Association and epistatic analysis of white matter related genes across the continuum schizophrenia and autism spectrum disorders: The joint effect of NRG1-ErbB genes.

BACKGROUND: Schizophrenia-spectrum disorders (SSD) and Autism spectrum disorders (ASD) are neurodevelopmental disorders that share clinical, cognitive, and genetic characteristics, as well as particular white matter (WM) abnormalities. In this study, we aimed to investigate the role of a set of oligodendrocyte/myelin-related (OMR) genes and their epistatic effect on the risk for SSD and ASD. METHODS: We examined 108 SNPs in a set of 22 OMR genes in 1749 subjects divided into three independent samples (187 SSD trios, 915 SSD cases/control, and 91 ASD trios). Genetic association and gene-gene interaction analyses were conducted with PLINK and MB-MDR, and permutation procedures were implemented in both. RESULTS: Some OMR genes showed an association trend with SSD, while after correction, the ones that remained significantly associated were MBP, ERBB3, and AKT1. Significant gene-gene interactions were found between (i) NRG1*MBP (perm p-value = 0.002) in the SSD trios sample, (ii) ERBB3*AKT1 (perm p-value = 0.001) in the SSD case-control sample, and (iii) ERBB3*QKI (perm p-value = 0.0006) in the ASD trios sample. DISCUSSION: Our results suggest the implication of OMR genes in the risk for both SSD and ASD and highlight the role of NRG1 and ERBB genes. These findings are in line with the previous evidence and may suggest pathophysiological mechanisms related to NRG1/ERBBs signalling in these disorders.

[Validation of a French version of the 16-item Prodromal Questionnaire (fPQ16) in adolescents and young adults seeking help]. / Validation d'une version française du 16-items Prodromal Questionnaire (fPQ16) chez des adolescents et jeunes adultes consultant en psychiatrie.

INTRODUCTION: The duration of untreated psychosis has been largely associated with poor outcomes in psychosis. Actual diagnostic tools may be used by very specialized teams and need sustained evaluation. We present a French version of a self-report questionnaire: the 16-item Prodromal Questionnaire (fPQ16). Our objective was to evaluate its predictive value for an ultra-high-risk state (UHR) or psychosis. The population enrolled was consulting in a young adults and adolescents center in Sainte-Anne hospital, Paris, France. METHODS: PQ16 had first been translated into French and independently back translated and validated by the original authors. Between November 2016 and May 2018, every C'JAAD consulting patient was proposed to fill in the fPQ16. Each patient was next evaluated with the French version of the comprehensive assessment of at-risk mental state (CAARMS), which detects UHR or psychosis. Statistical analysis of fPQ16 concurrent validity was performed using ROC curves. fPQ16 acceptability was studied by four additional questions especially designed for that purpose. RESULTS: One hundred participants were included. Mean age was 19.85years (SD 3.3 y). Fifty-eight percent of patients included were diagnosed with UHR (40%) or psychotic (18%) state after CAARMS evaluation. Mean score at fPQ16 was 5.7 (SD 3.8). Best cut-off score was 4 positive items, with excellent sensibility (91%) and correct specificity (60%). Positive predictive value of fPQ16 was 76%. Area under the curve was 0.85 (P<0.0001). fPQ16 showed good acceptability. DISCUSSION: fPQ16 had good screening performances in our population. Cut-off score was lower than in previous studies, but performances were equal or better. As a well-accepted and short questionnaire, the fPQ16 could be a great screening tool in primary care. A version with 18-items, including two items focused on thought content and disorganization that are missing in PQ16, is under evaluation.

[Management of cardiovascular co-morbidities in young patients with early onset psychosis: State of the art and therapeutic perspectives]. / Prise en charge des comorbidités cardio-vasculaires chez les jeunes patients souffrant d'une psychose débutante : état des lieux et perspectives thérapeutiques.

