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

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

[Problematic gambling and criminal responsibility]. / Jeu d'argent problématique et responsabilité pénale.

OBJECTIVES: In total, 14% to 30 % of individuals with gambling disorder engage in illegal acts to finance such behavior. This clinical situation could be explained by higher gambling severity, associated substance use disorder, antisocial personality disorder and economic factors (debts, financial problems). The present work focuses, more broadly, on criminal responsibility of problematic gamblers. METHODS: We will discuss this question through different typical situations that medical experts of criminal responsibility may have to face. We will address each of the following cases: 1) isolated problematic gambling; 2) problematic gambling associated with antisocial personality disorder; 3) problematic gambling associated with a manic episode; 4) problematic gambling associated with substance use disorders; and 5) problematic gambling associated wiht dopamine agonist treatment. RESULTS: Isolated problematic gambling, (not associated with any psychiatric or addictive disorder): it seems consensual that individuals committing infractions in this case are criminally responsible. However, impeded ability to action control and possible sentence attenuation could be discussed in case of severe gambling disorder. Problematic gambling associated with antisocial personality disorder: if the penal offence reports solely to personality disorder, criminal responsibility would be attributed. However, if illegal or violent acting is directly linked to co-cocurrent delusional symptoms, it could be a cause of criminal non-responsibility. Problematic gambling associated with manic episode: manic episode related offence could lead to negation of criminal responsibility, while a hypomanic episode may provide grounds for sentence reduction. Problematic gambling associated with substance use disorders: in France, addiction is not considered to remove nor to impede a person's ability to understand or control his actions and is excluded from criminal non-responsibility causes. However, substance induced delusional or confusional episodes could abolish a subject's discernment or his ability to control his actions yielding to penal non-responsibility. Problematic gambling associated with dopamine agonist treatment: Criminal responsibility for dopamine agonist induced gambling related illegal acts is still controversial. Nevertheless, people committing an infraction linked to associated dementia or dopamine agonist induced mania should be considered as criminally non-responsible. CONCLUSIONS: Some clinical dimensions such as craving intensity, compulsivity, disorder's severity, volitional control might be forensic targets to assess criminal responsibility.

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

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

[Neurodevelopment and cannabis]. / Cannabis et neurodéveloppement.

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

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

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

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

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

Methylomic changes during conversion to psychosis.

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

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

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

Further evidence of DEPDC7 DNA hypomethylation in depression: A study in adult twins.

Late and early stressful factors have widely been recognized to play a role in the aetiology of depression. Recent research indicates that such adverse environmental stimuli may alter gene expression in humans via epigenetic modifications. While epigenetic changes such as DNA methylation are likely involved in these processes, it is still unknown what specific genomic loci may be hyper- or hypo-methylated in depression. The association between depressive symptoms during the last 30 days (Brief Symptom Inventory [BSI]) and peripheral-blood DNA methylation levels at genomic loci previously reported as epigenetically altered in saliva and brain of depressive patients was evaluated in a community sample of 34 adult Caucasian MZ twins (17 pairs). Intrapair DNA methylation differences in an intron of DEPDC7 (chr11:33040743) were associated with intrapair differences in current depressive symptoms. Accordingly, a site-specific 10% DNA hypomethylation in a co-twin would correlate with a current depressive symptom score around 3.1 BSI points above the score of his/her less-depressed co-twin. These findings indicate that DEPDC7 hypomethylation in peripheral blood DNA may be associated with recent depressive symptomatology, in line with previous results.

Polymorphic variation in the epigenetic gene DNMT3B modulates the environmental impact on cognitive ability: a twin study.

