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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-value¼0.002) in the SSD trios sample, (ii) ERBB3 AKT1 (perm p-value¼0.001) in the SSD case-control sample, and (iii) ERBB3 QKI (perm p-value¼0.0006) 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.

Contains fulltext : 235396.pdf (Publisher’s version ) (Open Access) In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the 'New Frontiers Meeting' on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies.

Healthcare workers (HCW) are at high risk for suicide, yet little is known about the onset of suicidal thoughts and behaviors (STB) in this important segment of the population in conjunction with the COVID-19 pandemic. We conducted a multicenter, prospective cohort study of Spanish HCW active during the COVID-9 pandemic. A total of n = 4809 HCW participated at baseline (May-September 2020; i.e., just after the first wave of the pandemic) and at a four-month follow-up assessment (October-December 2020) using web-based surveys. Logistic regression assessed the individual- and population-level associations of separate proximal (pandemic) risk factors with four-month STB incidence (i.e., 30-day STB among HCW negative for 30-day STB at baseline), each time adjusting for distal (pre-pandemic) factors. STB incidence was estimated at 4.2% (SE = 0.5; n = 1 suicide attempt). Adjusted for distal factors, proximal risk factors most strongly associated with STB incidence were various sources of interpersonal stress (scaled 0-4; odds ratio [OR] range = 1.23-1.57) followed by personal health-related stress and stress related to the health of loved ones (scaled 0-4; OR range 1.30-1.32), and the perceived lack of healthcare center preparedness (scaled 0-4; OR = 1.34). Population-attributable risk proportions for these proximal risk factors were in the range 45.3-57.6%. Other significant risk factors were financial stressors (OR range 1.26-1.81), isolation/quarantine due to COVID-19 (OR = 1.53) and having changed to a specific COVID-19 related work location (OR = 1.72). Among other interventions, our findings call for healthcare systems to implement adequate conflict communication and resolution strategies and to improve family-work balance embedded in organizational justice strategies. This work was supported by grants from the Instituto de Salud Carlos III (ISCIII)/Ministerio de Ciencia e Innovación/FEDER, Spain (Jordi Alonso, grant number COV20/00711); ISCIII-FEDER, Spain (Jordi Alonso, grant number PI17/00521); ISCIII-FSE, Spain: Sara Borrell and Miguel Servet grants (Philippe Mortier, grant number CD18/00049 and CP21/00078); Generalitat de Catalunya, Spain (2017SGR452); and PERIS, Departament de Salut, Spain (Itxaso Alayo; SLT017/20/000009). Additional partial funding was received from the Gerencia Regional de Salud de Castilla y León (SACYL), Spain (José María Pelayo Terán, grant number GRS COVID 32/A/20). Sí

Funding Acknowledgements Type of funding sources: None. Background Venous to arterial CO2 gap (CO2gap) is calculated by subtracting partial pressure of arterial CO2 to central venous partial pressure of CO2 (ScvCO2). This marker has been studied in septic shock and indicates hypoperfusion when exceeds 6mmHg. Its kinetics and applicability in cardiogenic shock (CS) are unclear, being mixed/central venous saturation and lactate more commonly used. Purpose The objective of the study is to describe CO2gap kinetics in patients with CS. Secondary objective is to analyze if CO2gap is as marker of prognosis in CS. Methods Prospective observational study that included patients admitted for CS in the Acute Cardiovascular Care Unit of a tertiary hospital. Gasometric samples were obtained at admission, 6, 12, 24 and 48 hours from the onset of shock. In-hospital mortality was registered. Results We included 40 patients with CS during 1 year. Most patients were male (80%), average age was 68 years. There was a high incidence of cardiac arrest (58%), most frequent cause of CS was STEMI (45%), in-hospital mortality was 45%, most cases from non-cardiovascular causes (61%). Refractory shock was frequent (28%). Average lactate peak was 6.02 mmol / L. CO2gap kinetics consisted in a peak at admission (8.8mmHg), a valley 6h (7.7mmHg), new peak at 12h (8.5mmHg) and progressive decrease at at 24 (6.8mmHg) and 48h (5.7 mmHg). Significantly, higher CO2gap values at admission (10.97mmHg vs 8.16mmHg, p = 0.007) was predictor of cardiovascular mortality. Lactate values at 6, 12 and 48 hours were also predictors of cardiovascular mortality, as well as ScvO2 at admission. Conclusions Patients with CS present with high CO2gap values during first hours of admission. The kinetics of this marker consists in two peaks at admission and 12 hours from CS onset, a valley at 6 hours and a progressive decrease at 24 and 48 hours. Its determination at admission is associated with cardiovascular mortality. We suggest the potential benefit of combining this marker, along with lactate and ScvO2 values, to guide management of patients with CS. Abstract Figure. CO2 gap and cardiovascular mortality

