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Objectives: Impaired social, role, and neurocognitive functioning are preillness characteristics of people who later develop psychosis. In people with schizophrenia, neurocognition and negative symptoms are associated with functional impairment. We examined the relative contributions of neurocognition and symptoms to social and role functioning over time in clinically high-risk (CHR) individuals and determined if negative symptoms mediated the influence of cognition on functioning., Methods: Social, role, and neurocognitive functioning and positive, negative, and disorganized symptoms were assessed in 167 individuals at CHR for psychosis in the North American Prodrome Longitudinal Study Phase 1 (NAPLS-1), of whom 96 were reassessed at 12 months., Results: Regression analyses indicated that negative symptoms accounted for unique variance in social and role functioning at baseline and follow-up. Composite neurocognition accounted for unique, but modest, variance in social and role functioning at baseline and in role functioning at follow-up. Negative symptoms mediated the relationship between composite neurocognition and social and role functioning across time points. In exploratory analyses, individual tests (IQ estimate, Digit Symbol/Coding, verbal memory) selectively accounted for social and role functioning at baseline and follow-up after accounting for symptoms. When negative symptom items with content overlapping with social and role functioning measures were removed, the relationship between neurocognition and social and role functioning was strengthened., Conclusion: The modest overlap among neurocognition, negative symptoms, and social and role functioning indicates that these domains make substantially separate contributions to CHR individuals., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Improving upon the predictive validity of determining the transition from high risk to actual psychosis is a primary aim of early intervention research. Previous research has suggested that premorbid spontaneous dyskinesias may be one possible predictor. In this study, dyskinetic movements were assessed with the Abnormal Involuntary Movement Scale (AIMS) at baseline of a longitudinal study of 148 individuals at clinical high risk (CHR) of developing psychosis. Twenty-eight individuals transitioned to a psychotic disorder over the course of the study. Group comparisons between transitioned and non-transitioned individuals indicated that, relative to those that were not observed to transition, participants that developed a psychotic disorder exhibited greater spontaneous dyskinesias at baseline. Moreover, increased dyskinetic movements at baseline resulted in a more than two-fold increase in odds of developing a psychosis for each point increase in AIMS scale score. These findings suggest that individuals with greater premorbid dyskinetic movements may comprise a subset of CHR individuals at inordinate risk to decompensate into psychosis. Future work should employ assessments of spontaneous dyskinesias by instrumentation (e.g., electromyography) and look to ascertain whether specific dyskinesias (e.g., dystonia) or dyskinesias of specific body regions are associated with transitioning to psychosis., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Metacognition has been described as the knowledge of our own cognitive processes. Metacognitive deficits are common in schizophrenia, but little is known about metacognition before the onset of full-blown psychosis., Aims: This study aimed to longitudinally characterize metacognition in a sample of individuals at clinical high risk (CHR) for psychosis, and to determine if metacognition was related to later conversion to psychosis., Method: Participants (153 CHR individuals; 68 help seeking controls, HSC) were part of the large multi-site PREDICT study, which sought to determine predictors of conversion to psychosis. They were tested at baseline and 6 months using the Meta-Cognitions Questionnaire (MCQ) that has five sub-scales assessing different domains of metacognition., Results: RESULTS of the mixed-effect models demonstrated significantly poorer scores at baseline for the CHR group compared to the HSC group in Negative beliefs about uncontrollability, Negative beliefs and the overall MCQ score. At the 6-month assessment, no difference was observed in metacognition between the two groups, but both groups showed improvement in metacognition over time. Those who later converted to psychosis had poorer performance on metacognitive beliefs at baseline., Conclusions: A poorer performance in metacognition can be seen as a marker of developing a full blown psychotic illness and confirms the potential value of assessing metacognitive beliefs in individuals vulnerable for psychosis.

Background: Longitudinal studies of the clinical high risk (CHR) syndrome for psychosis have emphasized the conversion vs non-conversion distinction and thus far have not focused intensively on classification among non-converters. The present study proposes a system for classifying CHR outcomes over time when using the Structured Interview for Psychosis-risk Syndromes and evaluates its validity., Method: The system for classifying CHR outcomes is referred to as "current status specifiers," with "current" meaning over the month prior to the present evaluation and "specifiers" indicating a set of labels and descriptions of the statuses. Specifiers for four current statuses are described: progression, persistence, partial remission, and full remission. Data from the North American Prodromal Longitudinal Study were employed to test convergent, discriminant, and predictive validity of the current status distinctions., Results: Validity analyses partly supported current status distinctions. Social and role functioning were more impaired in progressive and persistent than in remitted patients, suggesting a degree of convergent validity. Agreement between CHR current statuses and current statuses for a different diagnostic construct (DSM-IV Major Depression) was poor, suggesting discriminant validity. The proportion converting to psychosis within a year was significantly higher in cases meeting progression criteria than in those meeting persistence criteria and tended to be higher than in those meeting full remission criteria, consistent with a degree of predictive validity., Discussion: CHR syndrome current status specifiers could offer a potentially valid and useful description of current clinical status among non-converters. Study in additional samples is needed., (Copyright © 2014. Published by Elsevier B.V.)

