Processing speed mediates the relationship between DDR1 and psychosocial functioning in euthymic patients with bipolar disorder presenting psychotic symptoms.

The DDR1 locus is associated with the diagnosis of schizophrenia and with processing speed in patients with schizophrenia and first-episode psychosis. Here, we investigated whether DDR1 variants are associated with bipolar disorder (BD) features. First, we performed a case‒control association study comparing DDR1 variants between patients with BD and healthy controls. Second, we performed linear regression analyses to assess the associations of DDR1 variants with neurocognitive domains and psychosocial functioning. Third, we conducted a mediation analysis to explore whether neurocognitive impairment mediated the association between DDR1 variants and psychosocial functioning in patients with BD. Finally, we studied the association between DDR1 variants and white matter microstructure. We did not find any statistically significant associations in the case‒control association study; however, we found that the combined genotypes rs1264323AA-rs2267641AC/CC were associated with worse neurocognitive performance in patients with BD with psychotic symptoms. In addition, the combined genotypes rs1264323AA-rs2267641AC/CC were associated with worse psychosocial functioning through processing speed. We did not find correlations between white matter microstructure abnormalities and the neurocognitive domains associated with the combined genotypes rs1264323AA-rs2267641AC/CC. Overall, the results suggest that DDR1 may be a marker of worse neurocognitive performance and psychosocial functioning in patients with BD, specifically those with psychotic symptoms.

Mapping gray and white matter volume abnormalities in early-onset psychosis: an ENIGMA multicenter voxel-based morphometry study.

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.

Antipsychotic drugs in first-episode psychosis: a target trial emulation in the FEP-CAUSAL Collaboration.

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.

Variation of subclinical psychosis across 16 sites in Europe and Brazil: findings from the multi-national EU-GEI study.

BACKGROUND: Incidence of first-episode psychosis (FEP) varies substantially across geographic regions. Phenotypes of subclinical psychosis (SP), such as psychotic-like experiences (PLEs) and schizotypy, present several similarities with psychosis. We aimed to examine whether SP measures varied across different sites and whether this variation was comparable with FEP incidence within the same areas. We further examined contribution of environmental and genetic factors to SP. METHODS: We used data from 1497 controls recruited in 16 different sites across 6 countries. Factor scores for several psychopathological dimensions of schizotypy and PLEs were obtained using multidimensional item response theory models. Variation of these scores was assessed using multi-level regression analysis to estimate individual and between-sites variance adjusting for age, sex, education, migrant, employment and relational status, childhood adversity, and cannabis use. In the final model we added local FEP incidence as a second-level variable. Association with genetic liability was examined separately. RESULTS: Schizotypy showed a large between-sites variation with up to 15% of variance attributable to site-level characteristics. Adding local FEP incidence to the model considerably reduced the between-sites unexplained schizotypy variance. PLEs did not show as much variation. Overall, SP was associated with younger age, migrant, unmarried, unemployed and less educated individuals, cannabis use, and childhood adversity. Both phenotypes were associated with genetic liability to schizophrenia. CONCLUSIONS: Schizotypy showed substantial between-sites variation, being more represented in areas where FEP incidence is higher. This supports the hypothesis that shared contextual factors shape the between-sites variation of psychosis across the spectrum.

Identification and treatment of individuals with childhood-onset and early-onset schizophrenia.

Approximately 8 % of patients with schizophrenia are diagnosed before age 18, and 18 % experience their first symptoms before age 18. This narrative review explores the management of patients with early-onset schizophrenia (EOS) and childhood-onset schizophrenia (COS) from diagnosis to their transition to adult care settings. Early diagnosis of schizophrenia in children and adolescents is essential for improving outcomes, but delays are common due to overlapping of symptoms with developmental phenomena and other psychiatric conditions, including substance use, and lack of clinicians' awareness. Once diagnosed, antipsychotic treatment is key, with specific second-generation agents generally being preferred due to better tolerability and their broader efficacy evidence-base in youth. Dosing should be carefully individualized, considering age-related differences in drug metabolism and side effect liability. Clinicians must be vigilant in detecting early non-response and consider switching or dose escalation when appropriate. Since early age of illness onset is a consistent risk factor for treatment-resistant schizophrenia (TRS), clinicians need to be competent in diagnosing TRS and using clozapine. Since COS and EOS are associated with cognitive deficits and impaired functioning, psychosocial interventions should be considered to improve overall functioning and quality of life. Good long-term outcomes depend on continuous treatment engagement, and successful transitioning from pediatric to adult care requires careful planning, early preparation, and collaboration between pediatric and adult clinicians. Targeting functional outcomes and quality of life in addition to symptom remission can improve overall patient well-being. Comprehensive evaluations, age-specific assessments, and targeted interventions are needed to address the unique challenges of EOS and COS.

