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Brain development is a complex phenomenon, stretching from fetal life to adolescence, during which brain maturation proceeds through a series of ordered events including critical periods of plasticity. The brain is particularly sensitive to the environment during these changes. The endocannabinoid system participates directly and indirectly in these plasticity and maturation processes. The main psychoactive component of cannabis, the delta-9-tetrahydrocanabinol, can cross the placental barrier, is present in breastmilk and diffuses in the brain. It interacts with the endocannabinoid signaling, especially through the activation of cannabinoid receptors 1 CB1R, which can lead to abnormal neurodevelopmental processes and neuronal circuits functions. Therefore, exposure to cannabis in utero, in perinatal phase, as well as during the adolescence disrupts the brain maturation and can cause disturbances on the cognitive, psychotic and addictive levels that persist far beyond the period of exposure. Several factors modulate the risk of such complications, but studies performed in animal models as well as in human cohorts have shown that exposure during both the critical perinatal and adolescence phases is a risk factor per se. Current knowledge encourages the dissemination of objective information to young people, to prevent and limit early exposure and its consequences., (© 2020 l'Académie nationale de médecine. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: The coronavirus disease 2019 (COVID-19) pandemic has caused major sanitary crisis worldwide. Half of the world has been placed in quarantine. In France, this large-scale health crisis urgently triggered the restructuring and reorganization of health service delivery to support emergency services, medical intensive care units and continuing care units. Health professionals mobilized all their resources to provide emergency aid in a general climate of uncertainty. Concerns about the mental health, psychological adjustment, and recovery of health care workers treating and caring for patients with COVID-19 are now arising. The goal of the present article is to provide up-to-date information on potential mental health risks associated with exposure of health professionals to the COVID-19 pandemic., Methods: Authors performed a narrative review identifying relevant results in the scientific and medical literature considering previous epidemics of 2003 (SARS-CoV-1) and 2009 (H1N1) with the more recent data about the COVID-19 pandemic. We highlighted most relevant data concerning the disease characteristics, the organizational factors and personal factors that may contribute to developing psychological distress and other mental health symptoms., Results: The disease characteristics of the current COVID-19 pandemic provoked a generalized climate of wariness and uncertainty, particularly among health professionals, due to a range of causes such as the rapid spread of COVID-19, the severity of symptoms it can cause in a segment of infected individuals, the lack of knowledge of the disease, and deaths among health professionals. Stress may also be caused by organizational factors, such as depletion of personal protection equipment, concerns about not being able to provide competent care if deployed to new area, concerns about rapidly changing information, lack of access to up-to-date information and communication, lack of specific drugs, the shortage of ventilators and intensive care unit beds necessary to care for the surge of critically ill patients, and significant change in their daily social and family life. Further risk factors have been identified, including feelings of being inadequately supported, concerns about health of self, fear of taking home infection to family members or others, and not having rapid access to testing through occupational health if needed, being isolated, feelings of uncertainty and social stigmatization, overwhelming workload, or insecure attachment. Additionally, we discussed positive social and organizational factors that contribute to enhance resilience in the face of the pandemic. There is a consensus in all the relevant literature that health care professionals are at an increased risk of high levels of stress, anxiety, depression, burnout, addiction and post-traumatic stress disorder, which could have long-term psychological implications., Conclusions: In the long run, this tragic health crisis should significantly enhance our understanding of the mental health risk factors among the health care professionals facing the COVID-19 pandemic. Reporting information such as this is essential to plan future prevention strategies. Protecting health care professionals is indeed an important component of public health measures to address large-scale health crisis. Thus, interventions to promote mental well-being in health care professionals exposed to COVID-19 need to be immediately implemented, and to strengthen prevention and response strategies by training health care professionals on mental help and crisis management., (Copyright © 2020 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by difficulties in communication and social interactions as well as by restricted and repetitive patterns of behavior and interests. They are frequently associated with motor signs. However, literature concerning these motor anomalies remains scarce when it comes to the adult population. Among motor aspects, those concerning manual motor skills warrant a particular attention as their alteration often persists through adulthood with a major impact on functioning and quality of life. The purpose of this article was to systematically review and analyze the literature on sensorimotor aspects and manual motor impairments in ASD., Methods: We have searched the Medline database using the Pubmed search engine and retaining all articles published since the year 2000 with either their title, abstract or key-words containing the root autis* and any combination of the following terms: hand, manual, finger, dexterity, prehension, grip or grasp. Reference lists where also reviewed. After irrelevant articles were excluded, 33 studies were retained for this work., Results: The basic motor anomaly in autism seems to be a deficit in sensorimotor integration. The central nervous system of individuals with ASD seems unable to efficiently extract sensory information and integrate it correctly into a motor plan and execution. This type of online correction aims to save time on the initial ballistic phase of a movement. Thus, its alteration results in generalized slowness and motor clumsiness that require retroactive feedback corrections. Moreover, difficulties in integrating external sensory information to correctly adapt movement to environmental requirements could explain stereotyped and inflexible behaviors characteristic of autism. The same sensorimotor alterations are found in both gross and fine manual dexterity tasks. They seem to persist significantly though adolescence and into adulthood. To explain these anomalies, the underlying neuroanatomical and neurofunctional substratum might be a hypoconnectivity within cortico-cerebellar tracts. However, several other cerebral structures are also implicated. A delay in the maturational processes of these structures appears to be the common determinant of motor signs found in ASD but also in neurodevelopmental disorders as a whole., Conclusions: Current works tackling motor aspects in autism comprise several limitations preventing homogenization of their findings. Firstly, characterization of the extremely diverse clinical forms of ASD does not always rely on the same clinical criteria or tools. Furthermore, the motor tasks and the clinical assessments used are not always the same across publications complicating comparison. Moreover, sample sizes are almost always small and only a few studies have addressed motor impairments in adults with ASD. Furthermore, only two studies examine the dynamic longitudinal evolution of motor aspects from childhood to adult age. Finally, despite a recent effort of a consistent number of publications converging towards the hypothesis of a deficit in sensorimotor integration, a common pathophysiological model explaining these deficits in ASD is lacking. A more precise description of these motor signs and further comprehension of the neurological mechanisms underpinning them would allow more tailored managements directed towards subgroups with more homogenous neurodevelopmental profiles., (Copyright © 2019 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: The number of DNA methylome and RNA transcriptome studies is growing, but investigators have to consider the cell type composition of tissues used. In blood samples, the data reflect the picture of a mixture of different cells. Specialized algorithms can address the cell-type heterogeneity issue. We tested if these corrections are correlated between two heterogeneous datasets., Results: We used methylome and transcriptome datasets derived from a cohort of ten individuals whose blood was sampled at two different timepoints. We examined how the cell composition derived from these omics correlated with each other using "CIBERSORT" for the transcriptome and "estimateCellCounts function" in R for the methylome. The correlation coefficients between the two omic datasets ranged from 0.45 to 0.81 but correlations were minimal between two different timepoints. Our results suggest that a posteriori correction of a mixture of cells present in blood samples is reliable. Using an omic dataset to correct a second dataset for relative fractions of cells appears to be applicable, but only when the samples are simultaneously collected. This could be beneficial when there are difficulties to control the cell types in the second dataset, even when the sample size is limited.

