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Background: Incorporating genomic data into risk prediction has become an increasingly popular approach for rapid identification of individuals most at risk for complex disorders such as PTSD. Our goal was to develop and validate Methylation Risk Scores (MRS) using machine learning to distinguish individuals who have PTSD from those who do not., Methods: Elastic Net was used to develop three risk score models using a discovery dataset (n = 1226; 314 cases, 912 controls) comprised of 5 diverse cohorts with available blood-derived DNA methylation (DNAm) measured on the Illumina Epic BeadChip. The first risk score, exposure and methylation risk score (eMRS) used cumulative and childhood trauma exposure and DNAm variables; the second, methylation-only risk score (MoRS) was based solely on DNAm data; the third, methylation-only risk scores with adjusted exposure variables (MoRSAE) utilized DNAm data adjusted for the two exposure variables. The potential of these risk scores to predict future PTSD based on pre-deployment data was also assessed. External validation of risk scores was conducted in four independent cohorts., Results: The eMRS model showed the highest accuracy (92%), precision (91%), recall (87%), and f1-score (89%) in classifying PTSD using 3730 features. While still highly accurate, the MoRS (accuracy = 89%) using 3728 features and MoRSAE (accuracy = 84%) using 4150 features showed a decline in classification power. eMRS significantly predicted PTSD in one of the four independent cohorts, the BEAR cohort (beta = 0.6839, p=0.006), but not in the remaining three cohorts. Pre-deployment risk scores from all models (eMRS, beta = 1.92; MoRS, beta = 1.99 and MoRSAE, beta = 1.77) displayed a significant (p < 0.001) predictive power for post-deployment PTSD., Conclusion: The inclusion of exposure variables adds to the predictive power of MRS. Classification-based MRS may be useful in predicting risk of future PTSD in populations with anticipated trauma exposure. As more data become available, including additional molecular, environmental, and psychosocial factors in these scores may enhance their accuracy in predicting PTSD and, relatedly, improve their performance in independent cohorts., (© 2024. The Author(s).)

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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: QJMH has obtained a research grant from Koa Health, and obtained fees and options for consultancies for Aya Technologies and Alto Neuroscience. All other authors report no conflicts of interest., (Copyright: © 2024 Malamud et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Hypothesis: Recent findings suggest the incidence of first-episode psychotic disorders (FEP) varies according to setting-level deprivation and cannabis use, but these factors have not been investigated together. We hypothesized deprivation would be more strongly associated with variation in FEP incidence than the prevalence of daily or high-potency cannabis use between settings., Study Design: We used incidence data in people aged 18-64 years from 14 settings of the EU-GEI study. We estimated the prevalence of daily and high-potency cannabis use in controls as a proxy for usage in the population at-risk; multiple imputations by chained equations and poststratification weighting handled missing data and control representativeness, respectively. We modeled FEP incidence in random intercepts negative binomial regression models to investigate associations with the prevalence of cannabis use in controls, unemployment, and owner-occupancy in each setting, controlling for population density, age, sex, and migrant/ethnic group., Study Results: Lower owner-occupancy was independently associated with increased FEP (adjusted incidence rate ratio [aIRR]: 0.76, 95% CI: 0.61-0.95) and non-affective psychosis incidence (aIRR: 0.68, 95% CI: 0.55-0.83), after multivariable adjustment. Prevalence of daily cannabis use in controls was associated with the incidence of affective psychoses (aIRR: 1.53, 95% CI: 1.02-2.31). We found no association between FEP incidence and unemployment or high-potency cannabis use prevalence. Sensitivity analyses supported these findings., Conclusions: Lower setting-level owner-occupancy and increased prevalence of daily cannabis use in controls independently contributed to setting-level variance in the incidence of different psychotic disorders. Public health interventions that reduce exposure to these harmful environmental factors could lower the population-level burden of psychotic disorders., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: Monitoring cognitive side-effects following electroconvulsive therapy (ECT) is crucial for balancing side-effects and clinical effectiveness. Unfortunately, evidence-based guidelines on cognitive testing following ECT are lacking. A frequently used test in global ECT practice is the Mini Mental State Examination (MMSE). We examined the change of the MMSE and its performance in identifying a decline in predefined neuropsychological measures sensitive to ECT-induced cognitive changes: verbal recall and verbal fluency., Methods: The mean MMSE scores pre- and one week post-ECT were compared using a Wilcoxon signed-rank test. The Reliable Change Index was calculated for all cognitive measures to indicate whether an individual's change score from pre- to post-ECT is considered statistically significant. The sensitivity and specificity of the MMSE were calculated., Results: 426 patients with depression from five sites were included from the Dutch ECT Consortium. The mean MMSE increased significantly from 26.2 (SD=3.9) pre-ECT to 26.8 (SD=3.8) post-ECT (p=0.002). 36 patients (8.5%) showed a significant decline in MMSE score post-ECT. The sensitivity of the MMSE in identifying patients who experienced a significant decline in verbal recall or verbal fluency ranged from 3.6% to 11.1%. The specificity of the MMSE in identifying patients who did not experience a significant decline in verbal recall or verbal fluency ranged from 95.6% to 96.6%., Conclusions: Given the very low sensitivity of the MMSE, we propose reconsidering the prominence of the MMSE in ECT practice and cognitive monitoring guidelines, advocating for a more comprehensive approach to assess ECT-induced cognitive changes., (Copyright © 2024. Published by Elsevier Inc.)

