Adjustment of Regional Cortical Thickness Measures for Global Cortical Thickness Obscures Deficits Across the Schizophrenia Spectrum: A Cautionary Note about Normative Modeling of Brain Imaging Data.

Recent neuroimaging studies and publicly-disseminated analytic tools advocate that regional morphometric analyses covary for global thickness. We empirically demonstrate that this statistical approach severely underestimates regional thickness dysmorphology in psychiatric disorders. Study 1 included 90 healthy controls, 51 clinical high-risk for psychosis, and 78 early illness schizophrenia participants. Study 2 included 56 healthy controls, 83 non-affective psychosis, and 30 affective psychosis participants. We examined global and regional thickness correlations, global thickness group differences, and regional thickness group differences with/without global thickness covariation. Global and regional thickness were strongly correlated across groups. Global thickness was lower in schizophrenia-spectrum groups versus other groups. Regional thickness deficits in schizophrenia-spectrum groups were attenuated/eliminated with global thickness covariation. Depriving regional thickness of its shared variance with global thickness removes disease-related effects. This statistical method results in erroneous conclusions that regional thickness is normal in disorders like schizophrenia or clinical high-risk syndrome.

Bring It Up: An Adapted Collaborative Care Model for Depression in a Safety-Net Primary Care Clinic.

Objective: Over 90 clinical trials demonstrate the efficacy of the collaborative care model (CoCM) to treat depression in primary care but there is significant variability in real-world CoCM implementation and scalability. This study aimed to determine the feasibility and effectiveness of an adapted CoCM in a safety-net primary care setting. Methods: Bring It Up! (BIU) is a pilot trial comparing an adapted CoCM (intervention group) to usual care (historical controls) for primary care safety-net clinic patients with depression. Inclusion criteria: (1) age ≥18; (2) Patient Health Questionnaire-9 (PHQ-9) score ≥10; and (3) major depressive disorder diagnosis. Patients who completed ≥6 months of treatment upon rolling enrollment (April 1, 2018-October 31, 2019) were included. Historical controls completed ≥6 months of usual care in 2017. BIU included all aspects of CoCM except accountable care and leveraged existing staff rather than a dedicated care manager. The primary outcome was depression remission (PHQ-9 <5) within 6 months. Secondary outcomes included depression response, adherence to treatment guidelines and care coordination process. Data were extracted from the electronic health record. Results: Thirty-six patients received the intervention; 41 controls received usual care. Depression remission was achieved in 33.3% of intervention patients and 0% of controls (p = 0.001). Of intervention patients, 44.4% achieved ≥50% reduction in PHQ-9 compared to 4.9% of controls (p = 0.003). Further, 66.7% of intervention patients had guideline-recommended antidepressant medication titration compared to 26.9% of controls (p = 0.003); 94.4% of intervention patients had PHQ-9 repeated compared to 53.7% of controls (p < 0.001). Conclusions: An adapted CoCM was feasible and improved depression care in a safety-net clinic.

Brain Age Gap in Early Illness Schizophrenia and the Clinical High-Risk Syndrome: Associations With Experiential Negative Symptoms and Conversion to Psychosis.

BACKGROUND AND HYPOTHESIS: Brain development/aging is not uniform across individuals,spawning efforts to characterize brain age from a biological perspective to model the effects of disease and maladaptive life processes on the brain. The brain age gap represents the discrepancy between estimated brain biological age and chronological age (in this case, based on structural magnetic resonance imaging, MRI). Structural MRI studies report an increased brain age gap (biological age > chronological age) in schizophrenia, with a greater brain age gap related to greater negative symptom severity. Less is known regarding the nature of this gap early in schizophrenia (ESZ), if this gap represents a psychosis conversion biomarker in clinical high-risk (CHR-P) individuals, and how altered brain development and/or agingmap onto specific symptom facets. STUDY DESIGN: Using structural MRI, we compared the brain age gap among CHR-P (n = 51), ESZ (n = 78), and unaffected comparison participants (UCP; n = 90), and examined associations with CHR-P psychosis conversion (CHR-P converters n = 10; CHR-P non-converters; n = 23) and positive and negative symptoms. STUDY RESULTS: ESZ showed a greater brain age gap relative to UCP and CHR-P (Ps < .010). CHR-P individuals who converted to psychosis showed a greater brain age gap (P = .043) relative to CHR-P non-converters. A larger brain age gap in ESZ was associated with increased experiential (P = .008), but not expressive negative symptom severity. CONCLUSIONS: Consistent with schizophrenia pathophysiological models positing abnormal brain maturation, results suggest abnormal brain development is present early in psychosis. An increased brain age gap may be especially relevant to motivational and functional deficits in schizophrenia.