Importance: The development of adverse clinical outcomes in patients with psychosis has been associated with behavioral and neuroanatomical deficits related to emotion processing. However, the association between alterations in brain regions subserving emotion processing and clinical outcomes remains unclear., Objective: To examine the association between alterations in emotion processing and regional gray matter volumes in individuals at clinical high risk (CHR) for psychosis, and the association with subsequent clinical outcomes., Design, Setting, and Participants: This naturalistic case-control study with clinical follow-up at 12 months was conducted from July 1, 2010, to August 31, 2016, and collected data from 9 psychosis early detection centers (Amsterdam, Basel, Cologne, Copenhagen, London, Melbourne, Paris, The Hague, and Vienna). Participants (213 individuals at CHR and 52 healthy controls) were enrolled in the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) project. Data were analyzed from October 1, 2018, to April 24, 2019., Main Measures and Outcomes: Emotion recognition was assessed with the Degraded Facial Affect Recognition Task. Three-Tesla magnetic resonance imaging scans were acquired from all participants, and gray matter volume was measured in regions of interest (medial prefrontal cortex, amygdala, hippocampus, and insula). Clinical outcomes at 12 months were evaluated for transition to psychosis using the Comprehensive Assessment of At-Risk Mental States criteria, and the level of overall functioning was measured through the Global Assessment of Functioning [GAF] scale., Results: A total of 213 individuals at CHR (105 women [49.3%]; mean [SD] age, 22.9 [4.7] years) and 52 healthy controls (25 women [48.1%]; mean [SD] age, 23.3 [4.0] years) were included in the study at baseline. At the follow-up within 2 years of baseline, 44 individuals at CHR (20.7%) had developed psychosis and 169 (79.3%) had not. Of the individuals at CHR reinterviewed with the GAF, 39 (30.0%) showed good overall functioning (GAF score, ≥65), whereas 91 (70.0%) had poor overall functioning (GAF score, <65). Within the CHR sample, better anger recognition at baseline was associated with worse functional outcome (odds ratio [OR], 0.88; 95% CI, 0.78-0.99; P = .03). In individuals at CHR with a good functional outcome, positive associations were found between anger recognition and hippocampal volume (ze = 3.91; familywise error [FWE] P = .02) and between fear recognition and medial prefrontal cortex volume (z = 3.60; FWE P = .02), compared with participants with a poor outcome. The onset of psychosis was not associated with baseline emotion recognition performance (neutral OR, 0.93; 95% CI, 0.79-1.09; P = .37; happy OR, 1.03; 95% CI, 0.84-1.25; P = .81; fear OR, 0.98; 95% CI, 0.85-1.13; P = .77; anger OR, 1.00; 95% CI, 0.89-1.12; P = .96). No difference was observed in the association between performance and regional gray matter volumes in individuals at CHR who developed or did not develop psychosis (FWE P < .05)., Conclusions and Relevance: In this study, poor functional outcome in individuals at CHR was found to be associated with baseline abnormalities in recognizing negative emotion. This finding has potential implications for the stratification of individuals at CHR and suggests that interventions that target socioemotional processing may improve functional outcomes.

Prevention is the most promising way to reduce the high personal, familial, societal, clinical and economic costs of mental disorders in Europe and worldwide. A complementary approach is to go beyond the prevention of mental ill health, to promote good mental health. This manuscript highlights the first European consortium fostering cutting-edge multidisciplinary research in these two areas. The ECNP-funded Network on the Prevention of Mental Disorders and Mental Health Promotion (ECNP PMD-MHP) brings together European sites of excellence with different expertise for translational research collaboration, including partnerships with the industry. The ECNP PMD-MHP Network adopts a transdiagnostic, lifespan, clinical staging model which cuts across different mental disorders and different methodologies. The main aims of the ECNP PMD-MHP Network are to facilitate multidisciplinary collaboration, enhance knowledge and data sharing, standardise core assessment and outcome measures, promote clinical research, apply for grant funding, and generate research reports. By supporting collaborative research, the ECNP PMD-MHP Network will be vital for fostering European psychiatry in the field of prevention of mental disorders and promotion of good mental health., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The Paris and Nice terrorist attacks affected a thousand of trauma victims and first-line responders. Because there were concerns that this might represent the first of several attacks, there was a need to quickly enhance the local capacities to treat a large number of individuals suffering from trauma-related disorders. Since Reconsolidation Therapy (RT) is brief, relatively easy to learn, well tolerated and effective, it appeared as the ideal first-line treatment to teach to clinicians in this context., Methods: This study protocol is a two-arm non-randomized, multicenter controlled trial, comparing RT to treatment as usual for the treatment of trauma-related disorders. RT consists of actively recalling one's traumatic event under the influence of the ß-blocker propranolol, once a week, for 10-25 min with a therapist, over 6 consecutive weeks. This protocol evaluates the feasibility, effectiveness, and cost-utility of implementing RT as part of a large multi-center (N = 400) pragmatic trial with a one-year follow-up., Discussion: Paris MEM is the largest trial to date assessing the efficiency of RT in the aftermath of a large-scale man-made disaster. RT could possibly reinforce the therapeutic arsenal for the treatment of patients suffering from trauma-related disorders, not only for communities in western countries but also worldwide for terror- or disaster-stricken communities., Trial Registration: Clinical Trials (ClinicalTrials.gov). June 3, 2016. NCT02789982.

The ability to infer from uncertain information is impaired in schizophrenia and is associated with hallucinations and false beliefs. The accumulation of information is a key process for generating a predictive internal model, which statistically estimates an outcome from a specific situation. This study examines if updating the predictive model by the accumulation of information in absence of feedback is impaired in schizophrenia. We explored the implicit adaptation to the probability of being instructed to perform a movement (33%-Go, 50%-Go, or 66%-Go) in a Go/NoGo task in terms of reaction times (RTs), electromyographic activity, and corticospinal excitability (CSE) of primary motor cortex (M1). CSE was assessed at two time points to evaluate prediction of the upcoming instruction based on previously accumulated information: at rest (preceding the warning signal) and at the Go/NoGo signal onset. Three groups were compared: patients with schizophrenia (n = 20), unaffected siblings (n = 16), and healthy controls (n = 20). Controls and siblings showed earlier movement onset and increased CSE with higher Go probability. CSE adaptation seemed long-lasting, because the two CSE measures, at least 1500 ms apart, strongly correlated. Patients with schizophrenia failed to show movement onset (RT) adaptation and modulation of CSE. In contrast, all groups decreased movement duration with increasing Go probability. Modulation of CSE in the anticipatory phase of the potential movement reflected the estimation of upcoming response probability in unaffected controls and siblings. Impaired modulation of CSE supports the hypothesis that implicit adaptation to probabilistic context is altered in schizophrenia., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cannabinoids are proposed in a wide array of medical indications. Yet, the evaluation of adverse effects in controlled clinical studies, following the evidence-based model, has partly been bypassed. On the other hand, studies on the consequences of recreational use of cannabis and experimental studies bring some insights on the potential long-term consequences of cannabinoids use., Results: Epidemiological studies have consistently demonstrated that cannabis use is associated with a risk of persistent cognitive deficits and increased risk of schizophrenia-like psychoses. These risks are modulated by the dose and duration of use, on top of age of use and genetic factors, including partially shared genetic predisposition with schizophrenia. Experimental studies in healthy humans showed that cannabis and its principal psychoactive component, the delta-9-tetrahydrocannabinol (THC), could produce transient, dose-dependent, psychotic symptoms as well as cognitive effects, which can be attenuated by cannabidiol (CBD). Studies in rodents have confirmed these effects and shown that adolescent exposure results in structural changes and impaired synaptic plasticity, impacting fronto-limbic systems that are critically involved in higher brain functions. The endocannabinoid system plays an important role in brain maturation. Its over-activation by cannabinoid receptor type 1 agonists (e.g., THC) during adolescence and the resulting changes in neuroplasticity could alter brain maturation and cause long-lasting changes that persist in the adult brain., Conclusions: Exposure to cannabinoids can have long-term impact on the brain, with an inter-individual variability that could be conveyed by personal and family history of psychiatric disorders and genetic background. Adolescence and early adulthood are critical periods of vulnerability., Significance: The assessment of benefice-risk balance of medical use of cannabis and cannabinoids needs to carefully explore populations that could be more at-risk of psychiatric and cognitive complications., (© 2019 European Pain Federation - EFIC®.)

Aim: Duration of untreated psychosis (DUP), or the time between onset of psychosis and treatment initiation, is a prognostic factor of schizophrenia. However, few studies evaluated the relative influence of individual-related factors on this duration. The objective of this study was to evaluate the influence of socio-demographic, clinical and cannabis use on DUP., Methods: This study was part of a large prospective study in help-seeking individuals referred to our specialized early detection / intervention clinic in the Service Hospitalo-Universitaire of Sainte-Anne Hospital in Paris (ICAAR study). We explored 33 consecutive patients who crossed the CAARMS' threshold of psychosis. The DUP and cannabis consumption history were explored during the baseline comprehensive assessment using all available sources (direct interviews of patients, parents, practitioners). Correlations between socio-demographic, clinical and cannabis use, and DUP were studied. A multiple linear regression model was used to determine the variables that could significantly predict DUP., Results: When considered individually, none of the socio-demographic and disease characteristic factors was associated with DUP, with the exception of level of education. In the multivariate analysis, age at inclusion, negative symptoms and history of cannabis use significantly influenced DUP., Conclusion: The determinants of DUP are multi-factorial and include individual centred factors, such as age, cannabis and negative symptoms. The identification of factors resulting in delayed access to care may promote the development of effective strategies to reduce DUP in early psychosis and target effective early intervention., (© 2018 John Wiley & Sons Australia, Ltd.)

