Clustering Schizophrenia Genes by Their Temporal Expression Patterns Aids Functional Interpretation.

BACKGROUND: Schizophrenia is a highly heritable brain disorder with a typical symptom onset in early adulthood. The 2-hit hypothesis posits that schizophrenia results from differential early neurodevelopment, predisposing an individual, followed by a disruption of later brain maturational processes that trigger the onset of symptoms. STUDY DESIGN: We applied hierarchical clustering to transcription levels of 345 genes previously linked to schizophrenia, derived from cortical tissue samples from 56 donors across the lifespan. We subsequently calculated clustered-specific polygenic risk scores for 743 individuals with schizophrenia and 743 sex- and age-matched healthy controls. STUDY RESULTS: Clustering revealed a set of 183 genes that was significantly upregulated prenatally and downregulated postnatally and 162 genes that showed the opposite pattern. The prenatally upregulated set of genes was functionally annotated to fundamental cell cycle processes, while the postnatally upregulated set was associated with the immune system and neuronal communication. We found an interaction between the 2 scores; higher prenatal polygenic risk showed a stronger association with schizophrenia diagnosis at higher levels of postnatal polygenic risk. Importantly, this finding was replicated in an independent clinical cohort of 3233 individuals. CONCLUSIONS: We provide genetics-based evidence that schizophrenia is shaped by disruptions of separable biological processes acting at distinct phases of neurodevelopment. The modeling of genetic risk factors that moderate each other's effect, informed by the timing of their expression, will aid in a better understanding of the development of schizophrenia.

Gene-environment interaction study on the polygenic risk score for neuroticism, childhood adversity, and parental bonding.

The present study examines whether neuroticism is predicted by genetic vulnerability, summarized as polygenic risk score for neuroticism (PRSN), in interaction with bullying, parental bonding, and childhood adversity. Data were derived from a general population adolescent and young adult twin cohort. The final sample consisted of 202 monozygotic and 436 dizygotic twins and 319 twin pairs. The Short Eysenck Personality questionnaire was used to measure neuroticism. PRSN was trained on the results from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB) cohorts, yielding two different PRSN. Multilevel mixed-effects models were used to analyze the main and interacting associations of PRSN, childhood adversity, bullying, and parental bonding style with neuroticism. We found no evidence of gene-environment correlation. PRSN thresholds of .005 and .2 were chosen, based on GPC and UKB datasets, respectively. After correction for confounders, all the individual variables were associated with the expression of neuroticism: both PRSN from GPC and UKB, childhood adversity, maternal bonding, paternal bonding, and bullying in primary school and secondary school. However, the results indicated no evidence for gene-environment interaction in this cohort. These results suggest that genetic vulnerability on the one hand and negative life events (childhood adversity and bullying) and positive life events (optimal parental bonding) on the other represent noninteracting pathways to neuroticism.

Gender differences in the associations between childhood adversity and psychopathology in the general population.

PURPOSE: To explore gender differences of the associations between childhood adversity (CA) subtypes and psychiatric symptoms in the general population. METHODS: Data of 791 participants were retrieved from a general population twin cohort. The Symptom Checklist-90 Revised (SCL-90) and the Childhood Trauma Questionnaire were used to assess overall psychopathology with nine symptom domains scores and total CA with exposure to five CA subtypes, respectively. The associations between CA and psychopathology were analyzed in men and women separately and were subsequently compared. RESULTS: Total CA was associated with total SCL-90 and all symptom domains without significant gender differences. However, the analyses of CA subtypes showed that the association between emotional abuse and total SCL-90 was stronger in women compared to men [χ2(1) = 4.10, P = 0.043]. Sexual abuse was significantly associated with total SCL-90 in women, but emotional neglect and physical neglect were associated with total SCL-90 in men. Exploratory analyses of CA subtypes and SCL-90 subdomains confirmed the pattern of gender-specific associations. In women, emotional abuse was associated with all symptom domains, and sexual abuse was associated with all except phobic anxiety and interpersonal sensitivity. In men, emotional neglect was associated with depression, and physical neglect was associated with phobic anxiety, anxiety, interpersonal sensitivity, obsessive-compulsive, paranoid ideation, and hostility subdomains. CONCLUSION: CA is a trans-syndromal risk factor regardless of gender. However, differential associations between CA subtypes and symptom manifestation might exist. Abuse might be particularly associated with psychopathology in women, whereas neglect might be associated with psychopathology in men.

