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Background and hypothesisNegative symptom trajectory in clinical high risk (CHR) for psychosis is ill defined. This study aimed to better characterize longitudinal patterns of change in negative symptoms, moderators of change, and differences in trajectories according to clinical subgroups. We hypothesized that negative symptom course will be nonlinear in CHR. Clinical subgroups known to be more severe variants of psychotic illness-deficit syndrome (DS), persistent negative syndrome (PNS), and acute psychosis onset-were expected to show more severe baseline symptoms, slower rates of change, and less stable rates of symptom resolution.Study designLinear, curvilinear, and stepwise growth curve models, with and without moderators, were fitted to negative symptom ratings from the NAPLS-3 CHR dataset (N = 699) and within clinical subgroups.Study resultsNegative symptoms followed a downward curvilinear trend, with marked improvement 0-6 months that subsequently stabilized (6-24 months), particularly among those with lower IQ and functioning. Clinical subgroups had higher baseline ratings, but distinct symptom courses; DS vs non-DS: more rapid initial improvement, similar stability of improvements; PNS vs non-PNS: similar rates of initial improvement and stability; transition vs no transition: slower rate of initial improvement, with greater stability of this rate.ConclusionsContinuous, frequent monitoring of negative symptoms in CHR is justified by 2 important study implications: (1) The initial 6 months of CHR program enrollment may be a key window for improving negative symptoms as less improvement is likely afterwards, (2) Early identification of clinical subgroups may inform distinct negative symptom trajectories and treatment needs.

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

The clinical high-risk period before a first episode of psychosis (CHR-P) has been widely studied with the goal of understanding the development of psychosis; however, less attention has been paid to the 75%-80% of CHR-P individuals who do not transition to psychosis. It is an open question whether multivariable models could be developed to predict remission outcomes at the same level of performance and generalizability as those that predict conversion to psychosis. Participants were drawn from the North American Prodrome Longitudinal Study (NAPLS3). An empirically derived set of clinical and demographic predictor variables were selected with elastic net regularization and were included in a gradient boosting machine algorithm to predict prodromal symptom remission. The predictive model was tested in a comparably sized independent sample (NAPLS2). The classification algorithm developed in NAPLS3 achieved an area under the curve of 0.66 (0.60-0.72) with a sensitivity of 0.68 and specificity of 0.53 when tested in an independent external sample (NAPLS2). Overall, future remitters had lower baseline prodromal symptoms than nonremitters. This study is the first to use a data-driven machine-learning approach to assess clinical and demographic predictors of symptomatic remission in individuals who do not convert to psychosis. The predictive power of the models in this study suggest that remission represents a unique clinical phenomenon. Further study is warranted to best understand factors contributing to resilience and recovery from the CHR-P state.

BackgroundA decline in cortical thickness during early life appears to be a normal neuromaturational process. Accelerated cortical thinning has been linked with conversion to psychosis among individuals at clinical high risk for psychosis (CHR-P). Previous research indicates that exposure to life event stress (LES) is associated with exaggerated cortical thinning in both healthy and clinical populations, and LES is also linked with conversion to psychosis in CHR-P. To date, there are no reports on the relationship of LES with cortical thickness in CHR-P. This study examines this relationship and whether LES is linked with cortical thinning to a greater degree in individuals at CHR-P who convert to psychosis compared with individuals at CHR-P who do not convert and healthy control subjects.MethodsControlling for age and gender (364 male, 262 female), this study examined associations between LES and baseline cortical thickness in 436 individuals at CHR-P (375 nonconverters and 61 converters) and 190 comparison subjects in the North American Prodrome Longitudinal Study.ResultsFindings indicate that prebaseline cumulative LES is associated with reduced baseline cortical thickness in several regions among the CHR-P and control groups. Evidence suggests that LES is a risk factor for thinner cortex to the same extent across diagnostic groups, while CHR-P status is linked with thinner cortex in select regions after accounting for LES.ConclusionsThis research provides additional evidence to support the role of LES in cortical thinning in both healthy youth and those at CHR-P. Potential underlying mechanisms of the findings and implications for future research are discussed.

