Brain-phenotype models fail for individuals who defy sample stereotypes.

Individual differences in brain functional organization track a range of traits, symptoms and behaviours1-12. So far, work modelling linear brain-phenotype relationships has assumed that a single such relationship generalizes across all individuals, but models do not work equally well in all participants13,14. A better understanding of in whom models fail and why is crucial to revealing robust, useful and unbiased brain-phenotype relationships. To this end, here we related brain activity to phenotype using predictive models-trained and tested on independent data to ensure generalizability15-and examined model failure. We applied this data-driven approach to a range of neurocognitive measures in a new, clinically and demographically heterogeneous dataset, with the results replicated in two independent, publicly available datasets16,17. Across all three datasets, we find that models reflect not unitary cognitive constructs, but rather neurocognitive scores intertwined with sociodemographic and clinical covariates; that is, models reflect stereotypical profiles, and fail when applied to individuals who defy them. Model failure is reliable, phenotype specific and generalizable across datasets. Together, these results highlight the pitfalls of a one-size-fits-all modelling approach and the effect of biased phenotypic measures18-20 on the interpretation and utility of resulting brain-phenotype models. We present a framework to address these issues so that such models may reveal the neural circuits that underlie specific phenotypes and ultimately identify individualized neural targets for clinical intervention.

Towards a youth mental health paradigm: a perspective and roadmap.

Most mental disorders have a typical onset between 12 and 25 years of age, highlighting the importance of this period for the pathogenesis, diagnosis, and treatment of mental ill-health. This perspective addresses interactions between risk and protective factors and brain development as key pillars accounting for the emergence of psychopathology in youth. Moreover, we propose that novel approaches towards early diagnosis and interventions are required that reflect the evolution of emerging psychopathology, the importance of novel service models, and knowledge exchange between science and practitioners. Taken together, we propose a transformative early intervention paradigm for research and clinical care that could significantly enhance mental health in young people and initiate a shift towards the prevention of severe mental disorders.

Abnormal levels of mitochondrial Ca2+ channel proteins in plasma neuron-derived extracellular vesicles of early schizophrenia.

Structural alterations or quantitative abnormalities of some mitochondrial ion channels and exchangers are associated with altered neuronal functions and increased susceptibility to mental illness. Here we have assessed levels of functionally prominent mitochondrial calcium ion channel proteins in plasma neuron-derived extracellular vesicles (NDEVs) of living patients with first episodes of psychosis (FP) and matched controls (Cs). NDEVs were enriched with an established method of precipitation and immunoabsorption by anti-human CD171 neural adhesion protein (L1CAM) antibody and extracted proteins quantified with ELISAs. CD81 exosome marker-normalized NDEV levels of leucine zipper EF-hand containing transmembrane 1 protein (LETM1), transient receptor potential cation channel subfamily M, member 4 (TRPM4), and solute carrier family 8 member B1 (SLC24A6) or mitochondrial Na+ /Ca2+ exchanger (NCLX) were significantly lower for FP patients (n = 10) than Cs (n = 10), whereas NDEV levels of voltage-dependent L-type calcium channel subunit α-1C (CACNA-1C) were significantly higher for FP patients than Cs. Abnormal structures or mitochondrial levels of LETM1, NCLX, and CACNA-1C have been linked through analyses of individual proteins, genome-wide association studies, and whole exome protein-coding sequence studies to neurodevelopmental disorders, mental retardation, schizophrenia, and major depressive diseases. A greater understanding of the altered calcium homeostasis in schizophrenia, that is attributable to underlying mitochondrial calcium channel abnormalities, will lead to improved diagnosis and treatment.

Neural cell-derived plasma exosome protein abnormalities implicate mitochondrial impairment in first episodes of psychosis.

