Tobacco use in first-episode psychosis, a multinational EU-GEI study.

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 (ß = -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.

Development and psychometric properties of the "Suicidality: Treatment Occurring in Paediatrics (STOP) Risk and Resilience Factors Scales" in adolescents.

Suicidality in the child and adolescent population is a major public health concern. There is, however, a lack of developmentally sensitive valid and reliable instruments that can capture data on risk, and clinical and psychosocial mediators of suicidality in young people. In this study, we aimed to develop and assess the validity of instruments evaluating the psychosocial risk and protective factors for suicidal behaviours in the adolescent population. In Phase 1, based on a systematic literature review of suicidality, focus groups, and expert panel advice, the risk factors and protective factors (resilience factors) were identified and the adolescent, parent, and clinician versions of the STOP-Suicidality Risk Factors Scale (STOP-SRiFS) and the Resilience Factors Scale (STOP-SReFS) were developed. Phase 2 involved instrument validation and comprised of two samples (Sample 1 and 2). Sample 1 consisted of 87 adolescents, their parents/carers, and clinicians from the various participating centres, and Sample 2 consisted of three sub-samples: adolescents (n = 259) who completed STOP-SRiFS and/or the STOP-SReFS scales, parents (n = 213) who completed one or both of the scales, and the clinicians who completed the scales (n = 254). The STOP-SRiFS demonstrated a good construct validity-the Cronbach Alpha for the adolescent (α = 0.864), parent (α = 0.842), and clinician (α = 0.722) versions of the scale. Test-retest reliability, inter-rater reliability, and content validity were good for all three versions of the STOP-SRiFS. The sub-scales generated using Exploratory Factor Analysis (EFA) were the (1) anxiety and depression risk, (2) substance misuse risk, (3) interpersonal risk, (4) chronic risk, and (5) risk due to life events. For the STOP-SRiFS, statistically significant correlations were found between the Columbia-Suicide Severity Rating Scale (C-SSRS) total score and the adolescent, parent, and clinical versions of the STOP-SRiFS sub-scale scores. The STOP-SRiFS showed good psychometric properties. This study demonstrated a good construct validity for the STOP-SReFS-the Cronbach Alpha for the three versions were good (adolescent: α = 0.775; parent: α = 0.808; α = clinician: 0.808). EFA for the adolescent version of the STOP-SReFS, which consists of 9 resilience factors domains, generated two factors (1) interpersonal resilience and (2) cognitive resilience. The STOP-SReFS Cognitive Resilience sub-scale for the adolescent was negatively correlated (r = - 0.275) with the C-SSRS total score, showing that there was lower suicidality in those with greater Cognitive Resilience. The STOP-SReFS Interpersonal resilience sub-scale correlations were all negative, but none of them were significantly different to the C-SSRS total scores for either the adolescent, parent, or clinician versions of the scales. This is not surprising, because the items in this sub-scale capture a much larger time-scale, compared to the C-SSRS rating period. The STOP-SReFS showed good psychometric properties. The STOP-SRiFS and STOP-SReFS are instruments that can be used in future studies about suicidality in children and adolescents.

Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Duration of untreated psychosis and neurocognitive functioning in first-episode psychosis: a systematic review and meta-analysis.

BACKGROUND: Previous reviews suggest there is minimal evidence for an association between duration of untreated psychosis (DUP) and neurocognition. This is based on tallied findings of studies with small samples and neurocognition viewed as a single construct. We aimed to conduct a systematic review and meta-analysis examining the association between DUP and individual neurocognitive domains and tests in first-episode psychosis (FEP). METHOD: MOOSE and PRISMA guidelines were followed. Forty-three studies involving 4647 FEP patients were included. For studies providing correlations between DUP and neurocognition, 12 separate meta-analyses were performed based on neurocognitive domains/indices. The influence of demographic/clinical variables was tested using weighted linear meta-regression analyses. RESULTS: The relationship between DUP and most neurocognitive domains/indices was not significant. Longer DUP was associated with a larger cognitive deterioration index, i.e. current minus premorbid intellectual functioning (N = 4; mean ES -0.213, 95% confidence interval (CI) (-0.344 to -0.074), p = 0.003). Findings were homogeneous, with no evidence of publication bias or significant influence from moderators. For studies providing mean and standard deviations for neurocognitive measures and DUP, 20 meta-regressions were performed on individual neurocognitive tests. One significant finding emerged showing that longer DUP was associated with fewer Wisconsin Card Sorting Test-perseverative errors (mean ES -0.031, 95% CI (-0.048 to -0.013), p < 0.001). Exploratory meta-regressions in studies with mean DUP <360 days showed longer DUP was significantly associated with poorer performance on Trail Making Test A and B and higher Full-Scale IQ. CONCLUSION: There may not be a generalised association between DUP and neurocognition, however, specific cognitive functions may be associated with longer DUP or delayed help-seeking.