Context v. algorithm: evidence that a transdiagnostic framework of contextual clinical characterization is of more clinical value than categorical diagnosis.

BACKGROUND: A transdiagnostic and contextual framework of 'clinical characterization', combining clinical, psychopathological, sociodemographic, etiological, and other personal contextual data, may add clinical value over and above categorical algorithm-based diagnosis. METHODS: Prediction of need for care and health care outcomes was examined prospectively as a function of the contextual clinical characterization diagnostic framework in a prospective general population cohort (n = 6646 at baseline), interviewed four times between 2007 and 2018 (NEMESIS-2). Measures of need, service use, and use of medication were predicted as a function of any of 13 DSM-IV diagnoses, both separately and in combination with clinical characterization across multiple domains: social circumstances/demographics, symptom dimensions, physical health, clinical/etiological factors, staging, and polygenic risk scores (PRS). Effect sizes were expressed as population attributable fractions. RESULTS: Any prediction of DSM-diagnosis in relation to need and outcome in separate models was entirely reducible to components of contextual clinical characterization in joint models, particularly the component of transdiagnostic symptom dimensions (a simple score of the number of anxiety, depression, mania, and psychosis symptoms) and staging (subthreshold, incidence, persistence), and to a lesser degree clinical factors (early adversity, family history, suicidality, slowness at interview, neuroticism, and extraversion), and sociodemographic factors. Clinical characterization components in combination predicted more than any component in isolation. PRS did not meaningfully contribute to any clinical characterization model. CONCLUSION: A transdiagnostic framework of contextual clinical characterization is of more value to patients than a categorical system of algorithmic ordering of psychopathology.

Adjusting for population stratification in polygenic risk score analyses: a guide for model specifications in the UK Biobank.

The current study was conducted to provide a general guidance for model specifications in polygenic risk score (PRS) analyses of the UK Biobank, such as adjusting for covariates (i.e. age, sex, recruitment centers, and genetic batch) and the number of principal components (PCs) that need to be included. To cover behavioral, physical and mental health outcomes, we evaluated three continuous outcomes (BMI, smoking, drinking) and two binary outcomes (Major Depressive Disorder and educational attainment). We applied 3280 (656 per phenotype) different models including different sets of covariates. We evaluated these different model specifications by comparing regression parameters such as R2, coefficients, and P values, as well as ANOVA tests. Findings suggest that only up to three PCs appears to be sufficient for controlling population stratification for most outcomes, whereas including other covariates (particularly age and sex) appears to be more essential for model performance.

Examining the association between exposome score for schizophrenia and cognition in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

BACKGROUND: People with schizophrenia spectrum disorders (SSD) frequently present cognitive impairments. Here, we investigated whether the exposome score for schizophrenia (ES-SCZ) - a cumulative environmental exposure score - was associated with impairments of neurocognition, social cognition, and perception in patients with SSD, their unaffected siblings, and healthy controls. METHODS: This cross-sectional sample consisted of 1200 patients, 1371 siblings, and 1564 healthy controls. Neurocognition, social cognition, and perception were assesed using a short version of the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III), the Degraded Facial Affect Recognition Task (DFAR), and the Benton Facial Recognition Test (BFR), respectively. Regression models were used to analyze the association between ES-SCZ and cognitive domains in each group. RESULTS: There were no statistically significant associations between ES-SCZ and cognitive domains in SSD. ES-SCZ was negatively associated with T-score of cognition in siblings (B=-0.40, 95% CI -0.76 to -0.03) and healthy controls (B=-0.63, 95% CI -1.06 to -0.21). Additionally, ES-SCZ was positively associated with DFAR-total in siblings (B=0.83, 95% CI 0.26 to 1.40). Sensitivity analyses excluding cannabis use history from ES-SCZ largely confirmed the main findings. CONCLUSIONS: Longitudinal cohorts may elucidate how environmental exposures influence the onset and course of cognitive impairments in trans-syndromic psychosis spectrum.

Association between exposome score for schizophrenia and functioning in first-episode psychosis: results from the Athens first-episode psychosis research study.

