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Introduction Disturbed sleep is a common feature of psychotic disorders that is also present in the clinical high risk (CHR) state. Evidence suggests a potential role of sleep disturbance in symptom progression, yet the interrelationship between sleep and CHR symptoms remains to be determined. To address this knowledge gap, we examined the association between disturbed sleep and CHR symptoms over time. Methods Data were obtained from the North American Prodrome Longitudinal Study (NAPLS)-3 consortium, including 688 CHR individuals and 94 controls (mean age 18.25, 46% female) for whom sleep was tracked prospectively for 8 months. We used Cox regression analyses to investigate whether sleep disturbances predicted conversion to psychosis up to >2 years later. With regressions and cross-lagged panel models, we analyzed longitudinal and bidirectional associations between sleep (the Pittsburgh Sleep Quality Index in conjunction with additional sleep items) and CHR symptoms. We also investigated the independent contribution of individual sleep characteristics on CHR symptom domains separately and explored whether cognitive impairments, stress, depression, and psychotropic medication affected the associations. Results Disturbed sleep at baseline did not predict conversion to psychosis. However, sleep disturbance was strongly correlated with heightened CHR symptoms over time. Depression accounted for half of the association between sleep and symptoms. Importantly, sleep was a significant predictor of CHR symptoms but not vice versa, although bidirectional effect sizes were similar. Discussion The critical role of sleep disturbance in CHR symptom changes suggests that sleep may be a promising intervention target to moderate outcome in the CHR state.

More than 20 years after the clinical high risk syndrome for psychosis (CHR) was first articulated, it remains controversial whether the CHR syndrome predicts onset of psychosis with diagnostic specificity or predicts pluripotential diagnostic outcomes. Recently, analyses of observational studies, however, have suggested that the CHR syndrome is not pluripotential for emergent diagnostic outcomes. The present report conducted additional analyses in previously reported samples to determine (1) whether comorbid disorders were more likely to persist in CHR patients compared to a comparison group of patients who responded to CHR recruitment efforts but did not meet criteria, termed help-seeking comparison subjects (HSC); and (2) whether clinically defined pluripotential CHR subgroups could be identified. All data were derived from 2 multisite studies in which DSM-IV structured diagnostic interviews were conducted at baseline and at 6-month intervals. Across samples we observed persistence of any nonpsychotic disorder in 80/147 CHR cases (54.4%) and in 48/84 HSC cases (57.1%, n.s.). Findings with persistence of anxiety, depressive, and bipolar disorders considered separately were similar. Efforts to discover pluripotential CHR subgroups were unsuccessful. These findings add additional support to the view that the CHR syndrome is not pluripotential for predicting various diagnostic outcomes but rather is specific for predicting emergent psychosis.

Background Groups at clinical high risk (CHR) of developing psychosis are heterogeneous, composed of individuals with different clusters of symptoms. It is likely that there exist subgroups, each associated with different symptom constellations and probabilities of conversion. Method Present study used latent profile analysis (LPA) to ascertain subgroups in a combined sample of CHR (n = 171) and help-seeking controls (HSCs; n = 100; PREDICT study). Indicators in the LPA model included baseline Scale of Prodromal Symptoms (SOPS), Calgary Depression Scale for Schizophrenia (CDSS), and neurocognitive performance as measured by multiple instruments, including category instances (CAT). Subgroups were further characterized using covariates measuring demographic and clinical features. Results Three classes emerged: class 1 (mild, transition rate 5.6%), lowest SOPS and depression scores, intact neurocognitive performance; class 2 (paranoid-affective, transition rate 14.2%), highest suspiciousness, mild negative symptoms, moderate depression; and class 3 (negative-neurocognitive, transition rate 29.3%), highest negative symptoms, neurocognitive impairment, social cognitive impairment. Classes 2 and 3 evidenced poor social functioning. Conclusions Results support a subgroup approach to research, assessment, and treatment of help-seeking individuals. Class 3 may be an early risk stage of developing schizophrenia.

