocampal-prefrontal connectivity (thalamus, amygdala, nucleus accumbens). Measures of WM microstructure were then examined in relation to episodic memory performance separately across each group. Both those with FEP and chronic SSDs demonstrated impaired episodic memory performance. However, abnormal WM microstructure was only observed in individuals with chronic SSDs. Abnormal WM microstructure in the hippocampal-thalamic pathway in the right hemisphere was associated with poorer memory performance in individuals with chronic SSDs. These findings suggest that disruptions in WM microstructure in the hippocampal-prefrontal pathway may contribute to memory impairments in individuals with chronic SSDs but not FEP.
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    Heschl's gyrus duplication pattern and clinical characteristics in borderline personality disorder: A preliminary study
    Takahashi, T ; Sasabayashi, D ; Velakoulis, D ; Suzuki, M ; McGorry, PD ; Pantelis, C ; Chanen, AM (FRONTIERS MEDIA SA, 2022-11-03)
    Inter-individual variations in the sulco-gyral pattern of Heschl's gyrus (HG) might contribute to emotional processing. However, it remains largely unknown whether borderline personality disorder (BPD) patients exhibit an altered HG gyrification pattern, compared with healthy individuals, and whether such a brain morphological feature, if present, might contribute to their clinical characteristics. The present study used magnetic resonance imaging to investigate the distribution of HG gyrification patterns (single or duplicated) and their relationship to clinical characteristics in teenage BPD patients with minimal treatment exposure. No significant difference was noted for the prevalence of HG patterns between 20 BPD and 20 healthy participants. However, the BPD participants with left duplicated HG were characterized by higher prevalence of comorbid disruptive behavior disorders, with higher externalizing score compared with those with left single HG. Our preliminary results suggest that neurodevelopmental pathology associated with gyral formation might be implicated in the neurobiology of early BPD, especially for emotional and behavioral control.