Background and Hypothesis: Cognition has been associated with socio-occupational functioning in individuals at Clinical High Risk for Psychosis (CHR-P). The present study hypothesized that clustering CHR-P participants based on cognitive data could reveal clinically meaningful subtypes., Study Design: A cohort of 291 CHR-P subjects was recruited through the multicentre EU-GEI high-risk study. We explored whether an underlying cluster structure was present in the cognition data. Clustering of cognition data was performed using k-means clustering and density-based spatial clustering of applications with noise. Cognitive subtypes were validated by comparing differences in functioning, psychosis symptoms, transition outcome, and grey matter volume between clusters. Network analysis was used to further examine relationships between cognition scores and clinical symptoms., Study Results: No underlying cluster structure was found in the cognitive data. K-means clustering produced "spared" and "impaired" cognition clusters similar to those reported in previous studies. However, these clusters were not associated with differences in functioning, symptomatology, outcome, or grey matter volume. Network analysis identified cognition and symptoms/functioning measures that formed separate subnetworks of associations., Conclusions: Stratifying patients according to cognitive performance has the potential to inform clinical care. However, we did not find evidence of cognitive clusters in this CHR-P sample. We suggest that care needs to be taken in inferring the existence of distinct cognitive subtypes from unsupervised learning studies. Future research in CHR-P samples could explore the existence of cognitive subtypes across a wider range of cognitive domains., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions., Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress., Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB . Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels., Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD., Competing Interests: Competing interests CYC is an employee of Biogen. NPD has served on scientific advisory boards for BioVie Pharma, Circular Genomics and Sentio Solutions for unrelated work. NRN serves as an unpaid member of the Ilumivu advisory board. SAMR receives support from the Wounded Warrior Project (WWP), Department of Veterans Affairs (VA), National Institute of Health (NIH), McCormick Foundation, Tonix Pharmaceuticals, Woodruff Foundation, and Department of Defense (DOD). Dr. Rauch receives royalties from Oxford University Press and American. KJR serves as a consultant for Acer, Bionomics, and Jazz Pharma; SABs for Sage, Boehringer Ingelheim, and Senseye. DJS has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. MBS has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, BigHealth, Biogen, Bionomics, BioXcel Therapeutics, Boehringer Ingelheim, Clexio, Delix Therapeutics, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, PureTech Health, Sage Therapeutics, Sumitomo Pharma, and Roche/Genentech. MBS has stock options in Oxeia Biopharmaceuticals and EpiVario. MBS has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). MBS has also received research support from NIH, Department of Veterans Affairs, and the Department of Defense. MBS is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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 [χ 2 (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., (© 2023. The Author(s).)

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.

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Healthcare workers (HCWs) were at increased risk for mental health problems during the COVID-19 pandemic, with prior data suggesting women may be particularly vulnerable. Our global mental health study aimed to examine factors associated with gender differences in psychological distress and depressive symptoms among HCWs during COVID-19. Across 22 countries in South America, Europe, Asia and Africa, 32,410 HCWs participated in the COVID-19 HEalth caRe wOrkErS (HEROES) study between March 2020 and February 2021. They completed the General Health Questionnaire-12, the Patient Health Questionnaire-9 and questions about pandemic-relevant exposures. Consistently across countries, women reported elevated mental health problems compared to men. Women also reported increased COVID-19-relevant stressors, including insufficient personal protective equipment and less support from colleagues, while men reported increased contact with COVID-19 patients. At the country level, HCWs in countries with higher gender inequality reported less mental health problems. Higher COVID-19 mortality rates were associated with increased psychological distress merely among women. Our findings suggest that among HCWs, women may have been disproportionately exposed to COVID-19-relevant stressors at the individual and country level. This highlights the importance of considering gender in emergency response efforts to safeguard women's well-being and ensure healthcare system preparedness during future public health crises., Competing Interests: The authors have no competing interests to declare that are relevant to the content of this article., (© The Author(s) 2024.)

Background: The kynurenine pathway (KP) is gaining more attention as a common pathway involved in age-related conditions. However, which changes in the KP occur due to normal ageing is still largely unclear. The aim of this systematic review was to summarize the available evidence for associations of KP metabolites with age., Methods: We used an broad search strategy and included studies up to October 2023., Results: Out of 8795 hits, 55 studies were eligible for the systematic review. These studies suggest that blood levels of tryptophan decrease with age, while blood and cerebrospinal fluid levels of kynurenine and its ratio with tryptophan increase. Studies investigating associations between cerebrospinal fluid and blood levels of kynurenic acid and quinolinic acid with age reported either positive or non-significant findings. However, there is a large heterogeneity across studies. Additionally, most studies were cross-sectional, and only few studies investigated associations with other downstream kynurenines., Conclusions: This systematic review suggests that levels of kynurenines are positively associated with age. Larger and prospective studies are needed that also investigate a more comprehensive panel of KP metabolites and changes during the life-course., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Self-esteem and self-esteem stability are important factors during adolescence and young adulthood that can be negatively impacted by childhood adversity and psychiatric symptoms. We examined whether childhood adversity and psychiatric symptoms are associated with decreased global self-esteem as well as increased self-esteem instability as measured with experience sampling method. In addition, we examined if childhood adversity moderates the association between psychiatric symptoms and self-esteem outcomes., Methods: Our study consisted of 788 adolescents and young adults who were part of a twin pair. The twin structure was not of interest to the current study. Mean age was 16.8 (SD = 2.38, range: 14-25), 42% was male. We used a multilevel modeling approach to examine our hypotheses to account for the presence of twins in the data set., Results: Childhood adversity and psychiatric symptoms were negatively associated with global self-esteem (respectively standardized β = -.18, SE = 0.04, p < .0001 and standardized β = -.45, SE = 0.04, p < .0001), with a larger effect for psychiatric symptoms. Similarly, both were associated with increased self-esteem instability (respectively standardized β = .076, SE = 0.025, p = .002 and standardized β = .11, SE = 0.021, p < .0001). In addition, interactions between childhood adversity and psychiatric symptoms on both global self-esteem (standardized β = .06, SE = 0.01, p < .0001) and self-esteem instability (standardized β = -.002, SE = 0.0006, p = .001) were found, showing that the negative association of psychiatric symptoms with self-esteem outcomes is less pronounced in young people with higher levels of childhood adversity, or formulated differently, is more pronounced in young people with little or no exposure to childhood adversity., Conclusion: Global self-esteem and self-esteem instability in young people are influenced by both current psychiatric symptomatology and exposure to childhood adversity. Those with more psychiatric symptoms show worse self-esteem and higher self-esteem instability, which is moderated by childhood adversity. For young people with high childhood adversity levels lower self-esteem and higher self-esteem instability are less influenced by reductions in psychiatric symptoms., (© 2023 Wiley Periodicals LLC.)