Neuroprotective and other functional proteins of mitochondria were quantified in extracts of plasma neural-derived exosomes from ten first-episode psychosis (FP) patients and ten matched psychiatrically normal controls (ctls). Astrocyte-derived extracellular vesicles (ADEVs) and neuron-derived extracellular vesicles (NDEVs) were immunoabsorbed separately from physically precipitated plasma total EVs. Extracted mitochondrial ATP synthase was specifically immunofixed to plastic wells for quantification of catalytic activity based on conversion of NADH to NAD+ . Other extracted mitochondrial functional proteins were quantified by ELISAs. All protein levels were normalized with EV content of the CD81 exosome marker. FP patient ADEV level but not NDEV level of mitochondrial ATP synthase activity was significantly lower than that of ctls. FP patient ADEV and NDEV levels of the functionally critical mitochondrial proteins mitofusin 2 and cyclophilin D, but not of transcription factor A of mitochondria, and of the mitochondrial short open-reading frame neuroprotective and metabolic regulatory peptides humanin and MOTS-c were significantly lower than those of ctls. In contrast, FP patient NDEV, but not ADEV, level of the mitochondrial-tethering protein syntaphilin, but not of myosin VI, was significantly higher than that of ctls. The distinctively different neural levels of some mitochondrial proteins in FP patients than ctls now should be correlated with diverse clinical characteristics. Drugs that increase depressed levels of proteins and mimetics of deficient short open-reading frame peptides may be of therapeutic value in early phases of schizophrenia.

Abnormal levels of mitochondrial proteins in plasma neuronal extracellular vesicles in major depressive disorder.

To characterize neuronal mitochondrial abnormalities in major depressive disorder (MDD), functional mitochondrial proteins (MPs) extracted from enriched plasma neuron-derived extracellular vesicles (NDEVs) of MDD participants (n = 20) were quantified before and after eight weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). Pretreatment baseline NDEV levels of the transcriptional type 2 nuclear respiratory factor (NRF2) which controls mitochondrial biogenesis and many anti-oxidant gene responses, regulators of diverse neuronal mitochondrial functions cyclophilin D (CYPD) and mitofusin-2 (MFN2), leucine zipper EF-hand containing transmembrane 1 protein (LETM1) component of a calcium channel/calcium channel enhancer, mitochondrial tethering proteins syntaphilin (SNPH) and myosin VI (MY06), inner membrane electron transport complexes I (subunit 6) and III (subunit 10), the penultimate enzyme of nicotinamide adenine dinucleotide (NAD) generation nicotinamide mononucleotide adenylytransferase 2 (NMNAT2), and neuronal mitochondrial metabolic regulatory and protective factors humanin and mitochondrial open-reading frame of the 12S rRNA-c (MOTS-c) all were significantly lower than those of NDEVs from matched controls (n = 10), whereas those of pro-neurodegenerative NADase Sterile Alpha and TIR motif-containing protein 1 (SARM1) were higher. The baseline NDEV levels of transcription factor A mitochondrial (TFAM) and the transcriptional master-regulator of mitochondrial biogenesis PPAR γ coactivator-1α (PGC-1α) showed no differences between MDD participants and controls. Several of these potential biomarker proteins showed substantially different changes in untreated MDD than those we reported in untreated first-episode psychosis. NDEV levels of MPs of all functional classes, except complex I-6, NRF2 and PGC-1α were normalized in MDD participants who responded to SSRI therapy (n = 10) but not in those who failed to respond (n = 10) by psychiatric evaluation. If larger studies validate NDEV MP abnormalities, they may become useful biomarkers and identify new drug targets.

First help-seeking attempt before and after psychosis onset: measures of delay and aversive pathways to care.