Exploring Data Collection Priorities of Community Partners in Early Psychosis Care.

OBJECTIVE: Learning health care networks can significantly improve the effectiveness, consistency, and cost-effectiveness of care delivery. As part of a data harmonization process, incorporation of the perspectives of community partners to maximize the relevance and utility of the data is critical. METHODS: A mixed-methods focus group study was conducted with early psychosis program providers, leadership, service users, and family members to explore their priorities regarding data collection in early psychosis care. Focus group transcripts were analyzed through thematic analysis. RESULTS: Twenty-two focus groups comprising 178 participants were conducted across 10 early psychosis programs. Participants considered functioning, quality of life, recovery, and symptoms of psychosis as key outcomes to assess, although variation by participants' roles was also evident. Participants emphasized the clinical utility of assessing a broad range of predictors of care outcomes, favored a broad conceptualization of the constructs assessed, and indicated a preference for client-reported measures. Participants also emphasized the importance of surveys adopting a recovery-oriented, strengths-based approach. CONCLUSIONS: Large-scale aggregation of health care data collected as part of routine care offers opportunities for research and may have a positive impact on care delivery and quality improvement activities. However, these benefits are contingent on the data being both relevant and accessible to those who deliver and receive such care. This study highlights an approach that may inform the development of core assessment batteries used, optimizing the utility of such data for all community partners.

Using brain structural neuroimaging measures to predict psychosis onset for individuals at clinical high-risk.

Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.

The diagnostic accuracy of screening for psychosis spectrum disorders in behavioral health clinics integrated into primary care.

Screening for psychosis spectrum disorders in primary care could improve early identification and reduce the duration of untreated psychosis. However, the accuracy of psychosis screening in this setting is unknown. To address this, we conducted a diagnostic accuracy study of screening for psychosis spectrum disorders in eight behavioral health services integrated into primary care clinics. Patients attending an integrated behavioral health appointment at their primary care clinic completed the Prodromal Questionnaire - Brief (PQ-B) immediately prior to their intake assessment. This was compared to a diagnostic phone interview based on the Structured Interview for Psychosis Risk Syndromes (SIPS). In total, 145 participants completed all study procedures, of which 100 screened positive and 45 negative at a provisional PQ-B threshold of ≥20. The PQ-B was moderately accurate at differentiating psychosis spectrum from no psychosis spectrum disorders; a PQ-B distress score of ≥27 had a sensitivity and specificity of 71.2 % and 57.0 % respectively. In total, 66 individuals (45.5 %) met criteria for a psychosis spectrum disorder and 24 (16.7 %) were diagnosed with full psychosis, indicating a high prevalence of psychosis in the sample. Overall, screening for psychosis spectrum disorders in an IBH primary care setting identified a relatively high number of individuals and may identify people that would otherwise be missed. The PQ-B performed slightly less well than in population-based screening in community mental health settings. However, the findings suggest this may represent an effective way to streamline the pathway between specialty early psychosis programs and primary care clinics for those in need.

The Cascade of Care for Early Psychosis Detection in a College Counseling Center.

OBJECTIVE: Programs for early detection of psychosis help identify individuals experiencing emerging psychosis and link them with appropriate services, thereby reducing the duration of untreated psychosis (DUP). The authors used the cascade-of-care framework to identify various care stages between screening and enrollment in coordinated specialty care (CSC) and to determine attrition at each stage, with the goal of identifying points in the referral process that may affect DUP. METHODS: Project partners included a college counseling center and CSC program. All college students seeking mental health services at a counseling center between 2020 and 2022 (N=1,945) completed the Prodromal Questionnaire-Brief (PQ-B) at intake. Students who met the distress cutoff score were referred for a phone screening. Those who met criteria on the basis of this screening were referred for assessment and possible enrollment into CSC. RESULTS: Six stages in the cascade of care for early detection were identified. Of the students who completed the PQ-B as part of intake (stage 1), 547 (28%) met the PQ-B cutoff score (stage 2). Counselors referred 428 (78%) students who met the PQ-B cutoff score (stage 3), and 212 (50%) of these students completed the phone screening (stage 4). Seventy-two (34%) students completed a CSC eligibility assessment (stage 5), 21 (29%) of whom were enrolled in CSC (stage 6). CONCLUSIONS: The cascade-of-care framework helped conceptualize the flow within a program for early psychosis detection in order to identify stages that may contribute to lengthier DUP. Future research is warranted to better understand the factors that contribute to DUP at these stages.

