Implementing and Evaluating a National Integrated Digital Registry and Clinical Decision Support System in Early Intervention in Psychosis Services (Early Psychosis Informatics Into Care): Co-Designed Protocol.

BACKGROUND: Early intervention in psychosis (EIP) services are nationally mandated in England to provide multidisciplinary care to people experiencing first-episode psychosis, which disproportionately affects deprived and ethnic minority youth. Quality of service provision varies by region, and people from historically underserved populations have unequal access. In other disease areas, including stroke and dementia, national digital registries coupled with clinical decision support systems (CDSSs) have revolutionized the delivery of equitable, evidence-based interventions to transform patient outcomes and reduce population-level disparities in care. Given psychosis is ranked the third most burdensome mental health condition by the World Health Organization, it is essential that we achieve the same parity of health improvements. OBJECTIVE: This paper reports the protocol for the program development phase of this study, in which we aimed to co-design and produce an evidence-based, stakeholder-informed framework for the building, implementation, piloting, and evaluation of a national integrated digital registry and CDSS for psychosis, known as EPICare (Early Psychosis Informatics into Care). METHODS: We conducted 3 concurrent work packages, with reciprocal knowledge exchange between each. In work package 1, using a participatory co-design framework, key stakeholders (clinicians, academics, policy makers, and patient and public contributors) engaged in 4 workshops to review, refine, and identify a core set of essential and desirable measures and features of the EPICare registry and CDSS. Using a modified Delphi approach, we then developed a consensus of data priorities. In work package 2, we collaborated with National Health Service (NHS) informatics teams to identify relevant data currently captured in electronic health records, understand data retrieval methods, and design the software architecture and data model to inform future implementation. In work package 3, observations of stakeholder workshops and individual interviews with representative stakeholders (n=10) were subject to interpretative qualitative analysis, guided by normalization process theory, to identify factors likely to influence the adoption and implementation of EPICare into routine practice. RESULTS: Stage 1 of the EPICare study took place between December 2021 and September 2022. The next steps include stage 2 building, piloting, implementation, and evaluation of EPICare in 5 demonstrator NHS Trusts serving underserved and diverse populations with substantial need for EIP care in England. If successful, this will be followed by stage 3, in which we will seek NHS adoption of EPICare for rollout to all EIP services in England. CONCLUSIONS: By establishing a multistakeholder network and engaging them in an iterative co-design process, we have identified essential and desirable elements of the EPICare registry and CDSS; proactively identified and minimized potential challenges and barriers to uptake and implementation; and addressed key questions related to informatics architecture, infrastructure, governance, and integration in diverse NHS Trusts, enabling us to proceed with the building, piloting, implementation, and evaluation of EPICare. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50177.

Corrigendum: The effect of antipsychotics on glutamate levels in the anterior cingulate cortex and clinical response: a 1H-MRS study in first-episode psychosis patients.

[This corrects the article DOI: 10.3389/fpsyt.2022.967941.].

Machine learning in small sample neuroimaging studies: Novel measures for schizophrenia analysis.

Novel features derived from imaging and artificial intelligence systems are commonly coupled to construct computer-aided diagnosis (CAD) systems that are intended as clinical support tools or for investigation of complex biological patterns. This study used sulcal patterns from structural images of the brain as the basis for classifying patients with schizophrenia from unaffected controls. Statistical, machine learning and deep learning techniques were sequentially applied as a demonstration of how a CAD system might be comprehensively evaluated in the absence of prior empirical work or extant literature to guide development, and the availability of only small sample datasets. Sulcal features of the entire cerebral cortex were derived from 58 schizophrenia patients and 56 healthy controls. No similar CAD systems has been reported that uses sulcal features from the entire cortex. We considered all the stages in a CAD system workflow: preprocessing, feature selection and extraction, and classification. The explainable AI techniques Local Interpretable Model-agnostic Explanations and SHapley Additive exPlanations were applied to detect the relevance of features to classification. At each stage, alternatives were compared in terms of their performance in the context of a small sample. Differentiating sulcal patterns were located in temporal and precentral areas, as well as the collateral fissure. We also verified the benefits of applying dimensionality reduction techniques and validation methods, such as resubstitution with upper bound correction, to optimize performance.

