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BackgroundSeverity of negative symptoms has been associated with poor functioning, cognitive deficits, and defeatist beliefs in schizophrenia patients. However, one area that remains understudied is persistent negative symptoms (PNS). Negative symptoms, including PNS, have been observed in those at clinical high-risk (CHR) for psychosis. The aim of this study was to determine if PNS were associated with functioning, neurocognition, and defeatist beliefs in a CHR sample.MethodCHR participants (n = 764) were recruited for the North American Prodrome Longitudinal Study. Negative symptoms were rated on the Scale of Psychosis-risk Symptoms. Generalized linear mixed models for repeated measures were used to examine changes over time between and within groups (PNS vs non-PNS).ResultsThe PNS group (n = 67) had significant deficits in functioning at baseline, 6, 12, 18, and 24-months compared to the non-PNS group (n = 673). Functioning improved over time in the non-PNS group, while functioning in the PNS group remained relatively stable and poor over a two-year period. A consistent trend emerged demonstrating higher defeatist beliefs in the PNS group; however, this result was lost when controlling for persistent depressive symptoms. There were no significant differences between the groups on neurocognition, social cognition, and transition to psychosis.ConclusionsPNS exist in youth at CHR for psychosis, resulting in significant and persistent functional impairment, which remains when controlling for persistent depressive symptoms. PNS remain even in CHR youth who do not transition to psychosis. Thus, PNS may represent an unmet therapeutic need in CHR populations for which there are currently no effective treatments.

Social cognition deficits have been observed in individuals at clinical high risk (CHR) for psychosis. Longitudinal change in social cognition were analyzed in CHR individuals from the North American Prodrome Longitudinal Study (NAPLS2) based on outcome at 24 months. Individuals (n = 359) were classified into remission, symptomatic, prodromal progression and transition to psychosis (CHR-T) groups. Social cognition was assessed using theory of mind, emotion perception, and social perception tasks. There were no differences at baseline or 24 months between the groups on social cognition. Non-transition groups improved significantly over time on social cognition, but CHR-T did not show this effect.

Machine learning techniques were used to identify highly informative early psychosis self-report items and to validate an early psychosis screener (EPS) against the Structured Interview for Psychosis-risk Syndromes (SIPS). The Prodromal Questionnaire-Brief Version (PQ-B) and 148 additional items were administered to 229 individuals being screened with the SIPS at 7 North American Prodrome Longitudinal Study sites and at Columbia University. Fifty individuals were found to have SIPS scores of 0, 1, or 2, making them clinically low risk (CLR) controls; 144 were classified as clinically high risk (CHR) (SIPS 3-5) and 35 were found to have first episode psychosis (FEP) (SIPS 6). Spectral clustering analysis, performed on 124 of the items, yielded two cohesive item groups, the first mostly related to psychosis and mania, the second mostly related to depression, anxiety, and social and general work/school functioning. Items within each group were sorted according to their usefulness in distinguishing between CLR and CHR individuals using the Minimum Redundancy Maximum Relevance procedure. A receiver operating characteristic area under the curve (AUC) analysis indicated that maximal differentiation of CLR and CHR participants was achieved with a 26-item solution (AUC=0.899±0.001). The EPS-26 outperformed the PQ-B (AUC=0.834±0.001). For screening purposes, the self-report EPS-26 appeared to differentiate individuals who are either CLR or CHR approximately as well as the clinician-administered SIPS. The EPS-26 may prove useful as a self-report screener and may lead to a decrease in the duration of untreated psychosis. A validation of the EPS-26 against actual conversion is underway.

Aim: Examining ethnically related variables in evaluating those at risk for psychosis is critical. This study investigated sociodemographic and clinical characteristics of Latino versus non-Latino clinical high-risk (CHR) subjects and healthy control (HC) subjects in the first North American Prodrome Longitudinal Study. Methods: Fifty-six Latino CHR subjects were compared to 25 Latino HC and 423 non-Latino CHR subjects across clinical and demographic variables. Thirty-nine of the 56 CHR subjects completed at least one subsequent clinical evaluation over the 2.5-year period with 39% developing a psychotic illness. Characteristics of Latino CHR subjects who later converted to psychosis ('converters') were compared to those who did not ('non-converters'). Results: Latino CHR subjects were younger than non-Latino CHR subjects and had less education than Latino HC subjects and non-Latino CHR counterparts. Latino CHR converters had higher scores than Latino non-converters on the Structured Interview for Prodromal Syndromes total negative symptoms that were accounted for by decreased expression of emotion and personal hygiene/social attentiveness subsections. Latino CHR converters scored lower on the global functioning:social scale, indicating worse social functioning than Latino non-converters. Conclusion: Based on this sample, Latino CHR subjects may seek treatment earlier and have less education than non-Latino CHR subjects. Deficits in social functioning and impaired personal hygiene/social attentiveness among Latino CHR subjects predicted later psychosis and may represent important areas for future study. Larger sample sizes are needed to more thoroughly investigate the observed ethnic differences and risk factors for psychosis in Latino youth.

BackgroundA series of research reports has indicated that the use of substances such as cannabis, alcohol and tobacco are higher in youth at clinical high risk (CHR) of developing psychosis than in controls. Little is known about the longitudinal trajectory of substance use, and findings on the relationship between substance use and later transition to psychosis in CHR individuals are mixed.MethodAt baseline and 6- and 12-month follow-ups, 735 CHR and 278 control participants completed the Alcohol and Drug Use Scale and a cannabis use questionnaire. The longitudinal trajectory of substance use was evaluated with linear mixed models.ResultsCHR participants endorsed significantly higher cannabis and tobacco use severity, and lower alcohol use severity, at baseline and over a 1-year period compared with controls. CHR youth had higher lifetime prevalence and frequency of cannabis, and were significantly younger upon first use, and were more likely to use alone and during the day. Baseline substance use did not differentiate participants who later transitioned to psychosis (n = 90) from those who did not transition (n = 272). Controls had lower tobacco use than CHR participants with a prodromal progression clinical outcome and lower cannabis use than those with a psychotic clinical outcome at the 2-year assessment.ConclusionsIn CHR individuals cannabis and tobacco use is higher than in controls and this pattern persists across 1 year. Evaluation of clinical outcome may provide additional information on the longitudinal impact of substance use that cannot be detected through evaluation of transition/non-transition to psychosis alone.