In the literature, there have been several attempts to develop prediction models for youth who are at clinical high risk (CHR) of developing psychosis. Although there are no specific clinical or demographic variables that seem to consistently predict the later transition to psychosis in those CHR youth, in addition to attenuated psychotic symptoms, the most commonly occuring predictors tend to be poor social functioning and certain cognitive tasks. Unfortunately, there has been little attempt to replicate alogorithms. A recently published article by Cornblatt et al suggested that, for individuals with attentuated psychotic symptoms (APS), disorganized communication, suspiciousness, verbal memory, and a decline in social functioning were the best predictors of later transition to psychosis (the RAP model). The purpose of this article was to first test the prediction model of Cornblatt et al with a new sample of individuals with APS from the PREDICT study. The RAP model was not the best fit for the PREDICT data. However, using other variables from PREDICT, it was demonstrated that unusual thought content, disorganized communication, baseline social functioning, verbal fluency, and memory, processing speed and age were predictors of later transition to psychosis in the PREDICT sample. Although the predictors were different in these 2 models, both supported that disorganized communication, poor social functioning, and verbal memory, were good candidates as predictors for later conversion to psychosis.

Background Studies in individuals at clinical high risk (CHR) for psychosis provide a powerful means to predict outcomes and inform putative mechanisms underlying conversion to psychosis. In previous work, we applied advanced diffusion imaging methods to reveal that white matter pathology in a CHR population is characterized by cellular-specific changes in white matter, suggesting a preexisting neurodevelopmental anomaly. However, it remains unknown whether these deficits relate to clinical symptoms and/or conversion to frank psychosis. To address this gap, we examined cross-sectional and longitudinal white matter maturation in the largest imaging population of CHR individuals to date, obtained from the North American Prodrome Longitudinal Study (NAPLS-3). Methods Multi-shell diffusion magnetic resonance imaging (MRI) data were collected across multiple timepoints (1–6 at ~2 month intervals) in 286 subjects (age range=12–32 years). These were 230 unmedicated CHR subjects, including 11% (n=25) who transitioned to psychosis (CHR-converters), as well as 56 age and sex-matched healthy controls. Raw diffusion signals were harmonized to remove scanner/site-induced effects, yielding a unified imaging dataset. Fractional anisotropy of cellular tissue (FAt) and the volume fraction of extracellular free-water (FW) were assessed in 12 major tracts from the IIT Human Brain Atlas (v.5.0). Linear mixed effects (LME) models were fitted to infer developmental trajectories of FAt and FW across age for CHR-converters, CHR-nonconverters and control groups, while accounting for the repeated measurements on each individual. Results The rate at which FAt changed with age significantly differed between the three groups across commissural and association tracts (5 in total; p Discussion Our results revealed that clinical high-risk for psychosis is associated with cellular-specific alterations in white matter, regardless of conversion status. Only converters showed excess extracellular free-water, which involved tracts connecting occipital, posterior temporal, and orbito-frontal areas. We also demonstrate a direct impact of free-water on positive symptomatology, collectively, suggesting that excess free-water may signal acute psychosis and its onset. This marker may be useful for patient selection for clinical trials and assessment of individuals with prodromal psychosis.

Memory deficits are a hallmark of psychotic disorders such as schizophrenia. However, whether the neural dysfunction underlying these deficits is present before the onset of illness and potentially predicts conversion to psychosis is unclear. In this study, we investigated brain functional alterations during memory processing in a sample of 155 individuals at clinical high risk (including 18 subjects who later converted to full psychosis) and 108 healthy controls drawn from the second phase of the North American Prodrome Longitudinal Study (NAPLS-2). All participants underwent functional magnetic resonance imaging with a paired-associate memory paradigm at the point of recruitment and were clinically followed up for approximately 2 years. We found that at baseline, subjects at high risk showed significantly higher activation during memory retrieval in the prefrontal, parietal, and bilateral temporal cortices (PFWE < .035). This effect was more pronounced in converters than nonconverters and was particularly manifested in unmedicated subjects (P < .001). The hyperactivation was significantly correlated with retrieval reaction time during scan in converters (P = .009) but not in nonconverters and controls, suggesting an exaggerated retrieval effort. These findings suggest that hyperactivation during memory retrieval may mark processes associated with conversion to psychosis, and such measures have potential as biomarkers for psychosis prediction.

