Publications by authors named "Christos Pantelis"

401 Publications

A Systematic Review of Cognition-Brain Morphology Relationships on the Schizophrenia-Bipolar Disorder Spectrum.

Schizophr Bull 2021 Jun 7. Epub 2021 Jun 7.

Centre for Mental Health, Faculty of Health, Arts and Design, School of Health Sciences, Swinburne University, Melbourne, Australia.

The nature of the relationship between cognition and brain morphology in schizophrenia-spectrum disorders (SSD) and bipolar disorder (BD) is uncertain. This review aimed to address this, by providing a comprehensive systematic investigation of links between several cognitive domains and brain volume, cortical thickness, and cortical surface area in SSD and BD patients across early and established illness stages. An initial search of PubMed and Scopus databases resulted in 1486 articles, of which 124 met inclusion criteria and were reviewed in detail. The majority of studies focused on SSD, while those of BD were scarce. Replicated evidence for specific regions associated with indices of cognition was minimal, however for several cognitive domains, the frontal and temporal regions were broadly implicated across both recent-onset and established SSD, and to a lesser extent BD. Collectively, the findings of this review emphasize the significance of both frontal and temporal regions for some domains of cognition in SSD, while highlighting the need for future BD-related studies on this topic.
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http://dx.doi.org/10.1093/schbul/sbab054DOI Listing
June 2021

Multimodal prognosis of negative symptom severity in individuals at increased risk of developing psychosis.

Transl Psychiatry 2021 May 24;11(1):312. Epub 2021 May 24.

Department of Psychiatry (UPK), University of Basel, Basel, Switzerland.

Negative symptoms occur frequently in individuals at clinical high risk (CHR) for psychosis and contribute to functional impairments. The aim of this study was to predict negative symptom severity in CHR after 9 months. Predictive models either included baseline negative symptoms measured with the Structured Interview for Psychosis-Risk Syndromes (SIPS-N), whole-brain gyrification, or both to forecast negative symptoms of at least moderate severity in 94 CHR. We also conducted sequential risk stratification to stratify CHR into different risk groups based on the SIPS-N and gyrification model. Additionally, we assessed the models' ability to predict functional outcomes in CHR and their transdiagnostic generalizability to predict negative symptoms in 96 patients with recent-onset psychosis (ROP) and 97 patients with recent-onset depression (ROD). Baseline SIPS-N and gyrification predicted moderate/severe negative symptoms with significant balanced accuracies of 68 and 62%, while the combined model achieved 73% accuracy. Sequential risk stratification stratified CHR into a high (83%), medium (40-64%), and low (19%) risk group regarding their risk of having moderate/severe negative symptoms at 9 months follow-up. The baseline SIPS-N model was also able to predict social (61%), but not role functioning (59%) at above-chance accuracies, whereas the gyrification model achieved significant accuracies in predicting both social (76%) and role (74%) functioning in CHR. Finally, only the baseline SIPS-N model showed transdiagnostic generalization to ROP (63%). This study delivers a multimodal prognostic model to identify those CHR with a clinically relevant negative symptom severity and functional impairments, potentially requiring further therapeutic consideration.
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http://dx.doi.org/10.1038/s41398-021-01409-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144430PMC
May 2021

Associations between cognitive and affective empathy and internalizing symptoms in late childhood.

J Affect Disord 2021 Jul 25;290:245-253. Epub 2021 Apr 25.

Melbourne Neuropsychiatry Centre (MNC), Department of Psychiatry, The University of Melbourne & Melbourne Health, Melbourne, Australia.

Background: Empathy is a multidimensional construct, which includes cognitive and affective components. Studies in adults have demonstrated that both cognitive and affective empathy are associated with anxious and depressive symptoms. The aim of this study was to examine these associations in childhood.

Methods: Participants were 127 9- and 10-year-old children, recruited from the community. Self-report measures of cognitive and affective empathy, and internalizing symptoms were administered, as well as a task-based measure of cognitive empathy.

Results: Canonical correlation analysis demonstrated that components of affective empathy, specifically affective sharing and empathic distress, were associated with internalizing (particularly social anxiety) symptoms (R = 0.63, non-parametric p < .001). Cognitive empathy was not associated with internalizing symptoms.

Limitations: Most of our findings were based around self-report measures of empathy, which may not accurately reflect empathy ability.

Conclusions: Findings suggests that children who share each other's emotions strongly are more likely to experience anxiety, particularly of a social nature.
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http://dx.doi.org/10.1016/j.jad.2021.04.034DOI Listing
July 2021

Association of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis: An ENIGMA Working Group Mega-analysis.

JAMA Psychiatry 2021 May 5. Epub 2021 May 5.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.

Importance: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk.

Objective: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-).

Design, Setting, And Participants: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020.

Main Outcomes And Measures: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group).

Results: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001).

Conclusions And Relevance: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.0638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100913PMC
May 2021

Associations between cognition and white matter microstructure in first-episode antipsychotic-naïve patients with schizophrenia and healthy controls: A multivariate pattern analysis.

Cortex 2021 Jun 18;139:282-297. Epub 2021 Mar 18.

Centre for Neuropsychiatric Schizophrenia Research, CNSR and Centre for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark; Department of Psychology, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Background: Cognitive functions have been associated with white matter (WM) microstructure in schizophrenia, but most studies are limited by examining only select cognitive measures and single WM tracts in chronic, medicated patients. It is unclear if the cognition-WM relationship differs between antipsychotic-naïve patients with schizophrenia and healthy controls, as differential associations have not been directly examined. Here we examine if there are differential patterns of associations between cognition and WM microstructure in first-episode antipsychotic-naïve patients with schizophrenia and healthy controls, and we characterize reliable contributors to the pattern of associations across multiple cognitive domains and WM regions, in order to elucidate white matter contribution to the neural underpinnings of cognitive deficits.

Methods: Thirty-six first-episode antipsychotic-naïve patients with schizophrenia and 52 matched healthy controls underwent cognitive tests and diffusion-weighted imaging on a 3T Magnetic Resonance Imaging scanner. Using a multivariate partial least squares correlation analysis, we included 14 cognitive variables and mean fractional anisotropy values of 48 WM regions.

Results: Initial analyses showed significant group differences in both measures of WM and cognition. There was no group interaction effect in the pattern of associations between cognition and WM microstructure. The combined analysis of patients and controls lead to a significant pattern of associations (omnibus test p = .015). Thirty-four regions and seven cognitive functions contributed reliably to the associations.

Conclusions: The lack of an interaction effect suggests similar associations in first-episode antipsychotic-naïve patients with schizophrenia and healthy controls. This, together with the differences in both WM and cognitive measurements, supports the involvement of WM in cognitive deficits in schizophrenia. Our findings add to the field by showing a coherent picture of the overall pattern of association between cognition and WM. These findings increase our understanding of the impact of WM on cognition, contributing to the search for neuromarkers of cognitive deficits in schizophrenia.
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http://dx.doi.org/10.1016/j.cortex.2021.03.003DOI Listing
June 2021

Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level: A Mega-analysis of Individual Participant-Level Data.