ObjectiveCannabis use has been examined as a predictor of psychosis in clinical high-risk (CHR) samples, but little is known about the impact of other substances on this relationship.MethodSubstance use was assessed in a large sample of CHR participants (N = 370, mean age = 18.3) enrolled in the multisite North American Prodrome Longitudinal Study Phase 1 project. Three hundred and forty-one participants with cannabis use data were divided into groups: No Use (NU, N = 211); Cannabis Use without impairment (CU, N = 63); Cannabis Abuse/Dependence (CA/CD, N = 67). Participants (N = 283) were followed for ≥2 years to determine psychosis conversion.ResultsAlcohol (45.3%) and cannabis (38.1%) were the most common substances. Cannabis use groups did not differ on baseline attenuated positive symptoms. Seventy-nine of 283 participants with cannabis and follow-up data converted to psychosis. Survival analysis revealed significant differences between conversion rates in the CA/CD group compared with the No Use (P = 0.031) and CU group (P = 0.027). CA/CD also significantly predicted psychosis in a regression analysis, but adjusting for alcohol use weakened this relationship.ConclusionThe cannabis misuse and psychosis association was confounded by alcohol use. Non-impairing cannabis use was not related to psychosis. Results highlight the need to control for other substance use, so as to not overstate the cannabis/psychosis connection.

Background: The default mode network (DMN) is a set of brain regions typically activated at rest and suppressed during extrinsic cognition. Schizophrenia has been associated with deficient DMN suppression, though the extent to which DMN dysfunction predate

Objective: Discontinuities in health insurance coverage may make it difficult for individuals early in psychosis to receive the services that are critical in determining long-term outcome. This study reports on the rates and continuity of insurance coverage among a cohort of early-psychosis patients enrolled in Specialized Treatment Early in Psychosis (STEP) at the Connecticut Mental Health Center.Methods: Insurance status at baseline, six months, and 12 months was collected from 82 participants from a combination of self-reports, clinical chart review, clinician reports, and a database maintained by the state Department of Social Services.Results: A total of 34 participants did not know whether they had health insurance or did not appear for follow-up assessments at six and 12 months. Among the remaining 48 participants, at baseline 18 had private insurance, 13 had public insurance, and 16 had no insurance. By the 12-month assessment, 13 (72%) privately insured and five (38%) publicly insured participants had lost coverage; less than one-third of the 48 participants (N=14) maintained continuous coverage.Conclusions: Specialty services for individuals experiencing early psychosis should address the difficulty of maintaining health insurance coverage during a period of illness in which continuity of care is critical to recovery. [ABSTRACT FROM AUTHOR]

We compared psychotropic medication adherence rates in monolingual-Hispanics (mostly Puerto Ricans), bilingual-Hispanics, and African-Americans as compared with Caucasians in 122 subjects recruited from a community mental health center (CMHC). After controlling for possible confounding factors monolingual-Hispanics and African-Americans had lower medication adherence rates (77% and 68%, respectively) than Caucasians (90%). Older age was a significant predictor of higher adherence among monolingual-Hispanics. Depressive symptoms were associated with lower adherence and more years of past treatment with higher adherence among Caucasians. Further studies are needed to better understand and improve adherence among Hispanics and African-Americans. [ABSTRACT FROM AUTHOR]

Context: Panic disorder (PD) may be treated with drugs, psychosocial intervention, or both, but the relative and combined efficacies have not been evaluated in an unbiased fashion.Objective: To evaluate whether drug and psychosocial therapies for PD are each more effective than placebo, whether one treatment is more effective than the other, and whether combined therapy is more effective than either therapy alone.Design and Setting: Randomized, double-blind, placebo-controlled clinical trial conducted in 4 anxiety research clinics from May 1991 to April 1998.Patients: A total of 312 patients with PD were included in the analysis.Interventions: Patients were randomly assigned to receive imipramine, up to 300 mg/d, only (n=83); cognitive-behavioral therapy (CBT) only (n=77); placebo only (n=24); CBT plus imipramine (n=65); or CBT plus placebo (n=63). Patients were treated weekly for 3 months (acute phase); responders were then seen monthly for 6 months (maintenance phase) and then followed up for 6 months after treatment discontinuation.Main Outcome Measures: Treatment response based on the Panic Disorder Severity Scale (PDSS) and the Clinical Global Impression Scale (CGI) by treatment group.Results: Both imipramine and CBT were significantly superior to placebo for the acute treatment phase as assessed by the PDSS (response rates for the intent-to-treat [ITT] analysis, 45.8%, 48.7%, and 21.7%; P=.05 and P=.03, respectively), but were not significantly different for the CGI (48. 2%, 53.9%, and 37.5%, respectively). After 6 months of maintenance, imipramine and CBT were significantly more effective than placebo for both the PDSS (response rates, 37.8%, 39.5%, and 13.0%, respectively; P=.02 for both) and the CGI (37.8%, 42.1%, and 13.0%, respectively). Among responders, imipramine produced a response of higher quality. The acute response rate for the combined treatment was 60.3% for the PDSS and 64.1% for the CGI; neither was significantly different from the other groups. The 6-month maintenance response rate for combined therapy was 57.1% for the PDSS (P=.04 vs CBT alone and P=.03 vs imipramine alone) and 56.3% for the CGI (P=.03 vs imipramine alone), but not significantly better than CBT plus placebo in either analysis. Six months after treatment discontinuation, in the ITT analysis CGI response rates were 41.0% for CBT plus placebo, 31.9% for CBT alone, 19.7% for imipramine alone, 13% for placebo, and 26.3% for CBT combined with imipramine.Conclusions: Combining imipramine and CBT appeared to confer limited advantage acutely but more substantial advantage by the end of maintenance. Each treatment worked well immediately following treatment and during maintenance; CBT appeared durable in follow-up. JAMA. 2000;283:2529-2536 [ABSTRACT FROM AUTHOR]