PURPOSE: Delay in receiving effective treatment for psychosis adversely impacts outcomes. We investigated the timing of the first help-seeking attempt in individuals with recent onset non-affective psychosis by comparing those who sought help during the prodrome to those who sought help after psychosis onset across sociodemographic and clinical characteristics, overall functioning, and occurrence of aversive events during their pathways to care. METHODS: Patients were admitted from February 1st, 2014 to January 31st, 2019 to the Program for Specialized Treatment Early in Psychosis (STEP) in New Haven, CT. Psychosis-onset date was ascertained using the Structured Interview for Psychosis-risk Syndromes. Key dates before and after psychosis onset, along with initiators and aversive events, were collected via semi-structured interview. RESULTS: Within 168 individuals, 82% had their first help-seeking episode after psychosis onset and did not differ in terms of sociodemographic characteristics from prodrome help seekers. When the first help-seeking episode started before (i.e., during prodrome) vs after psychosis onset it was mostly initiated by patients vs family members (Cramer's V = 0.23, p = 0.031) and led to a faster prescription of an antipsychotic once full-blown psychosis emerged (time to antipsychotic since psychosis onset = 21 vs 56 days, p = 0.03). No difference in aversive events before STEP enrollment was detected across groups. CONCLUSION: Help seeking during the prodrome is associated with faster initiation of antipsychotic treatment and is more likely to be self-initiated, compared to help seeking after psychosis onset. Early detection efforts that target prodromal samples may improve the length and experience of pathways to care.

Transforming the Treatment of Schizophrenia in the United States: The RAISE Initiative.

The schizophrenia spectrum disorders are neurodevelopmental illnesses with a lifetime prevalence near 1%, producing extensive functional impairment and low expectations for recovery. Until recently, treatment in the United States has largely attempted to stabilize individuals with chronic schizophrenia. The identification and promotion of evidence-based practices for schizophrenia via the Patient Outcomes Research Team, combined with international studies supporting the value of early intervention, provided the foundation for the Recovery After an Initial Schizophrenia Episode (RAISE) project. The RAISE studies further supported the value of reducing the duration of untreated psychosis and providing a multi-element treatment called coordinated specialty care (CSC) to improve outcomes for patients in usual treatment settings. Although CSC programs have proliferated rapidly in the United States, many challenges remain in the treatment and recovery of individuals with schizophrenia in the aftermath of RAISE.

An Economic Evaluation of Coordinated Specialty Care (CSC) Services for First-Episode Psychosis in the U.S. Public Sector.

BACKGROUND: Schizophrenia spectrum disorders exert a large and disproportionate economic impact. Early intervention services may be able to alleviate the burden of schizophrenia spectrum disorders on diagnosed individuals, caregivers, and society at large. Economic analyses of observational studies have supported investments in specialized team-based care for early psychosis; however, questions remain regarding the economic viability of first-episode services in the fragmented U.S. healthcare system. The clinic for Specialized Treatment Early in Psychosis (STEP) was established in 2006, to explicitly model a nationally-relevant U.S. public-sector early intervention service. The purpose of this study was to conduct an economic evaluation of STEP, a Coordinated Specialty Care service (CSC) based in a U.S. State-funded community mental health center, relative to usual treatment (UT). METHODS: Eligible patients were within 5 years of psychosis onset and had no more than 12 weeks of lifetime antipsychotic exposure. Participants were randomized to STEP or UT. The annual per-patient cost of the STEP intervention per se was estimated assuming a steady-state caseload of 30 patients. A cost-offset analysis was conducted to estimate the net value of STEP from a third-party payer perspective. Participant healthcare service utilization was evaluated at 6 months and over the entire 12 months post randomization. Generalized linear model multivariable regressions were used to estimate the effect of STEP on healthcare costs over time, and generate predicted mean costs, which were combined with the per-patient cost of STEP. RESULTS: The annual per-patient cost of STEP was $1,984. STEP participants were significantly less likely to have any inpatient or ED visits; among individuals who did use such services in a given period, the associated costs were significantly lower for STEP participants at month 12. We did not observe a similar effect with regard to other healthcare services. The predicted average total costs were lower for STEP than UT, indicating a net benefit for STEP of $1,029 at month 6 and $2,991 at month 12; however, the differences were not statistically significant. CONCLUSIONS: Our findings are promising with regard to the value of STEP to third-party payers.

High rates of obstructive sleep apnea symptoms among patients with schizophrenia.

