Marion Leboyer

The autism spectrum disorders (ASDs) are a group of conditions typically characterized by repetitive behaviour, severely restricted interests and difficulties with social interactions and communication. ASDs are highly heritable, yet the underlying genetic determinants remain largely unknown. A genome-wide analysis reveals that people with ASDs carry a higher load of rare copy-number variants — segments of DNA for which the copy number differs between individual genomes — which are either inherited or arise de novo. The results implicate several novel genes as ASD candidates and point to the importance of cellular proliferation, projection and motility as well as specific signalling pathways in this disorder. The autistic spectrum disorders (ASDs) are highly heritable, yet the underlying genetic determinants remain largely unknown. Here, a genome-wide analysis of rare copy number variants (CNVs) has been carried out, revealing that ASD sufferers carry a higher load of rare, genic CNVs than do controls. Many of these CNVs are de novo and inherited. The results implicate several novel genes in ASDs, and point to the importance of cellular proliferation, projection and motility, as well as specific signalling pathways, in these disorders. The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability2. Although ASDs are known to be highly heritable (∼90%)3, the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 × 10-4). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53–PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Many studies have supported a genetic etiology for autism. Here we report mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders. These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism.

SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage-sensitive synaptic pathway that is involved in autism spectrum disorders.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Social adaptation requires specific cognitive and emotional competences. Individuals with high-functioning autism or with Asperger syndrome cannot understand or engage in social situations despite preserved intellectual abilities. Recently, it has been suggested that oxytocin, a hormone known to promote mother-infant bonds, may be implicated in the social deficit of autism. We investigated the behavioral effects of oxytocin in 13 subjects with autism. In a simulated ball game where participants interacted with fictitious partners, we found that after oxytocin inhalation, patients exhibited stronger interactions with the most socially cooperative partner and reported enhanced feelings of trust and preference. Also, during free viewing of pictures of faces, oxytocin selectively increased patients' gazing time on the socially informative region of the face, namely the eyes. Thus, under oxytocin, patients respond more strongly to others and exhibit more appropriate social behavior and affect, suggesting a therapeutic potential of oxytocin through its action on a core dimension of autism.

Individuals with autism spectrum disorders (ASDs) often display symptoms from other diagnostic categories. Studies of clinical and psychosocial outcome in adult patients with ASDs without concomitant intellectual disability are few. The objective of this paper is to describe the clinical psychiatric presentation and important outcome measures of a large group of normal-intelligence adult patients with ASDs. Autistic symptomatology according to the DSM-IV-criteria and the Gillberg & Gillberg research criteria, patterns of comorbid psychopathology and psychosocial outcome were assessed in 122 consecutively referred adults with normal intelligence ASDs. The subjects consisted of 5 patients with autistic disorder (AD), 67 with Asperger's disorder (AS) and 50 with pervasive developmental disorder not otherwise specified (PDD NOS). This study group consists of subjects pooled from two studies with highly similar protocols, all seen on an outpatient basis by one of three clinicians. Core autistic symptoms were highly prevalent in all ASD subgroups. Though AD subjects had the most pervasive problems, restrictions in non-verbal communication were common across all three subgroups and, contrary to current DSM criteria, so were verbal communication deficits. Lifetime psychiatric axis I comorbidity was very common, most notably mood and anxiety disorders, but also ADHD and psychotic disorders. The frequency of these diagnoses did not differ between the ASD subgroups or between males and females. Antisocial personality disorder and substance abuse were more common in the PDD NOS group. Of all subjects, few led an independent life and very few had ever had a long-term relationship. Female subjects more often reported having been bullied at school than male subjects. ASDs are clinical syndromes characterized by impaired social interaction and non-verbal communication in adulthood as well as in childhood. They also carry a high risk for co-existing mental health problems from a broad spectrum of disorders and for unfavourable psychosocial life circumstances. For the next revision of DSM, our findings especially stress the importance of careful examination of the exclusion criterion for adult patients with ASDs.

Cannabis use is associated with increased risk of later psychotic disorder but whether it affects incidence of the disorder remains unclear. We aimed to identify patterns of cannabis use with the strongest effect on odds of psychotic disorder across Europe and explore whether differences in such patterns contribute to variations in the incidence rates of psychotic disorder.We included patients aged 18-64 years who presented to psychiatric services in 11 sites across Europe and Brazil with first-episode psychosis and recruited controls representative of the local populations. We applied adjusted logistic regression models to the data to estimate which patterns of cannabis use carried the highest odds for psychotic disorder. Using Europe-wide and national data on the expected concentration of Δ9-tetrahydrocannabinol (THC) in the different types of cannabis available across the sites, we divided the types of cannabis used by participants into two categories: low potency (THC <10%) and high potency (THC ≥10%). Assuming causality, we calculated the population attributable fractions (PAFs) for the patterns of cannabis use associated with the highest odds of psychosis and the correlation between such patterns and the incidence rates for psychotic disorder across the study sites.Between May 1, 2010, and April 1, 2015, we obtained data from 901 patients with first-episode psychosis across 11 sites and 1237 population controls from those same sites. Daily cannabis use was associated with increased odds of psychotic disorder compared with never users (adjusted odds ratio [OR] 3·2, 95% CI 2·2-4·1), increasing to nearly five-times increased odds for daily use of high-potency types of cannabis (4·8, 2·5-6·3). The PAFs calculated indicated that if high-potency cannabis were no longer available, 12·2% (95% CI 3·0-16·1) of cases of first-episode psychosis could be prevented across the 11 sites, rising to 30·3% (15·2-40·0) in London and 50·3% (27·4-66·0) in Amsterdam. The adjusted incident rates for psychotic disorder were positively correlated with the prevalence in controls across the 11 sites of use of high-potency cannabis (r = 0·7; p=0·0286) and daily use (r = 0·8; p=0·0109).Differences in frequency of daily cannabis use and in use of high-potency cannabis contributed to the striking variation in the incidence of psychotic disorder across the 11 studied sites. Given the increasing availability of high-potency cannabis, this has important implications for public health.Medical Research Council, the European Community's Seventh Framework Program grant, São Paulo Research Foundation, National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London and the NIHR BRC at University College London, Wellcome Trust.

The aim of this review is to summarize the key findings from genetic and epidemiological research, which show that autism is a complex disorder resulting from the combination of genetic and environmental factors. Remarkable advances in the knowledge of genetic causes of autism have resulted from the great efforts made in the field of genetics. The identification of specific alleles contributing to the autism spectrum has supplied important pieces for the autism puzzle. However, many questions remain unanswered, and new questions are raised by recent results. Moreover, given the amount of evidence supporting a significant contribution of environmental factors to autism risk, it is now clear that the search for environmental factors should be reinforced. One aspect of this search that has been neglected so far is the study of interactions between genes and environmental factors.

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view.Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task.Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression.This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability—more than 1 in 50—warrant its consideration for mutation screening in clinical practice.

Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15).We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls).We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10-6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23.This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.

The understanding of suicidal behavior is incomplete. The stress-diathesis model suggests that a deficit in serotonergic projections to the orbitofrontal cortex is involved in susceptibility to suicidal behavior. The orbitofrontal cortex has been implicated in decision making, a cognitive function dealing with complex choices that may be under serotonergic modulation. In this preliminary study, the authors assessed decision making in suicide attempters.The authors used the Iowa Gambling Task to investigate patients with a history of violent (N=32) or nonviolent (N=37) suicidal behavior, patients suffering from affective disorders with no history of suicidal behavior (N=25), and healthy comparison subjects (N=82). Patients were assessed when they were not suffering from a current axis I disorder. The authors also assessed the correlation of Iowa Gambling Task performance with psychometric measures of impulsivity, hostility, anger, aggression, and emotional instability.Both groups of suicide attempters scored significantly lower than healthy comparison subjects, and violent suicide attempters performed significantly worse than affective comparison subjects. No significant differences were observed between the groups of suicide attempters or between the two comparison groups. The differences in performance could not be accounted for by age, intellectual ability, educational level, number of suicide attempts, age at first suicide attempt, history of axis I disorder, or medication use. Iowa Gambling Task performances were correlated positively with affective lability and with anger expression but not with impulsivity.Impaired decision making, possibly due to emotional dysfunction, may be a neuropsychological risk factor for suicidal behavior.

Family and twin studies have suggested a genetic component in autism. We performed a genome-wide screen with 264 microsatellites markers in 51 multiplex families, using non-parametric linkage methods. Families were recruited by a collaborative group including clinicians from Sweden, France, Norway, the USA, Italy, Austria and Belgium. Using two-point and multipoint affected sib-pair analyses, 11 regions gave nominal P -values of 0.05 or lower. Four of these regions overlapped with regions on chromosomes 2q, 7q, 16p and 19p identified by the first genome-wide scan of autism performed by the International Molecular Genetic Study of Autism Consortium. Another of our potential susceptibility regions overlapped with the 15q11-q13 region identified in previous candidate gene studies. Our study revealed six additional regions on chromosomes 4q, 5p, 6q, 10q, 18q and Xp. We found that the most significant multipoint linkage was close to marker D6S283 (maximum lod score = 2.23, P = 0.0013).

Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level has been reported in individuals with autism spectrum disorders (ASD), but the underlying cause of this deficit was unknown. The ASMT gene, encoding the last enzyme of melatonin synthesis, is located on the pseudo-autosomal region 1 of the sex chromosomes, deleted in several individuals with ASD. In this study, we sequenced all ASMT exons and promoters in individuals with ASD (n=250) and compared the allelic frequencies with controls (n=255). Non-conservative variations of ASMT were identified, including a splicing mutation present in two families with ASD, but not in controls. Two polymorphisms located in the promoter (rs4446909 and rs5989681) were more frequent in ASD compared to controls (P=0.0006) and were associated with a dramatic decrease in ASMT transcripts in blood cell lines (P=2 x 10(-10)). Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in ASMT activity (P=2 x 10(-12)) and melatonin level (P=3 x 10(-11)) in individuals with ASD. These results indicate that a low melatonin level, caused by a primary deficit in ASMT activity, is a risk factor for ASD. They also support ASMT as a susceptibility gene for ASD and highlight the crucial role of melatonin in human cognition and behavior.

Advances in the understanding of the genetic and environmental causes of schizophrenia, and their relationship to aberrant patterns of neurodevelopment, have led to growing interest in the possibility that 'disease-modifying' strategies could alter the course to — and of — this debilitating disorder, rather than just alleviating its symptoms. This article provides a broad-based consideration of the challenges and opportunities inherent in such efforts. Despite a lack of recent progress in the treatment of schizophrenia, our understanding of its genetic and environmental causes has considerably improved, and their relationship to aberrant patterns of neurodevelopment has become clearer. This raises the possibility that 'disease-modifying' strategies could alter the course to — and of — this debilitating disorder, rather than simply alleviating symptoms. A promising window for course-altering intervention is around the time of the first episode of psychosis, especially in young people at risk of transition to schizophrenia. Indeed, studies performed in both individuals at risk of developing schizophrenia and rodent models for schizophrenia suggest that pre-diagnostic pharmacotherapy and psychosocial or cognitive-behavioural interventions can delay or moderate the emergence of psychosis. Of particular interest are 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder. This Review aims to provide a broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia.