To improve detection and management of diabetes at a community mental health center, a cross-sectional study of the prevalence and management of type 2 diabetes mellitus was conducted among patients receiving maintenance antipsychotic medication (N=494). Diabetes was more than two-and-a-half times as prevalent among participants (17.4%) as in the general population. Fourteen percent of patients classified as diabetic had previously undiagnosed disease, compared with national sample rates of over 30%. Impaired fasting glucose was found for 26% of the sample. Glucose dysregulation was common. The known poor cardiovascular profile of persons with serious mental illness, reflected in the high rates of tobacco use and obesity in the sample, requires contextualizing efforts to screen and monitor for diabetes within overall efforts to monitor cardiovascular health. [ABSTRACT FROM AUTHOR]

Which doses of atypical and typical antipsychotic drugs produce a near maximal response with minimal side effects in people with schizophrenia or schizoaffective disorder?METHODSDesign: Systematic review with meta-analysis.Data sources: MEDLINE, International Pharmaceutical Abstracts, CINAHL, PsycINFO, and the Cochrane Database of Systematic Reviews. Hand searches of reference lists plus data from Food and Drug Administration website, poster presentations, unpublished data from Cochrane reviews, conference abstracts, and manuscripts submitted for publication. Search date: December 2002.Study selection and analysis: Double blind, randomised controlled trials of people with schizophrenia or schizoaffective disorder comparing two or more doses of typical or atypical antipsychotics were eligible. Dose response curves were plotted and the median effective dose, defined as 50% of the maximum response (ED[50]), and the near maximal effective dose range (ED[85] to ED[95]) was established for each drug. Estimated equivalent doses were based on ED[50]. Meta-analysis determined whether medium and high doses vary in efficacy. The last-observation-carried-forward method and intent-to-treat sample were used for the meta-analysis. The possibility of other biases was explored using sensitivity analyses.Outcomes: Median effective dose (ED[50]) and the near maximal effective dose range (ED[85] to ED[95]). Schizophrenia symptoms were assessed in studies with the Positive and Negative Syndrome Scale (PANSS), the Brief Psychiatric Rating Scale, or the Clinical Global Rating Scale.MAIN RESULTSThe near maximal effective dose was determined for each drug (see http://www.ebmentalhealth.com/supplemental for table). Typical antipsychotics: the near maximal effective dose range for haloperidol was 3.3-10 mg/day. There was no evidence that higher doses of first generation antipsychotics were more effective than medium doses (3.3-10 mg/day haloperidol or equivalent). Atypical anti-psychotics: the near maximal efficacy dose for aripiprazole was 10 mg/day, clozapine >400 mg/day, olanzapine possibly >16 mg/ day, risperidone 4 mg/day, and ziprasidone 120 mg/day. Daily doses of 2 mg risperidone were about 50% less effective than higher doses. For olanzapine, 6 mg/day was 33% less effective than higher doses. For both atypical and typical antispychotics, there was no evidence that higher doses were less effective, arguing against a 'therapeutic window'.CONCLUSIONSThe doses reported are approximate (see notes) and treating people with schizophrenia empirically by varying doses is still recommended. Clinicians tend to use higher doses of typical antipsychotics than are needed. High doses have a no better or worse response than medium doses.NOTESThe range for individual patients may be wider than the estimated dose range for pharmacokinetic or pharmacodynamic reasons, or for patients in an acute exacerbated episode.There is also little information on people who are too psychotic to give informed consent, and different doses may be required in these situations. [ABSTRACT FROM AUTHOR]

