Clinical High Risk For Psychosis Individuals Research Articles

Effects of diazepam on hippocampal blood flow in people at clinical high risk for psychosis.

Elevated hippocampal perfusion has been observed in people at clinical highrisk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medicine study examined whether diazepam can normalize hippocampal perfusion in CHR-P individuals. Using a randomized, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with magnetic resonance imaging (MRI) on two occasions, once following a single oral dose of diazepam (5 mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labeling and sampled in native space using participant-specific hippocampus and subfield masks (CA1, subiculum, CA4/dentate gyrus). Twenty-two healthy controls (HC) were scanned using the same MRI acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield. Under the placebo condition, CHR-P individuals (mean [±SD] age: 24.1 [±4.8] years, 15 F) showed significantly elevated rCBF compared to HC (mean [±SD] age: 26.5 [±5.1] years, 11 F) in the hippocampus (F(1,41) = 24.7, pFDR < 0.001) and across its subfields (all pFDR < 0.001). Following diazepam, rCBF in the hippocampus (and subfields, all pFDR < 0.001) was significantly reduced (t(69) = -5.1, pFDR < 0.001) and normalized to HC levels (F(1,41) = 0.4, pFDR = 0.204). In conclusion, diazepam normalized hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in increased vulnerability for psychosis.

Effects of Benzodiazepine Exposure on Real-World Clinical Outcomes in Individuals at Clinical High Risk for Psychosis.

Animal models indicate GABAergic dysfunction in the development of psychosis, and that benzodiazepine (BDZ) exposure can prevent the emergence of psychosis-relevant phenotypes. However, whether BDZ exposure influences real-world clinical outcomes in individuals at clinical high risk for psychosis (CHR-P) is unknown. This observational cohort study used electronic health record data from CHR-P individuals to investigate whether BDZ exposure (including hypnotics, eg, zopiclone) reduces the risk of developing psychosis and adverse clinical outcomes. Cox proportional-hazards models were employed in both the whole-unmatched sample, and a propensity score matched (PSM) subsample. 567 CHR-P individuals (306 male, mean[±SD] age = 22.3[±4.9] years) were included after data cleaning. The BDZ-exposed (n = 105) and BDZ-unexposed (n = 462) groups differed on several demographic and clinical characteristics, including psychotic symptom severity. In the whole-unmatched sample, BDZ exposure was associated with increased risk of transition to psychosis (HR = 1.61; 95% CI: 1.03-2.52; P = .037), psychiatric hospital admission (HR = 1.93; 95% CI: 1.13-3.29; P = .017), home visit (HR = 1.64; 95% CI: 1.18-2.28; P = .004), and Accident and Emergency department attendance (HR = 1.88; 95% CI: 1.31-2.72; P < .001). However, after controlling for confounding-by-indication through PSM, BDZ exposure did not modulate the risk of any outcomes (all P > .05). In an analysis restricted to antipsychotic-naïve individuals, BDZ exposure reduced the risk of transition to psychosis numerically, although this was not statistically significant (HR = 0.59; 95% CI: 0.32-1.08; P = .089). BDZ exposure in CHR-P individuals was not associated with a reduction in the risk of psychosis transition or adverse clinical outcomes. Results in the whole-unmatched sample suggest BDZ prescription may be more likely in CHR-P individuals with higher symptom severity.

The hierarchical taxonomy of psychopathology in clinical high risk for psychosis: Validation and extension.