BACKGROUND: Patients with schizophrenia have high rates of obesity and cardiovascular morbidity, which are strongly associated with obstructive sleep apnea (OSA). The prevalence and risk factors for OSA are not well studied in patients with schizophrenia. OBJECTIVE: The purpose of this study was to evaluate the frequency of OSA symptoms in a sample of outpatients with schizophrenia. METHODS: This cross-sectional study was a secondary analysis of data generated from an insomnia study that evaluated 175 outpatients with schizophrenia or schizoaffective disorder in a single, large urban community mental health center. Results of scales evaluating insomnia were used to complete the STOP questionnaire, which is a screening tool for OSA validated in surgical populations. Appropriate statistical analysis was done to compare participants across groups. RESULTS: Patients were classified into high risk for OSA (STOP ≥ 2) (57.7%), and low risk for OSA (STOP score < 2) (42.3%). We also identified patients with a known diagnosis of OSA (14.9%). Patients with diagnosed OSA had significantly higher STOP scores (mean 2.7 vs. 1.6 [t = 6.3; p < 0.001]). Only 23.8% of patients in the high-risk group were diagnosed with OSA. Body mass index was significantly higher in the diagnosed group (F[2,169] = 25; p < 0.001) as was diabetes (χ2 [2, N = 175] = 35, p < 0.001). CONCLUSION: A large number of outpatients with severe mental illness are at high risk for OSA. The STOP questionnaire is easy to use and appears to have a very high clinical utility to detect OSA. Based on our findings, further studies are warranted to validate the tool in patients with severe mental illness.

Reducing the duration of untreated psychosis and its impact in the U.S.: the STEP-ED study.

BACKGROUND: Early intervention services for psychotic disorders optimally interlock strategies to deliver: (i) Early Detection (ED) to shorten the time between onset of psychotic symptoms and effective treatment (i.e. Duration of Untreated Psychosis, DUP); and (ii) comprehensive intervention during the subsequent 2 to 5 years. In the latter category, are teams ('First-episode Services' or FES) that integrate several empirically supported treatments and adapt their delivery to younger patients and caregivers. There is an urgent need to hasten access to established FES in the U.S. Despite improved outcomes for those in treatment, these FES routinely engage patients a year or more after psychosis onset. The Scandinavian TIPS study was able to effectively reduce DUP in a defined geographic catchment. The guiding questions for this study are: can a U.S. adaptation of the TIPS approach to ED substantially reduce DUP and improve outcomes beyond existing FES? METHODS/DESIGN: The primary aim is to determine whether ED can reduce DUP in the US, as compared to usual detection. ED will be implemented by one FES (STEP) based in southern Connecticut, and usual detection efforts will continue at a comparable FES (PREP(R)) serving the greater Boston metropolitan area. The secondary aim is to determine whether DUP reduction can improve presentation, engagement and early outcomes in FES care. A quasi-experimental design will compare the impact of ED on DUP at STEP compared to PREP(R) over 3 successive campaign years. The campaign will deploy 3 components that seek to transform pathways to care in 8 towns surrounding STEP. Social marketing approaches will inform a public education campaign to enable rapid and effective help-seeking behavior. Professional outreach and detailing to a wide variety of care providers, including those in the healthcare, educational and judicial sectors, will facilitate rapid redirection of appropriate patients to STEP. Finally, performance improvement measures within STEP will hasten engagement upon referral. DISCUSSION: STEP-ED will test an ED campaign adapted to heterogeneous U.S. pathways to care while also improving our understanding of these pathways and their impact on early outcomes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02069925 . Registered 20 February 2014.

The Italian adaptation of the Mini-SIPS, a tool for early detection of individuals at clinical high risk and first episode of psychosis: A preliminary study of implementation in an Italian FEP program.

