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Aim: Recent findings suggest that family-focused therapy (FFT) is effective for individuals at clinical high-risk for psychosis (CHR-P). As outcomes of CHR-P individuals are quite varied, certain psychosocial interventions may be differentially effective in subgroups. The present study examined change in positive symptoms for CHR-P individuals at different levels of predicted risk for conversion to psychosis who received either FFT, a brief form of family education termed enhanced care (EC) or treatment as usual. Methods: Participants were drawn from the North American Prodromal Longitudinal Study (NAPLS2). A subset of NAPLS2 participants completed a randomized study involving FFT or EC. The present study includes participants from the FFT-CHR sub-study and non-randomized NAPLS2 participants. Predicted risk of conversion was calculated using the Individualized Risk Calculator for Psychosis. Robust linear regressions evaluated whether the association between predicted risk of conversion and positive symptom change differed across intervention groups. Results: A total of 94 participants from the FFT-CHR sub-study (FFT-CHR n = 50, EC n = 44) and 401 non-randomized NAPLS2 participants were included in this study. There was a treatment group by predicted risk of conversion interaction that predicted positive symptom improvement: higher risk individuals improved more with FFT-CHR than EC or the non-randomized NAPLS group, whereas lower-risk individuals did not differ in positive symptom improvement across treatment groups (FFT-CHR vs EC: P =.03, �� = 20.27; FFT-CHR vs NAPLS2: P

Individuals face discrimination based on characteristics including race/ethnicity, gender, age, and disability. Discriminatory experiences (DE) are associated with poor psychological health in the general population and with worse outcomes among individuals at clinical high risk for psychosis (CHR). Though the brain is sensitive to stress, and brain structural change is a well-documented precursor to psychosis, potential relationships between DE and brain structure among CHR or healthy individuals are not known. This report assessed whether lifetime DE are associated with cortical thinning and clinical outcomes across time, after controlling for discrimination-related demographic factors among CHR individuals who ultimately do (N = 57) and do not convert to psychosis (N = 451), and healthy comparison (N = 208) participants in the North American Prodrome Longitudinal Study 2. Results indicate that DE are associated with thinner cortex across time in several cortical areas. Thickness in several right hemisphere regions partially mediates associations between DE and subsequent anxiety symptoms, but not attenuated positive symptoms of psychosis. This report provides the first evidence to date of an association between DE and brain structure in both CHR and healthy comparison individuals. Results also suggest that thinner cortex across time in areas linked with DE may partially explain associations between DE and cross-diagnostic indicators of psychological distress.

Prevailing models of psychosis risk incorporate positive subthreshold symptoms as defining features of risk or transition to psychotic disorders. Despite this, relatively few studies have focused on characterizing longitudinal symptom features, such as prevalence, concordance and structure, which may aid in refining methods and enhancing classification and prediction efforts. The present study aimed to fill these gaps using longitudinal 24-month follow-up data from the well-characterized NAPLS-2 multi-site investigation of youth at clinical high risk (CHR) who had (n = 86) and had not (n = 268) transitioned to a threshold psychotic disorder since baseline. At baseline, among sub-delusional ideas, unusual thought content and suspicious/persecutory thinking were very common in CHR youth, and were highly concordant. Perceptual abnormalities (P4) were also common across youth regardless of symptom course and eventual transition to psychosis. Grandiose ideas were rare. Exploratory factor analysis extracted two constituent factors at multiple follow-up intervals, but there was marked instability in the structure over 24 months, and clear indicators for a single positive symptom factor. Together these findings support suggestions to combine sub-delusional symptoms into a single symptom category for classification purposes, in efforts to reduce clinical heterogeneity and ease measurement burden.

Individuals at clinical high-risk (CHR) for psychosis comprise a heterogeneous group with respect to symptoms and functioning both at presentation and at a later outcome. Even those who do not develop psychosis are troubled by comorbid symptoms and poor functioning (Addington et al., 2018). A recent commentary in this journal (Woods et al., 2021) reports on several papers demonstrating that longitudinally CHR individuals are troubled by unresolved attenuated psychotic symptoms (APS), functional deficits, persistent negative symptoms, and depression. It is argued that before adequate treatments can be developed, a specific core battery of outcome variables is needed.