The contribution of first-episode illness characteristics and cumulative antipsychotic usage to progressive structural brain changes over a long-term follow-up in schizophrenia.

Exposure to antipsychotics as well as certain first-episode illness characteristics have been associated with greater gray matter (GM) deficits in the early phase of schizophrenia. Whether the first-episode illness characteristics affect the long-term progression of the structural brain changes remain unexplored. We therefore assessed the role of first-episode illness characteristics and life-time antipsychotic use in relation to long-term structural brain GM changes in schizophrenia. Individuals with schizophrenia (SZ, n = 29) and non-psychotic controls (n = 61) from the Northern Finland Birth Cohort 1966 underwent structural MRI at the ages of 34 (baseline) and 43 (follow-up) years. At follow-up, the average duration of illness was 19.8 years. Voxel-based morphometry was used to assess the effects of predictors on longitudinal GM changes in schizophrenia-relevant brain areas. Younger age of onset (AoO), higher cumulative antipsychotic dose and severity of symptoms were associated with greater GM deficits in the SZ group at follow-up. None of the first-episode illness characteristics were associated with longitudinal GM changes during 9-year follow-up period. We conclude that a younger AoO and high life-time antipsychotic use may contribute to progression of structural brain changes in schizophrenia. Apart from AoO, other first-episode illness characteristics may not contribute to longitudinal GM changes in midlife.

Reversal learning in those with early psychosis features contingency-dependent changes in loss response and learning.

INTRODUCTION: People with psychotic disorders commonly feature broad decision-making impairments that impact their functional outcomes. Specific associative/reinforcement learning problems have been demonstrated in persistent psychosis. But these phenotypes may differ in early psychosis, suggesting that aspects of cognition decline over time. METHODS: The present proof-of-concept study examined goal-directed action and reversal learning in controls and those with early psychosis. RESULTS: Equivalent performance was observed between groups during outcome-specific devaluation, and reversal learning at an 80:20 contingency (reward probability for high:low targets). But when the low target reward probability was increased (80:40) those with early psychosis altered their response to loss, whereas controls did not. Computational modelling confirmed that in early psychosis there was a change in punishment learning that increased the chance of staying with the same stimulus after a loss, multiple trials into the future. In early psychosis, the magnitude of this response was greatest in those with higher IQ and lower clinical severity scores. CONCLUSIONS: We show preliminary evidence that those with early psychosis present with a phenotype that includes altered responding to loss and hyper-adaptability in response to outcome changes. This may reflect a compensatory response to overcome the milieu of corticostriatal changes associated with psychotic disorders.

Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes.

Our understanding of the genetics of the human cerebral cortex is limited both in terms of the diversity and the anatomical granularity of brain structural phenotypes. Here we conducted a genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging-derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,663 individuals and identified 4,349 experiment-wide significant loci. These phenotypes include cortical thickness, surface area, gray matter volume, measures of folding, neurite density and water diffusion. We identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with cortical expansion are associated with cephalic disorders. Finally, we identified complex interphenotype and inter-regional genetic relationships among the 13 phenotypes, reflecting the developmental differences among them. Together, these analyses identify distinct genetic organizational principles of the cortex and their correlates with neurodevelopment.

A multicentre study on grey matter morphometric biomarkers for classifying early schizophrenia and parkinson's disease psychosis.