BACKGROUND: Evidence suggests that environmental factors not only increase psychosis liability but also influence the prognosis and outcomes of psychotic disorders. We investigated temporal and cross-sectional associations of a weighted score of cumulative environmental liability for schizophrenia - the exposome score for schizophrenia (ES-SCZ) - with functioning in first-episode psychosis (FEP). METHODS: Data were derived from the baseline and 1-month assessments of the Athens FEP Research Study that enrolled 225 individuals with FEP. The Global Assessment of Functioning (GAF) and the Personal and Social Performance Scale (PSP) were used to measure social, occupational, and psychological functioning. The ES-SCZ was calculated based on the previously validated method. RESULTS: ES-SCZ was associated with the total scores of GAF and PSP at baseline and 1-month assessments. These findings remained significant when accounting for several associated alternative explanatory variables, including other environmental factors (obstetric complications, migration, ethnic minority), clinical characteristics (duration of untreated psychosis, symptom severity, previous antipsychotic use), and family history of psychosis, demonstrating that the association between ES-SCZ and functioning is over and above other risk factors and cannot be explained by symptom severity alone. Functioning improved from baseline to 1-month assessment, but no significant ES-SCZ-by-time interaction was found on functioning, indicating that functioning changes were not contingent on ES-SCZ. CONCLUSIONS: Our findings suggest that rather than a predictor of functional improvement, ES-SCZ represents a stable severity indicator that captures poor functioning in early psychosis. Environmental risk loading for schizophrenia (ES-SCZ) can be beneficial for clinical characterization and incorporated into transdiagnostic staging models.

Bidirectional relationships between cannabis use, anxiety and depressive symptoms in the mediation of the association with psychotic experience: further support for an affective pathway to psychosis.

BACKGROUND: Empirical evidence suggests that people use cannabis to ameliorate anxiety and depressive symptoms, yet cannabis also acutely worsens psychosis and affective symptoms. However, the temporal relationship between cannabis use, anxiety and depressive symptoms and psychotic experiences (PE) in longitudinal studies is unclear. This may be informed by examination of mutually mediating roles of cannabis, anxiety and depressive symptoms in the emergence of PE. METHODS: Data were derived from the second longitudinal Netherlands Mental Health Survey and Incidence Study. Mediation analysis was performed to examine the relationship between cannabis use, anxiety/depressive symptoms and PE, using KHB logit in STATA while adjusting for age, sex and education status. RESULTS: Cannabis use was found to mediate the relationship between preceding anxiety, depressive symptoms and later PE incidence, but the indirect contribution of cannabis use was small (for anxiety: % of total effect attributable to cannabis use = 1.00%; for depression: % of total effect attributable to cannabis use = 1.4%). Interestingly, anxiety and depressive symptoms were found to mediate the relationship between preceding cannabis use and later PE incidence to a greater degree (% of total effect attributable to anxiety = 17%; % of total effect attributable to depression = 37%). CONCLUSION: This first longitudinal cohort study examining the mediational relationship between cannabis use, anxiety/depressive symptoms and PE, shows that there is a bidirectional relationship between cannabis use, anxiety/depressive symptoms and PE. However, the contribution of anxiety/depressive symptoms as a mediator was greater than that of cannabis.

Age- and sex-specific associations between risk scores for schizophrenia and self-reported health in the general population.

PURPOSE: The health correlates of polygenic risk (PRS-SCZ) and exposome (ES-SCZ) scores for schizophrenia may vary depending on age and sex. We aimed to examine age- and sex-specific associations of PRS-SCZ and ES-SCZ with self-reported health in the general population. METHODS: Participants were from the population-based Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2). Mental and physical health were measured with the 36-item Short Form Survey 4 times between 2007 and 2018. The PRS-SCZ and ES-SCZ were respectively calculated from common genetic variants and exposures (cannabis use, winter birth, hearing impairment, and five childhood adversity categories). Moderation by age and sex was examined in linear mixed models. RESULTS: For PRS-SCZ and ES-SCZ analyses, we included 3099 and 6264 participants, respectively (age range 18-65 years; 55.7-56.1% female). Age and sex did not interact with PRS-SCZ. Age moderated the association between ES-SCZ and mental (interaction: p = 0.02) and physical health (p = 0.0007): at age 18, + 1.00 of ES-SCZ was associated with - 0.10 of mental health and - 0.08 of physical health, whereas at age 65, it was associated with - 0.21 and - 0.23, respectively (all units in standard deviations). Sex moderated the association between ES-SCZ and physical health (p < .0001): + 1.00 of ES-SCZ was associated with - 0.19 of physical health among female and - 0.11 among male individuals. CONCLUSION: There were larger associations between higher ES-SCZ and poorer health among female and older individuals. Accounting for these interactions may increase ES-SCZ precision and help uncover populational determinants of environmental influences on health.

