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Objectives: The Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale) is the most widely used clinical measure of lithium response phenotypes. We assess its performance against recommended psychometric and clinimetric standards. Methods: We used data from the Consortium for Lithium Genetics and a French study of lithium response phenotypes (combined sample >2500) to assess reproducibility, responsiveness, validity, and interpretability of the A scale (assessing change in illness activity), the B scale, and its items (assessing confounders of response) and the previously established response categories derived from the Total Score for the Alda scale. Results: The key findings are that the B scale is vulnerable to error measurement. For example, some items contribute little to overall performance of the Alda scale (eg, B2) and that the B scale does not reliably assess a single construct (uncertainty in response). Machine learning models indicate that it may be more useful to employ an algorithm for combining the ratings of individual B items in a sequence that clarifies the noise to signal ratio instead of using a composite score. Conclusions: This study highlights three important topics. First, empirical approaches can help determine which aspects of the performance of any scale can be improved. Second, the B scale of the Alda is best applied as a multidimensional index (identifying several independent confounders of the assessment of response). Third, an integrated science approach to precision psychiatry is vital, otherwise phenotypic misclassifications will undermine the reliability and validity of findings from genetics and biomarker studies. [ABSTRACT FROM AUTHOR]

Introduction: Studies about mental health of medical students have highlighted higher rates of depression compared to the general population. However, comparisons to a general student population are rare. Objectives: The French Observatoire national de la Vie Etudiante (OVE) has conducted a national survey and has measured the 12-month prevalence of major depressive episode (MDE) with the CIDI-SF and suicidal thoughts in 18,875 students. Methods: This survey investigated 2,414 medical students including 975 in the 1st year, 607 in the preclinical phase, 342 clinical studentsand 485 residents. MDE was regressed on the sociodemographic data using univariate and multivariate logistic regression and a network analysis was performed to compare the symptoms between students. Results: There was no significant difference for MDE prevalence among medical students (15.4%) compared to other fields of studies (15.7%). There was also no difference comparing the networks of depressive symptoms. However, some categories were particularly at risk for MDE: 1st year of medical studies (OR=1.74, 95%CI=[1.41-2.13]); Letters, Humanities and Social Sciences (OR=1.39[1.23-1.58]) and Law or Economics (OR=1.20[1.04-1.39]). Other sociodemographic variables were also significant risk factors: having important financial difficulties (OR=2.93[2.61-3.29]), having a net parental income less than 1500€/month (OR=1.17[1.02-1.34]), receiving scholarships based on social criteria (OR=1.11[1.01-1.23]), being of a female gender (OR=1.45[1.32-1.60]), being single (OR=1.35[1.20-1.52]). Prevalence of suicidal ideation is no different betweenmedical students (8.53%) and other fields of studies (8.68%). Conclusions: This is the largest cross-sectional French study about student mental health. The prevalence of MDEremains higher than in the general population (9.8%). [ABSTRACT FROM AUTHOR]

Background In the Western world, more than 2 million people were exposed in utero to diethylstilbestrol. In exposed individuals and in their descendants, several adverse outcomes have been linked to such exposure, like cancers, genital malformations and, less consistently, psychiatric disorders. Disruption of epigenetic homeostasis was proposed as the molecular substratum of this environmental factor but was not fully proven. Methods We selected 69 siblings from 30 families. In each family, at least one sibling was exposed in utero to diethylstilbestrol. We analyzed DNA methylation using Human Methylation 450 DNA Analysis BeadChip ® . We performed a methylome-wide association analysis searching for specific methylation changes in exposed versus unexposed individuals. Secondary, we compared exposed individuals with and without genital malformation, and with and without psychosis. Results No differentially methylated regions were identified between exposed and unexposed individuals. Yet, our analyses showed that exposed individuals with genital or psychotic abnormalities have several specific differentially methylated regions compared with exposed individuals without complication. These CpGs were located in genes relevant for cancer (ADAMTS9), genital abnormalities (HOOK2) and psychiatric diseases (ZFP57). Conclusions In utero exposure to diethylstilbestrol is not associated with changes in methylation profiles. In exposed individuals though, specific traits are associated with methylomic modifications encompassing genomic regions, mostly involved in cancer and neurodevelopment, leading to heterogeneous consequences. [ABSTRACT FROM AUTHOR]

Background: Treatment resistance is a major challenge in psychiatric disorders. Early detection of potential future resistance would improve prognosis by reducing the delay to appropriate treatment adjustment and recovery. Here, we sought to determine whether neurodevelopmental markers can predict therapeutic response., Methods: Healthy controls ( N = 236), patients with schizophrenia ( N = 280) or bipolar disorder ( N = 78) with a known therapeutic outcome, were retrospectively included. Age, sex, education, early developmental abnormalities (obstetric complications, height, weight, and head circumference at birth, hyperactivity, dyslexia, epilepsy, enuresis, encopresis), neurological soft signs (NSS), and ages at first subjective impairment, clinical symptoms, treatment, and hospitalization, were recorded. A supervised algorithm leveraged NSS and age at first clinical signs to classify between resistance and response in schizophrenia., Results: Developmental abnormalities were more frequent in schizophrenia and bipolar disorder than in controls. NSS significantly differed between controls, responsive, and resistant participants with schizophrenia (5.5 ± 3.0, 7.0 ± 4.0, 15.0 ± 6.0 respectively, p = 3 × 10 -10 ) and bipolar disorder (5.5 ± 3.0, 8.3 ± 3.0, 12.5 ± 6.0 respectively, p < 1 × 10 -10 ). In schizophrenia, but not in bipolar disorder, age at first subjective impairment was three years lower, and age at first clinical signs two years lower, in resistant than responsive subjects ( p = 2 × 10 -4 and p = 9 × 10 -3 , respectively). Age at first clinical signs and NSS accurately predicted treatment response in schizophrenia (area-under-curve: 77 ± 8%, p = 1 × 10 -14 )., Conclusions: Neurodevelopmental features such as NSS and age of clinical onset provide a means to identify patients who may require rapid treatment adaptation.

