The biological processes associated with the onset of schizophrenia remain largely unknown. Current hypotheses favor gene × environment interactions as supported by our recent report about DNA methylation changes during the onset of psychosis. Here, we conducted the first longitudinal transcriptomic analysis of blood samples from 31 at-risk individuals who later converted to psychosis and 63 at-risk individuals who did not. Individuals were followed for a maximum of 1 year. Blood samples were collected at baseline and at the end of follow-up and individuals served as their own controls. Differentially expressed genes between the 2 groups were identified using the RNA sequencing of an initial discovery subgroup (n = 15 individuals). The most promising results were replicated using high-throughput real-time qPCR in the whole cohort (n = 94 individuals). We identified longitudinal changes in 4 brain-expressed genes based on RNAseq analysis. One of these genes (CPT1A) was replicated in the whole cohort. The previously observed hypermethylation in NRP1 and GSTM5 during the onset of psychosis correlated with a decrease in corresponding gene expression. RNA sequencing also identified 2 co-expression networks that were impaired after conversion compared with baseline-the Wnt pathway including AKT1, CPT1A and semaphorins, and the Toll-like receptor pathway, related to innate immunity. This longitudinal study of transcriptomic changes in individuals with at-risk mental state revealed alterations during conversion to psychosis in pathways and genes relevant to schizophrenia. These results may be a first step toward better understanding psychosis onset. They may also help to identify new biomarkers and targets for disease-modifying therapeutic strategies.

ObjectiveStructural MRI (sMRI) increasingly offers insight into abnormalities inherent to schizophrenia. Previous machine learning applications suggest that individual classification is feasible and reliable and, however, is focused on the predictive performance of the clinical status in cross‐sectional designs, which has limited biological perspectives. Moreover, most studies depend on relatively small cohorts or single recruiting site. Finally, no study controlled for disease stage or medication's effect. These elements cast doubt on previous findings’ reproducibility.MethodWe propose a machine learning algorithm that provides an interpretable brain signature. Using large datasets collected from 4 sites (276 schizophrenia patients, 330 controls), we assessed cross‐site prediction reproducibility and associated predictive signature. For the first time, we evaluated the predictive signature regarding medication and illness duration using an independent dataset of first‐episode patients.ResultsMachine learning classifiers based on neuroanatomical features yield significant intersite prediction accuracies (72%) together with an excellent predictive signature stability. This signature provides a neural score significantly correlated with symptom severity and the extent of cognitive impairments. Moreover, this signature demonstrates its efficiency on first‐episode psychosis patients (73% accuracy).ConclusionThese results highlight the existence of a common neuroanatomical signature for schizophrenia, shared by a majority of patients even from an early stage of the disorder.

ObjectifL’objectif de cette étude est de décrire le fonctionnement du dispositif Fil Harmonie, ligne téléphonique réservée aux professionnels de l’Académie de Paris faisant face à une situation d’un élève en souffrance psychologique ou psychiatrique.MéthodesIl s’agit d’une étude descriptive observationnelle réalisée entre le 18 septembre 2013 et le 12 mai 2014. Les informations transmises lors des 68 appels téléphoniques ont été recueillies, formalisées puis analysées. Nous avons utilisé une méthodologie mixte, associant des analyses de données quantitatives et de données textuelles.RésultatsLa profession de l’appelant était dans plus de 70 % des cas celle d’infirmière scolaire. L’âge moyen des élèves concernés était de 17,3 ans. Les deux classes les plus représentées étaient la seconde et la classe préparatoire (19,7 % dans les deux cas). Plus de la moitié des jeunes étaient déclarés comme n’ayant jamais eu de prise en charge psychologique antérieure (52,5 %). Les jeunes étaient décrits majoritairement comme isolés socialement (67,2 %), tristes ou anhédoniques (48,2 %). Plus d’un quart (26,7 %) avait déjà redoublé au moins une fois et la majorité (55,9 %) faisait preuve d’absentéisme. L’analyse qualitative a mis en évidence la complexité de la collaboration entre la famille de l’élève et l’établissement scolaire.ConclusionFil Harmonie propose une nouvelle modalité pour favoriser le dépistage des difficultés psychiques chez les jeunes en milieu scolaire. Ce dispositif aide à la résolution de problème et si nécessaire l’orientation vers des professionnels de santé adéquats grâce à l’intervention d’un professionnel relais. Cette étude de terrain pointe la nécessaire articulation entre professionnels de l’Éducation, professionnels de santé et entourage proche.