Subtle alterations in white matter microstructure are observed in youth at clinical high risk (CHR) for psychosis. However, the timing of these changes and their relationships to the emergence of psychosis remain unclear. Here, we track the evolution of white matter abnormalities in a large, longitudinal cohort of CHR individuals comprising the North American Prodrome Longitudinal Study (NAPLS-3). Multi-shell diffusion magnetic resonance imaging data were collected across multiple timepoints (1-5 over 1 year) in 286 subjects (aged 12-32 years): 25 CHR individuals who transitioned to psychosis (CHR-P; 61 scans), 205 CHR subjects with unknown transition outcome after the 1-year follow-up period (CHR-U; 596 scans), and 56 healthy controls (195 scans). Linear mixed effects models were fitted to infer the impact of age and illness-onset on variation in the fractional anisotropy of cellular tissue (FAT) and the volume fraction of extracellular free water (FW). Baseline measures of white matter microstructure did not differentiate between HC, CHR-U and CHR-P individuals. However, age trajectories differed between the three groups in line with a developmental effect: CHR-P and CHR-U groups displayed higher FAT in adolescence, and 4% lower FAT by 30 years of age compared to controls. Furthermore, older CHR-P subjects (20+ years) displayed 4% higher FW in the forceps major (p

BackgroundAdolescence/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.MethodsAn 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.ResultsInput-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.ConclusionsInput-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.

While functional neuroimaging studies typically focus on a particular paradigm to investigate network connectivity, the human brain appears to possess an intrinsic "trait" architecture that is independent of any given paradigm. We have previously proposed the use of "cross-paradigm connectivity (CPC)" to quantify shared connectivity patterns across multiple paradigms and have demonstrated the utility of such measures in clinical studies. Here, using generalizability theory and connectome fingerprinting, we examined the reliability, stability, and individual identifiability of CPC in a group of highly-sampled healthy traveling subjects who received fMRI scans with a battery of five paradigms across multiple sites and days. Compared with single-paradigm connectivity matrices, the CPC matrices showed higher reliability in connectivity diversity, lower reliability in connectivity strength, higher stability, and higher individual identification accuracy. All of these assessments increased as a function of number of paradigms included in the CPC analysis. In comparisons involving different paradigm combinations and different brain atlases, we observed significantly higher reliability, stability, and identifiability for CPC matrices constructed from task-only data (versus those from both task and rest data), and higher identifiability but lower stability for CPC matrices constructed from the Power atlas (versus those from the AAL atlas). Moreover, we showed that multi-paradigm CPC matrices likely reflect the brain's "trait" structure that cannot be fully achieved from single-paradigm data, even with multiple runs. The present results provide evidence for the feasibility and utility of CPC in the study of functional "trait" networks and offer some methodological implications for future CPC studies.

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

Psychotic symptoms are not only an important feature of severe neuropsychiatric disorders, but are also common in the general population, especially in youth. The genetic etiology of psychosis symptoms in youth remains poorly understood. To characterize genetic risk for psychosis spectrum symptoms (PS), we leverage a community-based multiethnic sample of children and adolescents aged 8-22 years, the Philadelphia Neurodevelopmental Cohort (n = 7225, 20% PS). Using an elastic net regression model, we aim to classify PS status using polygenic scores (PGS) based on a range of heritable psychiatric and brain-related traits in a multi-PGS model. We also perform univariate PGS associations and evaluate age-specific effects. The multi-PGS analyses do not improve prediction of PS status over univariate models, but reveal that the attention deficit hyperactivity disorder (ADHD) PGS is robustly and uniquely associated with PS (OR 1.12 (1.05, 1.18) P = 0.0003). This association is driven by subjects of European ancestry (OR = 1.23 (1.14, 1.34), P = 4.15 × 10-7) but is not observed in African American subjects (P = 0.65). We find a significant interaction of ADHD PGS with age (P = 0.01), with a stronger association in younger children. The association is independent of phenotypic overlap between ADHD and PS, not indirectly driven by substance use or childhood trauma, and appears to be specific to PS rather than reflecting general psychopathology in youth. In an independent sample, we replicate an increased ADHD PGS in 328 youth at clinical high risk for psychosis, compared to 216 unaffected controls (OR 1.06, CI(1.01, 1.11), P = 0.02). Our findings suggest that PS in youth may reflect a different genetic etiology than psychotic symptoms in adulthood, one more akin to ADHD, and shed light on how genetic risk can be investigated across early disease trajectories.