Scaling between subcomponents of cortical folding and total brain volume (TBV) in healthy individuals (HI) is allometric, i.e. non-linear. It is unclear whether this is also true in individuals with schizophrenia (SZ) or first-episode psychosis (FEP). The current study first confirmed normative allometric scaling norms in HI using discovery and replication samples. Cross-sectional and longitudinal diagnostic differences in folding subcomponents were then assessed using an allometric analytic framework.Structural imaging from a longitudinal (sample 1: HI and SZ, nHI Baseline= 298, nSZ Baseline= 169, nHI Follow-up= 293, nSZ Follow-up= 168, a total of 1087 images, all individuals ≥ 2 images, age 16-69 years) and a cross-sectional sample (sample 2: nHI= 61 and nFEP= 89, age 10-30 years) is leveraged to calculate global folding and its nested subcomponents: sulcation index (SI, total sulcal/cortical hull area) and determinants of sulcal area; sulcal length and sulcal depth.Scaling of the SI, sulcal area, and sulcal length with TBV in SZ and FEP was allometric and did not differ from HI. Longitudinal age trajectories demonstrated steeper loss of SI and sulcal area through adulthood in SZ. Longitudinal allometric analysis revealed that both annual change in SI and sulcal area was significantly stronger related to change in TBV in SZ compared to HI.Our results detail the first evidence of the disproportionate contribution of changes in SI and sulcal area to TBV changes in SZ. Longitudinal allometric analysis of sulcal morphology provides deeper insight into lifespan trajectories of cortical folding in SZ.

De novo mutations (DNMs), including germinal and postzygotic mutations (PZMs), are a strong source of causality for Autism Spectrum Disorder (ASD). However, the biological processes involved behind them remain unexplored. Our aim was to detect DNMs (germinal and PZMs) in a Spanish ASD cohort (360 trios) and to explore their role across different biological hierarchies (gene, biological pathway, cell and brain areas) using bioinformatic approaches. For the majority of the analysis, a combined ASD cohort (N = 2171 trios) was created using previously published data by the Autism Sequencing Consortium (ASC). New plausible candidate genes for ASD such as FMR1 and NFIA were found. In addition, genes harboring PZMs were significantly enriched for miR-137 targets in comparison with germinal DNMs that were enriched in GO terms related to synaptic transmission. The expression pattern of genes with PZMs was restricted to early mid-fetal cortex. In contrast, the analysis of genes with germinal DNMs revealed a spatio-temporal window from early to mid-fetal development stages, with expression in the amygdala, cerebellum, cortex and striatum. These results provide evidence of the pathogenic role of PZMs and suggest the existence of distinct mechanisms between PZMs and germinal DNMs that are influencing ASD risk AA-G was supported by Fundación María José Jove. CR-F was supported by a contract from the FEDER. Instituto de Salud Carlos III/PI1900809/Cofinanciado FEDER supported this study SI