Patients with bipolar disorder are known to be at high risk of premature death. Comorbid cardio-vascular diseases are a leading cause of excess mortality, well above the risk associated with suicide. In this review, we explore comorbid medical disorders, highlighting evidence that bipolar disorder can be effectively conceptualized as a multi-systemic inflammatory disease. We conducted a systematic PubMed search of all English-language articles recently published with bipolar disorder cross-referenced with the following terms: mortality and morbidity, cardio-vascular, diabetes, obesity, metabolic syndrome, inflammation, auto-antibody, retro-virus, stress, sleep and circadian rhythm. Evidence gathered so far suggests that the multi-system involvement is present from the early stages, and therefore requires proactive screening and diagnostic procedures, as well as comprehensive treatment to reduce progression and premature mortality. Exploring the biological pathways that could account for the observed link show that dysregulated inflammatory background could be a common factor underlying cardio-vascular and bipolar disorders. Viewing bipolar disorder as a multi-system disorder should help us to re-conceptualize disorders of the mind as “disorders of the brain and the body”. The current literature substantially lacks longitudinal and mechanistic studies, as well as comparison studies to explore the magnitude of the medical burden in bipolar disorder compared to major mood disorders as well as psychotic disorders. It is also necessary to look for subgroups of bipolar disorder based on their rates of comorbid disorders. Comorbid medical illnesses in bipolar disorder might be viewed not only as the consequence of health behaviors and of psychotropic medications, but rather as an early manifestation of a multi-systemic disorder. Medical monitoring is thus a critical component of case assessment. Exploring common biological pathways of inflammation should help biomarkers discovery, ultimately leading to innovative diagnostic tools, new methods of prevention and personalized treatments.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23–4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11–q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the “multiple hit model” for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

La pandémie de la maladie à coronavirus (COVID-19) a provoqué une crise sanitaire majeure et mis en quarantaine la moitié de la population planétaire. En France, elle a provoqué une réorganisation en urgence de l’offre de soins mobilisant les soignants dans un climat d’incertitude. L’objectif du présent article est de faire le point sur les risques associés à l’exposition des soignants au COVID-19 pour leur santé mentale. Les auteurs ont conduit une revue de la littérature internationale tenant compte des données des précédentes épidémies (SARS-CoV-1, H1N1) et des données plus récentes concernant le COVID-19. Les caractéristiques de cette pandémie (rapidité de diffusion, connaissances incertaines, sévérité, décès de soignants) ont installé un climat anxiogène. Des facteurs organisationnels peuvent être source de stress : déficit d’équipement de protection individuel, réaffectation de postes, manque de communication, manque de matériels de soins, bouleversement de la vie quotidienne familiale et sociale. D’autres facteurs de risque sont identifiés comme l’absence de soutien, la crainte de contaminer un proche, l’isolement ou la stigmatisation sociale, le haut niveau de stress au travail ou les patterns d’attachement insécure. Les soignants ont ainsi un risque augmenté d’anxiété, de dépression, d’épuisement, d’addiction et de trouble de stress post-traumatique. Cette crise sanitaire devrait nous aider à mieux comprendre la vulnérabilité des soignants à la souffrance psychologique afin de renforcer les stratégies de prévention primaire et la formation aux enjeux psychologiques des soins, de la relation, et de la gestion des situations de crises sanitaires. 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. 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. 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. 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.

Precision medicine is a new and important topic in psychiatry. Psychiatry has not yet benefited from the advanced diagnostic and therapeutic technologies that form an integral part of other clinical specialties. Thus, the vision of precision medicine as applied to psychiatry – ‘precision psychiatry’ – promises to be even more transformative than in other fields of medicine, which have already lessened the translational gap. Herein, we describe ‘precision psychiatry’ and how its several implications promise to transform the psychiatric landscape. We pay particular attention to biomarkers and to how the development of new technologies now makes their discovery possible and timely. The adoption of the term ‘precision psychiatry’ will help propel the field, since the current term ‘precision medicine’, as applied to psychiatry, is impractical and does not appropriately distinguish the field. Naming the field ‘precision psychiatry’ will help establish a stronger, unique identity to what promises to be the most important area in psychiatry in years to come. In summary, we provide a wide-angle lens overview of what this new field is, suggest how to propel the field forward, and provide a vision of the near future, with ‘precision psychiatry’ representing a paradigm shift that promises to change the landscape of how psychiatry is currently conceived.

Objective To perform a meta‐analysis on studies reporting prevalence of T oxoplasma gondii ( T . gondii ) infection in any psychiatric disorder compared with healthy controls. Our secondary objective was to analyze factors possibly moderating heterogeneity. Method A systematic search was performed to identify studies into T . gondii infection for all major psychiatric disorders versus healthy controls. Methodological quality, publication bias, and possible moderators were assessed. Results A total of 2866 citations were retrieved and 50 studies finally included. Significant odds ratios ( OR s) with I g G antibodies were found in schizophrenia ( OR 1.81, P &lt; 0.00001), bipolar disorder ( OR 1.52, P = 0.02), obsessive–compulsive disorder ( OR 3.4, P &lt; 0.001), and addiction ( OR 1.91, P &lt; 0.00001), but not for major depression ( OR 1.21, P = 0.28). Exploration of the association between T . gondii and schizophrenia yielded a significant effect of seropositivity before onset and serointensity, but not I g M antibodies or gender. The amplitude of the OR was influenced by region and general seroprevalence. Moderators together accounted for 56% of the observed variance in study effects. After controlling for publication bias, the adjusted OR (1.43) in schizophrenia remained significant. Conclusion These findings suggest that T . gondii infection is associated with several psychiatric disorders and that in schizophrenia reactivation of latent T . gondii infection may occur.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear.To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2).In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk.Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level.The SNP that achieves the smallest P-value from secondary analyses is rs1718101.It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD.This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2.In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample.Despite being significant, the variance explained by these allele scores was small (Vm< 1%).Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19 779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19 423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case–control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically.

Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD.

Lithium is a first-line treatment in bipolar disorder, but individual response is variable. Previous studies have suggested that lithium response is a heritable trait. However, no genetic markers of treatment response have been reproducibly identified.Here, we report the results of a genome-wide association study of lithium response in 2563 patients collected by 22 participating sites from the International Consortium on Lithium Genetics (ConLiGen). Data from common single nucleotide polymorphisms (SNPs) were tested for association with categorical and continuous ratings of lithium response. Lithium response was measured using a well established scale (Alda scale). Genotyped SNPs were used to generate data at more than 6 million sites, using standard genomic imputation methods. Traits were regressed against genotype dosage. Results were combined across two batches by meta-analysis.A single locus of four linked SNPs on chromosome 21 met genome-wide significance criteria for association with lithium response (rs79663003, p=1·37 × 10(-8); rs78015114, p=1·31 × 10(-8); rs74795342, p=3·31 × 10(-9); and rs75222709, p=3·50 × 10(-9)). In an independent, prospective study of 73 patients treated with lithium monotherapy for a period of up to 2 years, carriers of the response-associated alleles had a significantly lower rate of relapse than carriers of the alternate alleles (p=0·03268, hazard ratio 3·8, 95% CI 1·1-13·0).The response-associated region contains two genes for long, non-coding RNAs (lncRNAs), AL157359.3 and AL157359.4. LncRNAs are increasingly appreciated as important regulators of gene expression, particularly in the CNS. Confirmed biomarkers of lithium response would constitute an important step forward in the clinical management of bipolar disorder. Further studies are needed to establish the biological context and potential clinical utility of these findings.Deutsche Forschungsgemeinschaft, National Institute of Mental Health Intramural Research Program.

A wide range of cognitive deficits have been demonstrated in schizophrenia, but their longitudinal course remains unclear.To bring together all the available information from longitudinal studies of cognitive performance in people with schizophrenia.We carried out a meta-analysis of 53 studies. Unlike previous reviewers, we included all studies (regardless of the type of medication), analysed each variable separately and compared results with data from controls.Participants with schizophrenia showed a significant improvement in most cognitive tasks. The available data for controls showed, with one exception (the Stroop test), a similar or greater improvement. Performance in semantic verbal fluency remained stable in both individuals with schizophrenia and controls.Participants with schizophrenia displayed improvement in most cognitive tasks, but practice was more likely than cognitive remediation to account for most of the improvements observed. Semantic verbal fluency may be the best candidate cognitive endophenotype.

Autism spectrum disorders (ASD) are characterized by impairments in reciprocal social communication, and repetitive, stereotyped verbal and non-verbal behaviors. Genetic studies have provided a relatively large number of genes that constitute a comprehensive framework to better understand this complex and heterogeneous syndrome. Based on the most robust findings, three observations can be made. First, genetic contributions to ASD are highly heterogeneous and most probably involve a combination of alleles with low and high penetrance. Second, the majority of the mutations apparently affect a single allele, suggesting a key role for gene dosage in susceptibility to ASD. Finally, the broad expression and function of the causative genes suggest that alteration of synaptic homeostasis could be a common biological process associated with ASD. Understanding the mechanisms that regulate synaptic homeostasis should shed new light on the causes of ASD and could provide a means to modulate the severity of the symptoms.

Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. We identify a hemizygous SHANK1 deletion that segregates in a four-generation family in which male carriers--but not female carriers--have ASD with higher functioning. A de novo SHANK1 deletion was also detected in an unrelated male individual with ASD with higher functioning, and no equivalent SHANK1 mutations were found in >15,000 controls (p = 0.009). The discovery of apparent reduced penetrance of ASD in females bearing inherited autosomal SHANK1 deletions provides a possible contributory model for the male gender bias in autism. The data are also informative for clinical-genetics interpretations of both inherited and sporadic forms of ASD involving SHANK1.

We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.

There is increasing recognition in the neurological and psychiatric literature of patients with so-called isolated psychotic presentations (ie, with no, or minimal, neurological features) who have tested positive for neuronal autoantibodies (principally N-methyl-D-aspartate receptor antibodies) and who have responded to immunotherapies. Although these individuals are sometimes described as having atypical, mild, or attenuated forms of autoimmune encephalitis, some authors feel that that these cases are sufficiently different from typical autoimmune encephalitis to establish a new category of so-called autoimmune psychosis. We briefly review the background, discuss the existing evidence for a form of autoimmune psychosis, and propose a novel, conservative approach to the recognition of possible, probable, and definite autoimmune psychoses for use in psychiatric practice. We also outline the investigations required and the appropriate therapeutic approaches, both psychiatric and immunological, for probable and definite cases of autoimmune psychoses, and discuss the ethical issues posed by this challenging diagnostic category.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.

Staging models are used routinely in general medicine for potentially serious or chronic physical disorders such as diabetes, arthritis and cancers, describing the links between biomarkers, clinical phenotypes and disease extension, and promoting a personalised or stratified medicine approach to treatment planning. Clinical staging involves a detailed description of where an individual exists on a continuum of disorder progression from stage 0 (an at-risk or latency stage) through to stage IV (late or end-stage disease). The approach is popular owing to its clinical utility and is increasingly being applied in psychiatry. The concept offers an informed approach to research and the active promotion of indicated prevention and early intervention strategies. We suggest that for young persons with emerging bipolar disorder, such transdiagnostic staging models could provide a framework that better reflects the developmental psychopathology and matches the complex longitudinal inter-relationships between subsyndromal and syndromal mood, psychotic and other disorders.