Difficulties in social cognition are present both in persons with schizophrenia (SCZ) and persons with autism spectrum disorders (ASD). However, qualitative similarities and differences in this field remain unclear. The aim of this study was to explore attribution of intentionality in patients with recent onset SCZ in comparison to patients with high functioning ASD, and to explore relationships between alterations in attribution and clinical profile. Animated shapes are a non-verbal Theory of Mind (ToM) task involving the interpretation of geometric figure interactions in three conditions: random, goal-directed and ToM. We compared 51 young adults with SCZ, 32 with ASD and 23 healthy controls (HC) matched for age and gender. In random, goal-directed and ToM conditions, persons with SCZ attributed less intentionality with less appropriate answers than HC, while the same anomalies were only found in the ToM condition in persons with ASD. In SCZ, thought and langage disorganization and earlier age at onset were correlated with intentionality score in the random condition. Moreover, a mixed ToM impairment was found in SCZ, combining undermentalizing (for movements involving a mental state) similar to what was found in ASD, and overmentalizing (for random movements), related to dizorganization and precocity of the first psychotic episode. In the frame of the hypothesis of a continuum, these results underline both similarities and differences between autism and schizophrenia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Impairments in attentional, working memory and sensorimotor processing have been consistently reported in schizophrenia. However, the interaction between cognitive and sensorimotor impairments and the underlying neural mechanisms remains largely uncharted. We hypothesized that altered attentional processing in patients with schizophrenia, probed through saccadic inhibition, would partly explain impaired sensorimotor control and would be reflected as altered task-dependent modulation of cortical excitability and inhibition. Twenty-five stabilized patients with schizophrenia, 17 unaffected siblings and 25 healthy control subjects were recruited. Subjects performed visuomotor grip force-tracking alone (single-task condition) and with increased cognitive load (dual-task condition). In the dual-task condition, two types of trials were randomly presented: trials with visual distractors (requiring inhibition of saccades) or trials with addition of numbers (requiring saccades and addition). Both dual-task trial types required divided visual attention to the force-tracking target and to the distractor or number. Gaze was measured during force-tracking tasks, and task-dependent modulation of cortical excitability and inhibition were assessed using transcranial magnetic stimulation. In the single-task, patients with schizophrenia showed increased force-tracking error. In dual-task distraction trials, force-tracking error increased further in patients, but not in the other two groups. Patients inhibited fewer saccades to distractors, and the capacity to inhibit saccades explained group differences in force-tracking performance. Cortical excitability at rest was not different between groups and increased for all groups during single-task force-tracking, although, to a greater extent in patients (80%) compared to controls (40%). Compared to single-task force-tracking, the dual-task increased cortical excitability in control subjects, whereas patients showed decreased excitability. Again, the group differences in cortical excitability were no longer significant when failure to inhibit saccades was included as a covariate. Cortical inhibition was reduced in patients in all conditions, and only healthy controls increased inhibition in the dual-task. Siblings had similar force-tracking and gaze performance as controls but showed altered task-related modulation of cortical excitability and inhibition in dual-task conditions. In patients, neuropsychological scores of attention correlated with visuomotor performance and with task-dependant modulation of cortical excitability. Disorganization symptoms were greatest in patients with weakest task-dependent modulation of cortical excitability. This study provides insights into neurobiological mechanisms of impaired sensorimotor control in schizophrenia showing that deficient divided visual attention contributes to impaired visuomotor performance and is reflected in impaired modulation of cortical excitability and inhibition. In siblings, altered modulation of cortical excitability and inhibition is consistent with a genetic risk for cortical abnormality., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Gender differences in symptomatology in chronic schizophrenia and first episode psychosis patients have often been reported. However, little is known about gender differences in those at risk of psychotic disorders. This study investigated gender differences in symptomatology, drug use, comorbidity (i.e. substance use, affective and anxiety disorders) and global functioning in patients with an at-risk mental state (ARMS) for psychosis., Methods: The sample consisted of 336 ARMS patients (159 women) from the prodromal work package of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI; 11 centers). Clinical symptoms, drug use, comorbidity and functioning were assessed at first presentation to an early detection center using structured interviews., Results: In unadjusted analyses, men were found to have significantly higher rates of negative symptoms and current cannabis use while women showed higher rates of general psychopathology and more often displayed comorbid affective and anxiety disorders. No gender differences were found for global functioning. The results generally did not change when corrected for possible cofounders (e.g. cannabis use). However, most differences did not withstand correction for multiple testing., Conclusions: Findings indicate that gender differences in symptomatology and comorbidity in ARMS are similar to those seen in overt psychosis and in healthy controls. However, observed differences are small and would only be reliably detected in studies with high statistical power. Moreover, such small effects would likely not be clinically meaningful., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: Exposure to endocrine disruptors is on the rise, with new compounds regularly incriminated. In animals and humans, this exposure during critical developmental windows has been associated with various developmental abnormalities, including the emergence of psychiatric disorders. We aimed to review the association between perinatal endocrine disruptor exposure and neurodevelopmental disorders in humans, focusing on cognitive and psychiatric disorders. Methods: We performed a systematic review with key words referring to the fields of neurodevelopment and endocrine disruptors. We reviewed 896 titles, choosing studies on the basis of titles and abstracts. We searched through the methodology sections to find perinatal exposure and neurodevelopmental disorders, following the categories indicated in the Diagnostic and Statistic Manual of Mental Disorders (5 th edition). References in some studies brought us to a total of 47 studies included here. Results: Convergent studies report an association between exposure to endocrine disruptors and autism spectrum disorder, attention-deficit hyperactivity disorder, global developmental delay, intellectual disability, communication disorders and unspecified neurodevelopmental disorders. Conclusion: Sufficient data exist to report that exposure to some endocrine disruptors is a risk factor for the emergence of neurodevelopmental disorders. Studying endocrine disruptor exposure in humans is still associated with some limits that are difficult to overcome.

Background: Applying the concept of burnout to medical students before residency is relatively recent. Its estimated prevalence varies significantly between studies. Our objective was to estimate the prevalence of burnout in medical students worldwide., Methods: We systematically searched Medline for English-language articles published between January 1, 2010 and December 31, 2017. We selected all the original studies about the prevalence of burnout in medical students before residency, using validated questionnaires for burnout. Statistical analyses were conducted using the OpenMetaAnalyst software., Results: Prevalence of current burnout was extracted from 24 studies encompassing 17,431 medical students. Among them, 8060 suffered from burnout and we estimated the prevalence to be 44.2% [33.4%-55.0%]. The information about the prevalence of each subset of burnout dimensions was given in nine studies including 7588 students. Current prevalence was estimated to be 40.8% for 'emotional exhaustion' [32.8%-48.9%], 35.1% [27.2%-43.0%] for 'depersonalization' and 27.4% [20.5%-34.3%] for 'personal accomplishment'. There is no significant gender difference in burnout. The prevalence of burnout is slightly different across countries with a higher prevalence in Oceania and the Middle East than in other continents., Conclusions: The results of this meta-analysis suggest that one student out of two is suffering from burnout, even before residency. Again, our findings highlight the high level of distress in the medical population. These results should encourage the development of preventive strategies., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

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.

Olanzapine long-acting injections (OLAIs) are often prescribed to patients with severe schizophrenia who are typically excluded from randomized clinical trials. To date, no mirror-image study has examined the impact of OLAIs on healthcare resource utilizations in these patients. We conducted a retrospective, one-year mirror-image study of OLAIs on 40 patients with severe schizophrenic disorder. Illness severity was defined by failure to respond to two sequential antipsychotics. Outcomes included: (i) healthcare resource utilizations via hospitalization admissions, bed days, outpatient visits, and inpatient service costs computations (ii) clinical efficacy through changes in the Brief Psychiatric Rating Scale (BPRS) and in the Clinical Global Impression-Schizophrenia Scale (CGI-SCH), and (iii) adverse effects. After one year, OLAIs were associated with significant decreases of 65.7%, 86.2% and 86.2% in hospitalization admissions, bed days, and inpatient service costs respectively. A significant mean change of -0.47 and -0.63 was determined the BPRS and the CGI-SCH scores, respectively. There were no significant differences in the number of outpatient visits and adverse effects, except for post-injection sedation/delirium syndrome whose incidence was 0.30% per injection. This mirror-image study provides the first evidence that prescribing OLAIs reduces in a cost-effective manner average bed days and hospital admissions in patients with severe schizophrenia., (Copyright © 2018. Published by Elsevier B.V.)

