On the proportion of patients who experience a prodrome prior to psychosis onset: A systematic review and meta-analysis.

BACKGROUND: Preventing or delaying the onset of psychosis requires identification of those at risk for developing psychosis. For predictive purposes, the prodrome - a constellation of symptoms which may occur before the onset of psychosis - has been increasingly recognized as having utility. However, it is unclear what proportion of patients experience a prodrome or how this varies based on the multiple definitions used. METHODS: We conducted a systematic review and meta-analysis of studies of patients with psychosis with the objective of determining the proportion of patients who experienced a prodrome prior to psychosis onset. Inclusion criteria included a consistent prodrome definition and reporting the proportion of patients who experienced a prodrome. We excluded studies of only patients with a prodrome or solely substance-induced psychosis, qualitative studies without prevalence data, conference abstracts, and case reports/case series. We searched Ovid MEDLINE, Embase (Ovid), APA PsycInfo (Ovid), Web of Science Core Collection (Clarivate), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, APA PsycBooks (Ovid), ProQuest Dissertation & Thesis, on March 3, 2021. Studies were assessed for quality using the Critical Appraisal Checklist for Prevalence Studies. Narrative synthesis and proportion meta-analysis were used to estimate prodrome prevalence. I2 and predictive interval were used to assess heterogeneity. Subgroup analyses were used to probe sources of heterogeneity. (PROSPERO ID: CRD42021239797). RESULTS: Seventy-one articles were included, representing 13,774 patients. Studies varied significantly in terms of methodology and prodrome definition used. The random effects proportion meta-analysis estimate for prodrome prevalence was 78.3% (95% CI = 72.8-83.2); heterogeneity was high (I2 97.98% [95% CI = 97.71-98.22]); and the prediction interval was wide (95% PI = 0.411-0.936). There were no meaningful differences in prevalence between grouped prodrome definitions, and subgroup analyses failed to reveal a consistent source of heterogeneity. CONCLUSIONS: This is the first meta-analysis on the prevalence of a prodrome prior to the onset of first episode psychosis. The majority of patients (78.3%) were found to have experienced a prodrome prior to psychosis onset. However, findings are highly heterogenous across study and no definitive source of heterogeneity was found despite extensive subgroup analyses. As most studies were retrospective in nature, recall bias likely affects these results. While the large majority of patients with psychosis experience a prodrome in some form, it is unclear if the remainder of patients experience no prodrome, or if ascertainment methods employed in the studies were not sensitive to their experiences. Given widespread investment in indicated prevention of psychosis through prospective identification and intervention during the prodrome, a resolution of this question as well as a consensus definition of the prodrome is much needed in order to effectively direct and organize services, and may be accomplished through novel, densely sampled and phenotyped prospective cohort studies that aim for representative sampling across multiple settings.

Characterizing the dynamics, reactivity and controllability of moods in depression with a Kalman filter.

BACKGROUND: Mood disorders involve a complex interplay between multifaceted internal emotional states, and complex external inputs. Dynamical systems theory suggests that this interplay between aspects of moods and environmental stimuli may hence determine key psychopathological features of mood disorders, including the stability of mood states, the response to external inputs, how controllable mood states are, and what interventions are most likely to be effective. However, a comprehensive computational approach to all these aspects has not yet been undertaken. METHODS: Here, we argue that the combination of ecological momentary assessments (EMA) with a well-established dynamical systems framework-the humble Kalman filter-enables a comprehensive account of all these aspects. We first introduce the key features of the Kalman filter and optimal control theory and their relationship to aspects of psychopathology. We then examine the psychometric and inferential properties of combining EMA data with Kalman filtering across realistic scenarios. Finally, we apply the Kalman filter to a series of EMA datasets comprising over 700 participants with and without symptoms of depression. RESULTS: The results show a naive Kalman filter approach performs favourably compared to the standard vector autoregressive approach frequently employed, capturing key aspects of the data better. Furthermore, it suggests that the depressed state involves alterations to interactions between moods; alterations to how moods responds to external inputs; and as a result an alteration in how controllable mood states are. We replicate these findings qualitatively across datasets and explore an extension to optimal control theory to guide therapeutic interventions. CONCLUSIONS: Mood dynamics are richly and profoundly altered in depressed states. The humble Kalman filter is a well-established, rich framework to characterise mood dynamics. Its application to EMA data is valid; straightforward; and likely to result in substantial novel insights both into mechanisms and treatments.

The relationship between childhood trauma, psychotic symptoms, and cognitive schemas in patients with schizophrenia, their siblings, and healthy controls: results from the EU-GEI study.

