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This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Aim: Although violent behaviour has been studied in schizophrenia, violence risk has received little attention in individuals at clinical high risk for psychosis (CHR). This manuscript aims to report and discuss the overall results of the Structured Assessment for Violence Risk in Youth (SAVRY) from the NAPLS-3 project to explore the risk of violence in CHR youth and to determine the relationship between SAVRY violence risk scores, psychosis risk symptoms, and global functioning. We hypothesized that CHR young people are at higher risk of violence as compared to healthy comparison participants due to a similarity between risk factors for psychosis and risk factors for violence, and that this risk is associated with greater severity of symptoms, poor functioning, and risk for conversion to psychosis., Methods: Participants from the North American Prodrome Longitudinal Study consortium phase 3 (NAPLS-3) included 684 CHR and 96 HC. Assessments included the Structural Assessment of Violence Risk in Youth (SAVRY), clinical and functional measures., Results: The majority of participants across groups were deemed to be at low risk for violence. There were significantly more CHR participants (29.8%) who had moderate or high scores on the SAVRY Summary Risk Rating compared to HC participants (3.1%). Low versus moderate-high SAVRY scores were associated with better social (p < .005) and role (p < .002) functioning and fewer positive (p < .002), negative (p < .002), disorganized (p < .01) and general symptoms (p < .002). CHR participants with higher SAVRY scores were more likely to be diagnosed with borderline personality disorder, ADHD and substance misuse. Among CHR, overall violence risk was not associated with conversion to psychosis. However, those who converted to psychosis scored lower on the protective factors index, primarily driven by less prosocial involvement and fewer resilient personality traits., Conclusions: This is the first study to assess violence risk in CHR adolescents. Violence risk factors overlap with risk factors for psychosis in general, perhaps accounting for the association. These findings have implications for intervention efforts to reduce violence risk and bolster resiliency in CHR youth., (© 2023 John Wiley & Sons Australia, Ltd.)

Background: While comorbidity of clinical high-risk for psychosis (CHR-P) status and social anxiety is well-established, it remains unclear how social anxiety and positive symptoms covary over time in this population. The present study aimed to determine whether there are more than one covariant trajectory of social anxiety and positive symptoms in the North American Prodrome Longitudinal Study cohort (NAPLS 2) and, if so, to test whether the different trajectory subgroups differ in terms of genetic and environmental risk factors for psychotic disorders and general functional outcome., Methods: In total, 764 CHR individuals were evaluated at baseline for social anxiety and psychosis risk symptom severity and followed up every 6 months for 2 years. Application of group-based multi-trajectory modeling discerned three subgroups based on the covariant trajectories of social anxiety and positive symptoms over 2 years., Results: One of the subgroups showed sustained social anxiety over time despite moderate recovery in positive symptoms, while the other two showed recovery of social anxiety below clinically significant thresholds, along with modest to moderate recovery in positive symptom severity. The trajectory group with sustained social anxiety had poorer long-term global functional outcomes than the other trajectory groups. In addition, compared with the other two trajectory groups, membership in the group with sustained social anxiety was predicted by higher levels of polygenic risk for schizophrenia and environmental stress exposures., Conclusions: Together, these analyses indicate differential relevance of sustained v. remitting social anxiety symptoms in the CHR-P population, which in turn may carry implications for differential intervention strategies.

Background: The auditory N100 is an event related potential (ERP) that is reduced in schizophrenia, but its status in individuals at clinical high risk for psychosis (CHR) and its ability to predict conversion to psychosis remains unclear. We examined whether N100 amplitudes are reduced in CHR subjects relative to healthy controls (HC), and this reduction predicts conversion to psychosis in CHR., Methods: Subjects included CHR individuals (n = 552) and demographically similar HC subjects (n = 236) from the North American Prodrome Longitudinal Study. Follow-up assessments identified CHR individuals who converted to psychosis (CHRC; n = 73) and those who did not (CHR-NC; n = 225) over 24 months. Electroencephalography data were collected during an auditory oddball task containing Standard, Novel, and Target stimuli. N100 peak amplitudes following each stimulus were measured at electrodes Cz and Fz., Results: The CHR subjects had smaller N100 absolute amplitudes than HC subjects at Fz (F(1,786) = 4.00, p 0.046). A model comparing three groups (CHRC, CHR-NC, HC) was significant for Group at the Cz electrode (F(2,531) = 3.58, p = 0.029). Both Standard (p = 0.019) and Novel (p = 0.017) stimuli showed N100 absolute amplitude reductions in CHR-C relative to HC. A smaller N100 amplitude at Cz predicted conversion to psychosis in the CHR cohort (Standard: p = 0.009; Novel: p = 0.001) and predicted shorter time to conversion (Standard: p = 0.013; Novel: p = 0.001)., Conclusion: N100 amplitudes are reduced in CHR individuals which precedes the onset of psychosis. N100 deficits in CHR individuals predict a greater likelihood of conversion to psychosis. Our results highlight N100's utility as a biomarker of psychosis risk., Competing Interests: Declaration of competing interest Infrastructure support was provided by the Office of Research and Development, the Mental Health Service Lines, and the Center of Visual and Neurocognitive Rehabilitation at the Atlanta Veterans Affairs Medical Center, Decatur, GA. Additional infrastructure support was provided by the Department of Psychiatry and Behavioral Sciences of the Emory University School of Medicine, Atlanta, GA. ED has received research support for work unrelated to this project from Auspex Pharmaceuticals, Inc. and Teva Pharmaceuticals, Inc. DHM is a consultant for Boehringer Ingelheim and Cadent Therapeutics. Other authors have nothing to disclose. ED is a full-time attending psychiatrist in the Mental Health Service Line at the Atlanta Veterans Affairs Medical Center, Decatur, GA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs., (Published by Elsevier B.V.)

Importance: Although clinical criteria for identifying youth at risk for psychosis have been validated, they are not sufficiently accurate for predicting outcomes to inform major treatment decisions. The identification of biomarkers may improve outcome prediction among individuals at clinical high risk for psychosis (CHR-P)., Objective: To examine whether mismatch negativity (MMN) event-related potential amplitude, which is deficient in schizophrenia, is reduced in young people with the CHR-P syndrome and associated with outcomes, accounting for effects of antipsychotic medication use., Design, Setting, and Participants: MMN data were collected as part of the multisite case-control North American Prodrome Longitudinal Study (NAPLS-2) from 8 university-based outpatient research programs. Baseline MMN data were collected from June 2009 through April 2013. Clinical outcomes were assessed throughout 24 months. Participants were individuals with the CHR-P syndrome and healthy controls with MMN data. Participants with the CHR-P syndrome who developed psychosis (ie, converters) were compared with those who did not develop psychosis (ie, nonconverters) who were followed up for 24 months. Analysis took place between December 2019 and December 2021., Main Outcomes and Measures: Electroencephalography was recorded during a passive auditory oddball paradigm. MMN elicited by duration-, pitch-, and duration + pitch double-deviant tones was measured., Results: The CHR-P group (n = 580; mean [SD] age, 19.24 [4.39] years) included 247 female individuals (42.6%) and the healthy control group (n = 241; mean age, 20.33 [4.74] years) included 114 female individuals (47.3%). In the CHR-P group, 450 (77.6%) were not taking antipsychotic medication at baseline. Baseline MMN amplitudes, irrespective of deviant type, were deficient in future CHR-P converters to psychosis (n = 77, unmedicated n = 54) compared with nonconverters (n = 238, unmedicated n = 190) in both the full sample (d = 0.27) and the unmedicated subsample (d = 0.33). In the full sample, baseline medication status interacted with group and deviant type indicating that double-deviant MMN, compared with single deviants, was reduced in unmedicated converters compared with nonconverters (d = 0.43). Further, within the unmedicated subsample, deficits in double-deviant MMN were most strongly associated with earlier conversion to psychosis (hazard ratio, 1.40 [95% CI, 1.03-1.90]; P = .03], which persisted over and above positive symptom severity., Conclusions and Relevance: This study found that MMN amplitude deficits were sensitive to future psychosis conversion among individuals at risk of CHR-P, particularly those not taking antipsychotic medication at baseline, although associations were modest. While MMN shows limited promise as a biomarker of psychosis onset on its own, it may contribute novel risk information to multivariate prediction algorithms and serve as a translational neurophysiological target for novel treatment development in a subgroup of at-risk individuals.