It is not well established whether the incident outcomes of the clinical high-risk (CHR) syndrome for psychosis are diagnostically specific for psychosis or whether CHR patients also are at elevated risk for a variety of nonpsychotic disorders. We collected 2 samples (NAPLS-1, PREDICT) that contained CHR patients and a control group who responded to CHR recruitment efforts but did not meet CHR criteria on interview (help-seeking comparison patients [HSC]). Incident diagnostic outcomes were defined as the occurrence of a SIPS-defined psychosis or a structured interview diagnosis from 1 of 3 nonpsychotic Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) groups (anxiety, bipolar, or nonbipolar mood disorder), when no diagnosis in that group was present at baseline. Logistic regression revealed that the CHR vs HSC effect did not vary significantly across study for any emergent diagnostic outcome; data from the 2 studies were therefore combined. CHR (n = 271) vs HSC (n = 171) emergent outcomes were: psychosis 19.6% vs 1.8%, bipolar disorders 1.1% vs 1.2%, nonbipolar mood disorders 4.4% vs 5.3%, and anxiety disorders 5.2% vs 5.3%. The main effect of CHR vs HSC was statistically significant (OR = 13.8, 95% CI 4.2–45.0, df = 1, P < .001) for emergent psychosis but not for any emergent nonpsychotic disorder. Sensitivity analyses confirmed these findings. Within the CHR group emergent psychosis was significantly more likely than each nonpsychotic DSM-IV emergent disorder, and within the HSC group emergent psychosis was significantly less likely than most emergent nonpsychotic disorders. The CHR syndrome is specific as a marker for research on predictors and mechanisms of developing psychosis.

BACKGROUND: Childhood adversity is strongly associated with increased risk for psychosis. Research on the relationship between childhood adversity and psychosis not only links childhood abuse and neglect to psychotic symptoms, specifically hallucinations, but also indicates that the relationship is causal, with a dose-effect. Preliminary evidence of this relationship has been replicated within the clinical high risk (CHR) population through the North American Prodrome Longitudinal Study (NAPLS) where, relative to controls, individuals at CHR reported having experienced significantly more trauma and bullying, resulting in higher levels of anxiety and depression, as well as poorer functioning. Indices of stressful life events, family history of psychotic illness, and trauma represent robust predictors for presence of CHR syndrome and are included as part of the NAPLS Individualized Risk Calculator for Psychosis. Despite clear evidence for an association between childhood trauma and psychosis, the biological mechanisms that mediate this relationship remain largely unknown. Previous research has implicated the role of hypothalamic-pituitary-adrenal (HPA) axis dysregulation in development of both physical and mental illness. The HPA axis is highly responsive to environmental adversities both in childhood and in adulthood. Further, the HPA-axis is known to be a powerful modulator of inflammatory activity, as measured by peripheral markers of inflammation, and is in turn modulated by inflammatory processes. Immune system activation and dysregulation may serve as a biological mediator between childhood trauma and vulnerability for developing psychosis. The aim of this paper is to establish whether early-life adversity is associated with a pro-inflammatory phenotype in individuals at CHR for psychosis using a validated multiplex blood assay index previously established by Perkins et al. (2014). METHODS: 35 healthy controls and 62 CHR subjects (N=117) that participated in the NAPLS2 study, ages 12–35, were included. 32 of the CHR subjects later converted to psychosis. Experience of trauma was assessed using the Childhood Trauma and Abuse Scale, a semi‐structured interview used to detect the occurrence of psychological bullying, physical bullying, emotional neglect, physical abuse, psychological abuse, or sexual abuse, before the age of 16. Experience and sensitivity to stressful life events was assessed using a modified version of the Life Events Scale (LES). Subjective stress for endorsed items is coded on a 7-point Likert scale. Inflammation and oxidative stress were measured using a 15-analyte blood biomarker index previously established to reliably distinguish between healthy control subjects, CHR subjects who developed psychosis, and CHR subjects who did not develop psychosis. RESULTS: Across subjects, the 15-analyte index was significantly correlated with total number of unique traumas endorsed. Increased trauma exposure was associated with a higher analyte index value (r= .26, p< 0.01). Additionally, the 15-analyte index was significantly correlated with total number of reported undesirable life events (r=.20, p