Psychotic symptoms occur in a majority of schizophrenia patients and in ~50% of all Parkinson's disease (PD) patients. Altered grey matter (GM) structure within several brain areas and networks may contribute to their pathogenesis. Little is known, however, about transdiagnostic similarities when psychotic symptoms occur in different disorders, such as in schizophrenia and PD. The present study investigated a large, multicenter sample containing 722 participants: 146 patients with first episode psychosis, FEP; 106 individuals in at-risk mental state for developing psychosis, ARMS; 145 healthy controls matching FEP and ARMS, Con-Psy; 92 PD patients with psychotic symptoms, PDP; 145 PD patients without psychotic symptoms, PDN; 88 healthy controls matching PDN and PDP, Con-PD. We applied source-based morphometry in association with receiver operating curves (ROC) analyses to identify common GM structural covariance networks (SCN) and investigated their accuracy in identifying the different patient groups. We assessed group-specific homogeneity and variability across the different networks and potential associations with clinical symptoms. SCN-extracted GM values differed significantly between FEP and Con-Psy, PDP and Con-PD, PDN and Con-PD, as well as PDN and PDP, indicating significant overall grey matter reductions in PD and early schizophrenia. ROC analyses showed that SCN-based classification algorithms allow good classification (AUC ~0.80) of FEP and Con-Psy, and fair performance (AUC ~0.72) when differentiating PDP from Con-PD. Importantly, the best performance was found in partly the same networks, including the thalamus. Alterations within selected SCNs may be related to the presence of psychotic symptoms in both early schizophrenia and PD psychosis, indicating some commonality of underlying mechanisms. Furthermore, results provide evidence that GM volume within specific SCNs may serve as a biomarker for identifying FEP and PDP.

Impact and centrality of attention dysregulation on cognition, anxiety, and low mood in adolescents.

Functional impairments in cognition are frequently thought to be a feature of individuals with depression or anxiety. However, documented impairments are both broad and inconsistent, with little known about when they emerge, whether they are causes or effects of affective symptoms, or whether specific cognitive systems are implicated. Here, we show, in the adolescent ABCD cohort (N = 11,876), that attention dysregulation is a robust factor underlying wide-ranging cognitive task impairments seen in adolescents with moderate to severe anxiety or low mood. We stratified individuals high in DSM-oriented depression or anxiety symptomology, and low in attention deficit hyperactivity disorder (ADHD), as well as vice versa - demonstrating that those high in depression or anxiety dimensions but low in ADHD symptoms not only exhibited normal task performance across several commonly studied cognitive paradigms, but out-performed controls in several domains, as well as in those low in both dimensions. Similarly, we showed that there were no associations between psychopathological dimensions and performance on an extensive cognitive battery after controlling for attention dysregulation. Further, corroborating previous research, the co-occurrence of attention dysregulation was associated with a wide range of other adverse outcomes, psychopathological features, and executive functioning (EF) impairments. To assess how attention dysregulation relates to and generates diverse psychopathology, we performed confirmatory and exploratory network analysis with different analytic approaches using Gaussian Graphical Models and Directed Acyclic Graphs to examine interactions between ADHD, anxiety, low mood, oppositional defiant disorder (ODD), social relationships, and cognition. Confirmatory centrality analysis indicated that features of attention dysregulation were indeed central and robustly connected to a wide range of psychopathological traits across different categories, scales, and time points. Exploratory network analysis indicated potentially important bridging traits and socioenvironmental influences in the relationships between ADHD symptoms and mood/anxiety disorders. Trait perfectionism was uniquely associated with both better cognitive performance and broad psychopathological dimensions. This work suggests that attentional dysregulation may moderate the breadth of EF, fluid, and crystalized cognitive task outcomes seen in adolescents with anxiety and low mood, and may be central to disparate pathological features, and thus a target for attenuating wide-ranging negative developmental outcomes.

Predicting treatment resistance from first-episode psychosis using routinely collected clinical information.

Around a quarter of people who experience a first episode of psychosis (FEP) will develop treatment-resistant schizophrenia (TRS), but there are currently no established clinically useful methods to predict this from baseline. We aimed to explore the predictive potential for clozapine use as a proxy for TRS of routinely collected, objective biomedical predictors at FEP onset, and to externally validate the model in a separate clinical sample of people with FEP. We developed and externally validated a forced-entry logistic regression risk prediction Model fOr cloZApine tReaTment, or MOZART, to predict up to 8-year risk of clozapine use from FEP using routinely recorded information including age, sex, ethnicity, triglycerides, alkaline phosphatase levels, and lymphocyte counts. We also produced a least-absolute shrinkage and selection operator (LASSO) based model, additionally including neutrophil count, smoking status, body mass index, and random glucose levels. The models were developed using data from two UK psychosis early intervention services (EIS) and externally validated in another UK EIS. Model performance was assessed via discrimination and calibration. We developed the models in 785 patients, and validated externally in 1,110 patients. Both models predicted clozapine use well at internal validation (MOZART: C 0.70; 95%CI 0.63,0.76; LASSO: 0.69; 95%CI 0.63,0.77). At external validation, discrimination performance reduced (MOZART: 0.63; 0.58,0.69; LASSO: 0.64; 0.58,0.69) but recovered after re-estimation of the lymphocyte predictor (C: 0.67; 0.62,0.73). Calibration plots showed good agreement between observed and predicted risk in the forced-entry model. We also present a decision-curve analysis and an online data visualisation tool. The use of routinely collected clinical information including blood-based biomarkers taken at FEP onset can help to predict the individual risk of clozapine use, and should be considered equally alongside other potentially useful information such as symptom scores in large-scale efforts to predict psychiatric outcomes.

Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis.

INTRODUCTION: Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis. METHODS AND ANALYSIS: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6<0.7 pg/mL) and 30 matched healthy controls will be recruited to complete identical baseline assessments to allow for comparison of the characteristic features of inflammation-associated psychosis. ETHICS AND DISSEMINATION: The study is sponsored by the University of Bristol and has been approved by the Cambridge East Research Ethics Committee (reference: 22/EE/0010; IRAS project ID: 301682). Study findings will be published in peer-review journals. Findings will also be disseminated by scientific presentation and other means. TRIAL REGISTRATION NUMBER: ISRCTN23256704.

Action selection in early stages of psychosis: an active inference approach.

BACKGROUND: To interact successfully with their environment, humans need to build a model to make sense of noisy and ambiguous inputs. An inaccurate model, as suggested to be the case for people with psychosis, disturbs optimal action selection. Recent computational models, such as active inference, have emphasized the importance of action selection, treating it as a key part of the inferential process. Based on an active inference framework, we sought to evaluate previous knowledge and belief precision in an action-based task, given that alterations in these parameters have been linked to the development of psychotic symptoms. We further sought to determine whether task performance and modelling parameters would be suitable for classification of patients and controls. METHODS: Twenty-three individuals with an at-risk mental state, 26 patients with first-episode psychosis and 31 controls completed a probabilistic task in which action choice (go/no-go) was dissociated from outcome valence (gain or loss). We evaluated group differences in performance and active inference model parameters and performed receiver operating characteristic (ROC) analyses to assess group classification. RESULTS: We found reduced overall performance in patients with psychosis. Active inference modelling revealed that patients showed increased forgetting, reduced confidence in policy selection and less optimal general choice behaviour, with poorer action-state associations. Importantly, ROC analysis showed fair-to-good classification performance for all groups, when combining modelling parameters and performance measures. LIMITATIONS: The sample size is moderate. CONCLUSION: Active inference modelling of this task provides further explanation for dysfunctional mechanisms underlying decision-making in psychosis and may be relevant for future research on the development of biomarkers for early identification of psychosis.

Neural Circuitry of Salience and Reward Processing in Psychosis.

The processing of salient and rewarding stimuli is integral to engaging our attention, stimulating anticipation for future events, and driving goal-directed behaviors. Widespread impairments in these processes are observed in psychosis, which may be associated with worse functional outcomes or mechanistically linked to the development of symptoms. Here, we summarize the current knowledge of behavioral and functional neuroimaging in salience, prediction error, and reward. Although each is a specific process, they are situated in multiple feedback and feedforward systems integral to decision making and cognition more generally. We argue that the origin of salience and reward processing dysfunctions may be centered in the subcortex during the earliest stages of psychosis, with cortical abnormalities being initially more spared but becoming more prominent in established psychotic illness/schizophrenia. The neural circuits underpinning salience and reward processing may provide targets for delaying or preventing progressive behavioral and neurobiological decline.

Specific adolescent prodromal symptoms associated with onset of psychosis in the Northern Finland Birth Cohort 1986.