Patients with psychiatric disorders have a decrease in their life expectancy. Excess mortality of patients with schizophrenia was demonstrated by a meta-analysis in the late 1990s and has not decreased for the past 30years. A recent meta-analysis including nearly 250,000 patients with schizophrenia found an average decrease in life expectancy of 14.5years (CI95: 11,2-17,8), more important for men than for women: 15.9 (CI95: 13,8-18,0) vs 13.6 (CI95: 11,4-15,8). A closer look at the somatic comorbidities, including metabolic syndrome, and investigation of causes of death of these patients highlighted already well-known factors, namely late diagnosis and insufficient treatment of physical diseases, side effects of antipsychotics, unhealthy lifestyle (poor diet, smoking, excessive alcohol consumption and lack of exercise), and higher risk of suicide and accident. Concerning ultra-high risk (UHR) patients, a 2016 meta-analysis of 47 studies evaluated the cardiovascular risk factors. They reported a higher prevalence of smoking in UHR (odds ratio 2,3) and a lower level of physical activity associated with a normal BMI (Body Mass Index) compared to the control population. A meta-analysis about patients with a first episode of psychosis (FEP) found reduced total and LDL cholesterol levels and an increased triglyceride level compared to the control population. One study found alteration of the fasting plasmatic levels of glucose and insulin, as well as insulin resistance in FEP patients, compared to controls albeit the HbA1c level was not significantly different. A meta-analysis reported a prevalence of metabolic syndrome of 10 % in FEP or drug naïve patients versus 35 % and 20 % in treated and untreated patients with chronic schizophrenia respectively. Somatic comorbidities usually appear during the first two years of the disease. Some interventions have proven their efficacy in reducing the occurrence of metabolic syndrome and other cardiovascular risk factors. For instance, metformin, a treatment for type 2 diabetes that is allowed from the age of 10, has shown benefits in children and adolescents receiving second-generation antipsychotics in a recent meta-analysis, with a mean weight loss of 3.23kg (IC95 % -5.59 -0.86) after 16 weeks. Dietary-hygienic interventions are also effective in reducing cardiovascular risk. Other interventions such as omega-3 supplementation, vitamin D, N-acetylcysteine, and fasting have not proven to be effective. Comprehensive care programs have been developed to promote somatic care in psychiatric patients, such as the Canadian HeAL (Healthy Active Lives) program. These programs are more effective when proposed from the beginning of the disease and the introduction of antipsychotics. In this review, because there is no French recommendation, we translate a tool for the prescription of metformin and the Canadian recommendations from the HeAL program. Generalization of these programs to all young psychotic patients could improve their life expectancy and reduce the overall mortality. Prevention of cardiovascular risk factors and cardio-metabolic monitoring of treatments must be part of the standard of care in early psychosis. These programs aim at providing patients with the quality of somatic and mental care they are entitled to. This requires the involvement of all stakeholders, including patients and their families but also psychiatrists and other caregivers.

[Health professionals facing the coronavirus disease 2019 (COVID-19) pandemic: What are the mental health risks?] / Les professionnels de santé face à la pandémie de la maladie à coronavirus (COVID-19) : quels risques pour leur santé mentale ?

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.

[Neurodevelopment and cannabis]. / Cannabis et neurodéveloppement.

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.

[Membrane lipids in schizophrenia and early phases of psychosis: Potential biomarkers and therapeutic targets?] / Lipides membranaires dans la schizophrénie et la psychose débutante : de potentiels biomarqueurs et pistes thérapeutiques ?