The Hierarchical Taxonomy of Psychopathology (HiTOP) consortium's transdiagnostic dimensional model of psychopathology has considerable support; however, this model has been underresearched in individuals at clinical high risk for psychosis (CHR-P), a population that may advance the model. CHR-P individuals not only have attenuated psychotic symptoms that vary in severity, but also have many comorbid diagnoses and varied clinical outcomes, including disorders with uncertain relations to HiTOP (e.g., obsessive-compulsive disorder). The present study used self-report and interview data from North American Prodrome Longitudinal Study-3 (710 CHR, 96 controls) to replicate the HiTOP model and test specific hypotheses regarding disorders with uncertain relations to its dimensions. Additionally, the present study examined the HiTOP model in relation to childhood trauma, declines in social functioning, and development of full psychosis. Confirmatory factor analysis indicated that the HiTOP model's fit was nearly adequate (e.g., comparative fit index = .89), though several theory-relevant modifications were indicated. Additionally, specific tests were conducted to gain a more fine-grained perspective on how disorders with less clear prior evidence were related to the HiTOP model. Notable findings from these analyses include bipolar spectrum disorders relating to the psychosis super spectrum (i.e., .39 loading), and obsessive-compulsive disorder showing a complex pattern of loadings (e.g., internalizing and psychosis). The final model parsimoniously accounted for childhood trauma (e.g., super spectra rs = .22-.32), associations with current functioning, and predicted future conversion to a psychotic disorder (e.g., super spectra R² = .13). Overall, these results inform the HiTOP model and suggest its promise for CHR-P research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Subgroups of Clinical High Risk for Psychosis Based on Baseline Antipsychotic Exposure: Clinical and Outcome Comparisons Across a 2-Year Follow-up Period.

Antipsychotic (AP) prescription in clinical high risk for psychosis (CHR-P) subjects remains a divisive issue. Although official guidelines currently discourage AP treatment in CHR-P, it is common in clinical practice, especially for psychosis prevention. The aim of this study was to investigate whether baseline AP need (especially in high-dose) indexes a CHR-P subgroup with poorer prognosis and differs from AP-naïve subjects in terms of sociodemographic, clinical, and outcome parameters across a 2-year follow-up. CHR-P participants were treated within an "Early Intervention in Psychosis" program and completed the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF) scale both at baseline and every 12 months. Individuals with baseline AP prescription were included in the high-dose or low-dose CHR-P-AP+ subgroup. The others were grouped as AP-naïve. Cox regression analyses and mixed-design ANOVA were performed. 180 CHR-P individuals were enrolled (32 high-dose, 60 low-dose, and 88 AP-naïve). Compared to AP-naive, CHR-P AP+ subgroups showed older age and more severe clinical presentation. High-dose subgroup also had grater functioning decline at entry and poorer functional recovery at follow-up. No inter-group differences in psychosis transition and symptomatic remission were found. Significant improvement in clinical outcomes were found over time in all subgroups. Baseline AP prescription was specifically associated with a more relevant improvement in PANSS total score, and in negative and disorganized symptoms. Our results suggest that baseline AP need is an important prognostic parameter in CHR-P and should be considered in risk/benefit calculators.

Connectome dysfunction in patients at clinical high risk for psychosis and modulation by oxytocin.

Abnormalities in functional brain networks (functional connectome) are increasingly implicated in people at Clinical High Risk for Psychosis (CHR-P). Intranasal oxytocin, a potential novel treatment for the CHR-P state, modulates network topology in healthy individuals. However, its connectomic effects in people at CHR-P remain unknown. Forty-seven men (30 CHR-P and 17 healthy controls) received acute challenges of both intranasal oxytocin 40 IU and placebo in two parallel randomised, double-blind, placebo-controlled cross-over studies which had similar but not identical designs. Multi-echo resting-state fMRI data was acquired at approximately 1 h post-dosing. Using a graph theoretical approach, the effects of group (CHR-P vs healthy control), treatment (oxytocin vs placebo) and respective interactions were tested on graph metrics describing the topology of the functional connectome. Group effects were observed in 12 regions (all pFDR < 0.05) most localised to the frontoparietal network. Treatment effects were found in 7 regions (all pFDR < 0.05) predominantly within the ventral attention network. Our major finding was that many effects of oxytocin on network topology differ across CHR-P and healthy individuals, with significant interaction effects observed in numerous subcortical regions strongly implicated in psychosis onset, such as the thalamus, pallidum and nucleus accumbens, and cortical regions which localised primarily to the default mode network (12 regions, all pFDR < 0.05). Collectively, our findings provide new insights on aberrant functional brain network organisation associated with psychosis risk and demonstrate, for the first time, that oxytocin modulates network topology in brain regions implicated in the pathophysiology of psychosis in a clinical status (CHR-P vs healthy control) specific manner.