JAMA Psychiatry 2021 Jun;78(6):667-681

Department of Psychiatry, Columbia University, New York State Psychiatric Institute, New York.

Importance: Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear.

Objective: To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites.

Data Sources: The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data.

Study Selection: In total, 45 1H-MRS studies contributed data.

Data Extraction And Synthesis: Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor.

Main Outcomes And Measures: Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL).

Results: In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose.

Conclusions And Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.0380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060889PMC
June 2021

Brain morphology is differentially impacted by peripheral cytokines in schizophrenia-spectrum disorder.

Brain Behav Immun 2021 Jul 8;95:299-309. Epub 2021 Apr 8.

Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Australia; Department of Psychiatry, The University of Melbourne, Australia; Centre for Mental Health, Faculty of Health, Arts and Design, School of Health Sciences, Swinburne University, Melbourne, Australia.

Deficits in brain morphology are one of the most widely replicated neuropathological features in schizophrenia-spectrum disorder (SSD), although their biological underpinnings remain unclear. Despite the existence of hypotheses by which peripheral inflammation may impact brain structure, few studies have examined this relationship in SSD. This study aimed to establish the relationship between peripheral markers of inflammation and brain morphology and determine whether such relationships differed across healthy controls and individuals with first episode psychosis (FEP) and chronic schizophrenia. A panel of 13 pro- and anti-inflammatory cytokines were quantified from serum in 175 participants [n = 84 Healthy Controls (HC), n = 40 FEP, n = 51 Chronic SCZ]. We first performed a series of permutation tests to identify the cytokines most consistently associated with brain structural regions. Using moderation analysis, we then determined the extent to which individual variation in select cytokines, and their interaction with diagnostic status, predicted variation in brain structure. We found significant interactions between cytokine level and diagnosis on brain structure. Diagnostic status significantly moderated the relationship of IFNγ, IL4, IL5 and IL13 with frontal thickness, and of IFNγ and IL5 and total cortical volume. Specifically, frontal thickness was positively associated with IFNγ, IL4, IL5 and IL13 cytokine levels in the healthy control group, whereas pro-inflammatory cytokines IFNγ and IL5 were associated with lower total cortical volume in the FEP group. Our findings suggest that while there were no relationships detected in chronic schizophrenia, the relationship between peripheral inflammatory markers and select brain regions are differentially impacted in FEP and healthy controls. Longitudinal investigations are required to determine whether the relationship between brain structure and peripheral inflammation changes over time.
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http://dx.doi.org/10.1016/j.bbi.2021.04.002DOI Listing
July 2021

Increased peripheral inflammation in schizophrenia is associated with worse cognitive performance and related cortical thickness reductions.

Eur Arch Psychiatry Clin Neurosci 2021 Jun 24;271(4):595-607. Epub 2021 Mar 24.

School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.

While the biological substrates of brain and behavioural changes in persons with schizophrenia remain unclear, increasing evidence implicates that inflammation is involved. In schizophrenia, including first-episode psychosis and anti-psychotic naïve patients, there are numerous reports of increased peripheral inflammation, cognitive deficits and neuropathologies such as cortical thinning. Research defining the relationship between inflammation and schizophrenia symptomatology and neuropathology is needed. Therefore, we analysed the level of C-reactive protein (CRP), a peripheral inflammation marker, and its relationship with cognitive functioning in a cohort of 644 controls and 499 schizophrenia patients. In a subset of individuals who underwent MRI scanning (99 controls and 194 schizophrenia cases), we tested if serum CRP was associated with cortical thickness. CRP was significantly increased in schizophrenia patients compared to controls, co-varying for age, sex, overweight/obesity and diabetes (p < 0.006E-10). In schizophrenia, increased CRP was mildly associated with worse performance in attention, controlling for age, sex and education (R =- 0.15, p = 0.001). Further, increased CRP was associated with reduced cortical thickness in three regions related to attention: the caudal middle frontal, the pars opercularis and the posterior cingulate cortices, which remained significant after controlling for multiple comparisons (all p < 0.05). Together, these findings indicate that increased peripheral inflammation is associated with deficits in cognitive function and brain structure in schizophrenia, especially reduced attention and reduced cortical thickness in associated brain regions. Using CRP as a biomarker of peripheral inflammation in persons with schizophrenia may help to identify vulnerable patients and those that may benefit from adjunctive anti-inflammatory treatments.
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http://dx.doi.org/10.1007/s00406-021-01237-zDOI Listing
June 2021

Network Analysis of Symptom Comorbidity in Schizophrenia: Relationship to Illness Course and Brain White Matter Microstructure.

Schizophr Bull 2021 Mar 8. Epub 2021 Mar 8.

Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, Victoria, Australia.

Introduction: Recent network-based analyses suggest that schizophrenia symptoms are intricately connected and interdependent, such that central symptoms can activate adjacent symptoms and increase global symptom burden. Here, we sought to identify key clinical and neurobiological factors that relate to symptom organization in established schizophrenia.

Methods: A symptom comorbidity network was mapped for a broad constellation of symptoms measured in 642 individuals with a schizophrenia-spectrum disorder. Centrality analyses were used to identify hub symptoms. The extent to which each patient's symptoms formed clusters in the comorbidity network was quantified with cluster analysis and used to predict (1) clinical features, including illness duration and psychosis (positive symptom) severity and (2) brain white matter microstructure, indexed by the fractional anisotropy (FA), in a subset (n = 296) of individuals with diffusion-weighted imaging (DWI) data.

Results: Global functioning, substance use, and blunted affect were the most central symptoms within the symptom comorbidity network. Symptom profiles for some patients formed highly interconnected clusters, whereas other patients displayed unrelated and disconnected symptoms. Stronger clustering among an individual's symptoms was significantly associated with shorter illness duration (t = 2.7; P = .0074), greater psychosis severity (ie, positive symptoms expression) (t = -5.5; P < 0.0001) and lower fractional anisotropy in fibers traversing the cortico-cerebellar-thalamic-cortical circuit (r = .59, P < 0.05).

Conclusion: Symptom network structure varies over the course of schizophrenia: symptom interactions weaken with increasing illness duration and strengthen during periods of high positive symptom expression. Reduced white matter coherence relates to stronger symptom clustering, and thus, may underlie symptom cascades and global symptomatic burden in individuals with schizophrenia.
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http://dx.doi.org/10.1093/schbul/sbab015DOI Listing
March 2021

Systematic Review: Quantitative Susceptibility Mapping (QSM) of Brain Iron Profile in Neurodegenerative Diseases.

Front Neurosci 2021 18;15:618435. Epub 2021 Feb 18.

Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia.

Iron has been increasingly implicated in the pathology of neurodegenerative diseases. In the past decade, development of the new magnetic resonance imaging technique, quantitative susceptibility mapping (QSM), has enabled for the more comprehensive investigation of iron distribution in the brain. The aim of this systematic review was to provide a synthesis of the findings from existing QSM studies in neurodegenerative diseases. We identified 80 records by searching MEDLINE, Embase, Scopus, and PsycInfo databases. The disorders investigated in these studies included Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Wilson's disease, Huntington's disease, Friedreich's ataxia, spinocerebellar ataxia, Fabry disease, myotonic dystrophy, pantothenate-kinase-associated neurodegeneration, and mitochondrial membrane protein-associated neurodegeneration. As a general pattern, QSM revealed increased magnetic susceptibility (suggestive of increased iron content) in the brain regions associated with the pathology of each disorder, such as the amygdala and caudate nucleus in Alzheimer's disease, the substantia nigra in Parkinson's disease, motor cortex in amyotrophic lateral sclerosis, basal ganglia in Huntington's disease, and cerebellar dentate nucleus in Friedreich's ataxia. Furthermore, the increased magnetic susceptibility correlated with disease duration and severity of clinical features in some disorders. Although the number of studies is still limited in most of the neurodegenerative diseases, the existing evidence suggests that QSM can be a promising tool in the investigation of neurodegeneration.
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http://dx.doi.org/10.3389/fnins.2021.618435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930077PMC
February 2021

Cognitive ability and metabolic physical health in first-episode psychosis.

Schizophr Res Cogn 2021 Jun 13;24:100194. Epub 2021 Feb 13.

Orygen, Parkville, VIC 3052, Australia.

Cognitive impairments are a core feature of first-episode psychosis (FEP), arising before illness onset and antipsychotic exposure. Individuals with chronic psychosis experience poorer physical health while taking antipsychotic medication, but health disparities may be evident at FEP onset, prior to antipsychotic exposure. Given the links between cognition and physical health in healthy populations, the aim was to explore whether cognition and physical health are associated in FEP, which could inform early physical health interventions for cognition in FEP. Participants were aged 15 to 25 and included 86 individuals experiencing FEP with limited antipsychotic exposure and duration of untreated psychosis of ≤six months, and 43 age- and sex-matched controls. Individuals with FEP performed significantly poorer than controls in most cognitive domains (Cohen's  = 0.38 to 1.59). Groups were similar in metabolic health measures, excluding a significantly faster heart rate in FEP ( = 0.68). Through hierarchical regression analyses, we found that in the overall sample, BMI was negatively related to current IQ after controlling for education and group (FEP/control). Relationships between BMI and cognition were consistent across the FEP and healthy control groups. In FEP, current IQ and working memory were negatively correlated with lipid profiles. Findings suggest that in FEP, impaired cognition is exhibited earlier than physical health problems, and that compared to controls, similar relationships with cognition are demonstrated. Causal pathways and trajectories of relationships between health and cognition in FEP require investigation, especially as antipsychotic medications are introduced. The findings have implications for cognitive and health interventions.
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http://dx.doi.org/10.1016/j.scog.2021.100194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895837PMC
June 2021

Association between age of cannabis initiation and gray matter covariance networks in recent onset psychosis.

Neuropsychopharmacology 2021 Jul 3;46(8):1484-1493. Epub 2021 Mar 3.

Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.

Cannabis use during adolescence is associated with an increased risk of developing psychosis. According to a current hypothesis, this results from detrimental effects of early cannabis use on brain maturation during this vulnerable period. However, studies investigating the interaction between early cannabis use and brain structural alterations hitherto reported inconclusive findings. We investigated effects of age of cannabis initiation on psychosis using data from the multicentric Personalized Prognostic Tools for Early Psychosis Management (PRONIA) and the Cannabis Induced Psychosis (CIP) studies, yielding a total sample of 102 clinically-relevant cannabis users with recent onset psychosis. GM covariance underlies shared maturational processes. Therefore, we performed source-based morphometry analysis with spatial constraints on structural brain networks showing significant alterations in schizophrenia in a previous multisite study, thus testing associations of these networks with the age of cannabis initiation and with confounding factors. Earlier cannabis initiation was associated with more severe positive symptoms in our cohort. Greater gray matter volume (GMV) in the previously identified cerebellar schizophrenia-related network had a significant association with early cannabis use, independent of several possibly confounding factors. Moreover, GMV in the cerebellar network was associated with lower volume in another network previously associated with schizophrenia, comprising the insula, superior temporal, and inferior frontal gyrus. These findings are in line with previous investigations in healthy cannabis users, and suggest that early initiation of cannabis perturbs the developmental trajectory of certain structural brain networks in a manner imparting risk for psychosis later in life.
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http://dx.doi.org/10.1038/s41386-021-00977-9DOI Listing
July 2021

Differentiating the effect of antipsychotic medication and illness on brain volume reductions in first-episode psychosis: A Longitudinal, Randomised, Triple-blind, Placebo-controlled MRI Study.

Neuropsychopharmacology 2021 Jul 26;46(8):1494-1501. Epub 2021 Feb 26.

Orygen, Parkville, VIC, Australia.

Changes in brain volume are a common finding in Magnetic Resonance Imaging (MRI) studies of people with psychosis and numerous longitudinal studies suggest that volume deficits progress with illness duration. However, a major unresolved question concerns whether these changes are driven by the underlying illness or represent iatrogenic effects of antipsychotic medication. In this study, 62 antipsychotic-naïve patients with first-episode psychosis (FEP) received either a second-generation antipsychotic (risperidone or paliperidone) or a placebo pill over a treatment period of 6 months. Both FEP groups received intensive psychosocial therapy. A healthy control group (n = 27) was also recruited. Structural MRI scans were obtained at baseline, 3 months and 12 months. Our primary aim was to differentiate illness-related brain volume changes from medication-related changes within the first 3 months of treatment. We secondarily investigated long-term effects at the 12-month timepoint. From baseline to 3 months, we observed a significant group x time interaction in the pallidum (p < 0.05 FWE-corrected), such that patients receiving antipsychotic medication showed increased volume, patients on placebo showed decreased volume, and healthy controls showed no change. Across the entire patient sample, a greater increase in pallidal grey matter volume over 3 months was associated with a greater reduction in symptom severity. Our findings indicate that psychotic illness and antipsychotic exposure exert distinct and spatially distributed effects on brain volume. Our results align with prior work in suggesting that the therapeutic efficacy of antipsychotic medications may be primarily mediated through their effects on the basal ganglia.
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http://dx.doi.org/10.1038/s41386-021-00980-0DOI Listing
July 2021

Obsessive-Compulsive Symptoms and Other Symptoms of the At-risk Mental State for Psychosis: A Network Perspective.