Mental disorders of known aetiology and precision medicine in psychiatry: a promising but neglected alliance.

Personalized or precision medicine is predicated on the assumption that the average response to treatment is not necessarily representative of the response of each individual. A commitment to personalized medicine demands an effort to bring evidence-based medicine and personalized medicine closer together. The use of relatively homogeneous groups, defined using a priori criteria, may constitute a promising initial step for developing more accurate risk-prediction models with which to advance the development of personalized evidence-based medicine approaches to heterogeneous syndromes such as schizophrenia. However, this can lead to a paradoxical situation in the field of psychiatry. Since there has been a tendency to loosely define psychiatric disorders as ones without a known aetiology, the discovery of an aetiology for psychiatric syndromes (e.g. 22q11.2 deletion syndrome in some cases of schizophrenia), while offering a path toward more precise treatments, may also lead to their reclassification away from psychiatry. We contend that psychiatric disorders with a known aetiology should not be removed from the field of psychiatry. This knowledge should be used instead to guide treatment, inasmuch as psychotherapies, pharmacotherapies and other treatments can all be valid approaches to mental disorders. The translation of the personalized clinical approach inherent to psychiatry into evidence-based precision medicine can lead to the development of novel treatment options for mental disorders and improve outcomes.

Services for people at high risk improve outcomes in patients with first episode psychosis.

OBJECTIVE: About one-third of patients referred to services for people at high risk for psychosis may have already developed a first episode of psychosis (FEP). We compared clinical outcomes in FEP patients who presented to either high risk or conventional mental health services. METHOD: Retrospective study comparing duration of hospital admission, referral-to-diagnosis time, need for compulsory hospital admission and frequency of admission in patients with FEP who initially presented to a high-risk service (n = 164) to patients with FEP who initially presented to conventional mental health services (n = 2779). Regression models were performed, controlling for several confounders. RESULTS: FEP patients who had presented to a high-risk service spent 17 fewer days in hospital [95% CI: -33.7 to (-0.3)], had a shorter referral-to-diagnosis time [B coefficient -74.5 days, 95% CI: -101.9 to -(47.1)], a lower frequency of admission [IRR: 0.49 (95% CI: 0.39-0.61)] and a lower likelihood of compulsory admission [OR: 0.52 (95% CI: 0.34-0.81)] in the 24 months following referral, as compared to FEP patients who were first diagnosed at conventional services. CONCLUSION: Services for people at high risk for psychosis are associated with better clinical outcomes in patients who are already psychotic.

Spatial Dynamic Subspaces Encode Sex-Specific Schizophrenia Disruptions in Transient Network Overlap and its Links to Genetic Risk.

