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IntroductionArea-level residential instability (ARI), an index of social fragmentation, has been shown to explain the association between urbanicity and psychosis. Urban upbringing has been shown to be associated with reduced gray matter volumes (GMV)s of brain regions corresponding to the right caudal middle frontal gyrus (CMFG) and rostral anterior cingulate cortex (rACC). We hypothesize that greater ARI will be associated with reduced right CMFG and rACC GMVs.MethodsData were collected at baseline as part of the North American Prodrome Longitudinal Study Phase 2. Counties where participants resided during childhood were geographically coded using the US Census to area-level factors. ARI was defined as the percentage of residents living in a different house 5years ago. Generalized linear mixed models tested associations between ARI and GMVs.ResultsThis study included 29 healthy controls (HC)s and 64 clinical high risk for psychosis (CHR-P) individuals who were aged 12 to 24years, had remained in their baseline residential area, and had magnetic resonance imaging scans. ARI was associated with reduced right CMFG (adjusted β=-0.258; 95% CI=-0.502 to -0.015) and right rACC volumes (adjusted β=-0.318; 95% CI=-0.612 to -0.023). The interaction term (ARI-by-diagnostic group) in the prediction of both brain regions was not significant, indicating that the relationships between ARI and regional brain volumes held for both CHR-P and HCs.ConclusionsARI may adversely impact similar brain regions as urban upbringing. Further investigation into the potential mechanisms of the relationship between ARI and neurobiology, including social stress, is needed.

Background A 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. Methods Controlling 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. Results Findings 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. Conclusions This 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.

Aims Young people with attenuated psychotic symptoms (APS), brief intermittent psychosis, and/or genetic risk and functional deterioration are at high risk for developing psychotic disorders. In a prior trial, family-focused therapy for clinical high risk youth (FFT-CHR) was more effective than brief psychoeducation in reducing APS severity over 6 months. This 7-site trial will compare the efficacy of FFT-CHR to a psychoeducational and supportive intervention (enhanced care) on APS and social functioning in CHR individuals over 18 months. Methods Participants (N = 220, ages 13-25 years) with a CHR syndrome will be randomly assigned to FFT-CHR (18 1-h sessions of family psychoeducation and communication/problem-solving skills training) or enhanced care (3 1-h family psychoeducational sessions followed by 5 individual support sessions), both given over 6 months. Participants will rate their weekly progress during treatment using a mobile-enhanced online platform. Family communication will be assessed in a laboratory interactional task at baseline and post-treatment. Independent evaluators will assess APS (primary outcome) and psychosocial functioning (secondary outcome) every 6 months over 18 months. Results We hypothesize that, compared to enhanced care, FFT-CHR will be associated with greater improvements in APS and psychosocial functioning over 18 months. Secondarily, improvements in family communication over 6 months will mediate the relationship between treatment condition and primary and secondary outcomes over 18 months. The effects of FFT-CHR are predicted to be greater in individuals with higher baseline risk for psychosis conversion. Conclusions Results of the trial will inform treatment guidelines for individuals at high risk for psychosis.

Reductions in hippocampal volume (HV) have been associated with both prolonged exposure to stress and psychotic illness. This study sought to determine whether higher levels of neighborhood poverty would be associated with reduced HV among individuals at clinical high-risk for psychosis (CHR-P), and whether social engagement would moderate this association. This cross-sectional study included a sample of participants (N = 174, age-range = 12–33 years, 35.1% female) recruited for the second phase of the North American Prodrome Longitudinal Study. Generalized linear mixed models tested the association between neighborhood poverty and bilateral HV, as well as the moderating role of social engagement on this association. Higher levels of neighborhood poverty were associated with reduced left (β = −0.180, P = .016) and right HV (β = −0.185, P = .016). Social engagement significantly moderated the relation between neighborhood poverty and bilateral HV. In participants with lower levels of social engagement (n = 77), neighborhood poverty was associated with reduced left (β = −0.266, P = .006) and right HV (β = −0.316, P = .002). Among participants with higher levels of social engagement (n = 97), neighborhood poverty was not significantly associated with left (β = −0.010, P = .932) or right HV (β = 0.087, P = .473). In this study, social engagement moderated the inverse relation between neighborhood poverty and HV. These findings demonstrate the importance of including broader environmental influences and indices of social engagement when conceptualizing adversity and potential interventions for individuals at CHR-P.

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.