Schizophr Bull 2021 Feb 17. Epub 2021 Feb 17.

Department of Psychology, Psychological Methods, University of Amsterdam, Amsterdam, the Netherlands.

Background: The high prevalence of obsessive-compulsive symptoms (OCS) among subjects at Ultra-High Risk (UHR) for psychosis is well documented. However, the network structure spanning the relations between OCS and symptoms of the at risk mental state for psychosis as assessed with the Comprehensive Assessment of At Risk Mental States (CAARMS) has not yet been investigated. This article aimed to use a network approach to investigate the associations between OCS and CAARMS symptoms in a large sample of individuals with different levels of risk for psychosis.

Method: Three hundred and forty-one UHR and 66 healthy participants were included, who participated in the EU-GEI study. Data analysis consisted of constructing a network of CAARMS symptoms, investigating central items in the network, and identifying the shortest pathways between OCS and positive symptoms.

Results: Strong associations between OCS and anxiety, social isolation and blunted affect were identified. Depression was the most central symptom in terms of the number of connections, and anxiety was a key item in bridging OCS to other symptoms. Shortest paths between OCS and positive symptoms revealed that unusual thought content and perceptual abnormalities were connected mainly via anxiety, while disorganized speech was connected via blunted affect and cognitive change.

Conclusions: Findings provide valuable insight into the central role of depression and the potential connective component of anxiety between OCS and other symptoms of the network. Interventions specifically aimed to reduce affective symptoms might be crucial for the development and prospective course of symptom co-occurrence.
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http://dx.doi.org/10.1093/schbul/sbaa187DOI Listing
February 2021

Heterogeneity and Classification of Recent Onset Psychosis and Depression: A Multimodal Machine Learning Approach.

Schizophr Bull 2021 Feb 5. Epub 2021 Feb 5.

Institute for Mental Health, University of Birmingham, Birmingham, UK.

Diagnostic heterogeneity within and across psychotic and affective disorders challenges accurate treatment selection, particularly in the early stages. Delineation of shared and distinct illness features at the phenotypic and brain levels may inform the development of more precise differential diagnostic tools. We aimed to identify prototypes of depression and psychosis to investigate their heterogeneity, with common, comorbid transdiagnostic symptoms. Analyzing clinical/neurocognitive and grey matter volume (GMV) data from the PRONIA database, we generated prototypic models of recent-onset depression (ROD) vs. recent-onset psychosis (ROP) by training support-vector machines to separate patients with ROD from patients with ROP, who were selected for absent comorbid features (pure groups). Then, models were applied to patients with comorbidity, ie, ROP with depressive symptoms (ROP+D) and ROD participants with sub-threshold psychosis-like features (ROD+P), to measure their positions within the affective-psychotic continuum. All models were independently validated in a replication sample. Comorbid patients were positioned between pure groups, with ROP+D patients being more frequently classified as ROD compared to pure ROP patients (clinical/neurocognitive model: χ2 = 14.874; P < .001; GMV model: χ2 = 4.933; P = .026). ROD+P patient classification did not differ from ROD (clinical/neurocognitive model: χ2 = 1.956; P = 0.162; GMV model: χ2 = 0.005; P = .943). Clinical/neurocognitive and neuroanatomical models demonstrated separability of prototypic depression from psychosis. The shift of comorbid patients toward the depression prototype, observed at the clinical and biological levels, suggests that psychosis with affective comorbidity aligns more strongly to depressive rather than psychotic disease processes. Future studies should assess how these quantitative measures of comorbidity predict outcomes and individual responses to stratified therapeutic interventions.
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http://dx.doi.org/10.1093/schbul/sbaa185DOI Listing
February 2021

The impact of smoking status on cognition and brain morphology in schizophrenia spectrum disorders.

Psychol Med 2021 Jan 14:1-19. Epub 2021 Jan 14.

Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Melbourne, Australia.

Background: Cigarette smoking is associated with worse cognition and decreased cortical volume and thickness in healthy cohorts. Chronic cigarette smoking is prevalent in schizophrenia spectrum disorders (SSD), but the effects of smoking status on the brain and cognition in SSD are not clear. This study aimed to understand whether cognitive performance and brain morphology differed between smoking and non-smoking individuals with SSD compared to healthy controls.

Methods: Data were obtained from the Australian Schizophrenia Research Bank. Cognitive functioning was measured in 299 controls and 455 SSD patients. Cortical volume, thickness and surface area data were analysed from T1-weighted structural scans obtained in a subset of the sample (n = 82 controls, n = 201 SSD). Associations between smoking status (cigarette smoker/non-smoker), cognition and brain morphology were tested using analyses of covariance, including diagnosis as a moderator.

Results: No smoking by diagnosis interactions were evident, and no significant differences were revealed between smokers and non-smokers across any of the variables measured, with the exception of a significantly thinner left posterior cingulate in smokers compared to non-smokers. Several main effects of smoking in the cognitive, volume and thickness analyses were initially significant but did not survive false discovery rate (FDR) correction.

Conclusions: Despite the general absence of significant FDR-corrected findings, trend-level effects suggest the possibility that subtle smoking-related effects exist but were not uncovered due to low statistical power. An investigation of this topic is encouraged to confirm and expand on our findings.
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http://dx.doi.org/10.1017/S0033291720005152DOI Listing
January 2021

Neural Correlates of Audiovisual Temporal Binding Window in Individuals With Schizotypal and Autistic Traits: Evidence From Resting-State Functional Connectivity.

Autism Res 2021 04 14;14(4):668-680. Epub 2020 Dec 14.

Neuropsychology and Applied Cognitive Neuroscience Laboratory, CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.

Temporal proximity is an important clue for multisensory integration. Previous evidence indicates that individuals with autism and schizophrenia are more likely to integrate multisensory inputs over a longer temporal binding window (TBW). However, whether such deficits in audiovisual temporal integration extend to subclinical populations with high schizotypal and autistic traits are unclear. Using audiovisual simultaneity judgment (SJ) tasks for nonspeech and speech stimuli, our results suggested that the width of the audiovisual TBW was not significantly correlated with self-reported schizotypal and autistic traits in a group of young adults. Functional magnetic resonance imaging (fMRI) resting-state activity was also acquired to explore the neural correlates underlying inter-individual variability of TBW width. Across the entire sample, stronger resting-state functional connectivity (rsFC) between the left superior temporal cortex and the left precuneus, and weaker rsFC between the left cerebellum and the right dorsal lateral prefrontal cortex were correlated with a narrower TBW for speech stimuli. Meanwhile, stronger rsFC between the left anterior superior temporal gyrus and the right inferior temporal gyrus was correlated with a wider audiovisual TBW for non-speech stimuli. The TBW-related rsFC was not affected by levels of subclinical traits. In conclusion, this study indicates that audiovisual temporal processing may not be affected by autistic and schizotypal traits and rsFC between brain regions responding to multisensory information and timing may account for the inter-individual difference in TBW width. LAY SUMMARY: Individuals with ASD and schizophrenia are more likely to perceive asynchronous auditory and visual events as occurring simultaneously even if they are well separated in time. We investigated whether similar difficulties in audiovisual temporal processing were present in subclinical populations with high autistic and schizotypal traits. We found that the ability to detect audiovisual asynchrony was not affected by different levels of autistic and schizotypal traits. We also found that connectivity of some brain regions engaging in multisensory and timing tasks might explain an individual's tendency to bind multisensory information within a wide or narrow time window. Autism Res 2021, 14: 668-680. © 2020 International Society for Autism Research and Wiley Periodicals LLC.
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http://dx.doi.org/10.1002/aur.2456DOI Listing
April 2021

Basic Symptoms Are Associated With Age in Patients With a Clinical High-Risk State for Psychosis: Results From the PRONIA Study.