Multi-site neuroimaging studies offer an efficient means to study brain functioning in large samples of individuals with rare conditions; however, they present new challenges given that aggregating data across sites introduces additional variability into measures of interest. Assessing the reliability of brain activation across study sites and comparing statistical methods for pooling functional data are critical to ensuring the validity of aggregating data across sites. The current study used two samples of healthy individuals to assess the feasibility and reliability of aggregating multi-site functional magnetic resonance imaging (fMRI) data from a Sternberg-style verbal working memory task. Participants were recruited as part of the North American Prodrome Longitudinal Study (NAPLS), which comprises eight fMRI scanning sites across the United States and Canada. In the first study sample (n=8), one participant from each home site traveled to each of the sites and was scanned while completing the task on two consecutive days. Reliability was examined using generalizability theory. Results indicated that blood oxygen level-dependent (BOLD) signal was reproducible across sites and was highly reliable, or generalizable, across scanning sites and testing days for core working memory ROIs (generalizability ICCs=0.81 for left dorsolateral prefrontal cortex, 0.95 for left superior parietal cortex). In the second study sample (n=154), two statistical methods for aggregating fMRI data across sites for all healthy individuals recruited as control participants in the NAPLS study were compared. Control participants were scanned on one occasion at the site from which they were recruited. Results from the image-based meta-analysis (IBMA) method and mixed effects model with site covariance method both showed robust activation in expected regions (i.e. dorsolateral prefrontal cortex, anterior cingulate cortex, supplementary motor cortex, superior parietal cortex, inferior temporal cortex, cerebellum, thalamus, basal ganglia). Quantification of the similarity of group maps from these methods confirmed a very high (96%) degree of spatial overlap in results. Thus, brain activation during working memory function was reliable across the NAPLS sites and both the IBMA and mixed effects model with site covariance methods appear to be valid approaches for aggregating data across sites. These findings indicate that multi-site functional neuroimaging can offer a reliable means to increase power and generalizability of results when investigating brain function in rare populations and support the multi-site investigation of working memory function in the NAPLS study, in particular., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Neurocognition and social cognition are separate but related constructs known to be impaired in schizophrenia. The aim of this study was to extend the current knowledge of the relationship between social cognition and neurocognition in individuals at clinical high risk (CHR) of developing psychosis by examining, in a large sample, the associations between a wide range of neurocognitive tasks and social cognition. Participants included 136 young people at CHR. Specific domains within neurocognition and social cognition were compared using Spearman correlations. Results showed that poor theory of mind correlated with low ratings on a wide range of neurocognitive tasks. Facial affect was more often associated with low ratings on spatial working memory and attention. These results support a link between neurocognition and social cognition even at this early stage of potential psychosis, with indication that poorer performance on social cognition may be associated with deficits in attention and working memory. Understanding these early associations may have implications for early intervention., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Clozapine, an evidence-based treatment of refractory schizophrenia, is associated with increased weight gain and metabolic dysregulation compared with most antipsychotics in short-term clinical trials. However, there are limited data describing comparative long-term metabolic risks. In this report, we examined whether short-term differences persist with long-term exposure to clozapine., Methods: The data of all patients in a university-based clinic with a psychotic illness or a mood disorder with psychotic features, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis, and treated with an antipsychotic in calendar year 2012 were examined. A total of 307 patients met the criteria; 96 patients were treated with clozapine and the remaining 211 patients were treated with 1 or more non-clozapine antipsychotics. Body mass index, type 2 diabetes, hypertension, dyslipidemia, and obesity were compared., Results: The mean duration of the clozapine treatment was 7.6 years (range, 2 months to 21 y). On all metabolic measures, there were no statistically significant differences between the clozapine and non-clozapine groups (mean body mass index, 31 vs 32; type 2 diabetes, 17% vs 18%; dyslipidemia, 35% vs 38%; hypertension, 32% vs 39%; and obesity, 48% vs 54%). Removing the olanzapine-treated patients (n = 51) from the non-clozapine group did not change the findings., Conclusions: In this university-based clinic sample with a large number of clozapine-treated patients, we found no evidence of increased risk in any individual measure for those receiving clozapine. Although speculative, the relative contribution of the increased short-term metabolic risk associated with clozapine may be diminished over time because multiple other variables likely also impact metabolic risk during the life span. Although speculative, the relative contribution of the increased short-term metabolic risk associated with clozapine may be diminished over time due to the accumulated impact of other variables that also impact metabolic risk across the life span.

Aim: There is evidence to suggest that perceived discrimination may be associated with psychosis. Less is known about its potential impact on those at clinical high risk (CHR) for psychosis. The aim of this study was to determine the prevalence of perceived discrimination in a CHR sample and its possible relationship to attenuated positive symptoms and negative self-beliefs., Methods: Participants were 360 CHR individuals and 180 healthy controls. Assessments included a self-report measure of perceived discrimination, the Scale of Prodromal Symptoms and the Brief Core Schema Scale., Results: CHR participants reported significantly more perceived discrimination. Perceived discrimination was significantly associated with negative schemas, but not with attenuated positive symptoms., Conclusions: These results suggest that individuals at CHR for psychosis endorse a higher level of perceived discrimination, which is associated with increased negative schemas, but not attenuated positive symptoms., (© 2013 Wiley Publishing Asia Pty Ltd.)

This study evaluates premorbid social and academic functioning in clinical high-risk individuals as predictors of transition to schizophrenia versus another psychotic disorder. Participants were 54 individuals enrolled in phase one of the North American Prodrome Longitudinal Study who over two and a half years of follow-up met criteria for schizophrenia/schizophreniform disorder (n=28) or another psychotic disorder (n=26). Social and academic functioning in childhood, early adolescence, and late adolescence was assessed at baseline using the Cannon-Spoor Premorbid Adjustment Scale. Social maladjustment in late adolescence predicted significantly higher odds of transition to schizophrenia versus another psychotic disorder independent of childhood and early adolescent adjustment (OR=4.02) and conveyed unique risk over academic maladjustment (OR=5.64). Premorbid academic maladjustment was not associated with psychotic disorder diagnosis. Results support diagnostic specificity of premorbid social dysfunction to schizophrenia in clinical high-risk youth and underscore an important role for social maladjustment in the developmental pathology of schizophrenia and its prediction., (© 2013 Published by Elsevier Ireland Ltd.)

Deterioration in premorbid functioning is a common feature of schizophrenia, but sensitivity to psychosis conversion among clinical high-risk samples has not been examined. This study evaluates premorbid functioning as a predictor of psychosis conversion among a clinical high-risk sample, controlling for effects of prior developmental periods. Participants were 270 clinical high-risk individuals in the North American Prodrome Longitudinal Study-I, 78 of whom converted to psychosis over the next 2.5 years. Social, academic, and total maladjustment in childhood, early adolescence, and late adolescence were rated using the Cannon-Spoor Premorbid Adjustment Scale. Early adolescent social dysfunction significantly predicted conversion to psychosis (hazard ratio = 1.30, p = .014), independently of childhood social maladjustment and independently of severity of most baseline positive and negative prodromal symptoms. Baseline prodromal symptoms of disorganized communication, social anhedonia, suspiciousness, and diminished ideational richness mediated this association. Early adolescent social maladjustment and baseline suspiciousness together demonstrated moderate positive predictive power (59%) and high specificity (92.1%) in predicting conversion. Deterioration of academic and total functioning, although observed, did not predict conversion to psychosis. Results indicate early adolescent social dysfunction to be an important early predictor of conversion. As such, it may be a good candidate for inclusion in prediction algorithms and could represent an advantageous target for early intervention.

In schizophrenia, neurocognition, social cognition and functional outcome are all inter-related, with social cognition mediating the impact that impaired neurocognition has on functional outcome. Less clear is the nature of the relationship between neurocognition, social cognition and functional outcome in individuals at clinical high risk (CHR) for psychosis. 137 CHR participants completed a neurocognitive test battery, a battery of social cognition tasks and the Social Functioning Scale. Confirmatory factor analysis showed that all social cognition tasks were reliable and valid measures of the latent variable. The path from neurocognition to functioning was statistically significant (standardized coefficient β=0.22, p<0.01). The path from social cognition to functioning was also statistically significant (β=0.27, p<0.05). In the mediation model the bootstrapping estimate revealed a nonsignificant indirect effect that was the association of social cognition with neurocognition and with functional outcome (β=0.20, 95% CI=-0.07 to 0.52, p=0.11). However, social cognition was significantly associated with neurocognition (β=0.80, p<0.001) and the path from neurocognition to functioning was no longer significant as soon as the mediator (social cognition) was entered into the mediation model (β=0.02, p=0.92). All of the model fit indices were very good. Unlike what has been observed with psychotic patients, social cognition does not seem to mediate the pathway from neurocognition to functional outcome when assessed with a measure of social attainment in individuals at CHR for psychosis., (© 2013.)

