Search

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.)

Background: Immune dysregulation has been observed in patients with schizophrenia or first-episode psychosis, but few have examined dysregulation in those at clinical high-risk (CHR) for psychosis. The aim of this study was to examine whether the peripheral blood-based proteome was dysregulated in those with CHR. Secondly, we examined whether baseline dysregulation was related to current and future functioning and clinical symptoms., Methods: We used data from participants of the North American Prodromal Longitudinal Studies (NAPLS) 2 and 3 (n = 715) who provided blood samples (Unaffected Comparison subjects (UC) n = 223 and CHR n = 483). Baseline proteomic data was quantified from plasma samples using mass spectrometry. Differential expression was examined between CHR and UC using logistic regression. Psychosocial functioning was measured using the Global Assessment of Functioning scale (GAF). Symptoms were measured using the subscale scores from the Scale of Psychosis-risk Symptoms; positive, negative, general, and disorganised. Three measures of each outcome were included: baseline, longest available follow-up (last follow-up) and most severe follow-up (MSF). Associations between the proteomic data, GAF and symptoms were assessed using ordinal regression., Results: Of the 99 proteins quantified, six were differentially expressed between UC and CHR. However, only haptoglobin (HP) survived FDR-correction (OR:1.45, 95 %CI:1.23-1.69, p adj = <0.001). HP was cross-sectionally and longitudinally associated with functioning and symptoms such that higher HP values were associated with poorer functioning and more severe symptoms. Results were evident after stringent adjustment and poorer functioning was observed in both NAPLS cohort separately., Conclusion: We demonstrate that elevated HP is robustly observed in those at CHR for psychosis, irrespective of transition to psychosis. HP is longitudinally associated with poorer functioning and greater symptom severity. These results agree with previous reports of increased HP gene expression in individuals at-risk for psychosis and with the dysfunction of the acute phase inflammatory response seen in psychotic disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Mismatch negativity reductions are among the most reliable biomarkers for schizophrenia and have been associated with increased risk for conversion to psychosis in individuals who are at clinical high risk for psychosis (CHR-P). Here, we adopted a computational approach to develop a mechanistic model of mismatch negativity reductions in CHR-P individuals and patients early in the course of schizophrenia., Methods: Electroencephalography was recorded in 38 CHR-P individuals (15 converters), 19 patients early in the course of schizophrenia (≤5 years), and 44 healthy control participants during three different auditory oddball mismatch negativity paradigms including 10% duration, frequency, or double deviants, respectively. We modeled sensory learning with the hierarchical Gaussian filter and extracted precision-weighted prediction error trajectories from the model to assess how the expression of hierarchical prediction errors modulated electroencephalography amplitudes over sensor space and time., Results: Both low-level sensory and high-level volatility precision-weighted prediction errors were altered in CHR-P individuals and patients early in the course of schizophrenia compared with healthy control participants. Moreover, low-level precision-weighted prediction errors were significantly different in CHR-P individuals who later converted to psychosis compared with nonconverters., Conclusions: Our results implicate altered processing of hierarchical prediction errors as a computational mechanism in early psychosis consistent with predictive coding accounts of psychosis. This computational model seems to capture pathophysiological mechanisms that are relevant to early psychosis and the risk for future psychosis in CHR-P individuals and may serve as predictive biomarkers and mechanistic targets for the development of novel treatments., (Copyright © 2023 Society of Biological Psychiatry. All rights reserved.)

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.