BACKGROUND: Research criteria for a clinical high-risk (CHR) syndrome identify persons with ~20% risk of converting to a psychotic disorder within 2 years. The CHR syndrome is based on the presence of attenuated positive symptoms, however as with schizophrenia neurocognitive, social cognitive, mood symptoms, behavioral disturbances, and functional impairments often are prominent features. Interventions in persons at CHR offer the potential to prevent the emergence of psychotic disorders such as schizophrenia and schizoaffective disorder, potentially avoiding the development of a chronic mental disorder that requires lifelong treatment. METHODS: The evidence base for pharmacological and psychotherapeutic interventions for early psychosis is summarized based on a literature review. The currently status of active pharmacological and psychotherapeutic interventions are ascertained by a search of government registries (e.g. clinicaltrial.gov). RESULTS: Clinical trials in CHR subjects generally find that psychotherapeutic and antipsychotics reduce risk of psychosis conversion. However, the results of meta-analyses conclude that there in insufficient evidence to support any specific intervention at present. At present there are several clinical trials underway to examine the effects of specific pharmacological treatments, psychotherapies, and a stepped-approach to care. The CHR syndrome is not yet fully recognized by the ICD or DSM diagnostic systems used by clinicians to document medical services. CONCLUSIONS: Clinicians engaged in treatment of help-seeking persons with attenuated psychosis are challenged by the lack of an agreed-upon set of clinical diagnostic criteria and a relatively weak evidence base to guide treatment decision-making. Communicating this diagnostic and treatment uncertainties to patients and their families is a major issue. The risks of specific interventions, especially antipsychotic medications, is especially hampered by the lack of understanding of the risks for those clinical high-risk patients who do not progress to psychosis. Well-validated clinical and biological markers that enhance psychosis risk prediction, especially those that identify the underlying neuropathology driving psychosis risk together with specific interventions that address individual risk vulnerability are key to addressing heterogeneity.

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.

Background In spite of evidence for the premorbid and prodromal onset of cognitive deficits in schizophrenia and related psychotic disorders, there is some limited evidence to suggest that deficits may progress with psychosis onset. Cognitive remediation in youth at risk for psychosis is being touted as an opportunity not only to remediate deficits but to potentially prevent this progression. Yet trajectories of cognitive functioning over time remain poorly understood in youth at risk, including the degree to which age at assessment or illness onset, sociodemographic factors, or symptom progression influence these trajectories. Methods The North American Prodrome Longitudinal Study (NAPLS) -2 collected data on an extensive battery of neuropsychological (NP) tests at baseline, one year, two years, and post-conversion in a sample of clinical high risk (CHR) youth and healthy comparison (HC) subjects ages 12–35 (N= 960, 92% of the full sample) followed clinically for up to 2 years. NP data were available for 694 at CHR and 265 HC. Linear mixed effects analyses were used to test the effects of group, age, gender, age of onset, maternal education, and clinical outcome on cognitive trajectories. Results Those who transitioned to a psychotic disorder over the course of follow-up performed significantly below those who did not and well below healthy comparisons. Tasks reliant on attention, visual and auditory working memory, visuospatial and verbal memory, and processing speed best differentiated those who transitioned from those who did not at one year (Cohen’s d from -0.33 to -0.54). Discrepancies from normal functioning on these tests were generally large (Cohen’s d from -0.67 to -1.02) consistent with findings for first episode samples. Although clinical outcome was not associated with a significantly different trajectory over time on any cognitive domain, these are likely due to high rates of conversion in this sample within the first year. Predictors of different trajectories will be presented. Discussion These data from one of the largest CHR studies to date suggest that much of the neuropsychological dysfunction in major psychotic disorders is present early in the course of illness and prior to its full expression. However, trajectories are highly heterogeneous. More frequent assessment prior to and during the onset of illness are needed to fully understand the cognitive correlates of psychosis onset and the implications for early intervention.