BACKGROUND: The relationship between childhood trauma (CT) and psychotic symptoms in patients with schizophrenia (SCZ), and subthreshold psychotic experiences in non-clinical populations is well-established. However, little is known about the relationship between subtypes of trauma and specific symptoms in patients, their siblings, and controls. It is also not clear which variables mediate the relationship between trauma and psychotic symptoms. METHODS: Seven hundred and forty-two patients with SCZ, 718 of their unaffected siblings and 1039 controls from three EU-GEI sites were assessed for CT, symptom severity, and cognitive schemas about self/others. CT was assessed with the Childhood Trauma Questionnaire, and cognitive schemas were assessed by The Brief Core Schema Scale. RESULTS: Patients with psychosis were affected by CT more than their siblings and controls in all domains. Childhood emotional abuse and neglect were more common in siblings than controls. CT was related to negative cognitive schemas toward self/others in patients, siblings, and controls. We found that negative schemas about self-mediated the relationship between emotional abuse and thought withdrawal and thought broadcasting. Approximately 33.9% of the variance in these symptoms was explained by the mediator. It also mediated the relationship between sexual abuse and persecutory delusions in SCZ. CONCLUSIONS: Our findings suggest that childhood abuse and neglect are more common in patients with schizophrenia than their siblings and healthy controls, and have different impacts on clinical domains which we searched. The relationship between CT and positive symptoms seems to be mediated by negative cognitive schemas about self in schizophrenia.

The association between aberrant salience and psychotic experiences in general population twins, and genetic vulnerability as a modifier.

BACKGROUND: Previous studies assessing the hypothesis that the construct of 'aberrant salience' is associated with psychosis and psychotic symptoms showed conflicting results. For this reason, the association between measures to index aberrant salience and subclinical psychotic symptoms in a general population sample was analysed. In addition, genetic vulnerability was added to the analysis as a modifier to test the hypothesis that modification by genetic vulnerability may explain variability in the results. METHODS: The TwinssCan project obtained data from general population twins (N = 887). CAPE (Community Assessment of Psychic Experience) scores were used to index psychotic experiences. Aberrant salience was assessed with white noise task and ambiguous situations task. RESULTS: Measures of aberrant salience were not associated with psychotic experiences, nor was there evidence for an interaction with genetic predisposition in this association (Z = 1.08, p = 0.282). CONCLUSIONS: Various studies including the present could not replicate the association between aberrant salience and psychotic experiences in general population samples. The conflicting findings might be explained by moderation by genetic vulnerability, but results are inconsistent. If there was evidence for a main effect or interaction, this was in the positive symptom scale only. On the other hand, the association was more robust in so-called 'ultra-high risk' patients and first episode psychosis patients. Thus, this association may represent a state-dependent association, present only at the more severe end of the psychosis spectrum.

The Ethics of Risk Prediction for Psychosis and Suicide Attempt in Youth Mental Health.

OBJECTIVE: To identify potential clinical utility of polygenic risk scores (PRS) and exposomic risk scores (ERS) for psychosis and suicide attempt in youth and assess the ethical implications of these tools. STUDY DESIGN: We conducted a narrative literature review of emerging findings on PRS and ERS for suicide and psychosis as well as a literature review on the ethics of PRS. We discuss the ethical implications of the emerging findings for the clinical potential of PRS and ERS. RESULTS: Emerging evidence suggests that PRS and ERS may offer clinical utility in the relatively near future but that this utility will be limited to specific, narrow clinical questions, in contrast to the suggestion that population-level screening will have sweeping impact. Combining PRS and ERS might optimize prediction. This clinical utility would change the risk-benefit balance of PRS, and further empirical assessment of proposed risks would be necessary. Some concerns for PRS, such as those about counseling, privacy, and inequities, apply to ERS. ERS raise distinct ethical challenges as well, including some that involve informed consent and direct-to-consumer advertising. Both raise questions about the ethics of machine-learning/artificial intelligence approaches. CONCLUSIONS: Predictive analytics using PRS and ERS may soon play a role in youth mental health settings. Our findings help educate clinicians about potential capabilities, limitations, and ethical implications of these tools. We suggest that a broader discussion with the public is needed to avoid overenthusiasm and determine regulations and guidelines for use of predictive scores.

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.

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.

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.

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.

Longitudinal clinical and functional outcome in distinct cognitive subgroups of first-episode psychosis: a cluster analysis.

