Psychosis Endophenotypes: A Gene-Set-Specific Polygenic Risk Score Analysis.

BACKGROUND AND HYPOTHESIS: Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes. STUDY DESIGN: We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score. STUDY RESULTS: After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 µV; 95% CI: -1.70 to -0.59 µV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores. CONCLUSIONS: Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models.

Difference between forensic patients with schizophrenia spectrum disorders in Italy and other European countries: Results of the EU-VIORMED project.

BACKGROUND: There has been a substantial change in the law on the provision of secure health services for offender-patients in Italy, a country currently with the lowest general psychiatry bed availability per head of the population in Europe, raising questions about possible differences in offender-patient admissions between European countries. AIMS: In this multicentre case-control study, our aim was to compare the socio-demographic, clinical and criminological characteristics of a sample of Italian forensic in-patients with schizophrenia or similar psychosis with patients in a similar diagnostic range in specialist in-patient services elsewhere in Europe. METHODS: Secure hospital unit in-patients with psychosis were recruited across five European countries (Italy, Austria, Germany, Poland and England). Consenting patients were interviewed by researchers and assessed using a multidimensional standardised process. Within country similarities between Austria, Germany, Poland and England were confirmed. RESULTS: Overall, 39 Italian participants had had fewer years of education than the 182 patients in the other countries and were less likely to have ever had skilled or professional employment. The Italian patients had been older at first contact with any mental health services than the other Europeans. Diagnosed comorbidity rates were similar, but the Italian group reported higher levels of disability. Although the other European forensic patients were more likely to be undergoing treatment at the time of their index offence, they were also more likely to have been poorly compliant with treatment. The rate of suicide-related behaviours was significantly lower among the Italian patients than among the others. CONCLUSIONS: Notwithstanding similar diagnoses, important differences emerged between patients in Italian forensic mental health resident services and those in four other European countries, some possibly reflecting less access to earlier relevant services in Italy. Others, including lower disability ratings among the Italian patients and a lower rate of suicide-related behaviours, may indicate that the Italian reforms carry benefits. This is worthy of further evaluation.

RISK aversion in Italian forensic and non-forensic patients with schizophrenia spectrum disorders.

BACKGROUND: Goal-directed decision-making is a central component of the broader reward and motivation system, and requires the ability to dynamically integrate both positive and negative feedback from the environment in order to maximize rewards and minimize losses over time. Altered decision-making processes, in which individuals fail to consider the negative consequences of their decisions on both themselves and others, may play a role in driving antisocial behaviour. AIM: The main study aim was to investigate possible differences in loss and risk aversion across matched patients, all with a schizophrenia spectrum disorder (SSD), but who varied according to whether they had a history of serious interpersonal violence or not, and a sample of healthy controls with no history of violence. RESULTS: The sample included 14 forensic and 21 non-forensic patients with SSD, and 41 healthy controls. Among the three decision-making variables under investigation, risk aversion was the only significant predictor of membership of the three groups, with greater risk aversion among non-forensic patients with SSD compared to healthy controls. No differences were observed across groups in loss aversion and choice consistency. CONCLUSIONS: This evidence suggests a new potential treatment target for rehabilitative measures aimed at achieving functional improvements in patients with SSD by selectively leveraging the neuro-cognitive processing of reward.

Exposure to violence in childhood and risk of violence in adult schizophrenia: Results from a multinational study.

This study investigated the connection between childhood violence exposure and violent behavior in adults with schizophrenia spectrum disorders (SSDs). The case-control study included 398 SSD patients: 221 cases with a history of severe interpersonal violence in the past and 177 controls with no history of violence. The findings indicated that cases were significantly more likely to report childhood exposure to all forms of witnessed or personally sustained violence both within and outside the family, with those who had witnessed intra-familial violence being more likely to assault a family member in adulthood. Cases reported exposure to violence before the age of 12 years significantly more frequently than controls, and those with early-life violence exposure were significantly more likely to report that they were in a state of intense anger when they behaved violently. A dose-response relationship was observed, with evidence of an increased risk of later violence when the exposure occurred before the age of 12 and an increased likelihood of intrafamilial violence. The evidence suggests that childhood violence exposure was associated with an increased risk of violent behavior in adult SSD patients, and early exposure was linked to an increased likelihood of physical violence occurring in states of intense anger.