Background and Hypothesis: Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes., Study Design: We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score., Study Results: After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 µV; 95% CI: -1.70 to -0.59 µV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores., Conclusions: Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: The kynurenine pathway is the main metabolic pathway of tryptophan degradation and has been associated with stroke and impaired cognitive functioning, but studies on its role in post-stroke cognitive impairment (PSCI) are scarce. We aimed to investigate associations between metabolites of the kynurenine pathway at baseline and post-stroke cognitive functioning over time., Methods: Baseline plasma kynurenines were quantified in 198 stroke patients aged 65.4 ± 10.8 years, 138 (69.7%) men, who were followed up over a period of three years after stroke. Baseline and longitudinal associations of kynurenines with PSCI and cognitive domain scores were investigated using linear mixed models, adjusted for several confounders., Results: No evidence of associations between kynurenines and odds of PSCI were found. However, considering individual cognitive domains, higher plasma levels of anthranilic acid (AA) were associated with better episodic memory at baseline (β per SD 0.16 [0.05, 0.28]). Additionally, a linear-quadratic association was found for the kynurenic acid/ quinolinic acid ratio (KA/QA), a neuroprotective index, with episodic memory (Wald χ 2  = 8.27, p = .016). Higher levels of KA were associated with better processing speed in women only (p interaction  = .008; β per SD 0.15 [95% CI 0.02, 0.27]). These associations did not change over time., Conclusions: Higher levels of KA, AA and KA/QA were associated with better scores on some cognitive domains at baseline. These associations did not change over time. Given the exploratory nature and heterogeneity of findings, these results should be interpreted with caution, and verified in other prospective studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

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.

The present study examines whether neuroticism is predicted by genetic vulnerability, summarized as polygenic risk score for neuroticism (PRS N ), 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. PRS N was trained on the results from the Genetics of Personality Consortium (GPC) and United Kingdom Biobank (UKB) cohorts, yielding two different PRS N . Multilevel mixed-effects models were used to analyze the main and interacting associations of PRS N , childhood adversity, bullying, and parental bonding style with neuroticism. We found no evidence of gene-environment correlation. PRS N 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 PRS N 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., Competing Interests: The authors have no relevant financial or nonfinancial interests to disclose., (© The Author(s) 2023.)

Introduction: Altered levels of kynurenines in blood and cerebrospinal fluid (CSF) have been reported in Alzheimer's disease (AD). However, it is still largely unknown whether peripheral kynurenine concentrations resemble those found in CSF and how they relate to AD pathology. We therefore studied correlations between kynurenines in plasma and CSF and their associations with CSF amyloid-beta (Aβ 1-42 ) and tau levels in patients from the memory clinic spanning the whole cognitive spectrum., Methods: The Biobank Alzheimer Center Limburg study is a prospective cohort study of consecutive patients referred to the memory clinic of the Alzheimer Center Limburg. Plasma and CSF concentrations of tryptophan (TRP), eight kynurenines and neopterin from 138 patients were determined by means of LC-MS/MS. Additionally, CSF Aβ 1-42 , total-tau (t-tau) and phosphorylated tau (p-tau) concentrations were determined using commercially available single-parameter ELISA methods. Partial correlations were used to analyze cross-sectional associations between kynurenines in plasma and CSF and their relation to AD related CSF-biomarkers adjusted for age, sex, educational level, and kidney function., Results: Moderate to strong correlations were observed between plasma and CSF levels for quinolinic acid (QA; r = 0.63), TRP (r = 0.47), anthranilic acid (r = 0.59), picolinic acid (r = 0.55), and the kynurenine (KYN)/TRP ratio (KTR; r = 0.55; all p < 0.0001), while other kynurenines correlated only weakly with their corresponding CSF values. No correlations were found between plasma and CSF levels of KA/QA. Several kynurenines were also weakly correlated with Aβ 1-42 , t-tau or p-tau. Plasma levels of KA/QA were negatively correlated with Aβ 1-42 (r = -0.21, p < 0.05). Plasma levels of TRP were negatively correlated with t-tau (r = -0.19) and levels of KYN with p-tau (r = -0.18; both p < 0.05). CSF levels of KYN (r = 0.20, p < 0.05), KA (r = 0.23, p < 0.01), and KTR (r = 0.18, p < 0.05) were positively correlated with Aβ 1-42 . Finally, TRP and KYN were negatively (r = -0.22 and r = -0.18, respectively), and neopterin positively (r = 0.19) correlated with p-tau (all p < 0.05)., Conclusions: Plasma concentrations of TRP, KP metabolites, KTR, and neopterin all significantly correlated positively with their corresponding CSF concentrations, but many correlations were weak. Additionally, our results suggest a relation between higher kynurenine levels and lower AD pathology load. These results need verification in future studies and require more research into (shared) underlying mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Individuals at clinical high risk (CHR) for psychosis have been found to have altered cytokine levels, but whether these changes are related to clinical outcomes remains unclear. We addressed this issue by measuring serum levels of 20 immune markers in 325 participants (n = 269 CHR, n = 56 healthy controls) using multiplex immunoassays, and then followed up the CHR sample to determine their clinical outcomes. Among 269 CHR individuals, 50 (18.6 %) developed psychosis by two years. Univariate and machine learning techniques were used to compare levels of inflammatory markers in CHR subjects and healthy controls, and in CHR subjects who had (CHR-t), or had not (CHR-nt) transitioned to psychosis. An ANCOVA identified significant group differences (CHR-t, CHR-nt and controls) and post-hoc tests indicated that VEGF levels and the IL-10/IL-6 ratio were significantly higher in CHR-t than CHR-nt, after adjusting for multiple comparisons. Using a penalised logistic regression classifier, CHR participants were distinguished from controls with an area-under the curve (AUC) of 0.82, with IL-6 and IL-4 levels the most important discriminating features. Transition to psychosis was predicted with an AUC of 0.57, with higher VEGF level and IL-10/IL-6 ratio the most important discriminating features. These data suggest that alterations in the levels of peripheral immune markers are associated with the subsequent onset of psychosis. The association with increased VEGF levels could reflect altered blood-brain-barrier (BBB) permeability, while the link with an elevated IL-10/IL-6 ratio points to an imbalance between anti- and pro-inflammatory cytokines., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: VM has received research funding from Johnson & Johnson as part of a research program on depression and inflammation, but this is unrelated to the work presented in this study. The remaining authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to the number of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing polygenic vulnerability. Here, we investigated, in the largest sample of first-episode psychosis (FEP) cases to date, whether childhood adversity and high polygenic risk scores for schizophrenia (SZ-PRS) combine synergistically to increase the risk of psychosis, over and above the effect of each alone., Methods: We assigned a schizophrenia-polygenic risk score (SZ-PRS), calculated from the Psychiatric Genomics Consortium (PGC2), to all participants in a sample of 384 FEP patients and 690 controls from the case-control component of the EU-GEI study. Only participants of European ancestry were included in the study. A history of childhood adversity was collected using the Childhood Trauma Questionnaire (CTQ). Synergistic effects were estimated using the interaction contrast ratio (ICR) [odds ratio (OR) exposure and PRS - OR exposure - OR PRS + 1] with adjustment for potential confounders., Results: There was some evidence that the combined effect of childhood adversities and polygenic risk was greater than the sum of each alone, as indicated by an ICR greater than zero [i.e. ICR 1.28, 95% confidence interval (CI) -1.29 to 3.85]. Examining subtypes of childhood adversities, the strongest synergetic effect was observed for physical abuse (ICR 6.25, 95% CI -6.25 to 20.88)., Conclusions: Our findings suggest possible synergistic effects of genetic liability and childhood adversity experiences in the onset of FEP, but larger samples are needed to increase precision of estimates.

