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Background: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the life span. Studies have reported a shared genetic basis between schizophrenia and cortical thickness. However, no genes whose expression is related to abnormal cortical thinning in schizophrenia have been identified., Methods: We conducted linear mixed models to estimate the rates of accelerated cortical thinning across 68 regions from the Desikan-Killiany atlas in individuals with schizophrenia compared with healthy control participants from a large longitudinal sample (n cases  = 169 and n controls  = 298, ages 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. Finally, we explored the functional and genetic underpinnings of the genes that contribute most to accelerated thinning., Results: We found a global pattern of accelerated cortical thinning in individuals with schizophrenia compared with healthy control participants. Genes underexpressed in cortical regions that exhibit this accelerated thinning were downregulated in several psychiatric disorders and were enriched for both common and rare disrupting variation for schizophrenia and neurodevelopmental disorders. In contrast, none of these enrichments were observed for baseline cross-sectional cortical thickness differences., Conclusions: Our findings suggest that accelerated cortical thinning, rather than cortical thickness alone, serves as an informative phenotype for neurodevelopmental disruptions in schizophrenia. We highlight the genetic and transcriptomic correlates of this accelerated cortical thinning, emphasizing the need for future longitudinal studies to elucidate the role of genetic variation and the temporal-spatial dynamics of gene expression in brain development and aging in schizophrenia., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Good adherence to antipsychotic therapy helps prevent relapses in first-episode psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts, to emulate a target trial comparing antipsychotics, with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from the European First Episode Schizophrenia Trial, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse-probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone were 61.5% (95% CI, 52.5-70.6), 73.5% (95% CI, 60.5-84.9), 76.8% (95% CI, 67.2-85.3), 58.4% (95% CI, 40.4-77.4), 76.5% (95% CI, 62.1-88.5), and 74.4% (95% CI, 67.0-81.2), respectively. Compared with aripiprazole, the 12-month risk differences were -15.3% (95% CI, -30.0 to 0.0) for olanzapine, -12.8% (95% CI, -25.7 to -1.0) for risperidone, and 3.0% (95% CI, -21.5 to 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration sufficed to remove confounding for these clinical questions. This article is part of a Special Collection on Mental Health., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Schizophrenia research reveals sex differences in incidence, symptoms, genetic risk factors, and brain function. However, a knowledge gap remains regarding sex-specific schizophrenia alterations in brain function. Schizophrenia is considered a dysconnectivity syndrome, but the dynamic integration and segregation of brain networks are poorly understood. Recent advances in resting-state functional magnetic resonance imaging allow us to study spatial dynamics, the phenomenon of brain networks spatially evolving over time. Nevertheless, estimating time-resolved networks remains challenging due to low signal-to-noise ratio, limited short-time information, and uncertain network identification., Methods: We adapted a reference-informed network estimation technique to capture time-resolved networks and their dynamic spatial integration and segregation for 193 individuals with schizophrenia and 315 control participants. We focused on time-resolved spatial functional network connectivity, an estimate of network spatial coupling, to study sex-specific alterations in schizophrenia and their links to genomic data., Results: Our findings are consistent with the dysconnectivity and neurodevelopment hypotheses and with the cerebello-thalamo-cortical, triple-network, and frontoparietal dysconnectivity models, helping to unify them. The potential unification offers a new understanding of the underlying mechanisms. Notably, the posterior default mode/salience spatial functional network connectivity exhibits sex-specific schizophrenia alteration during the state with the highest global network integration and is correlated with genetic risk for schizophrenia. This dysfunction is reflected in regions with weak functional connectivity to corresponding networks., Conclusions: Our method can effectively capture spatially dynamic networks, detect nuanced schizophrenia effects including sex-specific ones, and reveal the intricate relationship of dynamic information to genomic data. The results also underscore the clinical potential of dynamic spatial dependence and weak connectivity., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Morphometric similarity is a recently developed neuroimaging phenotype of inter-regional connectivity by quantifying the similarity of a region to other regions based on multiple MRI parameters. Altered average morphometric similarity has been reported in psychotic disorders at the group level, with considerable heterogeneity across individuals. We used normative modeling to address cross-sectional and longitudinal inter-individual heterogeneity of morphometric similarity in health and schizophrenia., Methods: Morphometric similarity for 62 cortical regions was obtained from baseline and follow-up T1-weighted scans of healthy individuals and patients with chronic schizophrenia. Cortical regions were classified into seven predefined brain functional networks. Using Bayesian Linear Regression and taking into account age, sex, image quality and scanner, we trained and validated normative models in healthy controls from eleven datasets (n = 4310). Individual deviations from the norm (z-scores) in morphometric similarity were computed for each participant for each network and region at both timepoints. A z-score ≧ than 1.96 was considered supra-normal and a z-score ≦ -1.96 infra-normal. As a longitudinal metric, we calculated the change over time of the total number of infra- or supra-normal regions per participant., Results: At baseline, patients with schizophrenia had decreased morphometric similarity of the default mode network and increased morphometric similarity of the somatomotor network when compared with healthy controls. The percentage of patients with infra- or supra-normal values for any region at baseline and follow-up was low (<6%) and did not differ from healthy controls. Mean intra-group changes over time in the total number of infra- or supra-normal regions were small in schizophrenia and healthy control groups (<1) and there were no significant between-group differences., Conclusions: In a case-control setting, a decrease of morphometric similarity within the default mode network may be a robust finding implicated in schizophrenia. However, normative modeling suggests that significant reductions and changes over time of regional morphometric similarity are evident only in a minority of patients., Competing Interests: Disclosures Dr. Díaz-Caneja has received honoraria from Angelini and Viatris. Dr. Arango has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen-Cilag, Lundbeck, Otsuka, Roche, Sage, Servier, Shire, Schering-Plough, Sumitomo Dainippon Pharma, Sunovion, and Takeda. Dr. Cahn has received unrestricted research grants from or served as an independent symposium speaker or consultant for Eli Lilly, Bristol-Myers Squibb, Lundbeck, Sanofi-Aventis, Janssen-Cilag, AstraZeneca, and Schering-Plough. The other authors report no financial relationships with commercial interests.

Competing Interests: Declaration of competing interest This work has been supported by the European Union under grant number 101057182 (project Youth-GEMs). Views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or European Health and Digital Executive Agency. CDC has received funding from Instituto de Salud Carlos III (JR19/00024, PI20/00721, PI23/00625). She has also received honoraria from Angelini and Viatris and travel support from Janssen and Angelini for activities not related to this work. SG reports no conflicts of interest related to this work.

Schizophrenia and bipolar disorder exhibit substantial clinical overlap, particularly in individuals at familial high risk, who frequently present sub-threshold symptoms before the onset of illness. Severe mental disorders are highly polygenic traits, but their impact on the stages preceding the manifestation of mental disorders remains relatively unexplored. Our study aimed to examine the influence of polygenic risk scores (PRS) on sub-clinical outcomes over a 2-year period in youth at familial high risk for schizophrenia and bipolar disorder and controls. The sample included 222 children and adolescents, comprising offspring of parents with schizophrenia (n = 38), bipolar disorder (n = 80), and community controls (n = 104). We calculated PRS for psychiatric disorders, neuroticism and cognition using the PRS-CS method. Linear mixed-effects models were employed to investigate the association between PRS and cognition, symptom severity and functioning. Mediation analyses were conducted to explore whether clinical features acted as intermediaries in the impact of PRS on functioning outcomes. SZoff exhibited elevated PRS for schizophrenia. In the entire sample, PRS for depression, neuroticism, and cognitive traits showed associations with sub-clinical features. The effect of PRS for neuroticism and general intelligence on functioning outcomes were mediated by cognition and symptoms severity, respectively. This study delves into the interplay among genetics, the emergence of sub-clinical symptoms and functioning outcomes, providing novel evidence on mechanisms underpinning the continuum from sub-threshold features to the onset of mental disorders. The findings underscore the interplay of genetics, cognition, and clinical features, providing insights for personalized early interventions., Competing Interests: Declaration of competing interest CM Díaz-Caneja has received grant support from the Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (PI17/00481, PI20/00721, JR19/00024) and honoraria from Exeltis and Angelini. The other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

