Longitudinal Trajectories of Premorbid Social and Academic Adjustment in Youth at Clinical High Risk for Psychosis: Implications for Conversion.

BACKGROUND AND HYPOTHESIS: Social and academic adjustment deteriorate in the years preceding a psychotic disorder diagnosis. Analyses of premorbid adjustment have recently been extended into the clinical high risk for psychosis (CHR) syndrome to identify risk factors and developmental pathways toward psychotic disorders. Work so far has been at the between-person level, which has constrained analyses of premorbid adjustment, clinical covariates, and conversion to psychosis. STUDY DESIGN: Growth-curve models examined longitudinal trajectories in retrospective reports of premorbid social and academic adjustment from youth at CHR (n = 498). Interaction models tested whether known covariates of premorbid adjustment problems (attenuated negative symptoms, cognition, and childhood trauma) were associated with different premorbid adjustment trajectories in converters vs non-converters (ie, participants who did/did not develop psychotic disorders within 2-year follow-up). STUDY RESULTS: Converters reported poorer social adjustment throughout the premorbid period. Converters who developed psychosis with an affective component reported poorer academic adjustment throughout the premorbid period than those who developed non-affective psychosis. Tentatively, baseline attenuated negative symptoms may have been associated with worsening social adjustment in the premorbid period for non-converters only. Childhood trauma impact was associated with fewer academic functioning problems among converters. Cognition effects did not differ based on conversion status. CONCLUSIONS: Premorbid social function is an important factor in risk for conversion to psychosis. Negative symptoms and childhood trauma had different relationships to premorbid functioning in converters vs non-converters. Mechanisms linking symptoms and trauma to functional impairment may be different in converters vs non-converters, suggesting possible new avenues for risk assessment.

A polygenic resilience score moderates the genetic risk for schizophrenia: Replication in 18,090 cases and 28,114 controls from the Psychiatric Genomics Consortium.

Identifying heritable factors that moderate the genetic risk for schizophrenia (SCZ) could help clarify why some individuals remain unaffected despite having relatively high genetic liability. Previously, we developed a framework to mine genome-wide association (GWAS) data for common genetic variants that protect high-risk unaffected individuals from SCZ, leading to derivation of the first-ever "polygenic resilience score" for SCZ (resilient controls n = 3786; polygenic risk score-matched SCZ cases n = 18,619). Here, we performed a replication study to verify the moderating effect of our polygenic resilience score on SCZ risk (OR = 1.09, p = 4.03 × 10-5 ) using newly released GWAS data from 23 independent case-control studies collated by the Psychiatric Genomics Consortium (PGC) (resilient controls n = 2821; polygenic risk score-matched SCZ cases n = 5150). Additionally, we sought to optimize our polygenic resilience-scoring formula to improve subsequent modeling of resilience to SCZ and other complex disorders. We found significant replication of the polygenic resilience score, and found that strict pruning of SNPs based on linkage disequilibrium to known risk SNPs and their linked loci optimizes the performance of the polygenic resilience score.

Relations of Lifetime Perceived Stress and Basal Cortisol With Hippocampal Volume Among Healthy Adolescents and Those at Clinical High Risk for Psychosis: A Structural Equation Modeling Approach.

BACKGROUND: Hippocampal volume (HV) is sensitive to environmental influences. Under normative conditions in humans, HV increases linearly into childhood and asymptotes in early adulthood. Studies of humans and nonhuman animals have provided evidence of inverse relationships between several measures of stress and HV. METHODS: Using structural equation modeling, this study aimed to characterize the relationships of age, basal cortisol, biological sex, and lifetime perceived stress with bilateral HV in a sample of healthy adolescents and adolescents at clinical high risk for psychosis (CHR-P) (N = 571, 43% female; age range = 12-19.9 years). This sample included 469 individuals at CHR-P and 102 healthy comparison participants from the combined baseline cohorts of the second and third NAPLS (North American Prodrome Longitudinal Study). RESULTS: A structural model that constrained the individual effects of basal cortisol and perceived stress to single path coefficients, and freely estimated the effects of age and biological sex in group models, optimized model fit and parsimony relative to other candidate models. Significant inverse relationships between basal cortisol and bilateral HV were observed in adolescents at CHR-P and healthy comparison participants. Significant sex differences in bilateral HV were also observed, with females demonstrating smaller HV than males in both groups. CONCLUSIONS: Multigroup structural equation modeling revealed heterogeneity in the relationships of age and biological sex with basal cortisol, lifetime perceived stress, and bilateral HV in individuals at CHR-P and healthy comparison participants. Moreover, the findings support previous literature indicating that elevated basal cortisol is a nonspecific risk factor for reduced HV.