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., (© 2023 The Foundation for Professionals in Services for Adolescents.)

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.

Perinatal brain injury following hypoxia-ischemia (HI) is characterized by high mortality rates and long-term disabilities. Previously, we demonstrated that depletion of Annexin A1, an essential mediator in BBB integrity, was associated with a temporal loss of blood-brain barrier (BBB) integrity after HI. Since the molecular and cellular mechanisms mediating the impact of HI are not fully scrutinized, we aimed to gain mechanistic insight into the dynamics of essential BBB structures following global HI in relation to ANXA1 expression. Global HI was induced in instrumented preterm ovine fetuses by transient umbilical cord occlusion (UCO) or sham occlusion (control). BBB structures were assessed at 1, 3, or 7 days post-UCO by immunohistochemical analyses of ANXA1, laminin, collagen type IV, and PDGFRβ for pericytes. Our study revealed that within 24 h after HI, cerebrovascular ANXA1 was depleted, which was followed by depletion of laminin and collagen type IV 3 days after HI. Seven days post-HI, increased pericyte coverage, laminin and collagen type IV expression were detected, indicating vascular remodeling. Our data demonstrate novel mechanistic insights into the loss of BBB integrity after HI, and effective strategies to restore BBB integrity should potentially be applied within 48 h after HI. ANXA1 has great therapeutic potential to target HI-driven brain injury.

Cognitive and behavioral aspects may mask posttraumatic stress disorder (PTSD) in people with dementia. PTSD severely lowers quality of life in people with dementia. Proper recognition of PTSD is essential to ensure adequate treatment. However, a valid diagnostic tool for PTSD in dementia is lacking. A Delphi study was conducted among 20 Dutch and 6 international experts in the field of PTSD and dementia care or research. The aim was to reach consensus in 3 rounds on the added value, form, content, and application for developing such an instrument. The first round confirmed the need for a new diagnostic tool for research and clinical practice. Consensus was reached on 23 statements regarding the support base and 19 related to content of the instrument. In the third round, opinions on several conceptual problems were gathered. Based on the experts' opinions, a draft version of an instrument, the TRAuma and DEmentia-interview (TRADE-interview), was developed. Clinical and research implications of this new measure are discussed.

Hypothalamic-pituitary adrenal (HPA)axis dysregulation has long been implicated in stress-related disorders such as major depression and post-traumatic stress disorder. Glucocorticoids (GCs) are released from the adrenal glands as a result of HPA-axis activation. The release of GCs is implicated with several neurobiological changes that are associated with negative consequences of chronic stress and the onset and course of psychiatric disorders. Investigating the underlying neurobiological effects of GCs may help to better understand the pathophysiology of stress-related psychiatric disorders. GCs impact a plethora of neuronal processes at the genetic, epigenetic, cellular, and molecular levels. Given the scarcity and difficulty in accessing human brain samples, 2D and 3D in vitro neuronal cultures are becoming increasingly useful in studying GC effects. In this review, we provide an overview of in vitro studies investigating the effects of GCs on key neuronal processes such as proliferation and survival of progenitor cells, neurogenesis, synaptic plasticity, neuronal activity, inflammation, genetic vulnerability, and epigenetic alterations. Finally, we discuss the challenges in the field and offer suggestions for improving the use of in vitro models to investigate GC effects., Competing Interests: The authors have no conflicts of interest to declare that are relevant to the content of this article., (© 2023 The Authors.)