To assess the role of age (early onset psychosis-EOP < 18 years vs. adult onset psychosis-AOP) and diagnosis (schizophrenia spectrum disorders-SSD vs. bipolar disorders-BD) on the duration of untreated psychosis (DUP) and prodromal symptoms in a sample of patients with a first episode of psychosis. 331 patients with a first episode of psychosis (7-35 years old) were recruited and 174 (52.6%) diagnosed with SSD or BD at one-year follow-up through a multicenter longitudinal study. The Symptom Onset in Schizophrenia (SOS) inventory, the Positive and Negative Syndrome Scale and the structured clinical interviews for DSM-IV diagnoses were administered. Generalized linear models compared the main effects and group interaction. 273 AOP (25.2 ± 5.1 years; 66.5% male) and 58 EOP patients (15.5 ± 1.8 years; 70.7% male) were included. EOP patients had significantly more prodromal symptoms with a higher frequency of trouble with thinking, avolition and hallucinations than AOP patients, and significantly different median DUP (91 [33-177] vs. 58 [21-140] days; Z = - 2.006, p = 0.045). This was also significantly longer in SSD vs. BD patients (90 [31-155] vs. 30 [7-66] days; Z = - 2.916, p = 0.004) who, moreover had different profiles of prodromal symptoms. When assessing the interaction between age at onset (EOP/AOP) and type of diagnosis (SSD/BD), avolition was significantly higher (Wald statistic = 3.945; p = 0.047), in AOP patients with SSD compared to AOP BD patients (p = 0.004). Awareness of differences in length of DUP and prodromal symptoms in EOP vs. AOP and SSD vs. BD patients could help improve the early detection of psychosis among minors., (© 2023. The Author(s).)

Background: Bullying is a common form of violence among children and adolescents. Young people with neurodevelopmental or psychiatric conditions might have an increased risk of bullying victimisation and perpetration. We aimed to assess the odds of bullying involvement and its association with mental health measures in these populations., Methods: In this systematic review and meta-analysis, we searched PubMed, ERIC, Psychology and Behavioural Sciences Collection, Web of Science Core Collection, PsycArticles, and PsycInfo databases from inception up to Aug 8, 2023, and included articles reporting data on bullying outcomes of current bullying (within the past year) among children and adolescents (aged 4-17 years) with a diagnosis of a neurodevelopmental or psychiatric condtion provided by a health professional. Bullying type was classified as traditional (physical, verbal, or relational) or as cyberbullying (intentional and repeated harm inflicted through electronic devices and social media), and bullying involvement was classified as victimisation, perpetration, and perpetration-victimisation. Mental health measures were collected and the associations with bullying involvement assessed. We used random-effects meta-analyses to estimate prevalence and odds ratios (ORs) for bullying involvement. Heterogeneity was assessed using the I 2 statistic, and publication bias was tested with Egger's regression. This study is registered with PROSPERO, CRD42021235043., Findings: We included 212 studies in the meta-analysis. The total sample comprised 126 717 cases (mean age 12·34 years [SD 1·82], 37·6% girls) and 504 806 controls (12·5 years [SD 1·86], 47·6% girls). For traditional bullying, the pooled prevalence was 42·2% (95% CI 39·6-44·9) for victimisation, 24·4% (22·6-26·3) for perpetration, and 14·0% (11·4-17·1) for perpetration-victimisation. For cyberbullying, the prevalence was 21·8% (16·0-28·9) for victimisation, 19·6% (13·4-27·7) for perpetration, and 20·7% (8·4-42·6) for perpetration-victimisation. Compared with controls, young people with neurodevelopmental or psychiatric conditions were more likely to be involved in traditional and cyberbullying as a victim (OR 2·85 [95% CI 2·62-3·09] and 2·07 [1·63-2·61]), perpetrator (2·42 [2·20-2·66] and 1·91 [1·60-2·28]), and perpetrator-victim (3·66 [2·83-4·74] and 1·85 [1·05-3·28]). Bullying involvement was associated with higher scores in mental health measures in young people with neurodevelopmental or psychiatric conditions, particularly internalising symptoms and externalising symptoms., Interpretation: Our study underscores bullying involvement as a prevalent risk factor in young people with neurodevelopmental or psychiatric conditions that might add to their disease burden through its negative effects on mental health. Interventions targeting these vulnerable populations are warranted to improve their mental health and their future social integration., Funding: Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Consorcio Centro de Investigación Biomédica en Red., Competing Interests: Declaration of interests CA has been a consultant to or has received honoraria or grants from Acadia AMGEN, Angelini, AstraZeneca, Bristol-Myers Squibb, Caja Navarra, Comunidad de Madrid, Dainippon Pharma, Exeltis, Fundación Alicia Koplowitz, Geodon Richter, Instituto de Salud Carlos III, Jansssen-Cilag, Lundbeck, Ministerio Educación, Otsuka, Roche, Sage, Sanofi, Schering Plough, Shire, Stanley Foundation, Sumitomo, Sunovion, Takeda, and Teva. DF has received funding as an advisor or speaker from Angelini, Casen Recordati, Eisai, Lundbeck, Otsuka, and Rovi. He has also received research funds from the Instituto de Salud Carlos III, Fundación Alicia Koplowitz, and Fundación La Caixa. CMD-C has received honoraria from Angelini and support to attend conferences from Janssen and Angelini. She has also received research funds from the Instituto de Salud Carlos III and European Comission. MA has held a Río Hortega grant from Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Regional gray matter (GM) alterations have been reported in early-onset psychosis (EOP, onset before age 18), but previous studies have yielded conflicting results, likely due to small sample sizes and the different brain regions examined. In this study, we conducted a whole brain voxel-based morphometry (VBM) analysis in a large sample of individuals with EOP, using the newly developed ENIGMA-VBM tool., Methods: 15 independent cohorts from the ENIGMA-EOP working group participated in the study. The overall sample comprised T1-weighted MRI data from 482 individuals with EOP and 469 healthy controls. Each site performed the VBM analysis locally using the standardized ENIGMA-VBM tool. Statistical parametric T-maps were generated from each cohort and meta-analyzed to reveal voxel-wise differences between EOP and healthy controls as well as the individual-based association between GM volume and age of onset, chlorpromazine (CPZ) equivalent dose, and other clinical variables., Results: Compared with healthy controls, individuals with EOP showed widespread lower GM volume encompassing most of the cortex, with the most marked effect in the left median cingulate (Hedges' g = 0.55, p = 0.001 corrected), as well as small clusters of lower white matter (WM), whereas no regional GM or WM volumes were higher in EOP. Lower GM volume in the cerebellum, thalamus and left inferior parietal gyrus was associated with older age of onset. Deficits in GM in the left inferior frontal gyrus, right insula, right precentral gyrus and right superior frontal gyrus were also associated with higher CPZ equivalent doses., Conclusion: EOP is associated with widespread reductions in cortical GM volume, while WM is affected to a smaller extent. GM volume alterations are associated with age of onset and CPZ equivalent dose but these effects are small compared to case-control differences. Mapping anatomical abnormalities in EOP may lead to a better understanding of the role of psychosis in brain development during childhood and adolescence., (© 2023. The Author(s).)