Background While an established clinical outcome of high importance, social functioning has been emerging as possibly having a broader significance to the evolution of psychosis and long term disability. In the current study we explored the association between social decline, conversion to psychosis, and functional outcome in individuals at clinical high risk (CHR) for psychosis. Methods 585 subjects collected in the North American Prodrome Longitudinal Study (NAPLS2) were divided into 236 Healthy Controls (HCs), and CHR subjects that developed psychosis (CHR + C, N = 79), or those that did not (Non-Converters, CHR-NC, N = 270). CHR + C subjects were further divided into those that experienced an atypical decline in social functioning prior to baseline (beyond typical impairment levels) when in min-to-late adolescence (CHR + C-SD, N = 39) or those that did not undergoing a decline (CHR + C-NSD, N = 40). Results Patterns of poor functional outcomes varied across the CHR subgroups: CHR-NC (Poor Social 36.3%, Role 42.2%) through CHR + C-NSD (Poor Social 50%, Poor Role 67.5%) to CHR + C-SD (Poor Social 76.9%, Poor Role 89.7%) functioning. The two Converter subgroups had comparable positive symptoms at baseline. At 12 months, the CHR + C-SD group stabilized, but social functioning levels remained significantly lower than the other two subgroups. Conclusions The current study demonstrates that pre-baseline social decline in mid-to-late adolescence predicts psychosis. In addition, we found that this social decline in converters is strongly associated with especially poor functional outcome and overall poorer prognosis. Role functioning, in contrast, has not shown similar predictor potential, and rather appears to be an illness indicator that worsens over time.

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.

Prevailing models of psychosis risk incorporate positive subthreshold symptoms as defining features of risk or transition to psychotic disorders. Despite this, relatively few studies have focused on characterizing longitudinal symptom features, such as prevalence, concordance and structure, which may aid in refining methods and enhancing classification and prediction efforts. The present study aimed to fill these gaps using longitudinal 24-month follow-up data from the well-characterized NAPLS-2 multi-site investigation of youth at clinical high risk (CHR) who had (n = 86) and had not (n = 268) transitioned to a threshold psychotic disorder since baseline. At baseline, among sub-delusional ideas, unusual thought content and suspicious/persecutory thinking were very common in CHR youth, and were highly concordant. Perceptual abnormalities (P4) were also common across youth regardless of symptom course and eventual transition to psychosis. Grandiose ideas were rare. Exploratory factor analysis extracted two constituent factors at multiple follow-up intervals, but there was marked instability in the structure over 24 months, and clear indicators for a single positive symptom factor. Together these findings support suggestions to combine sub-delusional symptoms into a single symptom category for classification purposes, in efforts to reduce clinical heterogeneity and ease measurement burden.

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 < 0.05). The change rates of network efficiency and network diversity were significantly correlated (P = 0.003), suggesting these changes may reflect shared underlying neural mechanisms. In addition, change rates of global efficiency and node diversity were significantly correlated with change rate of cortical thinning in the prefrontal cortex in converters (P < 0.03) and could be predicted by visuospatial memory scores at baseline (P < 0.04). These results provide preliminary evidence for longitudinal reconfiguration of resting-state brain networks during psychosis development and suggest that decreased network efficiency, reflecting an increase in path length between nodes, and increased network diversity, reflecting a decrease in the consistency of functional network organization, are implicated in the progression to full psychosis.

OBJECTIVE: The 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. METHODS: Persons 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. RESULTS: For 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 R(2) (R(2) 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. CONCLUSIONS: The 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.

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.

Reduced hippocampal volume is an established brain morphological feature of psychiatric conditions. Hippocampal volume is associated with brain connectivity in humans and nonhuman animals, and altered connectivity is associated with risk for psychiatric illness. Associations between hippocampal volume and connectivity are poorly characterized in humans, especially in phases of psychiatric illness that precede disease onset. This study examined associations between hippocampal volume and hippocampal functional connectivity during rest in 141 healthy control participants and 248 individuals at risk for psychosis. Significant inverse associations between hippocampal volume and hippocampal functional connectivity with the inferior parietal lobe (IPL) and thalamus were observed. Select associations between hippocampal functional connectivity and hippocampal volume were moderated by diagnostic group. Significant moderation results shifted from implicating the IPL to the temporal pole after we excluded participants on antipsychotic medication. Considered together, these findings imply that hippocampal functional connectivity with the temporoparietal junction, within a specialized subsystem of the default mode network, is sensitive to hippocampal volume.