BACKGROUND: Though cognitive abilities in adulthood are largely influenced by individual genetic background, they have also been shown to be importantly influenced by environmental factors. Some of these influences are mediated by epigenetic mechanisms. Accordingly, polymorphic variants in the epigenetic gene DNMT3B have been linked to neurocognitive performance. Since monozygotic (MZ) twins may show larger or smaller intrapair phenotypic differences depending on whether their genetic background is more or less sensitive to environmental factors, a twin design was implemented to determine if particular polymorphisms in the DNMT3B gene may be linked to a better (worse) response to enriched (deprived) environmental factors. METHODS: Applying the variability gene methodology in a sample of 54 healthy MZ twin pairs (108 individuals) with no lifetime history of psychopathology, two DNMT3B polymorphisms were analyzed in relation to their intrapair differences for either intellectual quotient (IQ) or working memory performance. RESULTS: MZ twin pairs with the CC genotype for rs406193 SNP showed statistically significant larger intrapair differences in IQ than CT pairs. CONCLUSIONS: Results suggest that DNMT3B polymorphisms may explain variability in the IQ response to either enriched or impoverished environmental conditions. Accordingly, the applied methodology is shown as a potentially valuable tool for determining genetic markers of cognitive plasticity. Further research is needed to confirm this specific result and to expand on other putative genetic markers of environmental sensitivity.

[Epigenetics of schizophrenia: a review]. / Hypothèse épigénétique de la schizophrénie : revue de la littérature.

BACKGROUND: Schizophrenia is a frequent and disabling disease associated with heterogeneous psychiatric phenotypes. It emerges during childhood, adolescence or young adulthood and has dramatic consequences for the affected individuals, causing considerable familial and social burden, as well as increasing health expenses. Although some progress has been made in the understanding of their physiopathology, many questions remain unsolved, and the disease is still poorly understood. The prevailing hypothesis regarding psychotic disorders proposes that a combination of genetic and/or environmental factors, during critical periods of brain development increases the risk for these illnesses. Epigenetic regulations, such as DNA methylation, can mediate gene x environment interactions at the level of the genome and may provide a potential substrate to explain the variability in symptom severity and family heritability. Initially, epigenetics was used to design mitotic and meiotic changes in gene transcription that could not be attributed to genetic mutations. It referred later to changes in the epigenome not transmitted through the germline. Thus, epigenetics refers to a wide range of molecular mechanisms including DNA methylation of cytosine residues in CpG dinucleotides and post-translational histone modifications. These mechanisms alter the way the transcriptional factors bind the DNA, modulating its expression. Prenatal and postnatal environmental factors may affect these epigenetics factors, having responsability in long-term DNA transcription, and influencing the development of psychiatric disorders. OBJECT: The object of this review is to present the state of knowledge in epigenetics of schizophrenia, outlining the most recent findings in the matter. METHODS: We did so using Pubmed, researching words such as 'epigenetics', 'epigenetic', 'schizophrenia', 'psychosis', 'psychiatric'. This review summarizes evidences mostly for two epigenetic mechanisms: DNA methylation and post-translational histone modifications. RESULTS: First, in terms of epidemiology and transmission, the theoretical model of epigenetics applies to schizophrenia. Then, most environmental factors that have proved a link with this disease, may generate epigenetic mechanisms. Next, mutations have been found in regions implied in epigenetic mechanism among populations with schizophrenia. Some epigenetic alterations in DNA regions have been previously linked with neurodevelopmental abnormalities. In psychosis, some authors have found methylation differences in COMT gene, in reelin gene and in some genes implicated in dopaminergic, serotoninergic, GABAergic and glutamatergic pathways. Histone modifications have been described, in particular the H3L4 histone methylation. Finally, we tried to underline the difficulties in epigenetic research, notably in psychiatry, and the limits in this matter. CONCLUSION: The epigenetic field may explain a lot of questions around the physiopathology of the complex psychiatric disease that is schizophrenia. It may be a substratum to the prevailing hypothesis of gene x environment interaction. The research in the matter is definitely expanding. It justifies easily the need to improve the effort in the domain to overpass some limits inherent to the matter.

Association of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia.

Three common missense variants of the Disrupted in Schizophrenia 1 (DISC1) gene, rs3738401 (Q264R), rs6675281 (L607F) and rs821616 (S704C), have been variably associated with the risk of schizophrenia. In a case-control study, we examine whether these gene variants are associated with schizophrenia and ultra-resistant schizophrenia (URS) in a population of French Caucasian patients. The URS phenotype is characterized according to stringent criteria as patients who experience no clinical, social and/or occupational remission in spite of treatment with clozapine and at least two periods of treatment with distinct conventional or atypical antipsychotic drugs. We find a significant association between DISC1 missense variants and URS. The association with rs3738401 remains significant after appropriate correction for multiple testing. These results suggest that the DISC1 rs3738401 missense variant is statistically linked with ultra-resistance to antipsychotic treatment.