Early detection and early intervention programs in early adolescent and young adult psychosis have developed in many countries and have shown their effectiveness. The main lesson of these programs is to have demonstrated that the progression of at-risk mental state into to a full-blown psychosis or of a psychotic episode to a chronic schizophrenic disorder is evitable. They have also shown that the earlier appropriate care is set up the better the functional remission and that the period of "early psychosis" encompassing the period preceding the emergence of psychosis and the first months after the first psychotic episode, is a period of opportunity for a preventive or curative intervention. Specialized therapeutic strategies shall include patient's centered integrative care. According to international recommendations, early intervention provides an extensive multidisciplinary assessment in search of possible organic etiologies and in instrumental to adapt care strategies to the person's need. It helps to identify levers for a psychosocial approach (psychoeducation, cognitive and behavioral therapies, cognitive remediation, case management) and for adressing aggravating factors (substance use, family interventions, educational support, etc.). A second-generation antipsychotic should be introduced, at lower doses than for a chronic disorder. The young patient must be accompanied until recovery by a specialized multidisciplinary team, usually for a period of 2 to 3 years. Deployment of such programs is a societal challenge and represents a paradigm shift: it questions the practices and organization of the healthcare system, but also the way healthcare professionals and the general public look at these diseases. In France, the Transition Network, a founding member of the French-speaking branch of IEPA, aims to facilitate the dissemination of these practices on a National scale, and to help to harmonize emerging initiatives., (© 2018 L’Encéphale, Paris.)

Despite progress, our understanding of psychiatric and neurological illnesses remains poor, at least in part due to the inability to access neurons directly from patients. Currently, there are in vitro models available but significant work remains, including the search for a less invasive, inexpensive and rapid method to obtain neuronal-like cells with the capacity to deliver reproducible results. Here, we present a new protocol to transdifferentiate human circulating monocytes into neuronal-like cells in 20 days and without the need for viral insertion or reprograming. We have thoroughly characterized these monocyte-derived-neuronal-like cells (MDNCs) through various approaches including immunofluorescence (IF), flow cytometry, qRT-PCR, single cell mRNA sequencing, electrophysiology and pharmacological techniques. These MDNCs resembled human neurons early in development, expressed a variety of neuroprogenitor and neuronal genes as well as several neuroprogenitor and neuronal proteins and also presented electrical activity. In addition, when these neuronal-like cells were exposed to either dopamine or colchicine, they responded similarly to neurons by retracting their neuronal arborizations. More importantly, MDNCs exhibited reproducible differentiation rates, arborizations and expression of dopamine 1 receptors (DR1) on separate sequential samples from the same individual. Differentiation efficiency measured by cell morphology was on average 11.9 ± 1.4% (mean, SEM, n = 38,819 cells from 15 donors). To provide context and help researchers decide which in vitro model of neuronal development is best suited to address their scientific question,we compared our results with those of other in vitro models currently available and exposed advantages and disadvantages of each paradigm.

Scaffolding proteins represent an evolutionary solution to controlling the specificity of information transfer in intracellular networks. They are highly concentrated in complexes located in specific subcellular locations. One of these complexes is the postsynaptic density of the excitatory synapses. There, scaffolding proteins regulate various processes related to synaptic plasticity, such as glutamate receptor trafficking and signalling, and dendritic structure and function. Most scaffolding proteins can be grouped into 4 main families: discs large (DLG), discs-large-associated protein (DLGAP), Shank and Homer. Owing to the importance of scaffolding proteins in postsynaptic density architecture, it is not surprising that variants in the genes that code for these proteins have been associated with neuropsychiatric diagnoses, including schizophrenia and autism-spectrum disorders. Such evidence, together with the clinical, neurobiological and genetic overlap described between schizophrenia and autism-spectrum disorders, suggest that alteration of scaffolding protein dynamics could be part of the pathophysiology of both. However, despite the potential importance of scaffolding proteins in these psychiatric conditions, no systematic review has integrated the genetic and molecular data from studies conducted in the last decade. This review has the following goals: to systematically analyze the literature in which common and/or rare genetic variants (single nucleotide polymorphisms, single nucleotide variants and copy number variants) in the scaffolding family genes are associated with the risk for either schizophrenia or autism-spectrum disorders; to explore the implications of the reported genetic variants for gene expression and/or protein function; and to discuss the relationship of these genetic variants to the shared genetic, clinical and cognitive traits of schizophrenia and autism-spectrum disorders.

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., (Copyright © 2017 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Competing Interests: M.-O. Krebs déclare faire ou avoir fait des interventions ponctuelles (conseils, colloques, formation) pour Otsuka Lundbeck et Janssen ; et déclare avoir été prise en charge (transport, hôtel, repas), à l’occasion de déplacements pour congrès, par Otsuka Lundbeck, Janssen T. M. Jay déclare n'avoir aucun lien d'intérêts.

Conversion to psychosis is a longitudinal process during which several epigenetic changes have been described. We tested the hypothesis that epigenetic variability in the methylomes of ultra-high risk (UHR) individuals may contribute to the risk of conversion. We studied a longitudinal cohort of UHR individuals (n = 39) and compared two groups (converters, n = 14 vs. non-converters, n = 25). A longitudinal methylomic study was conducted using Infinium HumanMethylation450 BeadChip covering half a million cytosine-phosphate-guanine (CpG) sites across the human genome from whole-blood samples. We used two statistical methods to investigate the variability of methylation probes. (i) The search for longitudinal variable methylation probes (VMPs) based on median comparisons identified two VMPs in converters only. The first CpG was located in the MACROD2 gene and the second CpG was in an intergenic region at 8q24.21. (ii) The detection of outliers using variance analysis related to private epimutations identified a dozen CpGs in converters only and highlighted two genes (RAC1 and SPHK1) from the sphingolipid signaling pathway. Our study is the first to support increased methylome variability during conversion to psychosis. We speculate that stochastic factors could increase DNA methylation variability and have a role in the complex pathophysiology of conversion to psychosis as well as in other psychiatric diseases.

Introduction: Despite extensive testing, the efficacy of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of temporo-parietal targets for the treatment of auditory verbal hallucinations (AVH) in patients with schizophrenia is still controversial, but promising results have been reported with both high-frequency and neuronavigated rTMS. Here, we report a double-blind sham-controlled study to assess the efficacy of high-frequency (20 Hz) rTMS applied over a precise anatomical site in the left temporal region using neuronavigation., Methods: Fifty-nine of 74 randomized patients with schizophrenia or schizoaffective disorders (DSM-IV R) were treated with rTMS or sham treatment and fully evaluated over 4 weeks. The rTMS target was determined by morphological MRI at the crossing between the projection of the ascending branch of the left lateral sulcus and the superior temporal sulcus (STS)., Results: The primary outcome was response to treatment, defined as a 30% decrease of the Auditory Hallucinations Rating Scale (AHRS) frequency item, observed at 2 successive evaluations. While there was no difference in primary outcome between the treatment groups, the percentages of patients showing a decrease of more than 30% of AHRS score (secondary outcome) did differ between the active (34.6%) and sham groups (9.1%) (P = .016) at day 14., Discussion: This controlled study reports negative results on the primary outcome but demonstrates a transient effect of 20 Hz rTMS guided by neuronavigation and targeted on an accurate anatomical site for the treatment of AVHs in schizophrenia patients.

Aim: The aim is to describe a centre operating in Paris that pioneers the early intervention for young people at the onset and at high risk of psychosis in France., Methods: Comprehensive descriptive analysis of different clinical and service measures is used in describing the implementation of the C'JAAD (Evaluation Centre for Young Adults and Adolescents) using data from an ongoing prospective non-interventional research programme., Results: Over a 2-year period, 151 patients were referred to the C'JAAD and included in the ICAAR research programme. After evaluation by the Comprehensive Assessment of the At-Risk Mental States Scale, 53.7% were identified at risk of developing a psychosis, 20.6% presented a full-blown psychosis and 25.7% were considered not at risk of developing a psychosis. A total of 84% of the at-risk subjects suffered from a psychiatric co-morbidity, of which anxiodepressive symptoms being the most frequent (39%). The global functioning of these at-risk subjects was seriously impaired (average Social and Occupational Functioning Assessment Scale score = 48.9). More than one third of the patients was self-referred (33.8%), 22.5% were addressed by a psychiatrist whereas 10.6% were referred by a general practitioner., Conclusions: In this paper, we report for the first time the activities of the C'JAAD, the pioneer unit in France for early detection and treatment of young adults with early psychosis. These observations indicate that such early intervention centre is a feasible and sustainable extension of traditional care for people with mental disorders in this country and offers promising perspective for the development of further centres., (© 2016 John Wiley & Sons Australia, Ltd.)