Background In the clinical high risk (CHR) for psychosis literature, typically, the focus is on determining the risk of conversion to psychosis. However, between 70% and 85% of youth who meet CHR criteria do not develop psychosis during the follow-up period of the study in which they participate. The aim of this study is to focus on CHR youth who did not transition to psychosis and to determine whether there are differences amongst them. Methods The North American Prodrome Longitudinal Study (NAPLS-2) is an 8-site prospective, longitudinal study including 764 help-seeking youth, age 12–35, meeting criteria for a psychosis risk syndrome based on the Structured Interview for Psychosis-risk Syndromes (SIPS), and 279 healthy controls (HC). For this analysis, only youth who did not make a transition to psychosis and completed 2 years of follow-up (n=278, 154 males, 124 females; mean age 18.8) were included. At the 24-month final assessment, the sample was divided into 3 groups: 1) those in remission, determined by scores ≤2 on all 5 attenuated psychotic symptoms on The Scale of Psychosis-risk Symptoms (SOPS); 2) symptomatic, determined by still having a rating of 3–5 on any one of the 5 attenuated psychotic symptoms on the SOPS; 3) prodromal progression, determined by continuing to meet the Criteria of Psychosis-risk Syndromes (COPS). The groups were compared at baseline and at 24-month follow-up on: age, gender, the presence of a current and lifetime psychiatric diagnosis, and social and role functioning. The use of antipsychotic medication was examined across all assessments (baseline, 6-, 12-, 18- & 24 months) using Generalized Linear Models to examine differences among the 3 groups. Results Among the participants, 110 (39.57%) were in-remission, 93 (33.45%) symptomatic, and 75 (26.98%) prodromal progression. At baseline there were no significant differences in age, gender, social and role functioning, or SCID diagnoses except on current PTSD (p=.001) with most cases in the prodromal progression group, and on current anxiety disorder (p=≤.0001) with most cases in the symptomatic group. The prodromal progression had significantly higher ratings on unusual thought content compared to the in-remission group and significantly higher ratings on suspiciousness than the symptomatic group. At 24-month follow-up there were significant differences in negative symptoms (p=≤.0001) between prodromal progression (M=9.19), symptomatic (M=8.84), and in remission (M=5.99) groups; and social functioning (p=≤.005; M=6.56, M=6.68, M=7.20 respectively). Although the in-remission group had the highest ratings on social functioning these were significantly lower in social (M=7.20) and role (M=6.68) functioning than HC (M=8.73, M=8.62 respectively). The groups did not differ on their use of antipsychotics over the course of their 2 years in the study. Discussion There were very few differences on baseline measures amongst the different two-year outcome groups. At 2 years, even though those in remission had improved social and role functioning relative to the other 2 groups, they still had lower social and role functioning than HC.

Background Individuals with autism spectrum disorders (ASD) have symptoms, including social and sensory deficits, and neurobiological alterations that overlap with schizophrenia. Though there is evidence of high rates of psychosis symptoms in ASD, little is known about psychosis prodrome in ASD, or about predictors of psychosis conversion in this population. In this study, we leverage data from clinical high risk (CHR) patients from the NAPLS2 consortium to examine: a) baseline differences in psychosis symptoms and social functioning, b) relative risk of conversion, and c) whether neural response to sensory stimuli yields differential predictors of conversion in CHR individuals with and without ASD (CHR/ASD+; CHR/ASD-). Methods Clinical, electrophysiological, and 24-month follow-up data were available for 305 individuals (14 CHR/ASD+; 291 CHR/ASD-). We examined baseline differences on the SOPS, GFS, and TASIT. Conversion risk was computed with the Cannon conversion calculator, and conversion was defined as SOPS>6 at 2-year outcome. P300 event-related potentials (ERP) were extracted from ongoing EEG collected at baseline in response to Target and Novel auditory and visual stimuli, each presented on 10% of trials within streams of 80% standard stimuli in the same modality. Results In line with our expectations, CHR/ASD+ had worse functioning than CHR/ASD- on the GF-Social scale (t=-4.2, p