Finding the Right Setting for the Right Treatment During the Acute Treatment of Individuals with Schizophrenia: A Narrative Review and Clinical Practice Guideline.

Background: Schizophrenia is most times a chronic and often debilitating illness associated with poor mental health outcomes. Early and effective treatment of schizophrenia in the most appropriate setting can make a significant difference in the long-term recovery. The aim of this narrative review was to provide suggestions and recommendations for effectively managing patients with schizophrenia during acute exacerbations and to enhance awareness and skills related to personalized medicine. Methods: A panel of academics and clinicians with experience in the field of psychosis met virtually on July 13th 2023 to narratively review and discuss the research evidence and their clinical experience about the most appropriate acute treatments for patients with schizophrenia. This manuscript represents a synthesis of the panel analysis and discussion. Results: First contact is very important for service users, as is finding the most adequate treatment setting. If patients present to the emergency department, which may be a traumatic setting for service users, a dedicated environment with adequate space and specialized mental health support, including personnel trained in de-escalation techniques, is recommended. A well-connected continuum of care is strongly recommended, possibly with seamless links between inpatient units, day hospital services, outpatient facilities and rehabilitation services. Ideally, this should be structured as part of a coordinated step-down service line. Treatment challenges include suboptimal response, side effects, and nonadherence, which is reduced by the use of long-acting injectable antipsychotics. Conclusion: Individual circumstances, including age, gender, and presence of hostility/aggression or self-harm, cognitive impairment and negative symptoms, comorbidities (depression, substance use disorders) or associated symptoms (anxiety, insomnia), should be considered when selecting the most appropriate treatment for the acute phase of schizophrenia. Efficacy and feasibility, as well as acceptability and tolerability of treatments, require joint consideration from the early stages of schizophrenia, thereby enhancing the possibility of improved short- and long-term outcomes.

Effect of long-acting antipsychotic treatment on psychiatric hospitalization rate in early psychosis patients: a naturalistic study.

Background: The effectiveness of long-acting injectable (LAI) antipsychotics in preventing relapses of first-episode psychosis is currently debated. Objectives: The study aimed to investigate the number of psychiatric hospitalizations comparing the LAI cohort versus the oral cohort during different phases of the illness, pre-LAI treatment, during LAI treatment, and after LAI treatment. Design: A naturalistic study was conducted on two independent cohorts of early psychosis patients receiving treatment from a specific early intervention service. The first cohort comprised 228 patients who received LAIs, while the second cohort comprised 667 patients who had never received LAIs. Methods: This study was designed as a longitudinal observational study conducted within a naturalistic clinical setting in two cohorts of early psychosis patients. Repeated series ANCOVA (ANCOVA-r) was used to study the number of hospitalizations in the different study periods (T1 = from the date of the first psychiatric record to the beginning of the mirror period; T2 = the mirror period; T3 = from the LAI implementation to the LAI discontinuation; and T4 = from the LAI discontinuation to the end). In all cases, discontinuation of LAI involved the return to oral treatment. In all, 35 patients had not T4 as they were still on LAI treatment at the time of database closing (September 2020), and their data were not included in the analysis of the effect of the LAI discontinuation. Results: The patients in the LAI cohort were younger, more frequently males, presented more schizophrenia diagnoses, and had a higher number of hospitalizations (2.50 ± 2.61 versus 1.19 ± 1.69; p < 0.001) than the oral cohort. The number of hospitalizations at the end of the follow-up was higher in the LAI cohort [0.20 (standard deviation (SD)) = 0.79] versus 0.45 [SD = 0.45 (SD = 1.13); F(23.90), p < 0.001]. However, after the introduction of LAIs, the differences in hospitalization rates between the two cohorts became less pronounced. Once LAI treatment was ceased, the hospitalization rate increased again. Conclusion: In our study, early psychosis patients receiving LAIs experienced a greater decrease in hospitalizations after introducing the LAI treatment than those treated solely with oral medication. These findings support using LAIs as a viable strategy for preventing rehospitalization and improving the overall course of treatment for individuals with early psychosis.