Background: There is a need for more sustainable interventions and for assessing the effectiveness of school-based universal anti-bullying programmes in vulnerable populations. We assessed the efficacy of a multicomponent, web-enabled, school-based intervention that aims to improve school climate and reduce bullying (LINKlusive) relative to conventional practices (control condition)., Methods: We conducted a cluster randomised controlled trial in primary and secondary schools in Madrid, Spain. The primary outcome measure was peer-reported bullying victimisation after the 12-week intervention (study endpoint). We analysed data using longitudinal mixed-effects models. The trial was registered with the ISRCTN registry (15719015)., Findings: We included 20 schools (10 in each group); 6542 students participated at baseline; 6403 were assessed at study endpoint. After the intervention, there was a statistically significant reduction in bullying victimisation in both the intervention (OR 0.61, 95% CI [0.41, 0.90]) and control groups (OR 0.69, 95% CI [0.51, 0.92]), with no evidence of differences in the whole sample (OR 0.89, 95% CI [0.58, 1.36]; aOR 0.89, 95% CI [0.58, 1.37]). Subgroup analyses showed a statistically significant effect of LINKlusive on bullying victimisation in primary education (aOR 0.68, 95% CI [0.47, 0.98]). In students with peer-reported bullying victimisation at baseline, LINKlusive showed a statistically significant effect on depression (-1.43, 95% CI [-2.46, -0.40], adjusted standardised mean difference (SMD) -0.41) and quality of life (2.18, 95% CI [0.80, 3.56], adjusted SMD 0.45)., Interpretation: LINKlusive could be effective in reducing bullying victimisation in primary school students. Sustainable whole-school interventions to promote mental health and reduce risk factors are warranted to improve outcomes in young people, especially in the early years of education., Funding: Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation., Competing Interests: CA has been a consultant to or has received honoraria or grants from Acadia, AMGEN, Angelini, AstraZeneca, Bristol-Myers-Squibb, Caja Navarra, Comunidad de Madrid, Exeltis, Fundación Alicia Koplowitz, Fundación Familia Alonso, Fundación Mutua Madrileña, Gedeon Richter, Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation), Janssen Cilag, Lundbeck, Minerva, Ministerio de Educación, NARSAD, Otsuka, Roche, Sage, Sanofi, Schering Plough, Servier, Shire, Stanley Foundation, Sumitomo Dainippon Pharma, Sunovion, Takeda, and Teva. JMB developed the Sociescuela software, which is managed by a non-profit company. CDC has received grant support from Instituto de Salud Carlos III (Spanish Ministry of Science and Innovation), honoraria from Exeltis and Angelini, and travel support from Janssen and Angelini. The remaining authors declare no conflict of interest related to this work., (© 2024 The Authors.)

Background: Despite the evidence supporting the relationship between socioeconomic status (SES) and severe mental disorders (SMD), the directionality of the associations between income or education and mental disorders is still poorly understood., Objective: To investigate the potential bidirectional causal relationships between genetic liability to the two main components of SES (income and educational attainment (EA)) on three SMD: schizophrenia, bipolar disorder (BD) and depression., Methods: We performed a bidirectional, two-sample univariable Mendelian randomisation (UVMR) and multivariable Mendelian randomisation (MVMR) study using SES phenotypes (income, n=397 751 and EA, n=766 345) and SMD (schizophrenia, n=127 906; BD, n=51 710 and depression, n=500 119) genome-wide association studies summary-statistics to dissect the potential direct associations of income and EA with SMD., Findings: UVMR showed that genetic liability to higher income was associated with decreased risk of schizophrenia and depression, with a smaller reverse effect of schizophrenia and depression on income. Effects were comparable after adjusting for EA in the MVMR. UMVR showed bidirectional negative associations between genetic liability to EA and depression and positive associations between genetic liability to EA and BD, with no significant effects on schizophrenia. After accounting for income, MVMR showed a bidirectional positive direction between genetic liability to EA and BD and schizophrenia but not with depression., Conclusions: Our results suggest a heterogeneous link pattern between SES and SMD. We found a negative bidirectional association between genetic liability to income and the risk of schizophrenia and depression. On the contrary, we found a positive bidirectional relationship of genetic liability to EA with schizophrenia and BD, which only becomes apparent after adjusting for income in the case of schizophrenia., Clinical Implications: These findings shed light on the directional mechanisms between social determinants and mental disorders and suggest that income and EA should be studied separately in relation to mental illness., Competing Interests: Competing interests: CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. CMD-C. has received honoraria from AbbVie, Sanofi and Exeltis. The rest of the authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. Published by BMJ.)

Background: Tobacco is a highly prevalent substance of abuse in patients with psychosis. Previous studies have reported an association between tobacco use and schizophrenia. The aim of this study was to analyze the relationship between tobacco use and first-episode psychosis (FEP), age at onset of psychosis, and specific diagnosis of psychosis., Methods: The sample consisted of 1105 FEP patients and 1355 controls from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We assessed substance use with the Tobacco and Alcohol Questionnaire and performed a series of regression analyses using case-control status, age of onset of psychosis, and diagnosis as outcomes and tobacco use and frequency of tobacco use as predictors. Analyses were adjusted for sociodemographic characteristics, alcohol, and cannabis use., Results: After controlling for cannabis use, FEP patients were 2.6 times more likely to use tobacco [ p ⩽ 0.001; adjusted odds ratio (AOR) 2.6; 95% confidence interval (CI) [2.1-3.2]] and 1.7 times more likely to smoke 20 or more cigarettes a day ( p = 0.003; AOR 1.7; 95% CI [1.2-2.4]) than controls. Tobacco use was associated with an earlier age at psychosis onset ( β = -2.3; p ⩽ 0.001; 95% CI [-3.7 to -0.9]) and was 1.3 times more frequent in FEP patients with a diagnosis of schizophrenia than in other diagnoses of psychosis (AOR 1.3; 95% CI [1.0-1.8]); however, these results were no longer significant after controlling for cannabis use., Conclusions: Tobacco and heavy-tobacco use are associated with increased odds of FEP. These findings further support the relevance of tobacco prevention in young populations.

Background: Subjective response (SR) to antipsychotic medication is relevant for quality of life, adherence and recovery. Here, we evaluate (1) the extent of variation in SR in patients using a single antipsychotic; (2) the association between subjective and symptomatic response; and (3) predictors of SR., Methods: Open-label, single treatment condition with amisulpride in 339 patients with a first episode of a schizophrenia spectrum disorder, at most minimally treated before inclusion. Patients were evaluated at baseline, before start with amisulpride and after four weeks of treatment with the Subjective Wellbeing under Neuroleptic scale, the Positive and Negative Syndrome Scale, and the Calgary Depression Scale for Schizophrenia., Results: (1) 26.8% of the patients had a substantial favorable SR, and 12.4% of the patients experienced a substantial dysphoric SR during treatment with amisulpride. (2) Modest positive associations were found between SR and 4 weeks change on symptom subscales ( r = 0.268-0.390, p values < 0.001). (3) Baseline affective symptoms contributed to the prediction of subjective remission, demographic characteristics did not. Lower start dosage of amisulpride was associated with a more favorable SR ( r = -0.215, p < 0.001)., Conclusions: We conclude that variation in individual proneness for an unfavorable SR is substantial and only modestly associated with symptomatic response. We need earlier identification of those most at risk for unfavorable SR and research into interventions to improve SR to antipsychotic medication in those at risk.