BackgroundMental disorders might be a risk factor for severe COVID-19. We aimed to assess the specific risks of COVID-19-related mortality, hospitalisation, and intensive care unit (ICU) admission associated with any pre-existing mental disorder, and specific diagnostic categories of mental disorders, and exposure to psychopharmacological drug classes.MethodsIn this systematic review and meta-analysis, we searched Web of Science, Cochrane, PubMed, and PsycINFO databases between Jan 1, 2020, and March 5, 2021, for original studies reporting data on COVID-19 outcomes in patients with psychiatric disorders compared with controls. We excluded studies with overlapping samples, studies that were not peer-reviewed, and studies written in languages other than English, Danish, Dutch, French, German, Italian, and Portuguese. We modelled random-effects meta-analyses to estimate crude odds ratios (OR) for mortality after SARS-CoV-2 infection as the primary outcome, and hospitalisation and ICU admission as secondary outcomes. We calculated adjusted ORs for available data. Heterogeneity was assessed using the I2 statistic, and publication bias was tested with Egger regression and visual inspection of funnel plots. We used the GRADE approach to assess the overall strength of the evidence and the Newcastle Ottawa Scale to assess study quality. We also did subgroup analyses and meta-regressions to assess the effects of baseline COVID-19 treatment setting, patient age, country, pandemic phase, quality assessment score, sample sizes, and adjustment for confounders. This study is registered with PROSPERO, CRD42021233984.Findings841 studies were identified by the systematic search, of which 33 studies were included in the systematic review and 23 studies in the meta-analysis, comprising 1 469 731 patients with COVID-19, of whom 43 938 had mental disorders. The sample included 130 807 females (8·9% of the whole sample) and 130 373 males (8·8%). Nine studies provided data on patient race and ethnicity, and 22 studies were rated as high quality. The presence of any mental disorder was associated with an increased risk of COVID-19 mortality (OR 2·00 [95% CI 1·58–2·54]; I2=92·66%). This association was also observed for psychotic disorders (2·05 [1·37–3·06]; I2=80·81%), mood disorders (1·99 [1·46–2·71]; I2=68·32%), substance use disorders (1·76 [1·27–2·44]; I2=47·90%), and intellectual disabilities and developmental disorders (1·73 [1·29–2·31]; I2=90·15%) but not for anxiety disorders (1·07 [0·73–1·56]; I2=11·05%). COVID-19 mortality was associated with exposure to antipsychotics (3·71 [1·74–7·91]; I2=90·31%), anxiolytics (2·58 [1·22–5·44]; I2=96·42%), and antidepressants (2·23 [1·06–4·71]; I2=95·45%). For psychotic disorders, mood disorders, antipsychotics, and anxiolytics, the association remained significant after adjustment for age, sex, and other confounders. Mental disorders were associated with increased risk of hospitalisation (2·24 [1·70–2·94]; I2=88·80%). No significant associations with mortality were identified for ICU admission. Subgroup analyses and meta-regressions showed significant associations of baseline COVID-19 treatment setting (p=0·013) and country (p<0·0001) with mortality. No significant associations with mortality were identified for other covariates. No evidence of publication bias was found. GRADE assessment indicated high certainty for crude mortality and hospitalisation, and moderate certainty for crude ICU admission.InterpretationPre-existing mental disorders, in particular psychotic and mood disorders, and exposure to antipsychotics and anxiolytics were associated with COVID-19 mortality in both crude and adjusted models. Although further research is required to determine the underlying mechanisms, our findings highlight the need for targeted approaches to manage and prevent COVID-19 in at-risk patient groups identified in this study.FundingNone.TranslationsFor the Italian, French and Portuguese translations of the abstract see Supplementary Materials section.

Although the etiology of bipolar disorder remains uncertain, multiple studies examining neuroimaging, peripheral markers and genetics have provided important insights into the pathophysiologic processes underlying bipolar disorder. Neuroimaging studies have consistently demonstrated loss of gray matter, as well as altered activation of subcortical, anterior temporal and ventral prefrontal regions in response to emotional stimuli in bipolar disorder. Genetics studies have identified several potential candidate genes associated with increased risk for developing bipolar disorder that involve circadian rhythm, neuronal development and calcium metabolism. Notably, several groups have found decreased levels of neurotrophic factors and increased pro-inflammatory cytokines and oxidative stress markers. Together these findings provide the background for the identification of potential biomarkers for vulnerability, disease expression and to help understand the course of illness and treatment response. In other areas of medicine, validated biomarkers now inform clinical decision-making. Although the findings reviewed herein hold promise, further research involving large collaborative studies is needed to validate these potential biomarkers prior to employing them for clinical purposes. Therefore, in this positional paper from the ISBD-BIONET (biomarkers network from the International Society for Bipolar Disorders), we will discuss our view of biomarkers for these three areas: neuroimaging, peripheral measurements and genetics; and conclude the paper with our position for the next steps in the search for biomarkers for bipolar disorder.

Bipolar disorder (BD) is often misdiagnosed or tardily detected, leading to inadequate treatment and devastating consequences. The identification of objective biomarkers, such as functional and structural brain abnormalities of BD might improve diagnosis and help elucidate its pathophysiology.To identify neurobiological markers of BD, two meta-analyses, one of functional neuroimaging studies related to emotional processing and a second of structural whole-brain neuroimaging studies in BD were conducted in the present study. Conducting a literature search on studies published up to September 2009 we identified 28 studies that were eligible for the meta-analyses: 13 functional magnetic resonance imaging studies, related to emotional processing and 15 structural imaging studies using whole-brain voxel-based morphometry. Only studies comparing patients with bipolar disorder to healthy controls were considered. Data were extracted or converted to a single anatomical reference (Talairach space). The activation likelihood estimation technique was used to assess the voxel-wise correspondence of results between studies.In patients with BD, decreased activation and diminution of gray matter were identified in a cortical-cognitive brain network that has been associated with the regulation of emotions. By contrast, patients with BD exhibited increased activation in ventral limbic brain regions that mediate the experience of emotions and generation of emotional responses. The present study provides evidence for functional and anatomical alterations in BD in brain networks associated with the experience and regulation of emotions.These alterations support previously proposed neurobiological models of BD and might represent valid neurobiological markers of the disorder. The specificity of these results to unipolar depression remains to be explored.

The lack of resources and coordination to face the coronavirus epidemic raises concerns for the health of patients with mental disorders in a country where we still have memories of the dramatic experience of famine in psychiatric hospitals during the Second World War. This article aims to propose guidance to ensure mental health care during the SARS-CoV epidemic in France.The authors performed a narrative review identifying relevant results in the scientific and medical literature and in local initiatives in France.We identified four types of major vulnerabilities among patients with mental disorders during this pandemic: (1) medical comorbidities that are more frequently found among patients with mental disorders (cardiovascular and pulmonary pathologies, diabetes, obesity, etc.) which are risk factors for severe covid-19 infection; (2) age (the elderly form the population most vulnerable to the coronavirus); (3) cognitive and behavioural disorders, which can hamper compliance with confinement and hygiene measures and finally and (4) psychosocial vulnerability as a result of stigmatization and/or socio-economic difficulties. Furthermore, the mental health healthcare system is more vulnerable than other healthcare systems. Current government plans are poorly suited to psychiatric establishments in a context of major shortages of organizational, material and human resources. In addition, a certain number of structural aspects make the psychiatric institution particularly vulnerable: many beds have been closed, wards have high densities of patients, mental health community facilities are closed, and medical teams are understaffed and poorly trained to face infectious diseases. There are also major issues when referring patients with acute mental disorders to intensive care units. To maintain the continuity of psychiatric care in this pandemic situation, several directions can be considered, in particular with the creation of "COVID+ units". These units are under the dual supervision of a psychiatrist and an internist/infectious disease specialist; all new entrants are placed in quarantine for 14 days; the nursing staff receives specific training, daily medical check-ups and close psychological support. Family visits are prohibited and replaced by videoconference. At the end of hospitalization, in particular for the population of patients in compulsory ambulatory care situations, specific case-management are organized with the possibility of home visits, in order to support patients when they get back home and to help them cope with the experience of confinement, which is liable to induce recurrences of mental disorders. The total or partial closure of community mental health facilities is particularly disturbing for patients, but a regular follow-up is possible with telemedicine and should include the monitoring of suicide risk and psycho-education strategies; developing support platforms could also be very helpful in this context. Private practice psychiatrists also have a crucial role of information towards their patients on confinement and barrier measures, and also on measures to prevent the psychological risks inherent in confinement: maintenance of regular sleep r, physical exercise, social interactions, stress management and coping strategies, prevention of addictions, etc. They should also be trained to prevent, detect and treat early warning symptoms of post-traumatic stress disorder, because their prevalence was high in the regions of China most affected by the pandemic.French mental healthcare is now facing a great and urgent need for reorganization and must also prepare in the coming days and weeks to face an epidemic of emotional disorders due to the confinement of the general population.

White matter abnormalities are one of the most consistently reported findings in neuroimaging studies of bipolar disorder (BD). We conducted an anatomical likelihood estimation meta-analysis of BD whole-brain diffusion tensor imaging (DTI) studies, with the aim of identifying statistically consistent fractional anisotropy (FA) changes reflecting microstructural modifications to white matter in BD. We performed online searches of the PUBMED and EMBASE databases in January 2011. Studies were considered for inclusion if they used diffusion tensor MRI, compared a group of subjects with BD with healthy controls and involved whole-brain white matter analysis of FA. The analyses were conducted in Talairach space, using the activation likelihood estimation technique. We carried out a meta-analysis restricted to studies reporting a lower FA in patients with BD than in healthy controls. Ten studies were included. We identified two significant clusters of decreased FA on the right side of the brain. The first was located in the right white matter, close to the parahippocampal gyrus. Four of the ten studies included contributed to this cluster. The second cluster was located close to the right anterior and subgenual cingulate cortex. These two clusters of decreased FA in BD are crossed by several white matter tracts. These two clusters of altered FA may underlie the abnormal emotional processing and altered functional limbic connectivity in BD. Explorations based on DTI-based tractography are required to identify the tracts involved in the pathophysiology of BD.

More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

Duration of untreated illness represents a potentially modifiable component of any diagnosis-treatment pathway. In bipolar disorder (BD), this concept has rarely been systematically defined or not been applied to large clinically representative samples.In a well-characterized sample of 501 patients with BD, we estimated the duration of untreated bipolar disorder (DUB: the interval between the first major mood episode and first treatment with a mood stabilizer). Associations between DUB and clinical onset and the temporal sequence of key clinical milestones were examined.The mean DUB was 9.6 years (SD 9.7; median 6). The median DUB for those with a hypomanic onset (14.5 years) exceeded that for depressive (13 years) and manic onset (8 years). Early onset BD cases have the longest DUB (P < 0.0001). An extended DUB was associated with more mood episodes (P < 0.0001), more suicidal behaviour (P = 0.0003) and a trend towards greater lifetime mood instability (e.g. rapid cycling, possible antidepressant-induced mania).Duration of untreated bipolar disorder (DUB) will only be significantly reduced by more aggressive case finding strategies. Reliable diagnosis (especially for BD-II) and/or instigation of recommended treatments is currently delayed by insufficient awareness of the early, polymorphous presentations of BD, lack of systematic screening and/or failure to follow established guidelines.

Mental and brain disorders represent the greatest health burden to Europe-not only for directly affected individuals, but also for their caregivers and the wider society. They incur substantial economic costs through direct (and indirect) health-care and welfare spending, and via productivity losses, all of which substantially affect European development. Funding for research to mitigate these effects lags far behind the cost of mental and brain disorders to society. Here, we describe a comprehensive, coordinated mental health research agenda for Europe and worldwide. This agenda was based on systematic reviews of published work and consensus decision making by multidisciplinary scientific experts and affected stakeholders (more than 1000 in total): individuals with mental health problems and their families, health-care workers, policy makers, and funders. We generated six priorities that will, over the next 5-10 years, help to close the biggest gaps in mental health research in Europe, and in turn overcome the substantial challenges caused by mental disorders.

Objective We discuss the rationale behind staging systems described specifically for bipolar disorders. Current applications, future directions and research gaps in clinical staging models for bipolar disorders are outlined. Method We reviewed the literature pertaining to bipolar disorders, focusing on the first episode onwards. We systematically searched data on staging models for bipolar disorders and allied studies that could inform the concept of staging. Results We report on several dimensions that are relevant to staging concepts in bipolar disorder. We consider whether staging offers a refinement to current diagnoses by reviewing clinical studies of treatment and functioning and the potential utility of neurocognitive, neuroimaging and peripheral biomarkers. Conclusion Most studies to date indicate that globally defined late‐stage patients have a worse overall prognosis and poorer response to standard treatment, consistent with patterns for end‐stage medical disorders. We believe it is possible at this juncture to speak broadly of ‘early’‐ and ‘late’‐stage bipolar disorder. Next steps require further collaborative efforts to consider the details of preillness onset and intermediary stages, and how many additional stages are optimal.