A web-enabled, school-based intervention for bullying prevention (LINKlusive): a cluster randomised trial.

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.

Comorbid physical health burden of serious mental health disorders in 32 European countries.

BACKGROUND: Mental health disorders (MHDs) are associated with physical health disparities, but underlying excess risk and health burden have not yet been comprehensively assessed. OBJECTIVE: To assess the burden of comorbid physical health conditions (PHCs) across serious MHDs in Europe. METHODS: We estimated the relative prevalence risk of PHCs associated with alcohol use disorders (AUD), bipolar disorder (BD), depressive disorders (DD) and schizophrenia (SZ) across working-age populations of 32 European countries in 2019 based on a targeted literature review. Excess physical health burden was modelled using population-attributable fractions and country-level prevalence data. FINDINGS: We screened 10 960 studies, of which 41 were deemed eligible, with a total sample size of over 18 million persons. Relative prevalence of PHCs was reported in 54%, 20%, 15%, 5% and 7% of studies, respectively, for SZ, DD, BD, AUD or mixed. Significant relative risk estimates ranged from 1.44 to 3.66 for BD, from 1.43 to 2.21 for DD, from 0.81 to 1.97 for SZ and 3.31 for AUD. Excess physical health burden ranged between 27% and 67% of the total, corresponding to 84 million (AUD), 67 million (BD), 66 million (DD) and 5 million (SZ) PHC diagnoses in Europe. A 1% reduction in excess risk assuming causal inference could result in two million fewer PHCs across investigated MHDs. CONCLUSIONS: This is the first comprehensive study of the physical health burden of serious MHDs in Europe. The methods allow for updates, refinement and extension to other MHDs or geographical areas. CLINICAL IMPLICATIONS: The results indicate potential population health benefits achievable through more integrated mental and physical healthcare and prevention approaches.

Points to consider when initiating clinical investigations in autistic paediatric populations-A White Paper.

Many individuals with autism spectrum disorder (ASD) experience various degrees of impairment in social interaction and communication, restricted, repetitive behaviours, interests/activities. These impairments make a significant contribution to poorer everyday adaptive functioning. Yet, there are no pharmacological therapies to effectively treat the core symptoms of ASD. Since symptoms of ASD likely emerge from a complex interplay of vulnerabilities, environmental factors and compensatory mechanisms during the early developmental period, pharmacological interventions arguably would have the greatest impact to improve long-term outcomes when implemented at a young age. It is essential therefore, that clinical development programmes of investigational drugs in ASD include the paediatric population early on in clinical trials. Such trials need to offer the prospect of direct benefit (PDB) for participants. In most cases in drug development this prospect is supported by evidence of efficacy in adults. However, the effectiveness of treatment approaches may be age-dependent, so that clinical trials in adults may not provide sufficient evidence for a PDB in children. In this white paper, we consolidate recommendations from regulatory guidelines, as well as advice from the Food and Drug Administration, USA (FDA) and the Committee for Human Medicinal Products (CHMP) consultations on various development programmes on: 1) elements to support a PDB to participants in early paediatric clinical trials in ASD, including single-gene neurodevelopment disorders, 2) aspects of study design to allow for a PDB. This white paper is intended to be complementary to existing regulatory guidelines in guiding industry and academic sponsors in their conduct of early paediatric clinical trials in ASD.

Umbrella Review: Atlas of the Meta-Analytical Evidence of Early-Onset Psychosis.