Schizophrenia is a debilitating psychiatric disorder associated with a reduced fertility and decreased life expectancy, yet common predisposing variation substantially contributes to the onset of the disorder, which poses an evolutionary paradox. Previous research has suggested balanced selection, a mechanism by which schizophrenia risk alleles could also provide advantages under certain environments, as a reliable explanation. However, recent studies have shown strong evidence against a positive selection of predisposing loci. Furthermore, evolutionary pressures on schizophrenia risk alleles could have changed throughout human history as new environments emerged. Here in this study, we used 1000 Genomes Project data to explore the relationship between schizophrenia predisposing loci and recent natural selection (RNS) signatures after the human diaspora out of Africa around 100,000 years ago on a genome-wide scale. We found evidence for significant enrichment of RNS markers in derived alleles arisen during human evolution conferring protection to schizophrenia. Moreover, both partitioned heritability and gene set enrichment analyses of mapped genes from schizophrenia predisposing loci subject to RNS revealed a lower involvement in brain and neuronal related functions compared to those not subject to RNS. Taken together, our results suggest non-antagonistic pleiotropy as a likely mechanism behind RNS that could explain the persistence of schizophrenia common predisposing variation in human populations due to its association to other non-psychiatric phenotypes., (© 2023. Springer Nature Limited.)

Background: Use of illegal stimulants is associated with an increased risk of psychotic disorder. However, the impact of stimulant use on odds of first-episode psychosis (FEP) remains unclear. Here, we aimed to describe the patterns of stimulant use and examine their impact on odds of FEP., Methods: We included patients with FEP aged 18-64 years who attended psychiatric services at 17 sites across 5 European countries and Brazil, and recruited controls representative of each local population (FEP = 1130; controls = 1497). Patterns of stimulant use were described. We computed fully adjusted logistic regression models (controlling for age, sex, ethnicity, cannabis use, and education level) to estimate their association with odds of FEP. Assuming causality, we calculated the population-attributable fractions for stimulant use associated with the odds for FEP., Findings: Prevalence of lifetime and recent stimulant use in the FEP sample were 14.50% and 7.88% and in controls 10.80% and 3.8%, respectively. Recent and lifetime stimulant use was associated with increased odds of FEP compared with abstainers [fully adjusted odds ratio 1.74,95% confidence interval (CI) 1.20-2.54, P = .004 and 1.62, 95% CI 1.25-2.09, P < .001, respectively]. According to PAFs, a substantial number of FEP cases (3.35% [95% CI 1.31-4.78] for recent use and 7.61% [95% CI 3.68-10.54] for lifetime use) could have been prevented if stimulants were no longer available and the odds of FEP and PAFs for lifetime and recent stimulant use varied across countries., Interpretation: Illegal stimulant use has a significant and clinically relevant influence on FEP incidence, with varying impacts across countries., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Negative symptoms are one of the most incapacitating features of Schizophrenia but their pathophysiology remains unclear. They have been linked to alterations in grey matter in several brain regions, but findings have been inconsistent. This may reflect the investigation of relatively small patient samples, and the confounding effects of chronic illness and exposure to antipsychotic medication. We sought to address these issues by investigating concurrently grey matter volumes (GMV) and cortical thickness (CTh) in a large sample of antipsychotic-naïve or minimally treated patients with First-Episode Schizophrenia (FES)., Methods: T1-weighted structural MRI brain scans were acquired from 180 antipsychotic-naïve or minimally treated patients recruited as part of the OPTiMiSE study. The sample was stratified into subgroups with ( N = 88) or without ( N = 92) Prominent Negative Symptoms (PMN), based on PANSS ratings at presentation. Regional GMV and CTh in the two groups were compared using Voxel-Based Morphometry (VBM) and FreeSurfer (FS). Between-group differences were corrected for multiple comparisons via Family-Wise Error (FWE) and Monte Carlo z-field simulation respectively at p < 0.05 (2-tailed)., Results: The presence of PMN symptoms was associated with larger left inferior orbitofrontal volume ( p = 0.03) and greater CTh in the left lateral orbitofrontal gyrus ( p = 0.007), but reduced CTh in the left superior temporal gyrus ( p = 0.009)., Conclusions: The findings highlight the role of orbitofrontal and temporal cortices in the pathogenesis of negative symptoms of Schizophrenia. As they were evident in generally untreated FEP patients, the results are unlikely to be related to effects of previous treatment or illness chronicity.

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Background: The Collaborative Outcome study on Health and Functioning during Infection Times (COH-FIT; www.coh-fit.com) is an anonymous and global online survey measuring health and functioning during the COVID-19 pandemic. The aim of this study was to test concurrently the validity of COH-FIT items and the internal validity of the co-primary outcome, a composite psychopathology "P-score"., Methods: The COH-FIT survey has been translated into 30 languages (two blind forward-translations, consensus, one independent English back-translation, final harmonization). To measure mental health, 1-4 items ("COH-FIT items") were extracted from validated questionnaires (e.g. Patient Health Questionnaire 9). COH-FIT items measured anxiety, depressive, post-traumatic, obsessive-compulsive, bipolar and psychotic symptoms, as well as stress, sleep and concentration. COH-FIT Items which correlated r ≥ 0.5 with validated companion questionnaires, were initially retained. A P-score factor structure was then identified from these items using exploratory factor analysis (EFA) and confirmatory factor analyses (CFA) on data split into training and validation sets. Consistency of results across languages, gender and age was assessed., Results: From >150,000 adult responses by May 6th, 2022, a subset of 22,456 completed both COH-FIT items and validated questionnaires. Concurrent validity was consistently demonstrated across different languages for COH-FIT items. CFA confirmed EFA results of five first-order factors (anxiety, depression, post-traumatic, psychotic, psychophysiologic symptoms) and revealed a single second-order factor P-score, with high internal reliability (ω = 0.95). Factor structure was consistent across age and sex., Conclusions: COH-FIT is a valid instrument to globally measure mental health during infection times. The P-score is a valid measure of multidimensional mental health., Competing Interests: Conflict of interest Conflict of interest statements of all authors are detailed in Supplementary Table 7., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Neighborhood socioeconomic status seems to be related to functioning in patients with first episode of psychosis (FEP). The present study aimed to assess if neighborhood vulnerability and risk of social exclusion could predict functional outcomes in people with FEP after controlling for other key variables identified in previous literature., Methods: A total of 137 patients with FEP ( DSM-IV-TR criteria) and 90 controls comprised the study sample from February 2013 to May 2019. Functioning was assessed with the WHO Disability Assessment Schedule. Neighborhood vulnerability was measured using a multidimensional socioeconomic deprivation index; data for the index were collected by the Madrid City Council and based on the participant's home address. Multilevel mixed-effects regression analyses were conducted to estimate the effects of neighborhood vulnerability on functioning., Results: Our results show that FEP patients could be more vulnerable to the effects of neighborhood-level characteristics than healthy controls (B = 1,570.173; z  = 3.91; P  < .001). In addition, our findings suggest that higher neighborhood vulnerability is related to greater functional disability in people with FEP, after controlling for other relevant confounders (B = 1,230.332; z  = 2.59; P  = .010)., Conclusions: These results highlight the importance of incorporating contextual factors into assessment of patients with FEP, since psychosocial difficulties observed in these patients could be partially related to the quality of neighborhood social-related resources., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

Genetic overlap involving rare disrupting mutations may contribute to high comorbidity rates between autism spectrum disorders and epilepsy. Despite their polygenic nature, genome-wide association studies have not reported a significant contribution of common genetic variation to comorbidity between both conditions. Analysis of common genetic variation affecting specific shared pathways such as miRNA dysregulation could help to elucidate the polygenic mechanisms underlying comorbidity between autism spectrum disorders and epilepsy. We evaluated here the role of common predisposing variation to autism spectrum disorders and epilepsy across target genes of 14 miRNAs selected through bibliographic research as being dysregulated in both disorders. We considered 4,581 target genes from various in silico sources. We described negative genetic correlation between autism spectrum disorders and epilepsy across variants located within target genes of the 14 miRNAs selected ( p = 0.0228). Moreover, polygenic transmission disequilibrium test on an independent cohort of autism spectrum disorders trios (N = 233) revealed an under-transmission of autism spectrum disorders predisposing alleles within miRNAs' target genes across autism spectrum disorders trios without comorbid epilepsy, thus reinforcing the negative relationship at the common genetic variation between both traits. Our study provides evidence of a negative relationship between autism spectrum disorders and epilepsy at the common genetic variation level that becomes more evident when focusing on the miRNA regulatory networks, which contrasts with observed clinical comorbidity and results from rare variation studies. Our findings may help to conceptualize the genetic heterogeneity and the comorbidity with epilepsy in autism spectrum disorders., Competing Interests: CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Roche, Sage, Ser-vier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. CD-C has received honoraria from Exeltis and Angelini not related to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Stella, Díaz-Caneja, Penzol, García-Alcón, Solís, Andreu-Bernabeu, Gurriarán, Arango, Parellada and González-Peñas.)