Aim: Poor functioning has become a hallmark of many youth at clinical high-risk (CHR) of psychosis. Even for those who do not make the transition to psychosis remain troubled by functional deficits and a decline in functioning increases the odds of transitioning to psychosis. There are very few treatment studies that have attempted to improve social and role functioning. The aim of this paper is to describe the methods of a treatment study to address social and role functioning in CHR., Methods: This was a randomized controlled trial of cognitive-behavioural social skills training (CBSST) versus a supportive therapy. CBSST combines elements of cognitive behaviour therapy (CBT) and social skills training (SST), two evidence-based treatments for schizophrenia. By adding CBT to SST to target functioning outcomes, SST can be used to train new social skills, and thoughts that interfere with skilled performance in the real world can be addressed using CBT. We developed an adapted version of CBSST, more appropriate for the age range and illness severity of typical CHR individuals, to attempt to show improvements in social and role functioning for these young people., Results: Two hundred and three participants were recruited for this study. Results include initial baseline data., Conclusion: This article describes the baseline methodology of a CHR youth who have difficulties in social and/or role functioning. It is one of the first clinical trials to address this significant problem., (© 2021 John Wiley & Sons Australia, Ltd.)

Background: Adolescence/early adulthood coincides with accelerated pruning of cortical synapses and the onset of schizophrenia. Cortical gray matter reduction and dysconnectivity in schizophrenia are hypothesized to result from impaired synaptic plasticity mechanisms, including long-term potentiation (LTP), since deficient LTP may result in too many weak synapses that are then subject to over-pruning. Deficient plasticity has already been observed in schizophrenia. Here, we assessed whether such deficits are present in the psychosis risk syndrome (PRS), particularly those who subsequently convert to full psychosis., Methods: An interim analysis was performed on a sub-sample from the NAPLS-3 study, including 46 healthy controls (HC) and 246 PRS participants. All participants performed an LTP-like visual cortical plasticity paradigm involving assessment of visual evoked potentials (VEPs) elicited by vertical and horizontal line gratings before and after high frequency ("tetanizing") visual stimulation with one of the gratings to induce "input-specific" neuroplasticity (i.e., VEP changes specific to the tetanized stimulus). Non-parametric, cluster-based permutation testing was used to identify electrodes and timepoints that demonstrated input-specific plasticity effects., Results: Input-specific pre-post VEP changes (i.e., increased negative voltage) were found in a single spatio-temporal cluster covering multiple occipital electrodes in a 126-223 ms time window. This plasticity effect was deficient in PRS individuals who subsequently converted to psychosis, relative to PRS non-converters and HC., Conclusions: Input-specific LTP-like visual plasticity can be measured from VEPs in adolescents and young adults. Interim analyses suggest that deficient visual cortical plasticity is evident in those PRS individuals at greatest risk for transition to psychosis., Competing Interests: Declaration of competing interest The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Department of Veterans Affairs. Drs Jacob, Hamilton, Duncan, Niznikiewicz, and Mathalon are employees of the US government., (Published by Elsevier B.V.)

Background: Severity of negative symptoms has been associated with poor functioning, cognitive deficits, and defeatist beliefs in schizophrenia patients. However, one area that remains understudied is persistent negative symptoms (PNS). Negative symptoms, including PNS, have been observed in those at clinical high-risk (CHR) for psychosis. The aim of this study was to determine if PNS were associated with functioning, neurocognition, and defeatist beliefs in a CHR sample., Method: CHR participants (n = 764) were recruited for the North American Prodrome Longitudinal Study. Negative symptoms were rated on the Scale of Psychosis-risk Symptoms. Generalized linear mixed models for repeated measures were used to examine changes over time between and within groups (PNS vs non-PNS)., Results: The PNS group (n = 67) had significant deficits in functioning at baseline, 6, 12, 18, and 24-months compared to the non-PNS group (n = 673). Functioning improved over time in the non-PNS group, while functioning in the PNS group remained relatively stable and poor over a two-year period. A consistent trend emerged demonstrating higher defeatist beliefs in the PNS group; however, this result was lost when controlling for persistent depressive symptoms. There were no significant differences between the groups on neurocognition, social cognition, and transition to psychosis., Conclusions: PNS exist in youth at CHR for psychosis, resulting in significant and persistent functional impairment, which remains when controlling for persistent depressive symptoms. PNS remain even in CHR youth who do not transition to psychosis. Thus, PNS may represent an unmet therapeutic need in CHR populations for which there are currently no effective treatments., Competing Interests: Declaration of competing interest The authors have declared that there are no conflicts of interest in relation to the subject of this study. Dr. Cannon and Dr. Mathalon report that they are consultants to Boerhinger Ingelheim Pharmaceuticals. Dr. Cannon reports that he is a consultant to Lundbeck A/S., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Whilst elevations in basal cortisol levels have been reported among individuals at-risk for psychosis, the extent to which this represents hyperresponsivity of the hypothalamic-pituitary-adrenal (HPA) axis to psychosocial stressors encountered in the natural environment is currently unclear. We aimed to examine stressor-cortisol concordance among youth at clinical high-risk (CHR) for psychosis in the North American Prodrome Longitudinal Study 2 (NAPLS 2) and the relationship with clinical outcome. At baseline, CHR (N = 457) and healthy (N = 205) individuals provided salivary cortisol samples and completed daily stressor, life event, and childhood trauma measures. CHR youth were categorised as remitted, symptomatic, progression of positive symptoms, or psychosis conversion at the two-year follow-up. Within-group regression models tested associations between psychosocial stressors and cortisol; standardised beta coefficients (Stβ) were subsequently derived to enable within-group pooling of effect sizes across stressor types. After adjustment for potential confounders, all CHR subgroups reported greater exposure to life events and daily stressors, and more distress in relation to these events, relative to controls. All CHR groups were also more likely to experience childhood trauma; only CHR converters, however, were characterised by elevated basal cortisol. Daily stressor distress was significantly associated with cortisol in controls (β = 0.60, 95% CI: 0.12-1.08) and CHR youth who converted to psychosis (β = 0.91, 95% CI: 0.05-1.78). In controls only, life event exposure was associated with cortisol (β = 0.45, 95% CI: 0.08-0.83). When pooled across stressors, stressor-cortisol concordance was substantially higher among CHR converters (Stβ = 0.26, 95% CI: 0.07 to 0.44) relative to CHR progressed (Stβ = 0.02, 95% CI: -0.11 to 0.15), symptomatic (Stβ = 0.01, 95% CI: -0.11 to 0.12), and remitted groups (Stβ = 0.00, 95% CI: -0.13 to 0.13); however, unexpectedly, healthy controls showed intermediate levels of concordance (Stβ = 0.15, 95% CI: 0.05 to 0.26). In conclusion, whilst all CHR subgroups showed increased psychosocial stress exposure and distress relative to controls, only those who later converted to psychosis were characterised by significantly elevated basal cortisol levels. Moreover, only CHR converters showed a higher magnitude of stressor-cortisol concordance compared to controls, although confidence intervals overlapped considerably between these two groups. These findings do not support the notion that all individuals at CHR for psychosis show HPA hyperresponsiveness to psychosocial stressors. Instead, CHR individuals vary in their response to stressor exposure/distress, perhaps driven by genetic or other vulnerability factors., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Traditional measures for assessing functioning with adult patients with schizophrenia have been shown to be insufficient for assessing the issues that occur in adolescents and young adults at clinical high risk (CHR) for psychosis. The current study provides an expanded validation of the Global Functioning: Social (GF:Social) and Role (GF:Role) scales developed specifically for use with CHR individuals and explores the reliability and accuracy of the ratings, the validity of the scores in comparison to other established clinical measures, stability of functioning over a 2-year period, and psychosis predictive ability., Methods: Seven hundred fifty-five CHR individuals and 277 healthy control (HC) participants completed the GF:Social and Role scales at baseline as part of the North American Prodrome Longitudinal Study (NAPLS2)., Results: Inter-rater reliability and accuracy were high for both scales. Correlations between the GF scores and other established clinical measures demonstrated acceptable convergent and discriminant validity. In addition, GF:Social and Role scores were unrelated to positive symptoms. CHR participants showed large impairments in social and role functioning over 2-years, relative to the HCs, even after adjusting for age, IQ, and attenuated positive symptoms. Finally, social decline prior to baseline was more pronounced in CHR converters, relative to non-converters., Conclusions: The GF scales can be administered in a large-scale multi-site study with excellent inter-rater reliability and accuracy. CHR individuals showed social and role functioning impairments over time that were not confounded by positive symptom severity levels. The results of this study demonstrate that social decline is a particularly effective predictor of conversion outcome., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: There is an interest in the transition to psychosis for those at clinical high risk of developing psychosis. This transition is typically determined by a change in severity of the attenuated symptoms as they reach a psychotic level. However, any concomitant change in the content of such symptoms has not been examined. The current study aimed to examine potential qualitative changes in the symptom content from a clinical high-risk state to a first episode of psychosis., Methods: Sixty-seven individuals, who had been identified as meeting the attenuated psychotic syndrome based on the Structured Interview of Psychosis-Risk Syndromes and who later developed a full-blown psychosis were included in the study. Comprehensive clinical vignettes were written and raters were trained using the Content of Attenuated Psychotic Symptoms codebook to code for the presence of specific symptom content found within the attenuated psychotic symptoms of unusual thought content, suspicious ideas, grandiose ideas and perceptual abnormalities., Results: Two main changes in symptom content from baseline to conversion were observed. First, content that was vague and lacked intensity progressed to being more specific, concrete and severe. Second, new symptoms appeared whose onset occurred for the first time at conversion., Conclusion: A change in symptom content should be monitored by clinicians, as changes in content may be indications of a possible transition to psychosis., (© 2017 John Wiley & Sons Australia, Ltd.)