A multinational case-control study comparing forensic and non-forensic patients with schizophrenia spectrum disorders: the EU-VIORMED project.

BACKGROUND: The relationship between schizophrenia and violence is complex. The aim of this multicentre case-control study was to examine and compare the characteristics of a group of forensic psychiatric patients with a schizophrenia spectrum disorders and a history of significant interpersonal violence to a group of patients with the same diagnosis but no lifetime history of interpersonal violence. METHOD: Overall, 398 patients (221 forensic and 177 non-forensic patients) were recruited across five European Countries (Italy, Germany, Poland, Austria and the United Kingdom) and assessed using a multidimensional standardised process. RESULTS: The most common primary diagnosis in both groups was schizophrenia (76.4%), but forensic patients more often met criteria for a comorbid personality disorder, almost always antisocial personality disorder (49.1 v. 0%). The forensic patients reported lower levels of disability and better social functioning. Forensic patients were more likely to have been exposed to severe violence in childhood. Education was a protective factor against future violence as well as higher levels of disability, lower social functioning and poorer performances in cognitive processing speed tasks, perhaps as proxy markers of the negative syndrome of schizophrenia. Forensic patients were typically already known to services and in treatment at the time of their index offence, but often poorly compliant. CONCLUSIONS: This study highlights the need for general services to stratify patients under their care for established violence risk factors, to monitor patients for poor compliance and to intervene promptly in order to prevent severe violent incidents in the most clinically vulnerable.

The clinical effectiveness and cost effectiveness of clozapine for inpatients with severe borderline personality disorder (CALMED study): a randomised placebo-controlled trial.

Background: Data from case series suggest that clozapine may benefit inpatients with borderline personality disorder (BPD), but randomised trials have not been conducted. Methods: Multicentre, double-blind, placebo-controlled trial. We aimed to recruit 222 inpatients with severe BPD aged 18 or over, who had failed to respond to other antipsychotic medications. We randomly allocated participants on a 1:1 ratio to receive up to 400 mg of clozapine per day or an inert placebo using a remote web-based randomisation service. The primary outcome was total score on the Zanarini Rating scale for Borderline Personality Disorder (ZAN-BPD) at 6 months. Secondary outcomes included self-harm, aggression, resource use and costs, side effects and adverse events. We used a modified intention to treat analysis (mITT) restricted to those who took one or more dose of trial medication, using a general linear model fitted at 6 months adjusted for baseline score, allocation group and site. Results: The study closed early due to poor recruitment and the impact of the COVID-19 pandemic. Of 29 study participants, 24 (83%) were followed up at 6 months, of whom 21 (72%) were included in the mITT analysis. At 6 months, 11 (73%) participants assigned to clozapine and 6 (43%) of those assigned to placebo were still taking trial medication. Adjusted difference in mean total ZAN-BPD score at 6 months was -3.86 (95% Confidence Intervals = -10.04 to 2.32). There were 14 serious adverse events; 6 in the clozapine arm and 8 in the placebo arm of the trial. There was little difference in the cost of care between groups. Interpretation: We recruited insufficient participants to test the primary hypothesis. The study findings highlight problems in conducting placebo-controlled trials of clozapine and in using clozapine for people with BPD, outside specialist inpatient mental health units. Trial registration: ISRCTN18352058. https://doi.org/10.1186/ISRCTN18352058.

Decision-making and risk-taking in forensic and non-forensic patients with schizophrenia spectrum disorders: A multicenter European study.