BackgroundMalhi et al. in this issue critique the clinical high risk (CHR) syndrome for psychosis.MethodResponse to points of critique.ResultsWe agree that inconsistency in CHR nomenclature should be minimized. We respectfully disagree on other points. In our view: a) individuals with CHR and their families need help, using existing interventions, even though we do not yet fully understand disease mechanisms; b) substantial progress has been made in identification of biomarkers; c) symptoms used to identify CHR are specific to psychotic illnesses; d) CHR diagnosis is not "extremely difficult"; e) the pattern of progression, although heterogenous, is discernible; f) "psychosis-like symptoms" are common but are not used to identify CHR; and g) on the point described as 'the real risk,' CHR diagnosis does not frequently cause harmful stigma.DiscussionMalhi et al.'s arguments do not fairly characterize progress in the CHR field nor efforts to minimize stigma. That said, much work remains in areas of consistent nomenclature, mechanisms of disease, dissecting heterogeneity, and biomarkers. With regard to what the authors term the "real risk" of stigma associated with a CHR "label," however, our view is that avoiding words like "risk" and "psychosis" reinforces the stigma that both they and we mean to oppose. Moreover, patients and their families benefit from being given a term that describes what is happening to them.

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

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

ObjectivesWhile co-morbid depression is associated with poor functional outcome among patients with schizophrenia, whether depression similarly predicts poorer outcomes in individuals at clinical high-risk for psychosis (CHR-P) is not clear. The present study aimed to examine depressive symptoms in relation to long-term global functional outcomes in the North American Prodrome Longitudinal Study cohort (NAPLS2).MethodsCHR individuals were evaluated clinically at baseline and at 12- and 24-month follow-ups for depressive and prodromal symptom severity as well as general functioning. Regression models were built to investigate whether baseline positive and depressive symptom scores predicted longitudinal improvement in global functioning.ResultsA total of 406 CHR individuals completed the 12-month follow-up assessment and 259 CHR individuals completed the 24-month assessment. Baseline depressive symptoms in the CHR-P population were found to predict better global functional outcomes at 2 years. Furthermore, the degree of recovery of depressive symptoms in the first year following baseline completely mediated the association between depressive symptoms at baseline and functional improvement at 2 years.ConclusionsPresence of affective symptoms within the CHR-P population has different implications for prognosis compared with patients with schizophrenia. The present findings support the view that among those at risk for psychosis, depressive symptoms at baseline predict a more favorable course of functional recovery, and highlight the potential importance of treating co-occurring depressive symptoms at an early stage of psychosis risk.

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

ObjectiveTo determine the optimal methods for measuring mismatch negativity (MMN), an auditory event-related potential (ERP), and quantify sources of MMN variance in a multisite setting.MethodsReliability of frequency, duration, and double (frequency + duration) MMN was determined from eight traveling subjects, tested on two occasions at eight laboratory sites. Deviant-specific variance components were estimated for MMN peak amplitude and latency measures using different ERP processing methods. Generalizability (G) coefficients were calculated using two-facet (site and occasion), fully-crossed models and single-facet (occasion) models within each laboratory to assess MMN reliability.ResultsG-coefficients calculated from two-facet models indicated fair (0.4  0.5). MMN amplitude reliability was greater than latency reliability, and reliability with mastoid referencing significantly outperformed nose-referencing.ConclusionsEEG preprocessing methods have an impact on the reliability of MMN amplitude. Within site MMN reliability can be excellent, consistent with prior single site studies.SignificanceWith standardized data collection and ERP processing, MMN can be reliably obtained in multisite studies, providing larger samples sizeswithin rare patient groups.