Background: Most studies of neurocognitive functioning in Clinical High Risk (CHR) cohorts have examined group averages, likely concealing heterogeneous subgroups. We aimed to identify neurocognitive subgroups and to explore associated outcomes., Methods: Data were acquired from 324 participants (mean age 18.4) in the first phase of the North American Prodrome Longitudinal Study (NAPLS-1), a multi-site consortium following individuals for up to 2 1/2 years. We applied Ward's method for hierarchical clustering data to 8 baseline neurocognitive measures, in 166 CHR individuals, 49 non-CHR youth with a family history of psychosis, and 109 healthy controls. We tested whether cluster membership was associated with conversion to psychosis, social and role functioning, and follow-up diagnosis. Analyses were repeated after data were clustered based on independently developed clinical decision rules., Results: Four neurocognitive clusters were identified: Significantly Impaired (n = 33); Mildly Impaired (n = 82); Normal (n = 145) and High (n = 64). The Significantly Impaired subgroup demonstrated the largest deviations on processing speed and memory tasks and had a conversion rate of 58%, a 40% chance of developing a schizophrenia spectrum diagnosis (compared to 24.4% in the Mildly Impaired, and 10.3% in the other two groups combined), and significantly worse functioning at baseline and 12-months. Data clustered using clinical decision rules yielded similar results, pointing to high convergent validity., Conclusion: Neurocognitive profiles vary substantially in their severity and are associated with diagnostic and functional outcome, underscoring neurocognition as a predictor of illness outcomes. These findings, if replicated, are a first step toward personalized treatment for individuals at-risk for psychosis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Understanding the fundamental alterations in brain functioning that lead to psychotic disorders remains a major challenge in clinical neuroscience. In particular, it is unknown whether any state-independent biomarkers can potentially predict the onset of psychosis and distinguish patients from healthy controls, regardless of paradigm. Here, using multi-paradigm fMRI data from the North American Prodrome Longitudinal Study consortium, we show that individuals at clinical high risk for psychosis display an intrinsic "trait-like" abnormality in brain architecture characterized as increased connectivity in the cerebello-thalamo-cortical circuitry, a pattern that is significantly more pronounced among converters compared with non-converters. This alteration is significantly correlated with disorganization symptoms and predictive of time to conversion to psychosis. Moreover, using an independent clinical sample, we demonstrate that this hyperconnectivity pattern is reliably detected and specifically present in patients with schizophrenia. These findings implicate cerebello-thalamo-cortical hyperconnectivity as a robust state-independent neural signature for psychosis prediction and characterization.

Machine learning techniques were used to identify highly informative early psychosis self-report items and to validate an early psychosis screener (EPS) against the Structured Interview for Psychosis-risk Syndromes (SIPS). The Prodromal Questionnaire-Brief Version (PQ-B) and 148 additional items were administered to 229 individuals being screened with the SIPS at 7 North American Prodrome Longitudinal Study sites and at Columbia University. Fifty individuals were found to have SIPS scores of 0, 1, or 2, making them clinically low risk (CLR) controls; 144 were classified as clinically high risk (CHR) (SIPS 3-5) and 35 were found to have first episode psychosis (FEP) (SIPS 6). Spectral clustering analysis, performed on 124 of the items, yielded two cohesive item groups, the first mostly related to psychosis and mania, the second mostly related to depression, anxiety, and social and general work/school functioning. Items within each group were sorted according to their usefulness in distinguishing between CLR and CHR individuals using the Minimum Redundancy Maximum Relevance procedure. A receiver operating characteristic area under the curve (AUC) analysis indicated that maximal differentiation of CLR and CHR participants was achieved with a 26-item solution (AUC=0.899±0.001). The EPS-26 outperformed the PQ-B (AUC=0.834±0.001). For screening purposes, the self-report EPS-26 appeared to differentiate individuals who are either CLR or CHR approximately as well as the clinician-administered SIPS. The EPS-26 may prove useful as a self-report screener and may lead to a decrease in the duration of untreated psychosis. A validation of the EPS-26 against actual conversion is underway., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Levels of certain circulating cytokines and related immune system molecules are consistently altered in schizophrenia and related disorders. In addition to absolute analyte levels, we sought analytes in correlation networks that could be prognostic. We analyzed baseline blood plasma samples with a Luminex platform from 72 subjects meeting criteria for a psychosis clinical high-risk syndrome; 32 subjects converted to a diagnosis of psychotic disorder within two years while 40 other subjects did not. Another comparison group included 35 unaffected subjects. Assays of 141 analytes passed early quality control. We then used an unweighted co-expression network analysis to identify highly correlated modules in each group. Overall, there was a striking loss of network complexity going from unaffected subjects to nonconverters and thence to converters (applying standard, graph-theoretic metrics). Graph differences were largely driven by proteins regulating tissue remodeling (e.g. blood-brain barrier). In more detail, certain sets of antithetical proteins were highly correlated in unaffected subjects (e.g. SERPINE1 vs MMP9), as expected in homeostasis. However, for particular protein pairs this trend was reversed in converters (e.g. SERPINE1 vs TIMP1, being synthetical inhibitors of remodeling of extracellular matrix and vasculature). Thus, some correlation signals strongly predict impending conversion to a psychotic disorder and directly suggest pharmaceutical targets.