Background: Studies of biomarkers of hypothalamic-pituitary-adrenal activity indicate that psychotic disorders are associated with elevated cortisol. This study examined cortisol levels in healthy control subjects and individuals who met clinical high-risk (CHR) criteria for psychosis. It was hypothesized that cortisol levels would be 1) elevated in the CHR group relative to control subjects, 2) positively correlated with symptom severity, and 3) most elevated in CHR patients who transition to psychotic level severity., Methods: Baseline assessments were conducted at eight centers in the North American Prodrome Longitudinal Study. The present CHR sample included 256 individuals meeting the Scale for Prodromal Symptoms criteria and 141 control subjects, all of whom underwent baseline assessment and measurement of salivary cortisol., Results: Consistent with previous reports, there was an effect of age on cortisol, with increases through the adolescent/early adult years. Analysis of covariance showed a main effect of diagnostic group, with the CHR group showing higher cortisol. There were modest, positive correlations of cortisol with baseline symptom severity, and analysis of covariance revealed higher baseline cortisol in those who transitioned to psychotic level symptoms when compared with healthy control subjects and CHR subjects who remitted., Conclusions: The present findings add to accumulating evidence of heightened cortisol secretion in CHR individuals. The findings also indicate nonspecific associations between cortisol levels and symptom severity, as well as symptom progression. The role of hypothalamic-pituitary-adrenal activity in prediction of conversion to psychosis and its relation with other biomarkers of risk should receive attention in future research., (Copyright © 2013 Society of Biological Psychiatry. All rights reserved.)

Prepulse inhibition (PPI) and reactivity of the acoustic startle response are widely used biobehavioral markers in psychopathology research. Previous studies have demonstrated that PPI and startle reactivity exhibit substantial within-site stability; however, between-site stability has not been established. In two separate consortia investigating biomarkers of early psychosis, traveling participants studies were carried out as a part of quality assurance procedures to assess the fidelity of data across sites. In the North American Prodromal Longitudinal Studies (NAPLS) consortium, eight normal participants traveled to each of the eight NAPLS sites and were tested twice at each site on the startle PPI paradigm. In preparation for a binational study, 10 healthy participants were assessed twice in both San Diego and Mexico City. Intraclass correlations between and within sites were significant for PPI and startle response parameters, confirming the reliability of startle measures across sites in both consortia. There were between-site differences in startle magnitude in the NAPLS study that did not appear to be related to methods or equipment. In planning multisite studies, it is essential to institute quality assurance procedures early and establish between-site reliability to assure comparable data across sites.

Aim: Several lines of evidence suggest a possible association between a history of trauma in childhood and later psychosis or psychotic-like experiences. The purpose of this study was to determine the extent of childhood trauma and bullying in young people at clinical high risk (CHR) of developing psychosis., Methods: The sample consisted of 360 individuals who were at CHR of developing psychosis and 180 age- and gender-matched healthy controls. All participants were assessed on past trauma and bullying. The CHR participants were also assessed on a range of psychopathology and functioning., Results: Individuals at CHR reported significantly more trauma and bullying than healthy controls. Those who had experienced past trauma and bullying were more likely to have increased levels of depression and anxiety and a poorer sense of self., Conclusions: These results offer preliminary support for an association between a history of trauma and later subthreshold symptoms., (© 2013 Wiley Publishing Asia Pty Ltd.)

Background: Antipsychotic medication use rates have generally been rising among youth with psychiatric disorders, but little is known about use rates of antipsychotics or other psychotropic medications in patients at high risk for psychosis., Method: Baseline psychotropic medication use rates were compared in two research cohorts of patients at high risk for psychosis that enrolled between 1998-2005 (n=391) and 2008-2011 (n=346). Treatment durations and antipsychotic doses were described for cohort 2., Results: Median age was 17years in cohort 1 and 18years in cohort 2. The rate of prescription of any psychotropic at baseline was roughly 40% for each cohort. Antipsychotic prescription rates were 24% among sites that permitted baseline antipsychotic use in cohort 1 and 18% in the cohort 2; the decline did not quite reach statistical significance (p=0.064). In cohort 2 the mean±SD baseline chlorpromazine-equivalent dose was 121±108mg/d, and lifetime duration of antipsychotic treatment was 3.8±5.9months., Discussion: Although the rate of antipsychotic prescription among high-risk youth may have fallen slightly, the nearly one-in-five rate in the second cohort still constitutes a significant exposure. Mitigating factors were that doses and durations of treatment were low. As for other nonpsychotic conditions, it is incumbent on our field to develop alternative treatments for high-risk patients and to generate additional evidence for or against the efficacy of antipsychotics to help define their appropriate role if alternative treatments fail., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The Genomic Psychiatry Cohort (GPC) is a longitudinal resource designed to provide the necessary population-based sample for large-scale genomic studies, studies focusing on Research Domain Criteria (RDoC) and/or other alternate phenotype constructs, clinical and interventional studies, nested case-control studies, long-term disease course studies, and genomic variant-to-phenotype studies. We provide and will continue to encourage access to the GPC as an international resource. DNA and other biological samples and diagnostic data are available through the National Institute of Mental Health (NIMH) Repository. After appropriate review and approval by an advisory board, investigators are able to collaborate in, propose, and co-lead studies involving cohort participants., (Copyright © 2013 Wiley Periodicals, Inc.)

