Markers of Psychosis Risk in the General Population

Journal Pre-proof Markers of Psychosis Risk in the General Population Jerome H. Taylor, Monica E. Calkins, Raquel E. Gur PII:

S0006-3223(20)30064-0

DOI:

https://doi.org/10.1016/j.biopsych.2020.02.002

Reference:

BPS 14122

To appear in:

Biological Psychiatry

Received Date: 20 July 2019 Revised Date:

17 December 2019

Accepted Date: 5 February 2020

Please cite this article as: Taylor J.H., Calkins M.E. & Gur R.E., Markers of Psychosis Risk in the General Population, Biological Psychiatry (2020), doi: https://doi.org/10.1016/j.biopsych.2020.02.002. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.

Abstract: 239 Main text: 4,042 Tables: 2 References: 162

Markers of Psychosis Risk in the General Population

Authors: Jerome H. Taylor*, Monica E. Calkins*, Raquel E. Gur

Affiliations: Lifespan Brain Institute, Penn Medicine and Children’s Hospital of Philadelphia (CHOP); Department of Child and Adolescent Psychiatry and Behavioral Sciences, CHOP; Department of Psychiatry University of Pennsylvania, Perelman School of Medicine Corresponding Author: Raquel E. Gur, M.D. Ph.D., 10th floor, Gates Building, Hospital of the University of Pennsylvania, 34th and Spruce Street, Philadelphia, PA 19104 Email: [email protected] Tel: + (215) 662 2915

* Equal contributors

Short /running title: Psychosis risk in community

ABSTRACT The categorical approach to defining schizophrenia spectrum disorders requires meeting established criteria. To advance early identification and intervention in young people the field has progressed to studying help-seeking individuals who are at clinical high risk based on subthreshold psychosis spectrum symptoms, and criteria have been articulated for qualifying individuals as at-risk. A broader dimensional examination of psychosis has been applied to population- based studies on non-help seekers. The review highlights the ascertainment and assessment approaches to such population-based studies. Most studies are cross-sectional and rely on questionnaires with limited overlap of tools. However, several consistent findings emerge on symptoms, neurocognitive deficits and neuroimaging parameters and other biomarkers associated with emergence and persistence of psychotic features. The findings are consistent with the literature on abnormalities associated with schizophrenia, including the presence of neurocognitive deficits, abnormalities in brain structure, function and connectivity that are related to distress, impairment and functional outcome. These findings support the validity of studying psychosis experiences during development in a way that can chart the emergence of psychosis in the context of general psychopathology. Such studies are necessary for establishing developmental trajectories that characterize this emergence and for identifying risk and resilience biomarkers moderating or modulating the full range of schizophrenia-related manifestations. More community-based studies are needed, with better standardization and harmonization of measures and incorporating longitudinal followup, to establish mechanistic links between cellular-molecular aberrations and specific manifestations of psychosis as envisioned by the precision medicine agenda.

Keywords: Psychosis symptoms, Schizophrenia-related phenotype, Biomarkers, Neurocognition, Neuroimaging, Children and Adolescents

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Efforts at early identification of individuals at risk for psychosis are propelled by the realization that psychosis is neurodevelopmental and the product of genetic vulnerability and environmental adversity, with brain and behavioral abnormalities anteceding diagnosis by years (1). To bend the developmental trajectory in a favorable direction, early identification is important as longer duration of untreated psychosis portends poor outcome (2). Precision medicine envisions establishing mechanistic pathways leading from genomic to phenotypic manifestations with markers modulating and moderating course and outcome. Progress within this framework requires large genomic, environmental and phenotypic datasets that allow identification of risk and resilience factors for individualized detection and intervention. For clinical neuroscience, the challenge is magnified by the complexity of the organ system, brain, the phenotype, behavior, the genetic architecture, polygenicity, and multiplicity of relevant environmental factors. Compilation of adequate datasets was unthinkable until recent advances in acquisition and computational tools for efficient collection and analysis of multimodal brain-behavior parameters on a large scale (3). However, to step toward individualized prediction requires extensively characterized and strategically targeted smaller samples. Complementary approaches have been applied for early detection of individuals at risk for psychosis. Most studies, highlighted in the current issue, have relied on help-seeking people who meet established criteria for clinical high-risk (CHR) for psychosis. Longitudinal follow-up enables examination of predictors of transition to psychotic disorders. Such markers can be applied to new populations for screening, early identification and intervention. Another approach is to screen general populations for psychosis experiences, encompassing psychoticlike experiences, subthreshold or subclinical psychosis symptoms, schizotypal signs and symptoms, which we collectively refer to as “psychosis spectrum (PS) symptoms.” Subsamples can be selected for intensive investigation of brain-behavior parameters and other biomarkers predicting outcome. Population-based studies broaden the dimensional approach by examining the dynamically emerging psychosis during a critical period of brain maturation. In this review, we highlight approaches of studies examining population samples, including conceptual models of the risk state, ascertainment strategies, study design, and