Evidence suggests that early trauma may have a negative effect on cognitive functioning in individuals with psychosis, yet the relationship between childhood trauma and cognition among those at clinical high risk (CHR) for psychosis remains unexplored. Our sample consisted of 626 CHR children and 279 healthy controls who were recruited as part of the North American Prodrome Longitudinal Study 2. Childhood trauma up to the age of 16 (psychological, physical, and sexual abuse, emotional neglect, and bullying) was assessed by using the Childhood Trauma and Abuse Scale. Multiple domains of cognition were measured at baseline and at the time of psychosis conversion, using standardized assessments. In the CHR group, there was a trend for better performance in individuals who reported a history of multiple types of childhood trauma compared with those with no/one type of trauma (Cohen d = 0.16). A history of multiple trauma types was not associated with greater cognitive change in CHR converters over time. Our findings tentatively suggest there may be different mechanisms that lead to CHR states. Individuals who are at clinical high risk who have experienced multiple types of childhood trauma may have more typically developing premorbid cognitive functioning than those who reported minimal trauma do. Further research is needed to unravel the complexity of factors underlying the development of at-risk states.

Background: Risk calculators are useful tools that can help clinicians and researchers better understand an individual's risk of conversion to psychosis. The North American Prodrome Longitudinal Study (NAPLS2) Individualized Risk Calculator has good predictive accuracy but could be potentially improved by the inclusion of a biomarker. Baseline cortisol, a measure of hypothalamic-pituitary-adrenal (HPA) axis functioning that is impacted by biological vulnerability to stress and exposure to environmental stressors, has been shown to be higher among individuals at clinical high-risk for psychosis (CHR���P) who eventually convert to psychosis than those who do not. We sought to determine whether the addition of baseline cortisol to the NAPLS2 risk calculator improved the performance of the risk calculator. Methods: Participants were drawn from the NAPLS2 study. A subset of NAPLS2 participants provided salivary cortisol samples. A multivariate Cox proportional hazards regression evaluated the likelihood of an individual's eventual conversion to psychosis based on demographic and clinical variables in addition to baseline cortisol levels. Results: A total of 417 NAPLS2 participants provided salivary cortisol and were included in the analysis. Higher levels of cortisol were predictive of conversion to psychosis in a univariate model (C-index = 0.59, HR = 21.5, p-value = 0.004). The inclusion of cortisol in the risk calculator model resulted in a statistically significant improvement in performance from the original risk calculator model (C-index = 0.78, SE = 0.028). Conclusions: Salivary cortisol is an inexpensive and non-invasive biomarker that could improve individual predictions about conversion to psychosis and treatment decisions for CHR-P individuals.

Comorbid diagnoses are common in youth who are at clinical high-risk (CHR) for developing psychosis, with depression being the most common. The aim of this paper is to examine depression over two years in a large sample of CHR youth who do not make the transition to psychosis, considering both categorical and dimensional ratings of depression severity. The sample consisted of 267 CHR youth who were followed for two years. Based on DSM-IV diagnoses over this time period, 100 CHR individuals never received a diagnosis of depression, 64 individuals continuously met criteria for depression, 92 individuals received a diagnosis of depression at one or more timepoints, and 11 participants had a diagnosis of depression only at 24-months. These groupings were supported by six-monthly ratings on the Calgary Depression Scale. The majority of this sample experienced a major depressive episode on more than one occasion, suggesting that depression and depressive symptoms identify a domain of substantial unmet clinical need. Recommendations are that depression in CHR youth and young adults should be monitored more frequently and that there is a need for clinical trials to address depression systematically in this vulnerable population.

Aim: Childhood Adversity (CA) is strongly linked to psychotic-like symptoms across the clinical spectrum, though the mechanisms underlying these associations remain poorly understood. Negative cognitive schemas are associated with both CA exposure and psychotic symptoms, highlighting the possibility that cognitive schemas may be a key risk pathway. The purpose of this study was to determine whether negative cognitive schemas mediate the association between CA and specific attenuated psychotic symptoms in a large sample of clinical-high risk youth. Given the variability in experiences that encompass CA (eg, abuse, neglect and poverty) and attenuated psychotic symptoms (eg, suspiciousness and perceptual abnormalities), we also tested whether these associations differ by CA type (threat vs deprivation) and attenuated positive psychotic symptom domain. Methods: Data were collected from 531 clinical-high risk youth between 12 and 35 years of age (mean = 18.80, SD = 4.21) who completed a clinical assessment that included the Structured Interview of Prodromal Syndromes (SIPS), Childhood Trauma and Abuse scale and questionnaires on cognitive schemas and depressive symptoms. Results: No direct effects of threat or deprivation exposure on any of the psychotic symptom domains were found. However, there was a unique indirect effect of threat, but not deprivation, on delusional thinking and suspiciousness through negative cognitive schemas about others. Conclusion: Cognitive vulnerability in the form of negative schemas about others may be one mechanism linking childhood threat experiences and attenuated psychotic symptoms. The results underscore the importance of targeting negative schemas in interventions to mitigate psychosis risk.