Front Psychiatry 2020 17;11:552175. Epub 2020 Nov 17.

Department of Education, Psychology, Communication, University of Bari Aldo Moro, Bari, Italy.

In community studies, both attenuated psychotic symptoms (APS) and basic symptoms (BS) were more frequent but less clinically relevant in children and adolescents compared to adults. In doing so, they displayed differential age thresholds that were around age 16 for APS, around age 18 for perceptive BS, and within the early twenties for cognitive BS. Only the age effect has previously been studied and replicated in clinical samples for APS. Thus, we examined the reported age effect on and age thresholds of 14 criteria-relevant BS in a patient sample at clinical-high risk of psychosis ( = 261, age 15-40 yrs.), recruited within the European multicenter PRONIA-study. BS and the BS criteria, "Cognitive Disturbances" (COGDIS) and "Cognitive-perceptive BS" (COPER), were assessed with the "Schizophrenia Proneness Instrument, Adult version" (SPI-A). Using logistic regressions, prevalence rates of perceptive and cognitive BS, and of COGDIS and COPER, as well as the impact of social and role functioning on the association between age and BS were studied in three age groups (15-18 years, 19-23 years, 24-40 years). Most patients (91.2%) reported any BS, 55.9% any perceptive and 87.4% any cognitive BS. Furthermore, 56.3% met COGDIS and 80.5% COPER. Not exhibiting the reported differential age thresholds, both perceptive and cognitive BS, and, at trend level only, COPER were less prevalent in the oldest age group (24-40 years); COGDIS was most frequent in the youngest group (15-18 years). Functional deficits did not better explain the association with age, particularly in perceptive BS and cognitive BS meeting the frequency requirement of BS criteria. Our findings broadly confirmed an age threshold in BS and, thus, the earlier assumed link between presence of BS and brain maturation processes. Yet, age thresholds of perceptive and cognitive BS did not differ. This lack of differential age thresholds might be due to more pronounced the brain abnormalities in this clinical sample compared to earlier community samples. These might have also shown in more frequently occurring and persistent BS that, however, also resulted from a sampling toward these, i.e., toward COGDIS. Future studies should address the neurobiological basis of CHR criteria in relation to age.
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http://dx.doi.org/10.3389/fpsyt.2020.552175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707000PMC
November 2020

Multimodal Machine Learning Workflows for Prediction of Psychosis in Patients With Clinical High-Risk Syndromes and Recent-Onset Depression.

JAMA Psychiatry 2021 Feb;78(2):195-209

Department of Child and Adolescent Psychiatry and Psychotherapy, University of Zürich, Zürich, Switzerland.

Importance: Diverse models have been developed to predict psychosis in patients with clinical high-risk (CHR) states. Whether prediction can be improved by efficiently combining clinical and biological models and by broadening the risk spectrum to young patients with depressive syndromes remains unclear.

Objectives: To evaluate whether psychosis transition can be predicted in patients with CHR or recent-onset depression (ROD) using multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging (sMRI), and polygenic risk scores (PRS) for schizophrenia; to assess models' geographic generalizability; to test and integrate clinicians' predictions; and to maximize clinical utility by building a sequential prognostic system.

Design, Setting, And Participants: This multisite, longitudinal prognostic study performed in 7 academic early recognition services in 5 European countries followed up patients with CHR syndromes or ROD and healthy volunteers. The referred sample of 167 patients with CHR syndromes and 167 with ROD was recruited from February 1, 2014, to May 31, 2017, of whom 26 (23 with CHR syndromes and 3 with ROD) developed psychosis. Patients with 18-month follow-up (n = 246) were used for model training and leave-one-site-out cross-validation. The remaining 88 patients with nontransition served as the validation of model specificity. Three hundred thirty-four healthy volunteers provided a normative sample for prognostic signature evaluation. Three independent Swiss projects contributed a further 45 cases with psychosis transition and 600 with nontransition for the external validation of clinical-neurocognitive, sMRI-based, and combined models. Data were analyzed from January 1, 2019, to March 31, 2020.

Main Outcomes And Measures: Accuracy and generalizability of prognostic systems.

Results: A total of 668 individuals (334 patients and 334 controls) were included in the analysis (mean [SD] age, 25.1 [5.8] years; 354 [53.0%] female and 314 [47.0%] male). Clinicians attained a balanced accuracy of 73.2% by effectively ruling out (specificity, 84.9%) but ineffectively ruling in (sensitivity, 61.5%) psychosis transition. In contrast, algorithms showed high sensitivity (76.0%-88.0%) but low specificity (53.5%-66.8%). A cybernetic risk calculator combining all algorithmic and human components predicted psychosis with a balanced accuracy of 85.5% (sensitivity, 84.6%; specificity, 86.4%). In comparison, an optimal prognostic workflow produced a balanced accuracy of 85.9% (sensitivity, 84.6%; specificity, 87.3%) at a much lower diagnostic burden by sequentially integrating clinical-neurocognitive, expert-based, PRS-based, and sMRI-based risk estimates as needed for the given patient. Findings were supported by good external validation results.

Conclusions And Relevance: These findings suggest that psychosis transition can be predicted in a broader risk spectrum by sequentially integrating algorithms' and clinicians' risk estimates. For clinical translation, the proposed workflow should undergo large-scale international validation.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.3604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711566PMC
February 2021

Brain morphology does not clearly map to cognition in individuals on the bipolar-schizophrenia-spectrum: a cross-diagnostic study of cognitive subgroups.

J Affect Disord 2021 02 13;281:776-785. Epub 2020 Nov 13.

Centre for Mental Health, Faculty of Health, Arts and Design, School of Health Sciences, Swinburne University, Melbourne, Australia; Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health. Electronic address:

Background: Characterisation of brain morphological features common to cognitively similar individuals with bipolar disorder (BD) and schizophrenia spectrum disorders (SSD) may be key to understanding their shared neurobiological deficits. In the current study we examined whether three previously characterised cross-diagnostic cognitive subgroups differed among themselves and in comparison to healthy controls across measures of brain morphology.