Background: Dermatoglyphic pattern deviances have been associated with schizophrenia-spectrum disorders (SSD) and are considered neurodevelopment vulnerability markers based on the shared ectodermal origin of the epidermis and the central nervous system. The endocannabinoid system participates in epidermal differentiation, is sensitive to prenatal insults and is associated with SSD. Objective: We aimed to investigate whether the Cannabinoid Receptor 1 gene ( CNR1 ) modulates the dermatoglyphics-SSD association. Methods: In a sample of 112 controls and 97 patients with SSD, three dermatoglyphic markers were assessed: the total palmar a-b ridge count (TABRC), the a-b ridge count fluctuating asymmetry (ABRC-FA), and the pattern intensity index (PII). Two CNR1 polymorphisms were genotyped: rs2023239-T/C and rs806379-A/T. We tested: (i) the CNR1 association with SSD and dermatoglyphic variability within groups; and (ii) the CNR1 × dermatoglyphic measures interaction on SSD susceptibility. Results: Both polymorphisms were associated with SSD. The polymorphism rs2023239 modulated the relationship between PII and SSD: a high PII score was associated with a lower SSD risk within C-allele carriers and a higher SSD risk within TT-homozygotes. This result indicates an inverse relationship between the PII and the SSD predicted probability conditional to the rs2023239 genotype. Conclusions: These novel findings suggest the endocannabinoid system's role in the development and variability of dermatoglyphic patterns. The identified interaction encourages combining genetic and dermatoglyphics to assess neurodevelopmental alterations predisposing to SSD in future studies.