Clinical staging improved the possibility of intervening during the psychosis prodrome to limit progression of illness. The current study aimed to validate a novel 4-stage severity-based model with a focus on clinical change over time and risk for conversion to psychosis. One hundred seventy-one individuals at clinical high risk (CHR) for psychosis were followed prospectively (3 ± 1.6 y) as part of the Recognition and Prevention (RAP) program and divided into 4 diagnostic stages according to absence/presence and severity of attenuated positive symptoms. Twenty-two percent of the combined sample recovered (no prodromal symptoms) by study outcome. The negative symptoms only subgroup had the highest symptom stability (70%), but the lowest conversion rate at 5.9%. The subgroup with more severe baseline attenuated positive symptom levels had a higher conversion rate (28%) and a more rapid onset when compared to the moderate attenuated positive symptom subgroup (11%). Finally, the Schizophrenia-Like Psychosis (SLP) subgroup showed low stability (3%), with 49% developing a specific psychotic disorder. The proposed stage model provides a more finely grained classification system than the standard diagnostic approach for prodromal individuals. All 4 stages are in need of early intervention because of low recovery rates. The negative symptom only stage is possibly a separate clinical syndrome, with an increased risk of functional disability. Both subgroups with attenuated positive symptoms are appropriate for studying the mechanisms of psychosis risk, however, individuals with more severe baseline positive symptoms appear better suited to clinical trials. Finally, the SLP category represents an intermediate outcome group appropriate for preventative intervention research but questionable for inclusion in prodromal studies of mechanisms., (© The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

While attenuated psychotic symptoms (APS) and basic symptoms (BS) are the main current predictors of psychosis in adults, studies in adolescents are scarce. Thus, we (1) described the prevalence and severity of positive, negative, disorganization, general, and basic symptoms in adolescent patients at ultra-high risk for psychosis (UHR), with other non-psychotic psychiatric disorders (PC) and with early-onset psychosis (EOP); and (2) investigated BS criteria in relation to UHR criteria. Sixty-nine 12-18-year-old adolescents (15.3 ± 1.7 years, female = 58.0 %, UHR = 22, PC = 27, EOP = 20) were assessed with the structured interview for prodromal syndromes (SIPS) and the schizophrenia proneness instrument-child and youth version (SPI-CY). Despite similar current and past 12-month global functioning, both UHR and EOP had significantly higher SIPS total and subscale scores compared to PC, with moderate-large effect sizes. Expectedly, UHR had significantly lower SIPS positive symptom scores than EOP, but similar SIPS negative, disorganized, and general symptom scores. Compared to PC, both EOP and UHR had more severe basic thought and perception disturbances, and significantly more often met cognitive disturbances criteria (EOP = 50.0 %, UHR = 40.9 %, PC = 14.8 %). Compared to UHR, both EOP and PC significantly less often met cognitive-perceptive BS criteria (EOP = 35.0 %, UHR = 68.2 %, PC = 25.9 %). BS were significantly more prevalent in both EOP and UHR than PC, and UHR were similar to EOP in symptom domains. Given the uncertain outcome of adolescents at clinical high-risk of psychosis, future research is needed to determine whether the combined assessment of early subjective disturbances with observable APS can improve the accuracy of psychosis prediction.

Background: Prodromal syndromes often begin in adolescence - a period of neurodevelopmental changes and heightened stress sensitivity. Research has shown elevated stress and cortisol in individuals at clinical high risk (CHR) for psychosis. This cross-sectional study examined relations of age and pubertal status with cortisol and self-reported stress in healthy controls (HCs) and CHR adolescents. It was hypothesized that the relations of age and pubertal stage with cortisol and stress would be more pronounced in CHR youth., Methods: Participants were 93 HCs and 348 CHR adolescents from the North American Prodrome Longitudinal Study (NAPLS). At baseline, measures of stress (Daily Stress Inventory - DSI), Tanner stage (TS), and salivary cortisol were obtained., Results: ANCOVA revealed increased DSI scores with age for both groups, and higher DSI scores in CHR adolescents than HCs, with a more pronounced difference for females. Contrary to prediction, with age controlled, HCs showed greater TS-related DSI increases. Analysis of cortisol showed no significant interactions, but a main effect of age and a trend toward higher cortisol in the CHR group. Correlations of cortisol with TS were higher in HC than CHR group., Conclusions: Stress measures increased with age in HC and CHR adolescents, and DSI scores also increased with TS in HCs. The results do not support a more pronounced age or TS increase in stress measures in CHR adolescents, but instead suggest that stress indices tend to be elevated earlier in adolescence in the CHR group. Potential determinants of findings and future directions are discussed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Early intervention and prevention of psychosis remain a major challenge. Prediction would be greatly advanced with improved ability to identify individuals at true risk, which, at present, is moderate at best. The authors tested a modified strategy to improve prediction by selecting a more homogeneous high-risk sample (attenuated positive symptom criteria only, age range of mid-teens to early 20s) than is currently standard, combined with a systematic selection of neurodevelopmental deficits., Method: A sample of 101 treatment-seeking adolescents (mean age, 15.9 years) at clinical high risk for psychosis were followed clinically for up to 5 years (mean follow-up time, 3.0 years, SD=1.6). Adolescents were included only if they exhibited one or more attenuated positive symptoms at moderate to severe, but not psychotic, severity levels. Cox regression was used to derive a risk index., Results: The overall conversion rate to psychosis was 28.3%. The final predictor model, with a positive predictive validity of 81.8%, consisted of four variables: disorganized communication, suspiciousness, verbal memory deficits, and decline in social functioning during follow-up. Significant effects also suggest narrowing the risk age range to 15-22 years., Conclusions: Clinical high risk criteria that emphasize disorganized communication and suspiciousness while also including compromised verbal memory and declining social functioning have the potential to improve predictive accuracy compared with attenuated positive symptoms used alone. On the resulting risk index (a weighted combination of the predictors), low scores were interpreted as signifying minimal risk, with little treatment necessary, high scores as suggesting aggressive intervention, and intermediate scores, although less informative, as supporting psychosocial treatment., Competing Interests: The other authors report no financial relationships with commercial interests.