BACKGROUND: Several psychological symptoms in adolescence associate with later development of psychosis. However, it is unclear which symptoms specifically predict psychotic disorders rather than psychiatric disorders in general. We conducted a prospective study comparing how specific adolescent psychotic-like symptoms, predicted psychotic and non-psychotic hospital-treated psychiatric disorders in the population-based Northern Finland Birth Cohort 1986 (NFBC1986). METHODS: At age 15-16 years, 6632 members of the NFBC1986 completed the PROD-screen questionnaire. New hospital-treated mental disorders of the NFBC1986 participants were detected between age 17 and 30 years from the Finnish Care Register for Health Care. Multiple covariates were used in the analysis. RESULTS: During the follow-up, 1.1% of the participants developed a psychotic and 3.2% a non-psychotic psychiatric disorder. Three symptoms were specifically associated with onset of psychosis compared to non-psychotic psychiatric disorders: 'Difficulty in controlling one's speech, behaviour or facial expression while communicating' (adjusted OR 4.00; 95% CI 1.66-9.92), 'Difficulties in understanding written text or heard speech' (OR 2.25; 1.12-4.51), and 'Difficulty or uncertainty in making contact with other people' (OR 2.20; 1.03-4.67). Of these, the first one remained statistically significant after Bonferroni correction for multiple comparisons. CONCLUSION: To our knowledge, this is the first general-population-based prospective study exploring psychiatric symptoms predicting the onset of hospital-treated first-episode psychosis in comparison to non-psychotic disorders. We found three symptoms related with difficulties in social interaction which predicted onset of psychosis. This is a novel finding and should be replicated.

Educational attainment, structural brain reserve and Alzheimer's disease: a Mendelian randomization analysis.

Higher educational attainment is observationally associated with lower risk of Alzheimer's disease. However, the biological mechanisms underpinning this association remain unclear. The protective effect of education on Alzheimer's disease may be mediated via increased brain reserve. We used two-sample Mendelian randomization to explore putative causal relationships between educational attainment, structural brain reserve as proxied by MRI phenotypes and Alzheimer's disease. Summary statistics were obtained from genome-wide association studies of educational attainment (n = 1 131 881), late-onset Alzheimer's disease (35 274 cases, 59 163 controls) and 15 measures of grey or white matter macro- or micro-structure derived from structural or diffusion MRI (nmax = 33 211). We conducted univariable Mendelian randomization analyses to investigate bidirectional associations between (i) educational attainment and Alzheimer's disease; (ii) educational attainment and imaging-derived phenotypes; and (iii) imaging-derived phenotypes and Alzheimer's disease. Multivariable Mendelian randomization was used to assess whether brain structure phenotypes mediated the effect of education on Alzheimer's disease risk. Genetically proxied educational attainment was inversely associated with Alzheimer's disease (odds ratio per standard deviation increase in genetically predicted years of schooling = 0.70, 95% confidence interval 0.60, 0.80). There were positive associations between genetically predicted educational attainment and four cortical metrics (standard deviation units change in imaging phenotype per one standard deviation increase in genetically predicted years of schooling): surface area 0.30 (95% confidence interval 0.20, 0.40); volume 0.29 (95% confidence interval 0.20, 0.37); intrinsic curvature 0.18 (95% confidence interval 0.11, 0.25); local gyrification index 0.21 (95% confidence interval 0.11, 0.31)]; and inverse associations with cortical intracellular volume fraction [-0.09 (95% confidence interval -0.15, -0.03)] and white matter hyperintensities volume [-0.14 (95% confidence interval -0.23, -0.05)]. Genetically proxied levels of surface area, cortical volume and intrinsic curvature were positively associated with educational attainment [standard deviation units change in years of schooling per one standard deviation increase in respective genetically predicted imaging phenotype: 0.13 (95% confidence interval 0.10, 0.16); 0.15 (95% confidence interval 0.11, 0.19) and 0.12 (95% confidence interval 0.04, 0.19)]. We found no evidence of associations between genetically predicted imaging-derived phenotypes and Alzheimer's disease. The inverse association of genetically predicted educational attainment with Alzheimer's disease did not attenuate after adjusting for imaging-derived phenotypes in multivariable analyses. Our results provide support for a protective causal effect of educational attainment on Alzheimer's disease risk, as well as potential bidirectional causal relationships between education and brain macro- and micro-structure. However, we did not find evidence that these structural markers affect risk of Alzheimer's disease. The protective effect of education on Alzheimer's disease may be mediated via other measures of brain reserve not included in the present study, or by alternative mechanisms.