Purpose: The objective of this study was to analyze the clinical factors associated with changes in HRQoL in outpatients with schizophrenia using both generic and condition-specific HRQoL scales., Methods: Adult outpatients with schizophrenia at least 18 years of age who did not have an acute psychotic exacerbation in the 3 months prior to baseline were recruited. PANSS dimensions were calculated based on Lindenmayer et al.'s five factors. HRQoL data were assessed by patients using the Schizophrenia Quality of Life Scale (SQLS), the Short Form-36 (SF-36), and the EuroQol-5 Dimension (EQ-5D) questionnaires., Results: Out of the 1345 patients included at baseline, 1196 (89%) were evaluated at 12 months. Regression models showed that the factor most consistently associated with HRQoL at endpoint was change in the PANSS negative symptoms score. A decrease in the PANSS negative symptoms score from baseline to 1 year was associated with a decrease in HRQoL during the same period. There were also significant associations of the change in PANSS excitatory factor with all the HRQoL scales except the SF-36 PCS. Female gender was associated with a decrease in all HRQoL ratings. There was also a relationship between years since onset and HRQoL. The longer the time since illness onset, the larger the decrease in HRQoL., Conclusions: This study has found that, in outpatients with schizophrenia, changes in negative and excitement symptoms may have a greater an association with HRQoL than changes in positive, cognitive and depressive symptoms.

Theory of Mind (ToM) is compromised in schizophrenia, and responsible for social disability. We aim to study the correlation between ToM deficits and Executive Functions (EF), using the Faux Pas Test (FPT) for ToM evaluation, Behavioral Assessment of the Dysexecutive Syndrome (BADS) and Wisconsin Card Sorting Test (WCST) for EF assessment. Two groups of patients with schizophrenia were included: 22 young (18-35 years-old) and 18 middle-aged (>50 years-old) Patients, compared to age-matched Controls. We found worst FPT performances in both groups of patients, but with a more generalized pattern of dysfunction in the middle-aged patient group. This group had worse EF scores than both controls and younger patients. The association of EF with FPT items was uneven. In young patients only empathy (Q6) remained significant after controlling for EF and level of education, while in middle-aged patients faux pas explanation (Q4), false belief (Q5) and total scores remained significant. In young patients only affective TOM was impaired. No correlation was found with clinical symptoms, nor age at onset of the disease. We conclude that ToM deficit arises early during the course of the illness (already present in young patients), increases in middle-aged patients, and relates only partially with EF., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The unprecedented advances in technology and scientific research over the past few years have provided the scientific community with new and more complex forms of data. Large data sets collected from single groups or cross-institution consortiums containing hundreds of omic and clinical variables corresponding to thousands of patients are becoming increasingly commonplace in the research setting. Before any core analyses are performed, visualization often plays a key role in the initial phases of research, especially for projects where no initial hypotheses are dominant. Proper visualization of data at a high level facilitates researcher's abilities to find trends, identify outliers and perform quality checks. In addition, research has uncovered the important role of visualization in data analysis and its implied benefits facilitating our understanding of disease and ultimately improving patient care. In this work, we present a review of the current landscape of existing tools designed to facilitate the visualization of multidimensional data in translational research platforms. Specifically, we reviewed the biomedical literature for translational platforms allowing the visualization and exploration of clinical and omics data, and identified 11 platforms: cBioPortal, interactive genomics patient stratification explorer, Igloo-Plot, The Georgetown Database of Cancer Plus, tranSMART, an unnamed data-cube-based model supporting heterogeneous data, Papilio, Caleydo Domino, Qlucore Omics, Oracle Health Sciences Translational Research Center and OmicsOffice® powered by TIBCO Spotfire. In a health sector continuously witnessing an increase in data from multifarious sources, visualization tools used to better grasp these data will grow in their importance, and we believe our work will be useful in guiding investigators in similar situations., (© The Author 2016. Published by Oxford University Press.)

Alterations in eye tracking and motor impairments as well as Neurological Soft Signs (NSS) are frequently reported in patients with schizophrenia as well as in their relatives, and are proposed as endophenotype of the disease. This study investigated smooth pursuit eye movement and fixation task with distractors with a gap condition, two markers of inhibitory control mechanism, in 49 patients with schizophrenia, 24 ultra-high risk subjects, 41 full biological clinical siblings of patients and 48 controls. NSS were assessed as a marker of abnormal neurodevelopment. The results revealed more intrusive saccades respectively in smooth pursuit eye movement and in fixation task with distractors with a gap condition in patients, respect to controls and full siblings. Ultra high-risk participants with high NSS committed intrusive saccades compared to controls. Patients with schizophrenia with high NSS also displayed more of these abnormalities, compared to patients with schizophrenia with low NSS and controls. These findings highlight a global inhibitory control defect, and suggested that ultra-high risk subjects and patients with schizophrenia could share oculomotor abnormalities, especially when they express a high neurodevelopmental deviance. These oculomotor alterations might suggest that cerebral structures such as prefrontal and cerebellum could be involved in the expression of this vulnerability., (Copyright © 2017. Published by Elsevier B.V.)

To evaluate efficacy and tolerability of the combination of clozapine with an antipsychotic long-acting injectable (LAI) in multi-episode patients with schizophrenia or schizoaffective disorder. Efficacy and tolerability were assessed in seventeen patients admitted to a hospital in Paris between January 2010 and June 2015, using a one-year mirror-image design. Number and length of hospitalizations significantly decreased after introducing the combination (2.1 vs 0.8, p=0.004 and 155.4days vs 26.6days, p<0.001 respectively). No major adverse events occurred in terms of increased weight, agranulocytosis, hyperglycemia and/or dyslipidemia. This combination can be beneficial and safe in multi-episode patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Autism Spectrum Disorders (ASD) and psychosis share deficits in social cognition. The insular region has been associated with awareness of self and reality, which may be basic for proper social interactions., Methods: Total and regional insular volume and thickness measurements were obtained from a sample of 30 children and adolescents with ASD, 29 with early onset first-episode psychosis (FEP), and 26 healthy controls (HC). Total, regional, and voxel-level volume and thickness measurements were compared between groups (with correction for multiple comparisons), and the relationship between these measurements and symptom severity was explored., Results: Compared with HC, a shared volume deficit was observed for the right (but not the left) anterior insula (ASD: p = 0.007, FEP: p = 0.032), and for the bilateral posterior insula: (left, ASD: p = 0.011, FEP: p = 0.033; right, ASD: p = 0.004, FEP: p = 0.028). A voxel-based morphometry (VBM) conjunction analysis showed that ASD and FEP patients shared a gray matter volume and thickness deficit in the left posterior insula. Within patients, right anterior (r = -0.28, p = 0.041) and left posterior (r = -0.29, p = 0.030) insular volumes negatively correlated with the severity of insight deficits, and left posterior insular volume negatively correlated with the severity of 'autistic-like' symptoms (r = -0.30, p = 0.028)., Conclusions: The shared reduced volume and thickness in the anterior and posterior regions of the insula in ASD and FEP provides the first tentative evidence that these conditions share structural pathology that may be linked to shared symptomatology.

Sainte-Anne Hospital is the largest psychiatric hospital in Paris. Its long and fascinating history began in the 18th century. In 1952, it was at Sainte-Anne Hospital that Jean Delay and Pierre Deniker used the first neuroleptic, chlorpromazine, to cure psychiatric patients, putting an end to the expansion of psychosurgery. The Department of Neuro-psychosurgery was created in 1941. The works of successive heads of the Neurosurgery Department at Sainte-Anne Hospital summarized the history of psychosurgery in France. Pierre Puech defined psychosurgery as the necessary cooperation between neurosurgeons and psychiatrists to treat the conditions causing psychiatric symptoms, from brain tumors to mental health disorders. He reported the results of his series of 369 cases and underlined the necessity for proper follow-up and postoperative re-education, illustrating the relative caution of French neurosurgeons concerning psychosurgery. Marcel David and his assistants tried to follow their patients closely postoperatively; this resulted in numerous publications with significant follow-up and conclusions. As early as 1955, David reported intellectual degradation 2 years after prefrontal leucotomies. Jean Talairach, a psychiatrist who eventually trained as a neurosurgeon, was the first to describe anterior capsulotomy in 1949. He operated in several hospitals outside of Paris, including the Sarthe Psychiatric Hospital and the Public Institution of Mental Health in the Lille region. He developed stereotactic surgery, notably stereo-electroencephalography, for epilepsy surgery but also to treat psychiatric patients using stereotactic lesioning with radiofrequency ablation or radioactive seeds of yttrium-90. The evolution of functional neurosurgery has been marked by the development of deep brain stimulation, in particular for obsessive-compulsive disorder, replacing the former lesional stereotactic procedures. The history of Sainte-Anne Hospital's Neurosurgery Department sheds light on the initiation-yet fast reconsideration-of psychosurgery in France. This relatively more prudent attitude toward the practice of psychosurgery compared with other countries was probably due to the historically strong collaboration between psychiatrists and neurosurgeons in France.