OBJECTIVE: Early-onset psychosis (EOP) refers to the development of psychosis before the age of 18 years. We aimed to summarize, for the first time, the meta-analytical evidence in the field of this vulnerable population and to provide evidence-based recommendations. METHOD: We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant, pre-registered (PROSPERO: CRD42022350868) systematic review of several databases and registers to identify meta-analyses of studies conducted in EOP individuals to conduct an umbrella review. Literature search, screening, data extraction, and quality assessment were carried out independently. Results were narratively reported, clustered across core domains. Quality assessment was performed with the Assessment of Multiple Systematic Reviews-2 (AMSTAR-2) tool. RESULTS: A total of 30 meta-analyses were included (373 individual studies, 25,983 participants, mean age 15.1 years, 38.3% female). Individuals with EOP showed more cognitive impairments compared with controls and individuals with adult/late-onset psychosis. Abnormalities were observed meta-analytically in neuroimaging markers but not in oxidative stress and inflammatory response markers. In all, 60.1% of EOP individuals had a poor prognosis. Clozapine was the antipsychotic with the highest efficacy for overall, positive, and negative symptoms. Tolerance to medication varied among the evaluated antipsychotics. The risk of discontinuation of antipsychotics for any reason or side effects was low or equal compared to placebo. CONCLUSION: EOP is associated with cognitive impairment, involuntary admissions, and poor prognosis. Antipsychotics can be efficacious in EOP, but tolerability and safety need to be taken into consideration. Clozapine should be considered in EOP individuals who are resistant to 2 non-clozapine antipsychotics. Further meta-analytical research is needed on response to psychological interventions and other prognostic factors. PLAIN LANGUAGE SUMMARY: This umbrella review summarized the meta-analytical knowledge from 30 meta-analyses on early-onset psychosis. Early-onset psychosis refers to the development of psychosis before the age of 18 years and is associated with cognitive impairment, hospitalization, and poor prognosis. Individuals with early-onset psychosis show more cognitive impairments and abnormalities compared with controls. Clozapine was the antipsychotic with the highest efficacy for positive, negative, and overall symptoms and should be considered in individuals with early-onset psychosis. STUDY PREREGISTRATION INFORMATION: Early Onset Psychosis: Umbrella Review on Diagnosis, Prognosis and Treatment factors; https://www.crd.york.ac.uk/PROSPERO/; CRD42022350868.

New functional dissociations between prefrontal and parietal cortex during task switching: A combined fMRI and TMS study.

Preparatory control in task-switching has been suggested to rely upon a set of distributed regions within a frontoparietal network, with frontal and parietal cortical areas cooperating to implement switch-specific preparation processes. Although recent causal evidence using transcranial magnetic stimulation (TMS) have generally supported this model, alternative results from both functional neuroimaging and neurophysiological studies have questioned the switch-specific role of both frontal and parietal cortices. The aim of the present study was to clarify the involvement of prefrontal and parietal areas in preparatory cognitive control. With this purpose, an fMRI study was conducted to identify the brain areas activated during cue events in a task-switching paradigm, indicating whether to switch or to repeat among numerical tasks. Then, TMS was applied over the specific coordinates previously identified through fMRI, that is, the right inferior frontal gyrus (IFG) and right intraparietal sulcus (IPS). Results revealed that TMS over the right IFG disrupted performance in both switch and repeat trails in terms of delayed responses as compared to Sham condition. In contrast, TMS over the right IPS selectively interfered performance in switch trials. These findings support a multi-component model of executive control with the IFG being involved in more general switch-unspecific process such as the episodic retrieval of goals, and the IPS being related to the implementation of switch-specific preparation mechanisms for activating stimulus-response mappings. The results are discussed within the framework of contemporary hierarchical models of prefrontal cortex organization, suggesting that distinct prefrontal areas may carry out coordinated functions in preparatory control.

Duration of Untreated Psychosis and Outcomes in First-Episode Psychosis: Systematic Review and Meta-analysis of Early Detection and Intervention Strategies.