BACKGROUND: Cognitive deficits may be characteristic for only a subgroup of first-episode psychosis (FEP) and the link with clinical and functional outcomes is less profound than previously thought. This study aimed to identify cognitive subgroups in a large sample of FEP using a clustering approach with healthy controls as a reference group, subsequently linking cognitive subgroups to clinical and functional outcomes. METHODS: 204 FEP patients were included. Hierarchical cluster analysis was performed using baseline brief assessment of cognition in schizophrenia (BACS). Cognitive subgroups were compared to 40 controls and linked to longitudinal clinical and functional outcomes (PANSS, GAF, self-reported WHODAS 2.0) up to 12-month follow-up. RESULTS: Three distinct cognitive clusters emerged: relative to controls, we found one cluster with preserved cognition (n = 76), one moderately impaired cluster (n = 74) and one severely impaired cluster (n = 54). Patients with severely impaired cognition had more severe clinical symptoms at baseline, 6- and 12-month follow-up as compared to patients with preserved cognition. General functioning (GAF) in the severely impaired cluster was significantly lower than in those with preserved cognition at baseline and showed trend-level effects at 6- and 12-month follow-up. No significant differences in self-reported functional outcome (WHODAS 2.0) were present. CONCLUSIONS: Current results demonstrate the existence of three distinct cognitive subgroups, corresponding with clinical outcome at baseline, 6- and 12-month follow-up. Importantly, the cognitively preserved subgroup was larger than the severely impaired group. Early identification of discrete cognitive profiles can offer valuable information about the clinical outcome but may not be relevant in predicting self-reported functional outcomes.

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.

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.

Coping and sleep quality in youth: An Experience Sampling study.

INTRODUCTION: Sleep quality is closely linked with mental health. Two factors that influence sleep are coping style and locus of control, yet these have not been investigated in daily life. In this study, we examined associations between coping styles and sleep quality in daily life and the potential mediating effect of daily locus of control in a sample of youth, a group particularly vulnerable to developing psychopathology. METHODS: Three hundred and seventy-nine youths from the TwinssCan study participated in an Experience Sampling study, assessing sleep quality as well as state locus of control over the most negative event from the previous day. Participants also completed the Utrecht Coping List, which assessed engagement, disengagement, and emotion-focused coping. RESULTS: Disengagement, "passive reaction," and emotion-focused coping were associated with lower daily sleep quality. State locus of control did not mediate any effects of coping styles on quality of sleep. CONCLUSIONS: Disengagement, "passive reaction," and emotion-focused coping were associated with decreased sleep quality during several consecutive days, which may put youths at risk for developing future insomnia, and strain their mental well-being over time. Thus, there may be value in asking about coping when a young individual presents with sleep problems; however, impaired coping when sleeping poorly should also be considered.

"It has to be better, otherwise we will get stuck." A Review of Novel Directions for Mental Health Reform and Introducing Pilot Work in the Netherlands.

Background: The current state of mental health care in the Netherlands faces challenges such as fragmentation, inequality, inaccessibility, and a narrow specialist focus on individual diagnosis and symptom reduction. Methods: A review suggests that in order to address these challenges, an integrated public health approach to mental health care that encompasses the broader social, cultural, and existential context of mental distress is required. Results: A Mental Health Ecosystem social trial seeks to pilot such an approach in the Netherlands, focusing on empowering patients and promoting collaboration among various healthcare providers, social care organizations, and peer-support community organizations, working together in a regional ecosystem of care and committed to a set of shared values. In the ecosystem, mental health problems are examined through the prism of mental variation in context whilst scaling up the capacity of group-based treatment and introducing a flexible and modular approach of (2nd order) treatment by specialists across the ecosystem. The approach is to empower naturally available resources in the community beyond professionally run care facilities. Digital platforms such as psychosenet.nl and proud2bme.nl, which complement traditional mental health care services and enhance public mental health, will be expanded. The capacity of recovery colleges will be increased, forming a national network covering the entire country. GEM will be evaluated using a population-based approach, encompassing a broad range of small-area indicators related to mental health care consumption, social predictors, and clinical outcomes. The success of GEM relies heavily on bottom-up development backed by stakeholder involvement, including insurers and policy-making institutions, and cocreation. Conclusion: By embracing a social trial and leveraging digital platforms, the Dutch mental health care system can overcome challenges and provide more equitable, accessible, and high-quality care to individuals.

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.

A replication study of JTC bias, genetic liability for psychosis and delusional ideation.

BACKGROUND: This study attempted to replicate whether a bias in probabilistic reasoning, or 'jumping to conclusions'(JTC) bias is associated with being a sibling of a patient with schizophrenia spectrum disorder; and if so, whether this association is contingent on subthreshold delusional ideation. METHODS: Data were derived from the EUGEI project, a 25-centre, 15-country effort to study psychosis spectrum disorder. The current analyses included 1261 patients with schizophrenia spectrum disorder, 1282 siblings of patients and 1525 healthy comparison subjects, recruited in Spain (five centres), Turkey (three centres) and Serbia (one centre). The beads task was used to assess JTC bias. Lifetime experience of delusional ideation and hallucinatory experiences was assessed using the Community Assessment of Psychic Experiences. General cognitive abilities were taken into account in the analyses. RESULTS: JTC bias was positively associated not only with patient status but also with sibling status [adjusted relative risk (aRR) ratio : 4.23 CI 95% 3.46-5.17 for siblings and aRR: 5.07 CI 95% 4.13-6.23 for patients]. The association between JTC bias and sibling status was stronger in those with higher levels of delusional ideation (aRR interaction in siblings: 3.77 CI 95% 1.67-8.51, and in patients: 2.15 CI 95% 0.94-4.92). The association between JTC bias and sibling status was not stronger in those with higher levels of hallucinatory experiences. CONCLUSIONS: These findings replicate earlier findings that JTC bias is associated with familial liability for psychosis and that this is contingent on the degree of delusional ideation but not hallucinations.