Hippocampal Connectivity with the Default Mode Network is Linked to Hippocampal Volume in the Clinical High Risk for Psychosis Syndrome and Healthy Individuals.

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

Associations between childhood ethnoracial minority density, cortical thickness, and social engagement among minority youth at clinical high-risk for psychosis.

An ethnoracial minority density (EMD) effect in studies of psychotic spectrum disorders has been observed, whereby the risk of psychosis in ethnoracial minority group individuals is inversely related to the proportion of minorities in their area of residence. The authors investigated the relationships among area-level EMD during childhood, cortical thickness (CT), and social engagement (SE) in clinical high risk for psychosis (CHR-P) youth. Data were collected as part of the North American Prodrome Longitudinal Study. Participants included 244 ethnoracial minoritized (predominantly Hispanic, Asian and Black) CHR-P youth and ethnoracial minoritized healthy controls. Among youth at CHR-P (n = 164), lower levels of EMD during childhood were associated with reduced CT in the right fusiform gyrus (adjusted ß = 0.54; 95% CI 0.17 to 0.91) and right insula (adjusted ß = 0.40; 95% CI 0.05 to 0.74). The associations between EMD and CT were significantly moderated by SE: among youth with lower SE (SE at or below the median, n = 122), lower levels of EMD were significantly associated with reduced right fusiform gyrus CT (adjusted ß = 0.72; 95% CI 0.29 to 1.14) and reduced right insula CT (adjusted ß = 0.57; 95% CI 0.18 to 0.97). However, among those with greater SE (n = 42), the associations between EMD and right insula and fusiform gyrus CT were not significant. We found evidence that lower levels of ethnic density during childhood were associated with reduced cortical thickness in regional brain regions, but this association may be buffered by greater levels of social engagement.

The impact of early factors on persistent negative symptoms in youth at clinical high risk for psychosis.

Introduction: Persistent negative symptoms (PNS) are described as continuing moderate negative symptoms. More severe negative symptoms have been associated with poor premorbid functioning in both chronic schizophrenia and first episode psychosis patients. Furthermore, youth at clinical high risk (CHR) for developing psychosis may also present with negative symptoms and poor premorbid functioning. The aim of this current study was to: (1) define the relationship between PNS and premorbid functioning, life events, trauma and bullying, previous cannabis use, and resource utilization, and (2) to examine what explanatory variables best predicted PNS. Method: CHR participants (N = 709) were recruited from the North American Prodrome Longitudinal Study (NAPLS 2). Participants were divided into two groups: those with PNS (n = 67) versus those without PNS (n = 673). A K-means cluster analysis was conducted to distinguish patterns of premorbid functioning across the different developmental stages. The relationships between premorbid adjustment and other variables were examined using independent samples t-tests or chi square for categorical variables. Results: There was significantly more males in the PNS group. Participants with PNS had significantly lower levels of premorbid adjustment in childhood, early adolescence, and late adolescence, compared to CHR participants without PNS. There were no differences between the groups in terms of trauma, bullying, and resource utilization. The non-PNS group had more cannabis use and more desirable and non-desirable life events. Conclusion: In terms of better understanding relationships between early factors and PNS, a prominent factor associated with PNS was premorbid functioning, in particular poor premorbid functioning in later adolescence.