AIMS: The study aims are to present the Italian adaptation of the Abbreviated Clinical Structured Interview for DSM-5 Attenuated Psychosis Syndrome (Mini-SIPS) and illustrate its implementation in a clinical setting. METHODS: The Mini-SIPS was developed from the original extended version as a tool designed to identify, within the clinical high risk (CHR) framework, the DSM-5 Attenuated Psychosis Syndrome (APS) and to be implemented in clinical settings. The Mini-SIPS was translated in Italian by a Yale-certified SIPS trainer, then back-translated in English by a trained psychologist, then approved by the Mini-SIPS authors. Since September 2021, the adapted Italian version of the Mini-SIPS has been implemented at the First Episode Psychosis (FEP) Program in Ferrara, Italy. RESULTS: The Italian version of Mini-SIPS was successfully administered to 15 individuals subsequently referred to the First Episode Psychosis service in Ferrara. Within this sample, the tool has proven to be both an effective and efficient tool for the identification of CHR and FEP, and a valid instrument to help with the differential diagnosis. It also performed as a valuable guide for retrieving information about psychiatric history, to date the onset of APS and/or full-blown psychosis, to track the progression from CHR to psychosis or to symptoms resolution and to describe patients' pathways to care. CONCLUSION: The Mini-SIPS is an efficient and easy-to-use interview to identify the early stages of psychosis and established psychosis in clinical contexts. The Italian adaptation of this interview could be effectively implemented in other Italian FEP Programs as a screening and monitoring tool. Formal validation of the instrument is needed to assessed validity and reliability in the diagnosis of the CHR and FEP.

Obese schizophrenia spectrum patients have significantly higher 10-year general cardiovascular risk and vascular ages than obese individuals without severe mental illness.

BACKGROUND: Individuals with schizophrenia have a life expectancy that is 20 years less than the general population, along with high rates of obesity and cardiovascular disease (CVD) mortality. OBJECTIVE: This study assessed the 10-year general CVD risk and vascular ages of 106 obese schizophrenia spectrum patients and 197 demographically matched obese controls without severe mental illness (SMI) from the National Health and Nutrition Examination Survey (NHANES). METHODS: Vascular age and general CVD risk were calculated using the Framingham global CVD calculator, which incorporates age, sex, total and HDL cholesterol levels, systolic blood pressure, smoking status, and diabetes or hypertension treatment. RESULTS: Obese schizophrenia spectrum patients had a mean vascular age that was 14.1 years older than their mean actual age, whereas obese NHANES participants had only a 6.7-year difference. The probability of experiencing a CVD event within the next 10 years was 10.7% for obese patients and 8.5% for obese NHANES participants. CONCLUSION: These findings suggest that schizophrenia spectrum patients experience increased metabolic risk independent of weight. Primary care clinicians can utilize general CVD risk and vascular age scores to communicate metabolic risk more easily and to help make treatment decisions.

Investigating the safety and efficacy of naltrexone for anti-psychotic induced weight gain in severe mental illness: study protocol of a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Obesity is a growing health problem leading to high rates of mortality and morbidity in patients with severe mental illness (SMI). The increased rate of obesity is largely attributed to antipsychotic use. The effect of antipsychotic medications on H1 and 5HT2 receptors has been associated with weight gain, but there is also a substantial amount of evidence showing that D2 receptor blockade may be responsible for weight gain by interacting with the dopamine-opioid system. Unfortunately, current available medications for weight loss have limited efficacy in this population. Naltrexone, an opioid receptor antagonist, may be a promising agent to reduce antipsychotic induced weight gain by decreasing food cravings. We aim to investigate the safety and efficacy of two doses of naltrexone (25 mg & 50 mg) versus placebo for weight and health risk reduction in overweight and obese individuals (BMI ≥ 28) with SMI, who gained weight while being treated with antipsychotics. METHODS AND DESIGN: One hundred and forty four patients will be recruited throughout the greater New Haven area. The participants will be randomized to naltrexone 25 mg/day, naltrexone 50 mg/day, or placebo in a 1:1:1 ratio. Participants will be on the study medication for 52 weeks, and assessed weekly for the first 4 weeks and bi-weekly thereafter. The primary outcome measurements are weight reduction and percentage achieving clinically significant weight loss (5% of total body weight). Waist circumference, body mass index, serum lipid profile, fasting glucose, and glycosylated hemoglobin are the secondary outcome measures. The effect of naltrexone on other outcome measurements such as schizophrenia symptoms, depression, dietary consumption, quality of life, cognitive functioning, physical activity, metabolism/inflammation markers, serum leptin, ghrelin, peptide YY, adinopectin, high sensitivity CRP, interleukin 6, interleukin-1B, interleukin-18, and tumor necrosis factor alpha (TNF-α) will be evaluated. The data will be analyzed by applying linear mixed effect models. DISCUSSION: This is the first large scale study investigating the safety and efficacy of naltrexone in antipsychotic induced weight gain; and hopefully, this may lead to a novel pharmacological option for management of this major health problem. TRIAL REGISTRATION: This trial is registered in http://www.clinicaltrials.gov as NCT01866098.