Objective: Studies in first episode psychosis samples about status of cardiovascular risk factors have shown discordant results. We aimed to determine the 10-year risk of developing coronary heart disease in a sample of first episode psychosis patients referred to an early intervention clinic and compared the same with age, gender, and race matched controls from the U.S. National Health and Nutrition Examination Survey (NHANES).Method: We conducted a cross-sectional analysis of baseline data of 56 subjects enrolled in first episode psychosis clinic from April 2006 to January 2010. This sample was compared with age, gender, and race matched 145 individuals drawn from NHANES 2005-2006 database. Sociodemographic and clinical variables were collected. Physical examination including laboratory evaluation was used to screen for common medical illnesses. The 10-year risk of developing coronary heart disease was calculated by using a tool developed by the National Cholesterol Education Program (NCEP-ATP III).Results: There were elevated rates of smoking (46%) and hypertension (11%) albeit statistically significant differences from the control could not be demonstrated for these measures or weight, body mass index, or total or HDL cholesterol, fasting plasma glucose, status of diabetes and impaired fasting plasma glucose, HbA1C level. The 10-year median (range) risk of developing coronary heart disease in patients and controls was 1 (0-5)% and 0 (0-9)% respectively. The difference was not statistically significant.Conclusions: First episode psychosis patients do not present with significantly higher cardiovascular risk than age and race-matched controls despite clinically significant prevalence of individual risk factors. This sample presents an opportunity for early intervention for the primary prevention of cardiovascular morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: 22q11.2 deletion syndrome (22qDel) is a copy number variant that is associated with psychosis and other neurodevelopmental disorders. Adolescents who are at clinical high risk for psychosis (CHR) are identified based on the presence of subthreshold psychosis symptoms. Whether common neural substrates underlie these distinct high-risk populations is unknown. We compared functional brain measures in 22qDel and CHR cohorts and mapped the results to biological pathways., Methods: We analyzed 2 large multisite cohorts with resting-state functional magnetic resonance imaging data: 1) a 22qDel cohort (n = 164, 47% female) and typically developing (TD) control participants (n = 134, 56% female); and 2) a cohort of CHR individuals (n = 240, 41% female) and TD control participants (n = 149, 46% female) from the NAPLS-2 (North American Prodrome Longitudinal Study-2). We computed global brain connectivity (GBC), local connectivity (LC), and brain signal variability (BSV) across cortical regions and tested case-control differences for 22qDel and CHR separately. Group difference maps were related to published brain maps using autocorrelation-preserving permutation., Results: BSV, LC, and GBC were significantly disrupted in individuals with 22qDel compared with TD control participants (false discovery rate-corrected q < .05). Spatial maps of BSV and LC differences were highly correlated with each other, unlike GBC. In the CHR group, only LC was significantly altered versus the control group, with a different spatial pattern than the 22qDel group. Group differences mapped onto biological gradients, with 22qDel effects being strongest in regions with high predicted blood flow and metabolism., Conclusions: 22qDel carriers and CHR individuals exhibited different effects on functional magnetic resonance imaging temporal variability and multiscale functional connectivity. In 22qDel carriers, strong and convergent disruptions in BSV and LC that were not seen in CHR individuals suggest distinct functional brain alterations., (Copyright © 2024. Published by Elsevier Inc.)

Background and Hypothesis: In accordance with the Cognitive Model of Negative Symptoms, defeatist performance beliefs (DPBs) are an important psychosocial mechanism of negative symptoms in schizophrenia-spectrum groups. DPBs are also mediators of negative symptom improvement in clinical trials. Despite the clinical significance of DPBs and their inclusion as a mechanism of change measure in clinical trials, the psychometric properties of the DPB scale have not been examined in any schizophrenia-spectrum group., Study Design: This study evaluated the factor structure, reliability, and validity of the DPB scale in 943 schizophrenia and 250 clinical high-risk for psychosis (CHR) participants from multiple US sites. Confirmatory factor analyses tested competing factor structures: a unidimensional model-consistent with how DPBs are currently assessed-and multifactorial models with up to 4 factors identified with exploratory factor analyses., Study Results: Models with 3 and 4 factors provided superior fit compared to the unidimensional model, with an advantage for the 3-factor model. The 3-factor model, consisting of Overvaluing Success, Overvaluing Failure, and Overvaluing Social Evaluation factors, demonstrated good replicability, temporal stability, and measurement invariance in schizophrenia and CHR samples. Convergent validity was demonstrated via significant correlations with negative symptoms and functioning, but limited associations were present with neurocognition. Discriminant validity was supported by low correlations with positive symptoms., Conclusions: Findings support the validity and reliability of the 3-factor structure of the DPB scale across phases of psychosis. Use of a 3-factor structure may clarify the most critical DPB targets for negative symptom treatment and early prevention and intervention., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Mismatch negativity (MMN) event-related potential (ERP) component reduction, indexing N-methyl-D-aspartate receptor (NMDAR)-dependent auditory echoic memory and short-term plasticity, is a well-established biomarker of schizophrenia that is sensitive to psychosis risk among individuals at clinical high-risk (CHR-P). Based on the NMDAR-hypofunction model of schizophrenia, NMDAR-dependent plasticity is predicted to contribute to aberrant neurodevelopmental processes involved in the pathogenesis of schizophrenia during late adolescence or young adulthood, including gray matter loss. Moreover, stress and inflammation disrupt plasticity. Therefore, using data collected during the 8-center North American Prodrome Longitudinal Study (NAPLS-2), we explored relationships between MMN amplitudes and salivary cortisol, gray matter volumes, and inflammatory cytokines. Participants included 303 CHR-P individuals with baseline electroencephalography (EEG) data recorded during an MMN paradigm as well as structural magnetic resonance imaging (MRI) and salivary cortisol, of which a subsample (n = 57) also completed blood draws. More deficient MMN amplitudes were associated with greater salivary cortisol and pro-inflammatory cytokine levels in future CHR-Converters, but not among those who did not convert to psychosis within the next two years. More deficient MMN amplitude was also associated with smaller total gray matter volume across participants regardless of future clinical outcomes, and with subcortical gray matter volumes among future CHR-Converters only. These findings are consistent with the theory that deficient NMDAR-dependent plasticity results in an overabundance of weak synapses that are subject to over-pruning during psychosis onset, contributing to gray matter loss. Further, MMN plasticity mechanisms may interact with stress, cortisol, and neuroinflammatory processes, representing a proximal influence of psychosis., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Duncan has received research support for work unrelated to this project from Posit Science Inc, Auspex Pharmaceuticals, Teva Pharmaceuticals, and GrayMatters Health. Dr. Johannesen reports grants from the National Institute of Mental Health and received salary support during the conduct of the study and also receives compensation by salary and stock shares from Sage Therapeutics outside the submitted work. Dr. Light reports consulting for Astellas Pharma, NeuroSig, Neurocrine, Boehringer Ingelheim Pharmaceuticals, and Heptares Therapeutics outside the submitted work. Dr. Addington reports grants from the University of Calgary during the conduct of the study. Dr. Bearden reports grants from the National Institute of Mental Health during the conduct of the study and outside the submitted work and served on the scientific advisory board for One Mind outside the submitted work. Dr. Cornblatt reports grants from the National Institute of Mental Health during the conduct of the study. Dr. Perkins is a consultant to Sunovion and Alkermes. Dr Woods reports grants from the National Institute of Mental Health during the conduct of the study and outside the submitted work; grants from Substance Abuse and Mental Health Services Administration, Boehringer Ingelheim, Amarex, Teva, and One Mind outside the submitted work; personal fees from Boehringer Ingelheim, Takeda, and New England Research Institute outside the submitted work; and has a patent for US 8492418 B2 for a method of treating the schizophrenia prodrome issued. Dr. Cannon is a consultant to Boehringer Ingelheim Pharmaceuticals and Lundbeck A/S. No other disclosures were reported.