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screening tools applied. We then summarize data obtained on symptom patterns and functioning, neurobehavioral domains, neuroimaging, potential biomarkers, and genetic findings. We discuss the significance of findings, point out remaining gaps, highlight future directions and emphasize ethical and societal challenges.

ASCERTAINMENT APPROACHES AND TOOLS Accumulating evidence indicates that PS symptoms are distributed continuously in the general population (4), and may have varying predictive significance for psychotic disorders and other psychopathology (5, 6). Many investigations focus on positive symptoms and sub-types (e.g. hallucinatory vs. non-hallucinatory (5, 7)). However, there is growing evidence for significance of other symptom domains (8, 9), singly or interacting with other symptoms (10), including negative (8), disorganized, and basic symptoms (11). Importantly, in the general population (12), some of these constructs overlap schizotypy (13), a potential indicator of latent liability or vulnerability for psychotic disorders (14). Developmentally, schizotypal signs and symptoms are related to longitudinal psychosis outcomes in the general population (15). Thus, consideration of the multi-dimensionality and transdiagnostic expression (9) of PS symptoms, beyond positive symptoms, has been advocated (14, 15) as they relate to the boundaries between phenotypic expressions in the general population (9, 14, 16) [though see (17)]. Such considerations have generated a range of ascertainment strategies, terminologies, and tools for screening and identifying subthreshold psychosis symptoms in non-help-seeking populations. Most studies have employed population sampling frames (18), including birth cohorts (19, 20); representative general population cohorts (21, 22) and samples of undergraduate students (14, 18). With increased focus on younger ages, studies have included samples from pediatric care clinics (23) and school students (5, 8, 24-26). These investigations have mostly been cross-sectional, informing on contemporaneous associations of PS symptoms. They also allow for dimensional characterization of PS features by factor analyses or latent class analyses (27, 28). General population studies have now spanned the globe (12, 25, 26, 29-41), permitting critical cross-cultural comparisons of the expression, experience and clinical significance of PS symptoms (42).

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However, cross-sectional designs cannot address the prognostic significance or longterm outcomes. Only followup can distinguish among transient non-significant symptoms, longstanding traits, and intensification to psychosis (16). The psychosis proneness-persistenceimpairment model (4, 16, 43) posits that initially transient developmentally non-significant symptoms can become increasingly persistent and later associated with clinically salient functional impairments. There is also evidence that even seemingly transient symptoms may, over time, be associated with later psychopathology or otherwise poor health (27). Adolescence is a critical window of investigation for this transactional and multidimensional expression of PS symptoms. Thus, recent prospective longitudinal reports have evaluated dynamic (44), diverse trajectories of PS symptoms (10, 20, 21, 45-47) from a developmental framework (15, 16, 48, 49). Prospective designs span childhood, adolescence and young adulthood and require consideration of age effects on interpretation of symptoms. Most studies begin in early-mid adolescence but increasingly children as young as 3 are studied (49, 50). Commensurate with other investigations (7, 51), in the Philadelphia Neurodevelopmental Cohort (PNC) we found that among participants age 11-21, younger individuals endorsed more symptoms than older participants (34). Such findings signify the importance of considering normative expressions and experience of symptoms at different ages (52). Moreover, short-lived or transitory PS symptoms may be developmentally normative and clinically benign (50). Because many youths experiencing subthreshold psychosis symptoms will not develop psychotic disorders (21), general population screening invokes a risk of stigmatization in “false positive” cases (53, 54). These risks can be mitigated by thoughtful approaches to frame and disseminate individual results. Follow-ups have varied considerably from 1 to 26 years (10), as have the intervals of follow-ups. As younger youths are studied, it is important to consider whether the samples are followed through the age range of peak risk for psychotic disorders (18). Screening tools and methods to assess PS symptoms have been reviewed (16, 48, 52). Methods include self-report questionnaires and diagnostic interviews, each having strengths and limitations (5, 6). Commonly employed self-report measures are listed in Table 1. Various tools have been used, and the field lacks guidelines defining severity or clinical significance