Background: While an established clinical outcome of high importance, social functioning has been emerging as possibly having a broader significance to the evolution of psychosis and long term disability. In the current study we explored the association between social decline, conversion to psychosis, and functional outcome in individuals at clinical high risk (CHR) for psychosis. Methods: 585 subjects collected in the North American Prodrome Longitudinal Study (NAPLS2) were divided into 236 Healthy Controls (HCs), and CHR subjects that developed psychosis (CHR + C, N = 79), or those that did not (Non-Converters, CHR-NC, N = 270). CHR + C subjects were further divided into those that experienced an atypical decline in social functioning prior to baseline (beyond typical impairment levels) when in min-to-late adolescence (CHR + C-SD, N = 39) or those that did not undergoing a decline (CHR + C-NSD, N = 40). Results: Patterns of poor functional outcomes varied across the CHR subgroups: CHR-NC (Poor Social 36.3%, Role 42.2%) through CHR + C-NSD (Poor Social 50%, Poor Role 67.5%) to CHR + C-SD (Poor Social 76.9%, Poor Role 89.7%) functioning. The two Converter subgroups had comparable positive symptoms at baseline. At 12 months, the CHR + C-SD group stabilized, but social functioning levels remained significantly lower than the other two subgroups. Conclusions: The current study demonstrates that pre-baseline social decline in mid-to-late adolescence predicts psychosis. In addition, we found that this social decline in converters is strongly associated with especially poor functional outcome and overall poorer prognosis. Role functioning, in contrast, has not shown similar predictor potential, and rather appears to be an illness indicator that worsens over time.

The North American Prodrome Longitudinal Study (NAPLS) is a consortium of nine programs focusing on youth at clinical high risk (CHR) for psychosis. Funded by the National Institute of Mental Health (NIMH), the sites are located at Emory University, Harvard University, University of Calgary, University of California at Los Angeles, at San Diego, and at San Francisco, University of North Carolina Chapel Hill, Yale University, and Zucker Hillside Hospital. There have been two previous endeavors completed by this consortium, known as NAPLS-1 and NAPLS-2. This paper first offers an overview of the methodology of the third phase of the NAPLS consortium, the second five-year prospective study NAPLS-3, which aims to determine mechanisms of the development of psychosis. In addition, we report on the ascertainment and demographics of the 710 CHR participants in NAPLS-3.

Objective: The authors sought to characterize differences in outcomes among help-seeking individuals at clinical high risk for psychosis by identifying covariant longitudinal patterns of symptoms and functioning. Methods: Group-based multitrajectory modeling was applied to longitudinal ratings of four symptom domains (positive, negative, disorganized, general) and general functioning among clinical high-risk individuals in an initial discovery sample (N=422). An independent sample (N=133) was used to test replicability. Results: Three trajectory groups were identified among clinical high-risk individuals in the discovery sample: group 1 (30%) exhibited substantial improvement across all domains, with half reaching positive outcomes for both functioning and positive symptoms; group 2 (49%) exhibited moderate impairments across domains, with approximately one-quarter meeting criteria for positive outcomes; the remaining participants (group 3; 22%) exhibited consistent levels of severe impairment across domains and did not experience positive outcomes. These trajectory groups and remission patterns were replicated in an independent sample. Conclusions: Replicable subgroups of help-seeking clinical high-risk cases can be ascertained based on distinctive profiles of change over time in symptoms and functioning. Within each of the three identified subgroups, similar patterns of change (i.e., rapid, moderate, or no improvement) were observed across the four symptom domains and functioning. This consistency of change over time across domains within each subgroup is a novel observation supporting the syndrome consistency of clinical high-risk symptoms and signs. The observed trajectory subgroups are suggestive of different degrees of need for clinical interventions, ranging from minimal or supportive for about one-third of cases to increasingly intensive among the remainder.