Background and Hypothesis: Social and academic adjustment deteriorate in the years preceding a psychotic disorder diagnosis. Analyses of premorbid adjustment have recently been extended into the clinical high risk for psychosis (CHR) syndrome to identify risk factors and developmental pathways toward psychotic disorders. Work so far has been at the between-person level, which has constrained analyses of premorbid adjustment, clinical covariates, and conversion to psychosis., Study Design: Growth-curve models examined longitudinal trajectories in retrospective reports of premorbid social and academic adjustment from youth at CHR (n = 498). Interaction models tested whether known covariates of premorbid adjustment problems (attenuated negative symptoms, cognition, and childhood trauma) were associated with different premorbid adjustment trajectories in converters vs non-converters (ie, participants who did/did not develop psychotic disorders within 2-year follow-up)., Study Results: Converters reported poorer social adjustment throughout the premorbid period. Converters who developed psychosis with an affective component reported poorer academic adjustment throughout the premorbid period than those who developed non-affective psychosis. Tentatively, baseline attenuated negative symptoms may have been associated with worsening social adjustment in the premorbid period for non-converters only. Childhood trauma impact was associated with fewer academic functioning problems among converters. Cognition effects did not differ based on conversion status., Conclusions: Premorbid social function is an important factor in risk for conversion to psychosis. Negative symptoms and childhood trauma had different relationships to premorbid functioning in converters vs non-converters. Mechanisms linking symptoms and trauma to functional impairment may be different in converters vs non-converters, suggesting possible new avenues for risk assessment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Neighborhood ethnoracial composition has been associated with schizophrenia, but mechanisms are unclear. This study investigates the moderators and mediators of the association between neighborhood ethnoracial diversity and positive symptoms among youth at clinical high-risk for psychosis (CHR-P) and healthy comparisons (HC). Data were collected as part of The North American Prodrome Longitudinal Study and included 492 youth at CHR-P and 136 HCs. Neighborhood ethnoracial diversity measures the probability that two people chosen at random will be from different ethnoracial groups. Attenuated positive symptoms were derived from the Scale of Prodromal Symptoms. Peer victimization and discriminatory experiences were constructed as latent variables. Using structural equation modeling, this study tested the relationship of these variables and included the following covariates: age, sex, neighborhood poverty, and depressive symptoms. Greater neighborhood ethnoracial diversity was associated with reduced positive symptoms among ethnoracial minorities at CHR-P (β=-3.78; 95 % CI [-6.61, -0.84]). Fewer life events of peer victimization (β=-0.13; 95 % CI [-0.24, -0.03]) leading to perceived ethnoracial discrimination (β=0.56; 95 % CI [0.45, 0.67]) mediated 15.06 % of this association. These findings deepen our understanding of the social determinants of psychosis and may help develop effective interventions to prevent psychosis, especially among ethnoracial minority youth at high risk., Competing Interests: Declaration of competing interest Dr. Cannon has served as a consultant for Boehringer-Ingelheim Pharmaceuticals and Lundbeck A S(-1). Dr. Mathalon has served as a consultant for Aptinyx, Boehringer-Ingelheim Pharmaceuticals, Cadent Therapeutics, and Greenwich Biosciences. Dr. Perkins has served as a consultant for Sunovion and Alkermes, has received research support from Boehringer-Ingelheim, and has received royalties from American Psychiatric Association Publishing. Dr. Woods has received investigator-initiated research support from Pfizer and sponsor-initiated research support from Auspex and Teva; he has served as a consultant for Biomedisyn (unpaid), Boehringer-Ingelheim, and Merck and as an unpaid consultant to DSM-5; he has been granted a patent for a method of treating prodromal schizophrenia with glycine; and he has received royalties from Oxford University Press. The other authors report no financial relationships with commercial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., (© 2024 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Introduction: Research has established that adverse childhood experiences (ACEs) confer risk for psychiatric diagnoses, and that protective factors moderate this association. Investigation into the effect of protective factors in the relationship between ACEs and internalizing disorders (e.g., depression, anxiety) is limited in high-risk groups. The present study investigated the relationship between ACEs and risk for internalizing disorders in youth at clinical high risk for psychosis (CHR-P) and tests the hypothesis that protective factors moderate this relationship., Methods: 688 participants aged 12-30 (M = 18; SD = 4.05) meeting criteria for CHR-P were administered measures of child adversity, protective factors (SAVRY), and diagnostic assessment (SCID- 5). Logistic regression tested whether ACEs predicted internalizing disorders. Moderation regression analyses determined whether these associations were weaker in the presence of protective factors., Results & Conclusions: Higher levels of ACEs predicted history of depressive disorder (β = 0.26(1.30), p < .001), self-harm/suicide attempts (β = 0.34(1.40), p < .001), and substance use (β = 0.14(1.15), p = .04). Childhood sexual abuse (β = 0.77(2.15), p = .001), emotional neglect (β = 0.38(1.46), p = .05), and psychological abuse (β = 0.42(1.52), p = .04), predicted self- harm/suicide attempts. Sexual abuse (β = 1.00 (2.72), p = .001), and emotional neglect (β = 0.53(1.71), p = .011), were also linked to depressive disorder. There was no association between ACEs and anxiety disorder, and no moderation effect of protective factors in the relationship between ACEs and psychiatric outcomes. These findings add nuance to a growing literature linking ACEs to psychopathology and highlight the importance of investigation into the mechanisms that may buffer this relationship., Competing Interests: Declaration of competing interest Authors declare they have no conflict of interest with respect to this study., (Published by Elsevier B.V.)