The EUGEI project was supported by the European Community’s Seventh Framework Program under grant agreement no. HEALTH-F2-2009-241909 (Project EU-GEI). Dr O’Donovan is supported by MRC programme grant (G08005009) and an MRC Centre grant (MR/ L010305/1). Dr Rutten was funded by a VIDI award number 91718336 from the Netherlands Scientific Organisation. Drs Guloksuz and van Os are supported by the Ophelia research project, ZonMw grant number: 636340001. Dr Arango was supported by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024); CIBERSAM; Madrid Regional Government (B2017/BMD-3740, AGES-CM-2); Fundación Familia Alonso and Fundación Alicia Koplowitz., Pries, L.-K., Dal Ferro, G.A., Van Os, J., Delespaul, P., Kenis, G., Lin, B.D., Luykx, J.J., Richards, A.L., Akdede, B., Binbay, T., Altlnyazar, V., Yallnçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Åžahin Cankurtaran, E., Ulusoy Kaymak, S., Mihaljevic, M.M., Andric Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., Garciá-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Penãs, J., Parellada, M., Maric, N.P., AtbaşoÄalu, C., Ucok, A., Alptekin, K., Can Saka, M., Arango, C., O'Donovan, M., Tosato, S., Rutten, B.P.F., Guloksuz, S., and Genetic Risk and Outcome of Psychosis (GROUP) investigators

In previous work we developed a pharmacogenetic predictor of antipsychotic (AP) induced extrapyramidal symptoms (EPS) based on four genes involved in mTOR regulation. The main objective is to improve this predictor by increasing its biological plausibility and replication. We re-sequence the four genes using next-generation sequencing. We predict functionality "in silico" of all identified SNPs and test it using gene reporter assays. Using functional SNPs, we develop a new predictor utilizing machine learning algorithms (Discovery Cohort, N = 131) and replicate it in two independent cohorts (Replication Cohort 1, N = 113; Replication Cohort 2, N = 113). After prioritization, four SNPs were used to develop the pharmacogenetic predictor of AP-induced EPS. The model constructed using the Naive Bayes algorithm achieved a 66% of accuracy in the Discovery Cohort, and similar performances in the replication cohorts. The result is an improved pharmacogenetic predictor of AP-induced EPS, which is more robust and generalizable than the original.

Brain plasticity has demonstrated to play a role in the pathophysiology of schizophrenia. Cognitive deterioration in these patients can be prevented by ensuring the adequate functioning of signaling pathways associated with brain plasticity. As BDNF exerts its action through receptors, in this study, we hypothesized that levels of some BDNF receptors during a first episode of psychosis (FEP) would correlate with the cognitive and global functioning of patients in the long term. We also hypothesized that the improvement of the ratio of full-length (TrKB-FL) and truncated (TrKB-T) TrKB receptors, and the predominance of the full-length isoform would be associated with better cognition and functioning. Peripheral levels of full-length (TrKB-FL) and truncated (TrKB-T) TrKB receptors were assessed in a sample of 97 FEP patients and 97 matched healthy controls. TrKB-FL/TrKB-T ratio(hereinafter, FL/T) was calculated for each patient. Cognitive and global functioning was measured at inclusion and at two years. A high baseline FL/T ratio was found to be related to a better cognitive function (global cognition, verbal memory, working memory and premorbid IQ). Cognitive performance at disease onset and at two years improved when the levels of the ratio were higher than one, with functional BDNF receptor (TrKB-FL) exceeding the value of the truncated isoform (TrKB-T). In addition the increase in the FL/T ratio during the two years of follow-up had positive effects on global functioning. This may be due either to a reduction in TrKB-T or to an increase in TrKB-FL, or both. In conclusion FL / T ratio was related to general functioning and cognition in the long-term.

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. © 2019, The Author(s).