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., (© The Author(s) 2021. 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: Attenuated psychosis syndrome (APS), a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders-5, comprises psychotic symptoms that are qualitatively similar to those observed in schizophrenia but are less severe. Patients with APS are at high risk of converting to first-episode psychosis (FEP). As evidence for effective pharmacological interventions in APS is limited, novel treatments may provide symptomatic relief and delay/prevent psychotic conversion. This trial aims to investigate the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase-9 inhibitor, versus placebo in APS. Novel biomarkers of psychosis are being investigated., Methods: In this Phase II, multinational, double-blind, parallel-group trial, randomized (1:1) patients will receive BI 409306 50 mg or placebo twice daily for 52 weeks. Patients (n = 300) will be enrolled to determine time to remission of APS, time to FEP, change in everyday functional capacity (Schizophrenia Cognition Rating Scale), and change from baseline in Brief Assessment of Cognition composite score and Positive and Negative Syndrome Scale scores. Potential biomarkers of psychosis under investigation include functional measures of brain activity and automated speech analyses. Safety is being assessed throughout., Conclusions: This trial will determine whether BI 409306 is superior to placebo in achieving sustainable remission of APS and improvements in cognition and functional capacity. These advances may provide evidence-based treatment options for symptomatic relief in APS. Furthermore, the study will assess the effect of BI 409306 on psychotic conversion and explore the identification of patients at risk for conversion using novel biomarkers., (© 2020 The Authors. Early Intervention in Psychiatry published by 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.)

Research suggests that early identification and intervention with individuals at clinical high risk (CHR) for psychosis may be able to improve the course of illness. The first generation of studies suggested that the identification of CHR through the use of specialized interviews evaluating attenuated psychosis symptoms is a promising strategy for exploring mechanisms associated with illness progression, etiology, and identifying new treatment targets. The next generation of research on psychosis risk must address two major limitations: (1) interview methods have limited specificity, as recent estimates indicate that only 15%-30% of individuals identified as CHR convert to psychosis and (2) the expertise needed to make CHR diagnosis is only accessible in a handful of academic centers. Here, we introduce a new approach to CHR assessment that has the potential to increase accessibility and positive predictive value. Recent advances in clinical and computational cognitive neuroscience have generated new behavioral measures that assay the cognitive mechanisms and neural systems that underlie the positive, negative, and disorganization symptoms that are characteristic of psychotic disorders. We hypothesize that measures tied to symptom generation will lead to enhanced sensitivity and specificity relative to interview methods and the cognitive intermediate phenotype measures that have been studied to date that are typically indicators of trait vulnerability and, therefore, have a high false positive rate for conversion to psychosis. These new behavioral measures have the potential to be implemented on the internet and at minimal expense, thereby increasing accessibility of assessments., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

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.)

Identification of neurophysiological abnormalities associated with schizophrenia that predate and predict psychosis onset may improve clinical prediction in the psychosis risk syndrome (PRS) and help elucidate the pathogenesis of schizophrenia. Amplitude reduction of the P300 event-related potential component reflects attention-mediated processing deficits and is among the most replicated biological findings in schizophrenia, making it a candidate biomarker of psychosis risk. The relative extent to which deficits in P300 amplitudes elicited by auditory and visual oddball stimuli precede psychosis onset during the PRS and predict transition to psychosis, however, remains unclear. Forty-three individuals meeting PRS criteria, 19 schizophrenia patients, and 43 healthy control (HC) participants completed baseline electroencephalography recording during separate auditory and visual oddball tasks. Two subcomponents of P300 were measured: P3b, elicited by infrequent target stimuli, and P3a, elicited by infrequent nontarget novel stimuli. Auditory and visual target P3b and novel P3a amplitudes were reduced in PRS and schizophrenia participants relative to HC participants. In addition, baseline auditory and visual target P3b, but not novel P3a, amplitudes were reduced in 15 PRS participants who later converted to psychosis, relative to 18 PRS non-converters who were followed for at least 22 months. Furthermore, target P3b amplitudes predicted time to psychosis onset among PRS participants. These results suggest that P300 amplitude deficits across auditory and visual modalities emerge early in the schizophrenia illness course and precede onset of full psychosis. Moreover, target P3b may represent an important neurophysiological vulnerability marker of the imminence of risk for psychosis., (Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2018.)

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.)