Cerebral adrenoleukodystrophy (CALD) is an X-linked rapidly progressive demyelinating disease leading to death usually within a few years. The standard of care is haematopoietic stem cell transplantation (HSCT), but many men are not eligible due to age, absence of a matched donor or lesions of the corticospinal tracts (CST). Based on the ADVANCE study showing that leriglitazone decreases the occurrence of CALD, we treated 13 adult CALD patients (19-67 years of age) either not eligible for HSCT (n = 8) or awaiting HSCT (n = 5). Patients were monitored every 3 months with standardized neurological scores, plasma biomarkers and brain MRI comprising lesion volumetrics and diffusion tensor imaging. The disease stabilized clinically and radiologically in 10 patients with up to 2 years of follow-up. Five patients presented with gadolinium enhancing CST lesions that all turned gadolinium negative and, remarkably, regressed in four patients. Plasma neurofilament light chain levels stabilized in all 10 patients and correlated with lesion load. The two patients who continued to deteriorate were over 60 years of age with prominent cognitive impairment. One patient died rapidly from coronavirus disease 2019. These results suggest that leriglitazone can arrest disease progression in adults with early-stage CALD and may be an alternative treatment to HSCT., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Psychiatric disorders often emerge during adolescence or young adulthood, leading to significant disability among youth. The transition from Child and Adolescent Mental Health Services (CAMHS) to Adult Mental Health Services (AMHS) is critical for individuals experiencing emerging psychopathology, with delayed access to care negatively impacting long-term outcomes. Accessing mental health services for adolescents and young adults is often complex and delayed due to challenges in service visibility, accessibility and appropriateness., Methods: This study examines the care trajectories of individuals consecutively accessing the early detection and intervention (EDI) centre C'JAAD (Evaluation Centre for Young Adults and Adolescents) in Paris (France) over the year 2021. The main goal was to clarify the role of this EDI centre in the continuity of care and transition to AMHS. Data about their history of care, hospitalisations and referral sources were collected retrospectively., Results: The sample comprised 194 individuals, with 57.2% males and a median age of 20 years. Most patients (67.5%) were ≥18 years old upon arrival, with 31% in a situation of not being in education, employment, or training (NEET). Over one-third (35.2%) had prior psychiatric hospitalisations. Patients were mainly referred to our EDI centre from other hospital departments (42.3%). Regarding care in CAMHS, 50.3% of the total sample had medical follow-up during childhood, of whom 41.9% had discontinued care upon arrival at the EDI centre. The median onset age of care in CAMHS was 14, with a median duration of 12 months. Adult patients experienced an approximately 3-year gap between the end of CAMHS care and assessment at the EDI centre., Discussion: The sample's characteristics resemble those of other EDI centres, but concerns persist regarding referral timing and the NEET status of many youths. Lack of prior medical follow-up and challenges in transitioning to AMHS underscore the need to enhance care continuity and address difficulties in accessing care during the transition to adulthood., (© 2024 The Author(s). Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Detecting patients with a high-risk profile for treatment-resistant schizophrenia (TRS) can be beneficial for implementing individually adapted therapeutic strategies and better understanding the TRS etiology. The aim of this study was to explore, with machine learning methods, the impact of demographic and clinical patient characteristics on TRS prediction, for already established risk factors and unexplored ones. This was a retrospective study of 500 patients admitted during 2020 to the University Hospital Group for Paris Psychiatry. We hypothesized potential TRS risk factors. The selected features were coded into structured variables in a new dataset, by processing patients discharge summaries and medical narratives with natural-language processing methods. We compared three machine learning models (XGBoost, logistic elastic net regression, logistic regression without regularization) for predicting TRS outcome. We analysed feature impact on the models, suggesting the following factors as markers of a high-risk TRS profile: early age at first contact with psychiatry, antipsychotic treatment interruptions due to non-adherence, absence of positive symptoms at baseline, educational problems and adolescence mental disorders in the personal psychiatric history. Specifically, we found a significant association with TRS outcome for age at first contact with psychiatry and medication non-adherence. Our findings on TRS risk factors are consistent with the review of the literature and suggest potential in using early pathophysiologic features for TRS prediction. Results were encouraging with the use of natural-langage processing techniques to leverage raw data provided by discharge summaries, combined with machine leaning models. These findings are a promising step for helping clinicians adapt their guidelines to early detection of TRS., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Relatives of ADHD probands are known to be at increased risk of schizophrenia and bipolar disorder, suggesting shared genetic factors. In this study, we aim to identify shared common risk variants (i.e., Single-Nucleotide Polymorphisms, SNPs) between ADHD and schizophrenia, and between ADHD and bipolar disorder., Methods: With the summary data from three GWAS, one on ADHD (20,183 cases with ADHD and 35,191 controls), another on schizophrenia (76,755 cases with schizophrenia and 243,649 controls) and another on bipolar disorder (41,917 cases with bipolar disorder and 371,549 controls), we used colocalization analysis to identify SNPs shared by ADHD and schizophrenia, and SNPs shared by ADHD and bipolar disorder. Functional genomic analyses were then conducted on these two sets of shared common genetic variants., Results: We found that three of the 12 SNPs associated with ADHD colocalized with schizophrenia SNPs and one of the 12 SNPs associated with ADHD colocalized with bipolar disorder. Only 0.4% of the SNPs associated with schizophrenia (2 out of 431) and 2.3% of the SNPs associated with bipolar disorder (2 out of 86), colocalized with ADHD SNPs. Some genes mapped to these shared genetic variants (SCN2A and UNC5D) are involved in the development of the nervous system., Conclusions: Using colocalization analysis, the present study uncovers shared genetic variants associated with ADHD and schizophrenia as well as ADHD and bipolar disorder, and may at least partially explain the increased risk of schizophrenia and bipolar disorder in relatives of ADHD probands., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Bipolar disorder (BD) is a multifactorial psychiatric illness affecting ∼1% of the global adult population. Lithium (Li), is the most effective mood stabilizer for BD but works only for a subset of patients and its mechanism of action remains largely elusive., Methods: In the present study, we used iPSC-derived neurons from patients with BD who are responsive (LR) or not (LNR) to lithium. Combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics were employed to provide mechanistic insights into neuronal hyperactivity in BD, investigate Li's mode of action, and identify alternative treatment strategies., Findings: We show a selective rescue of the neuronal hyperactivity phenotype by Li in LR neurons, correlated with changes to Na + conductance. Whole transcriptome sequencing in BD neurons revealed altered gene expression pathways related to glutamate transmission, alterations in cell signalling and ion transport/channel activity. We found altered Akt signalling as a potential therapeutic effect of Li in LR neurons from patients with BD, and that Akt activation mimics Li effect in LR neurons. Furthermore, the increased neural network activity observed in both LR & LNR neurons from patients with BD were reversed by AMP-activated protein kinase (AMPK) activation., Interpretation: These results suggest potential for new treatment strategies in BD, such as Akt activators in LR cases, and the use of AMPK activators for LNR patients with BD., Funding: Supported by funding from ERA PerMed, Bell Brain Canada Mental Research Program and Brain & Behavior Research Foundation., Competing Interests: Declaration of interests All the authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Maternal smoking during pregnancy (MSDP) is considered a risk factor for ADHD. While the mechanisms underlying this association are not well understood, MSDP may impact the developing brain in ways that lead to ADHD. Here, we investigated the effect of prenatal smoking exposure on cortical brain structures in children with ADHD using two methods of assessing prenatal exposure: maternal recall and epigenetic typing. Exposure groups were defined according to: (1) maternal recall (+MSDP: n = 24; -MSDP: n = 85) and (2) epigenetic markers (EM) (+EM: n = 14 -EM: n = 21). CIVET-1.1.12 and RMINC were used to acquire cortical brain measurements and perform statistical analyses, respectively. The vertex with highest significance was tested for association with Continuous Performance Test (CPT) dimensions. While no differences of brain structures were identified between +MSDP and -MSDP, +EM children (n = 10) had significantly smaller surface area in the right orbitofrontal cortex (ROFc), middle temporal cortex (RTc) and parahippocampal gyrus (RPHg) (15% FDR) compared to -EM children (n = 20). Cortical surface area in the RPHg significantly correlated with CPT commission errors T-scores. This study suggests that molecular markers may better define exposure to environmental risks, as compared to human recall., Competing Interests: Declaration of competing interest Dr B. Chaumette has received research funding from the foundation Bettencourt Schueller, speaking fees from Janssen-Cilag, Lundbeck, and Eisai outside the submitted work. Dr N. Grizenko is a member of the advisory board of Purdue and Shire. Dr R. Joober is on the advisory boards and speakers’ bureaus of Pfizer, Janssen, Ortho, BMS, Sunovion, Otsuka, Lundbeck, Perdue and Myelin. He has received grant funding from them and from AstraZeneca and HLS. He has received honoraria from Janssen Canada, Shire, Lundbeck, Otsuka, Pfizer, and from Perdue for CME presentations and royalties for Henry Stewart talks. The other authors report no biomedical financial interests nor potential conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Hypothesis: The emergence of psychosis in ultra-high-risk subjects (UHR) is influenced by gene-environment interactions that rely on epigenetic mechanisms such as microRNAs. However, whether they can be relevant pathophysiological biomarkers of psychosis' onset remains unknown., Study Design: We present a longitudinal study of microRNA expression, measured in plasma by high-throughput sequencing at baseline and follow-up, in a prospective cohort of 81 UHR, 35 of whom developed psychosis at follow-up (converters). We combined supervised machine learning and differential graph analysis to assess the relative weighted contribution of each microRNA variation to the difference in outcome and identify outcome-specific networks. We then applied univariate models to the resulting microRNA variations common to both strategies, to interpret them as a function of demographic and clinical covariates., Study Results: We identified 207 microRNA variations that significantly contributed to the classification. The differential network analysis found 276 network-specific correlations of microRNA variations. The combination of both strategies identified 25 microRNAs, whose gene targets were overrepresented in cognition and schizophrenia genome-wide association studies findings. Interpretable univariate models further supported the relevance of miR-150-5p and miR-3191-5p variations in psychosis onset, independent of age, sex, cannabis use, and medication., Conclusions: In this first longitudinal study of microRNA variation during conversion to psychosis, we combined 2 methodologically independent data-driven strategies to identify a dynamic epigenetic signature of the emergence of psychosis that is pathophysiologically relevant., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction and Methods: We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers., Results: These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers' data are close to physicians' data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age, and age at first words., Discussion: Each of the two datasets provides complementary knowledge. We confirmed that symptoms are similar to those in the literature and provides more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder were most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety, and sleep disorders need to be treated., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Background: Quantitative electroencephalography (EEG) analysis offers the opportunity to study high-level cognitive processes across psychiatric disorders. In particular, EEG microstates translate the temporal dynamics of neuronal networks throughout the brain. Their alteration may reflect transdiagnostic anomalies in neurophysiological functions that are impaired in mood, psychosis, and autism spectrum disorders, such as sensorimotor integration, speech, sleep, and sense of self. The main questions this study aims to answer are as follows: 1) Are EEG microstate anomalies associated with clinical and functional prognosis, both in resting conditions and during sleep, across psychiatric disorders? 2) Are EEG microstate anomalies associated with differences in sensorimotor integration, speech, sense of self, and sleep? 3) Can the dynamic of EEG microstates be modulated by a non-drug intervention such as light hypnosis?, Methods: This prospective cohort will include a population of adolescents and young adults, aged 15 to 30 years old, with ultra-high-risk of psychosis (UHR), first-episode psychosis (FEP), schizophrenia (SCZ), autism spectrum disorder (ASD), and major depressive disorder (MDD), as well as healthy controls (CTRL) (N = 21 × 6), who will be assessed at baseline and after one year of follow-up. Participants will undergo deep phenotyping based on psychopathology, neuropsychological assessments, 64-channel EEG recordings, and biological sampling at the two timepoints. At baseline, the EEG recording will also be coupled to a sensorimotor task and a recording of the characteristics of their speech (prosody and turn-taking), a one-night polysomnography, a self-reference effect task in virtual reality (only in UHR, FEP, and CTRL). An interventional ancillary study will involve only healthy controls, in order to assess whether light hypnosis can modify the EEG microstate architecture in a direction opposite to what is seen in disease., Discussion: This transdiagnostic longitudinal case-control study will provide a multimodal neurophysiological assessment of clinical dimensions (sensorimotor integration, speech, sleep, and sense of self) that are disrupted across mood, psychosis, and autism spectrum disorders. It will further test the relevance of EEG microstates as dimensional functional biomarkers., Trial Registration: ClinicalTrials.gov Identifier NCT06045897., (© 2023. The Author(s).)