Exposome and Trans-syndromal Developmental Trajectories Toward Psychosis.

The prenatal period, early childhood, and adolescence are considered sensitive periods for brain and behavior development, when environmental exposures may have long-lasting effects on mental health. Psychosis spectrum disorder (PSD) is a developmental disorder that often manifests with nonspecific clinical presentations long before full-blown PSD is diagnosed. Genetic factors only partly explain PSD. Multiple early-life environmental exposures are associated with PSD. In this review, we describe the conceptual framework of the exposome and its relevance to PSD research in developmental cohorts and beyond and discuss key challenges for the field as it attempts to move beyond studying environment (in the sense of "searching under the lamppost because this is where the light is") to a more comprehensive assessment of environment and its contribution to PSD. We then suggest that the field should aspire to studying environmental origins of PSD through a developmental lens focusing on young cohorts and using multilevel phenotyping of environment, adopting an exposome framework that embraces the dynamic complex nature of environment and acknowledges the effect of additive and interactive environmental exposures alongside the genome. Furthermore, we highlight the need for a developmental perspective when studying exposome effects on psychopathology, accepting the nonspecificity of child/adolescent psychopathology and encouraging the study of trans-syndromal manifestations, shifting the research paradigm from categorical outcomes (e.g., schizophrenia) and going beyond clinical settings to investigate trajectories of risk and resilience.

Estimating the Association Between Exposome and Psychosis as Well as General Psychopathology: Results From the ABCD Study.

Background: The exposome comprises all nongenetic factors an individual is exposed to across their lifespan. Research suggests that exposomic vulnerability for schizophrenia is associated not only with psychosis but also, to a degree, with general psychopathology. Here, we investigated to what degree exposome factors are associated with psychosis and general psychopathology. Methods: Data were retrieved from the 1-year follow-up assessment of a large U.S. adolescent sample (n = 11,235), the Adolescent Brain Cognitive Development (ABCD) Study. Iterative factor analyses of environmental exposures (n = 798) allowed calculation of 6 exposome factors: household adversity, neighborhood environment, day-to-day experiences, state-level environment, family values, pregnancy/birth complications. Bifactor modeling of clinical symptoms (n = 93) allowed calculation of a general psychopathology factor (p-factor) and 6 subdomains, including a psychosis subdomain. We applied linear regression analyses to estimate the association of exposome factors with the p-factor and psychosis subdomain, respectively. Results: Individual analyses showed that 5 exposome factors were significantly associated with the p-factor after multiple-comparison correction. In the mutually adjusted model, all exposome factors were significantly associated with the p-factor. Psychosis was particularly associated with 3 exposome factors, with the mutually adjusted model yielding the following results: household adversity (ß = 0.04, 95% CI, 0.01 to 0.07), day-to-day experiences (ß = 0.10, 95% CI, 0.08 to 0.12), and pregnancy/birth complications (ß = 0.03, 95% CI, 0.01 to 0.05). Conclusions: Our findings demonstrate that multifaceted environmental background is associated with mental disorders. Psychosis was particularly associated with prenatal, perinatal, and childhood (household and school) adversities, although these exposome domains were also associated with psychopathology. The exposome approach can help understand neurodevelopmental psychopathology.

The association between cannabis use and facial emotion recognition in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