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I 2  = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions., (© 2022. The Author(s).)

Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age = 16.6 years, interquartile range (IQR) = 2.14, 46.4% females) and 265 adolescent healthy controls (median age = 16.2 years, IQR = 2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d = 0.37), posterior corona radiata (d = 0.32), and superior fronto-occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness., (© 2022. The Author(s).)

The relationship between structural brain alterations and prediction of clinical improvement in first-episode psychosis (FEP) has been scarcely studied. We investigated whether structural covariance, a well-established approach to identify abnormal patterns of volumetric correlation across distant brain regions, which allows incorporating network-level information to structural assessments, is associated with longitudinal clinical course. We assessed a sample of 74 individuals from a multicenter study. Magnetic resonance imaging scans were acquired at baseline, and clinical assessments at baseline and at a 2-year follow-up. Participants were split in two groups as a function of their clinical improvement after 2 years (i.e., ≥ < 40% reduction in psychotic symptom severity, (n = 29, n = 45)). We performed a seed-based approach and focused our analyses on 3 cortical and 4 subcortical regions of interest to identify alterations in cortical and cortico-subcortical networks. Improvers presented an increased correlation between the volumes of the right posterior cingulate cortex (PCC) and the left precentral gyrus, and between the left PCC and the left middle occipital gyrus. They also showed an increased correlation between right posterior hippocampus and left angular gyrus volumes. Our study provides a novel mean to identify structural correlates of clinical improvement in FEP, describing clinically-relevant anatomical differences in terms of large-scale brain networks, which is better aligned with prevailing neurobiological models of psychosis. The results involve brain regions considered to participate in the multisensory processing of bodily signals and the construction of bodily self-consciousness, which resonates with recent theoretical accounts in psychosis research., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Whether there is a relationship between oxytocin (OXT) use in labor and the risk of autism (ASD), and the nature of such relationship, is unclear. By integrating genetic and clinical data in a sample of 176 ASD participants, we tested the hypothesis that OXT is a marker for abnormal prenatal development which leads to impairments in the process of labor. OXT-exposed ASD had more obstetric complications (P = 0.031), earlier onset of symptoms (P = 0.027), poorer cognitive development (P = 0.011), higher mutation burden across neurodevelopment genes (P = 0.020; OR = 5.33) and lower transmission of polygenic risk for ASD (P = 0.0319), than non-exposed ASD. OXT seems to constitute a risk indicator rather than a risk factor for ASD, which is relevant for diagnostic and genetic counselling., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Cognitive impairment is an important feature of schizophrenia (SZ) and bipolar disorder (BP) with severity across the two disorders characterized by significant heterogeneity. Youth at family risk for SZ and BP were clustered based on cognitive function and examined in terms of the clinical, genetic, and brain imaging correlates of cluster membership., Method: One hundred sixty participants, 32 offspring of patients with SZ, 59 offspring of patients with BP and 69 offspring of healthy control parents underwent clinical and cognitive assessments, genotyping and structural MRI. K-means clustering was used to group family risk participants based on cognitive measures. Clusters were compared in terms of cortical and subcortical brain measures as well as polygenic risk scores., Results: Participants were grouped in 3 clusters with intact, intermediate, and impaired cognitive performance. The intermediate and impaired clusters had lower total brain surface area compared with the intact cluster, with prominent localization in frontal and temporal cortices. No between-cluster differences were identified in cortical thickness and subcortical brain volumes. The impaired cluster also had poorer psychosocial functioning and worse PRS-COG compared with the other 2 clusters and with offspring of healthy control parents, while there was no significant between-cluster difference in terms of PRS-SZ and PRS-BP. PRS-COG predicted psychosocial functioning, yet this effect did not appear to be mediated by an effect of PRS-COG on brain area., Conclusion: Stratification based on cognition may help to elucidate the biological underpinnings of cognitive heterogeneity across SZ and BP risk., (Copyright © 2022 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Introduction: Social functioning is severely affected in psychotic disorders. Negative symptoms and social cognition seem to play an important role in social functioning, although the preponderance and relationship between these three domains is not clear. In this study, we sought to assess the interrelation between social cognition, social functioning, and the expressiveness and experiential factors of negative symptoms in first-episode psychosis (FEP)., Sample and Methods: 216 patients, participants in a multicentre study (AGES-CM), comprised our study sample. The WHO Disability Assessment Schedule (WHODAS 2.0) was used to assess functioning, whereas the Positive and Negative Schizophrenia Syndrome Scale (PANSS) was used to measure the severity of negative symptoms, and the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) was applied to assess the emotional processing component of social cognition. Network analyses were conducted with the aim of analysing the patterns of relationships between social cognition, social functioning, and the expressiveness and experiential factors of negative symptoms., Results: Our findings suggest that there is a direct relationship between social cognition and social functioning (weight = -.077), but also an indirect connection between them, mediated by the experiential (but not the expressiveness) factor of negative symptoms (weight = 0.300)., Discussion: The importance of the affectation of subdomains of social cognition, as well as the role of negative symptoms, specifically the experiential factor, in the functioning of patients with FEP seems to be relevant. The inclusion of these factors in prevention and treatment programs would thus allow us to reduce their impact on the social functioning of these patients., Competing Interests: Declaration of competing interest Roberto Rodriguez-Jimenez has been a consultant for, spoken in activities of, or received grants from: Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/BMD-2422 AGES; S2017/BMD-3740), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Angelini, and Casen-Recordati. Angela Ibáñez has received research support from or served as speaker or advisor for Janssen-Cilag, Lundbeck, and Otsuka. Covadonga M. Díaz-Caneja has received grant support from Instituto de Salud Carlos III and the Spanish Ministry of Science and Innovation (PI17/00481, PI20/00721, JR19/00024), and has received honoraria or travel support from Exeltis, Angelini, Otsuka, and Janssen outside the submitted work. Celso Arango has been a consultant to or has received honoraria or grants from Acadia, Abbot, AMGEN, Angelini, AstraZeneca, Bristol-Myers Squibb, Caja Navarra, CIBERSAM, Fundación Alicia Koplowitz, Forum, Instituto de Salud Carlos III, Gedeon Richter, Janssen Cilag, Lundbeck, Merck, Medscape, Ministerio de Ciencia e Innovación, Ministerio de Sanidad, Ministerio de Economía y Competitividad, Mutua Madrileña, Otsuka, Pfizer, Roche, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovio, and Takeda. The other authors have not conflict of interest to declare., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life., Methods: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed., Results: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth., Conclusions: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: Historically, assessment of the psychometric properties of the Positive and Negative Syndrome Scale (PANSS) has had several foci: (1) calculation of reliability indexes, (2) extraction of subdimensions from the scale, and (3) assessment of the validity of the total score. In this study, we aimed to examine the scalability and to assess the clinical performance of the 30-item PANSS total score as well as the scalability of a shorter version (PANSS-6) of the scale., Methods: A composite data set of 1073 patients with first-episode schizophrenia or schizophrenia spectrum disorder was subjected to Rasch analysis of PANSS data from baseline and 4-6 weeks follow-up., Results: The central tests of fit of the Rasch model failed to satisfy the statistical requirements behind item homogeneity for the PANSS-30 as well as the PANSS-6 total score. For the PANSS-30, Differential Item Functioning was pronounced both for the 7-point Likert scale rating categories and when dichotomizing the rating categories. Subsequently, the Rasch structure analysis in the context of dichotomized items was used to isolate and estimate a systematic error because of item inhomogeneity, as well as a random error. The size of the combined sources of error for the PANSS-30 total score approximated 20% which is often regarded as clinical cut-off between response versus no-response., Conclusion: The results demonstrate the operational consequences of a lack of statistical fit of the Rasch model and suggest that the calculated measure of uncertainty needs to be considered when using the PANSS-30 total score., (© 2022 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Schizophrenia is a severely debilitating neurodevelopmental disorder that requires continuous multidisciplinary treatment. Early onset schizophrenia (EOS, onset before 18) is associated with poorer outcomes than the adult-onset type. The transition from adolescent to adult mental healthcare services (AMHS) poses various challenges for maintaining continuity of care. The heterogeneous availability of specialized mental health services and resources for people with schizophrenia across Europe and the inadequacy of training programs in creating a shared culture and knowledge base between child and adult mental health professionals are major challenges at the policy level. More flexible and individualized transition timing is also needed. While changes in the relationship between patients, caregivers and mental health professionals at a time when young people should acquire full responsibility for their own care are challenges common to all mental health disorders, these are particularly relevant to the care of schizophrenia because of the severe associated disability. This Expert Opinion Paper examines the main aspects of transitioning of care in schizophrenia with the aim of identifying the challenges and the potential approaches that could enhance continuity of care., Competing Interests: Declaration of Competing Interest CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Biogen, Boehringer, Gedeon Richter, Janssen Cilag, Lundbeck, Medscape, Minerva, Otsuka, Pfizer, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda., (Copyright © 2022. Published by Elsevier B.V.)