Rare mutations in N-methyl-D-aspartate glutamate receptors in autism spectrum disorders and schizophrenia.

Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function.

[Inhibition of return in schizophrenia: a review]. / Le phénomène de l'inhibition de retour dans la schizophrénie: revue de la littérature.

INTRODUCTION: Most visual environments contain more information than the human brain can process in real time. To overcome this limitation, the attention system acts as a filter by selectively orienting attention to specific regions of the visual field. This ability to orient attention can be reflected in covert shift processes of attention. LITERATURE FINDINGS: In a typical covert orienting task, subjects have to maintain fixation on a central cross and respond as quickly as possible to a target, which appears in a peripheral box following a cue that summons attention to the direction where the target is going to appear (valid cueing) or to the contralateral direction (invalid cueing). When the cues are nonpredictive, the response characteristics critically depend on stimulus-onset asynchrony (SOA). With short SOAs (<300ms), valid cues result in a reaction time advantage over invalid trials, which is due to a reflexive shift of attention towards the source of stimulation. In contrast, with longer SOAs, valid cues result in longer reaction times to the subsequent target. DISCUSSION: This phenomenon is known as the inhibition of return and is mostly thought to reflect an inhibitory mechanism protecting the organism from redirecting attention to previously scanned insignificant locations. Many studies have reported blunted or delayed inhibition of return in patients with schizophrenia. However, some authors reported normal amounts of inhibition of return. This can be partly explained by the use of manipulations of the covert orienting of the attention paradigm that is known to enhance the course of inhibition of return. CONCLUSION: The deficit of inhibition of return seems to be time-stable and to be unrelated to psychopathology or length of illness. The contribution of neuroleptic medication to this deficit cannot be determined. Recent data suggest a deficit of inhibition of return in two human models of psychosis (dimethyltryptamine and ketamine). Further studies should clarify whether blunted inhibition of return might represent a trait marker of schizophrenia.

[Working memory in schizophrenia: a review]. / La mémoire de travail dans la schizophrénie: revue de la littérature.

INTRODUCTION: Working memory refers to a limited capacity system for temporary storage and processing of information that is known to depend on the integrity of the prefrontal cortex. It has been classically described as composed of a "central executive" that performs control, selection and planning functions, and two "slave" systems: on the one hand, the phonological loop that holds verbal, speech-based representations, and on the other hand, the visuospatial sketchpad that manipulates spatial and object visual representations. LITERATURE FINDINGS: Studies in schizophrenia have used different tasks that tap different processes within the working memory. Despite the variety of measures, there is solid neuropsychological evidence that patients with schizophrenia demonstrate deficits in all subsystems of working memory. Several studies have shown no correlations between working memory deficits and age, gender, premorbid IQ, duration of disease or positive syndrome, but a correlation has been found with a low-educational level, and negative and disorganization symptoms. Neuroimaging studies have provided evidence of an involvement of the dorsolateral-prefrontal cortex during working memory performance. Many studies have demonstrated a functional deficit in this area. However, several recent studies have reported either equal or increased activation of the dorsolateral-prefrontal cortex in schizophrenia during working memory performance. Working memory deficits are present early in the course of schizophrenia and they have been shown to be consistently associated with reduced levels of elementary social skills and learning capacity. Unaffected relatives of individuals with schizophrenia and individuals diagnosed with schizotypal personality demonstrate deficits in tasks designed to measure working memory function. Working memory dysfunctions might be suitable candidate markers for vulnerability. Certain executive sub-processes seem to be the most heritable component of the working memory. Working memory deficits in schizophrenia may benefit from specific stimulation of receptors such as the dopaminergic D1 receptor, adrenergic alpha-2A receptor or nicotinic receptors. Few studies on the effect of antipsychotic medication on working memory in schizophrenia have been carried out and their results are highly variable. Atypical antipsychotic drugs, notably risperidone, have appeared to improve performance in working memory tasks. Cognitive exercises can improve working memory with a six-month persistent effect.