Tobacco use in first-episode psychosis, a multinational EU-GEI study.

BACKGROUND: Tobacco is a highly prevalent substance of abuse in patients with psychosis. Previous studies have reported an association between tobacco use and schizophrenia. The aim of this study was to analyze the relationship between tobacco use and first-episode psychosis (FEP), age at onset of psychosis, and specific diagnosis of psychosis. METHODS: The sample consisted of 1105 FEP patients and 1355 controls from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We assessed substance use with the Tobacco and Alcohol Questionnaire and performed a series of regression analyses using case-control status, age of onset of psychosis, and diagnosis as outcomes and tobacco use and frequency of tobacco use as predictors. Analyses were adjusted for sociodemographic characteristics, alcohol, and cannabis use. RESULTS: After controlling for cannabis use, FEP patients were 2.6 times more likely to use tobacco [p ⩽ 0.001; adjusted odds ratio (AOR) 2.6; 95% confidence interval (CI) [2.1-3.2]] and 1.7 times more likely to smoke 20 or more cigarettes a day (p = 0.003; AOR 1.7; 95% CI [1.2-2.4]) than controls. Tobacco use was associated with an earlier age at psychosis onset (ß = -2.3; p ⩽ 0.001; 95% CI [-3.7 to -0.9]) and was 1.3 times more frequent in FEP patients with a diagnosis of schizophrenia than in other diagnoses of psychosis (AOR 1.3; 95% CI [1.0-1.8]); however, these results were no longer significant after controlling for cannabis use. CONCLUSIONS: Tobacco and heavy-tobacco use are associated with increased odds of FEP. These findings further support the relevance of tobacco prevention in young populations.

Mental impact of Covid-19 among Spanish healthcare workers. A large longitudinal survey.

AIMS: Longitudinal data on the mental health impact of the coronavirus disease 2019 (Covid-19) pandemic in healthcare workers is limited. We estimated prevalence, incidence and persistence of probable mental disorders in a cohort of Spanish healthcare workers (Covid-19 waves 1 and 2) -and identified associated risk factors. METHODS: 8996 healthcare workers evaluated on 5 May-7 September 2020 (baseline) were invited to a second web-based survey (October-December 2020). Major depressive disorder (PHQ-8 ≥ 10), generalised anxiety disorder (GAD-7 ≥ 10), panic attacks, post-traumatic stress disorder (PCL-5 ≥ 7), and alcohol use disorder (CAGE-AID ≥ 2) were assessed. Distal (pre-pandemic) and proximal (pandemic) risk factors were included. We estimated the incidence of probable mental disorders (among those without disorders at baseline) and persistence (among those with disorders at baseline). Logistic regression of individual-level [odds ratios (OR)] and population-level (population attributable risk proportions) associations were estimated, adjusting by all distal risk factors, health care centre and time of baseline interview. RESULTS: 4809 healthcare workers participated at four months follow-up (cooperation rate = 65.7%; mean = 120 days s.d. = 22 days from baseline assessment). Follow-up prevalence of any disorder was 41.5%, (v. 45.4% at baseline, p < 0.001); incidence, 19.7% (s.e. = 1.6) and persistence, 67.7% (s.e. = 2.3). Proximal factors showing significant bivariate-adjusted associations with incidence included: work-related factors [prioritising Covid-19 patients (OR = 1.62)], stress factors [personal health-related stress (OR = 1.61)], interpersonal stress (OR = 1.53) and financial factors [significant income loss (OR = 1.37)]. Risk factors associated with persistence were largely similar. CONCLUSIONS: Our study indicates that the prevalence of probable mental disorders among Spanish healthcare workers during the second wave of the Covid-19 pandemic was similarly high to that after the first wave. This was in good part due to the persistence of mental disorders detected at the baseline, but with a relevant incidence of about 1 in 5 of HCWs without mental disorders during the first wave of the Covid-19 pandemic. Health-related factors, work-related factors and interpersonal stress are important risks of persistence of mental disorders and of incidence of mental disorders. Adequately addressing these factors might have prevented a considerable amount of mental health impact of the pandemic among this vulnerable population. Addressing health-related stress, work-related factors and interpersonal stress might reduce the prevalence of these disorders substantially. Study registration number: NCT04556565.

Four-month incidence of suicidal thoughts and behaviors among healthcare workers after the first wave of the Spain COVID-19 pandemic.

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.

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.

A longitudinal study of gene expression in first-episode schizophrenia; exploring relapse mechanisms by co-expression analysis in peripheral blood.