Article Abstract Objective: Beyond genetic risk variants, the pathophysiology of bipolar disorders is likely to be partly determined by environmental susceptibility factors. Our study is one of the first to investigate, in a large sample of well-characterized bipolar patients, associations between clinical presentations and childhood trauma subtypes, including neglect and abuse items. Method: 587 patients with DSM-IV-defined bipolar disorder were recruited from France and Norway between 1996-2008 and 2007-2012, respectively. History of childhood trauma was obtained using the Childhood Trauma Questionnaire. Clinical variables were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders (Norwegian sample) or the Diagnostic Interview for Genetic Studies (French sample). Results: Earlier age at onset of bipolar illness, suicide attempts, rapid cycling, and an increased number of depressive episodes each had significant associations (P ≤ .001) with at least 1 subtype of childhood trauma (emotional abuse, sexual abuse, and emotional neglect). Multivariate analyses investigating trauma variables together showed that both emotional and sexual abuse were independent predictors of lower age at onset (P = .002 for each) and history of suicide attempts (OR = 1.60 , P = .023; OR = 1.80 , P = .012, respectively), while sexual abuse was the strongest predictor of rapid cycling (OR = 2.04 , P = .007). Females reported overall higher childhood trauma frequency and greater associations to clinical expressions than males (P values < .05). Conclusions: Our results demonstrate consistent associations between childhood trauma and more severe clinical characteristics in bipolar disorder. Further, they show the importance of including emotional abuse as well as the more frequently investigated sexual abuse when targeting clinical characteristics of bipolar disorder. J Clin Psychiatry 2013;74(10):991-998 © Copyright 2013 Physicians Postgraduate Press, Inc. Submitted: January 4, 2013; accepted March 2, 2013 (doi:10.4088/JCP.13m08353). Corresponding author: Monica Aas, PhD, TOP Study Group, KG Jebsen Centre of Psychosis Research, Division of Mental Health and Addiction, Institute of Clinical Medicine, Bygg 49, Ullevål sykehus, PO Box 4956, Nydalen, 0424 Oslo, Norway (monica.aas@medisin.uio.no).

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 − 9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 − 9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

Sleep dysregulation is highly prevalent in bipolar disorders (BDs), with previous actigraphic studies demonstrating sleep abnormalities during depressive, manic, and interepisode periods. We undertook a meta-analysis of published actigraphy studies to identify whether any abnormalities in the reported sleep profiles of remitted BD cases differ from controls.A systematic review identified independent studies that were eligible for inclusion in a random effects meta-analysis. Effect sizes for actigraphy parameters were expressed as standardized mean differences (SMD) with 95% confidence intervals (95% CI).Nine of 248 identified studies met eligibility criteria. Compared with controls (N=210), remitted BD cases (N=202) showed significant differences in SMD for sleep latency (0.51 [0.28-0.73]), sleep duration (0.57 [0.30-0.84]), wake after sleep onset (WASO) (0.28 [0.06-0.50]) and sleep efficiency (-0.38 [-0.70-0.07]). Moderate heterogeneity was identified for sleep duration (I2=44%) and sleep efficiency (I2=44%). Post hoc meta-regression analyses demonstrated that larger SMD for sleep duration were identified for studies with a greater age difference between BD cases and controls (β=0.22; P=0.03) and non-significantly lower levels of residual depressive symptoms in BD cases (β=-0.13; P=0.07).This meta-analysis of sleep in remitted bipolar disorder highlights disturbances in several sleep parameters. Future actigraphy studies should pay attention to age matching and levels of residual depressive symptoms.

The gut microbiota is increasingly considered as a symbiotic partner in the maintenance of good health. Metagenomic approaches could help to discover how the complex gut microbial ecosystem participates in the control of the host's brain development and function, and could be relevant for future therapeutic developments, such as probiotics, prebiotics and nutritional approaches for psychiatric disorders. Previous reviews focused on the effects of microbiota on the central nervous system in in vitro and animal studies. The aim of the present review is to synthetize the current data on the association between microbiota dysbiosis and onset and/or maintenance of major psychiatric disorders, and to explore potential therapeutic opportunities targeting microbiota dysbiosis in psychiatric patients.

The lack of ressources and coordination to face the epidemic of coronavirus raises concerns for the health of patients with mental disorders in a country where we keep in memory the dramatic experience of famine in psychiatric hospitals during the Second World War. This article aims at proposing guidance to ensure mental health care during the SARS-CoV epidemy in France.Authors performed a narrative review identifying relevant results in the scientific and medical literature and local initiatives in France.We identified four types of major vulnerabilities in patients suffering from mental disorders during this pandemic: (1) medical comorbidities that are more frequently found in patients suffering from mental disorders (cardiovascular and pulmonary pathologies, diabetes, obesity, etc.) which represent risk factors for severe infections with Covid-19; (2) age (the elderly constituting the population most vulnerable to coronavirus); (3) cognitive and behavioral troubles which can hamper compliance with confinement and hygiene measures and finally and (4) psychosocial vulnerability due to stigmatization and/or socio-economic difficulties. Furthermore, the mental health healthcare system is more vulnerable than other healthcare systems. Current government plans are poorly adapted to psychiatric establishments in a context of major shortage of organizational, material and human resources. In addition, a certain number of structural aspects make the psychiatric institution particularly vulnerable: many beds are closed, wards have a high density of patients, mental health community facilities are closed, medical teams are understaffed and poorly trained to face infectious diseases. We could also face major issues in referring patients with acute mental disorders to intensive care units. To maintain continuity of psychiatric care in this pandemic situation, several directions can be considered, in particular with the creation of Covid+ units. These units are under the dual supervision of a psychiatrist and of an internist/infectious disease specialist; all new entrants should be placed in quarantine for 14 days; the nurse staff should benefit from specific training, from daily medical check-ups and from close psychological support. Family visits would be prohibited and replaced by videoconference. At the end of hospitalization, in particular for the population of patients in compulsory ambulatory care situations, specific case-management should be organized with the possibility of home visits, in order to support them when they get back home and to help them to cope with the experience of confinement, which is at risk to induce recurrences of mental disorders. The total or partial closure of mental health community facilities is particularly disturbing for patients but a regular follow-up is possible with telemedicine and should include the monitoring of the suicide risk and psychoeducation strategies; developing support platforms could also be very helpful in this context. Private psychiatrists have also a crucial role of information with their patients on confinement and barrier measures, but also on measures to prevent the psychological risks inherent to confinement: maintenance of sleep regularity, physical exercise, social interactions, stress management and coping strategies, prevention of addictions, etc. They should also be trained to prevent, detect and treat early warning symptoms of post-traumatic stress disorder, because their prevalence was high in the regions of China most affected by the pandemic.French mental healthcare is now in a great and urgent need for reorganization and must also prepare in the coming days and weeks to face an epidemic of emotional disorders due to the containment of the general population.

Fronto-limbic white matter (WM) abnormalities are assumed to lie at the heart of the pathophysiology of bipolar disorder (BD); however, diffusion tensor imaging (DTI) studies have reported heterogeneous results and it is not clear how the clinical heterogeneity is related to the observed differences. This study aimed to identify WM abnormalities that differentiate patients with BD from healthy controls (HC) in the largest DTI dataset of patients with BD to date, collected via the ENIGMA network. We gathered individual tensor-derived regional metrics from 26 cohorts leading to a sample size of N = 3033 (1482 BD and 1551 HC). Mean fractional anisotropy (FA) from 43 regions of interest (ROI) and average whole-brain FA were entered into univariate mega- and meta-analyses to differentiate patients with BD from HC. Mega-analysis revealed significantly lower FA in patients with BD compared with HC in 29 regions, with the highest effect sizes observed within the corpus callosum (R2 = 0.041, Pcorr < 0.001) and cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and short disease duration were related to higher FA along multiple ROIs. Results of the meta-analysis showed similar effects. We demonstrated widespread WM abnormalities in BD and highlighted that altered WM connectivity within the corpus callosum and the cingulum are strongly associated with BD. These brain abnormalities could represent a biomarker for use in the diagnosis of BD. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10-7) and PKP4 (P=8.67 × 10-7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10-3]), SCZ (rg=0.34 [P=4.37 × 10-5]) and MDD (rg=0.57 [P=1.04 × 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.

No established treatment algorithm exists for patients with schizophrenia. Whether switching antipsychotics or early use of clozapine improves outcome in (first-episode) schizophrenia is unknown.This three-phase study was done in 27 centres, consisting of general hospitals and psychiatric specialty clinics, in 14 European countries and Israel. Patients aged 18-40 years who met criteria of the DSM-IV for schizophrenia, schizophreniform disorder, or schizoaffective disorder were treated for 4 weeks with up to 800 mg/day amisulpride orally in an open-label design (phase 1). Patients who did not meet symptomatic remission criteria at 4 weeks were randomly assigned to continue amisulpride or switch to olanzapine (≤20 mg/day) during a 6-week double-blind phase, with patients and staff masked to treatment allocation (phase 2). Randomisation was done online by a randomisation website; the application implemented stratification by site and sex, and applied the minimisation method for randomisation. Patients who were not in remission at 10 weeks were given clozapine (≤900 mg/day) for an additional 12 weeks in an open-label design (phase 3). The primary outcome was the number of patients who achieved symptomatic remission at the final visits of phases 1, 2, and 3, measured by intention-to-treat analysis. Data were analysed with a generalised linear mixed model, with a logistic link and binomial error distribution. This trial is registered with ClinicalTrials.gov, number NCT01248195, and closed to accrual.Between May 26, 2011, and May 15, 2016, we recruited 481 participants who signed informed consent. Of the 446 patients in the intention-to-treat sample, 371 (83%) completed open-label amisulpride treatment, and 250 (56%) achieved remission after phase 1. 93 patients who were not in remission continued to the 6-week double-blind switching trial, with 72 (77%) patients completing the trial (39 on olanzapine and 33 on amisulpride); 15 (45%) patients on amisulpride versus 17 (44%) on olanzapine achieved remission (p=0·87). Of the 40 patients who were not in remission after 10 weeks of treatment, 28 (70%) started on clozapine; 18 (64%) patients completed the 12-week treatment, and five (28%) achieved remission. The number of serious adverse events did not differ between the treatment arms in phase 2: one patient on olanzapine was admitted to hospital because of an epileptic seizure, and one patient on amisulpride was admitted to hospital twice because of exacerbations of psychotic symptoms. Over the course of the trial, two serious suicide attempts were reported.For most patients in the early stages of schizophrenia, symptomatic remission can be achieved using a simple treatment algorithm comprising the sequential administration of amisulpride and clozapine. Since switching to olanzapine did not improve outcome, clozapine should be used after patients fail a single antipsychotic trial-not until two antipsychotics have been tried, as is the current recommendation.European Commission Seventh Framework Program.

To precisely describe the initial psychiatric presentation of patients with anti-NMDA receptor (NMDAR) antibodies encephalitis (anti-NMDAR encephalitis) to identify potential clues enhancing its early diagnosis.We retrospectively studied the French Reference Centre medical records of every adult patient with anti-NMDAR encephalitis to specify the patients' initial psychiatric symptoms leading to hospitalization in a psychiatric department and the reasons underlying the diagnosis of anti-NMDAR encephalitis.The medical records of 111 adult patients were reviewed. Psychiatric features were the initial presentation in 65 patients (59%). Among them, several psychiatric manifestations were observed, including visual and auditory hallucinations (n = 26, 40%), depression (n = 15, 23%), mania (n = 5, 8%), acute schizoaffective episode (n = 15, 23%), and eating disorder or addiction (n = 4; 6%). Forty-five patients (40% of total cohort) were first hospitalized in a psychiatric institution (91% women), with a median duration of stay of 9 days (range 0.25-239 days). Among them, 24 patients (53%) had associated discreet neurologic signs at the first evaluation, while 17 additional patients (38%) developed neurologic signs within a few days. Twenty-one patients (47%) were transferred to a medical unit for a suspicion of antipsychotic intolerance characterized by high temperature, muscle rigidity, mutism or coma, and biological results suggesting rhabdomyolysis.Several psychiatric presentations were observed in patients with anti-NMDAR encephalitis, although none was specific; however, patients, mostly women, also had discreet neurologic signs that should be carefully assessed as well as signs of antipsychotic intolerance that should raise suspicion for anti-NMDAR encephalitis.