The Effects of Remote Cognitive Training Combined With a Mobile App Intervention on Psychosis: Double-Blind Randomized Controlled Trial.

BACKGROUND: Impairments in cognition and motivation are core features of psychosis and strong predictors of social and occupational functioning. Accumulating evidence indicates that cognitive deficits in psychosis can be improved by computer-based cognitive training programs; however, barriers include access and adherence to cognitive training exercises. Limited evidence-based methods have been established to enhance motivated behavior. In this study, we tested the effects of web-based targeted cognitive and social cognitive training (TCT) delivered in conjunction with an innovative digital smartphone app called Personalized Real-Time Intervention for Motivational Enhancement (PRIME). The PRIME app provides users with a motivational coach to set personalized goals and secure social networking for peer support. OBJECTIVE: This study investigated whether deficits in cognition and motivation in people with a psychosis spectrum disorder (N=100) can be successfully addressed with 30 hours of TCT+PRIME as compared with 30 hours of a computer games control condition (CG) plus PRIME (CG+PRIME). Here, we describe our study procedures, the feasibility and acceptability of the intervention, and the results on all primary outcomes. METHODS: In this double-blind randomized controlled trial, English-speaking participants completed all cognitive training, PRIME activities, and assessments remotely. Participants completed a diagnostic interview and remote cognitive, clinical, and self-report measures at baseline, posttraining, and at a 6-month follow-up. RESULTS: This study included participants from 27 states across the United States and 8 countries worldwide. The study population was 58% (58/100) female, with a mean age of 33.77 (SD 10.70) years. On average, participants completed more than half of the cognitive training regimen (mean 18.58, SD 12.47 hours of training), and logged into the PRIME app 4.71 (SD 1.58) times per week. The attrition rate of 22% (22/100) was lower than that reported in our previous studies on remote cognitive training. The total sample showed significant gains in global cognition (P=.03) and attention (P<.001). The TCT+PRIME participants showed significantly greater gains in emotion recognition (P<.001) and global cognition at the trend level (P=.09), although this was not statistically significant, relative to the CG+PRIME participants. The total sample also showed significant improvements on multiple indices of motivation (P=.02-0.05), in depression (P=.04), in positive symptoms (P=.04), and in negative symptoms at a trend level (P=.09), although this was not statistically significant. Satisfaction with the PRIME app was rated at 7.74 (SD 2.05) on a scale of 1 to 10, with higher values indicating more satisfaction. CONCLUSIONS: These results demonstrate the feasibility and acceptability of remote cognitive training combined with the PRIME app and that this intervention can improve cognition, motivation, and symptoms in individuals with psychosis. TCT+PRIME appeared more effective in improving emotion recognition and global cognition than CG+PRIME. Future analyses will test the relationship between hours of cognitive training completed; PRIME use; and changes in cognition, motivation, symptoms, and functioning. TRIAL REGISTRATION: ClinicalTrials.gov NCT02782442; https://clinicaltrials.gov/study/NCT02782442.

A Sequential Adaptive Intervention Strategy Targeting Remission and Functional Recovery in Young People at Ultrahigh Risk of Psychosis: The Staged Treatment in Early Psychosis (STEP) Sequential Multiple Assignment Randomized Trial.