Background and Hypothesis: The Structured Interview for Psychosis-Risk Syndromes (SIPS) and other assessments of psychosis risk define clinical high risk for psychosis (CHR) by the presence of attenuated psychotic symptoms. Despite extensive research on attenuated psychotic symptoms, substantial questions remain about their internal psychometric structure and relationships to comorbid non-psychotic symptoms., Study Design: Hierarchical and bifactor models were developed for the SIPS in a large CHR sample (NAPLS-3, N = 787) and confirmed through preregistered replication in an independent sample (NAPLS-2, N = 1043). Criterion validity was tested through relationships with CHR status, comorbid symptoms/diagnoses, functional impairment, demographics, neurocognition, and conversion to psychotic disorders., Study Results: Most variance in SIPS items (75%-77%) was attributable to a general factor. Hierarchical and bifactor models included a general factor and five specific/lower-order factors (positive symptoms, eccentricity, avolition, lack of emotion, and deteriorated thought process). CHR participants were elevated on the general factor and the positive symptoms factor. The general factor was associated with depressive symptoms; functional impairment; and mood, anxiety, and schizotypal personality diagnoses. The general factor was the best predictor of psychotic disorders (d ≥ 0.50). Positive symptoms and eccentricity had specific effects on conversion outcomes. The deteriorated thought process was least meaningful/replicable., Conclusions: Attenuated psychotic symptoms, measured by the SIPS, have a complex hierarchical structure with a strong general factor. The general factor relates to internalizing symptoms and functional impairment, emphasizing the roles of general psychopathological distress/impairment in psychosis risk. Shared symptom variance complicates the interpretation of raw symptom scores. Broad transdiagnostic assessment is warranted to model psychosis risk accurately., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Attention Deficit Hyperactivity Disorder (ADHD) affects a significant proportion of the population and is associated with numerous adverse outcomes including lower educational attainment, occupational challenges, increased substance use, and various mental health issues including psychosis. This study examined the demographic, clinical, cognitive, social cognitive, and functional differences between youth at clinical high-risk (CHR) for psychosis with and without comorbid ADHD., Method: Data were drawn from the North American Prodrome Longitudinal Studies (NAPLS2 and NAPLS3), which included 764 and 710 CHR individuals, respectively. After applying exclusion criteria, the sample consisted of 271 CHR participants with ADHD and 1118 without ADHD. All data were examined cross-sectionally., Results: Compared with the non-ADHD group, the ADHD group was younger, had more difficulties with role functioning, premorbid functioning, and social cognition, were more likely to have a comorbid learning disorder, and reported less depression symptoms. There were no significant differences between the groups on positive or negative psychotic symptoms, transition rates, adverse events, or other comorbid disorders including substance use and depression., Discussion: Comorbid ADHD is likely not a significant predictor of transition to psychosis among CHR youth; however, those CHR with ADHD may experience symptoms at a younger age than those without and present with a distinct clinical profile., Competing Interests: All authors declare that they have no conflicts with respect to this paper., (© The Author(s) 2024. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Background and Hypothesis: Studying individuals at Clinical High Risk (CHR) for psychosis provides an opportunity to examine protective factors that predict resilient outcomes. Here, we present a model for the study of protective factors in CHR participants at the very highest risk for psychotic conversion based on the Psychosis Risk Calculator., Study Design: CHR participants (N = 572) from NAPLS3 were assessed on the Risk Calculator. Those who scored in the top half of the distribution and had 2 years of follow-up (N = 136) were divided into those who did not convert to psychosis (resilient, N = 90) and those who did (nonresilient, N = 46). Groups were compared based on candidate protective factors that were not part of the Risk Calculator. Better functional outcome was also examined as an outcome measure of resiliency. Study Results: Exploratory analyses suggest that Hispanic heritage, social engagement, desirable life experiences, premorbid functioning and IQ are all potential protective factors that predict resilient outcomes. Reduced startle reactivity, brain area and volume were also associated with greater resilience., Conclusions: The primary focus of CHR research has been the risk and prediction of psychosis, while less is known about protective factors. Clearly, a supportive childhood environment, positive experiences, and educational enrichment may contribute to better premorbid functioning and brain development, which in turn contribute to more resilient outcomes. Therapies focused on enhancing protective factors in the CHR population are logical preventive interventions that may benefit this vulnerable population. Future CHR research might use similar models to develop a "protective index" to predict resilient outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Insomnia and suicidal ideation (SI) are common in schizophrenia, including in individuals at clinical high-risk for psychosis (CHR-P). Previous studies have found associations between sleep disturbance, SI, and psychopathology in schizophrenia. We explored these associations in a CHR-P cohort. We leveraged data from CHR-P individuals in the North American Prodrome Longitudinal Studies (NAPLS-3) (n = 688) cohort. We investigated relationships between sleep disturbance (Scale of Prodromal Symptoms [SOPS]; Calgary Depression Scale for Schizophrenia [CDSS], and the Pittsburgh Sleep Quality Index [PSQI]), suicidal ideation (CDSS), and psychosis-risk symptoms. The prevalence of terminal insomnia, sleep disturbance, and SI in NAPLS3 was 25 %, 69 %, and 29 %, respectively. After controlling for potential confounders, multiple indices of sleep disturbance (SOPS, PSQI: OR = 1.05-1.40) were significant indicators of concurrent SI. Terminal insomnia was not associated with conversion to psychosis. Multiple indices of sleep problems were associated with higher total and subscale psychosis-risk symptom scores (β = 0.09-0.39). Sleep problems are prevalent and associated with SI and more severe psychosis-risk symptoms in CHR-P individuals. These findings underscore the importance of designing longitudinal intervention studies to investigate whether the treatment of sleep disturbances may reduce suicidality and symptoms in this population., Competing Interests: Declaration of competing interest We report that there are no conflicts of interest in relation to the subject of this study. In the past year, Dr. Miller received research support from NIMH, SMRI, and Augusta University; and Honoraria from Atheneum, Carlat Psychiatry, ClearView Healthcare Partners, Psychopharmacology Institute, and Psychiatric Times., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Although the clinical high risk for psychosis (CHR-P) criteria are widely used to ascertain individuals at heightened risk for imminent onset of psychosis, it remains controversial whether CHR-P status defines a diagnostic construct in its own right. In a previous study, CHR-P nonconverters were observed to follow 3 distinct trajectories in symptoms and functioning: remission, partial remission, and maintenance of symptoms and functional impairments at subthreshold levels of intensity., Methods: Here, we utilized the NAPLS3 (North American Prodrome Longitudinal Study phase 3) sample (N = 806) to determine whether 1) the same trajectory groups can be detected when assessing symptoms at 2-month intervals over an 8-month period and 2) the resulting trajectory groups differ from each other and from healthy control participants and converting CHR-P cases in terms of risk factors, comorbidities, and functional outcomes., Results: Three distinctive subgroups within the CHR nonconverters were identified, largely paralleling those observed previously. Importantly, these extracted groups, together with non-CHR control participants and CHR converters, differed from each other significantly on putative etiological risk factors (e.g., predicted risk scores, physiological and self-report measures of stress), affective comorbidities, and functional outcomes, thus providing converging evidence supporting the validity of the identified trajectory groups., Conclusions: This pattern, together with the fact that even the subgroup of CHR-P nonconverters who showed a remission trajectory deviated from healthy control participants, supports treating the CHR-P syndrome not only as a status that denotes risk for onset of full psychosis but also as a marker of ongoing distress for a population that is in need of interventions., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Hippocampal volume (HV) is sensitive to environmental influences. Under normative conditions in humans, HV increases linearly into childhood and asymptotes in early adulthood. Studies of humans and nonhuman animals have provided evidence of inverse relationships between several measures of stress and HV., Methods: Using structural equation modeling, this study aimed to characterize the relationships of age, basal cortisol, biological sex, and lifetime perceived stress with bilateral HV in a sample of healthy adolescents and adolescents at clinical high risk for psychosis (CHR-P) (N = 571, 43% female; age range = 12-19.9 years). This sample included 469 individuals at CHR-P and 102 healthy comparison participants from the combined baseline cohorts of the second and third NAPLS (North American Prodrome Longitudinal Study)., Results: A structural model that constrained the individual effects of basal cortisol and perceived stress to single path coefficients, and freely estimated the effects of age and biological sex in group models, optimized model fit and parsimony relative to other candidate models. Significant inverse relationships between basal cortisol and bilateral HV were observed in adolescents at CHR-P and healthy comparison participants. Significant sex differences in bilateral HV were also observed, with females demonstrating smaller HV than males in both groups., Conclusions: Multigroup structural equation modeling revealed heterogeneity in the relationships of age and biological sex with basal cortisol, lifetime perceived stress, and bilateral HV in individuals at CHR-P and healthy comparison participants. Moreover, the findings support previous literature indicating that elevated basal cortisol is a nonspecific risk factor for reduced HV., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The prodromal phase of schizophrenia provides an optimal opportunity to mitigate the profound functional disability that is often associated with fully expressed psychosis. Considerable evidence supports the importance of neurocognition in the development of interpersonal (social) and academic (role) skills. Further findings from adolescents and young adults at clinical high risk for developing psychosis (CHRP) suggest that treatment for functioning might be most effective when targeting early and specific neurocognitive deficits. The current study addresses this critical intervention issue by examining the potential of neurocognitive deficits at intake for predicting social and role functioning over time in CHR-P youth. The study included 345 CHR-P participants from the second phase of the North American Prodrome Longitudinal Study (NAPLS2) with baseline neurocognition and 2-year follow-up data on social and role functioning. Slower baseline processing speed consistently predicted poor social functioning over time, while attention deficits predicted poor role functioning at baseline and follow-up. In addition, the impact of processing speed and attention impairments on social and role functioning, respectively, persisted even when adjusting the regression models for attenuated positive, negative, and disorganized symptoms, and transition status. The current study demonstrates for, arguably the first time, that processing speed and attention are strongly predictive of social and role functioning over time, respectively, above and beyond the impact of symptoms and those CHR-P individuals that develop psychosis over the course of the study. These findings imply that early neurocognition is a critical treatment target linked to the developmental trajectory of social and role functioning., Competing Interests: Declaration of competing interest There are no conflicts of interest for any of the authors with respect to the data in this paper or for the study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sex differences have been observed in individuals with schizophrenia and for those at clinical high risk (CHR) for psychosis. However, specific differences in CHR individuals who transition to psychosis remain inconsistent and understudied. This study aimed to investigate sex differences in 156 CHR individuals who made the transition to psychosis. A wide range of demographics, positive and negative symptoms, depression, anxiety, social and role functioning, trauma, and substance use were assessed at baseline and symptoms and diagnoses at the time of transition. Fluctuations in positive and negative symptoms and different medications were also assessed. No sex differences were observed at baseline for those who later transitioned to psychosis. At transition, males were significantly more likely to be diagnosed as having schizophrenia or schizophreniform disorder and through the course of the study, males were more likely to be taking stimulants. Limitations in this study was the lack of longitudinal follow-up post transition. The study highlights the need for further research on sex differences in individuals who transition to psychosis. Understanding these differences can have implications for treatment and monitoring of CHR individuals., Competing Interests: Declaration of competing interest Authors declare they have no conflict of interest with respect to this study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Schizophrenia is a mental health condition that severely impacts well-being. Cognitive impairment is among its core features, often presenting well before the onset of overt psychosis, underscoring a critical need to study it in the psychosis proneness (clinical high risk; CHR) stage, to maximize the benefits of interventions and to improve clinical outcomes. However, given the heterogeneity of cognitive impairment in this population, a one-size-fits-all approach to therapeutic interventions would likely be insufficient. Thus, identifying cognitive subtypes in this population is crucial for tailored and successful therapeutic interventions. Here we identify, validate, and characterize cognitive subtypes in large CHR samples and delineate their baseline and longitudinal cognitive and functional trajectories., Methods: Using machine learning, we performed cluster analysis on cognitive measures in a large sample of CHR youth (n = 764), and demographically comparable controls (HC; n = 280) from the North American Prodrome Longitudinal Study (NAPLS) 2, and independently validated our findings with an equally large sample (NAPLS 3; n = 628 CHR, 84 HC). By utilizing several statistical approaches, we compared the clusters on cognition and functioning at baseline, and over 24 months of followup. We further delineate the conversion status within those clusters., Results: Two main cognitive clusters were identified, "impaired" and "intact" across all cognitive domains in CHR compared to HC. Baseline differences between the cognitively intact cluster and HC were found in the verbal abilities and attention and working memory domains. Longitudinally, those in the cognitively impaired cluster group demonstrated an overall floor effect and did not deteriorate further over time. However, a "catch up" trajectory was observed in the attention and working memory domain. This group had higher instances of conversion overall, with these converters having significantly more non-affective psychotic disorder diagnosis versus bipolar disorder, than those with intact cognition. In the cognitively intact group, we observed differences in trajectory based on conversion status, where those who start with intact cognition and later convert demonstrate a sharp decline in attention and functioning. Functioning was significantly better in the cognitively intact than in the impaired group at baseline. Most of the cognitive trajectories demonstrate a positive relationship with functional ones., Conclusion: Our findings provide evidence for intact and impaired cognitive subtypes in youth at CHR, independent of conversion status. They further indicate that attention and working memory are important to distinguish between the CHR with intact cognition and controls. The cognitively intact CHR group becomes less attentive after conversion, while the cognitively impaired one demonstrates a catch up trajectory on both attention and working memory. Overall, early evaluation, covering several cognitive domains, is crucial for identifying trajectories of improvement and deterioration for the purpose of tailoring intervention for improving outcomes in individuals at CHR for psychosis.