Background Accumulated evidence from non-human animal studies suggests that the prominent deficits in memory and executive function that characterise individuals with psychosis may, at least in part, be due to the effects of stress on the brain regions that support these functions. However, studies of patients with established psychosis have yielded inconsistent findings with regards to the relationship between stress and cognition, and research in high-risk populations is notably lacking. Utilising data from the North American Prodrome Longitudinal Study 2 (NAPLS 2), we aimed to further elucidate the relationship between stress (daily stressors, life events, and childhood trauma) and cognitive function in clinical high-risk (CHR) individuals and healthy controls (HC). We additionally explored the role of potential mediators [hypothalamic-pituitary-adrenal (HPA) axis function] and moderators (group status, sex, family history of illness). Methods The sample comprised 885 participants (CHR=646; HC=239) who completed measures of stress and cognitive function at the NAPLS 2 baseline assessment. Stress measures included the Daily Stress Inventory and a modified version of the Psychiatric Epidemiology Research Interview Life Events Scale, both of which provided continuous measures of stress exposure (number of events) and distress (subjective feelings of distress). Participants were also interviewed using the Childhood Trauma and Abuse Scale to determine any exposure to childhood trauma (abuse, neglect, and bullying occurring prior to age 16 years). Basal HPA axis activity was determined via salivary cortisol samples obtained at the baseline assessment and standardised scores from selected subtests from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) were used to derive two cognitive domain scores (memory and executive function). To examine relationships between stress and cognitive domain scores, linear regression analyses were performed on standardised variables. Results Daily stressor exposure, daily stressor distress, and life event exposure exhibited negative quadratic (i.e., inverted U-shaped) associations with both memory and executive function (P < 0.01 for all). In contrast, the reverse pattern (i.e., a negative linear relationship and a positive quadratic relationship) was shown in the model for life event distress and memory domain scores (P < 0.01) whilst trauma history showed only a trend-level association with poorer memory performance (P = 0.084). These relationships, which did not differ across CHR and healthy control groups, were largely unchanged after adjusting for demographic factors and salivary cortisol. Exploratory analyses suggested that trauma exposure and a family history of psychosis may moderate the relationship between daily stressors/life events and cognitive function. Discussion In this large sample of predominately CHR individuals, we observed that the association between stress and cognition is complex and differs across stressor types. The negative quadratic associations that we observed for daily stressor exposure, daily stressor distress, and life event exposure imply that whist lower levels of stress may facilitate memory and executive function, there may be a negative impact on cognition when these stressors become more frequent and distressing. Interventions aiming to minimise stress exposure and promote effective coping strategies might feasibly improve cognition in CHR individuals.

Schizophrenia is a symptomatically heterogeneous disorder characterized by the presence of positive and negative symptoms, and variable impairment in community functioning. Given the diversity of symptom presentations and functioning associated with schizophrenia, one of the key challenges facing the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial was the selection of efficient assessment measures appropriate to a community-based effectiveness trial. This article describes the rationale for the measurement approach adopted for the trial, provides a brief overview of the selected measures, and describes the process of training assessment raters for a large and geographically dispersed study group.

As the number of studies related to the early identification of and intervention in the schizophrenia prodrome continues to grow, it becomes increasingly critical to develop methods to diagnose this new clinical entity with validity. Furthermore, given the low incidence of patients and the need for multisite collaboration, diagnostic and symptom severity reliability is also crucial. This article provides further data on these psychometric parameters for the prodromal assessment instruments developed by the Prevention through Risk Identification, Management, and Education (PRIME) prodromal research team at Yale University: the Structured Interview for Prodromal Syndromes and the Scale of Prodromal Symptoms. It also presents data suggesting that excellent interrater reliability can be established for diagnosis in a day-and-a-half-long training workshop.