Objective: The 2-year risk of psychosis in persons who meet research criteria for a high-risk syndrome is about 15%225%; improvements in risk prediction accuracy would benefit the development and implementation of preventive interventions. The authors sought to assess polygenic risk score (PRS) prediction of subsequent psychosis in persons at high risk and to determine the impact of adding the PRS to a previously validated psychosis risk calculator. Methods: Persons meeting research criteria for psychosis high risk (N=764) and unaffected individuals (N=279) were followed for up to 2 years. The PRS was based on the latest schizophrenia and bipolar genome-wide association studies. Variables in the psychosis risk calculator included stressful life events, trauma, disordered thought content, verbal learning, information processing speed, and family history of psychosis. Results: For Europeans, the PRS varied significantly by group and was higher in the psychosis converter group compared with both the nonconverter and unaffected groups, but was similar for the nonconverter group compared with the unaffected group. For non-Europeans, the PRS varied significantly by group; the difference between the converters and nonconverters was not significant, but the PRS was significantly higher in converters than in unaffected individuals, and it did not differ between nonconverters and unaffected individuals. The R2liability (R2 adjusted for the rate of disease risk in the population being studied, here assuming a 2-year psychosis risk between 10% and 30%) for Europeans varied between 9.2% and 12.3% and for non-Europeans between 3.5% and 4.8%. The amount of risk prediction information contributed by the addition of the PRS to the risk calculator was less than severity of disordered thoughts and similar to or greater than for other variables. For Europeans, the PRS was correlated with risk calculator variables of information processing speed and verbal memory. Conclusions: The PRS discriminates psychosis converters from nonconverters and modestly improves individualized psychosis risk prediction when added to a psychosis risk calculator. The schizophrenia PRS shows promise in enhancing risk prediction in persons at high risk for psychosis, although its potential utility is limited by poor performance in persons of non-European ancestry.

Whilst elevations in basal cortisol levels have been reported among individuals at-risk for psychosis, the extent to which this represents hyperresponsivity of the hypothalamic-pituitary-adrenal (HPA) axis to psychosocial stressors encountered in the natural environment is currently unclear. We aimed to examine stressor-cortisol concordance among youth at clinical high-risk (CHR) for psychosis in the North American Prodrome Longitudinal Study 2 (NAPLS 2) and the relationship with clinical outcome. At baseline, CHR (N = 457) and healthy (N = 205) individuals provided salivary cortisol samples and completed daily stressor, life event, and childhood trauma measures. CHR youth were categorised as remitted, symptomatic, progression of positive symptoms, or psychosis conversion at the two-year follow-up. Within-group regression models tested associations between psychosocial stressors and cortisol; standardised beta coefficients (St��) were subsequently derived to enable within-group pooling of effect sizes across stressor types. After adjustment for potential confounders, all CHR subgroups reported greater exposure to life events and daily stressors, and more distress in relation to these events, relative to controls. All CHR groups were also more likely to experience childhood trauma; only CHR converters, however, were characterised by elevated basal cortisol. Daily stressor distress was significantly associated with cortisol in controls (�� = 0.60, 95% CI: 0.12���1.08) and CHR youth who converted to psychosis (�� = 0.91, 95% CI: 0.05���1.78). In controls only, life event exposure was associated with cortisol (�� = 0.45, 95% CI: 0.08���0.83). When pooled across stressors, stressor-cortisol concordance was substantially higher among CHR converters (St�� = 0.26, 95% CI: 0.07 to 0.44) relative to CHR progressed (St�� = 0.02, 95% CI: -0.11 to 0.15), symptomatic (St�� = 0.01, 95% CI: -0.11 to 0.12), and remitted groups (St�� = 0.00, 95% CI: -0.13 to 0.13); however, unexpectedly, healthy controls showed intermediate levels of concordance (St�� = 0.15, 95% CI: 0.05 to 0.26). In conclusion, whilst all CHR subgroups showed increased psychosocial stress exposure and distress relative to controls, only those who later converted to psychosis were characterised by significantly elevated basal cortisol levels. Moreover, only CHR converters showed a higher magnitude of stressor-cortisol concordance compared to controls, although confidence intervals overlapped considerably between these two groups. These findings do not support the notion that all individuals at CHR for psychosis show HPA hyperresponsiveness to psychosocial stressors. Instead, CHR individuals vary in their response to stressor exposure/distress, perhaps driven by genetic or other vulnerability factors.

The recognition of a prodromal period preceding the onset of frank psychosis dates back to its first descriptions. Despite insights gained from a prospective approach to the study of the Clinical High Risk syndrome for psychosis (CHR-P), a prospectively-based understanding of the duration of the psychosis prodrome and the factors that may influence is not well-established. Here we analyze data from the second North American Prodrome Longitudinal Study (NAPLS-2) to characterize prodrome duration in those who converted to psychosis. Of the 764 participants identified as being at CHR-P, 94 converted to psychosis and 92 of these had recorded estimates of prodrome onset. Estimates of prodrome duration were derived from CHR-P syndrome onset and conversion dates from the Structured Interview for Psychosis-risk Syndromes. Results identified a mean prodrome duration of 21.6 months. Neither CHR-P sub-syndrome nor medication exposure was found to significantly influence prodrome duration in this sample. These results provide the most precise estimate of prodrome duration to date, although results are limited to prodromes identified by ascertainment as being at CHR-P. Our findings also suggest a rule of thirds with regard to prodrome duration in those followed for two years: one third of CHR-P patients who convert will do so by 1 year after CHR-P syndrome onset, another third 1���2 years after onset, and the final third more than 2 years after onset.