Assessing evidence supporting cannabis harm reduction practices for adolescents at clinical high-risk for psychosis: a review and clinical implementation tool.

Cannabis use is consistently associated with both increased incidence of frank psychotic disorders and acute exacerbations of psychotic symptoms in healthy individuals and people with psychosis spectrum disorders. Although there is uncertainty around causality, cannabis use may be one of a few modifiable risk factors for conversion to psychotic disorders in individuals with Clinical High Risk for Psychosis (CHR-P) syndromes, characterized by functionally impairing and distressing subthreshold psychotic symptoms. To date, few recommendations beyond abstinence to reduce adverse psychiatric events associated with cannabis use have been made. This narrative review synthesizes existing scientific literature on cannabis' acute psychotomimetic effects and epidemiological associations with psychotic disorders in both CHR-P and healthy individuals to bridge the gap between scientific knowledge and practical mental health intervention. There is compelling evidence for cannabis acutely exacerbating psychotic symptoms in CHR-P, but its impact on conversion to psychotic disorder is unclear. Current evidence supports a harm reduction approach in reducing frequency of acute psychotic-like experiences, though whether such interventions decrease CHR-P individuals' risk of conversion to psychotic disorder remains unknown. Specific recommendations include reducing frequency of use, lowering delta-9-tetrahydrocannabinol content in favor of cannabidiol-only products, avoiding products with inconsistent potency like edibles, enhancing patient-provider communication about cannabis use and psychotic-like experiences, and utilizing a collaborative and individualized therapeutic approach. Despite uncertainty surrounding cannabis' causal association with psychotic disorders, cautious attempts to reduce acute psychosis risk may benefit CHR-P individuals uninterested in abstinence. Further research is needed to clarify practices associated with minimization of cannabis-related psychosis risk.

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis

The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (β = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (β = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Aberrant Hierarchical Prediction Errors Are Associated With Transition to Psychosis: A Computational Single-Trial Analysis of the Mismatch Negativity

BackgroundMismatch negativity reductions are among the most reliable biomarkers for schizophrenia and have been associated with increased risk for conversion to psychosis in individuals who are at clinical high risk for psychosis (CHR-P). Here, we adopted a computational approach to develop a mechanistic model of mismatch negativity reductions in CHR-P individuals and patients early in the course of schizophrenia. MethodsElectroencephalography was recorded in 38 CHR-P individuals (15 converters), 19 patients early in the course of schizophrenia (≤5 years), and 44 healthy control participants during three different auditory oddball mismatch negativity paradigms including 10% duration, frequency, or double deviants, respectively. We modeled sensory learning with the hierarchical Gaussian filter and extracted precision-weighted prediction error trajectories from the model to assess how the expression of hierarchical prediction errors modulated electroencephalography amplitudes over sensor space and time. ResultsBoth low-level sensory and high-level volatility precision-weighted prediction errors were altered in CHR-P individuals and patients early in the course of schizophrenia compared with healthy control participants. Moreover, low-level precision-weighted prediction errors were significantly different in CHR-P individuals who later converted to psychosis compared with nonconverters. ConclusionsOur results implicate altered processing of hierarchical prediction errors as a computational mechanism in early psychosis consistent with predictive coding accounts of psychosis. This computational model seems to capture pathophysiological mechanisms that are relevant to early psychosis and the risk for future psychosis in CHR-P individuals and may serve as predictive biomarkers and mechanistic targets for the development of novel treatments.

Baseline antipsychotic prescription and short-term outcome indicators in individuals at clinical high-risk for psychosis: Findings from the Parma At-Risk Mental States (PARMS) program.