Aim: Neuroimaging-based machine-learning predictions of psychosis onset rely on the hypothesis that structural brain anomalies may reflect the underlying pathophysiology. Yet, current predictors remain difficult to interpret in light of brain structure. Here, we combined an advanced interpretable supervised algorithm and a model of neuroanatomical age to identify the level of brain maturation of the regions most predictive of psychosis., Methods: We used the voxel-based morphometry of a healthy control dataset (N = 2024) and a prospective longitudinal UHR cohort (N = 82), of which 27 developed psychosis after one year. In UHR, psychosis was predicted at one year using Elastic-Net-Total-Variation (Enet-TV) penalties within a five-fold cross-validation, providing an interpretable map of distinct predictive regions. Using both the whole brain and each predictive region separately, a brain age predictor was then built and validated in 1605 controls, externally tested in 419 controls from an independent cohort, and applied in UHR. Brain age gaps were computed as the difference between chronological and predicted age, providing a proxy of whole-brain and regional brain maturation., Results: Psychosis prediction was performant with 80 ± 4% of area-under-curve and 69 ± 5% of balanced accuracy (P < 0.001), and mainly leveraged volumetric increases in the ventromedial prefrontal cortex and decreases in the left precentral gyrus and the right orbitofrontal cortex. These regions were predicted to have delayed and accelerated maturational patterns, respectively., Conclusion: By combining an interpretable supervised model of conversion to psychosis with a brain age predictor, we showed that inter-regional asynchronous brain maturation underlines the predictive signature of psychosis., (© 2023 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Background: Catatonia is a psychomotor syndrome frequently observed in disorders with neurodevelopmental impairments, including psychiatric disorders such as schizophrenia. The orbitofrontal cortex (OFC) has been repeatedly associated with catatonia. It presents with an important interindividual morphological variability, with three distinct H-shaped sulcal patterns, types I, II, and III, based on the continuity of the medial and lateral orbital sulci. Types II and III have been identified as neurodevelopmental risk factors for schizophrenia. The sulcal pattern of the OFC has never been investigated in catatonia despite the role of the OFC in the pathophysiology and the neurodevelopmental component of catatonia., Methods: In this context, we performed a retrospective analysis of the OFC sulcal pattern in carefully selected homogeneous and matched subgroups of schizophrenia patients with catatonia ( N  = 58) or without catatonia ( N  = 65), and healthy controls ( N  = 82)., Results: Logistic regression analyses revealed a group effect on OFC sulcal pattern in the left ( χ 2  = 18.1; p  < .001) and right ( χ 2  = 28.3; p  < .001) hemispheres. Catatonia patients were found to have more type III and less type I in both hemispheres compared to healthy controls and more type III on the left hemisphere compared to schizophrenia patients without catatonia., Conclusion: Because the sulcal patterns are indirect markers of early brain development, our findings support a neurodevelopmental origin of catatonia and may shed light on the pathophysiology of this syndrome.