Cognitive impairment is common in psychosis and has recently been observed in individuals at clinical high risk (CHR) of developing psychosis. The purpose of this study was to characterize longitudinal change in cognition among CHR individuals, and compare cognition of CHR individuals who later convert to psychosis to that of CHR who do not convert. Participants were tested at baseline and followed-up after six months using a comprehensive cognitive test battery. Individuals who did not convert to psychosis either remained stable or significantly improved in their cognitive performance. At baseline participants who converted to psychosis compared to non-converters exhibited poorer performance in several cognitive tests, suggesting that some cognitive impairment is already present before conversion. Future longitudinal research should address if further decline takes place during the prodrome or after conversion to psychosis., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Early symptoms of schizophrenia tend to emerge during adolescence, hich is a critical period for development of executive and emotional processing. While individuals with familial high risk (FHR) for schizophrenia may show cognitive and emotional changes, the neural mechanisms underlying the development of these changes remain unclear. The goal of this study was to identify functional differences in fronto-striato-limbic regions in children with FHR. Functional magnetic resonance imaging (MRI) data were collected from 21 children with a first-degree family member with schizophrenia and 21 controls without FHR. Participants performed an emotional oddball task requiring both selective attention and suppression of task-irrelevant emotional information. During selective attention, the group with FHR showed enhanced activation in the inferior frontal gyrus and caudate, with decreases in middle frontal gyrus and insular activation. The FHR group also showed greater age-related recruitment of anterior cingulate, temporal and occipital cortical areas during selective attention. During emotional processing, the FHR group showed decreased anterior cingulate activation, with decreased age-related recruitment of inferior frontal, parietal and occipital areas. The results suggest that FHR for schizophrenia may be associated with abnormal hyperactivation and hypoactivation of the neural circuitry engaged during executive and emotional processing and with age-related changes in neural recruitment during adolescence., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Sex differences in age at onset, symptomatology, clinical course (see Walker et al., 2002) and functional impairment (Thorup et al., 2007) are well documented in psychosis. The general pattern of findings is that males manifest an earlier onset, more severe symptoms and poorer prognosis than females. Limited studies examining individuals at clinical high-risk (CHR) suggest a similar pattern of sexual dimorphism (Holtzman et al., in review; Corcoran et al., 2011). As part of the North American Prodrome Longitudinal Study (NAPLS), the current study prospectively examined sexual dimorphisms in relationships among CHR symptoms, childhood (premorbid) academic and social functioning, baseline social and role functioning, and conversion to psychosis. Subjects included 276 (113F/163M) CHR NAPLS participants (ages 12-36.8years). All measures/criteria were assessed at baseline except conversion status, assessed at 6-month intervals up to 30months. Results show sex differences in baseline social and role functioning (though not in early childhood adjustment) that predate psychosis onset, with sexually dimorphic patterns in relation to prodromal symptoms. Among male (but not female) CHRs, baseline social functioning and positive prodromal symptoms predicted conversion. These findings help elucidate early course of vulnerability for, and maximally sensitive and specific etiological and prediction models of, psychosis conversion. Findings highlight the importance of considering sexually differentiated predictors of longitudinal course and outcome, in the context of emerging risk profiles. This may optimize efforts at early identification and individually tailored preventive interventions targeting different neurobiological markers/systems and/or cognitive-behavioral approaches. We speculate a contemporary, multidimensional model of psychosis risk that posits a role of sexually dimorphic, genetically linked influences that converge with a modulating role of gonadal hormones (see Walder et al., 2012) across a temporally sensitive neurodevelopmental trajectory towards conferring risk., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The North American Prodrome Longitudinal Study (NAPLS) is a consortium of eight programs focusing on the psychosis prodrome. Funded by the National Institute of Mental Health (NIMH), the sites are located at Emory University, Harvard University, University of Calgary, UCLA, UCSD, University of North Carolina Chapel Hill, Yale University, and Zucker Hillside Hospital. Although the programs initially developed independently, they previously collaborated to combine their historical datasets and to produce a series of analyses on predictors of psychosis in one of the largest samples of longitudinally followed prodromal subjects worldwide. This led to the development of a five year prospective study "Predictors and Mechanisms of Conversion to Psychosis", (also known as NAPLS-2) with three major aims: (1) to prospectively test the prediction algorithm developed in NAPLS-1, (2) to investigate the neuroanatomical, neurophysiological, neurocognitive, and neurohormonal factors that may contribute to the development of psychosis, and (3) to develop a repository of DNA, RNA, and plasma from participants meeting diagnostic criteria for a clinical high risk (CHR) state and from demographically similar healthy subjects. Funded by NIMH in 2008, NAPLS-2 will generate the largest CHR for psychosis sample with 720 CHR and 240 healthy comparison subjects, and thus will provide statistical power and scientific scope that cannot be duplicated by any single site study. This paper describes the overall methodology of the NAPLS-2 project and reports on the ascertainment and demographics at the midway point of the study with (360 CHR) and 180 controls., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Schizophrenia has been associated with reduced volumes of subcortical structures on magnetic resonance imaging (MRI), but the relation of these reductions to familial risk for the disorder is unclear. We investigated the effect of familial risk for schizophrenia on regional subcortical volumes during adolescence, a period marked by steep maturational changes in brain structure and the emergence of psychotic symptoms. A group of 26 non-help-seeking, first-degree relatives of patients with schizophrenia and 43 matched healthy comparisons, between 9 and 18 years of age, underwent MRI scanning and were rated for the presence of prodromal symptoms. Five subcortical regions-of-interest were tested for group differences and group by age interactions, as well as correlations with low-level prodromal symptoms in the familial risk group. Relative to comparisons, familial risk subjects demonstrated greater positive volume-age relationships in hippocampus, putamen, and globus pallidus. These results suggest that relatives of individuals with schizophrenia exhibit structural abnormalities in the subcortex as early as pre-adolescence, which may reflect altered neurodevelopment of these regions., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Risk for psychosis is currently defined primarily on the basis of attenuated positive symptoms (APS), with no inclusion of the functional deficits characteristic of schizophrenia. Impaired social and role functioning have been of interest for reflecting poor outcome but far less is known about the developmental impact of these deficits as vulnerability or risk factors., Methods: Age-appropriate social and role functioning were prospectively assessed in 100 individuals at clinical high risk (CHR) for psychosis included in the 8-site North American Prodromal Longitudinal Study database. A nested case-control design was used to compare changes in social and role functioning in 26 individuals converting to psychosis shortly after baseline assessment and 24 converting over a year later. Individuals in each converter subgroup were directly matched to a non-converter at the same site, controlling for time to conversion, age, gender, and severity of baseline symptoms., Results: At baseline, CHR subjects who later became psychotic were significantly more likely to be impaired socially than matched non-converters. Onset of psychosis did not further disrupt social difficulties. Role functioning showed some of the same trends, but the overall pattern was not as consistent as for the social domain. Controlling for neurocognition did not change the pattern of group differences., Conclusions: Early impaired social functioning appears to be a risk factor for psychosis and, added to APS, could potentially contribute to accurate identification of CHR individuals and provide a new direction for early intervention to reduce long-term disability.

Purpose: A growing body of research has demonstrated the potential for comprehensive, phase-specific care to improve clinical and functional outcomes in early psychosis. However, there have been no evaluations of such treatment models in the United States (US). This study is a naturalistic, prospective 1-year follow-up of an early psychosis cohort treated in one of the first US-based multi-element treatment centers., Methods: Participants were 163 individuals treated at the Outreach and Support Intervention Services (OASIS) clinic, a multi-element treatment center for early psychosis. Data were collected as part of routine care at 6-month intervals. Primary outcomes included role functioning and involvement in work or school., Results: Over the course of 1 year of treatment, individuals experienced significant improvements in positive and negative symptoms, role functioning, and global functioning. The proportion of individuals meeting symptom remission and functional remission criteria increased significantly from baseline to 1 year, as did the proportion of individuals attending school. There were also trend-level reductions in substance abuse., Conclusions: This study provides preliminary support for the efficacy of comprehensive early intervention services in the US.