Objective. - Most psychiatric disorders arise during adolescence, a period of life during which school takes an important place. School in France has an official mission of health education and prevention, and early detection of mental disorders is part of these goals. The aim of this study is to describe an innovative service operating in Paris that helps educational staff to deal with students having psychological or psychiatric symptoms. The Fil Harmonie program was launched in 2011. It consists of a telephone line available to all educational staff working for high schools in Paris. Methods. - When in need of assistance, a member of the educational staff can call the dedicated hotline and expose the situation of their student to a trained psychologist. Over the course of the study, data concerning these phone calls were collected such as: socio-demographic characteristics of the student, the reason behind the call, the caller's professional role within the school, and care pathway information. All data collected during the phone calls were anonymized and computerized. We performed an observational descriptive study based on this data by using mixed methods: we integrated quantitative analysis and qualitative research in order to provide a better understanding of the Fil Harmonie program. Results. - Between 18 September 2013 and 12 May 2014, the Fil Harmonie program handled 68 calls from educational staff. Students concerned by the calls were aged between 11 and 22 and the average age was 17.3 years. Over half (52.5%) of the pupils concerned had never seen a mental health professional before the call. In more than 70% of cases, the caller was a school nurse while other professionals such as teachers or headmasters represented only a minority of the callers. Approximately two thirds (67.2%) of students were described by the caller as socially isolated and 48.2% were described as sad or anhedonic. One out of four (26.7%) had repeated a school year at least once, and 55.9% of young people for whom a member of staff contacted Fil Harmonie had been missing class. In 56.7% of cases, there had been no contact with the student's family about the psychological situation. The qualitative analysis particularly highlighted the complexity of the collaboration between the family and the educational staff. Conclusion. - Schooling is an important opportunity to seize in mental health regarding early detection and access to care. By fostering collaboration between educational professionals and mental health services, Fil Harmonie meets a public health objective of prevention and should contribute to the reduction of care delays thus leading to better treatment outcome. Our study shows that such programs are feasible and answer a real need in our current health care system. (C) 2017 L'Encephale, Paris.

L'adolescence est une période de vulnérabilité qui peut s'exprimer sous forme de Symptômes Psychotiques Atténués (SPA) et/ou de Comportements Suicidaires (CS). Les objectifs sont de déceler la nature, l'intensité et la fréquence des SPA dans une population d'adolescents reçus en urgence puis d'établir quels SPA sont subjectivement pourvoyeurs de CS, enfin d'identifier le niveau d'association entre les items de la PQ16 (Prodromal Questionnaire en 16 items) [1] et les CS. Méthodologie 45 adolescents ont reçu plusieurs autoquestionnaires dont la PQ16. Le statut à ultra haut risque (UHR) de transition psychotique est caractérisé à l'aide de la CAARMS (Comprehensive Assessment of At Risk Mental State) [2]. Les CS sont évalués sous forme d'hétéro-questionnaire grâce à l'échelle SSI (Scale for Suicide Ideation) [3]. Sur le plan qualitatif, l'adolescent précise s'il souffre d'idées suicidaires et leur lien éventuel avec le vécu subjectif de SPA répertoriés par la PQ16. Résultats 69 % des sujets (n = 31) confirment la présence de SPA et la moitié de ces sujets met en lien leurs CS avec l'existence de SPA. Les sujets qui associent leurs CS avec certains SPA vécus diffèrent significativement sur le statut UHR (p = 0,009) de ceux qui ne font pas le lien entre ces deux dimensions cliniques. En revanche, ces deux groupes ne diffèrent pas significativement au score d'angoisse de la PQ16 (p = 0,09). Enfin, l'item 1 de la PQ16, l'athymhormie, est significativement associé à l'intensité suicidaire évaluée à la SSI (p = 0,03). Conclusion Le repérage des SPA chez les sujets jeunes qui présentent des conduites à risque est un enjeu clinique et thérapeutique afin d'adapter les soins le plus précocement possible.