Background: We aimed to investigate the state of cardiovascular risk/protection factors in early psychosis patients. Methods: A total 119 subjects were recruited during the first year after their first episode of psychosis. Eighty-five of these subjects were followed during the next 6 months. Cardiovascular risk/protection factors were measured in plasma and co-variated by sociodemographic/clinical characteristics. Multiple linear regression models detected the change of each biological marker from baseline to follow-up in relation to clinical scales, antipsychotic medication, and pro-/antiinflammatory mediators. Results: Glycosylated hemoglobin is a state biomarker in first episode of psychosis follow-up patients and inversely correlated to the Global Assessment of Functioning scale. We found opposite alterations in the levels of VCAM-1 and E-selectin in first episode of psychosis baseline conditions compared with control that were absent in the first episode of psychosis follow-up group. Adiponectin levels decreased in a continuum in both pathological time points studied. E-Selectin plasma levels were inversely related to total antipsychotic equivalents and adiponectin levels inversely co-related to the Global Assessment of Functioning scale. Finally, adiponectin levels were directly related to antiinflammatory nuclear receptor PPARy expression in first episode of psychosis baseline conditions and to proinflammatory nuclear factor nuclear factor kB activity in follow-up conditions, respectively. Conclusions: Our results support the need for integrating cardiovascular healthcare very early after the first episode of psychosis.

The objective of the study is to examine the association of baseline total antioxidant status (TAS) and glutathione (GSH) levels with short- and long-term cognitive functioning in patients with early onset first-episode psychosis, comparing affective and non-affective psychoses. We analysed 105 patients with an early onset-first episode psychosis (age 9–17 years) and 97 healthy controls. Blood samples were taken at admission for measurement of TAS and GSH, and cognitive performance was assessed at baseline and at 2 years of follow-up. Regression analysis was used to assess the relationship between TAS/GSH levels at baseline and cognitive performance at both time points, controlling for confounders. Baseline TAS and GSH levels were significantly lower in patients than healthy controls. In patients, baseline TAS was positively associated with the global cognition score at baseline (p = 0.048) and two years later (p = 0.005), while TAS was not associated with cognitive functioning in healthy controls. Further, baseline TAS in patients was specifically associated with the memory domain at baseline and with the memory and attention domains two years later. Stratifying by affective and non-affective psychoses, significant associations were only found between TAS and cognition in the non-affective psychosis group. Baseline GSH levels were not associated with cognitive functioning at either time point in either group. The antioxidant defence capacity in early onset first-episode psychotic patients is directly correlated with global cognition at baseline and at 2 years of follow-up, especially in non-affective psychosis.

Data is progressively and robustly accumulating regarding the biological basis of autism. Autism spectrum disorders (ASD) are currently considered a group of neurodevelopmental disorders with onset very early in life and a complex, heterogeneous, multifactorial aetiology. A comprehensive search of the last five years of the Medline database was conducted in order to summarize recent evidence on the neurobiological bases of autism. The main findings on genetic influence, neuropathology, neurostructure and brain networks are summarized. In addition, findings from peripheral samples of subjects with autism and animal models, which show immune, oxidative, mitochondrial dysregulations, are reported. Then, other biomarkers from very different systems associated with autism are reported. Finally, an attempt is made to try and integrate the available evidence, which points to a oligogenetic, multifactorial aetiology that converges in an aberrant micro-organization of the cortex, with abnormal functioning of the synapses and abnormalities in very general physiological pathways (such as inflammatory, immune and redox systems).