BACKGROUND: The role of duration of untreated psychosis (DUP) as an early detection and intervention target to improve outcomes for individuals with first-episode psychosis is unknown. STUDY DESIGN: PRISMA/MOOSE-compliant systematic review to identify studies until February 1, 2023, with an intervention and a control group, reporting DUP in both groups. Random effects meta-analysis to evaluate (1) differences in DUP in early detection/intervention services vs the control group, (2) the efficacy of early detection strategies regarding eight real-world outcomes at baseline (service entry), and (3) the efficacy of early intervention strategies on ten real-world outcomes at follow-up. We conducted quality assessment, heterogeneity, publication bias, and meta-regression analyses (PROSPERO: CRD42020163640). STUDY RESULTS: From 6229 citations, 33 intervention studies were retrieved. The intervention group achieved a small DUP reduction (Hedges' g = 0.168, 95% CI = 0.055-0.283) vs the control group. The early detection group had better functioning levels (g = 0.281, 95% CI = 0.073-0.488) at baseline. Both groups did not differ regarding total psychopathology, admission rates, quality of life, positive/negative/depressive symptoms, and employment rates (P > .05). Early interventions improved quality of life (g = 0.600, 95% CI = 0.408-0.791), employment rates (g = 0.427, 95% CI = 0.135-0.718), negative symptoms (g = 0.417, 95% CI = 0.153-0.682), relapse rates (g = 0.364, 95% CI = 0.117-0.612), admissions rates (g = 0.335, 95% CI = 0.198-0.468), total psychopathology (g = 0.298, 95% CI = 0.014-0.582), depressive symptoms (g = 0.268, 95% CI = 0.008-0.528), and functioning (g = 0.180, 95% CI = 0.065-0.295) at follow-up but not positive symptoms or remission (P > .05). CONCLUSIONS: Comparing interventions targeting DUP and control groups, the impact of early detection strategies on DUP and other correlates is limited. However, the impact of early intervention was significant regarding relevant outcomes, underscoring the importance of supporting early intervention services worldwide.

School bullying in children and adolescents with neurodevelopmental and psychiatric conditions: a systematic review and meta-analysis.

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 I2 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.

The aperiodic exponent of neural activity varies with vigilance state in mice and men.

Recently the 1/f signal of human electroencephalography has attracted attention, as it could potentially reveal a quantitative measure of neural excitation and inhibition in the brain, that may be relevant in a clinical setting. The purpose of this short article is to show that the 1/f signal depends on the vigilance state of the brain in both humans and mice. Therefore, proper labelling of the EEG signal is important as improper labelling may obscure disease-related changes in the 1/f signal. We demonstrate this by comparing EEG results from a longitudinal study in a genetic mouse model for synaptic dysfunction in schizophrenia and autism spectrum disorders to results from a large European cohort study with schizophrenia and mild Alzheimer's disease patients. The comparison shows when the 1/f is corrected for vigilance state there is a difference between groups, and this effect disappears when vigilance state is not corrected for. In conclusion, more attention should be paid to the vigilance state during analysis of EEG signals regardless of the species.

Shared vulnerability and sex-dependent polygenic burden in psychotic disorders.

Evidence suggests a remarkable shared genetic susceptibility between psychiatric disorders. However, sex-dependent differences have been less studied. We explored the contribution of schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) polygenic scores (PGSs) on the risk for psychotic disorders and whether sex-dependent differences exist (CIBERSAM sample: 1826 patients and 1372 controls). All PGSs were significantly associated with psychosis. Sex-stratified analyses showed that the variance explained in psychotic disorders risk was significantly higher in males than in females for all PGSs. Our results confirm the shared genetic architecture across psychotic disorders and demonstrate sex-dependent differences in the vulnerability to psychotic disorders.

Heterogeneity of morphometric similarity networks in health and schizophrenia.

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.

A naturalistic cohort study of first-episode schizophrenia spectrum disorder: A description of the early phase of illness in the PSYSCAN cohort.