Background: Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent childhood disorder. Maternal smoking during pregnancy is a replicated environmental risk factor for this disorder. It is also a robust modifier of gene methylation during the prenatal developmental period. In this study, we sought to identify loci differentially methylated by maternal smoking during pregnancy and relate their methylation levels to various behavioural and physical outcomes relevant to ADHD., Methods: We extracted DNA from blood samples from children diagnosed with ADHD and deeply phenotyped. Genome-wide DNA methylation was assessed using Infinium MethylationEPIC BeadChip. Maternal smoking during pregnancy was self-declared and assessed retrospectively., Results: Our sample included 231 children with ADHD. Statistically significant differences in DNA methylation between children exposed or not to maternal smoking during pregnancy were detected in 3457 CpGs. We kept 30 CpGs with at least 5% of methylation difference between the 2 groups for further analysis. Six genes were associated with varied phenotypes of clinical relevance to ADHD. The levels of DNA methylation in RUNX1 were positively correlated with the CBCL scores, and DNA methylation in MYO1G correlated positively with the score at the Conners rating scale. Methylation level in a CpG located in GFI1 correlated with birthweight, a risk factor for ADHD. Differentially methylated regions were also identified and confirmed the association of RUNX1 methylation levels with the CBCL score., Limitations: The study has several limitations, including the retrospective recall with self-report of maternal smoking during pregnancy as well as the grouping of individuals of varying age and developmental stage and of both males and females. In addition, the correlation design prevents the building of causation models., Conclusion: This study provides evidence for the association between the level of methylation at specific loci and quantitative dimensions highly relevant for ADHD as well as birth weight, a measure that has already been associated with increased risk for ADHD. Our results provide further support to public health educational initiatives to stop maternal smoking during pregnancy., Competing Interests: Competing interests: B. Chaumette has received research funding from the Fondation Bettencourt Schueller (180 000€/4 yr) and speaking fees from Janssen-Cilag, Lundbeck and Eisai, outside the submitted work. He has no direct employment in profit organizations nor consultancies. N. Grizenko reports receiving research funding from the Canadian Institutes of Health Research (CIHR) and is a member of the advisory board for Purdue and Shire. A. Labbe is an associate editor of JPN. She was not involved in the review or decision to accept this manuscript for publication. R. Joober reports having received research funding from CIHR. He is on the advisory boards and speakers’ bureaus of Pfizer, Janssen Ortho, BMS, Sunovion, Otsuka, Lundbeck, Perdue and Myelin. He has received grant funding from them and from AstraZeneca and HLS. He has received honoraria from Janssen Canada, Shire, Lundbeck, Otsuka, Pfizer and from Perdue for CME presentations and royalties for Henry Stewart talks. No other competing interests were declared., (© 2023 CMA Impact Inc. or its licensors.)

Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) and major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is a lack of knowledge and guidelines for psychiatric genetic testing (PsychGT) and genetic counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status of PsychGT and PsychGC across 35 participating European countries. Here, we present the results of a pan-European online survey in which we gathered the opinions, knowledge, and practices of a self-selected sample of professionals involved/interested in the field. We received answers from 181 respondents. The three main occupational categories were genetic counselor (21.0%), clinical geneticist (24.9%), and researcher (25.4%). Of all 181 respondents, 106 provide GC for any psychiatric disorder or NDD, corresponding to 58.6% of the whole group ranging from 43.2% in Central Eastern Europe to 66.1% in Western Europe. Overall, 65.2% of the respondents reported that genetic testing is offered to individuals with NDD, and 26.5% indicated the same for individuals with major psychiatric disorders. Only 22.1% of the respondents indicated that they have guidelines for PsychGT. Pharmacogenetic testing actionable for psychiatric disorders was offered by 15%. Interestingly, when genetic tests are fully covered by national health insurance, more genetic testing is provided for individuals with NDD but not those with major psychiatric disorders. Our qualitative analyses of responses highlight the lack of guidelines and knowledge on utilizing and using genetic tests and education and training as the major obstacles to implementation. Indeed, the existence of psychiatric genetic training courses was confirmed by only 11.6% of respondents. The question on the relevance of up-to-date education and training in psychiatric genetics on everyday related practice was highly relevant. We provide evidence that PsychGC and PsychGT are already in use across European countries, but there is a lack of guidelines and education. Harmonization of practice and development of guidelines for genetic counseling, testing, and training professionals would improve equality and access to quality care for individuals with psychiatric disorders within Europe., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Depression is one of the leading causes of morbidity worldwide and increases the risk of suicide. Students are known as a population at risk for depression. This study aimed to evaluate the prevalence of 12 months major depressive episode (MDE) and suicidal thoughts in French students and investigate associated factors. A questionnaire was sent by email to a representative sample of the French student population between April 28th and June 27th 2016. MDE was assessed using the Composite International Diagnostic Interview Short Form (CIDI-SF). The response rate was 18.7% (N= 18,875). Prevalence of 12 months MDE was 15.8%, and suicidal thoughts was 9%. Factors associated with MDE were being a woman, study field (law/eco, human/social sciences, and medical), having failed midterms exams or dropout, refusal or stop social scholarship, and subjective financial difficulties. Factors associated with suicidal thoughts were study field (human/social sciences), having failed midterms exams or dropout, and important subjective financial difficulties. The use of CIDI-SF allows comparison with the 2017 French national study, and showed more MDE in students than in the general population. This is the only national study on French students before COVID 19 pandemic., Competing Interests: Declaration of Competing Interest Y.M. received funding from the University of Paris Nanterre, Inserm, GHU Sainte-Anne, Fondation de France, Fondation Pierre Deniker. Yannick Morvan is or has been a member of various professional and scientific organisations of or involving psychologists (AEPU, AFTCC, AFRC, APA, APS, IdPsy, IEPA, FFPP, SFP). He is also a member of the scientific college of the Observatoire National de la Vie Etudiante (OVE) and of the scientific committee of the Encéphale congress. He carried out a consultancy mission for Ernst & Young in 2007. B.C. has received speaking fees from Janssen Cilag, Lundbeck and Eisai, outside the submitted work. A.C., and A.F. declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Electroencephalography (EEG) microstates translate resting-state temporal dynamics of neuronal networks throughout the brain and could constitute possible markers of psychiatric disorders. We tested the hypothesis of an increased imbalance between a predominant self-referential mode (microstate C) and a decreased attentional mode (microstate D) in psychosis, mood, and autism spectrum disorders., Methods: We retrospectively included 135 subjects from an early psychosis outpatient unit, with available eyes-closed resting-state 19 electrodes EEG. Individual-level then group-level modified K -means clustering in controls provided four microstate maps that were then backfitted to all groups. Differences between microstate parameters (occurrence, coverage, and mean duration) were computed between controls and each group, and between disease groups., Results: Microstate class D parameters were systematically decreased in disease groups compared with controls, with an effect size increasing along the psychosis spectrum, but also in autism. There was no difference in class C. C/D ratios of mean duration were increased only in SCZ compared with controls., Conclusions: The decrease in microstate class D may be a marker of stage of psychosis, but it is not specific to it and may rather reflect a shared dimension along the schizophrenia-autism spectrum. C/D microstate imbalance may be more specific to schizophrenia.