Mounting evidence has shown disrupted brain network architecture across the psychosis spectrum. However, whether these changes relate to the development of psychosis is unclear. Here, we used graph theoretical analysis to investigate longitudinal changes in resting-state brain networks in samples of 72 subjects at clinical high risk (including 8 cases who converted to full psychosis) and 48 healthy controls drawn from the North American Prodrome Longitudinal Study (NAPLS) consortium. We observed progressive reduction in global efficiency (P = 0.006) and increase in network diversity (P = 0.001) in converters compared with non-converters and controls. More refined analysis separating nodes into nine key brain networks demonstrated that these alterations were primarily driven by progressively diminished local efficiency in the default-mode network (P = 0.004) and progressively enhanced node diversity across all networks (P

The mismatch negativity (MMN) event-related potential (ERP) component is increasingly viewed as a prediction error signal elicited when a deviant sound violates the prediction that a frequent "standard" sound will repeat. Support for this predictive coding framework emerged with the identification of the repetition positivity (RP), a standard stimulus ERP component that increases with standard repetition and is thought to reflect strengthening of the standard's memory trace and associated predictive code. Using electroencephalographic recordings, we examined the RP elicited by repeating standard tones presented during a traditional "constant standard" MMN paradigm in individuals with the psychosis risk syndrome (PRS; n = 579) and healthy controls (HC; n = 241). Clinical follow-up assessments identified PRS participants who converted to a psychotic disorder (n = 77) and PRS nonconverters who were followed for the entire 24-month clinical follow-up period and either remained symptomatic (n = 144) or remitted from the PRS (n = 94). In HC, RP linearly increased from early- to late-appearing standards within local trains of repeating standards (p < .0001), consistent with auditory predictive code/memory trace strengthening. Relative to HC, PRS participants showed a reduced RP across standards (p = .0056). PRS converters showed a relatively small RP deficit for early appearing standards relative to HC (p = .0.0107) and a more prominent deficit for late-appearing standards (p = .0006) relative to both HC and PRS-remitted groups. Moreover, greater RP deficits predicted shorter time to conversion in a subsample of unmedicated PRS individuals (p = .02). Thus, auditory predictive coding/memory trace deficits precede psychosis onset and predict future psychosis risk in PRS individuals. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

ObjectivesMismatch negativity (MMN), an auditory event-related potential sensitive to deviance detection, is smaller in schizophrenia and psychosis risk. In a multisite study, a regression approach to account for effects of site and age (12-35 years) was evaluated alongside the one-year stability of MMN.MethodsStability of frequency, duration, and frequency + duration (double) deviant MMN was assessed in 167 healthy subjects, tested on two occasions, separated by 52 weeks, at one of eight sites. Linear regression models predicting MMN with age and site were validated and used to derive standardized MMN z-scores. Variance components estimated for MMN amplitude and latency measures were used to calculate Generalizability (G) coefficients within each site to assess MMN stability. Trait-like aspects of MMN were captured by averaging across occasions and correlated with subject traits.ResultsAge and site accounted for less than 7% of MMN variance. G-coefficients calculated at electrode Fz were stable (G = 0.63) across deviants and sites for amplitude measured in a fixed window, but not for latency (G = 0.37). Frequency deviant MMN z-scores averaged across tests negatively correlated with averaged global assessment of functioning.ConclusionMMN amplitude is stable and can be standardized to facilitate longitudinal multisite studies of patients and clinical features.

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

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.