Scaling between subcomponents of folding and total brain volume (TBV) in healthy individuals (HIs) is allometric. It is unclear whether this is true in schizophrenia (SZ) or first-episode psychosis (FEP). This study confirmed normative allometric scaling norms in HIs using discovery and replication samples. Cross-sectional and longitudinal diagnostic differences in folding subcomponents were then assessed using an allometric framework. Structural imaging from a longitudinal (Sample 1: HI and SZ, n HI Baseline = 298, n SZ Baseline = 169, n HI Follow-up = 293, n SZ Follow-up = 168, totaling 1087 images, all individuals ≥ 2 images, age 16-69 years) and a cross-sectional sample (Sample 2: n HI = 61 and n FEP = 89, age 10-30 years), all human males and females, is leveraged to calculate global folding and its nested subcomponents: sulcation index (SI, total sulcal/cortical hull area) and determinants of sulcal area: sulcal length and sulcal depth. Scaling of SI, sulcal area, and sulcal length with TBV in SZ and FEP was allometric and did not differ from HIs. Longitudinal age trajectories demonstrated steeper loss of SI and sulcal area through adulthood in SZ. Longitudinal allometric analysis revealed that both annual change in SI and sulcal area was significantly stronger related to change in TBV in SZ compared with HIs. Our results detail the first evidence of the disproportionate contribution of changes in SI and sulcal area to TBV changes in SZ. Longitudinal allometric analysis of sulcal morphology provides deeper insight into lifespan trajectories of cortical folding in SZ. SIGNIFICANCE STATEMENT Psychotic disorders are associated with deficits in cortical folding and brain size, but we lack knowledge of how these two morphometric features are related. We leverage cross-sectional and longitudinal samples in which we decompose folding into a set of nested subcomponents: sulcal and hull area, and sulcal depth and length. We reveal that, in both schizophrenia and first-episode psychosis, (1) scaling of subcomponents with brain size is different from expected scaling laws and (2) caution is warranted when interpreting results from traditional methods for brain size correction. Longitudinal allometric scaling points to loss of sulcal area as a principal contributor to loss of brain size in schizophrenia. These findings advance the understanding of cortical folding atypicalities in psychotic disorders., (Copyright © 2022 the authors.)

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: . High-quality comprehensive data on short-/long-term physical/mental health effects of the COVID-19 pandemic are needed., Methods: . The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is an international, multi-language (n=30) project involving >230 investigators from 49 countries/territories/regions, endorsed by national/international professional associations. COH-FIT is a multi-wave, on-line anonymous, cross-sectional survey [wave 1: 04/2020 until the end of the pandemic, 12 months waves 2/3 starting 6/24 months threreafter] for adults, adolescents (14-17), and children (6-13), utilizing non-probability/snowball and representative sampling. COH-FIT aims to identify non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to improve social/health outcomes in the general population/vulnerable subgrous during/after COVID-19. In adults, co-primary outcomes are change from pre-COVID-19 to intra-COVID-19 in well-being (WHO-5) and a composite psychopathology P-Score. Key secondary outcomes are a P-extended score, global mental and physical health. Secondary outcomes include health-service utilization/functioning, treatment adherence, functioning, symptoms/behaviors/emotions, substance use, violence, among others., Results: . Starting 04/26/2020, up to 14/07/2021 >151,000 people from 155 countries/territories/regions and six continents have participated. Representative samples of ≥1,000 adults have been collected in 15 countries. Overall, 43.0% had prior physical disorders, 16.3% had prior mental disorders, 26.5% were health care workers, 8.2% were aged ≥65 years, 19.3% were exposed to someone infected with COVID-19, 76.1% had been in quarantine, and 2.1% had been COVID 19-positive., Limitations: . Cross-sectional survey, preponderance of non-representative participants., Conclusions: . Results from COH-FIT will comprehensively quantify the impact of COVID-19, seeking to identify high-risk groups in need for acute and long-term intervention, and inform evidence-based health policies/strategies during this/future pandemics., (Copyright © 2021. Published by Elsevier B.V.)

Background: The COVID-19 pandemic has altered daily routines and family functioning, led to closing schools, and dramatically limited social interactions worldwide. Measuring its impact on mental health of vulnerable children and adolescents is crucial., Methods: The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT - www.coh-fit.com) is an on-line anonymous survey, available in 30 languages, involving >230 investigators from 49 countries supported by national/international professional associations. COH-FIT has thee waves (until the pandemic is declared over by the WHO, and 6-18 months plus 24-36 months after its end). In addition to adults, COH-FIT also includes adolescents (age 14-17 years), and children (age 6-13 years), recruited via non-probability/snowball and representative sampling and assessed via self-rating and parental rating. Non-modifiable/modifiable risk factors/treatment targets to inform prevention/intervention programs to promote health and prevent mental and physical illness in children and adolescents will be generated by COH-FIT. Co-primary outcomes are changes in well-being (WHO-5) and a composite psychopathology P-Score. Multiple behavioral, family, coping strategy and service utilization factors are also assessed, including functioning and quality of life., Results: Up to June 2021, over 13,000 children and adolescents from 59 countries have participated in the COH-FIT project, with representative samples from eleven countries., Limitations: Cross-sectional and anonymous design., Conclusions: Evidence generated by COH-FIT will provide an international estimate of the COVID-19 effect on children's, adolescents' and families', mental and physical health, well-being, functioning and quality of life, informing the formulation of present and future evidence-based interventions and policies to minimize adverse effects of the present and future pandemics on youth., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Previous research suggests an association of loneliness and social isolation (LNL-ISO) with schizophrenia. Here, we demonstrate a LNL-ISO polygenic score contribution to schizophrenia risk in an independent case-control sample (N = 3,488). We then subset schizophrenia predisposing variation based on its effect on LNL-ISO. We find that genetic variation with concordant effects in both phenotypes shows significant SNP-based heritability enrichment, higher polygenic contribution in females, and positive covariance with mental disorders such as depression, anxiety, attention-deficit hyperactivity disorder, alcohol dependence, and autism. Conversely, genetic variation with discordant effects only contributes to schizophrenia risk in males and is negatively correlated with those disorders. Mendelian randomization analyses demonstrate a plausible bi-directional causal relationship between LNL-ISO and schizophrenia, with a greater effect of LNL-ISO liability on schizophrenia than vice versa. These results illustrate the genetic footprint of LNL-ISO on schizophrenia., (© 2022. The Author(s).)