In a recent study, a neuroanatomical-based age prediction model observed neuromaturational deviance among clinical high-risk individuals who developed psychosis. Here we aimed to investigate whether incorporating "brain age gap" (discrepancy between neuroanatomical-based predicted age and chronological age) to the North American Prodromal Longitudinal Study risk calculator would enhance prediction of psychosis conversion. The effect of brain age gap was significant (HR = 1.21, P = 0.047), but its predictive variance was found to overlap entirely with age at ascertainment, consistent with the view that greater brain-age gap and earlier age at onset of prodromal symptoms are correlated indicators of insidious-onset forms of psychosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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.)

Response inhibition (RI) is a component of the cognitive control systems that support optimal cognition. Cognitive control deficits are well-described in schizophrenia, but are not well characterized in individuals at clinical high risk (CHR) for developing psychosis. Functional magnetic resonance imaging during Go/NoGo task performance was collected from 30 CHR youth, 23 early illness schizophrenia patients (ESZ), and 72 healthy adolescents and young adults (HC). Voxelwise main effects of group were examined (P < .005 height threshold, family-wise error-corrected cluster threshold, P < .05) for correct NoGo-Go contrast values and task-based functional connectivity. CHR and ESZ groups had slower and more variable reaction times (RT) on Go trials compared to HCs. Significant main effects of group in bilateral dorsal anterior cingulate (dACC) and right inferior frontal cortex stemmed from CHR and ESZ groups showing significantly less NoGo-Go activation, relative to HCs. Faster responding HCs had less functional coupling between dACC and medial prefrontal cortex, a default mode network (DMN) region during NoGo vs Go trials. This functional connectivity-performance relationship was not present in ESZ or CHR groups. The pattern of findings suggests CHR and ESZ groups were deficient in developing strong and consistent prepotent responding, based on their slow and variable motor responses and decreased engagement of dACC and right inferior frontal regions implicated in inhibitory control. Furthermore, only the control group showed a functional connectivity relationship consistent with greater response prepotency requiring more decoupling of inhibitory control regions from DMN regions during RI.

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.

A panel of experts assembled and analyzed a comprehensive item bank from which a highly sensitive and specific early psychosis screener could be developed. Twenty well-established assessments relating to the prodromal stage, early psychosis, and psychosis were identified. Using DSM-5 criteria, we identified the core concepts represented by each of the items in each of the assessments. These granular core concepts were converted into a uniform set of 490 self-report items using a Likert scale and a 'past 30days' time frame. Partial redundancy was allowed to assure adequate concept coverage. A panel of experts and TeleSage staff rated these items and eliminated 189 items, resulting in 301 items. The items were subjected to five rounds of cognitive interviewing with 16 individuals at clinically high risk for psychosis and 26 community mental health center patients. After each round, the expert panel iteratively reviewed, rated, revised, added, or deleted items to maximize clarity and centrality to the concept. As a result of the interviews, 36 items were revised, 52 items were added, and 205 items were deleted. By the last round of cognitive interviewing, all of the items were clearly understood by all participants. In future work, responses to the final set of 148 items and machine learning techniques will be used to quantitatively identify the subset of items that will best predict clinical high-risk status and conversion., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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.

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., (© 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.)

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.)

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.