Method: T1-weighted structural magnetic resonance imaging scans were obtained for 143 individuals; 65 healthy controls and 78 patients (SSD, n = 40; BD I, n = 38) classified into three cross-diagnostic cognitive subgroups: Globally Impaired (n = 24), Selectively Impaired (n = 32), and Superior/Near-Normal (n = 22). Cognitive subgroups were compared to each other and healthy controls on three separate analyses investigating (1) global, (2) regional, and (3) vertex-wise comparisons of brain volume, thickness, and surface area.

Results: No significant subgroup differences were evident in global measures of brain morphology. In region of interest analyses, the Selectively Impaired subgroup had greater right accumbens volume than those Superior/Near-Normal subgroup and healthy controls, and the Superior/Near-Normal subgroup had reduced volume of the left entorhinal region compared to all other groups. In vertex-wise comparisons, the Globally Impaired subgroup had greater right precentral volume than the Selectively Impaired subgroup, and thicker cortex in the postcentral region relative to the Superior/Near-Normal subgroup.

Limitations: Exploration of medication effects was limited in our data.

Conclusions: Although some differences were evident in this sample, generally cross-diagnostic cognitive subgroups of individuals with SSD and BD did not appear to be clearly distinguished by patterns in brain morphology.
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http://dx.doi.org/10.1016/j.jad.2020.11.064DOI Listing
February 2021

Large-Scale Evidence for an Association Between Peripheral Inflammation and White Matter Free Water in Schizophrenia and Healthy Individuals.

Schizophr Bull 2021 03;47(2):542-551

Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Carlton South, VIC, Australia.

Introduction: Clarifying the role of neuroinflammation in schizophrenia is subject to its detection in the living brain. Free-water (FW) imaging is an in vivo diffusion-weighted magnetic resonance imaging (dMRI) technique that measures water molecules freely diffusing in the brain and is hypothesized to detect inflammatory processes. Here, we aimed to establish a link between peripheral markers of inflammation and FW in brain white matter.

Methods: All data were obtained from the Australian Schizophrenia Research Bank (ASRB) across 5 Australian states and territories. We first tested for the presence of peripheral cytokine deregulation in schizophrenia, using a large sample (N = 1143) comprising the ASRB. We next determined the extent to which individual variation in 8 circulating pro-/anti-inflammatory cytokines related to FW in brain white matter, imaged in a subset (n = 308) of patients and controls.

Results: Patients with schizophrenia showed reduced interleukin-2 (IL-2) (t = -3.56, P = .0004) and IL-12(p70) (t = -2.84, P = .005) and increased IL-6 (t = 3.56, P = .0004), IL-8 (t = 3.8, P = .0002), and TNFα (t = 4.30, P < .0001). Higher proinflammatory signaling of IL-6 (t = 3.4, P = .0007) and TNFα (t = 2.7, P = .0007) was associated with higher FW levels in white matter. The reciprocal increases in serum cytokines and FW were spatially widespread in patients encompassing most major fibers; conversely, in controls, the relationship was confined to the anterior corpus callosum and thalamic radiations. No relationships were observed with alternative dMRI measures, including the fractional anisotropy and tissue-related FA.

Conclusions: We report widespread deregulation of cytokines in schizophrenia and identify inflammation as a putative mechanism underlying increases in brain FW levels.
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http://dx.doi.org/10.1093/schbul/sbaa134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965083PMC
March 2021

Does cortical brain morphology act as a mediator between childhood trauma and transition to psychosis in young individuals at ultra-high risk?

Schizophr Res 2020 10 15;224:116-125. Epub 2020 Oct 15.

Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne & Melbourne Health, Victoria, Australia; Orygen, Parkville, Victoria, Australia; Centre for Youth Mental Health, The University of Melbourne, Parkville, Victoria, Australia. Electronic address:

Background: Childhood trauma, particularly sexual abuse, has been associated with transition to psychosis in individuals at "ultra-high risk" (UHR). This study investigated whether the effects of various forms of childhood trauma on transition to psychosis are mediated by cortical thickness and surface area abnormalities.

Methods: This prospective study used data from 62 UHR individuals from a previous (PACE 400) cohort study. At follow-up, 24 individuals had transitioned to psychosis (UHR-T) and 38 individuals had not transitioned (UHR-NT). Student-t/Mann-Whitney-U tests were performed to assess morphological differences in childhood trauma (low/high) and transition. Mediation analyses were conducted using regression and bootstrapping techniques.

Results: UHR individuals with high sexual trauma histories presented with decreased cortical thickness in bilateral middle temporal gyri and the left superior frontal gyrus compared to those with low sexual trauma. Participants with high physical abuse had increased cortical thickness in the right middle frontal gyrus compared to those with low physical abuse. No differences were found for emotional abuse or physical/emotional neglect. Reduced cortical thickness in the right middle temporal gyrus and increased surface area in the right cingulate were found in UHR-T compared to UHR-NT individuals. Sexual abuse had an indirect effect on transition to psychosis, where decreased cortical thickness in the right middle temporal gyrus was a mediator.

Conclusions: Results suggest that childhood sexual abuse negatively impacted on cortical development of the right temporal gyrus, and this heightened the risk of transition to psychosis in our sample. Further longitudinal studies are needed to precisely understand this link.
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http://dx.doi.org/10.1016/j.schres.2020.09.017DOI Listing
October 2020

Symptom Remission and Brain Cortical Networks at First Clinical Presentation of Psychosis: The OPTiMiSE Study.

Schizophr Bull 2021 03;47(2):444-455

Center for Neuropsychiatric Schizophrenia Research, CNSR, and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, CINS, Mental Health Centre Glostrup, University of Copenhagen, Copenhagen, Denmark.

Individuals with psychoses have brain alterations, particularly in frontal and temporal cortices, that may be particularly prominent, already at illness onset, in those more likely to have poorer symptom remission following treatment with the first antipsychotic. The identification of strong neuroanatomical markers of symptom remission could thus facilitate stratification and individualized treatment of patients with schizophrenia. We used magnetic resonance imaging at baseline to examine brain regional and network correlates of subsequent symptomatic remission in 167 medication-naïve or minimally treated patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder entering a three-phase trial, at seven sites. Patients in remission at the end of each phase were randomized to treatment as usual, with or without an adjunctive psycho-social intervention for medication adherence. The final follow-up visit was at 74 weeks. A total of 108 patients (70%) were in remission at Week 4, 85 (55%) at Week 22, and 97 (63%) at Week 74. We found no baseline regional differences in volumes, cortical thickness, surface area, or local gyrification between patients who did or did not achieved remission at any time point. However, patients not in remission at Week 74, at baseline showed reduced structural connectivity across frontal, anterior cingulate, and insular cortices. A similar pattern was evident in patients not in remission at Week 4 and Week 22, although not significantly. Lack of symptom remission in first-episode psychosis is not associated with regional brain alterations at illness onset. Instead, when the illness becomes a stable entity, its association with the altered organization of cortical gyrification becomes more defined.
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http://dx.doi.org/10.1093/schbul/sbaa115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965060PMC
March 2021

Ondansetron augmentation for the management of obsessive-compulsive disorder in a patient with treatment-resistant schizophrenia.