The prognostic prediction of outcomes in individuals at clinical high-risk for psychosis (CHR-P) is still a significant clinical challenge. Among multiple baseline variables of risk calculator models, the role of ongoing pharmacological medications has been partially neglected, despite meta-analytical evidence of higher risk of psychosis transition associated with baseline prescription exposure to antipsychotics (AP) in CHR-P individuals. The main aim of the current study was to test the hypothesis that ongoing AP need at baseline indexes a subgroup of CHR-P individuals with more severe psychopathology and worse prognostic trajectories along a 1-year follow-up period. This research was settled within the 'Parma At-Risk Mental States' program. Baseline and 1-year follow-up assessment included the Positive And Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF). CHR-P individuals who were taking AP medications at entry were included in the CHR-P-AP+ subgroup. The remaining participants were grouped as CHR-P-AP-. Hundred and seventy-eight CHR-P individuals (aged 12-25 years) were enrolled (91 CHR-P-AP+, 87 CHR-P-AP-). Compared to CHR-P AP-, CHR-P AP+ individuals had older age, greater baseline PANSS 'Positive Symptoms' and 'Negative Symptoms' factor subscores and a lower GAF score. At the end of our follow-up, CHR-P-AP+ subjects showed higher rates of psychosis transition, new hospitalizations and urgent/non-planned visits compared to CHRP- AP- individuals. In agreement with increasing empirical evidence, also the results of the current study suggest that AP need is a significant prognostic variable in cohorts of CHR-P individuals and should be included in risk calculators.

Rich-club connectivity and structural connectome organization in youth at clinical high-risk for psychosis and individuals with early illness schizophrenia.

Brain dysconnectivity has been posited as a biological marker of schizophrenia. Emerging schizophrenia connectome research has focused on rich-club organization, a tendency for brain hubs to be highly-interconnected but disproportionately vulnerable to dysconnectivity. However, less is known about rich-club organization in individuals at clinical high-risk for psychosis (CHR-P) and how it compares with abnormalities early in schizophrenia (ESZ). Combining diffusion tensor imaging (DTI) and magnetic resonance imaging (MRI), we examined rich-club and global network organization in CHR-P (n=41) and ESZ (n=70) relative to healthy controls (HC; n=74) after accounting for normal aging. To characterize rich-club regions, we examined rich-club MRI morphometry (thickness, surface area). We also examined connectome metric associations with symptom severity, antipsychotic dosage, and in CHR-P specifically, transition to a full-blown psychotic disorder. ESZ had fewer connections among rich-club regions (ps<.024) relative to HC and CHR-P, with this reduction specific to the rich-club even after accounting for other connections in ESZ relative to HC (ps<.048). There was also cortical thinning of rich-club regions in ESZ (ps<.013). In contrast, there was no strong evidence of global network organization differences among the three groups. Although connectome abnormalities were not present in CHR-P overall, CHR-P converters to psychosis (n=9) had fewer connections among rich-club regions (ps<.037) and greater modularity (ps<.037) compared to CHR-P non-converters (n=19). Lastly, symptom severity and antipsychotic dosage were not significantly associated with connectome metrics (ps<.012). Findings suggest that rich-club and connectome organization abnormalities are present early in schizophrenia and in CHR-P individuals who subsequently transition to psychosis.

Neurobehavioral risk factors influence prevalence and severity of hazardous substance use in youth at genetic and clinical high risk for psychosis.

Elevated rates of alcohol, tobacco, and cannabis use are observed in both patients with psychotic disorders and individuals at clinical high risk for psychosis (CHR-P), and strong genetic associations exist between substance use disorders and schizophrenia. While individuals with 22q11.2 deletion syndrome (22qDel) are at increased genetic risk for psychosis, initial evidence suggests that they have strikingly low rates of substance use. In the current study, we aimed to directly compare substance use patterns and their neurobehavioral correlates in genetic and clinical high-risk cohorts. Data on substance use frequency and severity, clinical symptoms, and neurobehavioral measures were collected at baseline and at 12-month follow-up visits in two prospective longitudinal cohorts: participants included 89 22qDel carriers and 65 age and sex-matched typically developing (TD) controls (40.67% male, Mage = 19.26 ± 7.84 years) and 1,288 CHR-P youth and 371 matched TD controls from the North American Prodrome Longitudinal Study-2 and 3 (55.74% male; Mage = 18.71 ± 4.27 years). Data were analyzed both cross-sectionally and longitudinally using linear mixed effects models. Controlling for age, sex, and site, CHR-P individuals had significantly elevated rates of tobacco, alcohol, and cannabis use relative to TD controls, whereas 22qDel had significantly lower rates. Increased substance use in CHR-P individuals was associated with increased psychosis symptom severity, dysphoric mood, social functioning, and IQ, while higher social anhedonia was associated with lower substance use across all domains at baseline. These patterns persisted when we investigated these relationships longitudinally over one-year. CHR-P youth exhibited significantly increased positive psychosis symptoms, dysphoric mood, social functioning, social anhedonia, and IQ compared to 22qDel carriers, and lower rates of autism spectrum disorder (ASD) compared to 22qDel carriers, both at baseline and at 1 year follow-up. Individuals at genetic and CHR-P have strikingly different patterns of substance use. Factors such as increased neurodevelopmental symptoms (lower IQ, higher rates of ASD) and poorer social functioning in 22qDel may help explain this distinction from substance use patterns observed in CHR-P individuals.