Introduction Les expériences psychotiques font l'objet de plusieurs travaux récents en population générale. Leur évaluation en pratique clinique peut être complexe. Un outil simple et acceptable en population adolescente est l'auto-évaluation par le questionnaire Prodromal Questionnaire PQ16. Nos objectifs étaient d'évaluer la prévalence des différentes expériences psychotiques chez des patients hospitalisés pour la première fois en psychiatrie, en dehors de tout préjugé diagnostique. Matériel et Méthodes Population : jeunes(16-26ans) hospitalisés pour la 1re fois sans ATCD psychiatrique. L'évaluation reposait sur l'évaluation des expériences psychotiques et le diagnostic à la sortie d'hospitalisation, réactualisé 6 mois après le début des troubles. Les patients répondaient également aux questionnaires AUDIT, CUDIT et le Fagerström. Les expériences psychotiques ont été mesurées à l'aide de la PQ16. Résultats 50 patients ont été inclus dans l'étude. Le suivi prospectif des patients a montré à 6mois: schizophrénie 28 %, troubles de l'humeur 44 %, troubles anxieux 6 %, troubles de la personnalité 24 %, épisode psychotique bref : 2 %, autres 14 %. L'évaluation des expériences psychotiques a montré des scores élevés quel que soit le diagnostic de sortie et le diagnostic à 6 mois (figure 1). Tous les items étaient largement représentés (figure 2). Le risque de transition psychotique était évalué à 92%. La consommation de cannabis était associée à une augmentation des perceptions délirantes de présence (item 15, humeur « délirante », p = 0.041). Le tabagisme et l'alcool déclarés n'avaient pas d'impact. Approche prospective Association avec le traitement de sortie : Une seule expérience psychotique étaient associées avec un traitement de sortie antipsychotique à visée antiproductive(les hallucinations gustatives et olfactives (p(f) = 0.04)). Association des expériences psychotiques avec le diagnostic de schizophrénie à 6 Mois : Deux expériences étaient associées : les hallucinations gustatives/olfactives et les idées de référence. Discussion Nos résultats montrent une fréquence élevée des expériences psychotiques dans une population hospitalisée en psychiatrie pour la première fois, et ceci quel que soit le diagnostic. Peu de symptômes sont spécifiques d'un diagnostic de trouble schizophrénique. Nos résultats appuient l'importance d'une approche dimensionnelle et trans-nosographique des phénomènes psychotiques, en particulier hallucinatoires.

In today's society, every individual is subjected to stressful stimuli with different intensities and duration. This exposure can be a key trigger in several mental illnesses greatly affecting one's quality of life. Yet not all subjects respond equally to the same stimulus and some are able to better adapt to them delaying the onset of its negative consequences. The neural specificities of this adaptation can be essential to understand the true dynamics of stress as well as to design new approaches to reduce its consequences. In the current work, we employed ex vivo high field diffusion magnetic resonance imaging (MRI) to uncover the differences in white matter properties in the entire brain between Fisher 344 (F344) and Sprague-Dawley (SD) rats, known to present different responses to stress, and to examine the effects of a 2-week repeated inescapable stress paradigm. We applied a tract-based spatial statistics (TBSS) analysis approach to a total of 25 animals. After exposure to stress, SD rats were found to have lower values of corticosterone when compared with F344 rats. Overall, stress was found to lead to an overall increase in fractional anisotropy (FA), on top of a reduction in mean and radial diffusivity (MD and RD) in several white matter bundles of the brain. No effect of strain on the white matter diffusion properties was observed. The strain-by-stress interaction revealed an effect on SD rats in MD, RD and axial diffusivity (AD), with lower diffusion metric levels on stressed animals. These effects were localized on the left side of the brain on the external capsule, corpus callosum, deep cerebral white matter, anterior commissure, endopiriform nucleus, dorsal hippocampus and amygdala fibers. The results possibly reveal an adaptation of the SD strain to the stressful stimuli through synaptic and structural plasticity processes, possibly reflecting learning processes.