ObjectiveThe 2-year risk of psychosis in persons who meet research criteria for a high-risk syndrome is about 15%-25%; improvements in risk prediction accuracy would benefit the development and implementation of preventive interventions. The authors sought to assess polygenic risk score (PRS) prediction of subsequent psychosis in persons at high risk and to determine the impact of adding the PRS to a previously validated psychosis risk calculator.MethodsPersons meeting research criteria for psychosis high risk (N=764) and unaffected individuals (N=279) were followed for up to 2 years. The PRS was based on the latest schizophrenia and bipolar genome-wide association studies. Variables in the psychosis risk calculator included stressful life events, trauma, disordered thought content, verbal learning, information processing speed, and family history of psychosis.ResultsFor Europeans, the PRS varied significantly by group and was higher in the psychosis converter group compared with both the nonconverter and unaffected groups, but was similar for the nonconverter group compared with the unaffected group. For non-Europeans, the PRS varied significantly by group; the difference between the converters and nonconverters was not significant, but the PRS was significantly higher in converters than in unaffected individuals, and it did not differ between nonconverters and unaffected individuals. The R2liability (R2 adjusted for the rate of disease risk in the population being studied, here assuming a 2-year psychosis risk between 10% and 30%) for Europeans varied between 9.2% and 12.3% and for non-Europeans between 3.5% and 4.8%. The amount of risk prediction information contributed by the addition of the PRS to the risk calculator was less than severity of disordered thoughts and similar to or greater than for other variables. For Europeans, the PRS was correlated with risk calculator variables of information processing speed and verbal memory.ConclusionsThe PRS discriminates psychosis converters from nonconverters and modestly improves individualized psychosis risk prediction when added to a psychosis risk calculator. The schizophrenia PRS shows promise in enhancing risk prediction in persons at high risk for psychosis, although its potential utility is limited by poor performance in persons of non-European ancestry.

Although the clinical high risk for psychosis (CHR) paradigm has become well-established over the past two decades, one key component has received surprisingly little investigative attention: the predictive validity of the criteria for conversion or transition to frank psychosis. The current study evaluates the predictive validity of the transition to psychosis as measured by the Structured Interview for Psychosis-Risk Syndromes (SIPS) in CHR individuals. Participants included 33 SIPS converters and 399 CHR non-converters both from the North American Prodromal Longitudinal Study (NAPLS-2), as well as a sample of 67 separately ascertained first-episode psychosis (FEP) patients from the STEP program. Comparisons were made at baseline and one-year follow-up on demographic, diagnostic stability (SCID), and available measurement domains relating to severity of illness (psychotropic medication, psychosocial treatment, and resource utilization). Principal findings are: 1) a large majority of cases in both SIPS converters (n = 27/33, 81.8%) and FEP (n = 57/67, 85.1%) samples met criteria for continued psychosis at one-year follow-up; 2) follow-up prescription rates for current antipsychotic medication were higher in SIPS converters (n = 17/32, 53.1%) compared to SIPS non-converters (n = 81/397, 20.4%), and similar as compared to FEP cases (n = 39/65, 60%); and 3) at follow-up, SIPS converters had higher rates of resource utilization (psychiatric hospitalizations, day hospital admissions, and ER visits) than SIPS non-converters and were similar to FEP in most categories. The results suggest that the SIPS definition of psychosis onset carries substantial predictive validity. Limitations and future directions are discussed.

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

AbstractBiomarkers are important in the study of the prodromal period of psychosis because they can help to identify individuals at greatest risk for future psychotic illness and provide insights into disease mechanism underlying neurodevelopmental abnormalities. The biomarker abnormalities can then be targeted with treatment, with an aim toward prevention or mitigation of disease. The human startle paradigm has been used in translational studies of psychopathology including psychotic illness to assess preattentive information processing for over 50 years. In one of the largest studies to date in clinical high risk (CHR) for psychosis participants, we aimed to evaluate startle indices as biomarkers of risk along with the role of age, sex, treatment, and substance use in this population of high risk individuals.MethodsStartle response reactivity, latency, and prepulse inhibition (PPI) were assessed in 543 CHR and 218 Normal Comparison (NC) participants between the ages of 12 and 35.ResultsAt 1 year follow-up, 58 CHR participants had converted to psychosis. CHR and NC groups did not differ across any of the startle measures but those CHR participants who later converted to psychosis had significantly slower startle latency than did those who did not convert to psychosis, and this effect was driven by female CHR participants. PPI was significantly associated with age in the CHR, but not the NC, participants with the greatest positive age correlations present in those CHR participants who later converted to psychosis, consistent with a prior report. Finally, there was a significant group by cannabis use interaction due to greater PPI in cannabis users and opposite PPI group effects in users (CHR>NC) and non-users (NC>CHR).DiscussionThis is the first study to demonstrate a relationship of startle response latency to psychotic conversion in a CHR population. PPI is an important biomarker that may be sensitive to the neurodevelopmental abnormalities thought to be present in psychosis prone individuals and the effects of cannabis. The significant correlations with age in this sample as well as the finding of greater PPI in CHR cannabis users replicate findings from another large sample of CHR participants.