Importance: Severe neuropsychiatric conditions, such as schizophrenia, affect distributed neural computations. One candidate system profoundly altered in chronic schizophrenia involves the thalamocortical networks. It is widely acknowledged that schizophrenia is a neurodevelopmental disorder that likely affects the brain before onset of clinical symptoms. However, no investigation has tested whether thalamocortical connectivity is altered in individuals at risk for psychosis or whether this pattern is more severe in individuals who later develop full-blown illness., Objectives: To determine whether baseline thalamocortical connectivity differs between individuals at clinical high risk for psychosis and healthy controls, whether this pattern is more severe in those who later convert to full-blown illness, and whether magnitude of thalamocortical dysconnectivity is associated with baseline prodromal symptom severity., Design, Setting, and Participants: In this multicenter, 2-year follow-up, case-control study, we examined 397 participants aged 12-35 years of age (243 individuals at clinical high risk of psychosis, of whom 21 converted to full-blown illness, and 154 healthy controls). The baseline scan dates were January 15, 2010, to April 30, 2012., Main Outcomes and Measures: Whole-brain thalamic functional connectivity maps were generated using individuals' anatomically defined thalamic seeds, measured using resting-state functional connectivity magnetic resonance imaging., Results: Using baseline magnetic resonance images, we identified thalamocortical dysconnectivity in the 243 individuals at clinical high risk for psychosis, which was particularly pronounced in the 21 participants who converted to full-blown illness. The pattern involved widespread hypoconnectivity between the thalamus and prefrontal and cerebellar areas, which was more prominent in those who converted to full-blown illness (t(173) = 3.77, P < .001, Hedge g = 0.88). Conversely, there was marked thalamic hyperconnectivity with sensory motor areas, again most pronounced in those who converted to full-blown illness (t(173) = 2.85, P < .001, Hedge g = 0.66). Both patterns were significantly correlated with concurrent prodromal symptom severity (r = 0.27, P < 3.6 × 10(-8), Spearman ρ = 0.27, P < 4.75 × 10(-5), 2-tailed)., Conclusions and Relevance: Thalamic dysconnectivity, resembling that seen in schizophrenia, was evident in individuals at clinical high risk for psychosis and more prominently in those who later converted to psychosis. Dysconnectivity correlated with symptom severity, supporting the idea that thalamic connectivity may have prognostic implications for risk of conversion to full-blown illness.

In studies describing the long-term follow-up up of youth at clinical high risk (CHR) of psychosis, little attention has been given to details of specific prodromal symptoms. In this paper, we describe the prodromal symptoms of 764 CHR participants recruited in the multi-site North American Prodrome Longitudinal Study (NAPLS). Symptoms were rated on the Scale of Prodromal Symptoms (SOPS) at baseline and 6-, 12-, 18-, and 24-month follow-ups. Clinical outcome at the 2-year assessment was categorized as psychotic, prodromal progression, symptomatic or in remission. Most of the CHR sample (92%) met criteria for the attenuated positive symptoms syndrome (APSS). Significant improvements in SOPS symptoms were observed over time. Unusual thought content, disorganized communication, and overall ratings on disorganized symptoms differentiated those who transitioned to psychosis from the other clinical outcome groups. Suspiciousness and total positive symptoms differentiated those in remission from the other clinical outcome groups.

Recent research has started to focus on identifying individuals who are at clinical high risk of developing psychosis as a means to try and understand the predictors and mechanisms involved in the progress to a full psychotic episode. The aim of the current study was to provide an initial description and prevalence rates of specific content found within attenuated positive symptoms. The Content of Attenuated Positive Symptoms (CAPS) codebook was used by independent raters to determine the presence of content within a sample of written vignettes. Krippendorff's alpha was used to determine inter-rater reliability. Overall, the majority of items fell in or above an acceptable range of reliability. There was heterogeneity present in the types of content endorsed. However, the most commonly endorsed items included being perplexed by reality, increased hypervigilence, being gifted, hearing indistinct and distinct sounds, seeing figures or shadows, something touching the individual, and unpleasant smells. The use of the CAPS codebook is a reliable way to code the content of attenuated positive symptoms. Identifying and monitoring the presence of certain content may provide insight into the presence of other comorbid issues and the potential for future conversion., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

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.

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.)

Background: The Continuous Performance Test (CPT) has emerged as the most commonly administered measure of sustained attention, but use of discrepant versions reduces the ability of researchers and clinicians to accurately draw cross-study conclusions. In an effort to standardize use of the CPT, this study compared four versions of the Identical Pairs CPT for their reliability and ability to discriminate between patients with schizophrenia and healthy volunteers. The relationship of performance on the different versions of the CPT with measures of psychopathology, functioning, and other aspects of cognition was also examined., Methods: Performance on the 2-digit, 3-digit, 4-digit, and Shapes Identical Pairs CPT was assessed at three test sessions over five weeks, during which subjects also completed the Brief Assessment of Cognition in Schizophrenia (BACS) and questionnaires assessing psychopathology and functioning., Results: All four CPTs discriminated between patients with schizophrenia and healthy volunteers, but there were no statistical differences in sensitivity among the versions. The 3-digit CPT showed non-statistical advantages in that it had high test-retest reliability, low potential for a ceiling effect, and a very low rate of false alarms. There were also moderate correlations between CPT performance and performance of the BACS subtests, but no significant correlations between CPT performance and measures of psychopathology and functioning., Conclusions: While all versions of the CPT tested here had good psychometric characteristics, the 3-digit CPT-IP has some advantages in repeated measures studies such as clinical trials., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Aims: Dysfunction in social and role functioning is a hallmark of schizophrenia, which is present in both the prodromal phase and at the first episode of the illness. Two new measures, Global Functioning: Social and Global Functioning: Role, were developed to address functioning in the prodromal phase of the illness. The purpose of this study was to determine if these measures would be useful in a first episode population., Methods: Forty-eight stable outpatients were assessed using the new social and role scales. A subsample of 33 subjects was assessed at 6 and 12 months. All subjects were additionally assessed using standardized measures of psychotic symptoms, social functioning, self-esteem and beliefs about illness., Results: Average ratings on the Global Functioning: Social and Role scales were 6 (standard deviation (SD) = 1.60) and 5.5 (SD = 2.2), respectively. Both social and role scales were significantly correlated with relevant subscales on the Social Functioning Scale. Good social but not role functioning was related to low levels of both positive and negative symptoms and to high self-esteem. Role but not social functioning was related to personal beliefs about the illness, such as having control over illness and feeling less stigmatized. Repeated measures analyses demonstrated no change over time for either social or role functioning., Conclusion: The Global Functioning: Social and Role scales appear to be useful and valid measures of functioning in first-episode patients. These ratings are similar to those reported in prodromal studies supporting the idea that poor functioning may be a stable long-standing deficit., (© 2011 Blackwell Publishing Asia Pty Ltd.)

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.

Objective: Cognitive deficits have been well documented in schizophrenia and have been shown to impair quality of life and to compromise everyday functioning. Recent studies of adolescents and young adults at high risk for developing psychosis show that neurocognitive impairments are detectable before the onset of psychotic symptoms. However, it remains unclear how cognitive impairments affect functioning before the onset of psychosis. The authors assessed cognitive impairment in adolescents at clinical high risk for psychosis and examined its impact on social and role functioning., Method: A sample of 127 treatment-seeking patients at clinical high risk for psychosis and a group of 80 healthy comparison subjects were identified and recruited for research in the Recognition and Prevention Program. At baseline, participants were assessed with a comprehensive neurocognitive battery as well as measures of social and role functioning., Results: Relative to healthy comparison subjects, clinical high-risk patients showed significant impairments in the domains of processing speed, verbal memory, executive function, working memory, visuospatial processing, motor speed, sustained attention, and language. Clinical high-risk patients also displayed impaired social and role functioning at baseline. Among patients with attenuated positive symptoms, processing speed was related to social and role functioning at baseline., Conclusions: These findings demonstrate that cognitive and functional impairments are detectable in patients at clinical high risk for psychosis before the onset of psychotic illness and that processing speed appears to be an important cognitive predictor of poor functioning.