Negative symptoms are present in the psychosis prodrome. However, the extent to which these symptoms are present prior to the onset of the first episode of psychosis remains under-researched. The goal of this study is to examine negative symptoms in a sample of individuals at clinical high risk (CHR) for psychosis and to determine if they are predictive of conversion to psychosis. Participants (n=138) were all participants in the North American Prodrome Longitudinal Study (NAPLS 1) project. Negative symptoms were assessed longitudinally using the Scale of Prodromal Symptoms. The mean total negative symptom score at baseline was 11.0, with 82.0% of the sample scoring at moderate severity or above on at least one negative symptom. Over the course of 12 months, the symptoms remained in the above moderate severity range for 54.0% of participants. Associations between individual symptoms were moderate, and a factor analysis confirmed that all negative symptoms loaded heavily on one factor. Negative symptoms were more severe and persistent overtime in those who converted to psychosis, significantly predicting the likelihood of conversion. Thus, early and persistent negative symptoms may represent a vulnerability for risk of developing psychosis., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Emotion processing deficits are prominent in schizophrenia and exist prior to the onset of overt psychosis. However, developmental trajectories of neural circuitry subserving emotion regulation and the role that they may play in illness onset have not yet been examined in patients at risk for psychosis. The present study employed a cross-sectional analysis to examine age-related functional activation in amygdala and prefrontal cortex, as well as functional connectivity between these regions, in adolescents at clinical high risk (CHR) for psychosis relative to typically developing adolescents. Participants (n=34) performed an emotion processing fMRI task, including emotion labeling, emotion matching, and non-emotional control conditions. Regression analyses were used to predict activation in the amygdala and ventrolateral prefrontal cortex (vlPFC) based on age, group, sex, and the interaction of age by group. CHR adolescents exhibited altered age-related variation in amygdala and vlPFC activation, relative to controls. Controls displayed decreased amygdala and increased vlPFC activation with age, while patients exhibited the opposite pattern (increased amygdala and decreased vlPFC activation), suggesting a failure of prefrontal cortex to regulate amygdala reactivity. Moreover, a psychophysiological interaction analysis revealed decreased amygdala-prefrontal functional connectivity among CHR adolescents, consistent with disrupted brain connectivity as a vulnerability factor in schizophrenia. These results suggest that the at-risk syndrome is marked by abnormal development and functional connectivity of neural systems subserving emotion regulation. Longitudinal data are needed to confirm aberrant developmental trajectories intra-individually and to examine whether these abnormalities are predictive of conversion to psychosis, and of later deficits in socioemotional functioning., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Puberty is a critical period for the maturation of the fronto-limbic and fronto-striate brain circuits responsible for executive function and affective processing. Puberty also coincides with the emergence of the prodromal signs of schizophrenia, which may indicate an association between these two processes. Time-domain analysis and wavelet based time-frequency analysis was performed on electroencephalographic (EEG) data of 30 healthy control (HC) subjects and 24 individuals at familial risk (FR) for schizophrenia. All participants were between the ages of 13 and 18 years and were carefully matched for age, gender, ethnicity, education, and Tanner Stage. Electrophysiological recordings were obtained from 32 EEG channels while participants performed a visual oddball task, where they identified rare visual targets among standard "scrambled" images and rare aversive and neutral distracter pictures. The time-domain analysis showed that during target processing the FR group showed smaller event-related potentials in the P2 and P3 range as compared to the HC group. In addition, EEG activity in the theta (4-8 Hz) frequency range was significantly reduced during target processing in the FR group. Inefficient cortical information processing during puberty may be an early indicator of altered brain function in adolescents at FR for schizophrenia and may represent a vulnerability marker for illness onset. Longitudinal assessments will have to determine their predictive value for illness onset in populations at FR for psychotic illness.

Objective: A major focus of early intervention research is determining the risk of conversion to psychosis and developing optimal algorithms of prediction. Although reported rates of nonconversion vary in the literature, the nonconversion rate always encompasses a majority (50%-85%) of the sample participants. Less is known about the outcome among this group, referred to as false positive individuals., Method: A longitudinal study was conducted of more than 300 prospectively identified treatment-seeking individuals meeting criteria for a psychosis-risk syndrome. Participants were recruited and evaluated across eight clinical research centers as part of the North American Prodrome Longitudinal Study. Over a 2.5-year follow-up assessment period, 214 (71%) participants had not made the transition to psychosis., Results: The sample examined included 111 individuals who had at least 1 year of follow-up data available and did not transition to psychosis within the study duration. In year 1, there was significant improvement in ratings for attenuated positive and negative symptoms. However, at least one attenuated positive symptom was still present for 43% of the sample at 1 year and for 41% at 2 years. At the follow-up timepoints, social and role functioning were significantly poorer in the clinical sample relative to nonpsychiatric comparison subjects., Conclusions: Help-seeking individuals who meet prodromal criteria appear to represent those who are truly at risk for psychosis and are showing the first signs of illness, those who remit in terms of the symptoms used to index clinical high-risk status, and those who continue to have attenuated positive symptoms.

Although generally regarded as functional in the cytoplasm, a number of microRNAs (miRNAs) have been found in the nucleus, possibly with a role in gene regulation. Here we report that, in fact, a substantial fraction of all human miRNAs are present in the nucleus of neural stem cells. Further, subsets of these miRNAs display consistently higher standardized rank in the nucleus than in the cytoplasm of these cells, as identified with an RT-qPCR technology and confirmed by microarray analysis. Likewise, other miRNAs display higher cytoplasmic standardized ranks. Three samples were partitioned into nuclear and cytoplasmic fractions in six assays for 373 miRNAs. From the 100 most highly expressed miRNAs, standard scores of nuclear and cytoplasmic concentrations were determined. Among those, 21 miRNAs had all three nuclear standard scores higher than all three cytoplasmic scores; likewise, 31 miRNAs had consistently higher cytoplasmic scores. Random concentrations would result in only five in each set. Remarkably, if one miRNA has a high standard score in a compartment, then other miRNAs having the same 5' seeds and certain similar 3' end patterns are also highly scored in the same way. That is, in addition to the seed sequence, 3' sequence similarity criteria identify families of mature miRNAs with consistently high nuclear or cytoplasmic expression.

Neurocognitive deficits are a core feature of schizophrenia and, therefore, represent potentially critical outcome variables for assessing antipsychotic treatment response. We performed genome-wide association studies (GWAS) with 492K single nucleotide polymorphisms (SNPs) in a sample of 738 patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness study. Outcome variables consisted of a neurocognitive battery administered at multiple time points over an 18-month period, measuring processing speed, verbal memory, vigilance, reasoning, and working memory domains. Genetic mediation of improvements in each of these five domains plus a composite neurocognitive measure was assessed for each of five antipsychotics (olanzapine, perphenazine, quetiapine, risperidone, and ziprasidone). Six SNPs achieved genome-wide significance using a pre-specified threshold that ensures, on average, only 1 in 10 findings is a false discovery. These six SNPs were located within, or in close proximity to, genes EHF, SLC26A9, DRD2, GPR137B, CHST8, and IL1A. The more robust findings, that is those significant across multiple neurocognitive domains and having adjacent SNPs showing evidence for association, were rs286913 at the EHF gene (p-value 6.99 × 10(-8), q-value 0.034, mediating the effects of ziprasidone on vigilance), rs11240594 at SLC26A9 (p-value 1.4 × 10(-7), q-value 0.068, mediating the effects of olanzapine on processing speed), and rs11677416 at IL1A (p-value 6.67 × 10(-7), q-value 0.081, mediating the effects of olanzapine on working memory). This study has generated several novel candidate genes for antipsychotic response. However, our findings will require replication and functional validation. To facilitate replication efforts, we provide all GWAS p-values for download.

Schizophrenia is an often devastating neuropsychiatric illness. Understanding the genetic variation affecting response to antipsychotics is important to develop novel diagnostic tests to match individual schizophrenia patients to the most effective and safe medication. In this study, we use a genome-wide approach to detect genetic variation underlying individual differences in response to treatment with the antipsychotics olanzapine, quetiapine, risperidone, ziprasidone and perphenazine. Our sample consisted of 738 subjects with DSM-IV schizophrenia who took part in the Clinical Antipsychotic Trials of Intervention Effectiveness. Subjects were genotyped using the Affymetrix 500 K genotyping platform plus a custom 164 K chip to improve genome-wide coverage. Treatment outcome was measured using the Positive and Negative Syndrome Scale. Our criterion for genome-wide significance was a prespecified threshold that ensures that, on an average, only 10% of the significant findings are false discoveries. The top statistical result reached significance at our prespecified threshold and involved a single-nucleotide polymorphism (SNP) in an intergenic region on chromosome 4p15. In addition, SNPs in Ankyrin Repeat and Sterile Alpha Motif Domain-Containing Protein 1B (ANKS1B) and in the Contactin-Associated Protein-Like 5 gene (CNTNAP5), which mediated the effects of olanzapine and risperidone on Negative symptoms, were very close to our threshold for declaring significance. The most significant SNP in CNTNAP5 is nonsynonymous, giving rise to an amino-acid substitution. In addition to highlighting our top results, we provide all P-values for download as a resource for investigators with the requisite samples to carry out replication. This study demonstrates the potential of genome-wide association studies to discover novel genes that mediate the effects of antipsychotics, which could eventually help to tailor drug treatment to schizophrenic patients.