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across measures (48, 52). Self-reports allow for large-scale screening, correlate at least moderately with interview rated symptoms (5, 55), and can be easily implemented in clinical care settings. Though they may be less specific and over-estimate the prevalence of symptoms (5, 11), “false positives” do not necessarily signify absence of risk (19, 45). In the PNC (46), even youth whose PS symptoms had remitted at two-year follow-up exhibited increased psychopathology and reduced global function compared to youth who had never experienced such symptoms. Self-reports thus may be more sensitive to the “softest” expression of symptoms in the psychosis continuum (18), especially for certain symptom categories. Interview based methods reflect clinical judgment about the presence and significance of reported symptoms, yet are more time and labor intensive and therefore less amenable to wide scale implementation. The hybrid “close-in” strategy uses two-step wide-scale screening through self-report followed by in-person clinical interview where indicated, and has been successfully applied in several recent investigations (28, 56). In addition to symptom expression itself, increasing attention has been paid to the measurement of distress or functional impairment associated with endorsed symptoms (5, 22, 52) as potential prognostic indicators. [ TABLE 1] MAIN FINDINGS PS Symptom Prevalence and Course Estimates of prevalence and course of PS symptoms in the general population of youth vary, likely related to conceptual frameworks and associated methods applied (43, 48, 52). A systematic review reported that the median prevalence of threshold psychosis symptoms among youth age 9-12 years was 17%, and among 12-18 years was 7.5% (51). Prevalence of significant subthreshold symptoms have ranged from 15–38% in large samples (21, 50, 57), with endorsement of at least one PS symptom in many youths (8, 27, 33, 50). Prevalence estimates drop with added severity parameters including frequency (6), associated distress (52), or standardized cut-offs (24). Prevalence appears higher in young males than females (22, 34), though not ubiquitously (58, 59), and in some racial and ethnic groups including AfricanAmerican, Hispanic (22, 60), Asian and Multi-racial (29) youth compared to Caucasians in U.S.;

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and in African-Caribbean and African-British children compared to Caucasian-British children in U.K. (30, 31). PS symptom persistence rates range, over varying follow-up intervals, from 16-40% in adolescents (50, 52), and are transient in most youth (6, 20, 21). In a longitudinal birth cohort youth self-reporting PS symptoms at age 11 had significant odds of developing a psychotic disorder, but not mania or depression, by age 26 (19). Subsequent meta-analytic results found a 3.5 times higher yearly risk of conversion to psychotic disorders in youth with subclinical symptoms than in those without (18). Cross Sectional Associations of PS Symptoms With Other Clinical Features There are several reasons to evaluate cross-sectional or baseline associations of PS symptoms with other clinical features. They may: [1] relate directly to the clinical, functional or personal significance of current PS symptom expression; [2] mark risk of future development of psychotic disorders or other psychopathology (61); [3] mark resilience factors (58, 61) attributes or circumstances that can mitigate, mediate or moderate the future developmental expression of PS symptoms in the context of observed risk factors; [4] provide critical information regarding exposures, either synergistically or additively (24), which contribute to symptom persistence or worsening over time (21); and [5] inform development and implementation of preventive interventions (61). Cross-sectional investigations in youth have supported concurrent associations between PS symptoms and internalizing symptoms (22, 62), including depressive (45, 57-59), bipolar (63, 64), and anxiety (45, 59) dimensions; suicidal ideation or behaviors (26, 63-65) and selfinjurious behavior (65), and distress (5, 22, 57); fewer studies have included externalizing symptoms (21), but some associations have been observed (22, 58, 62). Multiple investigations have reported concurrent associations between cannabis use and PS symptoms, particularly positive symptoms (40, 41, 66, 67). However, in the PNC, we found that after adjusting for confounds, cannabis use was associated with increased odds of PS classification only in combination with tobacco or other substance use. The timing of cannabis exposure may also be a factor – earlier age of use reportedly increases risk of PS symptoms (38, 41).