Background: Adverse childhood experiences (ACE) can affect educational attainments, but little is known about their impact on educational achievements in people at clinical high risk of psychosis (CHR)., Methods: In total, 344 CHR individuals and 67 healthy controls (HC) were recruited as part of the European Community's Seventh Framework Programme-funded multicenter study the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI). The brief version of the Child Trauma Questionnaire was used to measure ACE, while educational attainments were assessed using a semi-structured interview., Results: At baseline, compared with HC, the CHR group spent less time in education and had higher rates of ACE, lower rates of employment, and lower estimated intelligence quotient (IQ). Across both groups, the total number of ACE was associated with fewer days in education and lower level of education. Emotional abuse was associated with fewer days in education in HC. Emotional neglect was associated with a lower level of education in CHR, while sexual abuse was associated with a lower level of education in HC. In the CHR group, the total number of ACE, physical abuse, and neglect was significantly associated with unemployment, while emotional neglect was associated with employment., Conclusions: ACE are strongly associated with developmental outcomes such as educational achievement. Early intervention for psychosis programs should aim at integrating specific interventions to support young CHR people in their educational and vocational recovery. More generally, public health and social interventions focused on the prevention of ACE (or reduce their impact if ACE occur) are recommended.

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., (© 2022. The Author(s).)

Posttraumatic stress disorder (PTSD) is a heritable (h 2  = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10 -8 ). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further., (© 2022. The Author(s).)

In the last decade, in vitro models has been attracting a great deal of attention for the investigation of a number of mechanisms underlying neurological and mental disorders, including stress-related disorders, for which human brain material has rarely been available. Neuronal cultures have been extensively used to investigate the neurobiological effects of stress hormones, in particular glucocorticoids. Despite great advancements in this area, several challenges and limitations of studies attempting to model and investigate stress-related mechanisms in vitro exist. Such experiments often come along with non-standardized definitions stress paradigms in vitro , variations in cell models and cell types investigated, protocols with differing glucocorticoid concentrations and exposure times, and variability in the assessment of glucocorticoid-induced phenotypes, among others. Hence, drawing consensus conclusions from in-vitro stress studies is challenging. Addressing these limitations and aligning methodological aspects will be the first step towards an improved and standardized way of conducting in vitro studies into stress-related disorders, and is indispensable to reach the full potential of in vitro neuronal models. Here, we consider the most important challenges that need to be overcome and provide initial guidelines to achieve improved use of in vitro neuronal models for investigating mechanisms underlying the development of stress-related mental disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bassil, De Nijs, Rutten, Van Den Hove and Kenis.)

Cognitive impairment is a debilitating symptom in Parkinson's disease (PD). We aimed to establish an accurate multivariate machine learning (ML) model to predict cognitive outcome in newly diagnosed PD cases from the Parkinson's Progression Markers Initiative (PPMI). Annual cognitive assessments over an 8-year time span were used to define two cognitive outcomes of (i) cognitive impairment, and (ii) dementia conversion. Selected baseline variables were organized into three subsets of clinical, biofluid and genetic/epigenetic measures and tested using four different ML algorithms. Irrespective of the ML algorithm used, the models consisting of the clinical variables performed best and showed better prediction of cognitive impairment outcome over dementia conversion. We observed a marginal improvement in the prediction performance when clinical, biofluid, and epigenetic/genetic variables were all included in one model. Several cerebrospinal fluid measures and an epigenetic marker showed high predictive weighting in multiple models when included alongside clinical variables., (© 2022. The Author(s).)

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.

Major depressive disorder (MDD) is the leading cause of disability worldwide. There is an urgent need for objective biomarkers to diagnose this highly heterogeneous syndrome, assign treatment, and evaluate treatment response and prognosis. MicroRNAs (miRNAs) are short non-coding RNAs, which are detected in body fluids that have emerged as potential biomarkers of many disease conditions. The present study explored the potential use of miRNAs as biomarkers for MDD and its treatment. We profiled the expression levels of circulating blood miRNAs from mice that were collected before and after exposure to chronic social defeat stress (CSDS), an extensively validated mouse model used to study depression, as well as after either repeated imipramine or single-dose ketamine treatment. We observed robust differences in blood miRNA signatures between stress-resilient and stress-susceptible mice after an incubation period, but not immediately after exposure to the stress. Furthermore, ketamine treatment was more effective than imipramine at re-establishing baseline miRNA expression levels, but only in mice that responded behaviorally to the drug. We identified the red blood cell-specific miR-144-3p as a candidate biomarker to aid depression diagnosis and predict ketamine treatment response in stress-susceptible mice and MDD patients. Lastly, we demonstrate that systemic knockdown of miR-144-3p, via subcutaneous administration of a specific antagomir, is sufficient to reduce the depression-related phenotype in stress-susceptible mice. RNA-sequencing analysis of blood after such miR-144-3p knockdown revealed a blunted transcriptional stress signature as well. These findings identify miR-144-3p as a novel target for diagnosis of MDD as well as for antidepressant treatment, and enhance our understanding of epigenetic processes associated with depression., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Electroconvulsive therapy (ECT) appears to be the most effective treatment for severe depression. However, its mechanisms of action are incompletely understood. Evidence suggests ECT enhances neuroplasticity and neurogenesis. While studies on ECT-induced neuroplasticity focused on brain-derived neurotrophic factor (BDNF), other factors of the BDNF/TrkB signaling cascade remain underinvestigated. We assessed longitudinal changes in depression scores, serum BDNF protein levels, and mRNA expression of BDNF/TrkB related genes (BDNF, AKT1, ERK1, CREB), NR3C1 and IGF1 in peripheral blood in 19 treatment-resistant depressed patients undergoing ECT. We also analysed DNA methylation patterns at various timepoints to explore possible epigenetic regulation of mRNA expression. Using multilevel regression, we found a negative association between depression scores and blood-based mRNA expression of BDNF/TrkB related genes and NR3C1. Expression of BDNF, ERK1 and NR3C1 increased significantly over time (BDNF: β = 0.0295, p = 0.003; ERK1: β = 0.0170, p = 0.034; NR3C1: β = 0.0035, p = 0.050). For these three genes changes in mRNA expression were highly correlated (R = 0.59 - 0.88) with changes in DNA methylation for multiple CpG sites in the respective genes. Also, serum BDNF protein levels increased across the study period (β = 0.11, p = 0.001). Our findings show that the antidepressant effects of ECT are associated with changes in expression of BDNF and its signaling molecules and that these molecular markers can be detected in peripheral blood. Alterations in DNA methylation could be a key mechanism whereby ECT influences gene expression., Competing Interests: Conflict of interest BR is supported by the European Community's Seventh Framework Programme under Grant agreement no. HEALTH-F2-2009-241909 (Project EU-GEI) and via VENI and VIDI Awards from the Netherlands Organization for Scientific Research (NWO, grant numbers 916.11.086 and 917.18.336). LRI received CME-related financing or served as speaker for Adamed, Angelini, Janssen-Cilag, Otsuka-Lundbeck, Pfizer and Servier. The other authors declare no competing interests and have nothing to disclose., (Copyright © 2022. Published by Elsevier B.V.)