Aust N Z J Psychiatry 2020 Oct 7:4867420963726. Epub 2020 Oct 7.

Adult Mental Health Rehabilitation Unit, NorthWestern Mental Health, Melbourne Health, Sunshine Hospital, St Albans, VIC, Australia.

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http://dx.doi.org/10.1177/0004867420963726DOI Listing
October 2020

Relationship between jumping to conclusions and clinical outcomes in people at clinical high-risk for psychosis.

Psychol Med 2020 Oct 6:1-9. Epub 2020 Oct 6.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Background: Psychosis is associated with a reasoning bias, which manifests as a tendency to 'jump to conclusions'. We examined this bias in people at clinical high-risk for psychosis (CHR) and investigated its relationship with their clinical outcomes.

Methods: In total, 303 CHR subjects and 57 healthy controls (HC) were included. Both groups were assessed at baseline, and after 1 and 2 years. A 'beads' task was used to assess reasoning bias. Symptoms and level of functioning were assessed using the Comprehensive Assessment of At-Risk Mental States scale (CAARMS) and the Global Assessment of Functioning (GAF), respectively. During follow up, 58 (16.1%) of the CHR group developed psychosis (CHR-T), and 245 did not (CHR-NT). Logistic regressions, multilevel mixed models, and Cox regression were used to analyse the relationship between reasoning bias and transition to psychosis and level of functioning, at each time point.

Results: There was no association between reasoning bias at baseline and the subsequent onset of psychosis. However, when assessed after the transition to psychosis, CHR-T participants showed a greater tendency to jump to conclusions than CHR-NT and HC participants (55, 17, 17%; χ2 = 8.13, p = 0.012). There was a significant association between jumping to conclusions (JTC) at baseline and a reduced level of functioning at 2-year follow-up in the CHR group after adjusting for transition, gender, ethnicity, age, and IQ.

Conclusions: In CHR participants, JTC at baseline was associated with adverse functioning at the follow-up. Interventions designed to improve JTC could be beneficial in the CHR population.
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http://dx.doi.org/10.1017/S0033291720003396DOI Listing
October 2020

No Effects of Cognitive Remediation on Cerebral White Matter in Individuals at Ultra-High Risk for Psychosis-A Randomized Clinical Trial.

Front Psychiatry 2020 28;11:873. Epub 2020 Aug 28.

Copenhagen Research Center for Mental Health, CORE, Mental Health Centre Copenhagen, University of Copenhagen, Hellerup, Denmark.

Background: Individuals at ultra-high risk for psychosis (UHR) present with subtle alterations in cerebral white matter (WM), which appear to be associated with clinical and functional outcome. The effect of cognitive remediation on WM organization in UHR individuals has not been investigated previously.

Methods: In a randomized, clinical trial, UHR individuals aged 18 to 40 years were assigned to treatment as usual (TAU) or TAU plus cognitive remediation for 20 weeks. Cognitive remediation comprised 20 x 2-h sessions of neurocognitive and social-cognitive training. Primary outcome was whole brain fractional anisotropy derived from diffusion weighted imaging, statistically tested as an interaction between timepoint and treatment group. Secondary outcomes were restricted to five predefined region of interest (ROI) analyses on fractional anisotropy, axial diffusivity, radial diffusivity and mean diffusivity. For significant timepoint and treatment group interactions within these five ROIs, we explored associations between longitudinal changes in WM and cognitive functions/clinical symptoms. Finally, we explored dose-response effects of cognitive remediation on WM.

Results: A total of 111 UHR individuals were included. Attrition-rate was 26%. The cognitive remediation group completed on average 12 h of neurocognitive training, which was considerably lower than per protocol. We found no effect of cognitive remediation on whole-brain FA when compared to treatment as usual. Secondary ROI analyses revealed a nominal significant interaction between timepoint*treatment of AD in left medial lemniscus (P=0.016) which did not survive control for multiple comparisons. The exploratory test showed that this change in AD correlated to improvements of mental flexibility in the cognitive remediation group (p=0.001). We found no dose-response effect of neurocognitive training on WM.

Conclusions: Cognitive remediation comprising 12 h of neurocognitive training on average did not improve global or regional WM organization in UHR individuals. Further investigations of duration and intensity of cognitive training as necessary prerequisites of neuroplasticity-based changes are warranted.

Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02098408.
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http://dx.doi.org/10.3389/fpsyt.2020.00873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485415PMC
August 2020

Neurological, neuropsychiatric and neurodevelopmental complications of COVID-19.

Aust N Z J Psychiatry 2020 Oct 1:4867420961472. Epub 2020 Oct 1.

Department of Neurology & Neurosciences, The Central Clinical School, Alfred Hospital, Monash University, Melbourne, VIC, Australia.

Although COVID-19 is predominantly a respiratory disease, it is known to affect multiple organ systems. In this article, we highlight the impact of SARS-CoV-2 (the coronavirus causing COVID-19) on the central nervous system as there is an urgent need to understand the longitudinal impacts of COVID-19 on brain function, behaviour and cognition. Furthermore, we address the possibility of intergenerational impacts of COVID-19 on the brain, potentially via both maternal and paternal routes. Evidence from preclinical models of earlier coronaviruses has shown direct viral infiltration across the blood-brain barrier and indirect secondary effects due to other organ pathology and inflammation. In the most severely ill patients with pneumonia requiring intensive care, there appears to be additional severe inflammatory response and associated thrombophilia with widespread organ damage, including the brain. Maternal viral (and other) infections during pregnancy can affect the offspring, with greater incidence of neurodevelopmental disorders, such as autism, schizophrenia and epilepsy. Available reports suggest possible vertical transmission of SARS-CoV-2, although longitudinal cohort studies of such offspring are needed. The impact of paternal infection on the offspring and intergenerational effects should also be considered. Research targeted at mechanistic insights into all aspects of pathogenesis, including neurological, neuropsychiatric and haematological systems alongside pulmonary pathology, will be critical in informing future therapeutic approaches. With these future challenges in mind, we highlight the importance of national and international collaborative efforts to gather the required clinical and preclinical data to effectively address the possible long-term sequelae of this global pandemic, particularly with respect to the brain and mental health.
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http://dx.doi.org/10.1177/0004867420961472DOI Listing
October 2020

Brain-Predicted Age Associates With Psychopathology Dimensions in Youths.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 04 1;6(4):410-419. Epub 2020 Aug 1.

Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Melbourne, Victoria, Australia; Department of Biomedical Engineering, University of Melbourne, Melbourne, Victoria, Australia.

Background: This study aimed to investigate whether dimensional constructs of psychopathology relate to variation in patterns of brain development and to determine whether these constructs share common neurodevelopmental profiles.

Methods: Psychiatric symptom ratings from 9312 youths (8-21 years old) from the Philadelphia Neurodevelopmental Cohort were parsed into 7 independent dimensions of clinical psychopathology representing conduct, anxiety, obsessive-compulsive, attention, depression, bipolar, and psychosis symptoms. Using a subset of this cohort with structural magnetic resonance imaging (n = 1313), a normative model of brain morphology was established and the model was then applied to predict the age of youths with clinical symptoms. We investigated whether the deviation of brain-predicted age from true chronological age, called the brain age gap, explained individual variation in each psychopathology dimension.

Results: Individual variation in the brain age gap significantly associated with clinical dimensions representing psychosis (t = 3.16, p = .0016), obsessive-compulsive symptoms (t = 2.5, p = .01), and general psychopathology (t = 4.08, p < .0001). Greater symptom severity along these dimensions was associated with brain morphology that appeared older than expected for typically developing youths of the same age. Psychopathology dimensions clustered into 2 modules based on shared brain loci where putative accelerated neurodevelopment was most prominent. Patterns of morphological development were accelerated in frontal cortices for depression, psychosis, and conduct symptoms (module 1), whereas acceleration was most evident in subcortex and insula for the remaining dimensions (module 2).

Conclusions: Our findings suggest that increased brain age, particularly in frontal cortex and subcortical nuclei, underpins clinical psychosis and obsessive-compulsive symptoms in youths. Psychopathology dimensions share common neural substrates, despite representing clinically independent symptom profiles.
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http://dx.doi.org/10.1016/j.bpsc.2020.07.014DOI Listing
April 2021

Individual deviations from normative models of brain structure in a large cross-sectional schizophrenia cohort.

Mol Psychiatry 2020 Sep 22. Epub 2020 Sep 22.

Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Melbourne, VIC, Australia.

The heterogeneity of schizophrenia has defied efforts to derive reproducible and definitive anatomical maps of structural brain changes associated with the disorder. We aimed to map deviations from normative ranges of brain structure for individual patients and evaluate whether the loci of individual deviations recapitulated group-average brain maps of schizophrenia pathology. For each of 48 white matter tracts and 68 cortical regions, normative percentiles of variation in fractional anisotropy (FA) and cortical thickness (CT) were established using diffusion-weighted and structural MRI from healthy adults (n = 195). Individuals with schizophrenia (n = 322) were classified as either within the normative range for healthy individuals of the same age and sex (5-95% percentiles), infra-normal (<5% percentile) or supra-normal (>95% percentile). Repeating this classification for each tract and region yielded a deviation map for each individual. Compared to the healthy comparison group, the schizophrenia group showed widespread reductions in FA and CT, involving virtually all white matter tracts and cortical regions. Paradoxically, however, no more than 15-20% of patients deviated from the normative range for any single tract or region. Furthermore, 79% of patients showed infra-normal deviations for at least one locus (healthy individuals: 59 ± 2%, p < 0.001). Thus, while infra-normal deviations were common among patients, their anatomical loci were highly inconsistent between individuals. Higher polygenic risk for schizophrenia associated with a greater number of regions with infra-normal deviations in CT (r = -0.17, p = 0.006). We conclude that anatomical loci of schizophrenia-related changes are highly heterogeneous across individuals to the extent that group-consensus pathological maps are not representative of most individual patients. Normative modeling can aid in parsing schizophrenia heterogeneity and guiding personalized interventions.
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http://dx.doi.org/10.1038/s41380-020-00882-5DOI Listing
September 2020

Development of Proteomic Prediction Models for Transition to Psychotic Disorder in the Clinical High-Risk State and Psychotic Experiences in Adolescence.

JAMA Psychiatry 2021 Jan;78(1):77-90

Institute of Psychiatry, Psychology & Neuroscience, Department of Psychosis Studies, King's College London, London, United Kingdom.

Importance: Biomarkers that are predictive of outcomes in individuals at risk of psychosis would facilitate individualized prognosis and stratification strategies.

Objective: To investigate whether proteomic biomarkers may aid prediction of transition to psychotic disorder in the clinical high-risk (CHR) state and adolescent psychotic experiences (PEs) in the general population.

Design, Setting, And Participants: This diagnostic study comprised 2 case-control studies nested within the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) and the Avon Longitudinal Study of Parents and Children (ALSPAC). EU-GEI is an international multisite prospective study of participants at CHR referred from local mental health services. ALSPAC is a United Kingdom-based general population birth cohort. Included were EU-GEI participants who met CHR criteria at baseline and ALSPAC participants who did not report PEs at age 12 years. Data were analyzed from September 2018 to April 2020.

Main Outcomes And Measures: In EU-GEI, transition status was assessed by the Comprehensive Assessment of At-Risk Mental States or contact with clinical services. In ALSPAC, PEs at age 18 years were assessed using the Psychosis-Like Symptoms Interview. Proteomic data were obtained from mass spectrometry of baseline plasma samples in EU-GEI and plasma samples at age 12 years in ALSPAC. Support vector machine learning algorithms were used to develop predictive models.

Results: The EU-GEI subsample (133 participants at CHR (mean [SD] age, 22.6 [4.5] years; 68 [51.1%] male) comprised 49 (36.8%) who developed psychosis and 84 (63.2%) who did not. A model based on baseline clinical and proteomic data demonstrated excellent performance for prediction of transition outcome (area under the receiver operating characteristic curve [AUC], 0.95; positive predictive value [PPV], 75.0%; and negative predictive value [NPV], 98.6%). Functional analysis of differentially expressed proteins implicated the complement and coagulation cascade. A model based on the 10 most predictive proteins accurately predicted transition status in training (AUC, 0.99; PPV, 76.9%; and NPV, 100%) and test (AUC, 0.92; PPV, 81.8%; and NPV, 96.8%) data. The ALSPAC subsample (121 participants from the general population with plasma samples available at age 12 years (61 [50.4%] male) comprised 55 participants (45.5%) with PEs at age 18 years and 61 (50.4%) without PEs at age 18 years. A model using proteomic data at age 12 years predicted PEs at age 18 years, with an AUC of 0.74 (PPV, 67.8%; and NPV, 75.8%).

Conclusions And Relevance: In individuals at risk of psychosis, proteomic biomarkers may contribute to individualized prognosis and stratification strategies. These findings implicate early dysregulation of the complement and coagulation cascade in the development of psychosis outcomes.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450406PMC
January 2021