Early auditory gamma-band responses in patients at clinical high risk for schizophrenia.

BACKGROUND: Gamma-band oscillations and their synchronization have been implicated in the coordination of activity between distributed neuronal assemblies in the service of sensory registration of stimuli and perceptual binding of their features. Prior electroencephalographic (EEG) studies of chronic schizophrenia patients have documented deficits in the magnitude and/or phase synchrony of stimulus-evoked gamma oscillations, findings that have been linked to neurotransmission abnormalities involving GABA and NMDA-glutamate receptors. However, it remains unclear whether these abnormalities are present at the onset of the illness, or indeed, whether they are present during the prodromal period preceding illness onset. Accordingly, we examined the magnitude and phase synchrony of the transient gamma-band response (GBR) elicited by an auditory stimulus in young patients with schizophrenia and in patients at clinical high risk for psychosis based on their manifestation of putatively prodromal symptoms. METHODS: EEG was recorded during an auditory oddball target detection task in three groups: young schizophrenia patients early in their illness (YSZ; n = 19), patients at clinical high risk for psychosis (CHR; n = 55), and healthy controls (HC; n = 42). Single-trial EEG epochs and the average event-related potential time-locked to standard tones from the oddball task were subjected to time-frequency decomposition using Morlet wavelet transformations. The GBR between 50 and 100 ms following the tone onset was quantified in terms of evoked power, total power, and the phase-locking factor (PLF) reflecting cross-trial phase synchrony. RESULTS: GBR evoked power was significantly reduced in YSZ (p < 0.01) and CHR (p < 0.05) patients, relative to HC. Similarly, GBR PLF was significantly reduced in YSZ (p < 0.01) and showed a marginal reduction in CHR patients (p = 0.057), relative to HC. GBR total power was not reduced in CHR patients (p = 0.68) and showed only a trend level reduction in YSZ (p = 0.072). Within the CHR group. there were no significant GBR differences between the patients who converted to a psychotic disorder and those who did not convert to psychosis during a 12-month follow-up period. CONCLUSION: Reductions in the transient auditory GBR, as reflected by evoked power and phase synchrony, are evident in the early stages of schizophrenia and appear to precede psychosis onset. However, the absence of total power GBR abnormalities in CHR patients, with only a trend toward reduction in YSZ patients, suggests that the magnitude of the GBR is intact early in the course

The effect of duration of untreated psychosis (DUP) on the risk for hospitalization after admission to a first episode service.

Engagement with a first episode-psychosis service (FES) reduces the risk of psychiatric hospitalization. However, the role of the duration of untreated psychosis (DUP) in impacting this outcome is disputed. This study aimed to examine whether DUP was an effect modifier of the post-FES reduction of risk of hospitalization, and to explore associations between patients' characteristics and hospitalization post-FES. Individuals aged 16-35 with recent onset (< 3 years) of non-affective psychosis, admitted to the Program for Specialized Treatment Early in Psychosis (STEP), a FES serving the Greater New Haven area, Connecticut, between 2014 and 2019 were included (N = 189). Medical records were queried from 2013 through 2020 for number and duration of psychiatric hospitalizations. Poisson regression models were used to estimate incidence rate ratios for hospitalization rates across all explanatory variables. Negative binomial regression was used to compare the length of stay (LOS) before vs after STEP enrollment. STEP admission was associated with a significant 90 % reduction in the frequency and duration of hospitalizations. This effect was moderated by DUP: with 30-day prolongations in components of DUP (supply, demand, and total) there was less reduction in hospitalizations and LOS after FES enrollment (p < .0001). Only DUP supply (time from first antipsychotic use to STEP admission) differentiated those who were hospitalized during the first year after STEP enrollment from those who were not (median: 35 vs. 15 weeks, p = .003). To fully harness the positive impact of FES on hospitalization, a detailed effort should be pursued to reduce all DUP components.