Early-onset psychosis disorders are serious mental disorders arising before the age of 18 years. Here, we investigate the largest neuroimaging dataset, to date, of patients with early-onset psychosis and healthy controls for differences in intracranial and subcortical brain volumes. The sample included 263 patients with early-onset psychosis (mean age: 16.4 ± 1.4 years, mean illness duration: 1.5 ± 1.4 years, 39.2% female) and 359 healthy controls (mean age: 15.9 ± 1.7 years, 45.4% female) with magnetic resonance imaging data, pooled from 11 clinical cohorts. Patients were diagnosed with early-onset schizophrenia (n = 183), affective psychosis (n = 39), or other psychotic disorders (n = 41). We used linear mixed-effects models to investigate differences in intracranial and subcortical volumes across the patient sample, diagnostic subgroup and antipsychotic medication, relative to controls. We observed significantly lower intracranial (Cohen's d = -0.39) and hippocampal (d = -0.25) volumes, and higher caudate (d = 0.25) and pallidum (d = 0.24) volumes in patients relative to controls. Intracranial volume was lower in both early-onset schizophrenia (d = -0.34) and affective psychosis (d = -0.42), and early-onset schizophrenia showed lower hippocampal (d = -0.24) and higher pallidum (d = 0.29) volumes. Patients who were currently treated with antipsychotic medication (n = 193) had significantly lower intracranial volume (d = -0.42). The findings demonstrate a similar pattern of brain alterations in early-onset psychosis as previously reported in adult psychosis, but with notably low intracranial volume. The low intracranial volume suggests disrupted neurodevelopment in adolescent early-onset psychosis., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Sex differences in the development and aging of human sulcal morphology have been understudied. We charted sex differences in trajectories and inter-individual variability of global sulcal depth, width, and length, pial surface area, exposed (hull) gyral surface area, unexposed sulcal surface area, cortical thickness, gyral span, and cortex volume across the lifespan in a longitudinal sample (700 scans, 194 participants 2 scans, 104 three scans, age range: 16-70 years) of neurotypical males and females. After adjusting for brain volume, females had thicker cortex and steeper thickness decline until age 40 years; trajectories converged thereafter. Across sexes, sulcal shortening was faster before age 40, while sulcal shallowing and widening were faster thereafter. Although hull area remained stable, sulcal surface area declined and was more strongly associated with sulcal shortening than with sulcal shallowing and widening. Males showed greater variability for cortex volume and lower variability for sulcal width. Our findings highlight the association between loss of sulcal area, notably through sulcal shortening, with cortex volume loss. Studying sex differences in lifespan trajectories may improve knowledge of individual differences in brain development and the pathophysiology of neuropsychiatric conditions., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To study the differences in early-life characteristics between patients with an early onset of psychotic disorders (EOP, aged < 18 years) versus adult onset of psychotic disorders (AOP, aged ≥ 18 years) and to identify predictors of earlier onset., Methods: 278 patients with a first episode of psychosis between the ages of 7 and 35 years were recruited as part of a multicenter prospective longitudinal study conducted in Spain between January 1, 2009, and December 31, 2011, with diagnoses made for AOP using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and for EOP using the Schedule for Affective Disorders and Schizophrenia for School-Aged Children (K-SADS). Early-stage factors such as prenatal, perinatal, and other premorbid factors were registered and compared between EOP and AOP patients. To analyze the association between baseline variables and outcome, univariate and multivariate logistic regression models were used, and the association or odds ratios (ORs) for significant risk factors were calculated., Results: 224 patients with AOP (mean ± SD age = 25.6 ± 5.0 years; 65.6% male) and 54 patients with EOP (16.1 ± 1.7 years; 68.5% male) were included. Univariate analysis revealed significant differences between the groups. Specifically, compared to AOP subjects, EOP patients had more frequent obstetric complications (OCs) ( P  < .001), birth weight < 2.500 g ( P  < .028), a background of any personal psychiatric disorder ( P  < .001), a previous diagnosis of attention-deficit/hyperactivity disorder ( P  = .001), and premorbid IQ < 85 ( P  < .001). In the multivariate model, only OCs (OR = 5.44), personal psychiatric background (OR = 4.05), and IQ < 85 (OR = 3.96) predicted an onset of the first episode of psychosis before age 18 years., Conclusions: Premorbid factors such as OCs, personal psychiatric background, and IQ < 85 could help predict which patients are more likely to have an early onset of psychosis. Awareness of these factors could help clinicians work to prevent the early transition to psychosis in children and adolescents., (© Copyright 2021 Physicians Postgraduate Press, Inc.)

Objective: To examine the relationship between exposure to multiple forms of child abuse and neglect within the family context and peer victimization at school, accounting for the moderator effect of sex and educational level. Methods: Two thousand four hundred fifteen children and adolescents, aged 9 to 15 years, attending public schools in Mexico completed the Childhood Trauma Questionnaire-Short Form and a modified version of the Olweus' Bully/Victim Questionnaire. We used linear regression models to assess the association of five different forms of child abuse (emotional, physical, and sexual abuse, and emotional and physical negligence) with three forms of peer victimization (direct, indirect, and cyberbullying). Results: Direct forms of child abuse within the family (i.e., emotional, physical, and sexual abuse), but not neglect, were significantly and positively associated with a risk for peer victimization. In the fully adjusted models, emotional abuse was significantly associated with the three types of peer victimization: [indirect b = 0.48, t = 6.75, p < 0.001, direct ( b = 0.47, t = 4.89, p < 0.001), and cyberbullying ( b = 0.85, t = 5.45, p < 0. 001)]; while physical abuse was positive and significantly associated with direct victimization ( b = 0.29, t = 3.28, p < 0.001). Boys suffering from sexual abuse within the family context showed higher levels of all subtypes of peer victimization. Students attending secondary school who suffered from sexual abuse showed higher levels of indirect victimization than did students attending primary schools. Conclusion: Child abuse within the family context seems to be associated with the risk of peer victimization. Preventive strategies to address bullying and promote resilience should take family factors into account. Interventions for high-risk families might be useful to prevent child multi-victimization., Competing Interests: CD-C has received grant support from Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (JR19/00024, PI17/00471, PI20/00721), co-financed by ERDF funds from the European Commission, “A way of making Europe”, and honoraria from Sanofi and Exeltis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Martín-Babarro, Toldos, Paredes-Becerra, Abregu-Crespo, Fernández-Sánchez and Díaz-Caneja.)

