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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.

IntroductionDisturbed 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.MethodsData 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.ResultsDisturbed 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.DiscussionThe 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.

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

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.

BackgroundTwin and multiplex family studies have established significant heritability for schizophrenia (SZ), often summarized as 81%. The Consortium on the Genetics of Schizophrenia (COGS-1) family study was designed to deconstruct the genetic architecture of SZ using neurocognitive and neurophysiological endophenotypes, for which heritability estimates ranged from 18% to 50% (mean = 30%). This study assessed the heritability of SZ in these families to determine whether there is a "heritability gap" between the diagnosis and related endophenotypes.MethodsNuclear families (N = 296) with a SZ proband, an unaffected sibling, and both parents (n = 1366 subjects; mean family size = 4.6) underwent comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives of interviewed subjects (N = 3304 subjects; mean family size = 11.2). Heritability estimates of psychotic disorders were computed for both nuclear and extended families.ResultsThe heritability of SZ was 31% and 44% for nuclear and extended families. The inclusion of bipolar disorder increased the heritability to 37% for the nuclear families. When major depression was added, heritability estimates dropped to 34% and 20% for nuclear and extended families, respectively.ConclusionsEndophenotypes and psychotic disorders exhibit comparable levels of heritability in the COGS-1 family sample. The ascertainment of families with discordant sibpairs to increase endophenotypic contrast may underestimate diagnostic heritability relative to other studies. However, population-based studies also report significantly lower heritability estimates for SZ. Collectively, these findings support the importance of endophenotype-based strategies and the dimensional view of psychosis.

Background The clinical high-risk (CHR) period offers a temporal window into neurobiological deviations preceding psychosis onset, but little attention has been given to regions outside the cerebrum in large-scale studies of CHR. Recently, the North American Prodrome Longitudinal Study (NAPLS)-2 revealed altered functional connectivity of the cerebello-thalamo-cortical circuitry among individuals at CHR; however, cerebellar morphology remains underinvestigated in this at-risk population, despite growing evidence of its involvement in psychosis. Study Design In this multisite study, we analyzed T1-weighted magnetic resonance imaging scans obtained from N = 469 CHR individuals (61% male, ages = 12–36 years) and N = 212 healthy controls (52% male, ages = 12–34 years) from NAPLS-2, with a focus on cerebellar cortex and white matter volumes separately. Symptoms were rated by the Structured Interview for Psychosis-Risk Syndromes (SIPS). The outcome by two-year follow-up was categorized as in-remission, symptomatic, prodromal-progression, or psychotic. General linear models were used for case-control comparisons and tests for volumetric associations with baseline SIPS ratings and clinical outcomes. Study Results Cerebellar cortex and white matter volumes differed between the CHR and healthy control groups at baseline, with sex moderating the difference in cortical volumes, and both sex and age moderating the difference in white matter volumes. Baseline ratings for major psychosis-risk dimensions as well as a clinical outcome at follow-up had tissue-specific associations with cerebellar volumes. Conclusions These findings point to clinically relevant deviations in cerebellar cortex and white matter structures among CHR individuals and highlight the importance of considering the complex interplay between sex and age when studying the neuromaturational substrates of psychosis risk. [ABSTRACT FROM AUTHOR]

Objective To assess cortical thickness (CT) and surface area (SA) of frontal, temporal, and parietal brain regions in a large clinical high risk for psychosis (CHR) sample, and to identify cortical brain abnormalities in CHR who convert to psychosis and in the whole CHR sample, compared with the healthy controls (HC). Methods Magnetic resonance imaging, clinical, and cognitive data were acquired at baseline in 92 HC, 130 non-converters, and 22 converters (conversion assessed at 1-year follow-up). CT and SA at baseline were calculated for frontal, temporal, and parietal subregions. Correlations between regions showing group differences and clinical scores and age were also obtained. Results CT but not SA was significantly reduced in CHR compared with HC. Two patterns of findings emerged: (1) In converters, CT was significantly reduced relative to non-converters and controls in the banks of superior temporal sulcus, Heschl's gyrus, and pars triangularis and (2) CT in the inferior parietal and supramarginal gyrus, and at trend level in the pars opercularis, fusiform, and middle temporal gyri was significantly reduced in all high-risk individuals compared with HC. Additionally, reduced CT correlated significantly with older age in HC and in non-converters but not in converters. Conclusions These results show for the first time that fronto-temporo-parietal abnormalities characterized all CHR, that is, both converters and non-converters, relative to HC, while CT abnormalities in converters relative to CHR-NC and HC were found in core auditory and language processing regions. [ABSTRACT FROM AUTHOR]

Objective: To assess cortical thickness (CT) and surface area (SA) of frontal, temporal, and parietal brain regions in a large clinical high risk for psychosis (CHR) sample, and to identify cortical brain abnormalities in CHR who convert to psychosis and in the whole CHR sample, compared with the healthy controls (HC)., Methods: Magnetic resonance imaging, clinical, and cognitive data were acquired at baseline in 92 HC, 130 non-converters, and 22 converters (conversion assessed at 1-year follow-up). CT and SA at baseline were calculated for frontal, temporal, and parietal subregions. Correlations between regions showing group differences and clinical scores and age were also obtained., Results: CT but not SA was significantly reduced in CHR compared with HC. Two patterns of findings emerged: (1) In converters, CT was significantly reduced relative to non-converters and controls in the banks of superior temporal sulcus, Heschl's gyrus, and pars triangularis and (2) CT in the inferior parietal and supramarginal gyrus, and at trend level in the pars opercularis, fusiform, and middle temporal gyri was significantly reduced in all high-risk individuals compared with HC. Additionally, reduced CT correlated significantly with older age in HC and in non-converters but not in converters., Conclusions: These results show for the first time that fronto-temporo-parietal abnormalities characterized all CHR, that is, both converters and non-converters, relative to HC, while CT abnormalities in converters relative to CHR-NC and HC were found in core auditory and language processing regions., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)