Community‐based studies have consistently shown a sex ratio heavily skewed towards males in autism spectrum disorders (ASD). The factors underlying this predominance of males are largely unknown, but the way girls score on standardized categorical diagnostic tools might account for the underrecognition of ASD in girls. Despite the existence of different norms for boys and girls with ASD on several major screening tests, the algorithm of the Autism Diagnosis Interview‐Revised (ADI‐R) has not been reformulated. The aim of our study was to investigate which ADI‐R items discriminate between males and females, and to evaluate their weighting in the final diagnosis of autism. We then conducted discriminant analysis (DA) on a sample of 594 probands including 129 females with ASD, recruited by the Paris Autism Research International Sibpair (PARIS) Study. A replication analysis was run on an independent sample of 1716 probands including 338 females with ASD, recruited through the Autism Genetics Resource Exchange (AGRE) program. Entering the raw scores for all ADI‐R items as independent variables, the DA correctly classified 78.9% of males and 72.9% of females ( P &lt; 0.001) in the PARIS cohort, and 72.2% of males and 68.3% of females ( P &lt; 0.0001) in the AGRE cohort. Among the items extracted by the stepwise DA, four belonged to the ADI‐R algorithm used for the final diagnosis of ASD. In conclusion, several items of the ADI‐R that are taken into account in the diagnosis of autism significantly differentiates between males and females. The potential gender bias thus induced may participate in the underestimation of the prevalence of ASD in females. Autism Res 2016 ,. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2017, 10: 680–689 . © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Functional connectivity alterations are conserved in multiple cohorts of patients with autism spectrum disorder.

On 17 March 2020, a national lockdown began in France in response to the COVID-19 pandemic. Loneliness and social isolation caused by social distancing are long-established major risk factors for a number of psychiatric disorders.1, 2 Quarantine and lockdown have other psychological consequences, such as boredom, irritability, and sleep dysregulation, which are associated with first-episode emergence of psychiatric disorders as well as the exacerbation of pre-existing psychiatric conditions.3, 4 Contamination fear has additional stress associations, for example anxious and obsessional symptoms, or delusional symptoms.5 In addition, psychiatric services have had to be reorganized5, 6 to reduce contact among patients and between patients and professionals; for example, restricting consultations to severe cases; reorganization of health care via teleconsultation; early hospital release and restrictions on new hospitalizations; and closure of daily care facilities. Consequently, patients may have experienced difficulties in accessing psychiatric services or worry about being fined for non-compliance of lockdown rules. Overall, such factors may create a treatment gap and/or lead to a break in follow-up and ongoing treatment, thereby increasing emergency consultations during lockdown.7 This study aimed to compare the number and characteristics of emergency psychiatric consultations during the first 4 weeks of the lockdown in three psychiatric emergency services from Paris and its suburbs, and to compare them to the same period in 2019. Three psychiatric emergency centers took part in the study: one in Paris, and one each in adjacent suburban cities, Colombes and Créteil. We assessed and compared the number and characteristics of emergency consultations during the first 4 weeks of the French lockdown and of the corresponding weeks of 2019. The data from the three centers were pooled. Concerning the categorical variables, the proportions of each sociodemographic, clinical, and outcome category were compared between 2019 and 2020 using two-tailed χ2-tests, with the null hypothesis of an absence of difference between 2019 and 2020. Additional details concerning the data collection and statistical analyses are available in the supplementary materials (Appendix S1). The study was performed in accordance with the Declaration of Helsinki. The data were extracted anonymously from registers, in accordance with the ethical standards of the French National Data Protection Authority. During the first 4 weeks of the national COVID-19-related lockdown, 553 emergency psychiatric consultations were carried out, representing less than half (45.2%) of the corresponding weeks in 2019 (1224 consultations). This decrease was evident in each of the three centers. The decrease concerned all psychiatric diagnoses, especially for anxiety disorders (number of consultations in 2020 representing 36.1% of consultations in 2019), mood disorders (41.1%), and psychotic disorders (67.2%). Total suicide attempts also decreased in 2020 to 42.6% of those in 2019. The diagnostic pattern of presentations significantly changed, with the percentage of consultations for psychotic disorders increasing (31.1% in 2020 vs 24.1% in 2019), and the percentage of anxiety and stress-related disorders decreasing (16.6% vs 20.8%). The rate of first-episode psychiatric consultations decreased (13.8% vs 20.1%). Hospitalization without patients' consent increased (54.2% vs 43.8%). More details are available in Table 1. Given the multifaceted stressors associated with lockdown, the above results show a surprising 54.8% drop in the number of psychiatric emergency consultations during the first 4 weeks of the COVID-19 pandemic. This decrease is evident in the three considered emergency departments and across all psychiatric diagnosis categories, and also concerns suicide attempts. This decrease is not specific to psychiatry: a greater than 50% decrease in daily total consultations was reported in the West China Hospital emergency,8 and similarly in England.9 Clearly, a fear of contamination in emergency departments has contributed to this. Moreover, unnecessary hospital emergency department visits may have decreased. In France, and elsewhere, recent decades have seen a significant increase in the number of emergency department consultations.10 This increase is contributed to by multiple complex factors, including a deterioration in accessibility of primary care services, leading to unnecessary visits. The treatment gap in psychiatry, the gap between experiencing a psychiatric disorder and using treatment services for this disorder, has already been described.7 Our results seem in line with this, given the significant increased proportion of consultations for psychotic disorders, and of hospitalizations without consent, coupled with the significant decrease in primary psychiatric consultations. For the most severe psychiatric disorders, emergency consultations are more necessary, and the decrease is less important. The development of telemedicine would also seem to have contributed to our results. The viability and feasibility of telemedicine consultations are likely to emerge subsequent to the COVID-19-triggered lockdown, possibly indicating a role for their sustained implementation. Finally, as some people may find new strengths and coping strategies during disasters, the current results may arise from an elevation in resilience capacity. Overall, despite the expectation of lockdown-induced stress increasing relapse risk across psychiatric conditions, the numbers of patients seeking emergency psychiatric consultations have decreased during lockdown. Clearly, COVID-19 has had an impact on psychiatric service utilization and will continue to do so,6 whilst also having possible implications for the nature of psychiatric service organization. The data are available on request. We want to thank Dr Yohann Dabi for his advice, Dr Andrei Szöke for his reviewing, and Dr George Anderson for his prompt editing work. No funding was secured for this study. The authors have declared that there are no conflicts of interest in relation to the subject of this study. Appendix S1 Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

Background Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

<h2>Abstract</h2> Failure to obtain convincing results in psychiatric genetics can partly be attributed to the fact that progress in molecular biology and genetic epidemiology has not been followed by an equivalent development in phenotypic description. Instead of relying entirely on classical nosological approaches, we argue that identifying more homogeneous forms of diseases through a `candidate symptom approach' among affected subjects and an endophenotype approach that identifies sub-clinical traits among non-affected relatives might yield better results. Examples where these strategies have already been fruitful when applied to complex diseases are presented in this review. Focusing on vulnerability traits might stimulate the redefinition of traditional psychiatric syndromes and help to bridge the gap between clinical and experimental approaches.

A genome scan was previously performed and pointed to chromosome 6q21 as a candidate region for autism. This region contains the glutamate receptor 6 (GluR6 or GRIK2) gene, a functional candidate for the syndrome. Glutamate is the principal excitatory neurotransmitter in the brain and is directly involved in cognitive functions such as memory and learning. We used two different approaches, the affected sib-pair (ASP) method and the transmission disequilibrium test (TDT), to investigate the linkage and association between GluR6 and autism. The ASP method, conducted with additional markers on the 51 original families and in eight new sibling pairs, showed a significant excess of allele sharing, generating an elevated multipoint maximum LOD score (ASPEX MLS = 3.28). TDT analysis, performed in the ASP families and in an independent data set of 107 parent-offspring trios, indicated a significant maternal transmission disequilibrium (TDTall P = 0.0004). Furthermore, TDT analysis (with only one affected proband per family) showed significant association between GluR6 and autism (TDT association P = 0.008). In contrast to maternal transmission, paternal transmission of GluR6 alleles was as expected in the absence of linkage, suggesting a maternal effect such as imprinting. Mutation screening was performed in 33 affected individuals, revealing several nucleotide polymorphisms (SNPs), including one amino acid change (M867I) in a highly conserved domain of the intracytoplasmic C-terminal region of the protein. This change is found in 8% of the autistic subjects and in 4% of the control population and seems to be more maternally transmitted than expected to autistic males (P = 0.007). Taken together, these data suggest that GluR6 is in linkage disequilibrium with autism.

Background: Conflicting results in genetic studies of bipolar disorders may be due to the clinical and genetic heterogeneity of the disease. Age at onset of bipolar disorders may be a key indicator for identifying more homogeneous clinical subtypes. We tested whether early onset and late onset bipolar illness represent two different forms of bipolar illness in terms of clinical features, comorbidity and familial risk. Methods: Among a consecutively recruited sample of 210 bipolar patients, we compared early onset (n=58) and late onset (n=39) bipolar patients; the cut-off points were age at onset before 18 years and after 40 years for the two subgroups. The subgroups were compared by independent t tests and a contingency table by raw chi-square test. Morbid risk among first-degree relatives was measured by the survival analysis method. Results: The early onset group had the most severe form of bipolar disorder with more psychotic features (P=0.03), more mixed episodes (P=0.01), greater comorbidity with panic disorder (P=0.01) and poorer prophylactic lithium response (P=0.04). First degree relatives of early onset patients also had a higher risk of affective disorders (P=0.0002), and exhibit the more severe phenotype, i.e bipolar disorder. Conclusion: Our data suggest that early and late onset bipolar disorders differ in clinical expression and familial risk and may therefore be considered to be different subforms of manic-depressive illness.

Bipolar affective disorder (BPAD) is a multifactorial disorder with various clinical presentations. Etiologic heterogeneity may partly underlie the phenotypic heterogeneity. Efforts to dissect BPAD have been based on the course of the disorders (BP I versus BP II or rapid cycling), cormorbidity pattern (panic attacks, suicide attempts, addiction or hyperactivity), differences between the sexes, and clinical pattern (cycloid and puerperal psychosis). The present article provides a comprehensive review of the existing data, showing that age at onset (AAO) identifies homogeneous sub‐groups of patients with BPAD. Recent work has demonstrated the existence of three – early, intermediate and late – onset bipolar sub‐groups based on AAO, following Kendell's criteria for validity ( The American Journal of Psychiatry 2003; 160 : 999). We will also show how these distinctions may be of use in the search for genetic vulnerability factors and other pathogenic influences. Following Kendell's criteria, we show that AAO of bipolar disorders has been tested with most of the available strategies for establishing the validity of clinical syndromes. We also present data from genetic epidemiologic studies in bipolar disorder, showing that AAO sub‐groups may reduce the underlying genetic heterogeneity. No accurate AAO thresholds to define valid sub‐groups have been identified precisely. Until recently, studies defined early‐ and late‐onset as corresponding to early or mid‐adulthood, not taking into account juvenile‐onset bipolar disorder. A recently proposed theoretical model with three AAO sub‐groups (onset age 17, 27 and 46) is discussed.

Mutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Lhermitte-Duclos disease. In addition, PTEN mutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as >or=2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation-dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5-year-old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte-Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN-related tumor syndromes.

Preliminary data suggested that there are three subgroups of bipolar affective disorder based on age at onset. The authors sought to replicate those findings and determine the cut-off age of each subgroup.Admixture analysis was used to determine the best-fitting model for the observed ages at onset of 368 consecutively admitted patients. The results obtained were compared with those of the previously described model. The authors also investigated whether affected siblings are more likely to belong to the same theoretical age-at-onset subgroup as identified by admixture analysis.The existence of three subgroups defined by age at onset was confirmed. The mean ages estimated in this model were 17.4 years (SD=2.3), 25.1 years (SD=6.2), and 40.4 years (SD=11.3). Affected siblings were more likely to belong to the same theoretical subgroup.There are three age-at-onset subgroups of bipolar patients, and specific familial vulnerability factors might underlie each subgroup.

Despite the demonstrated high heritability of bipolar disorder, few susceptibility genes have been identified and linkage and/or association studies have produced conflicting results. This search for susceptibility genes is hampered by several methodological limitations, and environmental risk factors for the disease (requiring incorporation into analyses) remain misunderstood. Among them, childhood trauma is probably the most promising environmental factor for further investigation. The objectives are to review the arguments in favor of an association between childhood trauma and bipolar disorder and to discuss the interpretations of such an observation.We computed a literature search using PubMed to identify relevant publications concerning childhood trauma and bipolar disorder. We also present some personal data in this field.Growing evidence suggests that incidences of childhood trauma are frequent and severe in bipolar disorder, probably affect the clinical expression of the disease in terms of suicidal behavior and age at onset, and also have an insidious influence on the affective functioning of patients between episodes. The relationships between childhood trauma and bipolar disorder suggest several interpretations, mainly a causal link, a neurodevelopmental consequence, or the intergenerational transmission of traumatic experiences. The neurobiological consequences of childhood trauma on a maturing brain remain unclear, although such stressors may alter the organization of brain development, leading to inadequate affective regulation.Childhood trauma is associated with bipolar disorder and its clinical expression and may interact with genetic susceptibility factors. Although not completely understood, the relationships between childhood trauma and bipolar disorder require further attention. Several suggestions for further exploration of this environmental factor and of its interaction with susceptibility genes are proposed.