Background. - Psychiatric disorders are consistent with the gene x environment model, and non-specific environmental factors such as childhood trauma, urbanity, and migration have been implicated. All of these factors have in common to dysregulate the biological pathways involved in response to stress. Stress is a well-known precipitating factor implicated in psychiatric disorders such as depression, bipolar disorder, anxiety, and possibly schizophrenia. More precisely, psychosocial stress induces dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) and could modify neurotransmission, which raises the question of the involvement of stress-related biological changes in psychotic disorders. Indeed, the literature reveals dysregulation of the HPA axis in schizophrenia. This dysregulation seems to be present in the prodromal phases (UHR subjects for ultra-high risk) and early schizophrenia (FEP for first episode psychosis). Thus, and following the stress vulnerability model, stress could act directly on psychotic onset and precipitate the transition of vulnerable subjects to a full-blown psychosis.Objective. - The present paper reviews the literature on stress and onset of schizophrenia, with consideration for the causal role vs. associated role of HPA axis dysregulation in schizophrenia and the factors that influence it, in particular during prodromal and earlier phases. We also discuss different methods developed to measure stress in humans.Methodology. - We performed a bibliographic search using the keywords 'cortisol', 'glucocorticoid', 'HPA' with 'UHR', 'CFIR', 'at-risk mental state', 'first episode psychosis', 'schizotypal', 'prodromal schizophrenia' in Medline, Web of Knowledge (WOS), and EBSCO completed by a screening of the references of the selected articles.Results. - Stress has been studied for many years in schizophrenia, either by subjective methods (questionnaires), or objective methods (standardized experimental protocols) with biological sampling and/or brain imaging methods. These methods have suggested a link between dysregulation of the HPA axis and psychotic symptoms both through abnormal basal levels of cortisol and flattened reactivity to social stress. Imaging results suggest indirect modifications, including abnormal pituitary or hippocampal volume. Several factors dysregulating the HPA axis have also been highlighted, such as consumption of drugs.(i.e. cannabis), childhood trauma or genetic factors (such as COMT, or MTHFR variants). Psychological stress induces subcortical dopaminergic activation attributable to hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This dysregulation is present in the prodromal phase (UHR) in patients who have experienced a first psychotic episode (FEP) and in siblings of schizophrenic patients. Stress dysregulation is a plausible hypothesis to understand the psychosis onset.Discussion.- The effect of stress on brain pathways could participate to the mechanisms underlying the onset of psychotic symptoms, both as a precipitating factor and as a marker of a predisposing vulnerability. This dysregulation fits into the gene x environment model: in subjects with genetic predispositions, stressful environmental factors can modify biological pathways implicated in psychiatric disorders, promoting the emergence of symptoms. However, many confounding factors obscure the literature, and further studies are needed in schizophrenic patients, UHR and FEP patients to clarify the precise role of stress in psychotic transition. Identification of stress biomarkers could help diagnosis and prognosis, and pave the way for specific care strategies based on stress-targeted therapies. (C) 2016 L'Encephale, Paris.