BackgroundThe interest in studying gene–gene interactions is increasing for psychiatric diseases such as schizophrenia-spectrum disorders (SSD), where multiple genes are involved. Dysbindin-1 (DTNBP1) and Neuritin-1 (NRN1) genes have been previously associated with SSD and both are involved in synaptic plasticity. We aimed to study whether these genes show an epistatic effect on the risk for SSD.MethodsThe sample comprised 388 SSD patients and 397 healthy subjects. Interaction was tested between: (i) three DTNBP1 SNPs (rs2619537, rs2743864, rs1047631) related to changes in gene expression; and (ii) an haplotype in NRN1 previously associated with the risk for SSD (rs645649-rs582262: HAP-risk C-C).ResultsAn interaction between DTNBP1 rs2743864 and NRN1 HAP-risk was detected by using the model based multifactor dimensionality reduction (MB-MDR) approach (P = 0.0049, after permutation procedure), meaning that the risk for SSD is significantly higher in those subjects carrying both the A allele of rs2743864 and the HAP-risk C-C. This interaction was confirmed by using a logistic regression model (P = 0.033, OR (95%CI) = 2.699 (1.08–6.71), R2 = 0.162).DiscussionOur results suggest that DTNBP1 and NRN1 genes show a joint effect on the risk for SSD. Although the precise mechanism underlying this effect is unclear, the fact that these genes have been involved in synaptic maturation, connectivity and glutamate signalling suggests that our findings could be of value as a link to the schizophrenia aetiology.

[FR] L’objectif du présent article est de passer en revue les études longitudinales évaluant des changements cérébraux évolutifs chez des patients souffrant de psychose précoce. Comprendre les trajectoires développementales des processus moléculaires et cellulaires du développement normal, et les différences entre le développement normal et anormal, est essentiel pour l’interprétation des études d’imagerie clinique, et pour la recherche d’une physiopathologie différentielle dans les affections psychiatriques liées au neurodéveloppement. Par conséquent, compte tenu de l’objectif de cet article, nous présenterons un bref sommaire des résultats d’études d’imagerie à résonnance magnétique (IRM) chez des sujets à développement cérébral normal. Nous présenterons ensuite un bref sommaire d’études longitudinales portant sur des psychoses précoces. Étant donné que la schizophrénie à début très précoce et la schizophrénie débutant à l’adolescence semblent se caractériser par des précurseurs et une évolution différents, et que l’expression génique diffère dans les différents groupes d’âge, nous diviserons les données en 2 groupes : début précoce et début à l’adolescence. Les résultats d’études longitudinales portant sur d’autres psychoses précoces seront examinés également afin d’évaluer la spécificité des résultats pour la schizophrénie, comparativement à d’autres maladies précoces avec symptômes psychotiques. Le sommaire des résultats sera suivi par des facteurs cliniques corrélés, et par une discussion des implications. Enfin, on soumettra des recommandations pour la recherche future., [EN] Progressive losses of cortical grey-matter volumes and increases in ventricular volumes have been reported in patients with childhood-onset schizophrenia (COS) during adolescence. Longitudinal studies suggest that the rate of cortical loss seen in COS during adolescence plateaus during early adulthood. Patients with first-episode adolescent onset schizophrenia show less marked progressive changes, although the number of studies in this population is small. Some studies show that, although less exaggerated, progressive changes are also present in non-schizophrenia early onset psychosis. The greater loss of brain tissue seen in COS, even some years after the first episode, as compared to adolescent- or adult-onset schizophrenia may be due to variables such as sample bias (more severe, treatment refractory sample of childhood-onset patients studied), a process uniquely related to adolescent development in COS, differential brain effects of drug treatment in this population, clinical outcome, or interactions among these variables. Findings from both cross-sectional studies of first-episode patients and longitudinal studies in COS and adolescent onset support the concept of early-onset schizophrenia as a progressive neurodevelopmental disorder with both early and late developmental abnormalities. Future studies should look for correlates at a cellular level and for pathophysiological explanations of volume changes in these populations. The association of risk genes involved in circuitries associated with schizophrenia and their relationship to developmental trajectories is another promising area of future research., [ES] Se han observado en la adolescencia unas pérdidas progresivas de volúmenes de sustancia gris y unos crecimientos ventriculares en pacientes con esquizofrenias de la niñez. Estudios longitudinales demuestran que en la adolescencia el ritmo de pérdida cortical observado en las esquizofrenias con inicios muy tempranos (COS) se estabiliza en los jóvenes adultos. Los pacientes en quienes el primer episodio sobreviene en la adolescencia presentan cambios evolutivos menos marcados, a pesar del reducido número de estudios en esta población. Ciertos estudios demuestran que unos cambios evolutivos menos marcados aparecen también en las psicosis no esquizofrénicas tempranas. La mayor pérdida de tejido cerebral observada en las esquizofrenias muy tempranas, aun varios años tras el primer episodio en comparación con las esquizofrenias de la adolescencia o la edad adulta podría estar vinculada con unas variables tales como el muestreo sesgado (enfermedad más severa; muestreo de pacientes con esquizofrenia temprana, refractarios al tratamiento), índole específica de la evolución en la adolescencia de las COS, efectos diferenciales de tratamientos medicamentosos en esta población, desenlace clínico, o interacción entre estas variables. Los resultados de estudios transversales en pacientes tras un primer episodio, así como estudios longitudinales sobre las COS y las esquizofrenias con inicio en la adolescencia, afianzan la idea que la esquizofrenia temprana es una afección del neurodesarrollo evolutiva, con anomalías del desarrollo tempranas y tardías. Los fururos estudios deberían buscar factores relacionados a nivel celular, y explicaciones patofisiolológicas para los cambios de volumen en estas poblaciones. La asociación de genes con crecimiento del riesgo en los circuitos neuronales vinculados con la esquizofrenia en relación con las trayectorias del desarrollo es otra pista prometedora para las investigaciones del porvenir., Cette recherche est soutenue en partie par CIBER de Salud Mental, ISCIII, Espagne.