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

Having a first-degree relative with a psychotic disorder increases an individual's risk for developing psychosis to 10% compared to 1% in the general population. The impact of being at family high-risk for psychosis (FHR) has been examined in samples of youth who are at clinical high-risk for psychosis (CHR). The second North American Prodrome Longitudinal Study (NAPLS-2) identified very few clinical differences between CHR individuals with and without FHR. This paper aims to confirm these results in a new CHR sample, NAPLS-3. The NAPLS-3 sample consisted of 703 CHR participants, of whom 82 were at FHR (CHR+FHR), and 621 were not (CHR+FHRneg). The Family Interview for Genetic Studies was used to determine the presence of a first-degree relative with a psychotic disorder. The groups were compared on social and role functioning, positive and negative symptoms, IQ, cannabis use, and trauma. At baseline, the CHR+FHR group reported a statistically significant increased severity of positive and negative symptoms, lower IQ scores, and increased reports of trauma, psychological and physical abuse. There were no differences in transition rates between the two groups. This study supports some of the already reported differences in trauma, physical and psychological abuse between CHR individuals with and without FHR.

Individuals at clinical high risk (CHR) for psychosis have been shown to experience more trauma than the general population. However, although the effects of trauma appear to impact some symptoms it does not seem to increase the risk of transition to psychosis. The aim of this article was to examine the prevalence of trauma, and its association with longitudinal clinical and functional outcomes in a large sample of CHR individuals.From the North American Prodrome Longitudinal Study-3 (NAPLS-3) 690 CHR individuals and 91 healthy controls from nine study sites between 2015 and 2018 were assessed. Historical trauma experiences were captured at baseline. Participants completed longitudinal assessments measuring clinical outcomes including positive and negative symptoms, depression, social and role functioning and assessing transition to psychosis.From the 690 CHR participants and 96 healthy controls, 343 (49.6%) and 15 (15.6%), respectively, reported a history of trauma (p .001). Emotional neglect (70.3%) was the most commonly reported type of trauma, followed by psychological abuse (57.4%). Among CHR participants, time to transition to psychosis was not associated with trauma. Baseline depression and suspiciousness/persecutory ideas were statistically significantly different between CHR individuals who did or did not experience trauma. However, when examining clinical and functional outcomes over 12-months of follow-up, there were no differences between those who experienced trauma and those who did not.Overall, trauma is a significantly prevalent among CHR individuals. The effects of trauma on transition and longitudinal clinical and functional outcomes were not significant.

Cannabis use is more prevalent among youth at clinical high-risk (CHR) for psychosis than healthy controls (HC). There is mixed evidence as to whether cannabis use is associated with increased severity of attenuated psychotic symptoms (APS) or whether current cannabis use is associated with the transition to psychosis. This study aims to assess cannabis use differences between CHR youth and HC and the impact of cannabis use on APS, clinical status, and transition to psychosis. Participants were from the North American Prodrome Longitudinal Study-3, a prospective longitudinal study including 710 individuals, age 12-30, meeting criteria for a psychosis risk syndrome based on the Structured Interview for Psychosis-Risk Syndromes, and 96 HC. Cannabis use, frequency, and severity of use were assessed with the Alcohol Use Scale/Drug Use Scale. Current and past cannabis use disorders were assessed with the Structured Clinical Interview for DSM-5. Compared to HC, CHR individuals reported significantly increased lifetime cannabis use, during the past six months, and at baseline; greater frequency and severity of cannabis use; and increased prevalence of cannabis use disorder. Relative to CHR youth without cannabis use, CHR cannabis users had significantly higher ratings on baseline grandiosity and lower 12-months social anhedonia. Severity of cannabis was unrelated to clinical status at 2-years, and it did not differentiate CHR individuals who transitioned to psychosis from those who did not. However, a major limitation was that the current number of CHR cannabis users was small, and survival analyses resulted in a smaller power than the 80 % recommended.

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.

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.

Bullying is associated with a heightened risk for poor outcomes, including psychosis. This study aimed to replicate previous findings on bullying prevalence in clinical high-risk (CHR) individuals, to assess the longitudinal course of clinical and functional variables between bullied and non-bullied CHR and the association of bullying with premorbid functioning, clinical outcome, transition to psychosis and risk of violence.The sample consisted of 691 CHR participants and 96 healthy controls. Participants reported whether they had experienced bullying and how long it had lasted. Assessments included DSM-5 diagnoses, attenuated psychotic symptoms, negative symptoms, social and role functioning, depression, stress, premorbid functioning, and risk of violence. The bullied and non-bullied CHR groups were compared at baseline and further longitudinally on clinical and functioning variables and transition to psychosis.Bullying was more prevalent among CHR individuals than healthy controls. Bullied CHR had a higher prevalence of PTSD and more severe depression and stress at baseline than non-bullied CHR. There was no impact of bullying on clinical and functional variables over time. Bullying was not related to final clinical status or transition to psychosis. However, bullied participants had poorer premorbid functioning and a greater risk of violence.While bullying may not impact the likelihood of CHR individuals to transition to psychosis, it may be a risk factor for development of the at-risk state and may be related to a greater risk of violence. Future studies should consider bullying perpetration among CHR individuals.