Background: There is an increased interest in early intervention strategies for severe mental disorders with hopes of mitigating the emergence and impact of the illness. Individuals at clinical high-risk (CHR) for schizophrenia have been primarily identified by the presence of attenuated positive symptoms. Although bipolar disorder and schizophrenia may have overlapping etiologies, few studies have investigated the potential prodrome in bipolar disorder. We sought to determine if there is a prodrome to bipolar disorder and if clinical or neurocognitive measures could distinguish between the bipolar and schizophrenia prodromes., Methods: We examined subjects who were initially identified as CHR for schizophrenia during the prodromal phase of the illness and followed them prospectively. Unexpectedly, eight subjects developed bipolar disorder. Baseline data from subjects who eventually developed bipolar disorder (pre-BP; N=8), schizophrenia or a psychotic disorder (pre-SZ; N=24) and a non-converter comparison group (NCC; N=115) were compared., Results: The pre-BP and pre-SZ groups did not differ on attenuated positive symptom severity, global measures of functioning or on the global neurocognitive score. Compared to NCC individuals, both pre-BP and pre-SZ patients reported more severe attenuated positive symptoms and were more likely to be on antipsychotic medication at baseline. The pre-SZ group had a significantly lower current IQ and was significantly more impaired than the NCC group on the overall neurocognitive score., Conclusions: This study provides preliminary support for a bipolar prodrome, which may be indistinguishable from the schizophrenia prodrome based on clinical and neurocognitive measures currently used in high-risk schizophrenia programs., (Copyright © 2010 Elsevier B.V. All rights reserved.)

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.

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: The aim of this study was to examine predictors of diagnostic and symptomatic outcome in adolescents with either psychotic disorder not otherwise specified (PsyNOS) or brief psychotic disorder (BrPsy) followed in a schizophrenia prodromal program., Methods: As part of a naturalistic study of adolescents considered at clinical high risk for schizophrenia, 26 youths (mean age, 15.9 +/- 2.6 years, 65.4% male) with psychosis not fulfilling criteria for schizophrenia/schizoaffective disorder and diagnosed with PsyNOS or BrPsy were evaluated for predictors of diagnostic and symptomatic outcome after at least 6 (mean, 22.8 +/- 19.4) months follow up., Results: Progression to schizophrenia, schizoaffective disorder, or psychotic bipolar disorder (n = 10, 38.5%) was predicted by fulfilling criteria for schizotypal personality disorder at baseline (p = 0.046). Development of schizophrenia/schizoaffective disorder (n = 7, 27.0%) was associated with worse executive functioning (p = 0.029) and absence of anxiety disorders (p = 0.027). Conversely, progression to bipolar disorder (n = 4, 15.4%), with (n = 3, 11.5%) or without (n = 1, 3.8%) psychosis, was associated with the presence of anxiety disorders (p = 0.014). Remission of all psychotic as well as attenuated positive or negative symptoms (n = 5, 19.4%) was predicted by Hispanic ethnicity (p = 0.0047), an initial diagnosis of BrPsy (p = 0.014), longer duration of antidepressant treatment (p = 0.035), and better attention at baseline (p = 0.042)., Conclusions: Results from this preliminary study suggest that patients with PsyNOS, BrPsy, or schizotypal personality disorder features in adolescence should be followed as separate risk groups in prodromal studies of schizophrenia and bipolar disorder. Executive function deficits and absence of anxiety disorders may be risk markers for schizophrenia, while presence of anxiety disorders may be linked to bipolar disorder risk. After achieving full remission, patients with sudden onset of psychosis and brief episodes could once be given the option of careful, supervised treatment discontinuation. The potential salutary effect of antidepressants during the psychotic prodrome and presence of characteristics differentiating patients at risk for schizophrenia or bipolar disorder should be investigated further.

Introduction: Research on prediction and prevention of schizophrenia has increasingly focused on prodromal (prepsychosis) social and role dysfunction as developmentally early, stable, and treatment-resistant illness components. In this report, 2 new measures, Global Functioning: Social and Global Functioning: Role, are presented, along with preliminary findings about psychometric properties and course of social and role (academic/work) functioning in the prodromal phase of psychosis., Methods: Subjects included 69 participants from the Recognition and Prevention program and 52 from the Center for the Assessment and Prevention of Prodromal States. Ages ranged from 12 to 29 years, and all met criteria for Attenuated Positive Symptom syndrome. Retrospective (past year) and baseline data are reported for all 121 prodromal subjects and for 44 normal controls (NCs). Prospective follow-up data are reported for a subsample of patients reevaluated at both 6 and 12 months (N = 44)., Results: For both scales, interrater reliability was high, and preliminary data supported construct validity. Relative to NCs, prodromal individuals displayed impaired social and role functioning at baseline. Analyses of change over time indicated that role functioning declined over the year before ascertainment and improved over 12-month follow-up, presumably with treatment. Social impairment, by contrast, was constant across time and predicted later psychosis (P = .002)., Discussion: Using 2 new global measures, social functioning was found to be a stable trait, unchanged by treatment, with considerable potential to be a marker of schizophrenia. Role functioning, by contrast, may be a more direct barometer of clinical change and may be responsive to treatment and environmental change.

Objective: The presence and specificity of a bipolar prodrome remains questioned. We aimed to characterize the prodrome prior to a first psychotic and nonpsychotic mania and to examine the phenotypic proximity to the schizophrenia prodrome., Methods: Using a semi-structured interview, the Bipolar Prodrome Symptom Scale-Retrospective, information regarding the mania prodrome was collected from youth with a research diagnosis of bipolar I disorder and onset before 19 years of age, and/or their caregivers. Only newly emerging, at least moderately severe, symptoms were analyzed. Prodromal characteristics were compared between patients with and without subsequent psychotic mania and with published bipolar and schizophrenia prodrome data., Results: In 52 youth (age at first mania: 13.4 +/- 3.3 years), the prodrome onset was predominantly "insidious" (>1 year, 51.9%) or "subacute" (1-12 months, 44.2%), while "acute" presentations (<1 month, 3.8%) were rare. The prodrome duration was similar in patients with (1.7 +/- 1.8 years, n = 34) and without (1.9 +/- 1.5 years, n = 18) subsequent psychotic mania (P = .70). Attenuated positive symptoms emerging late in the prodrome and increased energy/goal-directed activity were significantly more common in patients with later psychotic mania. Mania and schizophrenia prodrome characteristics overlapped considerably. However, subsyndromal unusual ideas were significantly more likely part of the schizophrenia prodrome, while obsessions/compulsions, suicidality, difficulty thinking/communicating clearly, depressed mood, decreased concentration/memory, tiredness/lack of energy, mood lability, and physical agitation were more likely part of the mania prodrome., Conclusions: A lengthy and symptomatic prodrome makes clinical high-risk research a feasible goal for bipolar disorder. The phenotypic overlap with the schizophrenia prodrome necessitates the concurrent study of both illness prodromes.