Impaired manual dexterity is commonly observed in schizophrenia. However, a quantitative description of key sensorimotor components contributing to impaired dexterity is lacking. Whether the key components of dexterity are differentially affected and how they relate to clinical characteristics also remains unclear. We quantified the degree of dexterity in 35 stabilized patients with schizophrenia and in 20 age-matched control subjects using four visuomotor tasks: (i) force tracking to quantify visuomotor precision, (ii) sequential finger tapping to measure motor sequence recall, (iii) single-finger tapping to assess temporal regularity, and (iv) multi-finger tapping to measure independence of finger movements. Diverse clinical and neuropsychological tests were also applied. A patient subgroup ( N  = 15) participated in a 14-week cognitive remediation protocol and was assessed before and after remediation. Compared to control subjects, patients with schizophrenia showed greater error in force tracking, poorer recall of tapping sequences, decreased tapping regularity, and reduced degree of finger individuation. A composite performance measure discriminated patients from controls with sensitivity = 0.79 and specificity = 0.9. Aside from force-tracking error, no other dexterity components correlated with antipsychotic medication. In patients, some dexterity components correlated with neurological soft signs, Positive and Negative Syndrome Scale (PANSS), or neuropsychological scores. This suggests differential cognitive contributions to these components. Cognitive remediation lead to significant improvement in PANSS, tracking error, and sequence recall (without change in medication). These findings show that multiple aspects of sensorimotor control contribute to impaired manual dexterity in schizophrenia. Only visuomotor precision was related to antipsychotic medication. Good diagnostic accuracy and responsiveness to treatment suggest that manual dexterity may represent a useful clinical marker in schizophrenia.

Schizophrenic (SCZ) and autism (ASD) spectrum disorders share several features including social cognition impairments. In SCZ, the link between symptomatic dimensions and social cognition deficits remains unclear. The Movie for the Assessment of Social Cognition (MASC) test, available in several languages including English, investigates mental state attribution capabilities in complex interpersonal situations. After its translation into French, we used MASC to direct compare social cognition in 36 young participants with SCZ to 19 with ASD and 20 healthy controls (HC) matched for gender, age (18-25y.o.) and level of education. The MASC discriminated each group from the others, patients with SCZ exhibiting difficulties compared to ASD (MASC total score 28.1 (4) and 24.2 (6.6), respectively; p<.001). In the whole sample, MASC scores were inversely correlated with autistic traits, evaluated by autism quotient, and with disorganization symptoms. Finally, in SCZ, over-mentalizing difficulties were correlated with age at disease onset. Our results demonstrate the validity of the French version of the MASC and bring direct evidence supporting the hypothesis of a phenotypic continuum between autism and schizophrenia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Cognitive disorders are currently considered as central components of disorders found in schizophrenia and are a major handicap for patients day to day. These disorders appear before the first psychotic episode, in the prodromal phase, during which time the symptoms are below the threshold for psychosis. People with these symptoms are considered as presenting an at-risk mental state (or at ultra-high risk, UHR of psychosis) and their risk for psychotic transition is between 20% and 40% within one year. Despite a number of studies, the chronology in which cognitive disorders appear in relation to the psychotic symptoms has not clearly been established and the study of the links between cognition and symptoms could improve our understanding of psychotic disorders. The detection of certain cognitive disorders before the onset of psychotic disorders could help improve early detection. We carried out a systematic analysis of the literature exploring cognitive disorders found in subjects with UHR for psychosis. The objective of most studies was to establish the predictive value for psychotic transition. Nevertheless study results have shown little consensus. Faced with this heterogeneity of results from past studies, we carried out a critical analysis of the literature and suggest areas of reflection for future research., (Copyright © 2017 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: In schizophrenic disorders, supportive psychosocial therapies have been used as adjuncts to pharmacotherapy to help alleviate residual symptoms and to improve social functioning and quality of life. Among these therapies, psychoeducational therapies showed a significant efficacy on improving drug adherence and on reducing relapses. However, according to the French Health Agency, fewer than 10% of psychiatric structures in France offer registered psychoeducation programs. Caregiver apprehension of patients' depressive reactions to the awareness of the disease could underlie the underuse of psychoeducation therapies. Indeed, the psychoeducation programs' impact on objective and subjective quality of life is discussed among the literature. In this context, we conducted a retrospective, monocentric, open-labelled and non-controlled pilot study to measure the impact of a registered psychoeducation program on objective and subjective quality of life of patients suffering from schizophrenia. Secondary objectives included measures of the effects on drug observance and awareness of the disease., Methods: We included stabilized patients over the age of eighteen suffering from schizophrenia. Referent psychiatrics were asked to inform the patient of the diagnosis and to prescribe psychoeducation therapy. From 2011 to 2014, we offered three ambulatory programs, each program including fifteen two-hour group sessions. The groups were opened for three to six patients and managed by two caregivers. Themes discussed during the sessions included: schizophrenic disease, treatments, relationships to family, diet, social issues, toxics, relaxation. Objective and subjective quality of life were evaluated one month before and one month after the program using respectively the global assessment functioning (GAF) and the subjective quality of life (SQoL) scales. The Medical Adherence Rating Scale (MARS) and the French IQ8 scale evaluated respectively drug adherence and awareness of the disease. All patients gave their written consent for the study. Based on medical records and scales, we compared data before and after the program using the Wilcoxon test, adapted for small samples., Results: Fourteen patients, with a mean age of 37.6 years, were included. All patients had a chronic antipsychotic treatment and four benefitted from a bitherapy with a mood stabilizer. The mean length of disease was 15.3 years, with a mean number of 3.4 hospitalizations before inclusion. The participation rate was nearly twelve sessions out of fifteen. Mean GAF score before the program was 48/100. After the program, mean GAF score was significantly increased to 54/100 (P=0.008). As to SQoL score, we found a significant difference of the sub item psychological well-being from 3.2/5 before the program to 3.8/5 after the program (P=0.03). Global SQoL score and other sub items (self-esteem, resilience, and physical well-being) showed a slight but not significant improvement. The sub items family relationships and sentimental life were diminished, non-significantly. Concerning the drug adherence, the mean MARS score was significantly increased from 6.1 to 6.4/8 (P=0.03). Comparison of the insight IQ8 scale showed a slight but non-significant increase. When asked to note the program, patients were globally very satisfied, with a mean rate of 8.6/10. Of fourteen patients, one needed to be hospitalized three years after program., Discussion: This retrospective study on a small sample of patients suffering from schizophrenic disorder pointed out a significant improvement on drug adherence, objective quality of life and psychological well-being, after an eight-month registered program of psychoeducational therapy. These results are in line with a recent report from the Cochrane group who reported a significant raise of GAF associated with psychoeducational therapies. The literature data for subjective quality of life are more contradictory. Despite the small sample and evaluation means that need to be corrected in further studies, we reproduced the results described in the literature regarding the improvement on drug adherence. However, the stability of these effects should be checked in the medium and long term., Conclusion: Adjunctive psychoeducation therapy has a positive impact on reducing relapses in schizophrenia. In this study, we showed a significant benefit on drug adherence, objective quality of life and psychological well-being on a small sample of patients and provide arguments for the development of psychoeducation programs which are currently underrepresented in France. Our results encourage conducting a further prospective multicenter controlled study on a larger sample to clarify the benefit of psychoeducational therapy on objective and subjective quality of life in schizophrenia., (Copyright © 2016 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Background: In the Western world, between 1940 and 1970, more than 2 million people were exposed in utero to diethylstilbestrol (DES). In exposed individuals, and in their descendants, adverse outcomes have been linked to such exposure, including cancers, genital malformations, and less consistently, psychiatric disorders. We aimed to explore whether prenatal DES exposure would be associated with DNA methylation changes, and whether these epigenetic modifications would be associated with increased risk of psychosis., Methods: From 247 individuals born from mothers exposed to DES, we selected 69 siblings from 30 families. In each family, at least one sibling was exposed in utero to DES. We performed a methylome-wide association study using HumanMethylation450 DNA Analysis BeadChip® in peripheral blood. We analyzed methylation changes at individual CpGs or regions in exposed (n = 37) versus unexposed individuals (n = 32). We also compared exposed individuals with (n = 7) and without psychosis (n = 30)., Results: There were more individuals with schizophrenia in the DES-exposed group. We found no significant differences between exposed and unexposed individuals with respect to differentially methylated CpGs or regions. The largest difference was in a region near the promoter of an ADAMTS proteoglycanase gene (ADAMTS9). Compared to exposed individuals without psychosis, exposed individuals with psychosis had differential methylation in the region encompassing the gene encoding the zinc finger protein 57 (ZFP57)., Conclusions: In utero exposure to DES was not associated with methylation changes at specific CpG or regions. In exposed individuals, however, psychosis was associated with specific methylomic modifications that could impact neurodevelopment and neuroplasticity.