Schizophrenia is frequently accompanied with social cognitive disturbances. Cannabis represents one established environmental factor associated with the onset and progression of schizophrenia. The present cross-sectional study aimed to investigate the association of facial emotion recognition (FER) performance with cannabis use in 2039 patients with schizophrenia, 2141 siblings, and 2049 healthy controls (HC). FER performance was measured using the Degraded Facial Affect Recognition Task (DFAR). Better FER performance as indicated by higher DFAR-total scores was associated with lifetime regular cannabis use in schizophrenia (B = 1.36, 95% CI 0.02 to 2.69), siblings (B = 2.17, 95% CI 0.79 to 3.56), and HC (B = 3.10, 95% CI 1.14 to 5.06). No associations were found between DFAR-total and current cannabis use. Patients with schizophrenia who started to use cannabis after the age of 16 showed better FER performance than patients who started earlier (B = 2.50, 95% CI 0.15 to 4.84) and non-users (B = 3.72, 95 CI 1.96 to 5.49). Better FER performance was found also in siblings who started to use cannabis after 16 compared to non-users (B = 2.37, 95% CI 0.58 to 4.16), while HC using cannabis performed better than non-users at DFAR-total regardless of the age at onset. Our findings suggest that lifetime regular cannabis use may be associated with better FER regardless of the psychosis risk, but that FER might be moderated by age at first use in people with higher genetic risk. Longitudinal studies may clarify whether there is a cause-and-effect relationship between cannabis use and FER performance in psychotic and non-psychotic samples.

Nongenetic Factors Associated With Psychotic Experiences Among UK Biobank Participants: Exposome-Wide Analysis and Mendelian Randomization Analysis.

Importance: Although hypothesis-driven research has identified several factors associated with psychosis, this one-exposure-to-one-outcome approach fails to embrace the multiplicity of exposures. Systematic approaches, similar to agnostic genome-wide analyses, are needed to identify genuine signals. Objective: To systematically investigate nongenetic correlates of psychotic experiences through data-driven agnostic analyses and genetically informed approaches to evaluate associations. Design, Setting, Participants: This cohort study analyzed data from the UK Biobank Mental Health Survey from January 1 to June 1, 2021. An exposome-wide association study was performed in 2 equal-sized split discovery and replication data sets. Variables associated with psychotic experiences in the exposome-wide analysis were tested in a multivariable model. For the variables associated with psychotic experiences in the final multivariable model, the single-nucleotide variant-based heritability and genetic overlap with psychotic experiences using linkage disequilibrium score regression were estimated, and mendelian randomization (MR) approaches were applied to test potential causality. The significant associations observed in 1-sample MR analyses were further tested in multiple sensitivity tests, including collider-correction MR, 2-sample MR, and multivariable MR analyses. Exposures: After quality control based on a priori criteria, 247 environmental, lifestyle, behavioral, and economic variables. Main Outcomes and Measures: Psychotic experiences. Results: The study included 155 247 participants (87 896 [57%] female; mean [SD] age, 55.94 [7.74] years). In the discovery data set, 162 variables (66%) were associated with psychotic experiences. Of these, 148 (91%) were replicated. The multivariable analysis identified 36 variables that were associated with psychotic experiences. Of these, 28 had significant genetic overlap with psychotic experiences. One-sample MR analyses revealed forward associations with 3 variables and reverse associations with 3. Forward associations with ever having experienced sexual assault and pleiotropy of risk-taking behavior and reverse associations without pleiotropy of experiencing a physically violent crime as well as cannabis use and the reverse association with pleiotropy of worrying too long after embarrassment were confirmed in sensitivity tests. Thus, associations with psychotic experiences were found with both well-studied and unexplored multiple correlated variables. For several variables, the direction of the association was reversed in the final multivariable and MR analyses. Conclusions and Relevance: The findings of this study underscore the need for systematic approaches and triangulation of evidence to build a knowledge base from ever-growing observational data to guide population-level prevention strategies for psychosis.

Gender differences in the association between environment and psychosis.

Various environmental exposures have been associated with psychosis spectrum disorder. However, the role of gender in this association has received little attention. Therefore, we conducted a systematic review to evaluate gender-related differences and identified 47 research articles investigating the associations of psychosis with childhood adversity, substance use, urbanicity, migration, season of birth, and obstetric complication in the PubMed database. The findings suggest that childhood abuse may be more strongly associated with a risk to develop psychosis and an earlier age at onset of illness in women than in men. Furthermore, childhood adversity has been associated with the severity of different symptom dimensions in men and women. Growing up in an urban environment and immigration are more strongly associated with psychosis risk in men than in women. Despite a higher prevalence of substance abuse comorbidity in men diagnosed with psychotic disorders, it appears that the association between substance use and psychosis risk may be stronger in women. These findings should be evaluated with caution considering several methodological limitations, limited number of studies, and lack of consistency across results. Overall, although further investigation is needed, our review shows that gender-related differences in the associations of environmental exposures with psychosis expression may exist.

Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway.