Background: Longitudinal studies examining youth at clinical high risk (CHR) of psychosis have predominantly focused on positive symptoms. However, youth at CHR often demonstrate persistent and significant negative symptoms, which have been reported to be predictive of conversion to psychosis. The goal of this study was to examine negative symptoms over time in youth at CHR of psychosis and compare baseline negative symptoms in those who convert to psychosis with those who did not convert. Methods: Youth at CHR (N=764) were recruited for the North American Prodrome Longitudinal Study (NAPLS 2)at 8 sites across North America. Negative symptoms were rated on the Scale of Prodromal Symptoms (SOPS) at baseline, 6, 12, 18, and 24months. Difference in prevalence of negative symptoms was assessed using Z test and change in negative symptom severity over time was assessed using repeated measures analysis of variance ANOVA. Wilcoxon rank sum test and 2-sample t test were utilized to compare baseline negative symptoms in converters vs nonconverters. Results: The mean total negative symptom score at baseline was 11.90 (SD=9.80). Amajority of participants (84.57%) had at least one negative symptom rated ≥3 at baseline. Negative symptom severity significantly decreased over time compared to baseline measures. Eighty-six participants converted in total. In participants with at least one negative symptom of moderate severity or above (N ≥ 3), nonconverters had lower severity ratings on expression of emotion (M=1.49, SD=1.47 vs M=1.94, SD=1.64, P=.02) and ideational richness (M=1.23, SD=1.37 vs M=1.60, SD=1.35, P=.04) compared to converters at baseline. In participants who completed 24months of assessment and had negative symptom severity of moderate severity or above (N ≥ 3), nonconverters had significantly better expression of emotion (M=1.40, SD=1.51) compared to converters (M=1.79, SD=1.63, P=.03). Conclusion: First, this study demonstrated that the majority of youth at CHR have moderate to severe negative symptoms at baseline. Second, both decreased expression of emotion and decreased ideational richness was significantly more severe in participants who converted and may be indicative of later conversion to psychosis. Thus, early and persistent higher negative symptom scores may represent subsequent risk of conversion to psychosis.

Recent research on the early detection and treatment of schizophrenia has generated significant scientific interest along with considerable controversy and debate. Because our ability to alleviate fully the symptoms and deficits of established schizophrenia is limited, the prospect of interrupting disease progression early is compelling. At the same time, in the absence of an infallible marker of disease risk, there are serious questions about the safety, feasibility, and ethics of intervention research on "at-risk" or putatively prodromal individuals. A workshop, Informed Consent in Early Psychosis Research, was convened by the National Institute of Mental Health (NIMH) on November 15, 2000, to review the results of recent research on early detection and intervention in schizophrenia. Beginning with the assumptions that (1) treatment of asymptomatic individuals with antipsychotic medication is not appropriate in research or clinical care, and (2) neither data nor clinical consensus defines optimal intervention for symptomatic at-risk individuals, workshop participants-including clinical researchers, mental health consumers and family members, bioethicists, community health care providers, and NIMH staff-systematically reviewed available data on the potential risks and benefits of alternate approaches to the management of prodromal states. Ethical issues involved in early detection and intervention studies were discussed. Workshop participants summarized information presented during the meeting into informed consent "bullets" that must be communicated to, and understood and appreciated by, potential research participants.

Cognitive deficits are a fundamental feature of the psychopathology of schizophrenia . Yet the effect of treatment on this dimension of the illness has been unclear. Atypical antipsychotic medications have been reported to reduce the neurocognitive impairment associated with schizophrenia. However, studies of the pattern and degree of cognitive improvement with these compounds have been methodologically limited and have produced variable results, and few findings have been replicated. To clarify our understanding of the effects of atypical antipsychotic drugs on neurocognitive deficits in patients with schizophrenia, we have (1) reported on newly established standards for research design in studies of treatment effects on cognitive function in schizophrenia, (2) reviewed the literature on this topic and determined the extent to which 15 studies on the effect of atypical antipsychotics met these standards, (3) performed a meta-analysis of the 15 studies, which suggested general cognitive enhancement with atypical antipsychotics, and (4) described the pharmacological profile of these agents and considered the pharmacological basis for their effects on neurocognition. Finally, we suggest directions for the development of new therapeutic strategies.