Background: Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely resemble those of schizophrenia, including negative symptoms. D-serine is a naturally occurring NMDAR modulator that reverses the effects of NMDAR antagonists in animal models of schizophrenia. D-serine effects have been assessed previously for treatment of established schizophrenia, but not in the early stages of the disorder. We aimed to assess effects of D-serine on negative symptoms in at risk individuals., Methods: We did a double-blind, placebo-controlled, parallel-group randomised clinical trial at four academic US centres. Individuals were eligible for inclusion in the study if they were at clinical high risk of schizophrenia, aged between 13-35 years, had a total score of more than 20 on the Scale of Prodromal Symptoms (SOPS), and had an interest in participation in the clinical trial. Exclusion criteria included a history of suprathreshold psychosis symptoms (ie, no longer qualifying as prodromal) or clinical judgment that the reported symptoms from the SOPS were accounted for better by another disorder (eg, depression). Randomisation was done using a generated list with block sizes of four. Participants were stratified by site, with participants, investigators, and assessors all masked through use of identical looking placebos and centralised drug dispensation to study assignment. D-serine (60 mg/kg) was given orally in divided daily doses for 16 weeks. The primary endpoint was for negative SOPS, measured weekly for the first 6 weeks, then every 2 weeks. Participants who received at least one post-baseline assessment were included in analysis. Serum cytokine concentrations were collected at baseline, midpoint, and endpoint to assess the mechanism of action. Safety outcomes including laboratory assessments were obtained for all individuals. This trial is registered with ClinicalTrials.gov, number NCT0082620., Findings: We enrolled participants between April 2, 2009, and July 23, 2012. 44 participants were randomly assigned to receive either D-serine (n=20) or placebo (n=24); 35 had assessable data (15 D-serine, 20 placebo). D-serine induced a 35·7% (SD 17·8) improvement in negative symptoms, which was significant compared with placebo (mean final SOPS negative score 7·6 [SEM 1·4] for D-serine group vs 11·3 [1·2] for placebo group; d=0·68, p=0·03). Five participants who received D-serine and nine participants who received placebo discontinued the study early because of withdrawn consent or loss to follow-up (n=8), conversion to psychosis (n=2), laboratory-confirmed adverse events (n=2), or protocol deviations (n=2)., Interpretation: This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia. On the basis of observed effect sizes, future studies with sample sizes of about 40 per treatment group would be needed for confirmation of beneficial effects on symptoms and NMDAR-related inflammatory changes. Long-term studies are needed to assess effects on psychosis conversion in individuals at clinical high risk of schizophrenia., Funding: National Institutes of Health., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Neurophysiological abnormalities in auditory deviance processing, as reflected by the mismatch negativity (MMN), have been observed across the course of schizophrenia. Studies in early schizophrenia patients have typically shown varying degrees of MMN amplitude reduction for different deviant types, suggesting that different auditory deviants are uniquely processed and may be differentially affected by duration of illness. To explore this further, we examined the MMN response to 4 auditory deviants (duration, frequency, duration+frequency "double deviant", and intensity) in 24 schizophrenia-spectrum patients early in the illness (ESZ) and 21 healthy controls. ESZ showed significantly reduced MMN relative to healthy controls for all deviant types (p<0.05), with no significant interaction with deviant type. No correlations with clinical symptoms were present (all ps>0.05). These findings support the conclusion that neurophysiological mechanisms underlying processing of auditory deviants are compromised early in illness, and these deficiencies are not specific to the type of deviant presented., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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.)