Alterations in membrane lipids are reported in schizophrenia. However, no conclusion can be drawn regarding the extended and predictive value of these alterations in persons at ultra-high risk of psychosis (UHR). Recent studies suggested that sterols' impact on psychiatric disorders was underestimated. Here, we simultaneously explored sterols, fatty acids (FA), and phospholipids (PL) in UHR persons for the first time. We analysed erythrocyte membrane lipids in 61 UHR persons, including 29 who later converted to psychosis (UHR-C) and 32 who did not (UHC-NC). We used gas chromatography for FA and liquid chromatography tandem with mass spectrometry for sterols and phospholipids. Among UHR individuals, elevated baseline membrane linoleic acid level was associated with conversion to psychosis (26.1% vs. 60.5%, p = 0.02). Combining sterols, FA, and PL membrane composition improved the prediction of psychosis onset (AUC = 0.73). This is the first report showing that membrane sterol participates, with other membrane lipids, in modulating the risk of psychosis. It suggests that membrane lipids could be used as biomarkers for personalised medicine in UHR patients.

On June 2022, the 2nd Webinar "Neurodevelopmental Disorders (NDD) without boundaries took place at the Imagine Institute in Paris and was broadcasted live and in replay. The aim of this webinar is to address NDD in a dimensional rather than in a categorical approach. Several speakers were invited to present their researches on the subject. Classifications in NDD were discussed: irritability in NDD, involvement of the immune system in neurodevelopment, nutrition and gut microbiota modulate brain inflammation and neurodevelopment, co-occurring conditions in autistic adolescents and adults without intellectual disability. Classifications in psychiatric disorders were asked: mapping the effect of genes on cognition and autism risk, epigenetics and symptomatic trajectory in neurodevelopmental disorders, the autism-schizophrenia continuum in two examples: minor neurological signs and EEG microstates, the cerebellum in schizophrenia and autism: from imaging to intervention perspectives. Both genetic and environmental factors, along with clinical and imaging features, argue toward a continnum between NDD but also with adult psychiatric presentations. This new paradigm could modify the therapeutic strategy, with the development of large-spectrum treatments or new psychotherapies addressing co-occuring symptoms. The complexity and the heterogeneity of NDD apply well to the next scientific and political challenges: developing international convergence to push back the frontiers of our knowledge. This article is a summary of the 2nd webinar "Neurodevelopmental Disorders (NDD) without boundaries: research and interventions beyond classifications" sponsored by the French National Academy of Medicine, the autism and neurodevelopmental disorders scientific interest group (GIS), the International Research Network Dev-O-Psy and the French Institute of Psychiatry (GDR3557). Oral presentations are available as a replay on the following website (in French): https://autisme-neurodev.org/evenements/2022/04/12/tnd-sans-frontieres-la-recherche-et-les-interventions-au-dela-des-classifications/ ., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Down syndrome (DS) is one of the most frequent genetic disorders and represents the first cause of intellectual disability of genetic origin. While the majority of patients with DS follow a harmonious evolution, an unusual neurodevelopmental regression may occur, distinct from that described in the context of autism spectrum disorders, called down syndrome regression disorder (DSRD). Based on four patients, two males and two females, with age range between 20 and 24, treated at the Reference Center for Rare Psychiatric Disorders of the GHU Paris Psychiatry and Neurosciences [Pôle hospitalo-universitaire d'Évaluation Prévention et Innovation Thérapeutique (PEPIT)], we describe this syndrome, discuss its etiologies and propose therapeutic strategies. DSRD often occurs in late adolescence. There is a sudden onset of language disorders, loss of autonomy and daily living skills, as well as behavioral symptoms such as depression, psychosis, or catatonia. These symptoms are non-specific and lead to an overlap with other diagnostic categories, thus complicating diagnosis. The etiologies of the syndrome are not clearly identified but certain predispositions of patients with trisomy 21 have suggested an underlying immune-mediated mechanism. Symptomatic therapeutic approaches (serotonergic antidepressants, atypical antipsychotics, benzodiazepines) were not effective, and generally associated with poor tolerance. Etiological treatments, including anti-inflammatory drugs and corticosteroids, led to partial or good recovery in the four cases. Early recognition of regressive symptoms and rapid implementation of adapted treatments are required to improve the quality of life of patients and their families., 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 © 2023 Bonne, Iftimovici, Mircher, Conte, Louveau, Legrand, Danset-Alexandre, Cannarsa, Debril, Consoli, Krebs, Ellul and Chaumette.)