The effect of antipsychotics on glutamate levels in the anterior cingulate cortex and clinical response: A 1H-MRS study in first-episode psychosis patients.

Introduction: Glutamatergic dysfunction is implicated in the pathophysiology of schizophrenia. It is unclear whether glutamatergic dysfunction predicts response to treatment or if antipsychotic treatment influences glutamate levels. We investigated the effect of antipsychotic treatment on glutamatergic levels in the anterior cingulate cortex (ACC), and whether there is a relationship between baseline glutamatergic levels and clinical response after antipsychotic treatment in people with first episode psychosis (FEP). Materials and methods: The sample comprised 25 FEP patients; 22 completed magnetic resonance spectroscopy scans at both timepoints. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Results: There was no significant change in glutamate [baseline 13.23 ± 2.33; follow-up 13.89 ± 1.74; t(21) = -1.158, p = 0.260], or Glx levels [baseline 19.64 ± 3.26; follow-up 19.66 ± 2.65; t(21) = -0.034, p = 0.973]. There was no significant association between glutamate or Glx levels at baseline and the change in PANSS positive (Glu r = 0.061, p = 0.777, Glx r = -0.152, p = 0.477), negative (Glu r = 0.144, p = 0.502, Glx r = 0.052, p = 0.811), general (Glu r = 0.110, p = 0.607, Glx r = -0.212, p = 0.320), or total scores (Glu r = 0.078, p = 0.719 Glx r = -0.155, p = 0.470). Conclusion: These findings indicate that treatment response is unlikely to be associated with baseline glutamatergic metabolites prior to antipsychotic treatment, and there is no major effect of antipsychotic treatment on glutamatergic metabolites in the ACC.

The psychosis metabolic risk calculator (PsyMetRiC) for young people with psychosis: International external validation and site-specific recalibration in two independent European samples.

Background: Cardiometabolic dysfunction is common in young people with psychosis. Recently, the Psychosis Metabolic Risk Calculator (PsyMetRiC) was developed and externally validated in the UK, predicting up-to six-year risk of metabolic syndrome (MetS) from routinely collected data. The full-model includes age, sex, ethnicity, body-mass index, smoking status, prescription of metabolically-active antipsychotic medication, high-density lipoprotein, and triglyceride concentrations; the partial-model excludes biochemical predictors. Methods: To move toward a future internationally-useful tool, we externally validated PsyMetRiC in two independent European samples. We used data from the PsyMetab (Lausanne, Switzerland) and PAFIP (Cantabria, Spain) cohorts, including participants aged 16-35y without MetS at baseline who had 1-6y follow-up. Predictive performance was assessed primarily via discrimination (C-statistic), calibration (calibration plots), and decision curve analysis. Site-specific recalibration was considered. Findings: We included 1024 participants (PsyMetab n=558, male=62%, outcome prevalence=19%, mean follow-up=2.48y; PAFIP n=466, male=65%, outcome prevalence=14%, mean follow-up=2.59y). Discrimination was better in the full- compared with partial-model (PsyMetab=full-model C=0.73, 95% C.I., 0.68-0.79, partial-model C=0.68, 95% C.I., 0.62-0.74; PAFIP=full-model C=0.72, 95% C.I., 0.66-0.78; partial-model C=0.66, 95% C.I., 0.60-0.71). As expected, calibration plots revealed varying degrees of miscalibration, which recovered following site-specific recalibration. PsyMetRiC showed net benefit in both new cohorts, more so after recalibration. Interpretation: The study provides evidence of PsyMetRiC's generalizability in Western Europe, although further local and international validation studies are required. In future, PsyMetRiC could help clinicians internationally to identify young people with psychosis who are at higher cardiometabolic risk, so interventions can be directed effectively to reduce long-term morbidity and mortality. Funding: NIHR Cambridge Biomedical Research Centre (BRC-1215-20014); The Wellcome Trust (201486/Z/16/Z); Swiss National Research Foundation (320030-120686, 324730- 144064, and 320030-173211); The Carlos III Health Institute (CM20/00015, FIS00/3095, PI020499, PI050427, and PI060507); IDIVAL (INT/A21/10 and INT/A20/04); The Andalusian Regional Government (A1-0055-2020 and A1-0005-2021); SENY Fundacion Research (2005-0308007); Fundacion Marques de Valdecilla (A/02/07, API07/011); Ministry of Economy and Competitiveness and the European Fund for Regional Development (SAF2016-76046-R and SAF2013-46292-R).For the Spanish and French translation of the abstract see Supplementary Materials section.