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

Background: Only about one third of patients at high risk for psychosis based on current clinical criteria convert to a psychotic disorder within a 2.5-year follow-up period. Targeting clinical high-risk (CHR) individuals for preventive interventions could expose many to unnecessary treatments, underscoring the need to enhance predictive accuracy with nonclinical measures. Candidate measures include event-related potential components with established sensitivity to schizophrenia. Here, we examined the mismatch negativity (MMN) component of the event-related potential elicited automatically by auditory deviance in CHR and early illness schizophrenia (ESZ) patients. We also examined whether MMN predicted subsequent conversion to psychosis in CHR patients., Methods: Mismatch negativity to auditory deviants (duration, frequency, and duration + frequency double deviant) was assessed in 44 healthy control subjects, 19 ESZ, and 38 CHR patients. Within CHR patients, 15 converters to psychosis were compared with 16 nonconverters with at least 12 months of clinical follow-up. Hierarchical Cox regression examined the ability of MMN to predict time to psychosis onset in CHR patients., Results: Irrespective of deviant type, MMN was significantly reduced in ESZ and CHR patients relative to healthy control subjects and in CHR converters relative to nonconverters. Mismatch negativity did not significantly differentiate ESZ and CHR patients. The duration + frequency double deviant MMN, but not the single deviant MMNs, significantly predicted the time to psychosis onset in CHR patients., Conclusions: Neurophysiological mechanisms underlying automatic processing of auditory deviance, as reflected by the duration + frequency double deviant MMN, are compromised before psychosis onset and can enhance the prediction of psychosis risk among CHR patients., (Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Clinicians need to know the right antipsychotic dose for optimized treatment, and the concept of dose equivalence is important for many clinical and scientific purposes., Methods: We refined a method presented in 2003, which was based on the minimum effective doses found in fixed-dose studies. We operationalized the selection process, updated the original findings, and expanded them by systematically searching more recent literature and by including 13 second-generation antipsychotics. To qualify for the minimum effective dose, a dose had to be significantly more efficacious than placebo in the primary outcome of at least one randomized, double-blind, fixed-dose trial. In a sensitivity analysis, 2 positive trials were required. The minimum effective doses identified were subsequently used to derive olanzapine, risperidone, haloperidol, and chlorpromazine equivalents., Results: We reviewed 73 included studies. The minimum effective daily doses/olanzapine equivalents based on our primary approach were: aripiprazole 10 mg/1.33, asenapine 10 mg/1.33, clozapine 300 mg/40, haloperidol 4 mg/0.53, iloperidone 8 mg/1.07, lurasidone 40 mg/5.33, olanzapine 7.5 mg/1, paliperidone 3 mg/0.4, quetiapine 150 mg/20, risperidone 2 mg/0.27, sertindole 12 mg/1.60, and ziprasidone 40 mg/5.33. For amisulpride and zotepine, reliable estimates could not be derived., Conclusions: This method for determining antipsychotic dose equivalence entails an operationalized and evidence-based approach that can be applied to the various antipsychotic drugs. As a limitation, the results are not applicable to specific populations such as first-episode or refractory patients. We recommend that alternative methods also be updated in order to minimize further differences between the methods and risk of subsequent bias.

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.)

Prodromal features of the schizophrenia syndrome have been described for a century, and work in the past two decades has produced a substantial literature based on these features to identify individuals at increased risk for developing a psychotic disorder. Sometimes conceptualized as a "risk state" and sometimes as early manifestations of a "disorder," the work has been conducted with several related but different constructs. Early in the preparation of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) public comment was sought on the proposal to create a new disorder termed attenuated psychosis syndrome (APS), and a range of issues emerged that generated interesting and important controversies. In this review, these criticisms are fully discussed, the APS concept is explicated; data relating to reliability, validity, and treatment are updated; the heterogeneity of APS is considered; and alternative views of the construct are presented with an emphasis on developmental pattern with timing for primary and secondary prevention and early treatment. Areas of future research are identified, and a potential roadmap for inclusion in DSM-5.1 is traced.

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.