Studies of patients with schizophrenia and offenders with severe mental disorders decision-making performance have produced mixed findings. In addition, most earlier studies have assessed decision-making skills in offenders or people with mental disorders, separately, thus neglecting the possible additional contribution of a mental disorder on choice patterns in people who offend. This study aimed to fill this gap by comparing risk-taking in patients with schizophrenia spectrum disorders (SSD), with and without a history of serious violent offending assessing whether, and to what extent, risk-taking represents a significant predictor of group membership, controlling for their executive skills, as well as for socio-demographic and clinical characteristics. Overall, 115 patients with a primary diagnosis of SSD were recruited: 74 were forensic patients with a lifetime history of severe interpersonal violence and 41 were patients with SSD without such a history. No significant group differences were observed on psychopathological symptoms severity. Forensic generally displayed lower scores than non-forensic patients in all cognitive subtests of the Brief Assessment of Cognition in Schizophrenia (except for the "token motor" and the "digit sequencing" tasks) and on all the six dimensions of the Cambridge Gambling Task, except for "Deliberation time", in which forensic scored higher than non-forensic patients. "Deliberation time" was also positively, although weakly correlated with "poor impulse control". Identifying those facets of impaired decision-making mostly predicting offenders' behaviour among individuals with mental disorder might inform risk assessment and be targeted in treatment and rehabilitation protocols.

Neurocognition and social cognition in patients with schizophrenia spectrum disorders with and without a history of violence: results of a multinational European study.

OBJECTIVE: Neurocognitive impairment has been extensively studied in people with schizophrenia spectrum disorders and seems to be one of the major determinants of functional outcome in this clinical population. Data exploring the link between neuropsychological deficits and the risk of violence in schizophrenia has been more inconsistent. In this study, we analyse the differential predictive potential of neurocognition and social cognition to discriminate patients with schizophrenia spectrum disorders with and without a history of severe violence. METHODS: Overall, 398 (221 cases and 177 controls) patients were recruited in forensic and general psychiatric settings across five European countries and assessed using a standardized battery. RESULTS: Education and processing speed were the strongest discriminators between forensic and non-forensic patients, followed by emotion recognition. In particular, increased accuracy for anger recognition was the most distinctive feature of the forensic group. CONCLUSIONS: These results may have important clinical implications, suggesting potential enhancements of the assessment and treatment of patients with schizophrenia spectrum disorders with a history of violence, who may benefit from consideration of socio-cognitive skills commonly neglected in ordinary clinical practice.

A Systematic Review of Non-pharmacological Strategies to Reduce the Risk of Violence in Patients With Schizophrenia Spectrum Disorders in Forensic Settings.

Background: The purpose of this systematic review is to systematically investigate which non-pharmacological interventions are effective in reducing violence risk among patients with schizophrenia spectrum disorders (SSD) in forensic settings. Methods: Six electronic data bases were searched. Two researchers independently screened 6,003 abstracts resulting in 143 potential papers. These were analyzed in detail by two independent researchers yielding 10 articles that could be used. Results: Of the 10 articles, four were non-randomized controlled trials, three were pre-post studies without controls, and one was observational. Only two studies applied a randomized controlled trial design. Cognitive behavioral treatment programs were investigated in three studies. A broad range of other interventions were studied. Often outcome measures were specific to each study and sample sizes were small. Frequently, important methodological information was missing from the papers. It was not possible to carry out a meta-analysis due to the heterogeneity of the study designs and outcome measures. Conclusion: Because of methodological limitations it is difficult to draw firm conclusions about the effectiveness of non-pharmacological interventions to reduce the risk of violence in patents with SSD in forensic psychiatry settings. Studies applying better methods in terms of study design, sample sizes and outcome measures are urgently needed.

Pharmacological interventions to reduce violence in patients with schizophrenia in forensic psychiatry.

BACKGROUND: The purpose was to systematically investigate which pharmacological strategies are effective to reduce the risk of violence among patients with Schizophrenia Spectrum Disorders (SSD) in forensic settings. METHODS: For this systematic review six electronic data bases were searched. Two researchers independently screened the 6,003 abstracts resulting in 143 potential papers. These were then analyzed in detail by two independent researchers. Of these, 133 were excluded for various reasons leaving 10 articles in the present review. RESULTS: Of the 10 articles included, five were merely observational, and three were pre-post studies without controls. One study applied a matched case-control design and one was a non-randomized controlled trial. Clozapine was investigated most frequently, followed by olanzapine and risperidone. Often, outcome measures were specific to the study and sample sizes were small. Frequently, relevant methodological information was missing. Due to heterogeneous study designs and outcomes meta-analytic methods could not be applied. CONCLUSION: Due to substantial methodological limitations it is difficult to draw any firm conclusions about the most effective pharmacological strategies to reduce the risk of violence in patents with SSD in forensic psychiatry settings. Studies applying more rigorous methods regarding case-definition, outcome measures, sample sizes, and study designs are urgently needed.