BACKGROUND: We examined the course of illness over a 12-month period in a large, international multi-center cohort of people with a first-episode schizophrenia spectrum disorder (FES) in a naturalistic, prospective study (PSYSCAN). METHOD: Patients with a first episode of schizophrenia, schizoaffective disorder (depressive type) or schizophreniform disorder were recruited at 16 institutions in Europe, Israel and Australia. Participants (N = 304) received clinical treatment as usual throughout the study. RESULTS: The mean age of the cohort was 24.3 years (SD = 5.6), and 67 % were male. At baseline, participants presented with a range of intensities of psychotic symptoms, 80 % were taking antipsychotic medication, 68 % were receiving psychological treatment, with 46.5 % in symptomatic remission. The mean duration of untreated psychosis was 6.2 months (SD = 17.0). After one year, 67 % were in symptomatic remission and 61 % were in functional remission, but 31 % had been readmitted to hospital at some time after baseline. In the cohort as a whole, depressive symptoms remained stable over the follow-up period. In patients with a current depressive episode at baseline, depressive symptoms slightly improved. Alcohol, tobacco and cannabis were the most commonly used substances, with daily users of cannabis ranging between 9 and 11 % throughout the follow-up period. CONCLUSIONS: This study provides valuable insight into the early course of a broad range of clinical and functional aspects of illness in FES patients in routine clinical practice.

Social dysfunction relates to shifts within socioaffective brain systems among Schizophrenia and Alzheimer's disease patients.

Social dysfunction represents one of the most common signs of neuropsychiatric disorders, such as Schizophrenia (SZ) and Alzheimer's disease (AD). Perturbed socioaffective neural processing is crucially implicated in SZ/AD and generally linked to social dysfunction. Yet, transdiagnostic properties of social dysfunction and its neurobiological underpinnings remain unknown. As part of the European PRISM project, we examined whether social dysfunction maps onto shifts within socioaffective brain systems across SZ and AD patients. We probed coupling of social dysfunction with socioaffective neural processing, as indexed by an implicit facial emotional processing fMRI task, across SZ (N = 46), AD (N = 40) and two age-matched healthy control (HC) groups (N = 26 HC-younger and N = 27 HC-older). Behavioural (i.e., social withdrawal, interpersonal dysfunction, diminished prosocial or recreational activity) and subjective (i.e., feelings of loneliness) aspects of social dysfunction were assessed using the Social Functioning Scale and De Jong-Gierveld loneliness questionnaire, respectively. Across SZ/AD/HC participants, more severe behavioural social dysfunction related to hyperactivity within fronto-parieto-limbic brain systems in response to sad emotions (P = 0.0078), along with hypoactivity of these brain systems in response to happy emotions (P = 0.0418). Such relationships were not found for subjective experiences of social dysfunction. These effects were independent of diagnosis, and not confounded by clinical and sociodemographic factors. In conclusion, behavioural aspects of social dysfunction across SZ/AD/HC participants are associated with shifts within fronto-parieto-limbic brain systems. These findings pinpoint altered socioaffective neural processing as a putative marker for social dysfunction, and could aid personalized care initiatives grounded in social behaviour.

PsyCog: A computerised mini battery for assessing cognition in psychosis.

Despite the functional impact of cognitive deficit in people with psychosis, objective cognitive assessment is not typically part of routine clinical care. This is partly due to the length of traditional assessments and the need for a highly trained administrator. Brief, automated computerised assessments could help to address this issue. We present data from an evaluation of PsyCog, a computerised, non-verbal, mini battery of cognitive tests. Healthy Control (HC) (N = 135), Clinical High Risk (CHR) (N = 233), and First Episode Psychosis (FEP) (N = 301) participants from a multi-centre prospective study were assessed at baseline, 6 months, and 12 months. PsyCog was used to assess cognitive performance at baseline and at up to two follow-up timepoints. Mean total testing time was 35.95 min (SD = 2.87). Relative to HCs, effect sizes of performance impairments were medium to large in FEP patients (composite score G = 1.21, subtest range = 0.52-0.88) and small to medium in CHR patients (composite score G = 0.59, subtest range = 0.18-0.49). Site effects were minimal, and test-retest reliability of the PsyCog composite was good (ICC = 0.82-0.89), though some practice effects and differences in data completion between groups were found. The present implementation of PsyCog shows it to be a useful tool for assessing cognitive function in people with psychosis. Computerised cognitive assessments have the potential to facilitate the evaluation of cognition in psychosis in both research and in clinical care, though caution should still be taken in terms of implementation and study design.