Background: Small RNAs are known to regulate diverse gene expression processes including translation, transcription, and splicing. Among small RNAs, the microRNAs (miRNAs) of 17 to 27 nucleotides (nts) undergo biogeneses including primary transcription, RNA excision and folding, nuclear export, cytoplasmic processing, and then bioactivity as regulatory agents. We propose that analogous hairpins from RNA molecules that function as part of the spliceosome might also be the source of small, regulatory RNAs (somewhat smaller than miRNAs)., Results: Deep sequencing technology has enabled discovery of a novel 16-nt RNA sequence in total RNA from human brain that we propose is derived from RNU1, an RNA component of spliceosome assembly. Bioinformatic alignments compel inquiring whether the novel 16-nt sequence or its precursor have a regulatory function as well as determining aspects of how processing intersects with the miRNA biogenesis pathway. Specifically, our preliminary in silico investigations reveal the sequence could regulate splicing factor Arg/Ser rich 1 (SFRS1), a gene coding an essential protein component of the spliceosome. All 16-base source sequences in the UCSC Human Genome Browser are within the 14 instances of RNU1 genes listed in wgEncodeGencodeAutoV3. Furthermore, 10 of the 14 instances of the sequence are also within a common 28-nt hairpin-forming subsequence of RNU1., Conclusions: An abundant 16-nt RNA sequence is sourced from a spliceosomal RNA, lies in a stem of a predicted RNA hairpin, and includes reverse complements of subsequences of the 3'UTR of a gene coding for a spliceosome protein. Thus RNU1 could function both as a component of spliceosome assembly and as inhibitor of production of the essential, spliceosome protein coded by SFRS1. Beyond this example, a general procedure is needed for systematic discovery of multiple alignments of sequencing, splicing, and RNA folding data.

Adolescents at genetic high risk (GHR) for schizophrenia have shown social skill impairments and there is some evidence to suggest they have Theory of Mind (ToM) deficits; however no research has used a standardized, performance-based behavioral measure to assess social functioning in this population nor evaluated ToM with a well-validated measure. We evaluated the psychometric properties of a new, theoretically-derived assessment of social functioning in GHR adolescents: the "High-Risk Social Challenge" task (HiSoC). The second aim was to explore whether GHR adolescents would show social skill and ToM deficits as compared to a non-psychiatric control (NPC) group. The present study evaluated social functioning with the HiSoC and ToM with the Eyes Test in 23 GHR adolescents and 31 NPCs. The HiSoC demonstrated high levels of reliability and validity. The GHR adolescents showed social skill impairments, but not ToM deficits. The results suggest that the HiSoC is a potentially useful new measure of social functioning in GHR adolescents. Furthermore, the findings add to the current body of literature that indicates that social skill impairments are related to schizophrenia vulnerability., ((c) 2010 Elsevier B.V. All rights reserved.)

In recent years microRNAs have become recognized as pervasive, versatile agents of gene regulation. Some widely embraced rules involving Watson-Crick hybridization of microRNAs with mRNAs have generated great interest as scientists envision potential RNA cargoes for gene therapy and other experimental systems. However, while researchers ardently seek simplifying principles, nature seems very uncooperative. This article reviews some small RNA mechanisms that potentially regulate genes and which are not covered by previous microRNAs characterizations. In addition, we report here results of fluorescence microscopy experiments to directly demonstrate nuclear import of small RNAs equal in length to typical mature microRNAs, implying that gene regulation at the locus of transcription might be possible., (Copyright 2009 Elsevier Ltd. All rights reserved.)

A promoter polymorphism in the serotonin transporter gene has been widely studied in neuropsychiatry. We genotyped the 5-HTTLPR/rs25531 triallelic polymorphism in 728 schizophrenia cases from the CATIE study and 724 control subjects. In a logistic regression with case/control status as dependent variable and 7 ancestry-informative principal components as covariates, the effect of 5-HTTLPR/rs25531 composite genotype was not significant (odds ratio = 1.008, 95% CI 0.868-1.172, P = 0.91). In cases only, 5-HTTLPR/rs25531 was not associated with neurocognition (summary neurocognitive index P = 0.21, working memory P = 0.32) or symptomatology (PANSS positive P = 0.67 and negative symptoms P = 0.46). We were unable to identify association of the triallelic 5-HTTLPR with schizophrenia, neurocognition, or core psychotic symptoms even at levels of significance unadjusted for multiple comparisons., ((c) 2010 Wiley-Liss, Inc.)

Context: Early detection and prospective evaluation of clinical high-risk (CHR) individuals who may develop schizophrenia or other psychotic disorders is critical for predicting psychosis onset and for testing preventive interventions., Objectives: To elucidate the neuropsychology of the CHR syndrome, to determine the association of neuropsychological function with conversion to psychosis and family history of psychosis, and to examine whether baseline neuropsychological functioning predicts subsequent psychosis., Design: Longitudinal study with 2(1/2) years of follow-up., Setting: Eight centers participating in the North American Prodrome Longitudinal Study., Participants: Three hundred four prospectively identified CHR individuals meeting Structured Interview for Prodromal Syndromes criteria, 52 non-CHR persons with a family history of psychosis in first- or second-degree relatives (family high-risk group), and 193 normal controls with neither a family history of psychosis nor a CHR syndrome, all of whom underwent baseline neuropsychological evaluations., Main Outcome Measures: A neurocognitive composite score, 8 individual neuropsychological measures, an IQ estimate, and high-risk status., Results: Global ("composite") neuropsychological functioning was comparably impaired in the CHR and family high-risk groups compared with controls, but profiles differed significantly between groups. Neuropsychological functioning in the CHR group was significantly lower in persons who progressed to psychosis than in those who did not and was worst in the subgroup with a family history of psychosis. Tests of processing speed and verbal learning and memory were most sensitive in discriminating CHR individuals from controls, although reductions were less severe than in established schizophrenia. Neuropsychological functioning did not contribute uniquely to the prediction of psychosis beyond clinical criteria, but worse verbal memory predicted more rapid conversion., Conclusions: These findings document that CHR individuals have significant neuropsychological difficulties, particularly those who later develop psychosis. This dysfunction is generally of moderate severity but less than in first-episode schizophrenia, suggesting that further decline may occur after baseline CHR assessment.