Importance: Clinical trials have not established the optimal type, sequence, and duration of interventions for people at ultrahigh risk of psychosis. Objective: To determine the effectiveness of a sequential and adaptive intervention strategy for individuals at ultrahigh risk of psychosis. Design, Setting, and Participants: The Staged Treatment in Early Psychosis (STEP) sequential multiple assignment randomized trial took place within the clinical program at Orygen, Melbourne, Australia. Individuals aged 12 to 25 years who were seeking treatment and met criteria for ultrahigh risk of psychosis according to the Comprehensive Assessment of At-Risk Mental States were recruited between April 2016 and January 2019. Of 1343 individuals considered, 342 were recruited. Interventions: Step 1: 6 weeks of support and problem solving (SPS); step 2: 20 weeks of cognitive-behavioral case management (CBCM) vs SPS; and step 3: 26 weeks of CBCM with fluoxetine vs CBCM with placebo with an embedded fast-fail option of ω-3 fatty acids or low-dose antipsychotic medication. Individuals who did not remit progressed through these steps; those who remitted received SPS or monitoring for up to 12 months. Main Outcomes and Measures: Global Functioning: Social and Role scales (primary outcome), Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Montgomery-Åsberg Depression Rating Scale, quality of life, transition to psychosis, and remission and relapse rates. Results: The sample comprised 342 participants (198 female; mean [SD] age, 17.7 [3.1] years). Remission rates, reflecting sustained symptomatic and functional improvement, were 8.5%, 10.3%, and 11.4% at steps 1, 2, and 3, respectively. A total of 27.2% met remission criteria at any step. Relapse rates among those who remitted did not significantly differ between SPS and monitoring (step 1: 65.1% vs 58.3%; step 2: 37.7% vs 47.5%). There was no significant difference in functioning, symptoms, and transition rates between SPS and CBCM and between CBCM with fluoxetine and CBCM with placebo. Twelve-month transition rates to psychosis were 13.5% (entire sample), 3.3% (those who ever remitted), and 17.4% (those with no remission). Conclusions and Relevance: In this sequential multiple assignment randomized trial, transition rates to psychosis were moderate, and remission rates were lower than expected, partly reflecting the ambitious criteria set and challenges with real-world treatment fidelity and adherence. While all groups showed mild to moderate functional and symptomatic improvement, this was typically short of remission. While further adaptive trials that address these challenges are needed, findings confirm substantial and sustained morbidity and reveal relatively poor responsiveness to existing treatments. Trial Registration: ClinicalTrials.gov Identifier: NCT02751632.

Cortical and subcortical brain morphometry abnormalities in youth at clinical high-risk for psychosis and individuals with early illness schizophrenia.

Neuroimaging studies have documented morphometric brain abnormalities in schizophrenia, but less is known about them in individuals at clinical high-risk for psychosis (CHR-P), including how they compare with those observed in early schizophrenia (ESZ). Accordingly, we implemented multivariate profile analysis of regional morphometric profiles in CHR-P (n = 89), ESZ (n = 93) and healthy controls (HC; n = 122). ESZ profiles differed from HC and CHR-P profiles, including 1) cortical thickness: significant level reduction and regional non-parallelism reflecting widespread thinning, except for entorhinal and pericalcarine cortex, 2) basal ganglia volume: significant level increase and regional non-parallelism reflecting larger caudate and pallidum, and 3) ventricular volume: significant level increase with parallel regional profiles. CHR-P and ESZ cerebellar profiles showed significant non-parallelism with HC profiles. Regional profiles did not significantly differ between groups for cortical surface area or subcortical volume. Compared to CHR-P followed for ≥18 months without psychosis conversion (n = 31), CHR-P converters (n = 17) showed significant non-parallel ventricular volume expansion reflecting specific enlargement of lateral and inferolateral regions. Antipsychotic dosage in ESZ was significantly correlated with frontal cortical thinning. Results suggest that morphometric abnormalities in ESZ are not present in CHR-P, except for ventricular enlargement, which was evident in CHR-P who developed psychosis.

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.

Effect of Technology-Enhanced Screening in Addition to Standard Targeted Clinician Education on the Duration of Untreated Psychosis: A Cluster Randomized Clinical Trial.