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

Facial emotion recognition in people with schizophrenia and a history of violence: a mediation analysis.

Evidence for an association between impaired facial emotion recognition and violence in people with schizophrenia is inconclusive. In particular, the role of misidentification patterns involving specific emotions such as anger and the influence of clinical characteristics on this association remain unclear. In this study, we compared facial emotion recognition performance in age- and gender-matched schizophrenia spectrum disorders subjects with (N = 52) and without (N = 52) a history of violence. Data on current symptom severity, Cluster B personality status, past victimization, and alcohol and substance misuse were also collected. Compared to those without, subjects with a history of violence showed worse facial emotion recognition performances, involving anger, fear, disgust, sadness, and happiness. When formally testing the reporting of angry faces, evidence of enhanced sensitivity to anger was not supported. Finally, when the impact of current symptoms was assessed, higher severity of activation symptoms, including motor hyperactivity, elevated mood, excitement and distractibility, mediated the relationship between history of violence and poor facial emotion recognition performance. As a whole, our findings seem to support the role of perceptual deficits involving different emotions as well as of a mediation played by activation symptoms. Facial emotion recognition deficits associated with the propensity to violence, as well certain symptoms mediating their relationship, should be targeted by specific treatment approaches.

European violence risk and mental disorders (EU-VIORMED): a multi-centre prospective cohort study protocol.

BACKGROUND: The link between schizophrenia spectrum disorders (SSD) and violence is a core issue for most forensic psychiatric services. However, the drivers of violence in this population remain unclear, and, to date tools to predict violence risk have a range of limitations. Perhaps because of this uncertainty about the nature of violence risk, treatment programmes and care pathways for mentally disordered offenders vary substantially across the European Union, and differences in legal and policy frameworks are highly relevant. METHODS: The three-year EU-VIORMED project (Grant Number PP-2-3-2016, November 2017-October 2020) involves forensic centres in Italy, Austria, Germany, Poland, and the U.K. It aims to: (a) identify and compare violence risk factors, clinical needs, and decision making capacity in violent (N = 200, "cases") and nonviolent patients with SSD (N = 200; "controls") using a case-control design; (b) test the predictive validity of the HCR-20v3, OxMIS and FoVOx among cases alone (N = 200), using a prospective cohort study; and (c) compare forensic-psychiatric care pathways across the EU, in a continent wide service mapping study. DISCUSSION: Data collection started in September 2018 and continues. By September 2019, 333 participants have been enrolled (201 cases and 132 controls were recruited). Experts from 23 countries provided data for the service mapping exercise. TRIAL REGISTRATION: Retrospectively registered on January 2, 2019 as researchregistry4604 January 2, 2019.

The effect of psychosis associated CACNA1C, and its epistasis with ZNF804A, on brain function.

CACNA1C-rs1006737 and ZNF804A-rs1344706 polymorphisms are among the most robustly associated with schizophrenia (SCZ) and bipolar disorder (BD), and recently with brain phenotypes. As these patients show abnormal verbal fluency (VF) and related brain activation, we asked whether the latter was affected by these polymorphisms (alone and in interaction)-to better understand how they might induce risk. We recently reported effects on functional VF-related (for ZNF804A-rs1344706) and structural (for both) connectivity. We genotyped and fMRI-scanned 54 SCZ, 40 BD and 80 controls during VF. With SPM, we assessed the main effect of CACNA1C-rs1006737, and its interaction with ZNF804A-rs1344706, and their interaction with diagnosis, on regional brain activation and functional connectivity (psychophysiological interactions-PPI). Using public data, we reported effects of CACNA1C-rs1006737 and diagnosis on brain expression. The CACNA1C-rs1006737 risk allele was associated with increased activation, particularly in the bilateral prefronto-temporal cortex and thalamus; decreased PPI, especially in the left temporal cortex; and gene expression in white matter and the cerebellum. We also found unprecedented evidence for epistasis (interaction between genetic polymorphisms) in the caudate nucleus, thalamus, and cingulate and temporal cortical activation; and CACNA1C up-regulation in SCZ and BD parietal cortices. Some effects were dependent on BD/SCZ diagnosis. All imaging results were whole-brain, voxel-wise, and familywise-error corrected. Our results support evidence implicating CACNA1C and ZNF804A in BD and SCZ, adding novel imaging evidence in clinical populations, and of epistasis-which needs further replication. Further scrutiny of the inherent neurobiological mechanisms may disclose their potential as putative drug targets.