Aim: Psychological well-being is a subjective component of quality of life (QOL) that has been previously unexplored in individuals recovering from an initial psychotic episode. This study examined predictors of psychological well-being among individuals with first-episode psychosis (FEP) and compared it to a non-clinical college-aged comparison group., Methods: The Scales of Psychological Well-Being (SPWB) Environmental Mastery and Purpose in Life subscales were administered to both clinical (n = 41) and control (n = 39) participants. Clinical participants were also assessed on symptom measures and QOL, and all participants completed a measure of perceived social support. Multiple regression analyses were carried out to determine predictors of well-being in the FEP sample., Results: SPWB scores were significantly lower for the FEP group in comparison to the control group. Additionally, greater perceived social support and lower levels of depression were found to be significant predictors of psychological well-being in the clinical sample, whereas gender and negative symptoms were not significant predictors., Conclusions: These results suggest that the development of a psychotic episode is associated with decreased subjective well-being, and that depression and social support may play an important role in this aspect of an individual's recovery. Additionally, the SPWB appear to be tapping into an important construct that has been relatively unexamined in first-episode research and may have potential utility in clinical practice and future treatment development.

Background: Improvements in high-throughput technology and its increasing use have led to the generation of many highly complex datasets that often address similar biological questions. Combining information from these studies can increase the reliability and generalizability of results and also yield new insights that guide future research., Results: This paper describes a novel algorithm called BLANKET for symmetric analysis of two experiments that assess informativeness of descriptors. The experiments are required to be related only in that their descriptor sets intersect substantially and their definitions of case and control are consistent. From resulting lists of n descriptors ranked by informativeness, BLANKET determines shortlists of descriptors from each experiment, generally of different lengths p and q. For any pair of shortlists, four numbers are evident: the number of descriptors appearing in both shortlists, in exactly one shortlist, or in neither shortlist. From the associated contingency table, BLANKET computes Right Fisher Exact Test (RFET) values used as scores over a plane of possible pairs of shortlist lengths 12. BLANKET then chooses a pair or pairs with RFET score less than a threshold; the threshold depends upon n and shortlist length limits and represents a quality of intersection achieved by less than 5% of random lists., Conclusions: Researchers seek within a universe of descriptors some minimal subset that collectively and efficiently predicts experimental outcomes. Ideally, any smaller subset should be insufficient for reliable prediction and any larger subset should have little additional accuracy. As a method, BLANKET is easy to conceptualize and presents only moderate computational complexity. Many existing databases could be mined using BLANKET to suggest optimal sets of predictive descriptors.

Few pharmacological intervention studies have examined the impact of medication on social cognition, particularly emotion perception. The goal of this randomized, double-blind study is to compare the effects of several second generation antipsychotics and a first generation antipsychotic, perphenazine, on emotion perception in individuals with schizophrenia. Patients were assigned to receive treatment with olanzapine, queitapine fumarate, risperidone, ziprasidone or perphenazine for up to 18 months. Eight hundred and seventy three patients completed an emotion perception test immediately prior to randomization and after 2 months of treatment. We also examined baseline predictors of emotion perception change. Most treatments were associated with a small, non-statistically significant improvement in emotion perception at two months, although they did not differ from one another. Greater improvement in emotion perception at 2 months was significantly predicted by lower baseline emotion perception and higher baseline neurocognitive functioning, and marginally predicted by less time on an antipsychotic.

Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

A substantial number of patients who meet criteria for a prodromal syndrome for first psychosis are treated with antipsychotic and/or antidepressant medications. There is suggestive evidence that both classes of medication may reduce prodromal symptoms. This longitudinal study examined the relation of antipsychotic and antidepressant medication with prodromal symptom severity at baseline and 6-month follow-up. Participants met Structured Interview for Prodromal Syndromes (SIPS) criteria for the prodrome, and were evaluated at eight centers as part of the North American Prodrome Longitudinal Study (NAPLS). Symptom ratings (positive, negative, disorganized and general) and data on antipsychotics, SSRIs, and other antidepressant medications were obtained at baseline and 6-month follow-up. Analyses revealed that all symptom dimensions declined in severity over time, but there were differences in the magnitude of the decline as a function of antipsychotic medication. Those never on antipsychotics showed less reduction in positive and disorganized symptoms over time. SSRIs and other antidepressants were not linked with declines in symptom severity. Consistent with findings from small-sample, clinical trials, the present results suggest that atypical antipsychotics may be effective in reducing the severity of attenuated positive symptoms associated with the prodrome to psychotic disorders. Limitations of the present study are noted, including the fact that it is not a randomized trial, and data on duration and dosage of medication and 2-year follow-up were not available for most participants. The results are discussed in light of the relative risks and benefits of preventive interventions, both medication and cognitive therapies, and the importance of future clinical trials.

Treatment and prevention studies over the past decade have enrolled patients believed to be at risk for future psychosis. These patients were considered at risk for psychosis by virtue of meeting research criteria derived from retrospective accounts of the psychosis prodrome. This study evaluated the diagnostic validity of the prospective "prodromal risk syndrome" construct. Patients assessed by the Structured Interview for Prodromal Syndromes as meeting criteria of prodromal syndromes (n = 377) from the North American Prodrome Longitudinal Study were compared with normal comparison (NC, n = 196), help-seeking comparison (HSC, n = 198), familial high-risk (FHR, n = 40), and schizotypal personality disorder (SPD, n = 49) groups. Comparisons were made on variables from cross-sectional demographic, symptom, functional, comorbid diagnostic, and family history domains of assessment as well as on follow-up outcome. Prodromal risk syndrome patients as a group were robustly distinguished from NC subjects across all domains and distinguished from HSC subjects and from FHR subjects on most measures in many of these domains. Adolescent and young adult SPD patients, while distinct from prodromal patients on definitional grounds, were similar to prodromals on multiple measures, consistent with SPD in young patients possibly being an independent risk syndrome for psychosis. The strong evidence of diagnostic validity for the prodromal risk syndrome for first psychosis raises the question of its evaluation for inclusion in Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition).

Objective: To further define the metabolic profiles of second-generation antipsychotics during the treatment of young patients with early psychosis, with a view to better inform prescribing clinicians., Method: Weight, body mass index (BMI), glucose, and serum lipids were measured in the 52-week Comparison of Atypicals for First Episode (CAFE) study, in which olanzapine, quetiapine, and risperidone were evaluated, and whose primary outcomes have been reported elsewhere. These metabolic data were analyzed using a mixed random coefficients model for continuous longitudinal measures and a logistic regression model for categorical responses., Results: Of the 400 patients recruited, 31% were overweight and 18% were obese at baseline, and 17 (4.3%) patients met criteria for metabolic syndrome. After 12 and 52 weeks of treatment, weight gain >or=7% from baseline was reported in 29.2% and 50.0% of quetiapine-treated patients, 59.8% and 80.0% of olanzapine-treated patients, and 32.5% and 57.6% of risperidone-treated patients, respectively. Weight gain after 12 and 52 weeks of treatment was estimated as [Least Squares Mean (SE)] 15.6 (+/-1.1) and 24.2 (+/-1.9) lb for olanzapine, 8.6 (+/-1.1) and 14.0 (+/-1.9) lb with risperidone and 7.9 (+/-1.1) and 12.1 (+/-1.8) lb for quetiapine respectively. In women, greater weight gain occurred during risperidone treatment compared with quetiapine treatment. By week 52, increases in BMI >or=1 unit occurred with significantly higher frequency in olanzapine-treated patients compared with quetiapine- or risperidone-treated patients. By 52 weeks, treatment-emergent metabolic syndrome was reported in 51 individuals (13.4% of the total population), of whom 22 were receiving olanzapine, 18 quetiapine, and 11 risperidone. Risperidone was associated with the smallest elevations in triglyceride and total cholesterol levels., Conclusion: Weight gain and metabolic syndrome occur commonly even in young patients receiving antipsychotic treatment for early psychosis. Targeted interventions are therefore warranted from the onset of antipsychotic therapy.