The various roles of membrane lipids in human health has urged researchers to study their impact in neuropsychiatric diseases, especially in schizophrenia spectrum disorders and more recently in early stages of psychosis. The progress in mass spectrometry technologies now allows a more comprehensive analysis of phospholipids (PL) and their fatty acid (FA) molecular species. FA are defined by a carbon chain of variable length and are said to be unsaturated when their chain has one or more carbon-carbon double bonds. The PL are composed of a hydrophilic polar head with a phosphoric acid group and an hydrophobic part with FAs; they encompass glycerophospholipids and sphingolipids. The plasma membrane is a complex and dynamic structure consisting of a lipid bilayer composed of an outer layer and an inner layer of specific lipid composition. The permanent remodeling of membrane lipids involves phospholipases especially the phospholipase A2. Seventy percent of the brain consists of lipids from different classes and molecular species. Most of the brain lipids are composed of polyunsaturated fatty acid (PUFA)-enriched diacyl classes where omega-3 and omega-6 molecular species predominate. The balance between omega-3 and omega-6 is important for the neurodevelopment. PUFA are also involved in neurogenesis and neurotransmission. Sphingomyelin (SM) is a sphingolipid that influences inflammation, cell proliferation and lipid rafts formation. It is an important component of myelin sheaths of white matter and therefore is involved in cerebral connectivity. In rat models, deficiency in omega-3 causes abnormalities in dopaminergic neurotransmission, impacts on the functioning of some receptors (including cannabinoids CB1, glutamatergic N-methyl-D-aspartate receptor, NMDA), and increases sensitivity to hallucinogens. In contrast, omega-3 supplementation improves cognitive function and prevents psychotic-like behavior in some animal models for schizophrenia. It also reduces oxidative stress and prevents demyelination. The historical membrane hypothesis of schizophrenia has led to explore the lipids abnormality in this disorder. This hypothesis was initially based on the observation of an abnormal membrane prostaglandin production in schizophrenia caused by a membrane arachidonic acid deficiency. It has evolved emphasizing the various PUFA membrane's roles in particular regarding oxidative stress, inflammation and regulation of the NMDA receptors. In patients with mental disorders, low omega-3 index is more frequent than in the general population. This lipid abnormality could lead to myelination abnormalities and cognitive deficits observed in patients. It could also participate in oxidative stress abnormalities and inflammation reported in schizophrenia. On the other hand, low omega-3 index deficit was reported to be associated with an increased cardiovascular risk, and omega-3 supplementation may also have a positive cardiovascular impact in psychiatric patients, even more than in the general population. The presence of membrane lipid abnormalities is also found in patients during the first psychotic episode (FEP). The omega-3 supplementation improved the recovery rate and prevented the loss of gray matter in FEP. In patients at ultra-high risk to develop a psychotic disorder (UHR), omega-3 supplementation has been associated with a reduction of the rate of conversion to psychosis and with metabolic changes, such as decreased activity of phospholipase A2. However, this study has not as yet been replicated. Not all patients exhibit lipid abnormalities. Several studies, including studies from our team, have found a bimodal distribution of lipids in patients with schizophrenia. But some studies have found differences (in PUFA) in the acute phase whereas our studies (on phospholipids) are in chronic phases. It will be interesting to study in more depth the links between these two parameters. Furthermore, we identified a subgroup which was identified with a deficit in sphingomyelin and PUFA whereas others have found an increase of sphingomyelin. Individuals with this abnormal lipid cluster had more cognitive impairments and more severe clinical symptoms. Because the niacin test is an indirect reflection of arachidonic acid levels, it has been proposed to identify a subset of patients with membrane lipids anomalies. Niacin test response is influenced by several factors related to lipid metabolism, including cannabis use and phospholipase A2 activity. Despite progress, the function and impact of membrane lipids are still poorly understood in schizophrenia. They could serve as biomarkers for identifying biological subgroups among patients with schizophrenia. In UHR patients, their predictive value on the conversion to psychosis should be tested. Omega-3 supplementation could be a promising treatment thanks to its good tolerance and acceptability. It could be more appropriate for patients with PUFA anomalies in a more personalized medical approach.

[Sensorimotor aspects and manual dexterity in autism spectrum disorders: A literature review]. / Aspects sensorimoteurs et motricité manuelle dans les troubles du spectre autistique : une revue de la littérature.

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.

Paris MEM: a study protocol for an effectiveness and efficiency trial on the treatment of traumatic stress in France after the 2015-16 terrorist attacks.