Introduction: Prader-Willi Syndrome (PWS) is a rare genetic condition, which affects one in 25,000 births and results in various phenotypes. It leads to a wide range of metabolic and endocrine disorders including growth delay, hypogonadism, narcolepsy, lack of satiety and compulsive eating, associated with mild to moderate cognitive impairment. Prognosis is especially determined by the complications of obesity (diabetes, cardiorespiratory diseases) and by severe behavioral disorders marked by impulsivity and compulsion. This heterogeneous clinical picture may lead to mis- or delayed diagnosis of comorbidities. Moreover, when diagnosis is made, treatment remains limited, with high interindividual differences in drug response. This may be due to the underlying genetic variability of the syndrome, which can involve several different genetic mutations, notably deletion or uniparental disomy (UPD) in a region of chromosome 15. Here, we propose to determine whether subjects with PWS differ for clinical phenotype and treatment response depending on the underlying genetic anomaly., Methods: We retrospectively included all 24 PWS patients who were referred to the Reference Center for Rare Psychiatric Disorders (GHU Paris Psychiatrie and Neurosciences) between November 2018 and July 2022, with either deletion ( N = 8) or disomy ( N = 16). The following socio-demographic and clinical characteristics were recorded: age, sex, psychiatric and non-psychiatric symptoms, the type of genetic defect, medication and treatment response to topiramate, which was evaluated in terms of eating compulsions and impulsive behaviors. We compared topiramate treatment doses and responses between PWS with deletion and those with disomy. Non-parametric tests were used with random permutations for p -value and bootstrap 95% confidence interval computations., Results: First, we found that disomy was associated with a more severe clinical phenotype than deletion. Second, we observed that topiramate was less effective and less tolerated in disomy, compared to deletion., Discussion: These results suggest that a pharmacogenomic-based approach may be relevant for the treatment of compulsions in PWS, thus highlighting the importance of personalized medicine for such complex heterogeneous 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 © 2023 Louveau, Turtuluci, Consoli, Poitou, Coupaye, Krebs, Chaumette and Iftimovici.)

Introduction: Folates, the main actors in one-carbon (C1) metabolism, are involved in synthesising monoamines and maintaining genomic stability. Previous studies support the association between C1 metabolism and schizophrenia. The main purpose of this study was to assess the prevalence of plasma folate, and/or vitamin B12 deficiencies and hyperhomocysteinemia in young patients with psychotic disorders., Methods: We included young inpatients (15-30 years old) with psychosis between 2014 and 2017 from Sainte-Anne Hospital in Paris. Plasma folate, vitamin B12 deficiency and homocysteinemia dosages were done at admission. Clinical data were extracted retrospectively, and patients diagnosed with a first-episode psychosis (FEP), schizophrenia, schizoaffective disorder, or persistent delusional disorder were retained for the analysis., Results: Among the 334 inpatients, 188 (56%) had C1 dosages available (135 males; 53 females). From the 188 patients, 32% had a C1 abnormality. This abnormality reached 38% of FEP patients. The most frequent abnormality was folate deficiency: 21% of all patients and 27% of FEP. Lower levels of folates were found in males compared to females ( p = 0.02) and were correlated with more severe disorder, as assessed by Clinical Global Impression - Severity (CGI-S; p = 0.009). Antipsychotic dosage was positively associated with B12 levels ( p = 0.013) and negatively with homocysteinemia ( p = 0.034)., Conclusion: One-carbon metabolism anomalies in young patients with psychotic disorders are highly prevalent, reaching almost half of the patients with FEP. Potential protective effects from females and antipsychotics have emerged. These results spotlight the need for new therapeutic prospects, such as folate supplementation, to achieve personalised medical approaches to the early stages of psychotic 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 © 2023 Frajerman, Urban, Rivollier, Plaze, Chaumette, Krebs and Scoriels.)