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.

Background: Neurological soft signs (NSS) include anomalies in motor integration, coordination, sensory integration and lateralization and could be endophenotypic markers in autism spectrum disorders (ASD). Their characterization provides a more precise phenotype of ASD and more homogeneous subtypes to facilitate clinical and genetic research. Few scales for NSS have been adapted and validated in children including children with ASD. Our objective was to perform an adaptation to the child of a scale assessing neurological soft signs and a validation study in both general and clinical populations., Methods: We have selected the NSS scale of Krebs et al. (2000) already validated in adults. It encompasses 5 dimensions: motor coordination, motor integration, sensory integration, involuntary movement, laterality. After a preliminary study that examined 42 children, several changes have been made to the original version to adapt it to the child and to increase its feasibility, particularly in children with ASD. Then we conducted a validation study by assessing the psychometric properties of this scale in a population of 86 children including 26 children with ASD (DSM 5 Criteria) and 60 typically developing children. Children's ages ranged between 6 and 12 years, and patients and controls were matched for gender, age and intelligence. Patients were assessed using the Autism diagnostic Interview-revised and the Childhood Autism Rating Scale to confirm diagnosis. Typically developing children were assessed using the semi-structured Mini International Neuropsychiatric Interview for Children and Adolescents to eliminate any psychiatric disorder. All children with neurological pathologies (history of cerebral palsy, congenital anomaly of the central nervous system, epilepsy, tuberous sclerosis, neurofibromatosis, antecedent of severe head trauma) and obvious physical deformities or sensory deficits that could interfere with neurological assessment were excluded from the study. Both patients and controls were assessed using the Raven Progressive Matrices to exclude intellectual disability, and the adapted Krebs' scale for the assessment of NSS., Results: Adaptation of the scale consisted of a modification in the order of items, in the use of concrete supports for the assessment of laterality and in the elimination of item constructive praxis. The internal consistency was good with a Cronbach alpha of 0.87. Inter-rater reliability was good, kappa coefficient was greater than 0.75 for 16 items, 3 items had a kappa value between 0.74 and 0.60, only 1 item had a kappa coefficient between 0.4 and 0.59. Good inter-rater reliability was also checked for the total score with a value of intra-class correlation coefficient (ICC) of 0.91. Principal component analysis found five factors accounting for 62.96 % of the total variance. About the comparison between patients and controls, significant differences were found for NSS total score (P=0.000) and all subscores., Conclusion: The adaptation for children of the Krebs et al.' NSS scale proved to be valid, especially in children with ASD., (Copyright © 2016 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Schizophrenia is a neurodevelopmental disease with cognitive and motor impairments. Motor dysfunctions, such as eye movements or Neurological Soft Signs (NSS), are proposed as endophenotypic markers. Antisaccade (AS) and memory-guided saccades (MGS), two markers of inhibitory control mechanism, are altered in both patients with schizophrenia and their relatives, although these tools may have different sensitivities. Recently, emphasis has been put on identifying markers predictive of psychosis transition in subjects with ultra-high-risk psychosis in order to develop targeted prevention. This study investigates AS and MGS in 46 patients with schizophrenia, 23 ultra-high-risk subjects, and 39 full siblings compared to 47 healthy volunteers. NSS were assessed as a marker of abnormal neurodevelopment. The results revealed more errors in MGS in patients, ultra-high-risk subjects and siblings, than in controls, and more specifically ultra-high-risk subjects with high NSS scores. By contrast, the error rate in AS was significantly higher only in patients with schizophrenia compared to controls. These findings suggest that MGS could be more accurate to detect deficient inhibitory processes as a marker of vulnerability before the onset of schizophrenia. The use of the different paradigms (AS, MGS) revealed distinct profiles depending on the stage of the disease, indicating that some alterations could be pure endophenotypic markers of vulnerability for schizophrenia, while others could be markers of the disease progression., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Several clinical and radiological markers of early neurodevelopmental deviations have been independently associated with cognitive impairment in patients with schizophrenia. The aim of our study was to test the cumulative and/or interactive effects of these early neurodevelopmental factors on cognitive control (CC) deficit, a core feature of schizophrenia., Methods: We recruited patients with first-episode schizophrenia-spectrum disorders, who underwent structural MRI. We evaluated CC efficiency using the Trail Making Test (TMT). Several markers of early brain development were measured: neurological soft signs (NSS), handedness, sulcal pattern of the anterior cingulate cortex (ACC) and ventricle enlargement., Results: We included 41 patients with schizophrenia in our analysis, which revealed a main effect of ACC morphology ( p = 0.041) as well as interactions between NSS and ACC morphology ( p = 0.005), between NSS and handedness ( p = 0.044) and between ACC morphology and cerebrospinal fluid (CSF) volume ( p = 0.005) on CC measured using the TMT-B score - the TMT-A score., Limitations: No 3- or 4-way interactions were detected between the 4 neurodevelopmental factors. The sample size was clearly adapted to detect main effects and 2-way interactions, but may have limited the statistical power to investigate higher-order interactions. The effects of treatment and illness duration were limited as the study design involved only patients with first-episode psychosis., Conclusion: To our knowledge, our study provides the first evidence of cumulative and interactive effects of different neurodevelopmental markers on CC efficiency in patients with schizophrenia. Such findings, in line with the neurodevelopmental model of schizophrenia, support the notion that CC impairments in patients with schizophrenia may be the final common pathway of several early neurodevelopmental mechanisms.

Schizophrenia and other psychoses are categorical psychiatric diagnoses corresponding to frequent and heterogeneous disorders. Their physiopathology still remains largely unknown despite numerous recent advances. In particular, the last decade has identified different types of genetic variants, thanks to emergence of high-throughput methods. These methods allow both the identification of rare variants with a large effect such as punctual mutations or copy-number variants and the identification of frequent variants with a limited effect such as polymorphisms. Many impacted genes have been identified showing a very high genetic heterogeneity of psychoses. These genes are overrepresented in synaptic and neurotransmission pathways. Only a small fraction of psychoses could be easily explained by genetics but this screening in clinical practice is important as it can lead to therapeutic challenge or genetic counselling. Nowadays, it is clear that the pathophysiology of the psychoses can only be understood by an integrative approach taking into account the interaction between genes and environment. This interaction could be mediated by the epigenome defined as the modification of gene expression without changes in DNA sequence. Epigenome is stable but could be modified by environmental factors. Several epigenetic mechanisms have been studied in psychosis, in particular the DNA methylation, the modification of histones and the microRNA. All of these mechanisms are under regulation by genetic factors and variants in these epigenetic-involved genes and cofactors have been also associated with schizophrenia. Thus, pathophysiology of psychosis is complex and morestudiesare needed before definitive conclusions. Altogether, the recent advances in the genetics and epigenetics of psychosis are promising and could open the way to a recategorization of these disorders as well as the identification of new therapeutic targets., (© Société de Biologie, 2017.)