Negative Symptom Trajectories in Individuals at Clinical High Risk for Psychosis: Differences Based on Deficit Syndrome, Persistence, and Transition Status.

Background and Hypothesis: Negative 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 Design: Linear, 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 Results: Negative 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. Conclusions: Continuous, 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.

Associations Between Childhood Area-Level Social Fragmentation, Maladaptation to School, and Social Functioning Among Healthy Youth and Those at Clinical High Risk for Psychosis.

BACKGROUND AND HYPOTHESIS: Although studies have identified social fragmentation as an important risk factor for schizophrenia and other psychotic disorders, it is unknown whether it may impact social functioning. This study investigates whether social fragmentation during childhood predicts maladaptation to school as well as social functioning during childhood and adulthood. STUDY DESIGN: Data were collected from the North American Prodrome Longitudinal Study. Participants included adults at clinical high risk for psychosis (CHR-P) and healthy comparisons (HC). Maladaptation to school and social functioning during childhood were assessed retrospectively and social functioning in adulthood was assessed at baseline. STUDY RESULTS: Greater social fragmentation during childhood was associated with greater maladaptation to school (adjusted ß = 0.21; 95% CI: 0.02 to 0.40). Social fragmentation was not associated with social functioning during childhood (unadjusted ß = -0.08; 95% CI: -0.31 to 0.15). However, greater social fragmentation during childhood predicted poorer social functioning in adulthood (adjusted ß = -0.43; 95% CI: -0.79 to -0.07). Maladaptation to school mediated 15.7% of the association between social fragmentation and social functioning. The association between social fragmentation and social functioning was stronger among adults at CHR-P compared to HC (adjusted ß = -0.42; 95% CI: -0.82 to -0.02). CONCLUSIONS: This study finds that social fragmentation during childhood is associated with greater maladaptation to school during childhood, which in turn predicts poorer social functioning in adulthood. Further research is needed to disentangle aspects of social fragmentation that may contribute to social deficits, which would have implications for the development of effective interventions at the individual and community levels.

Neurobehavioral risk factors influence prevalence and severity of hazardous substance use in youth at genetic and clinical high risk for psychosis.

Background: Elevated rates of alcohol, tobacco, and cannabis use are observed in both patients with psychotic disorders and individuals at clinical high risk for psychosis (CHR-P), and strong genetic associations exist between substance use disorders and schizophrenia. While individuals with 22q11.2 deletion syndrome (22qDel) are at increased genetic risk for psychosis, initial evidence suggests that they have strikingly low rates of substance use. In the current study, we aimed to directly compare substance use patterns and their neurobehavioral correlates in genetic and clinical high-risk cohorts. Methods: Data on substance use frequency and severity, clinical symptoms, and neurobehavioral measures were collected at baseline and at 12-month follow-up visits in two prospective longitudinal cohorts: participants included 89 22qDel carriers and 65 age and sex-matched typically developing (TD) controls (40.67% male, Mage = 19.26 ± 7.84 years) and 1,288 CHR-P youth and 371 matched TD controls from the North American Prodrome Longitudinal Study-2 and 3 (55.74% male; Mage = 18.71 ± 4.27 years). Data were analyzed both cross-sectionally and longitudinally using linear mixed effects models. Results: Controlling for age, sex, and site, CHR-P individuals had significantly elevated rates of tobacco, alcohol, and cannabis use relative to TD controls, whereas 22qDel had significantly lower rates. Increased substance use in CHR-P individuals was associated with increased psychosis symptom severity, dysphoric mood, social functioning, and IQ, while higher social anhedonia was associated with lower substance use across all domains at baseline. These patterns persisted when we investigated these relationships longitudinally over one-year. CHR-P youth exhibited significantly increased positive psychosis symptoms, dysphoric mood, social functioning, social anhedonia, and IQ compared to 22qDel carriers, and lower rates of autism spectrum disorder (ASD) compared to 22qDel carriers, both at baseline and at 1 year follow-up. Conclusion: Individuals at genetic and CHR-P have strikingly different patterns of substance use. Factors such as increased neurodevelopmental symptoms (lower IQ, higher rates of ASD) and poorer social functioning in 22qDel may help explain this distinction from substance use patterns observed in CHR-P individuals.