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

BackgroundEarly-onset first-episode psychosis (FEP) and high functioning autism spectrum disorders (ASD) are complex neuro–developmental disorders that share symptomatology but it is not clear if they also share neurobiological abnormalities (Chisholm et al., 2015). We examined thickness, surface area and volume in a direct comparison of children and adolescents with FEP (onset before 18 years), high-functioning ASD, and healthy subjects.MethodsMagnetic resonance imaging scans of 85 participants (30 ASD, 29 FEP, 26 healthy controls, age range 10–18 years) were obtained from the same MR scanner using the same acquisition protocol. The FreeSurfer analysis suite was used to quantify vertex-wise estimates of the metrics thickness, surface area, and volume.ResultsASD and FEP had spatially overlapping insular deficits for each metric. The transdiagnostic overlap of deficits was greatest for volume (55% of all insular vertices) and smallest for thickness (18%). Insular thickness and surface area deficits did not overlap in ASD and overlapped only in 8% of all insular vertices in FEP.ConclusionsMorphological insular deficits are common to FEP and high functioning ASD when compared to healthy participants. The pattern of deficits was similar in both disorders, i.e. a largely non-overlap of insular thickness and surface area. The non-overlap provides further evidence that these metrics represent two independent outcomes of corticogenesis, both of which are affected in FEP and ASD.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Diagnosis of schizophrenia spectrum disorders (SSD) may be difficult in clinical practice, particularly during the first episodes of early-onset psychosis (FE-EOP). Aims To develop a Support Vector Machine (SVM) algorithm as a predictive tool for diagnostic outcome in patients with FE-EOP, based on clinical and biomedical data at the emergence of the illness. Methods Two-year, prospective longitudinal study, where 81 patients (9-17 years of age) with a FE-EOP and stable diagnosis at follow-up and 41 age and sex-matched healthy controls (HC) were included. Structured diagnostic interviews, clinical and cognitive scales, a MRI scan and biochemical tests were conducted at baseline. Three SVM classification algorithms were developed (SSD vs HC group, non-SSD vs HC group, and SSD vs non-SSD group). Jackknifing was used to validate the algorithms and to calculate performance estimates. Enhanced-Recursive Feature Elimination was performed in order to gain information about the predictive weight for diagnosis of each variable. Results The SSD-versus-non-SSD classifier achieved an overall accuracy of 83.1%, sensitivity of 86.6% and specificity of 77.8%. The variables during a FE-EOP with higher predictive value for a diagnosis of SSD were clinical variables such as negative symptoms preceding or during the psychotic onset, poor insight and duration of illness until first psychiatric contact. Biochemical, neuroimaging, and cognitive variables at baseline did not provide any additional predictive value. Conclusions SVM may serve as a predictive tool for early diagnosis of SSD during a FE-EOP. The most discriminative variables during a FE-EOP for a future diagnosis of SSD are clinical variables.