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Among environmental stressors, there are associations with trauma exposure (35, 68), including childhood abuse (33), other early adverse life experiences (49) including bullying (58, 69, 70), cybersexual harassment (71), separation from parents (36), and urbanicity (48). PS youth have impairment in overall (34, 57, 72), social (7), and occupational (7) function, especially for subtypes of PS symptoms (7, 57). Despite these compelling indicators of the clinical significance of PS symptoms, the majority of youth experiencing them do not seek clinical care (20, 34). Prospective Evaluations of PS Symptoms Cross-sectional designs have varied in controlling for multiple factors when reporting associations with PS symptoms (73). Moreover, the above multi-morbid findings have led to the suggestion that psychosis experiences may be early markers for poor general mental health, rather than specifically for subsequent psychotic disorders (58, 74). Therefore, prospective designs to address specificity to psychotic disorders, have employed multi-variate analyses using path analyses and growth modeling (35), which can illuminate, dynamically (44), the complexity of distal and proximal risk and resilience markers, as well their interactions (39, 49). Findings are generally consistent with the notion that more severe or frequent baseline symptoms beget persistence and worsening of outcome symptoms (21, 46). Increasingly, evaluations of trajectories of PS symptoms have allowed comparisons of characteristics in youth with persisting and remitting symptoms (46, 47, 75). Yet, a recent review (48) concluded that very little is known about other replicable clinical predictors of symptom persistence in the general population. Neurocognition General population studies suggest that the neurocognitive deficits observed in schizophrenia are also present in individuals with PS symptoms and even presage subsequent PS symptoms. Adolescents reporting psychotic experiences perform poorly on processing speed, nonverbal working memory (76), and facial emotion recognition (77) tasks, and adults perform poorly on working memory and verbal fluency tasks (78). In the PNC (ages 8-21 years) psychotic experiences were associated with lower reading scores, and after adjusting for age, ethnicity,

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and parental education, with neurocognitive deficits across domains (executive, memory, complex cognition, and social cognition) (34). Furthermore, throughout childhood and adolescence, PS youth had younger cognitive age compared to youth with non-psychotic psychiatric symptoms and typically developing youth. This effect was most pronounced for complex cognition and social cognition (79). The Avon Longitudinal Study of Parents and Children (ALSPAC) (80) found that lower IQ and processing speed at age 8, poorer attention at age 11, and decline in processing speed from age 8 to 11 predicted psychotic experiences at age 12 after adjusting for potential confounders (81, 82). Lower processing speed at age 8 had a stronger association with psychotic experiences at age 12 compared to the domains of attention, working memory, and reasoning and problem solving at age 8 (82). However, facial emotion recognition performance in latency-aged children did not predict subsequent psychotic experiences in adolescents and young adults in ALSPAC (83, 84) or TRacking Adolescents Individual Lives Survey’ (TRAILS) (85). Overall, youth with psychotic experiences are more likely to have deficits across several cognitive domains, and a subset of cognitive deficits, particularly processing speed, during development predicts subsequent psychotic experiences. Neuroimaging The study of brain structure and function in community samples, while more limited, generated findings consistent with help-seeking and schizophrenia studies. In the PNC, using structural parameters, we noted decreased whole brain gray matter volume in PS youth, most pronounced in medial-temporal lobe and related to symptom severity (86). Resting-state functional connectivity showed multi-focal dysconnectivity driven by hyper-connectivity among default mode and diminished connectivity among cingulo-opercular regions, with diminished coupling between frontal and default mode regions (87). For task-activated fMRI we observed reduced activation in executive control circuitry for working memory, correlated with cognitive deficits, and increased amygdala activity for threatening faces, correlated with severity of positive symptoms (88).