The ability to detect our own errors is an essential component of action monitoring. Using a masking paradigm in normal adults, we recently discovered that some error-detection processes can proceed without awareness, while other markers of performance monitoring such as the Error-Related Negativity (ERN) are tightly linked to conscious perception. Interestingly, research on cognitive deficit in schizophrenia has shown that the ERN is altered in these patients. In the present study, we therefore tested if the error detection impairment in schizophrenia is specific to conscious perception or is also found under non-conscious conditions, probing whether these performance monitoring processes are truly distinct. Thirteen patients with schizophrenia and thirteen age-matched healthy control subjects performed a speeded number comparison task on masked stimuli while EEG and MEG signals were recorded. Conscious perception and error-detection were assessed on a trial-by-trial basis using subjective reports of visibility and confidence. We found that patients with schizophrenia presented altered cingulate error-detection responses in conscious trials, as reflected by a decreased ERN. By contrast, on unconscious trials, both controls and schizophrenia patients performed above chance in evaluating the likelihood of having made an error. This dissociation confirms the existence of two distinct performance monitoring systems, and suggests that conscious metacognition in schizophrenia is specifically altered while non-conscious performance monitoring remains preserved., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Psychiatry aims at detecting symptoms, providing diagnoses and treating mental disorders. We developed ONTOPSYCHIA, an ontology for psychiatry in three modules: social and environmental factors of mental disorders, mental disorders, and treatments. The use of ONTOPSYCHIA, associated with dedicated tools, will facilitate semantic research in Patient Discharge Summaries (PDS). To develop the first module of the ontology we propose a PDS text analysis in order to explicit psychiatry concepts. We decided to set aside classifications during the construction of the modu le, to focus only on the information contained in PDS (bottom-up approach) and to return to domain classifications solely for the enrichment phase (top-down approach). Then, we focused our work on the development of the LOVMI methodology (Les Ontologies Validées par Méthode Interactive - Ontologies Validated by Interactive Method), which aims to provide a methodological framework to validate the structure and the semantic of an ontology.

Inhibition is considered a key mechanism in schizophrenia. Short-latency intracortical inhibition (SICI) in the motor cortex is reduced in schizophrenia and is considered to reflect locally deficient γ-aminobutyric acid (GABA)-ergic modulation. However, it remains unclear how SICI is modulated during motor inhibition and how it relates to neural processing in other cortical areas. Here we studied motor inhibition Stop signal task (SST) in stabilized patients with schizophrenia (N = 28), healthy siblings (N = 21) and healthy controls (n = 31) matched in general cognitive status and educational level. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) were used to investigate neural correlates of motor inhibition. SST performance was similar in patients and controls. SICI was modulated by the task as expected in healthy controls and siblings but was reduced in patients with schizophrenia during inhibition despite equivalent motor inhibition performance. fMRI showed greater prefrontal and premotor activation during motor inhibition in schizophrenia. Task-related modulation of SICI was higher in subjects who showed less inhibition-related activity in pre-supplementary motor area (SMA) and cingulate motor area. An exploratory genetic analysis of selected markers of inhibition (GABRB2, GAD1, GRM1, and GRM3) did not explain task-related differences in SICI or cortical activation. In conclusion, this multimodal study provides direct evidence of a task-related deficiency in SICI modulation in schizophrenia likely reflecting deficient GABA-A related processing in motor cortex. Compensatory activation of premotor areas may explain similar motor inhibition in patients despite local deficits in intracortical processing. Task-related modulation of SICI may serve as a useful non-invasive GABAergic marker in development of therapeutic strategies in schizophrenia., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Several clinical and radiological markers of early neurodevelopmental deviations have been independently associated with cognitive impairment in patients with schizophrenia. The aim of our study was to test the cumulative and/or interactive effects of these early neurodevelopmental factors on cognitive control (CC) deficit, a core feature of schizophrenia., Methods: We recruited patients with first-episode schizophrenia-spectrum disorders, who underwent structural MRI. We evaluated CC efficiency using the Trail Making Test (TMT). Several markers of early brain development were measured: neurological soft signs (NSS), handedness, sulcal pattern of the anterior cingulate cortex (ACC) and ventricle enlargement., Results: We included 41 patients with schizophrenia in our analysis, which revealed a main effect of ACC morphology ( p = 0.041) as well as interactions between NSS and ACC morphology ( p = 0.005), between NSS and handedness ( p = 0.044) and between ACC morphology and cerebrospinal fluid (CSF) volume ( p = 0.005) on CC measured using the TMT-B score - the TMT-A score., Limitations: No 3- or 4-way interactions were detected between the 4 neurodevelopmental factors. The sample size was clearly adapted to detect main effects and 2-way interactions, but may have limited the statistical power to investigate higher-order interactions. The effects of treatment and illness duration were limited as the study design involved only patients with first-episode psychosis., Conclusion: To our knowledge, our study provides the first evidence of cumulative and interactive effects of different neurodevelopmental markers on CC efficiency in patients with schizophrenia. Such findings, in line with the neurodevelopmental model of schizophrenia, support the notion that CC impairments in patients with schizophrenia may be the final common pathway of several early neurodevelopmental mechanisms.

Objective: We examined Theory of Mind (ToM) abilities in adolescents with early-onset schizophrenia (EOS) and their correlation with clinical findings and Executive Functions (EF)., Methods: The ToM abilities of 12 adolescents with EOS were compared with those of healthy participants matched in age and educational level. The Moving Shapes Paradigm was used to explore ToM abilities in three modalities: random movement, goal-directed movement and ToM - scored on the dimensions of intentionality, appropriateness and length of each answer. EF was tested using Davidson's Battery and the clinical psychopathology with the Positive and Negative Syndrome Scale (PANSS)., Results: Adolescents with EOS were significantly more impaired than controls in the three dimensions evaluated for the goal-directed and ToM modalities. Regarding the random movement modality, the only difference was in appropriateness (p<0.01). No correlation with age or level of education was evident for ToM skills. Total PANSS score was negatively correlated with appropriateness score for the goal-directed (p=0.02) and ToM modalities (p=0.01). No correlation existed between performance in the ToM Animated Tasks and positive, negative or disorganisation PANSS subscores. No correlations were found among the three scores in the Moving Shapes Paradigm and any measures of the accuracy of the three tasks assessing EF., Conclusion: Our results confirm previous findings of ToM deficits in adult individuals with schizophrenia and attest the severity of these deficits in patients with EOS.

Introduction: Prognosis of schizophrenia has not significantly improved despite extensive research. There is often a relatively long delay between onset of symptoms and treatment initiation. Lately, duration of untreated psychosis (DUP), the time between the onset of psychosis and initiation of treatment, has been one of the most studied variables in patients presenting for a first psychotic episode in order to evaluate the impact of early intervention on the prognosis of schizophrenia. In the literature, a variety of criteria have been used to define both transition to psychosis and initiation of treatment. Furthermore, the dating of both of these variables is usually retrospective, further complicating the measurement of DUP., Methods: We conducted a comprehensive review about DUP using Pubmed and Google Scholar databases up to January 2015 using the following keywords "schizophrenia", "duration of untreated psychosis", "duration of untreated illness" and "early intervention". Papers were included if they were published in French or English., Results: The mean DUP was found to be 2 years but it can vary according to multiple factors such as denial of illness by the patient and family, withdrawal and isolation from friends and relatives, diagnostic errors, paranoid views of the mental health treatment systems, or negative symptoms. Long DUP may also be a correlate of poor premorbid functioning or of an insidiously unfolding psychosis. Considerable discrepancies exist in the way that DUP is estimated in different studies. Although the clinical interview remains the most common way of measuring DUP, so far there is no evidence for favoring one method over another. Regardless of measurement method, a longer DUP is found to be associated with poorer outcome in schizophrenia in both the short and long-term across a number of domains: symptoms severity, remission rates, the risk of relapse, global functioning and quality of life. Its role in functional outcome appears to be mediated largely by negative symptoms, for which there is still no effective treatment. A recent meta-analysis has shown that shorter DUP is associated with less severe negative symptoms at short and long-term follow-up, especially when DUP is shorter than 9 months. The mechanism of the relationship between DUP and outcome is still undefined. A hypothesis is that the shorter the DUP, the more likely the intervention is being applied during the period in which neurobiological deficit processes in schizophrenia are most active., Discussion: A study of the duration of untreated illness (DUI), which is defined as the DUP and the prodromal phase, seems necessary because results of studies evaluating the effect of early detection and intervention in individuals with clinical high risk for psychosis are promising. A number of interventions such as omega 3 fatty acids and integrated psychosocial interventions seem to delay transition in the at-risk population. However, replication studies are lacking, and a great proportion of at high-risk individuals will spontaneously remit or develop diseases other than chronic psychosis, making us question the advantages and disadvantages of a treatment. Taking into consideration the high prevalence of comorbidities in individuals referred for clinical high-risk state and their effect on the individual's functioning, future interventions in the field need to address not only the preventative efficacy on psychosis transition but also their effectiveness in improving the functioning of this population and their effect on the outcome of schizophrenia when transition to psychosis has occurred., Conclusion: Despite the huge advances in the field of schizophrenia, many questions remain unanswered and huge efforts are still necessary to understand the pathophysiology of this illness in order to improve its outcome., (Copyright © 2016 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)