Objective: Better understanding of the temporal development of cardiovascular risk will permit more targeted prevention of premature cardiovascular mortality in schizophrenia., Methods: The sample for this analysis was drawn from referrals (between 2006 and '11) to an early psychosis clinic based in a U.S. urban community mental health center. 76 individuals with schizophrenia who were young (mean 22.4 years, SD 4.8), early course (median duration of illness 31 weeks) and with minimal prior antipsychotic exposure (median 2 weeks) were compared to age-, gender-, and race-matched peers drawn from the National Health and Nutrition Survey (2007-'08). Measures of cardiovascular risk at baseline, 6 months, and 1 year are reported., Results: While indistinguishable from peers at entry, patients suffered pervasive adverse trajectories of cardiovascular risk factors over the subsequent year. 16 of 44 initial non-smokers became nicotine dependent and none of 32 entering smokers quit. 17 patients transitioned to overweight (BMI 25-29.9, n = 3) or obese (BMI>30, n = 14) categories, while only 24 of 38 (63%) sustained normal weight over one year. Similar adverse trends in blood pressure, lipids, and fasting glucose led to an increase in prevalence of metabolic syndrome (1.31% to 5.26%). 10-year cardiovascular risk estimates showed a small and significant increase although remaining in the low risk (<10%) category., Conclusions: The early emergence of obesity and smoking in younger schizophrenia samples provides a rational focus for primary prevention of premature cardiovascular mortality. The first year of treatment constitutes the beginning of a critical period for such preventive efforts., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Gamma-band oscillations and their synchronization have been implicated in the coordination of activity between distributed neuronal assemblies in the service of sensory registration of stimuli and perceptual binding of their features. Prior electroencephalographic (EEG) studies of chronic schizophrenia patients have documented deficits in the magnitude and/or phase synchrony of stimulus-evoked gamma oscillations, findings that have been linked to neurotransmission abnormalities involving GABA and NMDA-glutamate receptors. However, it remains unclear whether these abnormalities are present at the onset of the illness, or indeed, whether they are present during the prodromal period preceding illness onset. Accordingly, we examined the magnitude and phase synchrony of the transient gamma-band response (GBR) elicited by an auditory stimulus in young patients with schizophrenia and in patients at clinical high risk for psychosis based on their manifestation of putatively prodromal symptoms., Methods: EEG was recorded during an auditory oddball target detection task in three groups: young schizophrenia patients early in their illness (YSZ; n = 19), patients at clinical high risk for psychosis (CHR; n = 55), and healthy controls (HC; n = 42). Single-trial EEG epochs and the average event-related potential time-locked to standard tones from the oddball task were subjected to time-frequency decomposition using Morlet wavelet transformations. The GBR between 50 and 100 ms following the tone onset was quantified in terms of evoked power, total power, and the phase-locking factor (PLF) reflecting cross-trial phase synchrony., Results: GBR evoked power was significantly reduced in YSZ (p < 0.01) and CHR (p < 0.05) patients, relative to HC. Similarly, GBR PLF was significantly reduced in YSZ (p < 0.01) and showed a marginal reduction in CHR patients (p = 0.057), relative to HC. GBR total power was not reduced in CHR patients (p = 0.68) and showed only a trend level reduction in YSZ (p = 0.072). Within the CHR group. there were no significant GBR differences between the patients who converted to a psychotic disorder and those who did not convert to psychosis during a 12-month follow-up period., Conclusion: Reductions in the transient auditory GBR, as reflected by evoked power and phase synchrony, are evident in the early stages of schizophrenia and appear to precede psychosis onset. However, the absence of total power GBR abnormalities in CHR patients, with only a trend toward reduction in YSZ patients, suggests that the magnitude of the GBR is intact early in the course

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.)

Response monitoring abnormalities have been reported in chronic schizophrenia patients, but it is unknown whether they predate the onset of psychosis, are present in early stages of illness, or are late-developing abnormalities associated with illness progression. Response-synchronized event-related potentials (ERP) recorded during a picture-word matching task yielded error-related negativity (ERN), correct-response negativity (CRN), and error positivity (Pe) from 84 schizophrenia patients (SZ), 48 clinical high risk patients (CHR), and their age-matched healthy controls (HC; n = 110 and 88, respectively). A sub-sample of 35 early illness schizophrenia patients (ESZ) was compared to 93 age-matched HC and the CHR patients (after statistically removing the effects of normal aging). Relative to HC, 1) SZ, ESZ, and CHR had smaller ERNs, and 2) SZ and ESZ had larger CRNs and smaller Pes. Within the SZ, longer illness duration was associated with larger CRNs but was unrelated to ERN or Pe. CHR and ESZ did not differ on ERN or CRN, although Pe was smaller in ESZ than CHR. These results indicate that while ERN, CRN, and Pe abnormalities are present early in the illness, only the ERN abnormality is evident prior to psychosis onset, and only the CRN abnormality appears to worsen progressively over the illness course. Brain regions subserving response monitoring may be compromised early in the illness and possibly during its clinical prodrome.