IntroductionPro/antiinflammatory imbalance has been found in first-episode psychotic (FEP) patients, even 12 months later. Current research is every time more focused in the need to find biomarkers to understand the underlying pathophysiological mechanisms of this severe illness.ObjectivesTo assess peripherical levels of neurotrophins and their receptors and their correlation with inflammation, clinical symptomatology and response to antipsychotic treatment, over the time.MethodologyNinety-four FEP patients and 80 matched healthy controls were included. Blood samples were taken at baseline to measure BDNF and NGF and their receptor levels (TrkB-full, TrkB-truncated and TrkA) and pro/antiinflammatory parameters (NFkB, COX-2, iNOS, PPARgamma, 15d-PG12). Patients were followed-up during 12 months.ResultsBDNF TrkB-full receptor and NFG TrkA receptor levels increased during the follow-up whereas BDNF TrkB-truncated form receptor decreased. After adjusting for confounding variables, baseline levels of proinflamatory variables were significantly related to TrkB-full/TrkB-truncated ratio (FL/T), suggesting that a higher proinflammatory status is related to a higher FL/T ratio expression. Furthermore, baseline FL/T ratio could have a predictor role of patient's functionality 1 year after the illness onset, depending on whether patient is treated or not with antipsychotic drugs.ConclusionInflammatory processes, neurotrophic pathways and functional status of FEP patients seem to be related which is of great traslational relevance. Specific, the expression of the 2 isoforms of BDNF receptor should be taken into account before starting an antipsychotic drug treatment.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Subjects with autism spectrum disorders (ASD) have more medical needs and more difficulties accessing health care services than the general population. Their verbal and non-verbal communication difficulties and particular behaviors, along with lack of expertise on the part of physicians and failure of the services to make adjustments, make it difficult for them to obtain an appropriate health care.PurposeTo describe a model for health care delivery in an ASD population.MethodReview of relevant literature and a discussion process with stakeholders leading to the design of a service to meet the specialty health needs of subjects of all ages with ASD for a region with a population of 6,000,000.ResultsA service was designed centred around the concepts of case management, individualization, facilitation, accompaniment, continuous training and updating, and quality management. Five hundred and thirteen patients with ASD have been seen over a period of 18 months. The programme generated 1566 psychiatric visits and 1052 visits to other specialties (mainly Nutrition, Stomatology, Neurology, and Gastroenterology) in the same period.ConclusionPersons with ASD may benefit from adjustments of health care services in order to improve their access to adequate health care at the quality level of the rest of the population.

Cognitive deficits are a core feature of psychotic disorders. Both in adult and adolescent populations, studies have shown that patients with psychosis have poorer cognitive functioning than controls. The cognitive domains that seem to be affected are mainly attention, working memory, learning and memory, and executive function. However, with regard to the trajectory of cognitive function throughout the illness, there is still a dearth of prospective data in patients who develop psychosis during adolescence. In this article, neuropsychological functioning was assessed in a sample of 24 first episodes of early onset psychosis (EOP) and 29 healthy adolescents at baseline and after a two-year follow-up. Patients with EOP showed lower scores than controls in overall cognitive functioning and in all specific domains assessed (attention, working memory, executive function, and learning and memory) both at baseline and the two-year follow-up. When changes in cognitive functioning over two years were assessed, patients and controls showed significant improvement in almost all cognitive domains. However, this improvement disappeared in the patient group after controlling for improvement in symptomatology. Our findings support a neurodevelopmental pathological process in this sample of adolescents with psychosis.