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

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.

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

ObjectiveTraditional 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.MethodsSeven 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).ResultsInter-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.ConclusionsThe 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.

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

AimThere 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.MethodsSixty-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.ResultsTwo 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.ConclusionA change in symptom content should be monitored by clinicians, as changes in content may be indications of a possible transition to psychosis.

While graph theoretical modeling has dramatically advanced our understanding of complex brain systems, the feasibility of aggregating connectomic data in large imaging consortia remains unclear. Here, using a battery of cognitive, emotional and resting fMRI paradigms, we investigated the generalizability of functional connectomic measures across sites and sessions. Our results revealed overall fair to excellent reliability for a majority of measures during both rest and tasks, in particular for those quantifying connectivity strength, network segregation and network integration. Processing schemes such as node definition and global signal regression (GSR) significantly affected resulting reliability, with higher reliability detected for the Power atlas (vs. AAL atlas) and data without GSR. While network diagnostics for default-mode and sensori-motor systems were consistently reliable independently of paradigm, those for higher-order cognitive systems were reliable predominantly when challenged by task. In addition, based on our present sample and after accounting for observed reliability, satisfactory statistical power can be achieved in multisite research with sample size of approximately 250 when the effect size is moderate or larger. Our findings provide empirical evidence for the generalizability of brain functional graphs in large consortia, and encourage the aggregation of connectomic measures using multisite and multisession data.

BackgroundMost 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.MethodsData 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.ResultsFour 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.ConclusionNeurocognitive 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.

ObjectivePatients with schizophrenia have a high prevalence of metabolic disorders and cardiovascular mortality. It is possible that a vulnerability to metabolic abnormalities is associated with risk for psychosis, symptoms and functionality. In this study, we evaluate demographic information, cardiometabolic indices, symptoms and functioning in an antipsychotic free cohort at Clinical High Risk (CHR) for psychosis from the NAPLS Omega 3 fatty acid clinical trial.MethodSubjects received physical exams and metabolic monitoring prior to randomization into the Omega 3 versus Placebo trial. Anthropometrical measures, vital signs, glucose, and lipids were assessed along with symptoms, functioning, dietary Omega 3 fatty acids, erythrocyte polyunsaturated fatty acid content and a measure of lipid peroxidation (TBARS, Thiobarbituric acid-reactive substances).ResultsThe sample included 113 CHR subjects (42.1% female; 17.5% Latino) ages 12-29. The mean BMI was 24.3 with a trend toward higher BMI and a higher incidence of metabolic syndrome in Latino subjects; 36% of the sample was obese/overweight; 37.6% met criteria for prehypertension/hypertension; 4.2% met criteria for prediabetes/diabetes; 9.6% showed evidence of insulin resistance and 44.7% had dyslipidemia. The TBARS was elevated at 9.8 μM ± 6.1 (normal 1.86-3.94 μM). Metabolic parameters and a diet low in Omega 3 rich foods were significantly associated with prodromal symptoms and poor functioning.ConclusionsCHR subjects show a high percentage of metabolic abnormalities prior to exposure to antipsychotic medication. These findings reinforce that early detection of metabolic disturbances and food insecurity is crucial since these factors are modifiable with the potential for significant gains in terms of quality of life, physical and mental health.

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.

Atypical antipsychotics (AT) and stress are related to weight gain in individuals with severe mental illness. This cross-sectional study examines AT use, stressful life events, and baseline weight in a sample of youth at clinical high risk for psychosis. Results showed that dependent and desirable life events moderated the relationship between AT use and weight after controlling for demographic factors and selective serotonin reuptake inhibitor antidepressant (AD) use. The relation of AD and weight was explored as a secondary analysis and showed no relation between AD use and weight. Further, stress did not moderate the relationship between AD medication and weight after controlling for antipsychotic use. Results suggest that stress exposure may exacerbate the relationship between ATs and increased weight in clinical high-risk populations. Findings have implications for the development of interventions to address psychosocial factors that worsen or buffer the adverse effects of antipsychotic medication on weight.

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

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.

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

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.

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

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