Sampling from different populations: Sociodemographic, clinical, and functional differences between samples of first episode psychosis individuals and clinical high-risk individuals who progressed to psychosis.

Over the past two decades, research and clinical resources on clinical high risk (CHR) for psychosis have both expanded, with goals to better understanding risk and protective factors on the course of illness and inform early intervention efforts. However, some studies have highlighted potential sampling bias among CHR research studies, raising questions about generalizability of findings and inequitable access to early detection and intervention. The current study sought to explore these questions by comparing 94 participants in a CHR longitudinal monitoring study across North America (NAPLS-2) who converted to syndromal psychosis over the course of the study (CHR-CV) to 171 participants who presented for treatment at a localized first-episode psychosis service (FES) after converting. CHR-CV participants were significantly more likely to be White and have a college-educated parent, while FES participants were more likely to be Black and first- or second-generation immigrants. On average, CHR-CV participants were younger at onset of attenuated positive symptoms, had a longer period of attenuated symptoms prior to conversion, and were more likely to be treated with antipsychotics prior to conversion compared to those in FES programs. After controlling for time since conversion, CHR-CV participants had higher global functioning and were less likely to have experienced recent psychiatric hospitalization. Findings suggest that CHR research and FES clinics may be sampling from different populations, although conclusions are limited by inconsistent sampling frames and methods. Integrated early detection that targets defined geographic catchments may deliver more epidemiologically representative samples to both CHR research and FES.

Ethnoracial discrimination and the development of suspiciousness symptoms in individuals at clinical high-risk for psychosis.

BACKGROUND AND HYPOTHESIS: While individuals at clinical high-risk (CHR) for psychosis experience higher levels of discrimination than healthy controls, it is unclear how these experiences contribute to the etiology of attenuated positive symptoms. The present study examined the association of perceived discrimination with positive symptoms in a cohort from the North American Prodrome Longitudinal Study (NAPLS2). It predicted that CHR individuals will report higher levels of lifetime and past year perceived discrimination related to their race and ethnicity (ethnoracial discrimination) and that this form of discrimination will be significantly associated with baseline positive symptoms. STUDY DESIGN: Participants included 686 CHR and 252 healthy controls. The present study examined data from the perceived discrimination (PD) scale, the Brief Core Schema Scale, and the Scale for the Psychosis-Risk Symptoms. Structural equation modeling was employed to examine whether negative schema of self and others mediated the relation of past year ethnoracial PD to baseline suspiciousness symptoms. RESULTS: CHR individuals report higher levels of past year and lifetime PD compared to healthy controls. Lifetime ethnoracial PD was associated with suspiciousness and total positive symptoms. Negative schema of self and others scores partially mediated the relation of past year ethnoracial PD to suspiciousness, one of five positive symptom criteria for CHR. CONCLUSIONS: For CHR individuals, past year ethnoracial discrimination was associated with negative beliefs about themselves and others, which was associated with suspiciousness. These findings contribute to an emerging literature characterizing the mechanisms by which discrimination contributes to the positive symptoms characterizing the CHR syndrome.

BrainGENIE: The Brain Gene Expression and Network Imputation Engine.

In vivo experimental analysis of human brain tissue poses substantial challenges and ethical concerns. To address this problem, we developed a computational method called the Brain Gene Expression and Network-Imputation Engine (BrainGENIE) that leverages peripheral-blood transcriptomes to predict brain tissue-specific gene-expression levels. Paired blood-brain transcriptomic data collected by the Genotype-Tissue Expression (GTEx) Project was used to train BrainGENIE models to predict gene-expression levels in ten distinct brain regions using whole-blood gene-expression profiles. The performance of BrainGENIE was compared to PrediXcan, a popular method for imputing gene expression levels from genotypes. BrainGENIE significantly predicted brain tissue-specific expression levels for 2947-11,816 genes (false-discovery rate-adjusted p < 0.05), including many transcripts that cannot be predicted significantly by a transcriptome-imputation method such as PrediXcan. BrainGENIE recapitulated measured diagnosis-related gene-expression changes in the brain for autism, bipolar disorder, and schizophrenia better than direct correlations from blood and predictions from PrediXcan. We developed a convenient software toolset for deploying BrainGENIE, and provide recommendations for how best to implement models. BrainGENIE complements and, in some ways, outperforms existing transcriptome-imputation tools, providing biologically meaningful predictions and opening new research avenues.