Background: Little is known about clinical outcomes other than transition to psychosis in people at Clinical High-Risk for psychosis (CHR-P). Our aim was to comprehensively meta-analytically evaluate for the first time a wide range of clinical and functional outcomes beyond transition to psychosis in CHR-P individuals., Methods: PubMed and Web of Science were searched until November 2020 in this PRISMA compliant meta-analysis (PROSPERO:CRD42020206271). Individual longitudinal studies conducted in individuals at CHR-P providing data on at least one of our outcomes of interest were included. We carried out random-effects pairwise meta-analyses, meta-regressions, and assessed publication bias and study quality. Analyses were two-tailed with α=0.05., Findings: 75 prospective studies were included (n=5,288, age=20.0 years, females=44.5%). Attenuated positive symptoms improved at 12 (Hedges' g=0.753, 95%CI=0.495-1.012) and 24 (Hedges' g=0.836, 95%CI=0.463-1.209), but not ≥36 months (Hedges' g=0.315. 95%CI=-0.176-0.806). Negative symptoms improved at 12 (Hedges' g=0.496, 95%CI=0.315-0.678), but not 24 (Hedges' g=0.499, 95%CI=-0.137-1.134) or ≥36 months (Hedges' g=0.033, 95%CI=-0.439-0.505). Depressive symptoms improved at 12 (Hedges' g=0.611, 95%CI=0.441-0.782) and 24 (Hedges' g=0.583, 95%CI=0.364-0.803), but not ≥36 months (Hedges' g=0.512 95%CI=-0.337-1.361). Functioning improved at 12 (Hedges' g=0.711, 95%CI=0.488-0.934), 24 (Hedges' g=0.930, 95%CI=0.553-1.306) and ≥36 months (Hedges' g=0.392, 95%CI=0.117-0.667). Remission from CHR-P status occurred in 33.4% (95%CI=22.6-44.1%) at 12 months, 41.4% (95%CI=32.3-50.5%) at 24 months and 42.4% (95%CI=23.4-61.3%) at ≥36 months. Heterogeneity across the included studies was significant and ranged from I 2 =53.6% to I 2 =96.9%. The quality of the included studies (mean±SD) was 4.6±1.1 (range=2-8)., Interpretation: CHR-P individuals improve on symptomatic and functional outcomes over time, but these improvements are not maintained in the longer term, and less than half fully remit. Prolonged duration of care may be needed for this patient population to optimize outcomes., Funding: None., Competing Interests: Dr Salazar de Pablo has received honoraria from Janssen Cilag and grants from Alicia Koplowitz Foundation. Dr Vaquerizo-serrano has received grants from Alicia Koplowitz Foundation. Dr Moreno has been a consultant to or has received honoraria from Janssen Cilaq, Angelini, Servier, Nuvelution, Otsuka, Lundbeck, Pfizer and Esteve outside the submitted work. Prof Gonzalez-Pinto has received grants from the Spanish Ministry of Science and the European Framework and has been a consultant to or has received honoraria from Janssen-Cilag, Angelini, and Roche, support for attending meetings from Janssen, partecipations n a data advisory board for Jenssen, Takeda and Angelini and is president of the Spanish society of Biological Psichiatry and of the Spanish Foundation of Psichiatry and mental health. Dr Díaz-Caneja has received honoraria from AbbVie, Sanofi, Exeltis and Lundbeck. Dr Solmi has been a consultant to or has received honoraria from Angelini and Lundbeck. Prof Arango has received grants or contracts from Bristol-Myers Squibb, Narsad, Sumitomo Dainipon Pharma and Stanley Foundation. He has been a consultant to or has received honoraria or grants from Acadia, Angelini, AstraZeneca, Bristol-Myers Squibb, Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Stanley Foundation, Takeda and Alicia Koplowitz Foundation. Prof Correll has been receiving grants from Janssen, royalties form UpToDate, consulting fees from Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, and Teva, payment or honoraria for lectures from Angelini, Gedeon Richter, Janssen/J&J, Lundbeck, Mitsubishi Tanabe Pharma, Mylan, Sumitomo Dainippon. Otsuka, Recordati, Sunovion (no speakers bureau), payment for expert testimony from Janssen and Otsuka, participation on a data safety monitoring Board for Lundbeck, Rovi, Supernus, and Teva, leadership or fiduciary role in other boards for ASCP, receipt of equipment from Takeda and is a shareholder of LB Pharma. Prof Fusar-Poli has received research fees from Lundbeck and honoraria from Lundbeck, Angelini and Menarini outside the current study. All the other authors report no conflict of interests., (© 2021 The Authors.)

The extreme variability in symptom presentation reveals that individuals diagnosed with a first-episode psychosis (FEP) may encompass different sub-populations with potentially different illness courses and, hence, different treatment needs. Previous studies have shown that sociodemographic and family environment factors are associated with more unfavorable symptom trajectories. The aim of this study was to examine the dimensional structure of symptoms and to identify individuals' trajectories at early stage of illness and potential risk factors associated with poor outcomes at follow-up in non-affective FEP. One hundred and forty-four non-affective FEP patients were assessed at baseline and at 2-year follow-up. A Principal component analysis has been conducted to identify dimensions, then an unsupervised machine learning technique (fuzzy clustering) was performed to identify clinical subgroups of patients. Six symptom factors were extracted (positive, negative, depressive, anxiety, disorganization and somatic/cognitive). Three distinct clinical clusters were determined at baseline: mild; negative and moderate; and positive and severe symptoms, and five at follow-up: minimal; mild; moderate; negative and depressive; and severe symptoms. Receiving a low-dose antipsychotic, having a more severe depressive symptomatology and a positive family history for psychiatric disorders were risk factors for poor recovery, whilst having a high cognitive reserve and better premorbid adjustment may confer a better prognosis. The current study provided a better understanding of the heterogeneous profile of FEP. Early identification of patients who could likely present poor outcomes may be an initial step for the development of targeted interventions to improve illness trajectories and preserve psychosocial functioning., Competing Interests: Conflict of interest E. Vieta has received research support from or served as consultant, adviser or speaker for AB-Biotics, Actavis, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, Telefónica, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Programme (ENBREC), and the Stanley Medical Research Institute, unrelated to the present work. M. Bernardo has been a consultant for, received grant/research support and honoraria from, and been on the speakers/advisory board of ABBiotics, Adamed, Angelini, Casen Recordati, Janssen-Cilag, Lundbeck, Otsuka, Menarini and Takeda. C. De-la-Camara received financial support to attend scientific meetings from Janssen-Cilag, Almirall, Eli Lilly, Lundbeck, Rovi, Esteve, Novartis, and Astrazeneca M. Gómez-Ramiro reports grants from INSTITUTO CARLOS III, grants from ADAMED, non-financial support from JANSSENCILAG, non-financial support from LUNDBECK-OTSUKA, non-financial support from PFIZER, non-financial support from ANGELINI, outside the submitted work. R. Rodriguez-Jimenez has been a consultant for, spoken in activities of, or received grants from: Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/ BMD-2422 AGES; S2017/BMD-3740), JanssenCilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Casen-Recordati, Angelini. The rest of authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

The links between psychosis and socio-economic disadvantage have been widely studied. No previous study has analysed the interrelationships and mutual influences between functioning dimensions in first episode of psychosis (FEP) according to their neighbourhood household income, using a multidimensional and transdiagnostic perspective. 170 patients and 129 controls, participants in an observational study (AGES-CM), comprised the study sample. The WHO Disability Assessment Schedule (WHODAS 2.0) was used to assess functioning, whereas participants' postcodes were used to obtain the average household income for each neighbourhood, collected by the Spanish National Statistics Institute (INE). Network analyses were conducted with the aim of defining the interrelationships between the different dimensions of functioning according to the neighbourhood household income. Our results show that lower neighbourhood socioeconomic level is associated with lower functioning in patients with FEP. Moreover, our findings suggest that "household responsibilities" plays a central role in the disability of patients who live in low-income neighbourhoods, whereas "dealing with strangers" is the most important node in the network of patients who live in high-income neighbourhoods. These results could help to personalize treatments, by allowing the identification of potential functioning areas to be prioritized in the treatment of FEP according to the patient's neighbourhood characteristics., (Copyright © 2021 Elsevier Ltd. All rights reserved.)