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Similar to the PNC structural findings, individuals with PLEs, had reduced regional gray matter volume and T1 relaxation rate (89). Higher scores on schizotypy in healthy adults were associated with reduced gray matter volume in medial prefrontal, orbitofrontal, and temporal cortical regions (90). Functional networks associated with higher-order cognition were examined in resting-state fMRI data in the Human Connectome Project. PLEs were associated negatively with performance and positively with cingulo-opercular and default mode networks global efficiency (91). PLEs in community adults were associated with reduced functional connectivity between dorsal striatum and prefrontal and motor cortices, correlating with more severe positive, whereas increased connectivity in that network related to more severe negative PLEs (92). Similarly, adults with self-report PLEs had altered dynamic functional connectivity reflecting visual hyper-connectivity and default mode hypo-connectivity (93). Level and distress of delusional thinking were related to hippocampal perfusion obtained in structural and pulsed arterial spin labeling scans in healthy adults (94). Using task-activated fMRI probing the reward system, adolescents with high PLEs showed abnormal fronto-striatal activation (95). Thus, community samples of youths and adults experiencing psychosis symptoms show aberration on multi-modal imaging with patterns evident in help-seekers and schizophrenia. The literature comprises mostly cross-sectional studies. Table 2 summarizes longitudinal studies with neuroimaging or genetics data (48). [TABLE 2] Peripheral Blood Biomarkers Several studies investigated peripheral biomarkers of psychotic experiences in community samples to test the hypothesis that immune dysregulation plays a role in the onset of schizophrenia (96). In the Northern Finland Birth Cohort 1986 (NFBC 1986), C-reactive protein at age 15-16 predicted schizophrenia diagnosis (OR 1.25, 95% CI 1.07–1.46) at age 27 (97). In contrast, ALSPAC found that serum C-reactive protein at age 9 did not predict psychotic experiences at age 12 (98). Upregulation of six complement proteins (VTN, C1RL, C8B, C8A, CFG, and C5) at age 12 predicted psychotic experiences at age 18 (99). Interleukin 6 at age 9 predicted both psychotic experiences and psychotic disorder diagnosis at age 18, but not age 12 (98, 100). In summary, higher levels of CRP and complement proteins during childhood predict

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subsequent PS symptoms and psychotic disorder diagnosis in longitudinal studies, particularly when follow-up occurs during late adolescence and early adulthood, when psychotic disorders typically onset. A meta-analysis suggests that Toxoplasma gondii infection is associated with schizophrenia and bipolar disorder in adults (101), and relationships between infectious agent exposure and PS symptoms in community youth have also been reported. ALSPAC found that seropositivity for Epstein-Barr Virus (EBV) at age 4 was associated with psychotic experiences at age 12 (OR 5.37, 95% CI 1.71-16.87), and the strength of the association increased after adjusting for sociodemographic factors (aOR 9.94, CI 1.67 – 58.96) (102). However, TRAILS found boys but not girls with EBV seropositivity reported higher positive symptoms and no relationship between PS symptoms and Toxoplasma gondii or human herpes virus seropositivity for boys or girls (103). Ultimately, prospective longitudinal studies into early adulthood are needed to determine whether integrating infectious exposure and youth symptom profile data predict onset of psychotic disorders. Biospecimens from ALSPAC and NFBC 1986 were combined to determine whether a high-throughput nuclear magnetic resonance spectroscopy platform of 70 metabolic measures were associated with psychotic experiences in adolescents ages 15-17 (104). Only lower levels of acetate were associated with increased psychotic experiences (OR 0.37, 95% CI 0.16-0.57) after adjusting for multiple comparisons. The association remained significant after adjusting for maternal social class but not after adjusting for body mass index. Longer follow-up will determine whether biospecimen data can predict psychosis in community samples. Genetics Schizophrenia heritability estimates range from 60-85% (105) and polygenicity underlies the genetic architecture (106). Genome wide association studies (GWAS) comparing patients with schizophrenia to controls have yielded the polygenic risk score for schizophrenia (PRS-S), which quantifies genetic risk due to common variants based on the number and weight of schizophrenia risk alleles (106). PRS-S explains ~7% of variance in schizophrenia liability in the general population (106). Thus, PRS alone is insufficient for individual risk prediction.