Importance: Reducing the duration of untreated psychosis (DUP) is essential to improving outcomes for people with first-episode psychosis (FEP). Current US approaches are insufficient to reduce DUP to international standards of less than 90 days. Objective: To determine whether population-based electronic screening in addition to standard targeted clinician education increases early detection of psychosis and decreases DUP, compared with clinician education alone. Design, Setting, and Participants: This cluster randomized clinical trial included individuals aged 12 to 30 years presenting for services between March 2015 and September 2017 at participating sites that included community mental health clinics and school support and special education services. Eligible participants were referred to the Early Diagnosis and Preventative Treatment (EDAPT) Clinic. Data analyses were performed in September and October 2019 for the primary and secondary analyses, with the exploratory subgroup analyses completed in May 2021. Interventions: All sites in both groups received targeted education about early psychosis for health care professionals. In the active screening group, clients also completed the Prodromal Questionnaire-Brief using tablets at intake; referrals were based on those scores and clinical judgment. In the group receiving treatment as usual (TAU), referrals were based on clinical judgment alone. Main Outcomes and Measures: Primary outcomes included DUP, defined as the period from full psychosis onset to the date of the EDAPT diagnostic telephone interview, and the number of individuals identified with FEP or a psychosis spectrum disorder. Exploratory analyses examined differences by site type, completion rates between conditions, and days from service entry to telephone interview. Results: Twenty-four sites agreed to participate, and 12 sites were randomized to either the active screening or TAU group. However, only 10 community clinics and 4 school sites were able to fully implement population screening and were included in the final analysis. The total potentially eligible population size within each study group was similar, with 2432 individuals entering at active screening group sites and 2455 at TAU group sites. A total of 303 diagnostic telephone interviews were completed (178 [58.7%] female individuals; mean [SD] age, 17.09 years [4.57]). Active screening sites reported a significantly higher detection rate of psychosis spectrum disorders (136 cases [5.6%], relative to 65 [2.6%]; P < .001) and referred a higher proportion of individuals with FEP and DUP less than 90 days (13 cases, relative to 4; odds ratio, 0.30; 95% CI, 0.10-0.93; P = .03). There was no difference in mean (SD) DUP between groups (active screening group, 239.0 days [207.4]; TAU group 262.3 days [170.2]). Conclusions and Relevance: In this cluster trial, population-based technology-enhanced screening across community settings detected more than twice as many individuals with psychosis spectrum disorders compared with clinical judgment alone but did not reduce DUP. Screening could identify people undetected in US mental health services. Significant DUP reduction may require interventions to reduce time to the first mental health contact. Trial Registration: ClinicalTrials.gov Identifier: NCT02841956.

Youth Mental Health Screening and Linkage to Care.

One Mind, in partnership with Meadows Mental Health Policy Institute, convened several virtual meetings of mental health researchers, clinicians, and other stakeholders in 2020 to identify first steps toward creating an initiative for early screening and linkage to care for youths (individuals in early adolescence through early adulthood, ages 10-24 years) with mental health difficulties, including serious mental illness, in the United States. This article synthesizes and builds on discussions from those meetings by outlining and recommending potential steps and considerations for the development and integration of a novel measurement-based screening process in youth-facing school and medical settings to increase early identification of mental health needs and linkage to evidence-based care. Meeting attendees agreed on an initiative incorporating a staged assessment process that includes a first-stage brief screener for several domains of psychopathology. Individuals who meet threshold criteria on the first-stage screener would then complete an interview, a second-stage in-depth screening, or both. Screening must be followed by recommendations and linkage to an appropriate level of evidence-based care based on acuity of symptoms endorsed during the staged assessment. Meeting attendees proposed steps and discussed additional considerations for creating the first nationwide initiative for screening and linkage to care, an initiative that could transform access of youths to mental health screening and care.

Field Visit Contact Rate by Mobile Crisis Teams as a Crisis System Performance Metric.

OBJECTIVE: The authors investigated associations between rates of contact with individuals in distress during field visits by mobile crisis teams and client and referral source characteristics. METHODS: In this retrospective observational study of an urban mobile crisis program, call logs (N=2,581) were coded for whether an attempted field visit resulted in a client evaluation. Logistic regression analyses examined potential associations with client age, gender, race-ethnicity, primary language, living situation, insurance, and referral source. RESULTS: Contact was made with 77% of adults and 97% of children referred to mobile crisis teams. Field visit contact rates differed by age. Unsuccessful visits were more likely when the referral source was from institutional settings than from individuals. CONCLUSIONS: Approximately one-quarter of attempted field visits with adults by an urban mobile crisis team were not completed, particularly among referrals from institutional settings. As mobile crisis services proliferate, field visit contact rate could be a key performance metric for these critical services.

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.

Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia.