Impairments in goal-directed action and reversal learning in a proportion of individuals with psychosis.

Cognitive impairment in psychosis is one of the strongest predictors of functional decline. Problems with decision-making processes, such as goal-directed action and reversal learning, can reflect cortico-striatal dysfunction. The heterogenous symptoms and neurobiology observed in those with psychosis suggests that specific cognitive phenotypes may reflect differing causative mechanisms. As such, decision-making performance could identify subgroups of individuals with more severe cortico-striatal dysfunction and help to predict their functional decline. The present work evaluated the relationship between goal-directed action, reversal learning, and symptom profiles in those with psychosis. We assessed decision-making processes in healthy controls (N = 34) and those with persistent psychosis (N = 45), subclassifying subjects based on intact/impaired goal-directed action. Compared with healthy controls (<20%), a large proportion (58%) of those with persistent psychosis displayed impaired goal-directed action, predicting poor serial reversal learning performance. Computational approaches indicated that those with impaired goal-directed action had a decreased capacity to rapidly update their prior beliefs in the face of changing contingencies. Impaired decision-making also was associated with reduced levels of grandiosity and increased problems with abstract thinking. These findings suggest that prominent decision-making deficits, indicative of cortico-striatal dysfunction, are present in a large proportion of people with persistent psychosis. Moreover, these impairments would have significant functional implications in terms of planning and abstract thinking.

Investigating the relationship of COVID-19 related stress and media consumption with schizotypy, depression, and anxiety in cross-sectional surveys repeated throughout the pandemic in Germany and the UK.

Background: Studies report a strong impact of the COVID-19 pandemic and related stressors on the mental well-being of the general population. In this paper, we investigated whether COVID-19 related concerns and social adversity affected schizotypal traits, anxiety, and depression using structural equational modelling. In mediation analyses, we furthermore explored whether these associations were mediated by healthy (sleep and physical exercise) or unhealthy behaviours (drug and alcohol consumption, excessive media use). Methods: We assessed schizotypy, depression, and anxiety as well as healthy and unhealthy behaviours and a wide range of sociodemographic scores using online surveys from residents of Germany and the United Kingdom over 1 year during the COVID-19 pandemic. Four independent samples were collected (April/May 2020: N=781, September/October 2020: N=498, January/February 2021: N=544, May 2021: N=486). The degree of schizotypy was measured using the Schizotypal Personality Questionnaire (SPQ), anxiety, and depression symptoms were surveyed with the Symptom Checklist (SCL-27), and healthy and unhealthy behaviours were assessed with the Coronavirus Health Impact Survey (CRISIS). Structural equation models were used to consider the influence of COVID-19 related concerns and social adversity on depressive and anxiety-related symptoms and schizotypal traits in relation to certain healthy (sleep and exercise) and unhealthy behaviours (alcohol and drug consumption, excessive media use). Results: The results revealed that COVID-19 related life concerns were significantly associated with schizotypy in the September/October 2020 and May 2021 surveys, with anxiety in the September/October 2020, January/February 2021, and May 2021 surveys, and with depressive symptoms in all surveys. Social adversity significantly affected the expression of schizotypal traits and depressive and anxiety symptoms in all four surveys. Importantly, we found that excessive media consumption (>4 hr per day) fully mediated the relationship between COVID-19 related life concerns and schizotypal traits in the January/February 2021 survey. Furthermore, several of the surveys showed that excessive media consumption was associated with increased depressive and anxiety-related symptoms in people burdened by COVID-19 related life. Conclusions: The ongoing uncertainties of the pandemic and the restrictions on social life have a strong impact on mental well-being and especially the expression of schizotypal traits. The negative impact is further boosted by excessive media consumption, which is especially critical for people with high schizotypal traits. Funding: FK received funding from the European Union's Horizon 2020 (Grant number 754,462). SN received funding from the Cundill Centre for Child and Youth Depression at the Centre for Addiction and Mental Health, Toronto, Canada and the Wellcome Trust Institutional Strategic Support Fund from the University of Cambridge.