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Indeed, several studies including ALSPAC and the PNC have found no associations between PRS-S and psychotic experiences (107-110). Notably, PRS-S is associated with greater negative symptoms in some (107, 109) but not all (108) studies. PRS-S has been associated with anxiety, depression, attention deficit hyperactivity disorder, and oppositional defiant symptoms in community youth (111), though evidence is mixed (112). In the PNC, PRS-S was also associated with slower speeds of emotion identification and verbal reasoning (113) but not with broader measures of neurocognition (114). The extant evidence suggests that PRS-S is not associated with psychotic experiences or positive symptoms in community youth (112) but is associated with PS symptoms in adults (115) and general psychopathology and particular cognitive deficits in youth that often precede psychosis onset (111, 113). Longitudinal studies following youth from childhood to young adulthood are needed to understand how PRS-S and symptom profile interact to predict subsequent psychosis onset. Studies have also used family history of schizophrenia and psychosis as a proxy for genetic risk, noting that families often share environmental and sociodemographic risk factors. In the PNC, family history of PS symptoms was associated with lower functioning on the Children’s Global Assessment Scale and elevated psychosis, mood, externalizing, and fear symptoms (110). Other studies similarly report higher psychopathology in community youth with family histories of psychosis (116) and followup into early adulthood can inform how genetic and environmental factors interact to impact psychosis risk and resilience. Pre- and Peri-natal Findings Birth cohorts provide comprehensive data regarding pre and perinatal period, which likely interact with genetic risk to affect psychosis liability (117). The ALSPAC birth cohort found that pre- and peri-natal exposures during pregnancy such as maternal infection (aOR 1.44, 95% CI 1.11-1.86), diabetes (aOR 3.43, 95% CI 1.14-10.36), tobacco use (aOR 1.2,0, 95% CI 1.05-1.37), significant alcohol consumption, lower birth weight (aOR 0.82, 95% CI 0.73-0.92), and lower 5 minute APGAR scores (aOR 1.30, 95% CI 1.12-1.50) predicted subsequent psychotic experiences in offspring. However, gestational age, pre-eclampsia, maternal cannabis use, folate supplementation, and vitamin D levels did not predict psychotic experiences (118-122). Pointing to the immune system’s role in the etiology of psychotic experiences, ALSPAC also found that

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increasing frequency of maternal use of aspirin, an anti-inflammatory agent, predicted psychotic experiences at age 12 (aOR 1.44, 95% CI 1.08-1.92), and the highest risk for psychotic experiences was associated with frequent aspirin use (aOR 2.79, 95% CI 1.27-6.07). Paracetamol and other analgesics were not predictive of psychosis (123). Prenatal exposure to marijuana may also be associated with subsequently increased PS symptoms by age 10 (124). Together the findings suggest that pre- and peri-natal stressors and exposures have lasting effects on neurodevelopment and liability for PS symptoms. DISCUSSION The dimensional approach to psychosis posits that symptoms associated with the clinical presentation of schizophrenia spectrum disorders are present in the general population. The number, severity and degree of distress and impairment associated with such symptoms may vary, but they provide an opportunity to examine risk and resilience to psychosis. From the perspective of precision medicine, development of screening tools may advance early identification and intervention. While studies on help-seeking can help identify vulnerability or resilience to psychotic disorders, population-based studies can determine risk for emergence of psychosis. We have highlighted findings from studies that varied in age of participants, from children/adolescents to adults (e.g. 19, 89); the methods of evaluation including direct assessment (e.g., 34, 55) and questionnaires (e.g., 27, 125); cross-sectional (e.g., 45, 58) and longitudinal data (e.g., 20, 21, 45-47) and depth of phenotyping. There is generally a wealth of data on features related to symptoms but less on neurocognitive functioning, neuroimaging and other potential biomarkers. Nonetheless, convergent findings suggest that brain-behavior aberrations are evident in association with psychosis manifestations in community samples. Thus, PS symptoms are associated with neurocognitive impairment and with aberration of structural and functional neuroimaging parameters, especially related to brain systems implicated in schizophrenia. More longitudinal studies are needed to identify specific links between potential biomarkers and severity and course of symptoms across the lifespan. Such studies are essential to identify individuals for whom the distress and impairment associated with symptoms passes the threshold for clinical workup. The field needs more standardized