Schizophrenia spectrum disorders (SSDs) are characterized by substantial clinical and genetic heterogeneity. Multiple recurrent copy number variants (CNVs) increase risk for SSDs; however, how known risk CNVs and broader genome-wide CNVs influence clinical variability is unclear. The current study examined associations between borderline intellectual functioning or childhood-onset psychosis, known risk CNVs, and burden of deletions affecting genes in 18 previously validated neurodevelopmental gene-sets in 618 SSD individuals. CNV associations were assessed for replication in 235 SSD relatives and 583 controls, and 9,930 youth from the Adolescent Brain Cognitive Development (ABCD) Study. Known SSD- and neurodevelopmental disorder (NDD)-risk CNVs were associated with borderline intellectual functioning in SSD cases (odds ratios (OR) = 7.09 and 4.57, respectively); NDD-risk deletions were nominally associated with childhood-onset psychosis (OR = 4.34). Furthermore, deletion of genes involved in regulating gene expression during fetal brain development was associated with borderline intellectual functioning across SSD cases and non-cases (OR = 2.58), with partial replication in the ABCD cohort. Exploratory analyses of cortical morphology showed associations between fetal gene regulatory gene deletions and altered gray matter volume and cortical thickness across cohorts. Results highlight contributions of known risk CNVs to phenotypic variability in SSD and the utility of a neurodevelopmental framework for identifying mechanisms that influence phenotypic variability in SSDs, as well as the broader population, with implications for personalized medicine approaches to care.