Prevention of First-Episode Psychosis in People at Clinical High Risk: A Randomized Controlled, Multicentre Trial Comparing Cognitive-Behavioral Therapy and Clinical Management Plus Low-Dose Aripiprazole or Placebo (PREVENT).

There is limited knowledge of whether cognitive-behavioral therapy (CBT) or second-generation antipsychotics (SGAs) should be recommended as the first-line treatment in individuals at clinical high risk for psychosis (CHRp). To examine whether individual treatment arms are superior to placebo and whether CBT is non-inferior to SGAs in preventing psychosis over 12 months of treatment. PREVENT was a blinded, 3-armed, randomized controlled trial comparing CBT to clinical management plus aripiprazole (CM + ARI) or plus placebo (CM + PLC) at 11 CHRp services. The primary outcome was transition to psychosis at 12 months. Analyses were by intention-to-treat. Two hundred eighty CHRp individuals were randomized: 129 in CBT, 96 in CM + ARI, and 55 in CM + PLC. In week 52, 21 patients in CBT, 19 in CM + ARI, and 7 in CM + PLC had transitioned to psychosis, with no significant differences between treatment arms (P = .342). Psychopathology and psychosocial functioning levels improved in all treatment arms, with no significant differences. The analysis of the primary outcome transition to psychosis at 12 months and secondary outcomes symptoms and functioning did not demonstrate significant advantages of the active treatments over placebo. The conclusion is that within this trial, neither low-dose aripiprazole nor CBT offered additional benefits over clinical management and placebo.

Neurocognition and functioning in adolescents at clinical high risk for psychosis

BackgroundOnce psychosis has set in, it is difficult for patients to achieve full recovery. Prevention of psychosis and early intervention are promising for improving the outcomes of this disorder. In the last two decades, neurocognition has been studied as a biomarker for clinical-high risk for psychosis (CHR-P). However, neurocognitive functioning has been under-investigated in adolescents.MethodsWe enrolled 116 adolescents from 12 to 17 years old (mean = 15.27, SD = 1.56; 76 females). This 3-year cohort study aimed to identify differences in neurocognitive and overall functioning in three groups of adolescent patients divided according to the semi-structured interview Comprehensive Assessment of At-Risk Mental States (CAARMS): adolescents with established psychosis, adolescents with CHR-P, and adolescents not meeting either criteria (non-CHR-P). To differentiate the profiles, clinicians administered cognitive evaluation and neuropsychological tasks. Moreover, they filled in scales to assess their global, social, and role functioning and a questionnaire to assess the severity of the disease.ResultsWe made a between-group comparison on neurocognitive measures and found that the CHR-P and the psychosis groups differed in processing speed (TMT-A; p = .002 in BVN categorial fluency (p = .018), and Rey–Osterrieth complex figure drawing from memory task (p = .014), with psychosis group showing worse performance. No differences emerged between non-CHR-P and CHR-P (p = .014) individuals. CHR-P had better functioning than the psychosis group but worse than the non-CHR-P one.ConclusionsThese results confirm that neurocognition can be a helpful biomarker in identifying specific subgroups of adolescents with emerging psychopathology and help clinicians develop stratified preventive approaches.