The 2020 COVID-19 pandemic, and the measures different governments took to contain it, harmed many people's mental well-being. The restrictions, combined with pandemic-related uncertainty, caused many individuals to experience increased stress, depression, and anxiety. Many people turned to unhealthy behaviours to cope, including consuming more alcohol or drugs, using media excessively, developing poor sleeping habits, or reducing the amount of exercise they did. Stress, drugs, poor sleep, and uncertainty can increase an individual's risk of developing psychotic symptoms, including delusions, hallucinations, or difficulty thinking clearly. These symptoms may be temporary or part of a more lasting condition, like schizophrenia. The risk of developing these symptoms increases in people with 'schizotypal traits', such as a lack of close relationships, paranoia, or unusual or implausible beliefs. These individuals may be especially vulnerable to the harmful mental health effects of the pandemic. Daimer et al. demonstrated that people who were more worried about their life stability or financial situation during the 2020 COVID-19 pandemic had worse mental well-being than those who felt secure. In the experiments, volunteers completed a series of online mental health questionnaires at four different time points during the pandemic. People who reported feeling lonely, having negative thoughts, or experiencing fewer positive social interactions had more symptoms of mental illness. People who experienced more life disruptions also reported more anxiety or depression symptoms and more schizotypal traits. Daily consumption of at least four hours of digital media exacerbated negative mental health symptoms, and people with more pandemic-related life concerns also spent more time on digital media Daimer et al. suggest that increased media consumption among people with pandemic-related hardships may have increased mental health symptoms and schizotypal traits in these individuals. The survey results suggest that maintaining a healthy lifestyle, including meaningful relationships, is essential to staying mentally healthy during extreme situations like a global pandemic. Protective interventions ­ such as strengthening social support networks, providing mental health education, or increasing mental healthcare provisions ­ are essential to prevent poor mental health outcomes during future crises.

Facial Emotion Recognition in Psychosis and Associations With Polygenic Risk for Schizophrenia: Findings From the Multi-Center EU-GEI Case-Control Study.

BACKGROUND AND HYPOTHESIS: Facial Emotion Recognition is a key domain of social cognition associated with psychotic disorders as a candidate intermediate phenotype. In this study, we set out to investigate global and specific facial emotion recognition deficits in first-episode psychosis, and whether polygenic liability to psychotic disorders is associated with facial emotion recognition. STUDY DESIGN: 828 First Episode Psychosis (FEP) patients and 1308 population-based controls completed assessments of the Degraded Facial Affect Recognition Task (DFAR) and a subsample of 524 FEP and 899 controls provided blood or saliva samples from which we extracted DNA, performed genotyping and computed polygenic risk scores for schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MD). STUDY RESULTS: A worse ability to globally recognize facial emotion expressions was found in patients compared with controls [B= -1.5 (0.6), 95% CI -2.7 to -0.3], with evidence for stronger effects on negative emotions (fear [B = -3.3 (1.1), 95% CI -5.3 to -1.2] and anger [B = -2.3 (1.1), 95% CI -4.6 to -0.1]) than on happiness [B = 0.3 (0.7), 95% CI -1 to 1.7]. Pooling all participants, and controlling for confounds including case/control status, facial anger recognition was associated significantly with Schizophrenia Polygenic Risk Score (SZ PRS) [B = -3.5 (1.7), 95% CI -6.9 to -0.2]. CONCLUSIONS: Psychosis is associated with impaired recognition of fear and anger, and higher SZ PRS is associated with worse facial anger recognition. Our findings provide evidence that facial emotion recognition of anger might play a role as an intermediate phenotype for psychosis.