Background: Recent advances in resting-state fMRI allow us to study spatial dynamics, the phenomenon of brain networks spatially evolving over time. However, most dynamic studies still use subject-specific, spatially-static nodes. As recent studies have demonstrated, incorporating time-resolved spatial properties is crucial for precise functional connectivity estimation and gaining unique insights into brain function. Nevertheless, estimating time-resolved networks poses challenges due to the low signal-to-noise ratio, limited information in short time segments, and uncertain identification of corresponding networks within and between subjects. Methods: We adapt a reference-informed network estimation technique to capture time-resolved spatial networks and their dynamic spatial integration and segregation. We focus on time-resolved spatial functional network connectivity (spFNC), an estimate of network spatial coupling, to study sex-specific alterations in schizophrenia and their links to multi-factorial genomic data. Results: Our findings are consistent with the dysconnectivity and neurodevelopment hypotheses and align 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 spFNC exhibits sex-specific schizophrenia alteration during the state with the highest global network integration and correlates with genetic risk for schizophrenia. This dysfunction is also reflected in high-dimensional (voxel-level) space in regions with weak functional connectivity to corresponding networks. Conclusions: Our method can effectively capture spatially dynamic networks, detect nuanced SZ effects, and reveal the intricate relationship of dynamic information to genomic data. The results also underscore the potential of dynamic spatial dependence and weak connectivity in the clinical landscape.

A white paper on a neurodevelopmental framework for drug discovery in autism and other neurodevelopmental disorders.

In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the 'New Frontiers Meeting' on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies.

Social Cognition in Autism and Schizophrenia Spectrum Disorders: The Same but Different?

Social cognition impairment is a core shared phenotype in both schizophrenia spectrum disorders (SSD) and autism spectrum disorders (ASD). This study compares social cognition performance through four different instruments in a sample of 147 individuals with ASD or SSD and in healthy controls. We found that both clinical groups perform similarly to each other and worse than healthy controls in all social cognition tasks. Only performance on the Movie for the Assessment of Social Cognition (MASC) test was independent of age and intelligence. Proportionately, individuals in the control group made significantly more overmentalization errors than both patients group did and made fewer undermentalization errors than patients with SSD did. AUC analyses showed that the MASC was the instrument that best discriminated between the clinical and control groups. Multivariate analysis showed negative symptom severity as a potential mediator of the association between social cognition deficit and poor global functioning.

Neuropsychological development in the child and adolescent offspring of patients diagnosed with schizophrenia or bipolar disorder: A two-year follow-up comparative study.

There has been growing scientific evidence in recent years that schizophrenia and bipolar disorder share clinical, cognitive, neuroimaging and genetic characteristics. This overlap might also be present in their offspring, who have an increased risk of developing both disorders. Comparing the characteristics of these samples may have important implications for understanding etiological processes. This study aimed to assess the development of cognitive functions over two years in a sample of child and adolescent offspring of patients diagnosed with schizophrenia (SZoff) or bipolar disorder (BDoff), comparing them with a community control group (CCoff). METHODS: 90 BDoff, 41 SZoff and 107 CCoff aged between 6 and 17 years were included at baseline. At the two-year follow-up, 84.9% of the sample was re-assessed (78 BDoff, 32 SZoff and 92 CCoff). All subjects were assessed with a comprehensive neuropsychological test battery at baseline and at the two-year follow-up to evaluate: intelligence quotient, working memory, processing speed, verbal memory and learning, visual memory, executive functions and sustained attention. RESULTS: Processing speed, verbal memory and executive functions showed different developmental patterns among the SZoff, BDoff and CCoff groups. The SZoff group maintained baseline performances in the three variables over time, while the BDoff group presented improved processing speed and executive functioning and the CCoff group showed improvements in verbal memory and executive functions at follow-up. CONCLUSIONS: These findings suggest that the development of some cognitive functions might differ between child and adolescent SZoff and BDoff, indicating different trajectories during neurodevelopment.

Adherence, insight and disability in paranoid schizophrenia.

Insight has long been linked to both prognosis and functioning in patients with schizophrenia; likewise, it is key to treatment adherence. This study seeks to assess the association between insight, adherence to pharmacological treatment, and disability in schizophrenia, and to study the potential mediating role of adherence between insight and disability. Insight (SUMD), adherence (CRS), and disability (WHO-DAS) were measured in 80 clinically stable patients with DSM-IV TR paranoid schizophrenia. Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS). In a first step, predictors of disability were identified using linear regression to identify variables related to disability and further a mediation analysis was carried out. Negative symptoms, insight, and adherence account for 54.2% of the variance in disability. Negative symptoms act directly on disability, while the effect of insight on disability is partially mediated by adherence. Insight is key in disability in schizophrenia and should be leveraged in treatment programs.