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

BACKGROUND: Mismatch 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. METHODS: Electroencephalography 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. RESULTS: Both 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. CONCLUSIONS: Our 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.

Promoting the Success and Sustainability of Coordinated Specialty Care Teams in Ohio.

Recent COVID-19-related federal legislation has resulted in time-limited increases in Mental Health Block Grant (MHBG) set-aside dollars for coordinated specialty care (CSC) throughout the United States. The state of Ohio has opted to apply these funds to establish a learning health network of Ohio CSC teams, promote efforts to expand access to CSC, and quantify the operating costs and rates of reimbursement from private and public payers for these CSC teams. These efforts may provide other states with a model through which they can apply increased MHBG funds to support the success of their own CSC programs.

Sampling from different populations: Sociodemographic, clinical, and functional differences between samples of first episode psychosis individuals and clinical high-risk individuals who progressed to psychosis.

Over the past two decades, research and clinical resources on clinical high risk (CHR) for psychosis have both expanded, with goals to better understanding risk and protective factors on the course of illness and inform early intervention efforts. However, some studies have highlighted potential sampling bias among CHR research studies, raising questions about generalizability of findings and inequitable access to early detection and intervention. The current study sought to explore these questions by comparing 94 participants in a CHR longitudinal monitoring study across North America (NAPLS-2) who converted to syndromal psychosis over the course of the study (CHR-CV) to 171 participants who presented for treatment at a localized first-episode psychosis service (FES) after converting. CHR-CV participants were significantly more likely to be White and have a college-educated parent, while FES participants were more likely to be Black and first- or second-generation immigrants. On average, CHR-CV participants were younger at onset of attenuated positive symptoms, had a longer period of attenuated symptoms prior to conversion, and were more likely to be treated with antipsychotics prior to conversion compared to those in FES programs. After controlling for time since conversion, CHR-CV participants had higher global functioning and were less likely to have experienced recent psychiatric hospitalization. Findings suggest that CHR research and FES clinics may be sampling from different populations, although conclusions are limited by inconsistent sampling frames and methods. Integrated early detection that targets defined geographic catchments may deliver more epidemiologically representative samples to both CHR research and FES.

Early Intervention Services for Schizophrenia: Looking Back and Looking Ahead.

This invited commentary provides a conceptual history of modern early intervention services, briefly reviews the accomplishments of an international clinical and research community, and offers proposals for how such services might participate in the next generation of progress. In keeping with the theme of this column, we make the argument that such services should orient around bi-directional knowledge translation across basic, clinical and policy domains.

Timing of cannabis exposure relative to prodrome and psychosis onset in a community-based first episode psychosis sample.

Cannabis has been implicated as both a potential cause and adverse prognostic factor in psychotic disorders. Investigating the contributory role of cannabis toward the overall burden of psychotic illnesses may represent an important step toward psychosis prevention and treatment. The current study samples consecutive admissions (N = 246) to two community based first-episode psychosis services to characterize timing of cannabis use relative to psychosis and attenuated symptom onset, differences between those with and without cannabis exposure, and the association of age at first cannabis exposure with clinical and demographic variables. Both cannabis exposure (78%) and cannabis use disorders (47%) were highly prevalent at admission. In 94% of participants, cannabis use preceded the onset of both attenuated and full-threshold psychosis symptoms by several years. Earlier age at first exposure to cannabis was associated with younger age at prodrome and psychosis onset, worse premorbid functioning, and greater severity of cannabis use disorder at admission. The timing of first exposure to cannabis may have individual prognostic as well as public health significance. Documenting the prevalence and impact of cannabis use in early psychosis samples, as well as the overall incidence of psychotic disorders, will be of vital public health significance as the United States enacts cannabis legalization and cannabis products become more widely available.