Objective: There has been concern that racial minorities are disproportionately prescribed long-acting injectable antipsychotic drugs., Method: Comprehensive administrative data and clinician survey were used to identify all patients with a DSM-IV diagnosis of schizophrenia who received long-acting antipsychotic prescriptions from July 2009 to June 2010 at a community mental health center. Charts were reviewed retrospectively to validate long-acting antipsychotic prescription (eg, medication, dosage) and merged with administrative data from all center patients documenting sociodemographic characteristics (ie, age, race, gender) and comorbid diagnoses. We used bivariate χ2, t tests, and multivariate logistic regression to compare the subsample of patients receiving long-acting injectable drugs (n = 102) to patients not receiving long-acting injectable drugs (n = 799) who were diagnosed with schizophrenia for the same period., Results: White patients were significantly less likely to receive long-acting antipsychotic prescriptions than minority patients (OR = 0.52, P < .007); ie, nonwhites were 1.89 times more likely to receive such drugs. Age, gender, and comorbid diagnoses, including substance abuse, were unrelated to long-acting injectable prescription, and race/ethnicity was not associated with use of specific agents (haloperidol decanoate, fluphenazine decanoate, or risperidone microspheres) (P = .73)., Conclusions: Racial minorities are more likely than other patients with schizophrenia to receive long-acting injectionable antipsychotics, a finding that suggests their prescribers may consider them less adherent to antipsychotic prescriptions., (© Copyright 2012 Physicians Postgraduate Press, Inc.)

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.

Aims: The 19-item 'Scale Of Prodromal Symptoms' (SOPS) and its semi-structured interview, the Structured Interview for Prodromal Symptoms (SIPS), have been developed to assess prodromes of psychosis. We assessed psychometric properties of the Italian version of the instrument., Methods: We collected socio-demographic and clinical data of 128 people seeking first-time psychiatric help in a large Roman area, either as outpatients at community facilities or as inpatients in psychiatric wards of two general hospitals. Participants were administered the Italian version of the SOPS and the 24-item Brief Psychiatric Rating Scale (BPRS). Data were analysed through Pearson's correlation and factorial analysis., Results: The English and Italian SOPS versions showed similar psychometric properties and factorial structure. The best-fit model was trifactorial, explaining 90% of total variance, and roughly corresponding to the positive, negative, and general dimensions, with disorganisation spreading over the other dimensions. Compared with the BPRS, the Italian version of the SOPS showed construct validity and convergent validity., Conclusions: The factor-structure of the Italian version of the SOPS is similar to those of the English and Spanish versions, in that the factors emerged are the same (positive, negative, and general symptoms). The scale could be used to assess at-risk people in early intervention services.

Background: D-serine is an allosteric modulator of the brain N-methyl-d-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia. Double-blind studies have been performed at 30 mg/kg/day (approximately 2 g/day) with encouraging results, but no formal dose escalation studies have been performed. We describe the first evaluation of the efficacy and safety of d-serine at doses >30 mg/kg/day; a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day)., Methods: 42 antipsychotic-stabilized patients with schizophrenia or schizoaffective disorder participated. PANSS was obtained bi-weekly and neuropsychological (MATRICS) was obtained pre- and post medication phase. The pharmacokinetics/pharmacodynamics (PK/PD), and safety of doses> or =30 mg/kg was also evaluated., Results: Significant improvement in symptoms and neuropsychological measures was noted across doses. On the PANSS, improvement was observed for positive (p=0.006;d=0.46), negative (p<0.001;d=0.68), general (p=0.001;d=0.53), and total (p<0.0001;d=0.74) symptoms. On MATRICS, while only non-significant improvement was noted at 30 mg/kg, highly significant, large effect size improvement was noted on the composite score (p<0.01;d=1.0) for doses> or =60 mg/kg, leading to a significant dose-by-time interaction (p<0.01). In PK analyses, significant dose-dependent increases in plasma D-serine levels were seen during the study, predictive of significantly increased brain levels. Furthermore, increases in plasma levels correlated with improved symptomatic and neuropsychological function., Discussion: These findings support double-blind investigation of D-serine at doses> or =60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction., (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).