Background: The mental health of health students is considered a public health issue which increased dramatically with the COVID 19's pandemic. Few studies have assessed the prevalence of depression in medical, pharmacy, and dental students. Our goal was to assess mental health in health students from the same university and identify the associated factors., Methods: An online survey was sent to the health students of the University of Paris in 3 specialties (medicine, pharmacy, and dentistry). We used the Hospitalization Anxiety and Depression scale, the Composite International Diagnostic Interview-Short Form and the Maslach Burnout Inventory (with 2 versions: the Human Services Survey for clinical students and residents and the Student survey for the others). The presence of suicidal ideation, humiliation, sexual harassment, and sexual aggression over twelve-months was also measured. We performed multivariable logistic regression analyses to identify the associated factors of Major Depressive Episodes (MDE)., Findings: 1925 students answered the survey. The overall prevalence of 7-day anxiety and depressive symptoms, MDE, suicidal ideation, humiliation, sexual harassment, and sexual aggression were 55%, 23%, 26%, 19%, 19%, 22%, and 5.5%, respectively. Burnout was present in 42% of nonclinical students and 65% of clinical students and residents. Multivariable logistic regression identified several associated factors of MDE: moderate (OR = 1.49,CI95[1.17-1.90]) or major (OR = 2.32,CI95[1.68-3.20]) subjective financial difficulties, humiliation (OR = 1.71,CI95[1.28-2.28]), sexual abuse (OR = 1.65,CI95[1.04-2.60]), and sexual harassment (OR = 1.60,CI95[1.19-2.16])., Interpretation: This is one of the largest studies comparing dental, pharmacy and medical students from the same university. We found elevated prevalences of psychiatric symptoms with variation depending on specialty., Competing Interests: Ariel Frajerman: none. Boris Chaumette: has received speaking fees from Janssen Cilag, Lundbeck and Eisai outside the submitted work. Marie-Odile Krebs: received financial support for scientific dissemination from Otsuka Lundbeck, Jansen, Eisai Yannick Morvan: has received funding from the University of Paris Nanterre, Inserm, GHU Sainte-Anne, Fondation de France, Fondation Pierre Deniker. Yannick Morvan is or has been a member of various professional and scientific organisations of or involving psychologists (AEPU, AFTCC, AFRC, APA, APS, IdPsy, IEPA, FFPP, SFP). He is also a member of the scientific college of the Observatoire National de la Vie Etudiante (OVE), (© 2022 The Authors. Published by Elsevier B.V.)

Competing Interests: Competing interests: Boris Chaumette reports a grant from the Fondation Bettencourt Schueller (CCA-INSERMBettencourt program); speaking fees from Janssen-Cilag, EISAI and Lundbeck; and support from Janssen-Cilag for attending a 2019 meeting. No other competing interests were declared.

Schizophrenia is an illness characterized by positive symptoms, negative symptoms, and cognitive impairments. Cognitive impairments occur before the onset of psychosis and could reflect glutamatergic dysregulation. Thus, identifying associations between genetic variations in genes coding for glutamatergic receptors and cognitive impairment in schizophrenia may help in understanding the basis of these deficits and in identifying potential drug targets. In a discovery cohort of 144 first-episode of psychosis patients (FEP), we genotyped 58 candidate Single Nucleotide Polymorphisms (SNPs) located in NMDA and metabotropic glutamatergic receptors. These SNPs were selected according to the results from the Psychiatric Genomic Consortium and were tested for association with intellectual quotient (IQ) as assessed with the Wechsler Intelligence Scales. For replication, we used the ICAAR cohort including 121 ultra-high-risk patients (UHR) with the same cognitive assessment. A polymorphism located in GRM7, rs1396409, was significantly associated with performance IQ in the discovery cohort of FEP. This association was replicated in the UHR cohort. This polymorphism is also associated with total IQ and verbal IQ in the merged dataset, with a predominant effect on the arithmetic subtest. The rs1396409 polymorphism is significantly associated with cognitive impairment during the onset of psychosis. This genetic association highlights the possible impact of glutamatergic genes in cognitive deficits in the early phases of psychosis and enforces the interest for new therapeutic interventions targeting the glutamatergic pathway., Competing Interests: Declaration of competing interest Dr. Joober reports to be a speaker and/or consulting committee member for Pfizer, Janssen, BMS, Sunovian, Myelin, Otsuka, Lundbeck, shire and Perdue, and to have received grants from Janssen, BMS, Otsuka, Lundbeck, Astra Zeneca and HLS, and to have royalties from Henry Stewart talks, all outside the submitted work. Dr. Malla served as a research consultant to and gave lectures at conferences supported by Lundbeck and Otsuka and was on an advisory board meeting for the same two companies for which he received honoraria. Pr. Krebs has received honoraria from and participated in advisory boards or did educational conference for F. Hoffmann-La Roche, Janssen Cilag and Otsuka-Lundbeck. She received financial support for investigator-driven educational initiative from Eisai, Janssen Cilag and Otsuka-Lundbeck. Dr. Lepage reports grants from Otsuka Lundbeck Alliance, personal fees from Otsuka Canada, personal fees from Lundbeck Canada, grants and personal fees from Janssen, personal fees from MedAvante-Prophase, personal fees from Amplexor, outside the submitted work. Dr. Chaumette has received speaking fees from Janssen Cilag, outside the submitted work. All authors declare they have no conflict of interest related to this article. The contributing Group members (ICAAR study group) declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Treatment and prevention strategies for schizophrenia require knowledge about the mechanisms involved in the psychotic transition. Increasing evidence suggests a redox imbalance in schizophrenia patients. This narrative review presents an overview of the scientific literature regarding blood oxidative stress markers' evolution in the early stages of psychosis and chronic patients. Studies investigating peripheral levels of oxidative stress in schizophrenia patients, first episode of psychosis or UHR individuals were considered. A total of 76 peer-reviewed articles published from 1991 to 2022 on PubMed and EMBASE were included. Schizophrenia patients present with increased levels of oxidative damage to lipids in the blood, and decreased levels of non-enzymatic antioxidants. Genetic studies provide evidence for altered antioxidant functions in patients. Antioxidant blood levels are decreased before psychosis onset and blood levels of oxidative stress correlate with symptoms severity in patients. Finally, adjunct treatment of antipsychotics with the antioxidant N-acetyl cysteine appears to be effective in schizophrenia patients. Further studies are required to assess its efficacy as a prevention strategy. Redox imbalance might contribute to the pathophysiology of emerging psychosis and could serve as a therapeutic target for preventive or adjunctive therapies, as well as biomarkers of disease progression.