BACKGROUND: There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation. METHODS: We analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls. RESULTS: The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: -0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465). CONCLUSIONS: The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.

Examining facial emotion recognition as an intermediate phenotype for psychosis: Findings from the EUGEI study.

BACKGROUND: Social cognition impairments, such as facial emotion recognition (FER), have been acknowledged since the earliest description of schizophrenia. Here, we tested FER as an intermediate phenotype for psychosis using two approaches that are indicators of genetic risk for schizophrenia: the proxy-genetic risk approach (family design) and the polygenic risk score for schizophrenia (PRS-SCZ). METHODS: The sample comprised 2039 individuals with schizophrenia, 2141 siblings, and 2049 healthy controls (HC). The Degraded Facial Affect Recognition Task (DFAR) was applied to measure the FER accuracy. Schizotypal traits in siblings and HC were assessed using the Structured Interview for Schizotypy-Revised (SIS-R). The PRS-SCZ was trained using the Psychiatric Genomics Consortium results. Regression models were applied to test the association of DFAR with psychosis risk, SIS-R, and PRS-SCZ. RESULTS: The DFAR-total scores were lower in individuals with schizophrenia than in siblings (RR = 0.97 [95% CI 0.97, 0.97]), who scored lower than HC (RR = 0.99 [95% CI 0.99-1.00]). The DFAR-total scores were negatively associated with SIS-R total scores in siblings (B = -2.04 [95% CI -3.72, -0.36]) and HC (B = -2.93 [95% CI -5.50, -0.36]). Different patterns of association were observed for individual emotions. No significant associations were found between DFAR scores and PRS-SCZ. CONCLUSIONS: Our findings based on a proxy genetic risk approach suggest that FER deficits may represent an intermediate phenotype for schizophrenia. However, a significant association between FER and PRS-SCZ was not found. In the future, genetic mechanisms underlying FER phenotypes should be investigated trans-diagnostically.

What makes the psychosis 'clinical high risk' state risky: psychosis itself or the co-presence of a non-psychotic disorder?

AIMS: Although attenuated psychotic symptoms in the psychosis clinical high-risk state (CHR-P) almost always occur in the context of a non-psychotic disorder (NPD), NPD is considered an undesired 'comorbidity' epiphenomenon rather than an integral part of CHR-P itself. Prospective work, however, indicates that much more of the clinical psychosis incidence is attributable to prior mood and drug use disorders than to psychosis clinical high-risk states per se. In order to examine this conundrum, we analysed to what degree the 'risk' in CHR-P is indexed by co-present NPD rather than attenuated psychosis per se. METHODS: We examined the incidence of early psychotic experiences (PE) with and without NPD (mood disorders, anxiety disorders, alcohol/drug use disorders), in a prospective general population cohort (n = 6123 at risk of incident PE at baseline). Four interview waves were conducted between 2007 and 2018 (NEMESIS-2). The incidence of PE, alone (PE-only) or with NPD (PE + NPD) was calculated, as were differential associations with schizophrenia polygenic risk score (PRS-Sz), environmental, demographical, clinical and cognitive factors. RESULTS: The incidence of PE + NPD (0.37%) was lower than the incidence of PE-only (1.04%), representing around a third of the total yearly incidence of PE. Incident PE + NPD was, in comparison with PE-only, differentially characterised by poor functioning, environmental risks, PRS-Sz, positive family history, prescription of antipsychotic medication and (mental) health service use. CONCLUSIONS: The risk in 'clinical high risk' states is mediated not by attenuated psychosis per se but specifically the combination of attenuated psychosis and NPD. CHR-P/APS research should be reconceptualised from a focus on attenuated psychotic symptoms with exclusion of non-psychotic DSM-disorders, as the 'pure' representation of a supposedly homotypic psychosis risk state, towards a focus on poor-outcome NPDs, characterised by a degree of psychosis admixture, on the pathway to psychotic disorder outcomes.

Estimating Aggregate Environmental Risk Score in Psychiatry: The Exposome Score for Schizophrenia.