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 2years. 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 2years.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.

Background Transition to psychosis is among the most adverse outcomes of clinical high-risk (CHR) syndromes encompassing ultra-high risk (UHR) and basic symptom states. Clinical risk calculators may facilitate an early and individualized interception of psychosis, but their real-world implementation requires thorough validation across diverse risk populations, including young patients with depressive syndromes. Methods We validated the previously described NAPLS-2 (North American Prodrome Longitudinal Study 2) calculator in 334 patients (26 with transition to psychosis) with CHR or recent-onset depression (ROD) drawn from the multisite European PRONIA (Personalised Prognostic Tools for Early Psychosis Management) study. Patients were categorized into three risk enrichment levels, ranging from UHR, over CHR, to a broad-risk population comprising patients with CHR or ROD (CHR|ROD). We assessed how risk enrichment and different predictive algorithms influenced prognostic performance using reciprocal external validation. Results After calibration, the NAPLS-2 model predicted psychosis with a balanced accuracy (BAC) (sensitivity, specificity) of 68% (73%, 63%) in the PRONIA-UHR cohort, 67% (74%, 60%) in the CHR cohort, and 70% (73%, 66%) in patients with CHR|ROD. Multiple model derivation in PRONIA–CHR|ROD and validation in NAPLS-2–UHR patients confirmed that broader risk definitions produced more accurate risk calculators (CHR|ROD-based vs. UHR-based performance: 67% [68%, 66%] vs. 58% [61%, 56%]). Support vector machines were superior in CHR|ROD (BAC = 71%), while ridge logistic regression and support vector machines performed similarly in CHR (BAC = 67%) and UHR cohorts (BAC = 65%). Attenuated psychotic symptoms predicted psychosis across risk levels, while younger age and reduced processing speed became increasingly relevant for broader risk cohorts. Conclusions Clinical-neurocognitive machine learning models operating in young patients with affective and CHR syndromes facilitate a more precise and generalizable prediction of psychosis. Future studies should investigate their therapeutic utility in large-scale clinical trials.

Purpose: Migrant status is one of the most replicated and robust risk factors for developing a psychotic disorder. This study aimed to determine whether migrant status in people identified as Ultra-High Risk for Psychosis (UHR) was associated with risk of transitioning to a full-threshold psychotic disorder.Methods: Hazard ratios for the risk of transition were calculated from five large UHR cohorts (n = 2166) and were used to conduct a meta-analysis using the generic inverse-variance method using a random-effects model.Results: 2166 UHR young people, with a mean age of 19.1 years (SD ± 4.5) were included, of whom 221 (10.7%) were first-generation migrants. A total of 357 young people transitioned to psychosis over a median follow-up time of 417 days (I.Q.R.147–756 days), representing 17.0% of the cohort. The risk of transition to a full-threshold disorder was not increased for first-generation migrants, (HR = 1.08, 95% CI 0.62–1.89); however, there was a high level of heterogeneity between studies The hazard ratio for second-generation migrants to transition to a full-threshold psychotic disorder compared to the remainder of the native-born population was 1.03 (95% CI 0.70–1.51).Conclusions: This meta-analysis did not find a statistically significant association between migrant status and an increased risk for transition to a full-threshold psychotic disorder; however, several methodological issues could explain this finding. Further research should focus on examining the risk of specific migrant groups and also ensuring that migrant populations are adequately represented within UHR clinics.

Childhood adversity is among the strongest risk factors for psychosis-spectrum disorders, though the nature and specificity of the biological mechanisms underlying this association remains unclear. Previous research reveals overlaps in the volumetric alterations observed in both adversity-exposed individuals and in psychosis-spectrum populations, highlighting the possibility that deviations in corticolimbic gray matter development may be one mechanism linking adversity and psychosis. Given that childhood adversity encompasses a wide range of adverse experiences, there is also a critical need to examine whether these different types of experiences have unique effects on corticolimbic regions. This study examined the association between childhood adversity and cortical, hippocampal, and amygdalar volume in a large sample of youth at clinical-high risk (CHR) for psychosis. We utilized a novel differentiated adversity approach that distinguishes exposures along dimensions of threat (e.g., abuse) and deprivation (e.g., poverty, neglect) to test for differential associations. Participants were drawn from the North American Prodromal Longitudinal Study (NAPLS) and completed an MRI scan and a retrospective assessment of childhood adversity at baseline. We found that deprivation exposure, but not threat, was uniquely associated with smaller cortical volume and smaller right hippocampal volume in CHR youth. These associations were masked in a generalized risk model that utilized a total adversity score. The findings suggest that deprivation exposures during childhood contribute to the subtle volumetric reductions observed in clinical high-risk samples and highlight the importance of disentangling different dimensions of adversity.