Aim: On average, there is a 10% to 12% likelihood of developing a psychotic disorder solely based on being at familial high risk. However, the introduction of the criteria for clinical high risk (CHR) of psychosis suggested for CHR individuals, 20% to 30% will go on to develop a full-blown psychotic illness within 3 years. Several studies suggest a role for family history in conversion to psychosis among those at CHR. However, we know very little about those who meet the CHR criteria and have a positive family history for psychosis compared to those at CHR with no known family history. The aim of this study was to compare these 2 groups on demographics, clinical symptoms, social and role functioning, IQ, environmental factors and conversion to psychosis. Method: A total of 762 participants met criteria for being at CHR, 119 of whom had a family history (CHR + FH) and 643 without (CHR-FH). Groups were compared on attenuated symptoms, role and social functioning, IQ, past trauma, perceived discrimination and cannabis use. Survival analysis was used to compare groups on conversion rates. Results: There were no major differences between the groups in symptoms, functioning, IQ, cannabis use or in the rate of conversion between the groups. The CHR + FH group reported increased amounts of early trauma. Conclusion: There is a possibility that CHR + FH individuals believe that it is more difficult for them to cope with circumstances such as abuse or potential abuse. Future research on this subject should investigate family environment and its role in conversion to psychosis among CHR + FH individuals.

There has been growing interest on the effect of sleep problems on psychotic and prodromal symptoms. The current study investigated cross-sectional relations between sleep problems and attenuated psychotic symptoms in a large sample of 740 youth at Clinical High Risk (CHR) for psychosis in an attempt to replicate previous findings and assess whether findings from general population samples and psychotic samples extend to this CHR sample. Sleep problems were found to be significantly positively associated with attenuated psychotic symptom severity. Sleep problems were also found to be more closely associated with certain specific prodromal symptoms (e.g., suspiciousness and perceptual abnormalities) than other attenuated psychotic symptoms. Further, we found that depression mediated the cross-sectional association between sleep problems and paranoid symptoms only. This adds to a growing body of evidence suggesting the mediation role of depression is more pronounced for paranoid-type psychotic symptoms as compared to other psychotic symptoms (e.g., hallucinations).

In a recent machine learning study classifying ���brain age��� based on cross-sectional neuroanatomical data, clinical high-risk (CHR) individuals were observed to show deviation from the normal neuromaturational pattern, which in turn was predictive of greater risk of conversion to psychosis and a pattern of stably poor functional outcome. These effects were unique to cases who were between 12 and 17 years of age when their prodromal and psychotic symptoms began, suggesting that neuroanatomical deviance observable at the point of ascertainment of a CHR syndrome marks risk for an early onset form of psychosis. In the present study, we sought to clarify the pattern of neuroanatomical deviance linked to this ���early onset��� form of psychosis and whether this deviance is associated with poorer premorbid functioning. T1 MRI scans from 378 CHR individuals and 190 healthy controls (HC) from the North American Prodrome Longitudinal Study (NAPLS2) were analyzed. Widespread smaller cortical volume was observed among CHR individuals compared with HC at baseline evaluation, particularly among the younger group (i.e., those who were 12 to 17 years of age). Moreover, the younger CHR individuals who converted or presented worsened clinical symptoms at follow-up (within 2 years) exhibited smaller surface area in rostral anterior cingulate, lateral and medial prefrontal regions, and parahippocampal gyrus relative to the younger CHR individuals who remitted or presented a stable pattern of prodromal symptoms at follow-up. In turn, poorer premorbid functioning in childhood was associated with smaller surface area in medial orbitofrontal, lateral frontal, rostral anterior cingulate, precuneus, and temporal regions. Together with our prior report, these results are consistent with the view that neuroanatomical deviance manifesting in early adolescence marks vulnerability to a form of psychosis presenting with poor premorbid adjustment, an earlier age of onset (generally prior to the age of 18 years), and poor long-term outcome.

Childhood adversity is associated with poor mental and physical health outcomes across the life span. Alterations in the hypothalamic-pituitary-Adrenal axis are considered a key mechanism underlying these associations, although findings have been mixed. These inconsistencies suggest that other aspects of stress processing may underlie variations in this these associations, and that differences in adversity type, sex, and age may be relevant. The current study investigated the relationship between childhood adversity, stress perception, and morning cortisol, and examined whether differences in adversity type (generalized vs.Threat and deprivation), sex, and age had distinct effects on these associations. Salivary cortisol samples, daily hassle stress ratings, and retrospective measures of childhood adversity were collected from a large sample of youth at risk for serious mental illness including psychoses (n = 605, mean age = 19.3). Results indicated that childhood adversity was associated with increased stress perception, which subsequently predicted higher morning cortisol levels; however, these associations were specific to threat exposures in females. These findings highlight the role of stress perception in stress vulnerability following childhood adversity and highlight potential sex differences in the impact of threat exposures.