The prediction error account of delusions has had success. However, its explanation of delusions with different contents has been lacking. Persecutory delusions and paranoia are the common unfounded beliefs that others have harmful intentions towards us. Other delusions include believing that one's thoughts or actions are under external control or that events in the world have specific personal meaning. We compare learning in two different cognitive tasks, probabilistic reversal learning and Kamin blocking, that have relationships to paranoid and non-paranoid delusion-like beliefs, respectively. We find that clinical high-risk status alone does not result in different behavioural results in the probabilistic reversal learning task but that an individual's level of paranoia is associated with excessive switching behaviour. During the Kamin blocking task, paranoid individuals learned inappropriately about the blocked cue. However, they also had decreased learning about the control cue, suggesting more general learning impairments. Non-paranoid delusion-like belief conviction (but not paranoia) was associated with aberrant learning about the blocked cue but intact learning about the control cue, suggesting specific impairments in learning related to cue combination. We fit task-specific computational models separately to behavioural data to explore how latent parameters vary within individuals between tasks and how they can explain symptom-specific effects. We find that paranoia is associated with low learning rates in the probabilistic reversal learning task and the blocking task. Non-paranoid delusion-like belief conviction is instead related to parameters controlling the degree and direction of similarity between cue updating during simultaneous cue presentation. These results suggest that paranoia and other delusion-like beliefs involve dissociable deficits in learning and belief updating, which, given the transdiagnostic status of paranoia, might have differential utility in predicting psychosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)