Objective: This study reports the results of a prospective, naturalistic treatment study of adolescents considered to be in the prodromal (i.e., prepsychotic) phase of schizophrenia., Method: Forty-eight adolescents (mean age = 15.8 years) participating in the initial phase of the Recognition and Prevention (RAP) program (1998-2005) were included in the current report. Individuals were selected from the overall sample (N = 152) if they had: (1) displayed attenuated positive symptoms, (2) been treated pharmacologically for at least 8 weeks, and (3) been followed up for at least 6 months (mean follow-up = 30.5 months)., Results: Two types of medication were naturalistically prescribed: antidepressants (N = 20) or second-generation antipsychotics (N = 28), with polypharmacy common. The 2 treatment groups did not differ in baseline symptom profiles, with the exception of disorganized thinking, which was more severe in second-generation antipsychotic-treated adolescents. Twelve of the 48 adolescents (25%) developed a psychotic disorder, with all converters having been prescribed second-generation antipsychotics. There were no conversions among antidepressant-treated adolescents (log-rank chi(2) = 7.36, df = 1, p = .007). Treatment outcome, however, was confounded, since 11 of the 12 converters were nonadherent. Adolescents, in general, were more likely to be nonadherent to second-generation antipsychotics (61%, 17/28) than to antidepressants (20%, 4/20; chi(2) = 7.86, p = .005). Improvement in 3 of 5 positive symptoms over time was significant (p < .001) and similar for both medications. Disorganized thought, however, did not improve regardless of treatment., Conclusions: Nonrandom assignment limits comparisons between antidepressants and anti-psychotics in this study. However, with follow-up, a number of adolescents meeting criteria for prodromal schizophrenia were successfully treated with antidepressants. At present, a substantial number of false positives among the antidepressant-treated subgroup cannot be ruled out. However, the findings suggest that, in some cases, it might be preferable to begin treatment with antidepressants and progress to antipsychotics once symptoms intensify, since adherence to the latter is difficult to maintain.

Background: Neurocognitive deficits are considered to be central to the pathophysiology of schizophrenia, and the neurodevelopmental model suggests that such deficits precede full-blown psychosis. The present study examined performance on a broad neuropsychological battery of young subjects considered to be at clinical high risk for schizophrenia, who were subsequently followed to determine clinical outcome., Methods: Subjects were 38 clinical high-risk patients (58% male patients; mean age = 16.5) and 39 sex- and age-matched healthy control subjects. At baseline, all high-risk patients had attenuated (subpsychotic) schizophrenialike positive symptoms. Clinical follow-up data of at least 6 months duration was available on 33 patients, of whom 12 developed nonaffective psychotic disorders., Results: At baseline, clinical high-risk patients had significantly impaired global cognitive performance relative to control subjects and to estimates of their own prior intellectual functioning. Measures of verbal memory and executive functioning/working memory showed significantly greater impairments; visuospatial functioning was relatively spared. Prodromal patients who later developed psychosis had significantly lower verbal memory scores at baseline compared with patients who remained nonpsychotic., Conclusions: Verbal memory deficits may be an important risk marker for the development of schizophrenia-spectrum psychotic disorders, possibly indicating the presence of a prefrontal-hippocampal neurodevelopmental abnormality. Generalized neurocognitive impairment may be a nonspecific vulnerability marker.

The authors examined performance on the Continuous Performance Test-Identical Pairs "numbers" task in adolescents with schizophrenia (n=59) and healthy controls (n=55). Adjusting for an estimate of premorbid intelligence and socioeconomic status, patients performed worse than normal controls on all three d' conditions (2-digit, 3-digit, 4-digit). However, there was a significant group-by-age-by-condition interaction (F[4,100]=4.69, p<.01) indicating an interaction between development and disease state. At the simplest level of the task (2-digit) the difference between patients with schizophrenia and controls was evident at all ages; while for the more difficult levels of the task (3-digit, 4-digit), differences between groups gradually increased across the tested age span (10 to 20 years of age). Premorbid social isolation was associated with worse attentional performance in patients, suggesting a relationship and continuity with negative symptoms. These data suggest that attentional differences in adolescents with schizophrenia are better captured by different tasks at different ages. The discrepant findings of attentional impairments reported in the literature for adolescents with schizophrenia could reflect the underlying etiological complexity of the disorder that may have a variable impact on involved brain regions and neurocognitive functioning.

Despite the widespread acceptance of the neurodevelopmental model of schizophrenia, its application to research concerned with the prodromal phase of illness is limited. Little recognition has been given to the concept of an enduring biological vulnerability to illness that may be responsive to early intervention. Rather, the focus of most prodromal studies is on emerging positive symptoms. The Recognition and Prevention (RAP) program follows the strategy of being equally concerned with the nonspecific symptoms reflecting the core of schizophrenia and those directly related to psychosis. Data were collected from 62 adolescents (mean age = 16.4 years) during the initial 3-year pilot phase of the RAP program (1998-2001). Subjects were divided into three clinical high-risk groups, characterized by (1) negative and nonspecific symptoms (e.g., social isolation, school failures), the earliest prodrome stage; (2) emerging attenuated positive symptoms of moderate intensity; and (3) severe attenuated (but subpsychotic) positive symptoms, considered most proximal to psychosis. Four risk factors, derived from the neurodevelopmental literature, were selected to reflect the vulnerability core: cognitive deficits, affective disturbances, social isolation, and school failure. All four domains were equally impaired across the three risk groups, supporting the presence of the underlying vulnerability core regardless of the magnitude of emerging positive symptoms. An observational pilot study was also conducted to identify the medications typically used to treat emerging positive symptoms. Antidepressants were used as frequently as antipsychotics to treat adolescents presenting with moderate attenuated positive symptoms. Regardless of type of medication, moderately symptomatic youngsters did quite well over the approximately 1-year followup period. By contrast, adolescents presenting with more severe (but nonpsychotic) attenuated symptoms were treated with antipsychotics, often in combination with other agents. Outcome for the more symptomatic youngsters was, however, more guarded, with nearly half (i.e., 47%) of the group converting to a schizophrenia spectrum psychotic disorder. Nonadherence to medication appeared to be a major risk factor in this group. We conclude that a neurodevelopmental model of schizophrenia is supported by our data and that a range of novel treatment strategies may be neuroprotective by directly affecting the disorder's vulnerability core.

The early detection and prevention of schizophrenia and other psychotic disorders are receiving rapidly growing attention subsequent to the suggestion that poorer outcome is associated with delayed onset of treatment among patients in their first psychotic episode. Although the first generation of so-called "prodromal" research programs has produced encouraging preliminary results, more information is necessary on the conversion rates from prodromal states to schizophrenia in specific samples. Early recognition and prevention strategies require a new taxonomy that classifies subjects by their status of risk of imminent onset of psychosis. Without additional knowledge of the mechanisms through which particular constellations of vulnerability factors, precursors, and prodromal symptoms predict the onset of schizophrenia, it is difficult to judge the effects of existing programs. In this paper, we discuss three sets of issues that will need to be resolved before these preventive programs can be implemented into routine care: (1) optimization of predicting the onset of psychotic disorders; (2) development and evaluation of alternative treatment strategies depending on the presenting risk status; and (3) evaluation of costs and benefits of identifying subjects at risk of psychosis/schizophrenia and receiving a specific preventive treatment.

The sudden interest in initiating treatment before the onset of psychosis (i.e., during the prodromal stage of schizophrenia) has failed to integrate the earlier work on prediction generated by more traditional high-risk studies. Genetic high-risk research has most typically focused on the long-term, prospective study of children of parents with schizophrenia. In this paper, it will be argued that high-risk research can make at least two major contributions to prevention programs. First, previous findings can guide identification of risk factors and provide clues about causality, thus highlighting which pre-morbid deficits should be treatment targets. For example, as discussed here, data from the New York High Risk Project points to impaired attention as a highly promising candidate risk factor, with a possible causal association with later-emerging social deficits. Second, the high-risk approach can provide a framework for establishing the predictive validity of prodromal clinical indicators and for understanding the nature of the schizophrenia prodrome. Preliminary findings from the Hillside Recognition and Prevention (RAP) program, integrating high-risk methodology with an early intervention strategy, indicate that the prodrome is a developmentally complex phase of schizophrenia. In particular, a cluster of early features-including cognitive, academic, and social impairments, along with odd/disorganized behaviors-appear to anticipate positive symptoms and may constitute a core risk profile. Preliminary RAP treatment findings also suggest that medications other than anti-psychotics may be effective for treating early prodromal symptoms, challenging the widely held hypothesis that anti-psychotics should always be the first line preventive treatment., (Copyright 2002 Wiley-Liss, Inc.)