Background and aims:Psychosis with onset prior to 18 years of age, or early-onset psychosis (EOP), have a poorer prognosis than adult-onset psychosis. Further, a worse functional outcome of patients with EOP has been related to diagnosis of schizophrenia, severity of negative symptoms, behavioral problems, premorbid functioning, childhood onset, and insidious onset. We aim to examine the functional outcome of patients with EOP over a two-year follow-up.Methods:A total of 24 patients with first episode psychosis were enrolled. Subjects underwent a cross-sectional evaluation at the baseline visit that consisted of collecting sociodemographic data, including parental socioeconomic status as measured by the Hollingshead-Redlich Scale. Psychotic symptoms were assessed using the Spanish version of the Positive and Negative Syndrome Scale (PANSS). Social disability was measured with the Global Assessment of Functioning disability scale (GAF). Patients were assessed at a two-year follow-up. A linear regression analysis was used to predict the level of functioning (based on GAF scores) over the two-year follow-up. Variables entered into this equation were: GAF at two-year follow-up (as dependent variable), and gender, age at first onset, parental socioeconomic status, diagnosis, positive symptoms at baseline, and negative symptoms at baseline (as independent variables).Results:Negative symptoms at baseline were the only significant variable that predict the functional outcome at the two-year follow-up (p= 0.010).Conclusions:Functional prognosis of early-onset psychosis depends on the severity of negative symptoms, independently of diagnosis.

In previous work we developed a pharmacogenetic predictor of antipsychotic (AP) induced extrapyramidal symptoms (EPS) based on four genes involved in mTOR regulation. The main objective is to improve this predictor by increasing its biological plausibility and replication. We re-sequence the four genes using next-generation sequencing. We predict functionality “in silico” of all identified SNPs and test it using gene reporter assays. Using functional SNPs, we develop a new predictor utilizing machine learning algorithms (Discovery Cohort, N = 131) and replicate it in two independent cohorts (Replication Cohort 1, N = 113; Replication Cohort 2, N = 113). After prioritization, four SNPs were used to develop the pharmacogenetic predictor of AP-induced EPS. The model constructed using the Naive Bayes algorithm achieved a 66% of accuracy in the Discovery Cohort, and similar performances in the replication cohorts. The result is an improved pharmacogenetic predictor of AP-induced EPS, which is more robust and generalizable than the original.

This work was supported by the Spanish Ministry of Economy and Competiveness and the Carlos III Health Institute through CIBERSAM, and the Foundation Santander-UCM (GR 58/08), and partly supported by the Spanish Ministry of Economy and Competiveness directly, and by the European Regional Development Fund, FEDER (PI10/01746, PI11/01977, PI11/02708,PI12/02077), local grants from the Department of Education, Linguistic Policy and Culture of the Basque Country Government (2010111170, 2010112009), the Basque Foundation for Health Innovation and Research (BIOEF), ) and the University of the Basque Country (GIC10/80, GIC12/84)., Martinez-Cengotitabengoa, M., Macdowell, K.S., Alberich, S., Diaz, F.J., Garcia-Bueno, B., Rodriguez-Jimenez, R., Bioque, M., Berrocoso, E., Parellada, M., Lobo, A., Saiz, P.A., Matute, C., Bernardo, M., Gonzalez-Pinto, A., Leza, J.C.

Equitat en salut; Equity in Health; Equidad en salud L’equitat en salut ens ha de preocupar si considerem que tots els éssers humans són moralment iguals i que, per tant, mereixen el mateix respecte a la seva vida i dignitat. Però també és rellevant des d’una visió més utilitarista, atès que uns nivells pitjors de salut dels individus comprometen el benestar social i econòmic global de les comunitats. Així, doncs, l’aspiració a l’equitat no és només una qüestió d’altruisme o de bones intencions, sinó una obligació moral i una qüestió de dret.