The 'Parma At-Risk mental states' (PARMS) program: General description and process analysis after 5 years of clinical activity.

From January 2016, the Parma Department of Mental Health developed a specialized care protocol - the 'Parma At-Risk Mental States' (PARMS) program - as a diffused service for early intervention in individuals at Clinical High Risk for Psychosis (CHR-P). The aims of this investigation were (1) to describe the PARMS structural organization and (2) to examine specific process indicators during the first 5 years of its clinical activity. All participants were adolescent and young adult help-seekers (aged 12-25 years) at CHR-P in accordance with well-defined psychometric criteria. At entry, 52 subjects were provided with a dedicated protocol of care and only 14 dropped out during the first year of treatment. The Duration of Untreated Illness (DUI) overall decreased over time. Most of CHR-P participants suffered from 'Attenuated Psychotic Symptoms' and 'Brief, Limited, Intermittent Psychotic Symptoms' in the same percentage (48.1% [n= 25]). The most common DSM-IV-TR diagnosis was schizotypal personality disorder, followed by borderline personality disorder and brief psychotic disorder. A specialized, evidence-based care protocol for CHR-P individuals within Italian adult and child/adolescent psychiatric services is feasible, also in adolescents, who have a high risk of falling through the child/adult service gap.

Physical Health in Clinical High Risk for Psychosis Individuals: A Cross-Sectional Study.

The clinical high risk for psychosis (CHR-P) phase represents an opportunity for prevention and early intervention in young adults, which also could focus on improving physical health trajectories. We conducted a RECORD-compliant clinical register-based cohort study. The primary outcome was to describe the physical health of assessed CHR-P individuals, obtained via Electronic Health Records at the South London and Maudsley (SLaM) NHS Foundation Trust, UK (January 2013-October 2020). The final database included 194 CHR-P subjects (46% female). Mean age was 23.70 ± 5.12 years. Percentage of tobacco smokers was 41% (significantly higher than in the age-matched general population [24%]). We found that 49% of subjects who consumed alcohol had an AUDIT-C (Alcohol Use Disorder Identification Test) score above 5 (hazardous drinking), with an average score of 4.94 (significantly higher than in the general population [2.75]). Investigating diet revealed low fiber intake in most subjects and high saturated fat intake in 10% of the individuals. We found that 47% of CHR-P subjects met the UK recommended physical activity guidelines (significantly lower than in the general population [66%]). Physical parameters (e.g., weight, heart rate, blood pressure) were not significantly different from the general population. This evidence corroborates the need for monitoring physical health parameters in CHR-P subjects, to implement tailored interventions that target daily habits.

Mapping the implementation and challenges of clinical services for psychosis prevention in England.

Indicated primary prevention of psychosis is recommended by NICE clinical guidelines, but implementation research on Clinical High Risk for Psychosis (CHR-P) services is limited. Electronic audit of CHR-P services in England, conducted between June and September 2021, addressing core implementation domains: service configuration, detection of at-risk individuals, prognostic assessment, clinical care, clinical research, and implementation challenges, complemented by comparative analyses across service model. Descriptive statistics, Fisher's exact test and Mann-Whitney U-tests were employed. Twenty-four CHR-P clinical services (19 cities) were included. Most (83.3%) services were integrated within other mental health services; only 16.7% were standalone. Across 21 services, total yearly caseload of CHR-P individuals was 693 (average: 33; range: 4-115). Most services (56.5%) accepted individuals aged 14-35; the majority (95.7%) utilized the Comprehensive Assessment of At Risk Mental States (CAARMS). About 65% of services reported some provision of NICE-compliant interventions encompassing monitoring of mental state, cognitive-behavioral therapy (CBT), and family interventions. However, only 66.5 and 4.9% of CHR-P individuals actually received CBT and family interventions, respectively. Core implementation challenges included: recruitment of specialized professionals, lack of dedicated budget, and unmet training needs. Standalone services reported fewer implementation challenges, had larger caseloads (p = 0.047) and were more likely to engage with clinical research (p = 0.037) than integrated services. While implementation of CHR-P services is observed in several parts of England, only standalone teams appear successful at detection of at-risk individuals. Compliance with NICE-prescribed interventions is limited across CHR-P services and unmet needs emerge for national training and investments.

Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the ‘normativeness’ of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.

P535. Neighborhood Poverty and Hippocampal Volume Among Individuals at Clinical High Risk for Psychosis: The Moderating Role of Social Engagement

While hippocampal volume (HV) reduction has been shown in psychotic disorders, the relation of neighborhood poverty (NP) and HVs in clinical high risk for psychosis (CHR-P) individuals is unknown. In this study, we explore the associations between NP and HV, and whether social engagement (SE) moderated this relationship in CHR-P individuals.

MR-Spectroscopy of GABA and Glutamate/Glutamine Concentrations in Auditory Cortex in Clinical High-Risk for Psychosis Individuals.

Psychosis involves changes in GABAergic and glutamatergic neurotransmission in auditory cortex that could be important for understanding sensory deficits and symptoms of psychosis. However, it is currently unclear whether such deficits are present in participants at clinical high-risk for psychosis (CHR-P) and whether they are associated with clinical outcomes. Magnetic Resonance Spectroscopy (MEGAPRESS, 1H-MRS at 3 Tesla) was used to estimate GABA, glutamate, and glutamate-plus-glutamine (Glx) levels in auditory cortex in a large sample of CHR-P (n = 99), CHR-N (clinical high-risk negative, n = 32), and 45 healthy controls. Examined were group differences in metabolite concentrations as well as relationships with clinical symptoms, general cognition, and 1-year follow-up clinical and general functioning in the CHR-P group. Results showed a marginal (p = 0.039) main group effect only for Glx, but not for GABA and glutamate concentrations, and only in left, not right, auditory cortex. This effect did not survive multiple comparison correction, however. Exploratory post-hoc tests revealed that there were significantly lower Glx levels (p = 0.029, uncorrected) in the CHR-P compared to the CHR-N group, but not relative to healthy controls (p = 0.058, uncorrected). Glx levels correlated with the severity of perceptual abnormalities and disorganized speech scores. However, in the CHR-P group, Glx levels did not predict clinical or functional outcomes. Accordingly, the findings from the present study suggest that MRS-measured GABA, glutamate and Glx levels in auditory cortex of CHR-P individuals are largely intact.

Identifying Electroencephalography Biomarkers in Individuals at Clinical High Risk for Psychosis in an International Multi-Site Study.

BackgroundThe clinical high-risk for psychosis (CHR-P) paradigm was introduced to detect individuals at risk of developing psychosis and to establish preventive strategies. While current prediction of outcomes in the CHR-P state is based mostly on the clinical assessment of presenting features, several emerging biomarkers have been investigated in an attempt to stratify CHR-P individuals according to their individual trajectories and refine the diagnostic process. However, heterogeneity across subgroups is a key challenge that has limited the impact of the CHR-P prediction strategies, as the clinical validity of the current research is limited by a lack of external validation across sites and modalities. Despite these challenges, electroencephalography (EEG) biomarkers have been studied in this field and evidence suggests that EEG used in combination with clinical assessments may be a key measure for improving diagnostic and prognostic accuracy in the CHR-P state. The PSYSCAN EEG study is an international, multi-site, multimodal longitudinal project that aims to advance knowledge in this field.MethodsParticipants at 6 international sites take part in an EEG protocol including EEG recording, cognitive and clinical assessments. CHR-P participants will be followed up after 2 years and subcategorised depending on their illness progression regarding transition to psychosis. Differences will be sought between CHR-P individuals and healthy controls and between CHR-P individuals who transition and those who do not transition to psychosis using data driven computational analyses.DiscussionThis protocol addresses the challenges faced by previous studies of this kind to enable valid identification of predictive EEG biomarkers which will be combined with other biomarkers across sites to develop a prognostic tool in CHR-P. The PSYSCAN EEG study aims to pave the way for incorporating EEG biomarkers in the assessment of CHR-P individuals, to refine the diagnostic process and help to stratify CHR-P subjects according to risk of transition. This may improve our understanding of the CHR-P state and therefore aid the development of more personalized treatment strategies.