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approaches to screening on a larger-scale with established cut-off points for individualized determination of intervention approach when needed. Findings in community youth with PS symptoms resemble findings in help-seeking youth with PS symptoms (i.e. CHR). Both groups have deficits in executive, memory, and social cognition (79, 126, 127), reduced activation in executive control circuitry (88, 128), and elevated markers of inflammation in individuals who develop psychotic disorders (97, 129, 130). Furthermore, the progress made in identifying and treating help-seeking youth highlights the potential of ongoing efforts in community samples. The use of standardized tools (131, 132) in help-seeking youth has facilitated large multi-site longitudinal studies (133), enabled the development of risk calculators predicting transition to psychosis (134), advanced intervention efforts reducing rates of symptom progression to threshold psychosis (135), and deepened understanding of biological correlates of psychotic disorder onset (129, 130). Similar efforts in general population youth with PS symptoms require larger samples and may help identification of neurodevelopmental antecedents and risk factors for a broad range of psychopathology. Broadly accessible programs like Headspace (https://headspace.org.au/) focused on mental and physical wellbeing would provide opportunities to identify youth with PS symptoms and other risk factors for psychopathology (136) . How the symptoms are predictive of progression in a community sample compared to help-seeking CHR is an important question that requires more longitudinal data than are currently available.

The potential for early identification of youth at risk for psychosis, afforded by dimensional clinical measures combined with biomarkers (137), raises both practical and ethical issues. The pathways by which risk factors mediate or moderate psychosis symptom expression are likely influenced by resilience factors (138) such as adaptive coping strategies (139); identifying and potentially bolstering these factors is a critical avenue for future research (58). Yet, while early clinical intervention may be feasible, is it cost-effective and necessary? Is it likely to change the developmental trajectory, by how much and at what cost? Intervention when symptoms are at subthreshold levels may also stigmatize an individual when, even in the best-case scenario of predicting outcome there is reasonable likelihood that the individual will not progress to passing the clinical threshold. On the other hand, as is the case in other fields of

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medicine, reducing the psychosis burden directly or by treating modifiable biomarkers can improve outcome and quality of life.

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ACKNOWLEGEMENT AND DISCLOSURES

Our work was supported by NIMH T32 MH019112 (JHT), MH11219 (REG), MH081902 (REG), Brain and Behavior Research Foundation (JHT), National Center for Advancing Translational Sciences of the NIH KL2TR001879 (JHT), the Dowshen Neuroscience fund, and the Lifespan Brain Institute of Children’s Hospital of Philadelphia and Penn Medicine, University of Pennsylvania. The authors report no biomedical financial interests or potential conflicts of interest.

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Table 1. Common Psychosis Spectrum Self-Report Screening Tools Employed in General Population Studies Measure Acronym Authors Year N Adult (A), Items Adolescent (ADOL), or Child (C)* Physical Anhedonia PhysAnh Chapman et 1976 40 A Scale al. (140) Social Anhedonia SocAnh Chapman et 1976 48 A Scale al. (140) Perceptual PerAb Chapman et 1978 35 A Aberration Scale al. (141) Magical Ideation MagID Eckblad & 1983 30 A Scale Chapman (142) Schizotypal SPQ Raine et al. 1991 74 A Personality (143) Questionnaire Junior Schizotypy JSS Rawlings & 1994 95 ADOL Scales McFarlane (144) Schizotypal SPQ-B Raine & 1995 22 A Personality Benishay Questionnaire – (145) Brief Community CAPE Stefanis et al. 2002 40 A Assessment of (125) Psychic Experiences PROD-Screen PRODHeinimaa et 2003 21 A Screen al. (146) PRIME Screen PRIME Miller et al. 2004 12 A

Symptom Domain Coverage Positive Negative Disorganized Basic

X X X X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

17

Early Recognition Inventory Youth Psychosis AtRisk QuestionnaireBrief Prodromal Questionnaire Youth Psychosis AtRisk Questionnaire

ERI

Community Assessment of Psychic Experiences - Positive PRIME Screen Revised Self-Screen Prodrome Schizotypal Personality Questionnaire – Brief Revised Prodromal Questionnaire – Brief Psychosis-Like Symptoms Questionnaire Early Detection Primary Care

CAPE-P

(147) Hafner et al. (148) Ord et al. (149)

2004

12

A

X

X

X

2004

24

ADOL

X

Loewy et al. (150) MylesWorsley et al. (151) Brenner et al. (152)