Le stress psychologique induit une dérégulation de l’axe hypothalamo-hypophyso-surrénalien (HHS) qui entraîne une perturbation de la physiologie cérébrale. Ces éléments biologiques ont conduit à promouvoir l’hypothèse selon laquelle le stress pourrait influencer l’émergence de pathologies psychiatriques et en particulier l’émergence de la schizophrénie (transition psychotique). Cette revue de la littérature vise à réaliser un état des lieux de la question du stress dans la psychose et des méthodes d’investigation notamment le dosage du cortisol. Le rôle de la dérégulation de l’axe HHS dans le déclenchement de la schizophrénie est discuté. Cette dérégulation pourrait être une cause spécifique de l’entrée dans la maladie ou refléter uniquement la détresse psychologique liée à l’émergence des symptômes. La revue s’est attachée à mettre en relief les études sur l’implication du stress à différentes phases de la maladie psychotique. La littérature met en évidence une dérégulation de l’axe HHS dans la schizophrénie suivant le modèle vulnérabilité–stress. Cette dérégulation, présente dès la phase prodromique (sujets à ultra-haut risque) et dès le premier épisode psychotique, pourrait favoriser le déclenchement de la pathologie. En effet, la dérégulation de l’axe HHS et donc de la réponse au stress semble associée à l’émergence de symptômes psychotiques. Toutefois, les mécanismes précis de l’implication du stress dans le déclenchement de la maladie sont encore mal connus et nécessitent de plus amples investigations, d’autant que de nombreux facteurs confondants modulent le taux de cortisol et la réponse au stress, y compris la consommation de cannabis ou la prise de traitements. En outre, la réactivité au stress semble être modulée par des facteurs génétiques. La découverte de facteurs biologiques associés à la transition psychotique pourrait apporter une aide diagnostique et pronostique ainsi que des cibles thérapeutiques.

The onset of psychosis is the consequence of complex interactions between genetic vulnerability to psychosis and response to environmental and/or maturational changes. Epigenetics is hypothesized to mediate the interplay between genes and environment leading to the onset of psychosis. We believe we performed the first longitudinal prospective study of genomic DNA methylation during psychotic transition in help-seeking young individuals referred to a specialized outpatient unit for early detection of psychosis and enrolled in a 1-year follow-up. We used Infinium HumanMethylation450 BeadChip array after bisulfite conversion and analyzed longitudinal variations in methylation at 411 947 cytosine–phosphate–guanine (CpG) sites. Conversion to psychosis was associated with specific methylation changes. Changes in DNA methylation were significantly different between converters and non-converters in two regions: one located in 1q21.1 and a cluster of six CpG located in GSTM5 gene promoter. Methylation data were confirmed by pyrosequencing in the same population. The 100 top CpGs associated with conversion to psychosis were subjected to exploratory analyses regarding the related gene networks and their capacity to distinguish between converters and non-converters. Cluster analysis showed that the top CpG sites correctly distinguished between converters and non-converters. In this first study of methylation during conversion to psychosis, we found that alterations preferentially occurred in gene promoters and pathways relevant for psychosis, including oxidative stress regulation, axon guidance and inflammatory pathways. Although independent replications are warranted to reach definitive conclusions, these results already support that longitudinal variations in DNA methylation may reflect the biological mechanisms that precipitate some prodromal individuals into full-blown psychosis, under the influence of environmental factors and maturational processes at adolescence.

ContexteDans la majorité des cas, la schizophrénie est précédée par des symptômes prodromiques à l’adolescence ou au début de l’âge adulte. Le bénéfice des centres de détection et d’intervention précoces destinés aux sujets présentant ces prodromes est aujourd’hui établi. À partir des données recueillies au C’JAAD, le centre pilote français, l’objectif de notre travail est de comprendre comment les sujets parviennent jusqu’à ce type de structures.Matériel et méthodesLa recherche par les méthodes mixtes, courant méthodologique en plein essor, est particulièrement adaptée à notre problématique complexe. Nous avons intégré l’analyse quantitative de données issues de questionnaires remplis par les jeunes se présentant au C’JAAD et l’analyse qualitative d’entretiens.RésultatsAu total, 330 questionnaires et 8 entretiens ont été analysés. Il apparaît que l’accès aux soins est dépendant de nombreux déterminants. Les symptômes eux-mêmes, le modèle explicatif des troubles que le jeune retient, le sexe, la présence d’antécédents psychiatriques familiaux, le parcours scolaire, la dimension culturelle influencent la trajectoire de soins. Par ailleurs, l’entourage des sujets détient un rôle majeur. Parfois porteur de conduites stigmatisantes, l’entourage constitue le plus souvent un soutien important et ouvre la porte d’entrée vers les soins. Enfin, le degré de communication entre les différents professionnels de santé et le niveau de connaissance des intervenants sont déterminants dans le processus d’accès aux soins.DiscussionFavoriser l’accès aux soins des jeunes qui présentent une symptomatologie prodromique est primordial : on se situe à une période où les enjeux pour le futur sont majeurs. À notre connaissance, notre étude est la première à utiliser les méthodes mixtes pour explorer cette problématique. Toutefois, les données sont recueillies de manière rétrospective ce qui peut induire un biais de mémorisation. La lutte contre la stigmatisation, l’information du grand public et des professionnels doivent être une priorité pour favoriser cet accès aux soins.

Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95–1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset or at-risk individuals. The predictive performance achieved by the panel was excellent for identifying USA military personnel (AUC: 0.90 (0.86–0.95)) and help-seeking prodromal individuals (AUC: 0.82 (0.71–0.93)) who developed schizophrenia up to 2 years after baseline sampling. The performance increased further using the latter cohort following the incorporation of CAARMS (Comprehensive Assessment of At-Risk Mental State) positive subscale symptom scores into the model (AUC: 0.90 (0.82–0.98)). The current findings may represent the first successful step towards a test that could address the clinical need for early intervention in psychiatry. Further developments of a combined molecular/symptom-based test will aid clinicians in the identification of vulnerable patients early in the disease process, allowing more effective therapeutic intervention before overt disease onset.

Stress is known to precipitate psychiatric disorders in vulnerable people. Individual differences in the stress responsivity can dramatically affect the onset of these illnesses. Animal models of repeated stress represent valuable tools to identify region-specific volumetric changes in the brain. Here, using high resolution 7T MRI, we found that amygdala is the most significant parameter for distinction between F344 and SD rats known to have differential response to stress. A significant substantial increase (45%) was found in the amygdala volume of rats that do not habituate to the repeated stress procedure (F344 rats) compared to SD rats. This strain-specific effect of stress was evidenced by a significant strain-by-stress interaction. There were no significant strain differences in the volumes of hippocampi and prefrontal cortices though stress produces significant reductions of smaller amplitude in the medial prefrontal cortex (mPFC) (9% and 12%) and dorsal hippocampus (5% and 6%) in both strains. Our data further demonstrate the feasibility and relevance of high isotropic resolution structural ex vivo 7T MRI in the study of the brain effects of stress in small animals. Neuroimaging is a valuable tool to follow up brain volumetric reorganization during the stress response and could also be easily used to test pharmacological interventions to prevent the deleterious effects of stress.

Introduction:Identifying at-risk mental states of psychosis can reduce the duration of untreated psychosis and the rate of transition. Meanwhile, it may improve prevention strategies of suicide, substance abuse and anxiety disorders comorbidities.Objectives:We aim to investigate the clinical symptomatology differences at baseline, especially in non-specific symptoms, between UHR (Ultra High Risk) patients who did or did not make a transition to psychosis. Sharpening UHR inclusion criteria may improve prediction of transition to psychosis.Method:The study included 85 young help-seekers (mean age= 20 y.o.) meeting UHR CAARMS’ criteria. 46 were followed up over a period of 30 months and 27 of them were assessed in a comprehensive clinical interview. Out of 46 finally included UHR subjects, 11 (40%) made a transition to psychosis. Psychopathology was investigated with the Comprehensive Assessment of At-Risk Mental State (CAARMS), BPRS and GAF-score. To identify the most predictive variables of transition, we applied a stepwise logistic regression on CAARMS’ criteria plus other variables (premorbid adjustment scale, cannabis use, subjective experienced life events, treatment and suicide).Results:At baseline, premorbid adjustment and severity of CAARMS’ Obesssive-Compulsive Symptoms (OCS) were found to significantly influence the transition: poor premorbid adjustment, associated with moderate level of OCS increased the sensitivity (72.7%) and the specificity (92.8%) of the prediction.Conclusions:Premorbid adjustment and level of OCS were predictive of transition in subjects at UHR. These characteristics could increase the level of prediction of psychosis.