N-methyl-D-aspartate receptor (NMDAR) hypofunction is a leading pathophysiological model of schizophrenia. Resting-state functional magnetic resonance imaging (rsfMRI) studies demonstrate a thalamic dysconnectivity pattern in schizophrenia involving excessive connectivity with sensory regions and deficient connectivity with frontal, cerebellar, and thalamic regions. The NMDAR antagonist ketamine, when administered at sub-anesthetic doses to healthy volunteers, induces transient schizophrenia-like symptoms and alters rsfMRI thalamic connectivity. However, the extent to which ketamine-induced thalamic dysconnectivity resembles schizophrenia thalamic dysconnectivity has not been directly tested. The current double-blind, placebo-controlled study derived an NMDAR hypofunction model of thalamic dysconnectivity from healthy volunteers undergoing ketamine infusions during rsfMRI. To assess whether ketamine-induced thalamic dysconnectivity was mediated by excess glutamate release, we tested whether pre-treatment with lamotrigine, a glutamate release inhibitor, attenuated ketamine's effects. Ketamine produced robust thalamo-cortical hyper-connectivity with sensory and motor regions that was not reduced by lamotrigine pre-treatment. To test whether the ketamine thalamic dysconnectivity pattern resembled the schizophrenia pattern, a whole-brain template representing ketamine's thalamic dysconnectivity effect was correlated with individual participant rsfMRI thalamic dysconnectivity maps, generating "ketamine similarity coefficients" for people with chronic (SZ) and early illness (ESZ) schizophrenia, individuals at clinical high-risk for psychosis (CHR-P), and healthy controls (HC). Similarity coefficients were higher in SZ and ESZ than in HC, with CHR-P showing an intermediate trend. Higher ketamine similarity coefficients correlated with greater hallucination severity in SZ. Thus, NMDAR hypofunction, modeled with ketamine, reproduces the thalamic hyper-connectivity observed in schizophrenia across its illness course, including the CHR-P period preceding psychosis onset, and may contribute to hallucination severity.

Online Psychosis Screening: Characterizing an Underexamined Population to Improve Access and Equity.

OBJECTIVE: Online resources represent an important avenue to identify and support individuals who may be experiencing symptoms of psychosis but have yet to engage in care. Understanding the experiences and needs of this group is critical to inform outreach for early psychosis and improve outcomes by addressing barriers to early treatment. METHODS: The authors conducted a retrospective, explorative, cross-sectional analysis by using data collected by Mental Health America as part of their online psychosis screening and support program. Data included scores from the Prodromal Questionnaire-Brief, basic demographic information, and respondents' plans for next steps. RESULTS: Of 120,937 respondents, most (82.1%) reported distressing psychosis-like experiences at levels sufficient to merit a referral to specialty care for additional evaluation. However, only 17.1% planned to seek treatment as a next step, with most (53.6%) wanting instead more information. Higher distress was only weakly associated with the plan to seek treatment. In the multivariable analysis, respondents who were younger; lesbian, gay, bisexual, transgender, or queer; or Native American or who had lower income reported the greatest symptom-related distress. Younger and higher-income respondents were less likely to plan to seek treatment next. Across race-ethnicity, African Americans were most likely to plan to seek treatment. CONCLUSIONS: Most respondents reported that psychosis-like experiences caused significant distress, but they did not plan to seek treatment next. Addressing this treatment gap requires careful consideration regarding what services individuals want, how services should be presented, and what barriers may limit help seeking. These steps are critical to improve access to early intervention for individuals with psychosis spectrum disorders.

Baseline data of a sequential multiple assignment randomized trial (STEP study).

AIM: Research has shown that preventative intervention in individuals at ultra-high risk of psychosis (UHR) improves symptomatic and functional outcomes. The staged treatment in early psychosis (STEP) trial aims to determine the most effective type, timing and sequence of interventions in the UHR population by sequentially studying the effectiveness of (1) support and problem solving, (2) cognitive-behavioural case management and (3) antidepressant medication with an embedded fast-fail option of (4) omega-3 fatty acids or low-dose antipsychotic medication. This paper presents the recruitment flow and baseline clinical characteristics of the sample. METHODS: STEP is a sequential multiple assignment randomized trial. We present the baseline demographics, clinical characteristics and acceptability and feasibility of this treatment approach as indicated by the flow of participants from first contact up until enrolment into the trial. Recruitment took place between April 2016 and January 2019. RESULTS: Of 1343, help-seeking young people who were considered for participation, 402 participants were not eligible and 599 declined/disengaged, resulting in a total of 342 participants enrolled in the study. The most common reason for exclusion was an active prescription of antidepressant medication. Eighty-five percent of the enrolled sample had a non-psychotic DSM-5 diagnosis and symptomatic/functional measures showed a moderate level of clinical severity and functional impairment. DISCUSSION: The present study demonstrates the acceptability and participant's general positive appraisal of sequential treatment. It also shows, in line with other trials in UHR individuals, a significant level of psychiatric morbidity and impairment, demonstrating the clear need for care in this group and that treatment is appropriate.