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.

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.

BACKGROUND Individuals at clinical high-risk (CHR) for psychosis experience high rates of bullying. There is little research on the differences between CHR who did and did not experience bullying. However, there is evidence that bullying may be related to negative schemas and social impairment. OBJECTIVES To examine differences in core schemas, asocial and defeatist beliefs, and social functioning between those who did and did not report bullying experiences in a large sample of CHR individuals. We hypothesized that bullying in CHR youth would be associated with poorer social functioning, increased maladaptive beliefs, and negative core schemas. METHODS CHR participants (N = 203) were split into those who did and did not report experiencing bullying. The two groups were compared on demographic characteristics, social functioning, and belief variables, using the Brief Core Schemas Scale, the Asocial Beliefs Scale, the Defeatist Performance Attitudes Scale, and the First Episode Social Functioning Scale. RESULTS 72.9% reported experiencing bullying. These participants had greater severity of negative schemas about others and asocial and defeatist performance beliefs, and lower social functioning scores. CONCLUSIONS Prevalence of bullying among CHR participants is high. Bullying may be a risk factor for increased asocial and defeatist beliefs, negative core schemas, and poor social functioning. Targeting maladaptive schemas and beliefs during treatment may serve to improve functional outcomes in this group.

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.

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.

Introduction Research examining the role of inflammation in psychosis has produced inconsistent results. Variables that influence inflammation, including antipsychotic medication, are inconsistently controlled across studies and variation of inflammatory analytes across stages of psychosis may also influence findings. The purpose of this study was to assess for evidence of immuno-inflammatory dysregulation across the stages of early psychosis. We examined a immuno-inflammatory analytes in subjects at clinical high risk (CHR) for developing a psychotic disorder, antipsychotic-naive (-n) and antipsychotic treated (-a) subjects in their first episode of psychosis (FEP), and healthy control (HC) subjects. Methods A total of 11 subjects at CHR, 50 subjects within their FEP (40 FEP-n, 10 FEP-a), and 10 HC subjects were recruited from early psychosis programs in San Diego and Mexico City. Plasma was collected for biomarker assay. Results Immuno-inflammatory analytes significantly differed between groups: Interferon-gamma (IFN-γ), Interleukin-10 (IL-10), Eotaxin-1, Interferon Gamma-Induced Protein-10 (IP-10), Monocyte Chemotactic Protein-1 (MCP-1), Macrophage-Derived Chemokine (MDC), Macrophage Inflammatory Protein-1 beta (MIP-1β), Thymus and Activation Regulated Chemokine (TARC), and Brain Derived Neurotropic Factor (BDNF). Post-hoc analyses revealed an overall pattern of higher levels of IL-10, MCP-1, MIP-1β, TARC, and BDNF in CHR as compared to FEP-a, FEP-n, and HC subjects. Conclusions Results reveal a profile of immuno-inflammatory dysregulation in early stages of psychosis prior to psychotic conversion and treatment with antipsychotic medication. The CHR phase of early psychosis may represent a period of increased immuno-inflammatory activation, but due to limited sample size, these results deserve replication in a well characterized early psychosis population.

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

Efforts to prevent or lessen the functional impact of psychosis can be informed by a better understanding of the neurobiological underpinnings at the earliest stages of the disorder. Understanding these processes early in the psychosis spectrum will in turn allow more targeted efforts to prevent or minimize functional limitations among patients with psychosis. Advances in technology have enabled the study of a host of biomarkers implicated in the neurobiology of psychosis offering unique avenues to investigate mechanisms of disease while at the same time shedding some light on more patient-tailored treatments and setting the foundation for personalized medicine in psychosis. Insights into the neurobiology of psychosis are reviewed, including findings from neuroimaging, neurocognitive, and electrophysiologic studies and findings related to the role of hypothalamic-pituitary axis activity and neuroinflammation in the emergence of psychosis. Biomarker-informed treatments are discussed, and potential promising biomarkers and related treatments are proposed. This review contains 5 figures, 13 tables, and 85 references. Key words: attenuated risk syndrome, biomarkers, prodrome, psychosis, schizophrenia, treatment