Use of schizophrenia and bipolar disorder polygenic risk scores to identify psychotic disorders.

BACKGROUND: There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.AimsTo investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls. METHOD: Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls. RESULTS: Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest. CONCLUSIONS: Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.Declaration of interestR.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.

Schizophrenia moderates the relationship between white matter integrity and cognition.

Cognitive impairment is a primary feature of schizophrenia, with alterations in several cognitive domains appearing in the pre-morbid phase of the disorder. White matter microstructure is also affected in schizophrenia and considered to be related to cognition, but the relationship of the two is unclear. As interaction between cognition and white matter structure involves the interplay of several brain structures and cognitive abilities, investigative methods which can examine the interaction of multiple variables are preferred. A multiple-groups structural equation model (SEM) was used to assess the relationship between diffusion tension imaging data (fractional anisotropy of selected white matter tracts) and cognitive abilities of 196 subjects - 135 healthy subjects and 61 patients with schizophrenia. It was found that multiple-indicators, multiple-causes model best fitted the data analysed. Schizophrenia moderated the relation of white matter function on cognition with a large effect size. This paper extends previous work on modelling intelligence within a SEM framework by incorporating neurological elements into the model, and shows that white matter microstructure in patients with schizophrenia interacts with cognitive abilities.

A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains.

This large multi-center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi-modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first-degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event-related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis.

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project.

BACKGROUND: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. METHODS: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. RESULTS: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10-10). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. CONCLUSIONS: The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia.

Predictive validity of the Short-Term Assessment of Risk and Treatability (START) for multiple adverse outcomes: The effect of diagnosis.

The Short-Term Assessment of Risk and Treatability (START) assists risk assessment for seven risk outcomes based on scoring of risk and protective factors and assignment of clinically-informed risk levels. Its predictive validity for violence and self-harm has been established in males with schizophrenia, but accuracy across pathologically diverse samples is unknown. Routine START assessments and 3-month risk outcome data of N = 527 adult, inpatients in a UK secure mental health facility were collected. The sample was divided into diagnostic groups; predictive validity was established using receiver operating characteristics regression (rocreg) analysis in which potential covariates were controlled. In most single-diagnosis groups START risk factors ('vulnerabilities'), protective factors ('strengths'), and clinically-informed estimates predicted multiple risk outcomes with effect sizes similar to previous research. Self-harm was not predicted among patients with an organic diagnosis. The START risk estimates predicted physical aggression in all diagnostic groups, and verbal aggression, self-harm and self-neglect in most diagnostic groups. The START can assist assessment of aggressive, self-harm, and self-neglect across a range of diagnostic groups. Further research with larger sample sizes of those with multiple diagnoses is required.

White matter deficits in schizophrenia are global and don't progress with age.

INTRODUCTION: Diffusion tensor imaging has revealed differences in all examined white matter tracts in schizophrenia, with a range of explanations for why this may be. The distribution and timing of differences may help explain their origin; however, results are usually dependent on the analytical method. We therefore sought to examine the extent of differences and their relationship with age using two different methods. METHODS: A combined voxel-based whole-brain study and a tract-based spatial-statistics study of 104 patients with schizophrenia and 200 matched healthy controls, aged between 17 and 63 years. RESULTS: Fractional anisotropy was reduced throughout the brain in both analyses. The relationship of fractional anisotropy with age differed between patients and controls, with controls showing the gentle fractional anisotropy decline widely noted but patients showing an essentially flat relationship: younger patients had lower fractional anisotropy than controls, but the difference disappeared with age. Mean diffusivity was widely increased in patients. CONCLUSION: Reduction in fractional anisotropy and increase in mean diffusivity would be consistent with global disruption in myelination; the relationship with age would suggest this is present already at the onset of their illness, but does not progress.