Reduced positive future thinking has been associated with suicidal ideation and behavior in adults, and appears to be exacerbated by negative affect. Yet, this has received little attention in youth. Prior research has also focused on longer-term future thinking, e.g., months and years, and relied on lab-based assessments. Using the experience sampling method (ESM), we investigated whether short-term future thinking in daily life was associated with suicidal ideation in youth and explored the role of affect in the future thinking-suicidal ideation relationship. A community sample of N = 722 adolescent twins and their non-twin siblings completed ESM as part of the TwinssCan study ( n = 55 with, and n = 667 without, past-week suicidal ideation). Participants completed self-report questionnaires, including on past-week suicidal ideation as part of the SCL-90. Subsequently, daily future thinking was assessed each morning for six days with ESM. To investigate the relationship between daily positive future thinking and past-week suicidal ideation, we estimated a mixed-effects linear regression model with a random intercept for participant, including age and sex as covariates. The relationship between daily positive future thinking, past-week suicidal ideation, and average positive and negative affect from the previous day was investigated by estimating two separate mixed-effects linear regression models (one for negative affect, one for positive affect), with a random intercept for participant, and random slopes for average positive and negative affect. Our results showed that participants reporting higher past-week suicidal ideation also reported significantly less daily positive future thinking during the ESM period, and this association remained significant when controlling for previous-day average positive and negative affect. Higher average positive affect from the previous day was significantly associated with higher positive future thinking. Although average negative affect from the previous day was associated with lower positive future thinking, this association was not statistically significant. Our findings indicate that short-term future thinking relates to suicidal ideation among a non-clinical sample of adolescents. Future research should investigate the directionality of the future thinking-suicidal ideation relationship, in order to investigate whether impaired future thinking may be an early warning signal for escalating suicidal ideation in youth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kirtley, Lafit, Vaessen, Decoster, Derom, Gülöksüz, De Hert, Jacobs, Menne-Lothmann, Rutten, Thiery, van Os, van Winkel, Wichers and Myin-Germeys.)

Aims: Gene x environment (G×E) interactions, i.e. genetic modulation of the sensitivity to environmental factors and/or environmental control of the gene expression, have not been reliably established regarding aetiology of psychotic disorders. Moreover, recent studies have shown associations between the polygenic risk scores for schizophrenia (PRS-SZ) and some risk factors of psychotic disorders, challenging the traditional gene v. environment dichotomy. In the present article, we studied the role of GxE interaction between psychosocial stressors (childhood trauma, stressful life-events, self-reported discrimination experiences and low social capital) and the PRS-SZ on subclinical psychosis in a population-based sample., Methods: Data were drawn from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, in which subjects without psychotic disorders were included in six countries. The sample was restricted to European descendant subjects ( n = 706). Subclinical dimensions of psychosis (positive, negative, and depressive) were measured by the Community Assessment of Psychic Experiences (CAPE) scale. Associations between the PRS-SZ and the psychosocial stressors were tested. For each dimension, the interactions between genes and environment were assessed using linear models and comparing explained variances of 'Genetic' models (solely fitted with PRS-SZ), 'Environmental' models (solely fitted with each environmental stressor), 'Independent' models (with PRS-SZ and each environmental factor), and 'Interaction' models (Independent models plus an interaction term between the PRS-SZ and each environmental factor). Likelihood ration tests (LRT) compared the fit of the different models., Results: There were no genes-environment associations. PRS-SZ was associated with positive dimensions ( β = 0.092, R 2 = 7.50%), and most psychosocial stressors were associated with all three subclinical psychotic dimensions (except social capital and positive dimension). Concerning the positive dimension, Independent models fitted better than Environmental and Genetic models. No significant GxE interaction was observed for any dimension., Conclusions: This study in subjects without psychotic disorders suggests that (i) the aetiological continuum hypothesis could concern particularly the positive dimension of subclinical psychosis, (ii) genetic and environmental factors have independent effects on the level of this positive dimension, (iii) and that interactions between genetic and individual environmental factors could not be identified in this sample.

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.