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.

[Early detection of mental health disorders at school: The Fil Harmonie pilot program]. / Détection précoce des troubles psychiques en milieu scolaire : le dispositif Fil Harmonie.

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.

[Specific treatment of the first psychotic episodes]. / Prise en charge spécifique des premiers épisodes psychotiques.

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.

Insular pathology in young people with high-functioning autism and first-episode psychosis.

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.

Neuropsychology of subjects with ultra-high risk (UHR) of psychosis: A critical analysis of the literature.

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.

[Adaptation and validation of the neurological soft sign's scale of Krebs et al. to children]. / Adaptation et validation d'une échelle des signes neurologiques mineurs chez l'enfant.

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.

[Therapeutic benefit of a registered psychoeducation program on treatment adherence, objective and subjective quality of life: French pilot study for schizophrenia]. / Bénéfice d'un programme d'éducation thérapeutique agréé sur la qualité de vie et le bien-être psychologique de sujets souffrant de schizophrénie.

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.

Methylomic changes during conversion to psychosis.

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.

[Duration of untreated psychosis: A state-of-the-art review and critical analysis]. / Durée de psychose non traitée : état des lieux et analyse critique.

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.

[Stress and psychotic transition: A literature review]. / Stress et transition psychotique : revue de la littérature.

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

Influence of DAOA and RGS4 genes on the risk for psychotic disorders and their associated executive dysfunctions: A family-based study.

BACKGROUND: Glutamatergic neurotransmission dysfunction has classically been related to the aetiology of psychotic disorders. A substantial polygenic component shared across these disorders has been reported and molecular genetics studies have associated glutamatergic-related genes, such as d-amino acid oxidase activator (DAOA) and regulator of G-protein signalling 4 (RGS4) with the risk for psychotic disorders. Our aims were to examine: (i) the relationship between DAOA and RGS4 and the risk for psychotic disorders using a family-based association approach, and (ii) whether variations in these genes are associated with differences in patients' cognitive performance. METHODS: The sample comprised 753 subjects (222 patients with psychotic disorders and 531 first-degree relatives). Six SNPs in DAOA and 5 SNPs in RGS4 were genotyped. Executive cognitive performance was assessed with Trail Making Test B (TMT-B) and Wisconsin Card Sorting Test (WCST). Genetic association analyses were conducted with PLINK, using the transmission disequilibrium test (TDT) for the family-based study and linear regression for cognitive performance analyses. RESULTS: The haplotype GAGACT at DAOA was under-transmitted to patients (P=0.0008), indicating its association with these disorders. With regards to cognitive performance, the DAOA haplotype GAGGCT was associated with worse scores in TMT-B (P=0.018) in SZ patients only. RGS4 analyses did not report significant results. CONCLUSIONS: Our findings suggest that the DAOA gene may contribute to the risk for psychotic disorders and that this gene may play a role as a modulator of executive function, probably through the dysregulation of the glutamatergic signalling.

Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade.

A state of pathological uncertainty about environmental regularities might represent a key step in the pathway to psychotic illness. Early psychosis can be investigated in healthy volunteers under ketamine, an NMDA receptor antagonist. Here, we explored the effects of ketamine on contingency learning using a placebo-controlled, double-blind, crossover design. During functional magnetic resonance imaging, participants performed an instrumental learning task, in which cue-outcome contingencies were probabilistic and reversed between blocks. Bayesian model comparison indicated that in such an unstable environment, reinforcement learning parameters are downregulated depending on confidence level, an adaptive mechanism that was specifically disrupted by ketamine administration. Drug effects were underpinned by altered neural activity in a fronto-parietal network, which reflected the confidence-based shift to exploitation of learned contingencies. Our findings suggest that an early characteristic of psychosis lies in a persistent doubt that undermines the stabilization of behavioral policy resulting in a failure to exploit regularities in the environment.

Development of a blood-based molecular biomarker test for identification of schizophrenia before disease onset.

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