Attentional and executive impairments have been found both in patients with schizophrenia and in their unaffected first-degree relatives, suggesting that they might be considered as familial vulnerability markers. Several studies have shown that the performance of bipolar patients does not significantly differ from that of schizophrenic patients, so that executive and attentional deficits might not be specific to schizophrenia. In the present study, we aimed to identify executive dysfunctions in schizophrenia and bipolar disorder that might be vulnerability trait markers specific to one or common to both of these diseases. We assessed cognitive performance of euthymic bipolar and schizophrenic patients, their unaffected first-degree relatives and a healthy control group, using neuropsychological tasks to test different components of executive function: the Verbal Fluency Test, the Stroop Word Colour Test, the Wisconsin Card Sorting Test and the Trail Making Test. The two groups of patients and their unaffected relatives demonstrated disproportionately increased slowness on the Stroop test in comparison to the normal healthy group. Patients with schizophrenia performed poorly on all the tests in comparison to the normal healthy subjects, while no other impairment was observed in the bipolar patients and in the relatives of schizophrenic and bipolar patients. Enhanced susceptibility to interference and reduced inhibition could be transnosographical markers for a shared familial vulnerability common to schizophrenia and bipolar disorders.

The human anterior cingulate cortex (ACC), which is active during conflict-monitoring tasks, is thought to participate with prefrontal cortices in a distributed network for conscious self-regulation. This hypothesis predicts that conflict-related ACC activation should occur only when the conflicting stimuli are consciously perceived. To dissociate conflict from consciousness, we measured the behavioral and brain imaging correlates of a motor conflict induced by task-irrelevant subliminal or conscious primes. The same task was studied in normal subjects and in patients with schizophrenia in whom the ACC and prefrontal cortex are thought to be dysfunctional. Conscious, but not subliminal, conflict affected anterior cingulate activity in normal subjects. Furthermore, patients with schizophrenia, who exhibited a hypoactivation of the ACC and other frontal, temporal, hippocampal, and striatal sites, showed impaired conscious priming but normal subliminal priming. Those findings suggest that subliminal conflicts are resolved without ACC contribution and that the ACC participates in a distributed conscious control network that is altered in schizophrenia.

Genes encoding proteins involved in serotonergic metabolism are major candidates in association studies of mood disorders and suicidal behavior. This association study explores whether the tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, is a susceptibility factor for manic-depressive illness, with or without a history of suicide attempts.The TPH intron 7 A218C polymorphism was determined using a polymerase chain reaction-based method in DNA samples from 152 patients with bipolar disorder and 94 healthy control subjects.There was a significant association between TPH genotypes and manic-depressive illness. Among patients with bipolar disorder, no association was found between TPH alleles and suicidal behavior.This result suggests the involvement of the TPH gene in susceptibility to manic-depressive illness. This preliminary result requires confirmation in further groups of patients and controls.

Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750 000 high-quality genetic markers on a combined sample of ∼14 000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17 700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10−11 level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63 000 case–control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.

Bipolar disorders are usually defined by alternative mood states, but a more precise characterization of the euthymic period could provide further insights into the pathophysiology of bipolar disorders. Surprisingly, few studies have investigated core affective dimensions in euthymic bipolar patients. In this study, we assessed 179 euthymic bipolar patients (score<12 on the Montgomery-Asberg Depression Scale and a score<6 on the Bech-Rafaelsen Mania Scale) compared with 86 control subjects using French versions of the Affective Lability Scale (ALS) and the Affect Intensity Measure (AIM). Data were analyzed by logistic regression. Our results showed that euthymic bipolar subjects reported having more intense emotions than controls and also had a higher affective lability. High scores in both affective dimensions were associated with a significantly higher risk for psychiatric axis I comorbidity. Moreover, a high affective lability score was associated with an earlier age of onset for bipolar disease. Affective lability and affect intensity might be two core dimensions of bipolar disorder during euthymic periods, suggesting that bipolar disorder is not circumscribed to mood episodes but also affects emotional reactivity between episodes. Both dimensions could account for the stress reactivity of bipolar patients that may lead to relapses.

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.

Background: Whole blood serotonin (5-HT) and C-terminally directed β-endorphin protein immunoreactivity (C-ter-β-EP-ir) are known to be elevated in autistic subjects and might be possible markers of genetic liability to autism. This study thus investigates the familial aggregation of 5-HT and of C-ter-β-EP-ir levels in first degree relatives of autistic probands. Methods: In a sample of 62 autistic subjects and 122 of their first-degree relatives, compared to age and sex-matched controls, we measured 5-HT by radioenzymology and C-ter-β-EP-ir by radioimmunoassay. Results: We confirm the previously reported familiality of hyperserotoninemia in autism as mothers (51%), fathers (45%) and siblings (87%) have elevated levels of 5-HT, and we reveal presence of elevated levels of C-ter-β-EP-ir in mothers (53%) of autistic subjects. Conclusions: Familial aggregation of quantitative variables, such as concentration of neurotransmitters, within unaffected relative could serve as an intermediate phenotype and might thus help the search of genetic susceptibility factors in autism.

There are limited population-based estimates of tuberculosis incidence among human immunodeficiency virus (HIV)-infected and HIV-uninfected infants aged < or =12 months. We aimed to estimate the population-based incidence of culture-confirmed tuberculosis among HIV-infected and HIV-uninfected infants in the Western Cape Province, South Africa.The incidences of pulmonary, extrapulmonary, and disseminated tuberculosis were estimated over a 3-year period (2004-2006) with use of prospective representative hospital surveillance data of the annual number of culture-confirmed tuberculosis cases among infants. The total number of HIV-infected and HIV-uninfected infants was calculated using population-based estimates of the total number of live infants and the annual maternal HIV prevalence and vertical HIV transmission rates.There were 245 infants with culture-confirmed tuberculosis. The overall incidences of tuberculosis were 1596 cases per 100,000 population among HIV-infected infants (95% confidence interval [CI], 1151-2132 cases per 100,000 population) and 65.9 cases per 100,000 population among HIV-uninfected infants (95% CI, 56-75 cases per 100,000 population). The relative risk of culture-confirmed tuberculosis among HIV-infected infants was 24.2 (95% CI, 17-34). The incidences of disseminated tuberculosis were 240.9 cases per 100,000 population (95% CI, 89-433 cases per 100,000 population) among HIV-infected infants and 14.1 cases per 100,000 population (95% CI, 10-18 cases per 100,000 population) among HIV-uninfected infants (relative risk, 17.1; 95% CI, 6-34).This study indicates the magnitude of the tuberculosis disease burden among HIV-infected infants and provides population-based comparative incidence rates of tuberculosis among HIV-infected infants. This high risk of tuberculosis among HIV-infected infants is of great concern and may be attributable to an increased risk of tuberculosis exposure, increased immune-mediated tuberculosis susceptibility, and/or possible limited protective effect of bacille Calmette-Guérin vaccination. Improved tuberculosis control strategies, including maternal tuberculosis screening, contact tracing of tuberculosis-exposed infants coupled with preventive chemotherapy, and effective vaccine strategies, are needed for infants in settings where HIV infection and tuberculosis are highly endemic.

Abstract Context: Obsessive‐Compulsive Disorder (OCD) is a debilitating illness with putative glutamatergic abnormalities. Two separate proximal haplotypes in the glutamate transporter gene, SLC1A1 , were recently reported to be associated with OCD among males, but replication is required. Objectives: This study examines SLC1A1 as a candidate gene for OCD and explores gender influences. It was hypothesized that a significant association between SLC1A1 and OCD would be replicated in an independent sample of males but not females. Design: Family‐based association candidate gene study. Setting: Participants were recruited from tertiary care OCD specialty clinics. Participants: OCD probands and their first degree relatives. Main outcomes measures: Association of OCD with genotypes of single nucleotide polymorphism (SNP) markers and related haplotypes. Results: Association between OCD and the three‐marker haplotype rs12682807/ rs2072657/ rs301430, with overtransmission of A/T/T, was observed in both genders combined (global P = 0.0015) and in males (global P = 0.0031). Single‐marker associations with OCD in the region (rs3780412 and rs2228622) demonstrated modest significance (permuted P = 0.045). Conclusions: This study identifies a significant association between the SLC1A1 glutamate transporter gene and OCD in a haplotype overlapping with that recently reported. © 2007 Wiley‐Liss, Inc.

Autism spectrum disorders (ASDs) are a clinically heterogeneous group of neurodevelopmental disorders characterized by social and communication deficits and repetitive behaviors. In a subset of individuals with ASD, mutations in genes involved in synaptic function have been identified, and this Perspective discusses the evidence from mouse models of ASD that synaptic deficits can be ameliorated in the mature brain. The authors also suggest a strategy for designing more informative clinical trials for ASD therapies that stratify patients according to their specific synaptic mutations. Autism spectrum disorder (ASD) encompasses a range of disorders that are characterized by social and communication deficits and repetitive behaviors. For the majority of affected individuals, the cause of ASD remains unknown, but in at least 20% of the cases, a genetic cause can be identified. There is currently no cure for ASD; however, results from mouse models indicate that some forms of the disorder could be alleviated even at the adult stage. Genes involved in ASD seem to converge on common pathways altering synaptic homeostasis. We propose, given the clinical heterogeneity of ASD, that specific 'synaptic clinical trials' should be designed and launched with the aim of establishing whether phenotype 'reversals' could also occur in humans.

The present French–German cooperative study focuses on the genotype–phenotype relationship of mutations of the FMR-1 gene and psychiatric conditions in mothers with a full mutation in the FMR-1 gene of fra-X children (n=13), mothers with a premutation in the FMR-1 gene of fra-X children (n=61), as well as premutated siblings of these mothers without affected children (n=17) and two non-mutated control groups: (1) siblings of these mothers with normal CGG repeat (n=18); and (2) mothers of non-fra-X autistic children (n=42). Mothers with a full mutation in the FMR-1 gene and mothers with a premutation in the FMR-1 gene did not differ in the frequency of any axis I disorder; however, both groups were diagnosed with social phobia more often than the control group of mothers of autistic children. Moreover, mothers with a premutation in the FMR-1 gene of fra-X children and their siblings with the premutation (without affected offspring) revealed a similar frequency of social phobia. Furthermore avoidant personality disorder was more common in groups of carriers of the full premutation than in siblings without mutation or than the control group of mothers with autistic children. On the basis of our data, we therefore suggest that social avoidance (expressed as social phobia or avoidant personality disorder) has been underestimated in previous studies of carriers with the FMR-1 full mutation or premutation. Comorbidity of axis I and axis II psychiatric diagnoses was mainly restricted to the group of carriers of the full mutation and carriers of the premutation of FMR-1. Correlations between size of CGG repeat and IQ as well as CGG and age of onset of axis I diagnosis were non-significant. IQ of subjects had no impact on presence or absence of axis I and/or axis II diagnoses.

Previous studies have shown that individuals with autism show impaired performance on tests of executive function (Ozonoff et al. 1991, 1993; Hughes & Russell, 1993; Hughes et al. 1994). There is also strong evidence for genetic involvement in autism (see Rutter, 1991 for review). If executive dysfunction is a core impairment in autism, then similar impairments are hypothesized to exist in a subtler form among the parents of autistic children.Forty parents of autistic children were compared with 40 parents of learning disabled children and 36 adults from unaffected families on three computerized tests of executive function. These tasks tapped attentional-shifting skills, visuospatial planning and working memory. Participants also received a computerized control test of spatial memory-span. In addition, the interviewer's initial impressions of family members were coded using a new 33-item questionnaire.A significant proportion of parents of autistic children (especially fathers) showed impaired executive function. By contrast, parents did as well as both comparison groups on a control test of spatial span, and on other 'non-executive' measures from the tasks, indicating that the autism group were as able and motivated as comparison groups. Interestingly, impairment of executive function was significantly correlated with the interviewer's pre-test impression of social abnormality among parents of autistic children.The hypothesis that a significant proportion of parents of autistic children show impaired executive function was supported. Parents showed good memory ability, but relatively poor planning skills and attentional flexibility. The extent to which this is an inherent trait in family members, rather than a reflection of the difficulties involved in caring for an autistic child, remains to be examined.