Neural cell-derived plasma exosome protein abnormalities implicate mitochondrial impairment in first episodes of psychosis.

Neuroprotective and other functional proteins of mitochondria were quantified in extracts of plasma neural-derived exosomes from ten first-episode psychosis (FP) patients and ten matched psychiatrically normal controls (ctls). Astrocyte-derived extracellular vesicles (ADEVs) and neuron-derived extracellular vesicles (NDEVs) were immunoabsorbed separately from physically precipitated plasma total EVs. Extracted mitochondrial ATP synthase was specifically immunofixed to plastic wells for quantification of catalytic activity based on conversion of NADH to NAD+ . Other extracted mitochondrial functional proteins were quantified by ELISAs. All protein levels were normalized with EV content of the CD81 exosome marker. FP patient ADEV level but not NDEV level of mitochondrial ATP synthase activity was significantly lower than that of ctls. FP patient ADEV and NDEV levels of the functionally critical mitochondrial proteins mitofusin 2 and cyclophilin D, but not of transcription factor A of mitochondria, and of the mitochondrial short open-reading frame neuroprotective and metabolic regulatory peptides humanin and MOTS-c were significantly lower than those of ctls. In contrast, FP patient NDEV, but not ADEV, level of the mitochondrial-tethering protein syntaphilin, but not of myosin VI, was significantly higher than that of ctls. The distinctively different neural levels of some mitochondrial proteins in FP patients than ctls now should be correlated with diverse clinical characteristics. Drugs that increase depressed levels of proteins and mimetics of deficient short open-reading frame peptides may be of therapeutic value in early phases of schizophrenia.

Genetic Risk for Smoking: Disentangling Interplay Between Genes and Socioeconomic Status.

This study aims to disentangle the contribution of genetic liability, educational attainment (EA), and their overlap and interaction in lifetime smoking. We conducted genome-wide association studies (GWASs) in UK Biobank (N = 394,718) to (i) capture variants for lifetime smoking, (ii) variants for EA, and (iii) variants that contribute to lifetime smoking independently from EA ('smoking-without-EA'). Based on the GWASs, three polygenic scores (PGSs) were created for individuals from the Netherlands Twin Register (NTR, N = 17,805) and the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2, N = 3090). We tested gene-environment (G × E) interactions between each PGS, neighborhood socioeconomic status (SES) and EA on lifetime smoking. To assess if the PGS effects were specific to smoking or had broader implications, we repeated the analyses with measures of mental health. After subtracting EA effects from the smoking GWAS, the SNP-based heritability decreased from 9.2 to 7.2%. The genetic correlation between smoking and SES characteristics was reduced, whereas overlap with smoking traits was less affected by subtracting EA. The PGSs for smoking, EA, and smoking-without-EA all predicted smoking. For mental health, only the PGS for EA was a reliable predictor. There were suggestions for G × E for some relationships, but there were no clear patterns per PGS type. This study showed that the genetic architecture of smoking has an EA component in addition to other, possibly more direct components. PGSs based on EA and smoking-without-EA had distinct predictive profiles. This study shows how disentangling different models of genetic liability and interplay can contribute to our understanding of the etiology of smoking.

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings.

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.

Polygenic risk scores for predicting outcomes and treatment response in psychiatry: hope or hype?

Over the last years, the decreased costs and enhanced accessibility to large genome-wide association studies datasets have laid the foundations for the development of polygenic risk scores (PRSs). A PRS is calculated on the weighted sum of single nucleotide polymorphisms and measures the individual genetic predisposition to develop a certain phenotype. An increasing number of studies have attempted to utilize the PRSs for risk stratification and prognostic evaluation. The present narrative review aims to discuss the potential clinical utility of PRSs in predicting outcomes and treatment response in psychiatry. After summarizing the evidence on major mental disorders, we have discussed the advantages and limitations of currently available PRSs. Although PRSs represent stable trait features with a normal distribution in the general population and can be relatively easily calculated in terms of time and costs, their real-world applicability is reduced by several limitations, such as low predictive power and lack of population diversity. Even with the rapid expansion of the psychiatric genetic knowledge base, pure genetic prediction in clinical psychiatry appears to be out of reach in the near future. Therefore, combining genomic and exposomic vulnerabilities for mental disorders with a detailed clinical characterization is needed to personalize care.