Thalamic dysconnectivity in the psychosis risk syndrome and early illness schizophrenia.

BACKGROUND: Schizophrenia (SZ) is associated with thalamic dysconnectivity. Compared to healthy controls (HCs), individuals with SZ have hyperconnectivity with sensory regions, and hypoconnectivity with cerebellar, thalamic, and prefrontal regions. Despite replication of this pattern in chronically ill individuals, less is known about when these abnormalities emerge in the illness course and if they are present prior to illness onset. METHODS: Resting-state functional magnetic resonance imaging data were collected from psychosis risk syndrome (PRS) youth (n = 45), early illness SZ (ESZ) (n = 74) patients, and HCs (n = 85). Age-adjusted functional connectivity, seeded from the thalamus, was compared among the groups. RESULTS: Significant effects of group were observed in left and right middle temporal regions, left and right superior temporal regions, left cerebellum, and bilateral thalamus. Compared to HCs, ESZ demonstrated hyperconnectivity to all temporal lobe regions and reduced connectivity with cerebellar, anterior cingulate, and thalamic regions. Compared to HCs, PRS demonstrated hyperconnectivity with the left and right middle temporal regions, and hypoconnectivity with the cerebellar and other thalamic regions. Compared to PRS participants, ESZ participants were hyperconnected to temporal regions, but did not differ from PRS in hypoconnectivity with cerebellar and thalamic regions. Thalamic dysconnectivity was unrelated to positive symptom severity in ESZ or PRS groups. CONCLUSIONS: PRS individuals demonstrated an intermediate level of thalamic dysconnectivity, whereas ESZ showed a pattern consistent with prior observations in chronic samples. These cross-sectional findings suggest that thalamic dysconnectivity may occur prior to illness onset and become more pronounced in early illness stages.

Durable Cognitive Gains and Symptom Improvement Are Observed in Individuals With Recent-Onset Schizophrenia 6 Months After a Randomized Trial of Auditory Training Completed Remotely.

OBJECTIVE: Cognitive impairment in schizophrenia predicts functional outcomes and is largely unresponsive to pharmacology or psychotherapy; it is thus a critical unmet treatment need. This article presents the impact of remotely completed, intensive, targeted auditory training (AT) vs control condition computer games (CG) in a double-blind randomized trial in young adults with recent-onset schizophrenia. METHOD: Participants (N = 147) were assessed for cognition, symptoms, and functioning at baseline, post-intervention, and at 6-month follow-up. All participants were provided with laptop computers and were instructed to complete 40 hours remotely of training or computer games. An intent-to-treat analysis (N = 145) was performed using linear mixed models with time modeled as a continuous variable. Planned contrasts tested the change from baseline to post-training, baseline to 6-month follow-up, and post-training to 6-month follow-up. RESULTS: Global Cognition, which had improved in the AT group relative to the CG group at post-training, showed durable gains at 6-month follow-up in an omnibus group-by-time interaction test (F(1,179) = 4.80, P = .030), as did Problem-Solving (F(1,179) = 5.13, P = .025), and Speed of Processing improved at trend level significance (F(1,170) = 3.80, P = .053). Furthermore, the AT group showed significantly greater improvement than the CG group in positive symptoms (F(1,179) = 4.06, P = .045). CONCLUSIONS: These results provide the first evidence of durable cognitive gains and symptom improvement at follow-up of cognitive training (CT) in early schizophrenia completed independently and remotely. While functioning did not show significant improvement, these findings suggest that intensive targeted CT of auditory processing is a promising component of early intervention to promote recovery from psychosis.