Using time-lapse maps, we visualized the dynamics of schizophrenia progression, revealing spreading cortical changes that depend on the type of antipsychotic treatment. Dynamic, 4-dimensional models of disease progression were created from 4 repeated high-resolution brain magnetic resonance imaging scans of 36 first-episode schizophrenia patients (30 men/6 women; mean age: 24.2 +/- 5.1 SD years) randomized to haloperidol (HAL) (n = 15) or olanzapine (OLZ) treatment (n = 21), imaged at baseline, 3, 6, and 12 months (144 scans). Based on surface-based cortical models and point-by-point measures of gray matter volume, we generated time-lapse maps for each treatment. Disease trajectories differed for atypical versus typical neuroleptic drugs. A rapidly advancing parietal-to-frontal deficit trajectory, in HAL-treated patients, mirrored normal cortical maturation but greatly intensified. The disease trajectory advanced even after symptom normalization, involving the frontal cortex within 12 months with typical drug treatment. Areas with fastest tissue loss shifted anteriorly in the first year of psychosis. This trajectory was not seen with OLZ. Whether this association reflects either reduced neurotoxicity or neuroprotection cannot be addressed with neuroimaging; changes may relate to glial rather than neural components. These maps revise current models of schizophrenia progression; due to power limitations, the findings require confirmation in a sample large enough to model group x time interactions.

The Graduated Recovery Intervention Program (GRIP) is a novel cognitive-behavioral therapy program designed to facilitate functional recovery in people who have experienced an initial episode of psychosis. In this paper, the treatment development process of GRIP is described and data from an open feasibility trial are presented. Findings suggest clinical and psychosocial benefits associated with GRIP, and the treatment was well-received by clients and therapists. The retention rate of 67%, however, suggests the need for protocol modifications to improve engagement. Initial data on the efficacy of GRIP are encouraging, although the study design precludes more robust conclusions at this time.

The neuregulin 1 (NRG1) promoter single nucleotide polymorphism (SNP) rs6994992 has shown association with decreased activation of frontal and temporal lobe regions, increased risk of psychosis, and decreased premorbid IQ. This SNP is part of a putative schizophrenia risk-associated haplotype and was associated with increased expression of the type IV transcript in postmortem tissue. We tested for association between rs6994992 and chronic schizophrenia by genotyping 738 cases from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and 733 matched controls. We further tested for associations with age at onset and baseline neurocognition in cases with schizophrenia reasoning that these phenotypes might yield results similar to those seen for premorbid IQ. Affection status was weakly associated with rs6994992 genotypes and trended towards association under a recessive model. This association did not survive correction for multiple comparisons and was in the opposite direction than has been reported. There was no association between rs6994992 and age at onset, an estimate of premorbid IQ, or neurocognition at study baseline. We were unable to replicate previous associations of rs6994992 with schizophrenia and, moreover, did not find significant associations with age of onset, an estimate of pre-morbid IQ, or neurocognition.

Objective: There is uncertainty regarding the onset timing of the cognitive deficiencies of schizophrenia. We investigated whether conversion to psychosis and/or olanzapine altered the neuropsychological course of subjects within the first-ever double blind medication study of the putative schizophrenia first episode prodrome., Method: Sixty participants in a double blind trial of olanzapine as a treatment for putative prodromal states were assessed at entry (pre-randomization), and again at 6 and 12 months (if they remained non-psychotic), or at any of these points prior to psychosis followed by post-psychosis and 6 months post-psychosis assessments., Results: Participants who converted to psychosis did not differ from placebo non-converters in pre-randomization global neuropsychological status. Early converters did not differ from later converters in entry neuropsychological status. Subjects who converted after 6 months did not show neuropsychological declines during the initial, pre-psychosis, 6 months. Neuropsychological course did not differ between converters to psychosis and non-converters, or between olanzapine and placebo-assigned subjects., Conclusions: Neither the onset of frank psychosis nor olanzapine treatment of the prodrome significantly alters neuropsychological course in persons considered to be at high risk at their initial (pre-psychosis) assessment. These findings suggest that the neuropsychological deficiencies associated with psychotic conditions largely pre-exist the first frank psychotic episode.

Objectives: Social cognition plays an important role in the functioning of individuals with psychosis. In this study, we explored two areas of social cognition not previously investigated early in the course of psychosis., Method: Eighty-eight clinical high risk participants, 26 participants diagnosed with schizophrenia for less than 5 years, and 41 non-clinical control participants completed two measures of social cognition., Results: Clinical high risk participants demonstrated biased responses to untrustworthy faces compared to both of the other groups. Early schizophrenia participants performed more poorly on an advanced theory of mind task compared to the clinical high risk and control groups., Conclusions: There are different patterns of performance on social cognitive tasks in these groups, which require further examination in longitudinal studies.

Efficient and reliable assessments of cognitive treatment effects are essential for the comparative evaluation of procognitive effects of pharmacologic therapies. Yet, no studies have addressed the sensitivity and efficiency with which neurocognitive batteries evaluate cognitive abilities before and after treatment. Participants were primarily first episode schizophrenia patients who completed baseline (n = 367) and 12-week (n = 219) assessments with the BACS (Brief Assessment of Cognition in Schizophrenia) and CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) neuropsychological batteries in a clinical trial comparing olanzapine, quetiapine, and risperidone. Exploratory factor analysis revealed that performance on both batteries was characterized by a single factor of generalized cognitive deficit for both baseline performance and cognitive change after treatment. Both batteries estimated similar levels of change following treatment, although the BACS battery required half the administration time. Because a unitary factor characterized baseline cognitive abilities in early psychosis as well as cognitive change after treatment with atypical antipsychotic medications, short batteries such as the BACS may efficiently provide sufficient assessment of procognitive treatment effects with antipsychotic medications. Assessment of cognitive effects of adjunctive therapies targeting specific cognitive domains or impairments may require more extensive testing of the domains targeted to maximize sensitivity for detecting specific predicted cognitive outcomes.

Poor social functioning is a hallmark of schizophrenia. The purpose of this study was to examine social functioning in individuals at clinical high risk for psychosis. Social functioning was assessed in a sample of 86 clinical high risk (CHR) individuals and compared to that of 50 first-episode of psychosis (FE) subjects, 53 multi-episode schizophrenia subjects (ME) and 55 non-psychiatric controls (NPC). Subjects were assessed on the Social Functioning Scale (SFS), the Role Functioning subscale of the Quality of Life Scale (QLS-role), and the premorbid functioning scale. On the SFS, the CHR group did not differ significantly from the FE and ME groups and all were impaired relative to the NPCs. On QLS-role, the CHR group performed significantly better than the ME patients and significantly worse than NPCs. CHR subjects did not differ from patients in terms of premorbid functioning. This study demonstrates that even at the pre-psychotic phase of the illness, these young people are demonstrating significant deficits in social functioning, supporting that social deficits are present long before the onset of psychotic symptoms.