Childhood adversity is among the strongest risk factors for psychosis-spectrum disorders, though the nature and specificity of the biological mechanisms underlying this association remains unclear. Previous research reveals overlaps in the volumetric alterations observed in both adversity-exposed individuals and in psychosis-spectrum populations, highlighting the possibility that deviations in corticolimbic gray matter development may be one mechanism linking adversity and psychosis. Given that childhood adversity encompasses a wide range of adverse experiences, there is also a critical need to examine whether these different types of experiences have unique effects on corticolimbic regions. This study examined the association between childhood adversity and cortical, hippocampal, and amygdalar volume in a large sample of youth at clinical-high risk (CHR) for psychosis. We utilized a novel differentiated adversity approach that distinguishes exposures along dimensions of threat (e.g., abuse) and deprivation (e.g., poverty, neglect) to test for differential associations. Participants were drawn from the North American Prodromal Longitudinal Study (NAPLS) and completed an MRI scan and a retrospective assessment of childhood adversity at baseline. We found that deprivation exposure, but not threat, was uniquely associated with smaller cortical volume and smaller right hippocampal volume in CHR youth. These associations were masked in a generalized risk model that utilized a total adversity score. The findings suggest that deprivation exposures during childhood contribute to the subtle volumetric reductions observed in clinical high-risk samples and highlight the importance of disentangling different dimensions of adversity.

Objective: Traditional measures for assessing functioning with adult patients with schizophrenia have been shown to be insufficient for assessing the issues that occur in adolescents and young adults at clinical high risk (CHR) for psychosis. The current study provides an expanded validation of the Global Functioning: Social (GF:Social) and Role (GF:Role) scales developed specifically for use with CHR individuals and explores the reliability and accuracy of the ratings, the validity of the scores in comparison to other established clinical measures, stability of functioning over a 2-year period, and psychosis predictive ability. Methods: Seven hundred fifty-five CHR individuals and 277 healthy control (HC) participants completed the GF:Social and Role scales at baseline as part of the North American Prodrome Longitudinal Study (NAPLS2). Results: Inter-rater reliability and accuracy were high for both scales. Correlations between the GF scores and other established clinical measures demonstrated acceptable convergent and discriminant validity. In addition, GF:Social and Role scores were unrelated to positive symptoms. CHR participants showed large impairments in social and role functioning over 2-years, relative to the HCs, even after adjusting for age, IQ, and attenuated positive symptoms. Finally, social decline prior to baseline was more pronounced in CHR converters, relative to non-converters. Conclusions: The GF scales can be administered in a large-scale multi-site study with excellent inter-rater reliability and accuracy. CHR individuals showed social and role functioning impairments over time that were not confounded by positive symptom severity levels. The results of this study demonstrate that social decline is a particularly effective predictor of conversion outcome.

In a recent study, a neuroanatomical-based age prediction model observed neuromaturational deviance among clinical high-risk individuals who developed psychosis. Here we aimed to investigate whether incorporating ���brain age gap��� (discrepancy between neuroanatomical-based predicted age and chronological age) to the North American Prodromal Longitudinal Study risk calculator would enhance prediction of psychosis conversion. The effect of brain age gap was significant (HR = 1.21, P = 0.047), but its predictive variance was found to overlap entirely with age at ascertainment, consistent with the view that greater brain-age gap and earlier age at onset of prodromal symptoms are correlated indicators of insidious-onset forms of psychosis.

Objective: The overlap versus independence of autism spectrum disorder (ASD) and schizophrenia is a topic that has garnered the attention of generations of clinicians and scientists. Although high rates of psychotic symptoms have been identified in individuals with ASD, the nature, prevalence, and prognostic significance of subclinical psychotic experiences in ASD remain poorly understood. Method: This study sought to compare baseline characteristics, clinical profiles, and conversion outcomes between young individuals at clinical high risk for psychosis (CHR) who presented with or without a prior ASD diagnosis during the second phase of the North American Prodrome Longitudinal Study (NAPLS, N = 764). Results: Patients with CHR and ASD (CHR/ASD+, n = 26) tended to exhibit greater social and social cognitive difficulties, but expressed relatively levels of core psychosis symptoms similar to those of to patients with CHR but no ASD (CHR/ASD���). Risk for conversion to co-occurring psychosis (18.2% CHR/ASD+ versus 16.8% CHR/ASD���) was equivalent between CHR/ASD+ and CHR/ASD��� groups, and the NAPLS2 Psychosis Risk Calculator predicted conversion to psychosis equally well across groups. Conclusion: These results suggest that baseline psychosis symptoms, predictors of risk for conversion, and ultimate conversion rates are similar in patients with CHR with and without ASD. They further suggest that ASD must not be considered a mutually exclusive diagnosis when such youth present in CHR settings. Future research is needed to better track trajectories in larger cohorts of individuals with CHR and comorbid ASD and to understand whether treatment recommendations effective in the broader CHR population are useful for this particular population as well.