This paper presents a method for automatic segmentation of white matter fiber bundles from massive dMRI tractography datasets. The method is based on a multi-subject bundle atlas derived from a two-level intra-subject and inter-subject clustering strategy. This atlas is a model of the brain white matter organization, computed for a group of subjects, made up of a set of generic fiber bundles that can be detected in most of the population. Each atlas bundle corresponds to several inter-subject clusters manually labeled to account for subdivisions of the underlying pathways often presenting large variability across subjects. An atlas bundle is represented by the multi-subject list of the centroids of all intra-subject clusters in order to get a good sampling of the shape and localization variability. The atlas, composed of 36 known deep white matter bundles and 47 superficial white matter bundles in each hemisphere, was inferred from a first database of 12 brains. It was successfully used to segment the deep white matter bundles in a second database of 20 brains and most of the superficial white matter bundles in 10 subjects of the same database.

The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.

Bipolar disorder has been associated with anatomical as well as functional abnormalities in a brain network that mediates normal and impaired emotion regulation. Previous brain imaging studies have highlighted the subgenual cingulate (SC) and the amygdalo-hippocampal (AH) complex as core regions of this network. Thus we investigated white matter (WM) fiber tracts between the SC and the AH region, the uncinate fasciculus, as well as between two control regions (pons and cerebellum), using diffusion tensor imaging tractography in 16 euthymic bipolar patients (BP) and 16 sex-, age- and handedness-matched controls. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of the reconstructed fiber bundle and the number of virtual reconstructed fibers were compared between groups. The tractography results revealed a significantly increased number of reconstructed fibers between the left SC and left AH in BP as compared to healthy controls. FA and ADC of the reconstructed fiber tract did not differ significantly between the groups. Furthermore, no significant group differences were observed neither for reconstructed fiber tracts between the right SC and right AH nor between the control regions. The present results suggest an altered WM pathway between the left SC and AH region and thus extend previous findings of anatomical and functional modifications in these structures in BP.

Article AbstractObjective: High rates of misdiagnosis, delayed diagnosis, and lack of recognition and treatment of comorbid conditions often lead patients with bipolar illness to have a chronic course with high disability, unemployment rates, and mortality. Despite the recognition that long-term outcome of bipolar disorder depends on systematic assessment of both interepisodic dysfunctional domains and comorbid psychiatric and medical conditions, treatment of bipolar disorder still focuses primarily on alleviation of acute symptoms and prevention of future recurrences. We propose here to review the evidence offering a modern view of bipolar disorder defined as a chronic and progressive multisystem disorder, taking into account characteristics of each patient as well as biosignatures in order to help design personalized treatments.Data Sources: We conducted a systematic PubMed search of all English-language articles, published between 2000 and 2010, focusing on the English and French literature with bipolar disorder cross-referenced with the following search terms: emotional dysregulation, sleep and circadian rhythm disturbances, cognitive impairment, age at onset, comorbid medical and psychiatric conditions, psychosocial and medical interventions, outcome, remission, and personalized medicine. The search was conducted between July 2009 and July 2010. The literature on bipolar disorder was reviewed to provide supporting evidence that the assessment of various symptom domains that are dysfunctional between episodes should all be considered as core dimensions of the disorder.Study Selection: Forty-one articles were identified through the PubMed search described above and selected on the basis of addressing any combination of the search terms in conjunction with bipolar disorder.Data Synthesis: Current guidelines advocate the use of more or less similar treatment algorithms for all patients, ignoring the clinical, pathophysiological, and lifetime heterogeneity of bipolar disorder. Systematic assessment of interepisodic dimensions, along with comorbid medical and psychiatric risk factors, should be performed along the life cycle in order to plan specific and personalized pharmacologic, medical, and psychosocial interventions tailored to the needs of each patient and ready-to-test biosignatures to serve as risk factors or diagnostic or prognostic tools.Conclusions: Medical and research findings, along with health economic data, support a more modern view of bipolar disorder as a chronic, progressive, multisystem disorder. This new comprehensive framework should guide the search to identify biomarkers and etiologic factors and should help design a new policy for health care, including prevention, diagnosis, treatment, and training.J Clin Psychiatry:2010;71(12):1689-1695Submitted: June 22, 2010; accepted August 9, 2010 (doi:10.4088/JCP.10m06347yel).Corresponding author: Marion Leboyer, MD, PhD, Pole de Psychiatrie, Hôpital Albert Chenevier, 40 rue de Mesly, Créteil 94000, France (Marion.leboyer@inserm.fr).

Objective: Although euthymic bipolar patients show minimal manic and depressive symptoms, they continue to show impaired emotional regulation and cognitive functioning. Few studies have directly examined the interference of emotional information with cognitive processes and its underlying cerebral mechanisms in euthymic bipolar patients. The authors examined the emotional modulation of cognitive processes and its underlying neural mechanisms in euthymic bipolar patients. Method: Seventeen euthymic bipolar patients and 17 healthy comparison subjects underwent functional magnetic resonance imaging (MRI) while performing an emotional and nonemotional go/nogo task. Neural responses associated with the overall task performance, as well as with the impact of emotional information on the task performance, were assessed. Results: Bipolar disorder patients exhibited increased activity in the temporal cortex, specifically to emotional go/nogo conditions, as well as in the orbitofrontal cortex, the insula, the caudate nuclei, and the dorsal anterior and posterior cingulate cortices when inhibiting emotional stimuli compared with neutral stimuli. Conversely, no global attentional deficits were observed on either a behavioral or neural response level, indicated by similar task performances for all task conditions and similar brain activation patterns when comparing all the go/nogo conditions with the resting state. Conclusions: The present study provides evidence of an altered emotional modulation of cognitive processing in euthymic bipolar patients, indicated by an overactivation in ventral-limbic, temporal, and dorsal brain structures during emotional go/nogo conditions in patients relative to comparison subjects.

Autism Spectrum Disorders (ASD) are a group of heterogeneous neurodevelopmental conditions presenting in early childhood with a prevalence ranging from 0.7% to 2.64%. Social interaction and communication skills are impaired and children often present with unusual repetitive behavior. The condition persists for life with major implications for the individual, the family and the entire health care system. While the etiology of ASD remains unknown, various clues suggest a possible association with altered immune responses and ASD. Inflammation in the brain and CNS has been reported by several groups with notable microglia activation and increased cytokine production in postmortem brain specimens of young and old individuals with ASD. Moreover several laboratories have isolated distinctive brain and CNS reactive antibodies from individuals with ASD. Large population based epidemiological studies have established a correlation between ASD and a family history of autoimmune diseases, associations with MHC complex haplotypes, and abnormal levels of various inflammatory cytokines and immunological markers in the blood. In addition, there is evidence that antibodies that are only present in some mothers of children with ASD bind to fetal brain proteins and may be a marker or risk factor for ASD. Studies involving the injection of these ASD specific maternal serum antibodies into pregnant mice during gestation, or gestational exposure of Rhesus monkeys to IgG subclass of these antibodies, have consistently elicited behavioral changes in offspring that have relevance to ASD. We will summarize the various types of studies associating ASD with the immune system, critically evaluate the quality of these studies, and attempt to integrate them in a way that clarifies the areas of immune and autoimmune phenomena in ASD research that will be important indicators for future research.

To provide a systematic review of the literature regarding the efficacy of anti-inflammatory drugs in three major mental disorders [major depressive disorder (MDD), schizophrenia and bipolar disorders].Four databases were explored, without any year or language restrictions. The baseline search paradigm was limited to open-labelled clinical and randomized controlled trials (RCTs).Four major classes of anti-inflammatory drugs were identified, namely polyunsaturated fatty acids (PUFAs), cyclooxygenase (COX) inhibitors, anti-TNFalpha and minocycline. Effectiveness and benefit/risk ratio of each class in MDD, bipolar disorders and schizophrenia was detailed when data were available. Several meta-analyses indicated effectiveness of PUFAs in MDD with a good tolerance profile. One meta-analysis indicated that COX-2 specific inhibitors showed effectiveness in schizophrenia. Anti-TNFalpha showed important effectiveness in resistant MDD with blood inflammatory abnormalities. Minocycline showed effectiveness in schizophrenia.Polyunsaturated fatty acids seem to have the best benefit/risk ratio profile but proved their effectiveness only in MDD. A number of anti-inflammatory drugs are available as adjunct treatment for treatment-resistant patients with MDD, schizophrenia and bipolar disorder. If used with caution regarding their possible side-effects, they may be reasonable therapeutic alternatives for resistant symptomatology.

Mood spectrum disorders (bipolar disorder, recurrent depressive disorder and seasonal affective disorder) are accompanied by circadian deregulations, which can occur during acute mood episodes as well as during euthymic periods, and are particularly common among bipolar patients in remission. This suggests that altered circadian rhythms may be biological markers of these disorders. Rhythm dysfunctions have been observed in mood disorder patients by using actigraphic measures and by assessing social metric rhythms, diurnal preferences and melatonin secretion. Since many of these markers are heritable and therefore driven by clock genes, these genes may represent susceptibility factors for mood spectrum disorders. Indeed, several genetic association studies have suggested that certain circadian gene variants play a role in susceptibility to these disorders. Such connections to circadian genes such as CLOCK, ARNTL1, NPAS2, PER3 and NR1D1 have been repeatedly demonstrated for bipolar disorders, and to a lesser extent for recurrent depressive disorders and seasonal affective disorders. The study of circadian phenotypes and circadian genes in mood spectrum disorders represents a major field of research that may yet reveal the pathophysiological determinants of these disorders.

Abstract Childhood trauma has been suggested to be involved in the susceptibility to bipolar disorder. However, case‐control studies are lacking, and the preferential implication and the dose‐effect of different trauma subtypes remain poorly investigated. Two hundred six bipolar patients and 94 controls completed the Childhood Trauma Questionnaire (CTQ; Bernstein et al., 1994). The CTQ total score was higher for bipolar patients than for controls. The presence of multiple trauma was significantly more frequent in bipolar patients than in controls (63% vs. 33%). Multiple logistic regression suggested that only emotional abuse was associated with bipolar disorder with a suggestive dose‐effect. Clinical practice should include systematic assessment of childhood trauma among bipolar patients with a particular focus on emotional abuse.

Tractography studies investigating white matter (WM) abnormalities in patients with bipolar disorder have yielded heterogeneous results owing to small sample sizes. The small size limits their generalizability, a critical issue for neuroimaging studies of biomarkers of bipolar I disorder (BPI).To study WM abnormalities using whole-brain tractography in a large international multicenter sample of BPI patients and to compare these alterations between patients with or without a history of psychotic features during mood episodes.A cross-sectional, multicenter, international, Q-ball imaging tractography study comparing 118 BPI patients and 86 healthy control individuals. In addition, among the patient group, we compared those with and without a history of psychotic features. University hospitals in France, Germany, and the United States contributed participants.Participants underwent assessment using the Diagnostic Interview for Genetic Studies at the French sites or the Structured Clinical Interview for DSM-IV at the German and US sites. Diffusion-weighted magnetic resonance images were acquired using the same acquisition parameters and scanning hardware at each site. We reconstructed 22 known deep WM tracts using Q-ball imaging tractography and an automatized segmentation technique.Generalized fractional anisotropy values along each reconstructed WM tract.Compared with controls, BPI patients had significant reductions in mean generalized fractional anisotropy values along the body and the splenium of the corpus callosum, the left cingulum, and the anterior part of the left arcuate fasciculus when controlling for age, sex, and acquisition site (corrected for multiple testing). Patients with a history of psychotic features had a lower mean generalized fractional anisotropy value than those without along the body of the corpus callosum (corrected for multiple testing).In this multicenter sample, BPI patients had reduced WM integrity in interhemispheric, limbic, and arcuate WM tracts. Interhemispheric pathways are more disrupted in patients with than in those without psychotic symptoms. Together these results highlight the existence of an anatomic disconnectivity in BPI and further underscore a role for interhemispheric disconnectivity in the pathophysiological features of psychosis in BPI.