Risk of violent behaviour in young people at clinical high risk for psychosis from the North American Prodrome Longitudinal Studies consortium.

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

Accelerated cortical thinning precedes and predicts conversion to psychosis: The NAPLS3 longitudinal study of youth at clinical high-risk.

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.

Migrant status, clinical symptoms and functional outcome in youth at clinical high risk for psychosis: findings from the NAPLS-3 study.

PURPOSE: Migrant status is a known risk factor for psychosis, but the underlying causes of this vulnerability are poorly understood. Recently, studies have begun to explore whether migrant status predicts transition to psychosis in individuals at clinical high risk (CHR) for psychosis. Results, however, have been inconclusive. The present study assessed the impact of migrant status on clinical symptoms and functional outcome in individuals at CHR for psychosis who took part in the NAPLS-3 study. METHODS: Participants' migrant status was classified as native-born, first-generation, or second-generation migrant. Clinical symptoms were assessed using the Structured Interview for Psychosis-Risk Syndromes (SIPS); functional outcome was measured using the Global Functioning Scales:Social and Role (GF:S; GF:R). Assessments were conducted at baseline, 12-months, 18-months, and 24-months follow-up. Generalized linear mixed models for repeated measures were used to examine changes over time and differences between groups. RESULTS: The overall sample included 710 individuals at CHR for psychosis (54.2% males; Age: M = 18.19; SD = 4.04). A mixed model analysis was conducted, and no significant differences between groups in symptoms or functioning were observed at any time point. Over time, significant improvement in symptoms and functioning was observed within each group. Transition rates did not differ across groups. CONCLUSION: We discuss potential factors that might explain the lack of group differences. Overall, migrants are a heterogeneous population. Discerning the impact of migration from that of neighborhood ethnic density, social disadvantage or socio-economic status of different ethnic groups could help better understand vulnerability and resilience to psychosis.

Sex- and Age-Specific Deviations in Cerebellar Structure and Their Link With Symptom Dimensions and Clinical Outcome in Individuals at Clinical High Risk for 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.

Characterizing sustained social anxiety in individuals at clinical high risk for psychosis: trajectory, risk factors, and functional outcomes.

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.

Cannabis use and attenuated positive and negative symptoms in youth at clinical high risk for psychosis.

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.

Polygenic resilience scores capture protective genetic effects for Alzheimer's disease.

Polygenic risk scores (PRSs) can boost risk prediction in late-onset Alzheimer's disease (LOAD) beyond apolipoprotein E (APOE) but have not been leveraged to identify genetic resilience factors. Here, we sought to identify resilience-conferring common genetic variants in (1) unaffected individuals having high PRSs for LOAD, and (2) unaffected APOE-ε4 carriers also having high PRSs for LOAD. We used genome-wide association study (GWAS) to contrast "resilient" unaffected individuals at the highest genetic risk for LOAD with LOAD cases at comparable risk. From GWAS results, we constructed polygenic resilience scores to aggregate the addictive contributions of risk-orthogonal common variants that promote resilience to LOAD. Replication of resilience scores was undertaken in eight independent studies. We successfully replicated two polygenic resilience scores that reduce genetic risk penetrance for LOAD. We also showed that polygenic resilience scores positively correlate with polygenic risk scores in unaffected individuals, perhaps aiding in staving off disease. Our findings align with the hypothesis that a combination of risk-independent common variants mediates resilience to LOAD by moderating genetic disease risk.