Background Much of the interest in youth at clinical high risk (CHR) of psychosis has been in understanding conversion. Recent literature has suggested that less than 25% of those who meet established criteria for being at CHR of psychosis go on to develop a psychotic illness. However, little is known about the outcome of those who do not make the transition to psychosis. The aim of this paper was to examine clinical symptoms and functioning in the second North American Prodrome Longitudinal Study (NAPLS 2) of those individuals whose by the end of 2 years in the study had not developed psychosis.Methods In NAPLS-2 278 CHR participants completed 2-year follow-ups and had not made the transition to psychosis. At 2-years the sample was divided into three groups - those whose symptoms were in remission, those who were still symptomatic and those whose symptoms had become more severe.Results There was no difference between those who remitted early in the study compared with those who remitted at one or 2 years. At 2-years, those in remission had fewer symptoms and improved functioning compared with the two symptomatic groups. However, all three groups had poorer social functioning and cognition than healthy controls.Conclusions A detailed examination of the clinical and functional outcomes of those who did not make the transition to psychosis did not contribute to predicting who may make the transition or who may have an earlier remission of attenuated psychotic symptoms.

Aim: To evaluate the role of tobacco use in the development of psychosis in individuals at clinical high risk. Method: The North American Prodrome Longitudinal Study is a 2-year multi-site prospective case control study of persons at clinical high risk that aims to better understand predictors and mechanisms for the development of psychosis. The cohort consisted of 764 clinical high risk and 279 healthy comparison subjects. Clinical assessments included tobacco and substance use and several risk factors associated with smoking in general population studies. Results: Clinical high risk subjects were more likely to smoke cigarettes than unaffected subjects (light smoking odds ratio [OR] = 3.0, 95% confidence interval [CI] = 1.9-5; heavy smoking OR = 4.8, 95% CI = 1.7-13.7). In both groups, smoking was associated with mood, substance use, stress and perceived discrimination and in clinical high risk subjects with childhood emotional neglect and adaption to school. Clinical high risk subjects reported higher rates of several factors previously associated with smoking, including substance use, anxiety, trauma and perceived discrimination. After controlling for these potential factors, the relationship between clinical high risk state and smoking was no longer significant (light smoking OR = 0.9, 95% CI = 0.4-2.2; heavy smoking OR = 0.3, 95% CI = 0.05-2.3). Moreover, baseline smoking status (hazard ratio [HR] = 1.16, 95% CI = 0.82-1.65) and categorization as ever smoked (HR = 1.3, 95% CI = 0.8-2.1) did not predict time to conversion. Conclusion: Persons at high risk for psychosis are more likely to smoke and have more factors associated with smoking than controls. Smoking status in clinical high risk subjects does not predict conversion. These findings do not support a causal relationship between smoking and psychosis.

Background: Clinical high risk (CHR) status is characterized by impairments in social cognition, but questions remain concerning their stability over development. In cross-sectional analysis of a large naturalistic sample, the current study examined whether those at CHR status show deviant trajectories for age-related change in social cognitive ability, and whether these trajectories are influenced by treatment history. Method: Emotion perception (EP) and theory of mind (ToM) were assessed in 675 CHR and 263 healthy comparison (HC) participants aged 12���35. Age effects in CHR were modeled against HC age-expected performance. Prior medication status was tested for interactions with age. Results: CHR exhibited normal age trajectory for EP, but significantly lower slopes for ToM from age 17 onward. This effect was specific to stimuli exhibiting sarcasm and not to detection of lies. When treatment history was included in the model, age-trajectory appeared normal in CHR subjects previously prescribed both antipsychotics and antidepressant medication, although the blunted trajectory still characterized 80% of the sample. Discussion: Cross-sectional analyses suggested that blunting of ToM in CHR develops in adolescence, while EP abilities were diminished evenly across the age range. Exploratory analyses of treatment history suggested that ToM was not affected, however, in CHRs with lifetime histories of both antipsychotic and antidepressant medications. Reduction in age-expected ToM ability may impair the ability of individuals at CHR to meet social developmental challenges in adolescence. Medication effects on social cognition deserve further study.