It has been suggested that performance on the Wisconsin Card Sorting Test (WCST) may be an indicator of vulnerability to schizophrenia. WCST deficits have been demonstrated in schizophrenic patients and their relatives, but not as yet in their offspring. This study aimed to further establish the indicator potential of WCST deficits by analyzing data collected as part of the New York High-Risk Project (NYHRP), a longitudinal study of attention, cognition and clinical functioning in the offspring of schizophrenic (HRSz, n=73), affective disordered (HRAff, n=61) and normal comparison (NC, n=120) parents. Parental Research Diagnostic Criteria diagnoses were established by semi-structured interview (SADS-L). WCST testing was carried out when offspring were in their mid-20s. HRSz subjects performed significantly more poorly on the WCST than HRAff and NC subjects. High-risk subjects who developed psychotic symptoms prior to or shortly after testing did not differ significantly from HRSz subjects who did not become ill. Thus, WCST performance in the offspring of schizophrenics resembles that of schizophrenic patients and may distinguish HRSz from offspring at risk for nonschizophrenic illness. WCST deficits may be a specific familial indicator of vulnerability, but appear not to distinguish between those subjects at risk for schizophrenia who do or do not become ill.

Although the devastating consequences of schizophrenia have long been known, interest in preventive intervention has only recently emerged. The shift in focus toward early treatment has been encouraged by findings suggesting that the longer psychosis remains untreated, the poorer the prognosis, and by the recent introduction of novel antipsychotic medications with a more benign side effect profile than conventional neuroleptics. In this paper, we argue that interest in prevention has outpaced the necessary scientific and ethical underpinnings for clinical trials involving the schizophrenia prodrome. Specifically, we maintain that the prodromal phase of schizophrenia is, at present, essentially a retrospective construct and that, as a result, the defining signs and symptoms currently in use must be validated in naturalistic, longitudinal studies. In particular, it is essential to establish solid base rates for schizophrenia in prodromal individuals before early treatment can be effectively evaluated. Additional ethical/scientific issues discussed include: (1) the need for an exit strategy (i.e. the determination of when to discontinue treatment in an individual who does not develop schizophrenia), (2) the advisability of pharmacological interventions that specifically target neurocognitive deficits, and (3) the possibility that antidepressant medications may be as effective or more effective, with fewer side effects, than antipsychotic medication for prodromal individuals.

Attentional abnormalities have long been known to characterize patients with schizophrenia. The data discussed in this report suggest that impaired attention (at least as measured by a specific task, the Continuous Performance Test, Identical Pairs (CPT-IP) version) may also be an endophenotype of particular promise for use in molecular genetic studies of schizophrenia. This conclusion is based on findings indicating that the deficits in verbal and spatial attentional processing tapped by the CPT-IP are heritable, developmentally stable, independent of clinical state, and predict future spectrum disorders in the at-risk offspring of parents with schizophrenia.

In the New York High-Risk Project we have followed two samples of subjects (Sample A and Sample B) at risk for schizophrenic or affective disorders and low-risk controls from childhood to adulthood, in an attempt to identify early predictors of later psychopathology. We administered a large number of cognitive, psychometric and other types of measures to both samples as possible psychopathology predictors, including an index of attentional deviance assessed in childhood, the Physical Anhedonia Scale in adolescence, and three measures of social outcome in adulthood ('Suspicious Solitude', 'Social Insecurity', and 'Lack of Empathy'), derived from the Personality Disorders Examination. In the analysis of the combined samples, parental diagnostic group, gender, attentional deviance in childhood, and physical anhedonia in adolescence were used to predict three measures of social outcome in adulthood. While only physical anhedonia was directly related to all three social outcome measures, with the strongest relationship to Suspicious Solitude, attention deviance successfully predicted two of the three outcomes. Subjects at risk for affective disorder did not show increased levels of attention deviance, physical anhedonia, or social dysfunction, relative to the normal control subjects. Attention deviance appears to be a key neurobiological indicator and physical anhedonia appears to be a potentiating factor mediating the relationship between risk for schizophrenia and later social dysfunction.

Background: The New York High-Risk Project is a study of offspring of patients with schizophrenia (HRSz group) or affective illness (HRAff group) and psychiatrically normal parents (NC group) observed prospectively from childhood to adulthood. We herein present lifetime prevalence and comorbidity rates of Axis I disorders in subjects and their siblings from sample A of the project., Methods: Schedule for Affective Disorders and Schizophrenia-Lifetime Version interviews conducted with the offspring in adulthood were used to obtain diagnoses of Axis I disorders., Results: Schizophrenia and unspecified psychoses occurred only in the HRSz group. However, schizoaffective and psychotic affective disorders occurred equally in the HRSz and HRAff groups. Total rates of psychosis in these groups were significantly higher than in the NC group. All groups had similar rates of nonpsychotic affective and substance abuse disorders. The HRAff group, however, had significantly more total affective illness than the NC group and tended to have more anxiety disorders than the other groups. Comorbidity rates in the HRSz and HRAff groups were nearly twice those of the NC group., Conclusions: The familial liabilities to schizophrenia and affective disorders show specificities and commonalities, differing markedly from each other in their expression of some disorders and sharing others. Patterns of comorbidity are generally, although not entirely, similar to these liabilities.

Eye tracking abnormalities were studied in the offspring of schizophrenic, unipolar depressed and bipolar probands from the New York High-Risk Project to examine their familial specificity. Offspring of schizophrenic and depressed probands both had significant global performance deficits based on spectral purity measurements, but only the offspring of schizophrenic probands had an increased rate of intrusive anticipatory saccades. The greater specificity of high anticipatory saccade rate than global performance impairment suggests that this eye movement abnormality may provide a more specific biological marker of risk for schizophrenia than the global measure of eye tracking performance used in this study. Attention facilitation effectively normalized all performance deficits in the offspring of schizophrenic patients, suggesting that a problem sustaining focused visual attention may contribute to eye tracking deficits observed in the relatives of schizophrenic probands.

Background: We herein present lifetime prevalence rates of psychoses and DSM-III-R cluster A personality disorders in sample A of the New York High-Risk Project, a prospective study following offspring of parents with schizophrenia (HRSz subjects) and affective illness (HRAff subjects) and of psychiatrically normal parents (NC subjects) from midchildhood to adulthood., Methods: We interviewed the offspring in adulthood with the Schedule for Affective Disorders and Schizophrenia, Lifetime Version, for Axis I disorders and the Personality Disorder Examination for Axis II disorders., Results: Lifetime prevalence rates (+/- SE) of schizophrenia and unspecified psychosis were 11.1% +/- 4.3% and 5.6% +/- 3.1%, respectively, in the HRSz group and 0% in the HRAff and NC groups. Rates of schizoaffective disorder subclassified as mainly schizophrenic, however, were highest in the HRAff group. Rates of psychotic affective disorders did not differ between the HRSz and other groups. Age-corrected morbidity risks were similar to lifetime prevalence rates. Rates of the three cluster A personality disorders did not differ among the groups, but the combined rate was greater in the HRSz and HRAff groups than in the NC group., Conclusions: Our data strongly support a specific familial liability to narrowly defined schizophrenia that is not shared by families of probands with affective disorder. Schizoaffective disorder and cluster A personality disorders, however, occur in families of both schizophrenic probands and probands with affective disorder. Psychotic affective disorders, which are not increased in HRSz subjects, do not appear to be an expression of the liability to schizophrenia.