Background and Hypothesis: Facial Emotion Recognition is a key domain of social cognition associated with psychotic disorders as a candidate intermediate phenotype. In this study, we set out to investigate global and specific facial emotion recognition deficits in first-episode psychosis, and whether polygenic liability to psychotic disorders is associated with facial emotion recognition., Study Design: 828 First Episode Psychosis (FEP) patients and 1308 population-based controls completed assessments of the Degraded Facial Affect Recognition Task (DFAR) and a subsample of 524 FEP and 899 controls provided blood or saliva samples from which we extracted DNA, performed genotyping and computed polygenic risk scores for schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MD)., Study Results: A worse ability to globally recognize facial emotion expressions was found in patients compared with controls [B= -1.5 (0.6), 95% CI -2.7 to -0.3], with evidence for stronger effects on negative emotions (fear [B = -3.3 (1.1), 95% CI -5.3 to -1.2] and anger [B = -2.3 (1.1), 95% CI -4.6 to -0.1]) than on happiness [B = 0.3 (0.7), 95% CI -1 to 1.7]. Pooling all participants, and controlling for confounds including case/control status, facial anger recognition was associated significantly with Schizophrenia Polygenic Risk Score (SZ PRS) [B = -3.5 (1.7), 95% CI -6.9 to -0.2]., Conclusions: Psychosis is associated with impaired recognition of fear and anger, and higher SZ PRS is associated with worse facial anger recognition. Our findings provide evidence that facial emotion recognition of anger might play a role as an intermediate phenotype for psychosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Despite the widespread use of the SH-SY5Y human neuroblastoma cell line in modeling human neurons in vitro, protocols for growth, differentiation and experimentation differ considerably across the literature. Many studies fully differentiate SH-SY5Y cells before experimentation, to investigate plasticity measures in a mature, human neuronal-like cell model. Prior to experimentation, serum is often removed from cell culture media, to arrest the cell growth cycle and synchronize cells. However, the exact effect of this serum removal before experimentation on mature, differentiated SH-SY5Y cells has not yet been described. In studies using differentiated SH-SY5Y cells, any effect of serum removal on plasticity markers may influence results. The aim of the current study was to systematically characterize, in differentiated, neuronal-like SH-SY5Y cells, the potentially confounding effects of complete serum removal in terms of morphological and gene expression markers of plasticity. We measured changes in commonly used morphological markers and in genes related to neuroplasticity and synaptogenesis, particularly in the BDNF-TrkB signaling pathway. We found that complete serum removal from already differentiated SH-SY5Y cells increases neurite length, neurite branching, and the proportion of cells with a primary neurite, as well as proportion of βIII-Tubulin and MAP2 expressing cells. Gene expression results also indicate increased expression of PSD95 and NTRK2 expression 24 h after serum removal. We conclude that serum deprivation in differentiated SH-SY5Y cells affects morphology and gene expression and can potentially confound plasticity-related outcome measures, having significant implications for experimental design in studies using differentiated SH-SY5Y cells as a model of human neurons., (© 2021. The Author(s).)

Emotional complexity (EC) involves the ability to distinguish between distinct emotions (differentiation) and the experience of a large range of emotions (diversity). Lower EC has been related to psychopathology in cross-sectional studies. This study aimed to investigate (a) whether EC prospectively predicts psychopathology and (b) whether this effect is contingent on stressful life events. To further explore EC, we compared the effects of differentiation and diversity. Adolescents from the general population ( N = 401) rated 8 negatively valenced emotions 10 times a day for 6 consecutive days. Further, they completed the Symptom Checklist-90 (baseline and 1-year follow-up) and a questionnaire on past year's life events at follow-up. Logistic regression analyses tested whether EC-reflected by emotion differentiation (intraclass correlation coefficient [ICC]) and diversity (diversity index [DI])-predicted prognosis (good: remitting or lacking symptoms vs. bad: worsening or persisting symptoms). EC predicted prognoses but only when based on the ICC ( OR EC.ICC = 1.42, p = .02). An EC ICC 1 SD above average increased the probability of good prognosis from .67 to .74. This effect was not related to stressful life events ( OR EC × Life events = 1.03, p = .86) and disappeared when emotion intensity (mean level) was taken into account ( OR EC = 1.20, p = .20). Predicting future prognosis does not necessitate complex measures of emotional experience (ICC, DI) but rather might be achieved through simpler indices (mean). The discrepant effects of the ICC and DI on prognosis suggest that impaired emotion representation (ICC) plays a more important role in vulnerability to mental ill health than does low diversity of emotions (DI). (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Objective: People at ultra-high risk (UHR) for psychosis have a high prevalence of tobacco smoking, and rates are even higher among the subgroup that later develop a psychotic disorder. However, the longitudinal relationship between the course of tobacco smoking and clinical outcomes in UHR subjects is unknown., Methods: We investigated associations between tobacco smoking and clinical outcomes in a prospective study of UHR individuals ( n = 324). Latent class mixed model analyses were used to identify trajectories of smoking severity. Mixed effects models were applied to investigate associations between smoking trajectory class and the course of attenuated psychotic symptoms (APS) and affective symptoms, as assessed using the CAARMS., Results: We identified four different classes of smoking trajectory: (i) Persistently High ( n = 110), (ii) Decreasing ( n = 29), (iii) Persistently Low ( n = 165) and (iv) Increasing ( n = 20). At two-year follow-up, there had been a greater increase in APS in the Persistently High class than for both the Persistently Low (ES = 9.77, SE = 4.87, p = 0.046) and Decreasing (ES = 18.18, SE = 7.61, p = 0.018) classes. There were no differences between smoking classes in the incidence of psychosis. There was a greater reduction in the severity of emotional disturbance and general symptoms in the Decreasing class than in the High (ES = -10.40, SE = 3.41, p = 0.003; ES = -22.36, SE = 10.07, p = 0.027), Increasing (ES = -11.35, SE = 4.55, p = 0.014; ES = -25.58, SE = 13.17, p = 0.050) and Low (ES = -11.38, SE = 3.29, p = 0.001; ES = -27.55, SE = 9.78, p = 0.005) classes, respectively., Conclusions: These findings suggests that in UHR subjects persistent tobacco smoking is associated with an unfavorable course of psychotic symptoms, whereas decrease in the number of cigarettes smoked is associated with improvement in affective symptoms. Future research into smoking cessation interventions in the early stages of psychoses is required to shine light on the potential of modifying smoking behavior and its relation to clinical outcomes., (Copyright © 2022 Schirmbeck, van der Ven, Boyette, McGuire, Valmaggia, Kempton, van der Gaag, Riecher-Rössler, Barrantes-Vidal, Nelson, Krebs, Ruhrmann, Sachs, Rutten, Nordentoft, Group, de Haan and Vermeulen.)