Importance: Altered neurodevelopmental trajectories are thought to reflect heterogeneity in the pathophysiologic characteristics of schizophrenia, but whether neural indicators of these trajectories are associated with future psychosis is unclear. Objective: To investigate distinct neuroanatomical markers that can differentiate aberrant neurodevelopmental trajectories among clinically high-risk (CHR) individuals. Design, Setting, and Participants: In this prospective longitudinal multicenter study, a neuroanatomical-based age prediction model was developed using a supervised machine learning technique with T1-weighted magnetic resonance imaging scans of 953 healthy controls 3 to 21 years of age from the Pediatric Imaging, Neurocognition, and Genetics (PING) study and then applied to scans of 275 CHR individuals (including 39 who developed psychosis) and 109 healthy controls 12 to 21 years of age from the North American Prodrome Longitudinal Study 2 (NAPLS 2) for external validation and clinical application. Scans from NAPLS 2 were collected from January 15, 2010, to April 30, 2012. Main Outcomes and Measures: Discrepancy between neuroanatomical-based predicted age (hereafter referred to as brain age) and chronological age. Results: The PING-derived model (460 females and 493 males; age range, 3-21 years) accurately estimated the chronological ages of the 109 healthy controls in the NAPLS 2 (43 females and 66 males; age range, 12-21 years), providing evidence of independent external validation. The 275 CHR individuals in the NAPLS 2 (111 females and 164 males; age range, 12-21 years) showed a significantly greater mean (SD) gap between model-predicted age and chronological age (0.64 [2.16] years) compared with healthy controls (P = .008). This outcome was significantly moderated by chronological age, with brain age systematically overestimating the ages of CHR individuals who developed psychosis at ages 12 to 17 years but not the brain ages of those aged 18 to 21 years. Greater brain age deviation was associated with a higher risk for developing psychosis (F = 3.70; P = .01) and a pattern of stably poor functioning over time, but only among younger CHR adolescents. Previously reported evidence of accelerated reduction in cortical thickness among CHR individuals who developed psychosis was found to apply only to those who were 18 years of age or older. Conclusions and Relevance: These results are consistent with the view that neuroanatomical markers of schizophrenia may help to explain some of the heterogeneity of this disorder, particularly with respect to early vs later age of onset of psychosis, with younger and older individuals having differing intercepts and trajectories in structural brain parameters as a function of age. The results also suggest that baseline neuroanatomical measures are likely to be useful in estimating onset of psychosis, especially (or only) among CHR individuals with an earlier age of onset of prodromal symptoms.

The clinical-high-risk for psychosis (CHR-P) syndrome is heterogeneous in terms of clinical presentation and outcomes. Identifying more homogenous subtypes of the syndrome may help clarify its etiology and improve the prediction of psychotic illness. This study applied latent class cluster analysis (LCCA) to symptom ratings from the North American Prodrome Longitudinal Studies 1 and 2 (NAPLS 1 and 2). These analyses produced evidence for three to five subgroups within the CHR-P syndrome. Differences in negative and disorganized symptoms distinguished among the subgroups. Subgroup membership was found to predict conversion to psychosis. The authors contrast the methods employed within this study with previous attempts to identify more homogenous subgroups of CHR-P individuals and discuss how these results could be tested in future samples of CHR-P individuals.

Research into those at clinical high-risk (CHR) of psychosis is steadily increasing. Since these young people are difficult to find, and at times difficult to retain in longitudinal studies that often require lengthy clinical and biomarker assessments, drop-outs are not uncommon. For example, in the EPOS study 25.6% of participants were lost to follow-up over an 18-month follow-up (Ruhrmann et al., 2010). Since a major aim of CHR research is to understand more about the development of psychosis, it is important to know whether those who dropout do so with increased symptoms and are potentially more likely to be later converters, or if they dropout because of a remission of their attenuated symptoms.

The developmental course of daily functioning prior to first psychosis-onset remains poorly understood. This study explored age-related periods of change in social and role functioning. The longitudinal study included youth (aged 12-23, mean follow-up years = 1.19) at clinical high risk (CHR) for psychosis (converters [CHR-C], n = 83; nonconverters [CHR-NC], n = 275) and a healthy control group (n = 164). Mixed-model analyses were performed to determine age-related differences in social and role functioning. We limited our analyses to functioning before psychosis conversion; thus, data of CHR-C participants gathered after psychosis onset were excluded. In controls, social and role functioning improved over time. From at least age 12, functioning in CHR was poorer than in controls, and this lag persisted over time. Between ages 15 and 18, social functioning in CHR-C stagnated and diverged from that of CHR-NC, who continued to improve (p =.001). Subsequently, CHR-C lagged behind in improvement between ages 21 and 23, further distinguishing them from CHR-NC (p