To understand the role of environment in the pathoetiology of psychosis spectrum disorders, research has thus far mainly investigated the effects of single exposures in isolation, such as the association between cannabis use and schizophrenia. However, this approach fails to acknowledge the complexity of the exposome, which represents the totality of the environment involving many exposures over an individual's lifetime. Therefore, contemporary research adopting the exposome paradigm has aimed at capturing the combined effect of different environmental exposures by utilizing an aggregate environmental vulnerability score for schizophrenia: the exposome score for schizophrenia. Here, we attempt to provide a comprehensive overview of studies applying the exposome score for schizophrenia. First, we describe several approaches estimating exposomic vulnerability for schizophrenia, which falls into three categories: simple environmental sum scores (sum of dichotomized exposures), meta-analysis-based environmental risk score (sum scores weighted by estimates from meta-analyses), and the exposome score (sum score weighted by estimates from an analysis in an independent training dataset). Studies show that the exposome score for schizophrenia that assumes interdependency of exposures performs better than scores that assume independence of exposures, such as the environmental sum score and the meta-analysis-based environmental risk score. Second, we discuss findings on the pluripotency of the exposome score for schizophrenia and summarize findings from gene-environment studies using the exposome score for schizophrenia. Finally, we discuss possible scientific, clinical, and population-based applications of exposome score for schizophrenia, as well as limitations and future directions for exposome research to understand the etiology of psychosis spectrum disorders.

Examining the association between exposome score for schizophrenia and functioning in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

BACKGROUND: A cumulative environmental exposure score for schizophrenia (exposome score for schizophrenia [ES-SCZ]) may provide potential utility for risk stratification and outcome prediction. Here, we investigated whether ES-SCZ was associated with functioning in patients with schizophrenia spectrum disorder, unaffected siblings, and healthy controls. METHODS: This cross-sectional sample consisted of 1,261 patients, 1,282 unaffected siblings, and 1,525 healthy controls. The Global Assessment of Functioning (GAF) scale was used to assess functioning. ES-SCZ was calculated based on our previously validated method. The association between ES-SCZ and the GAF dimensions (symptom and disability) was analyzed by applying regression models in each group (patients, siblings, and controls). Additional models included polygenic risk score for schizophrenia (PRS-SCZ) as a covariate. RESULTS: ES-SCZ was associated with the GAF dimensions in patients (symptom: B = -1.53, p-value = 0.001; disability: B = -1.44, p-value = 0.001), siblings (symptom: B = -3.07, p-value < 0.001; disability: B = -2.52, p-value < 0.001), and healthy controls (symptom: B = -1.50, p-value < 0.001; disability: B = -1.31, p-value < 0.001). The results remained the same after adjusting for PRS-SCZ. The degree of associations of ES-SCZ with both symptom and disability dimensions were higher in unaffected siblings than in patients and controls. By analyzing an independent dataset (the Genetic Risk and Outcome of Psychosis study), we replicated the results observed in the patient group. CONCLUSIONS: Our findings suggest that ES-SCZ shows promise for enhancing risk prediction and stratification in research practice. From a clinical perspective, ES-SCZ may aid in efforts of clinical characterization, operationalizing transdiagnostic clinical staging models, and personalizing clinical management.

Schizophrenia and the Environment: Within-Person Analyses May be Required to Yield Evidence of Unconfounded and Causal Association-The Example of Cannabis and Psychosis.

Hypotheses about the link between cannabis use and psychosis apply to the within-person level but have been tested mostly at the between-person level. We used a within-person design, in which a person serves as his own control, thus removing the need to consider confounding by any fixed (genetic and nongenetic) characteristic to study the prospective association between cannabis use and the incidence of attenuated psychotic experiences, and vice versa, adjusted for time-varying confounders. We combined 2 general population cohorts (at baseline: Early Developmental Stages of Psychopathology Study, n = 1395; Netherlands Mental Health Survey and Incidence Study-2, n = 6603), which applied a similar methodology to study cannabis use and attenuated psychotic experiences with repeated interviews (T0, T1, T2, and T3) over a period of approximately 10 years. The Hausman test was significant for the adjusted models, indicating the validity of the fixed-effects model. In the adjusted fixed-effects model, prior cannabis use was associated with psychotic experiences (aOR = 7.03, 95% CI: 2.39, 20.69), whereas prior psychotic experiences were not associated with cannabis use (aOR = 0.59, 95% CI: 0.21, 1.71). Longitudinal studies applying random-effects models to study associations between risk factors and mental health outcomes, as well as reverse causality, may not yield precise estimates. Cannabis likely impacts causally on psychosis but not the other way round.