2005

92

ADOL

X

X

X

2007

92

ADOL

X

X

X

2007

20

A

X

Kobayashi et al. (153) Mueller et al. (154) Cohen et al. (155)

2008

12

ADOL

X

2009

32

A

X

X

2010

32

A

X

X

PQ-B

Loewy et al. (156)

2011

25

ADOL

X

PLIKS-Q

Zammit et al. (157)

2011

11

ADOL

X

PCCL

French et al. (158)

2012

20, 6

ADOL

X

YPARQ-B

PQ YPARQ

PS-R SPro SPQ-BR

X

X

X

X

18

Checklist Specific Psychotic Experiences Questionnaire Community Assessment of Psychic Experiences – 15 Prodromal Questionnaire – Brief – Child

SPEQ

Ronald et al. (59)

2014

--

ADOL

X

CAPE-15

Capra et al. (159)

2013

15

A

X

PQ-B-C

Karcher et al. (22)

2018

21

C

X

X

X

*Note: Categories based on age range of participants in cited scale development studies. Adult = age 18 and older; Adolescent = age 13 and older; Child = age 9 and older.

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Table 2. Longitudinal studies in community youth with psychosis spectrum symptom, genetic, and neuroimaging data Study Name N Age at Country Measure of Genotyping Neuroimaging Other measures cohort Psychosis initiation Spectrum (year) Symptoms Avon Longitudinal 14,062 Birth United Psychosis-LikeYes Structural Peripheral serum, Study of Parents and (1991Kingdom Symptoms MRI available abbreviated Wechsler Children (ALSPAC) 1992) questionnaires at age 20 in Intelligence Scale for (80) (PLIKS-Q) and subset (160) Children-III, Diagnostic Analysis of Nonverbal Psychosis Like Symptoms semiAccuracy (DANVA), structured umblical cord blood, Interview gestational urine, serum, (PLIKSi) and plasma samples Adolescent Brain 11,872 9-11 United Prodromal Yes Multimodal NIH Toolbox Cognitive Cognitive years States of Questionaire – MRI Battery, saliva, hair, urine, Development (ABCD) old America Brief Child baby teeth, Family History Version Assessment Module Study (124) (2016(USA) 2018) Screener Generation R Study 9,749 Birth Netherlands Youth SelfYes Multimodal Peripheral plasma and (49) (2002Report Scale; MRI serum, Nonverbal IQ and 2006) mother-report language comprehension, MRI (lung, heart, kidney, on Child Behavioral liver, testicles, ovaries); Checklist skin, nasopharyngeal, and fecal microbiome; gestational plasma and serum, umbilical cord blood, Philadelphia 9,498 8-21 USA PRIME ScreenYes Multimodal Computerized

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Neurodevelopmental Cohort (PNC) (34)

Northern Finland Birth Cohort 1986 (161)

9,432

IMAGEN (95)

2,257

Tracking Adolescents' 2,230 Individual Lives Survey (TRAILS) (162)

years old (20092011) Birth (19851986)

14 years old (2007)

10-12 years old

Finland

Revised supplemented with parts of the SOPS, K-SADS-PL PROD-Screen Yes

Yes Adolescent Psychotic-Like Symptoms Screener in subsample (n=410), selfreport Development and Well-Being Assessment – bipolar module at age 16, Community Assessment of Psychic Experiences Questionnaire (CAPE-42) at age 19 Netherlands Community Yes Assessment of Psychic

United Kingdom, Ireland, France, Germany

MRI in 1,445 subjects

Multimodal MRI data available at adult followup (161) Multimodal MRI

No

Neurocognitive Battery (CNB), abbreviated Family Interview for Genetic Studies Peripheral serum, highsensitivity C-reactive protein (97)

Wechsler Intelligence Scale for Children, Cambridge Neuropsychological Test Automated Battery (CANTAB)

Peripheral plasma, serum, cells; salivary cortisol Amsterdam

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(20012002)

Experiences (CAPE)

Neuropsychological Tasks, Wechsler Intelligence Scale for Children Revised (WISC-R) vocabulary and block design subscales; baroreflex sensitivity (heart rate and blood pressure)

K-SADS-PL = Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version; SOPS = Scale of Prodromal Syndromes

22

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