Article Abstract Objective: There is growing evidence that bipolar disorder (BD) is associated with inflammation, including abnormal levels of acute-phase C-reactive protein (CRP). Our meta-analysis was conducted to estimate the size of the association between CRP levels and BD, accounting also for subgroup differences (mood phases and treatment). Data Sources: MEDLINE, EMBASE, PsycINFO, and ISI Web of Science and references of identified articles were searched up to June 2013 using the keywords (bipolar disorder) AND (C-reactive protein OR CRP). Study Selection: English language studies measuring blood levels of CRP in patients with BD and control subjects were selected, 136 abstracts were reviewed, 20 articles retrieved, and 11 studies included. Data Extraction: Two independent reviewers extracted data. All studies were included in the primary analyses, and between-group differences for subanalyses were also reported. This meta-analysis was performed using random-effects models. Results: Eleven studies comprising 1,618 subjects were eligible for inclusion. Overall, CRP levels were significantly elevated in patients with BD versus controls (standardized mean difference = 0.39; 95% CI, 0.24 to 0.55; P < .0001). CRP levels were significantly higher in manic (SMD = 0.73; 95% CI, 0.44 to 1.02; P < .001) and euthymic (SMD = 0.26; 95% CI, 0.01 to 0.51; P = .04), but not in depressed (SMD = 0.28; 95% CI, −0.17 to 0.73; P = .22) patients with BD compared to controls. CRP levels were unrelated to use of lithium or antipsychotic medication. Conclusions: This meta-analysis supports an association between increased CRP levels and BD. Given that an elevated level of CRP is a marker of low-grade inflammation and a risk factor for cardiovascular and malignant diseases, measurement of CRP level might be relevant to the clinical care of bipolar patients.

BackgroundMaternally derived duplications of the 15q11-q13 region are the most frequently reported chromosomal aberrations in autism spectrum disorders (ASD). Prader-Willi and Angelman syndromes, caused by 15q11-q13 deletions or abnormal methylation of imprinted genes, are also associated with ASD. However, the prevalence of these disorders in ASD is unknown. The aim of this study was to assess the frequency of 15q11-q13 rearrangements in a large sample of patients ascertained for ASD.MethodsA total of 522 patients belonging to 430 families were screened for deletions, duplications, and methylation abnormalities involving 15q11-q13 with multiplex ligation-dependent probe amplification (MLPA).ResultsWe identified four patients with 15q11-q13 abnormalities: a supernumerary chromosome 15, a paternal interstitial duplication, and two subjects with Angelman syndrome, one with a maternal deletion and the other with a paternal uniparental disomy.ConclusionsOur results show that abnormalities of the 15q11-q13 region are a significant cause of ASD, accounting for approximately 1% of cases. Maternal interstitial 15q11-q13 duplications, previously reported to be present in 1% of patients with ASD, were not detected in our sample. Although paternal duplications of chromosome 15 remain phenotypically silent in the majority of patients, they can give rise to developmental delay and ASD in some subjects, suggesting that paternally expressed genes in this region can contribute to ASD, albeit with reduced penetrance compared with maternal duplications. These findings indicate that patients with ASD should be routinely screened for 15q genomic imbalances and methylation abnormalities and that MLPA is a reliable, rapid, and cost-effective method to perform this screening. Maternally derived duplications of the 15q11-q13 region are the most frequently reported chromosomal aberrations in autism spectrum disorders (ASD). Prader-Willi and Angelman syndromes, caused by 15q11-q13 deletions or abnormal methylation of imprinted genes, are also associated with ASD. However, the prevalence of these disorders in ASD is unknown. The aim of this study was to assess the frequency of 15q11-q13 rearrangements in a large sample of patients ascertained for ASD. A total of 522 patients belonging to 430 families were screened for deletions, duplications, and methylation abnormalities involving 15q11-q13 with multiplex ligation-dependent probe amplification (MLPA). We identified four patients with 15q11-q13 abnormalities: a supernumerary chromosome 15, a paternal interstitial duplication, and two subjects with Angelman syndrome, one with a maternal deletion and the other with a paternal uniparental disomy. Our results show that abnormalities of the 15q11-q13 region are a significant cause of ASD, accounting for approximately 1% of cases. Maternal interstitial 15q11-q13 duplications, previously reported to be present in 1% of patients with ASD, were not detected in our sample. Although paternal duplications of chromosome 15 remain phenotypically silent in the majority of patients, they can give rise to developmental delay and ASD in some subjects, suggesting that paternally expressed genes in this region can contribute to ASD, albeit with reduced penetrance compared with maternal duplications. These findings indicate that patients with ASD should be routinely screened for 15q genomic imbalances and methylation abnormalities and that MLPA is a reliable, rapid, and cost-effective method to perform this screening.

Little is known regarding the relationship between treatment adherence and residual cognitive dysfunction in euthymic bipolar disorder patients. This study aimed to investigate whether poor treatment adherence is associated with cognitive impairment in euthymic bipolar patients and whether other factors may be associated with both adherence and cognitive functioning.Euthymic DSM-IV bipolar I or II disorder patients (N = 103: 61 with high levels of treatment adherence and 42 with poor treatment adherence) were assessed using a neuropsychological battery targeting attention, psychomotor speed, verbal memory, and executive functions and compared with 35 healthy controls of similar age, sex distribution, and education. Data were collected from September 2005 to June 2007.Bipolar patients with poor treatment adherence had more hospitalizations than those with high adherence. After controlling for age, gender, estimated IQ score, and Young Mania Rating Scale and 17-item Hamilton Rating Scale for Depression scores, non-treatment-adherent patients performed less well than normal controls in verbal learning and some executive functions. Among treatment-adherent and poorly adherent bipolar disorder patients, performance was similar in attention tasks and short-term and long-term verbal recall, but non-treatment-adherent patients were more impaired in ability to inhibit interferences and in spatial working memory. Poorer treatment adherence also was associated with the bipolar I subtype and with greater illness severity, as indicated by number of manic episodes and hospitalizations and history of psychosis. Pharmacologic factors, such as treatment with lithium, may also influence the relationship between neurocognition and adherence.There is a close relationship between poor treatment adherence and cognitive impairment, but the causal inferences of these findings are uncertain. Poor treatment adherence may worsen the course of bipolar disorder and so indirectly worsen cognitive performance, or cognitive impairment may contribute to poor treatment adherence and reflect more severe illness.

Objective: Obsessive-compulsive disorder (OCD) and Tourette’s syndrome are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. The authors report a combined genome-wide association study (GWAS) of Tourette’s syndrome and OCD. Method: The authors conducted a GWAS in 2,723 cases (1,310 with OCD, 834 with Tourette’s syndrome, 579 with OCD plus Tourette’s syndrome/chronic tics), 5,667 ancestry-matched controls, and 290 OCD parent-child trios. GWAS summary statistics were examined for enrichment of functional variants associated with gene expression levels in brain regions. Polygenic score analyses were conducted to investigate the genetic architecture within and across the two disorders. Results: Although no individual single-nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels (expression quantitative loci, or eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10−4), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, Tourette’s syndrome had a smaller, nonsignificant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and co-occurring Tourette’s syndrome/chronic tics were included in the analysis (p=0.01). Conclusions: Previous work has shown that Tourette’s syndrome and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of these two disorders. Furthermore, OCD with co-occurring Tourette’s syndrome/chronic tics may have different underlying genetic susceptibility compared with OCD alone.

Elevated whole-blood serotonin and decreased plasma melatonin (a circadian synchronizer hormone that derives from serotonin) have been reported independently in patients with autism spectrum disorders (ASDs). Here, we explored, in parallel, serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD and their relatives. We then investigated the clinical correlates of these biochemical parameters. Whole-blood serotonin, platelet NAS and plasma melatonin were assessed in 278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls. We confirmed the previously reported hyperserotonemia in ASD (40% (35–46%) of patients), as well as the deficit in melatonin (51% (45–57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41–54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS–melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS–melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD.

Abstract Despite the high impact of mental disorders in society, European mental health research is at a critical situation with a relatively low level of funding, and few advances been achieved during the last decade. The development of coordinated research policies and integrated research networks in mental health is lagging behind other disciplines in Europe, resulting in lower degree of cooperation and scientific impact. To reduce more efficiently the burden of mental disorders in Europe, a concerted new research agenda is necessary. The ROAMER (Roadmap for Mental Health Research in Europe) project, funded under the European Commission's Seventh Framework Programme, aims to develop a comprehensive and integrated mental health research agenda within the perspective of the European Union (EU) Horizon 2020 programme, with a translational goal, covering basic, clinical and public health research. ROAMER covers six major domains: infrastructures and capacity building, biomedicine, psychological research and treatments, social and economic issues, public health and well‐being. Within each of them, state‐of‐the‐art and strength, weakness and gap analyses were conducted before building consensus on future research priorities. The process is inclusive and participatory, incorporating a wide diversity of European expert researchers as well as the views of service users, carers, professionals and policy and funding institutions. Copyright © 2013 John Wiley &amp; Sons, Ltd.

The clinical presentation, course, and comorbidities of bipolar disorder type I are highly heterogeneous, and this variability remains poorly predictable. Certain onset characteristics (eg, age and polarity at onset) may delineate subgroups differing in clinical expression and outcome.We retrospectively investigated the association between both age and polarity at onset and the clinical characteristics of bipolar I disorder (DSM-IV) in 2 independent adult samples: 480 French patients assessed in 1992-2006 (patients had been recruited from 3 university-affiliated psychiatry departments) and 714 US patients assessed in 1991-2003 (data were extracted from the Bipolar Disorder Phenome Database).Polarity at onset correlated with subsequent predominance (P < .001). Most patients experienced a depressive onset (57.9% in France vs 71.0% in the United States; P < .001) associated with a higher density of depressive episodes, suicidal behavior, and alcohol misuse. A manic onset was associated with a higher density of manic episodes. Early onset was frequent in both countries (42% in France vs 68% in the United States; P < .001) and was associated with suicidal behavior and cannabis and cocaine/opiate misuse. Sensitivity for the prediction of clinical characteristics was 1%-35% for age at onset and 26%-47% for polarity at onset.Onset characteristics are associated with subsequent predominant polarity, suicidal behavior, and substance misuse in bipolar I disorder. These findings may facilitate personalized treatment strategies based on type of onset and may also facilitate early focused strategies for preventing comorbidity. Given the relatively low sensitivity and specificity of these onset characteristics for predicting clinical variables, the relevance of age and polarity at onset as specifiers in nosographical classifications will require further studies. However, polarity at onset may be the more relevant specifier, with further investigation required for age at onset.

Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.

Clinicians have found that fasting was frequently accompanied by an increased level of vigilance and a mood improvement, a subjective feeling of well-being, and sometimes of euphoria. Therapeutic fasting, following an established protocol, is safe and well tolerated. We aim in this article to explore the biological mechanisms activated during fasting that could have an effect on brain function with particular focus on mood (we do not discuss here the mechanisms regulating eating behavior) and to provide a comprehensive review on the potential positive impact of therapeutic fasting on mood. We explored Medline, Web of Science and PsycInfo according to the PRISMA criteria (Preferred Reporting Items for Systematic reviews and Meta-Analysis). The initial research paradigm was: [(fasting OR caloric restriction) AND (mental health OR depressive disorders OR mood OR anxiety)]. Many neurobiological mechanisms have been proposed to explain fasting effects on mood, such as changes in neurotransmitters, quality of sleep, and synthesis of neurotrophic factors. Many clinical observations relate an early (between day 2 and day 7) effect of fasting on depressive symptoms with an improvement in mood, alertness and a sense of tranquility reported by patients. The persistence of mood improvement over time remains to be determined.

Objective Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date. Method The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios. Results Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%). Conclusion Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes. Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date. The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios. Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p = .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p = .08 in the current study, p = .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%). Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.