Background: Adolescence is a period of both great social change, and of vulnerability to psychiatric distress. However, little is known about the associations between early psychopathology and social interactions at the fundamental level of daily life. To better understand the social correlates of subclinical psychopathology in adolescence, we assessed associations between general psychopathology and the quantity and quality of daily-life social interactions., Methods: During a six-day experience sampling period, adolescent and young adult participants in Study 1 (n = 663) and Study 2 (n = 1027) reported the quantity and quality of their everyday social interactions. General psychopathology was assessed using the Symptom Checklist-90 and Brief Symptom Inventory-53. The relationship between psychopathology and each outcome variable was tested in separate multilevel linear and logistic regression models., Results: General psychopathology was associated with social interaction quality. Associations between psychopathology and the number of social interactions were less apparent: In Study 1, participants with more psychopathology were not more alone, whereas Study 2 participants with higher levels of psychopathology were alone more., Limitations: Limitations include no separate investigation of distinct types of psychopathology, and relatively low compliance to the experience sampling in Study 2., Conclusions: Consistent associations between subclinical psychopathology and the quality of social interactions support the fundamentally social nature of early psychopathology. Moreover, negative experiences of social interactions may be more valuable markers of early psychopathology than a reduced quantity of social behaviors. Conceptualizations of daily-life social functioning, and prevention/intervention efforts would benefit from a greater consideration of the quality of everyday social experiences., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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.

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.

Epigenetic clocks are widely used aging biomarkers calculated from DNA methylation data, but this data can be surprisingly unreliable. Here we show technical noise produces deviations up to 9 years between replicates for six prominent epigenetic clocks, limiting their utility. We present a computational solution to bolster reliability, calculating principal components from CpG-level data as input for biological age prediction. Our retrained principal-component versions of six clocks show agreement between most replicates within 1.5 years, improved detection of clock associations and intervention effects, and reliable longitudinal trajectories in vivo and in vitro . This method entails only one additional step compared to traditional clocks, requires no replicates or prior knowledge of CpG reliabilities for training, and can be applied to any existing or future epigenetic biomarker. The high reliability of principal component-based clocks is critical for applications to personalized medicine, longitudinal tracking, in vitro studies, and clinical trials of aging interventions., Competing Interests: Competing Interests Statement MEL and AHC have built epigenetic aging metrics involving the technology described in the present manuscript, and these metrics are licensed by Elysium Health through Yale University. Elysium provided paired blood and saliva replicate datasets reported in this study, but otherwise did not fund the study and did not play a role in conceptualization, design, decision to publish, or preparation of the manuscript. MEL previously acted as a Scientific Advisor for, and received consulting fees from, Elysium Health, Inc. THS was previously an employee of Elysium Health, Inc. AHC received consulting fees from FOXO Technologies, Inc. for work unrelated to the present manuscript. All other authors report no biomedical financial interests or potential conflicts of interest.

Objective: To examine the association between baseline alterations in grey matter volume (GMV) and clinical and functional outcomes in people at clinical high risk (CHR) for psychosis., Methods: 265 CHR individuals and 92 healthy controls were recruited as part of a prospective multi-center study. After a baseline assessment using magnetic resonance imaging (MRI), participants were followed for at least two years to determine clinical and functional outcomes, including transition to psychosis (according to the Comprehensive Assessment of an At Risk Mental State, CAARMS), level of functioning (according to the Global Assessment of Functioning), and symptomatic remission (according to the CAARMS). GMV was measured in selected cortical and subcortical regions of interest (ROI) based on previous studies (ie orbitofrontal gyrus, cingulate gyrus, gyrus rectus, inferior temporal gyrus, parahippocampal gyrus, striatum, and hippocampus). Using voxel-based morphometry, we analysed the relationship between GMV and clinical and functional outcomes., Results: Within the CHR sample, a poor functional outcome (GAF < 65) was associated with relatively lower GMV in the right striatum at baseline ( P < .047 after Family Wise Error correction). There were no significant associations between baseline GMV and either subsequent remission or transition to psychosis., Conclusions: In CHR individuals, lower striatal GMV was associated with a poor level of overall functioning at follow-up. This finding was not related to effects of antipsychotic or antidepressant medication. The failure to replicate previous associations between GMV and later psychosis onset, despite studying a relatively large sample, is consistent with the findings of recent large-scale multi-center studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Due to the unprecedented impact of the COVID-19 pandemic on health care systems, there has been great interest in the mental wellbeing of healthcare workers. While most studies investigated mental health outcomes among frontline vs. non-frontline healthcare workers, little is known about the impact of various work-related variables. The present study aimed to examine the association between work-related [i.e., having contact with COVID-19 patients, being redeployed due to the pandemic and availability of sufficient personal protective equipment (PPE)] and subjective (i.e., worries about getting infected or infecting others) exposures and self-reported mental health outcomes (i.e., psychological distress, depressive symptoms, and posttraumatic stress symptoms). Between February and May 2021, 994 healthcare workers employed at a variety of healthcare settings in the Netherlands filled out an online survey as part of the COVID-19 HEalth caRe wOrkErS (HEROES) study. Mental health outcomes were measured using the General Health Questionnaire-12, the Patient Health Questionnaire-9, and the Primary Care PTSD Screen for DSM-5. Approximately 13% reported depressive symptoms, 37% experienced psychological distress, and 20% reported posttraumatic stress symptoms. Multilevel linear models consisted of three levels: individual (work-related and subjective exposures), healthcare center (aggregated redeployment and availability of sufficient PPE), and regional (cumulative COVID-19 infection and death rates). Worries about infection were associated with all three mental health outcomes, whereas insufficient PPE was associated with psychological distress and depressive symptoms. There were no differences in outcomes between healthcare centers or provinces with different COVID-19 infection and death rates. Our findings highlight the importance of adequate PPE provision and the subjective experience of the COVID-19 pandemic. These factors should be part of interventions aimed at mitigating adverse mental health outcomes among healthcare workers during the COVID-19 pandemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Czepiel, Hoek, van der Markt, Rutten, Veling, Schirmbeck, Mascayano, Susser and van der Ven.)