Little is known about the pathophysiological mechanisms of relapse in first-episode schizophrenia, which limits the study of potential biomarkers. To explore relapse mechanisms and identify potential biomarkers for relapse prediction, we analyzed gene expression in peripheral blood in a cohort of first-episode schizophrenia patients with less than 5 years of evolution who had been evaluated over a 3-year follow-up period. A total of 91 participants of the 2EPs project formed the sample for baseline gene expression analysis. Of these, 67 provided biological samples at follow-up (36 after 3 years and 31 at relapse). Gene expression was assessed using the Clariom S Human Array. Weighted gene co-expression network analysis was applied to identify modules of co-expressed genes and to analyze their preservation after 3 years of follow-up or at relapse. Among the 25 modules identified, one module was semi-conserved at relapse (DarkTurquoise) and was enriched with risk genes for schizophrenia, showing a dysregulation of the TCF4 gene network in the module. Two modules were semi-conserved both at relapse and after 3 years of follow-up (DarkRed and DarkGrey) and were found to be biologically associated with protein modification and protein location processes. Higher expression of DarkRed genes was associated with higher risk of suffering a relapse and early appearance of relapse (p = 0.045). Our findings suggest that a dysregulation of the TCF4 network could be an important step in the biological process that leads to relapse and suggest that genes related to the ubiquitin proteosome system could be potential biomarkers of relapse.

A white paper on a neurodevelopmental framework for drug discovery in autism and other neurodevelopmental disorders.

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.

Exploring the biological role of postzygotic and germinal de novo mutations in ASD.

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.

Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum.

AIMS: Psychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum. METHODS: The sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components). RESULTS: Both genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene-environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions. CONCLUSIONS: The interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.

Social Cognition in Autism and Schizophrenia Spectrum Disorders: The Same but Different?

Social cognition impairment is a core shared phenotype in both schizophrenia spectrum disorders (SSD) and autism spectrum disorders (ASD). This study compares social cognition performance through four different instruments in a sample of 147 individuals with ASD or SSD and in healthy controls. We found that both clinical groups perform similarly to each other and worse than healthy controls in all social cognition tasks. Only performance on the Movie for the Assessment of Social Cognition (MASC) test was independent of age and intelligence. Proportionately, individuals in the control group made significantly more overmentalization errors than both patients group did and made fewer undermentalization errors than patients with SSD did. AUC analyses showed that the MASC was the instrument that best discriminated between the clinical and control groups. Multivariate analysis showed negative symptom severity as a potential mediator of the association between social cognition deficit and poor global functioning.

The role of schizotypal traits and the OXTR gene in theory of mind in schizophrenia: A family-based study.

BACKGROUND: There is consistent evidence that theory of mind (ToM) is impaired in schizophrenia (SZ); however, it remains unclear whether such deficits are trait- or state-dependent. We evaluated ToM in patients with schizophrenia spectrum disorders (SSDs), their healthy first-degree relatives, and controls to test its suitability as an endophenotypic marker. We also studied the modifying effect of markers of clinical and genetic liability to SZ (schizotypy and genetic variability in the oxytocin receptor gene: OXTR) on ToM in healthy individuals. METHODS: The sample included 38 stable SSD patients, 80 unaffected first-degree relatives, and 81 controls. ToM was assessed using the Hinting Task (HT) and schizotypy via the Schizotypal Personality Questionnaire-Brief (SPQ-B), which generates interpersonal (SPQ-IP), cognitive-perceptual (SPQ-CP), and disorganization (SPQ-D) scores. The polymorphism rs53576 of OXTR was genotyped. RESULTS: Patients presented poorer HT performance than relatives and controls (p = 0.003 and p < 0.001). High SPQ-IP and SPQ-CP scores correlated with poorer ToM performance in relatives (p = 0.010 and p = 0.030), but not in controls. OXTR was not associated with HT scores, but it showed a modifying effect within controls; high SPQ-CP was related to HT poorer performance conditional to GG genotype (p = 0.007). CONCLUSIONS: ToM deficits were present in patients but not in unaffected relatives or controls. However, our data indicate the usefulness of clinical and genetic liability markers to characterize differences in ToM abilities within healthy individuals. Then, the observed link between ToM and SZ liability suggests the putative role of ToM as an endophenotypic marker. Nevertheless, new analyses in larger samples are needed.

Influence of social cognition as a mediator between cognitive reserve and psychosocial functioning in patients with first episode psychosis.

BACKGROUND: Social cognition has been associated with functional outcome in patients with first episode psychosis (FEP). Social cognition has also been associated with neurocognition and cognitive reserve. Although cognitive reserve, neurocognitive functioning, social cognition, and functional outcome are related, the direction of their associations is not clear. Therefore, the main aim of this study was to analyze the influence of social cognition as a mediator between cognitive reserve and cognitive domains on functioning in FEP both at baseline and at 2 years. METHODS: The sample of the study was composed of 282 FEP patients followed up for 2 years. To analyze whether social cognition mediates the influence of cognitive reserve and cognitive domains on functioning, a path analysis was performed. The statistical significance of any mediation effects was evaluated by bootstrap analysis. RESULTS: At baseline, as neither cognitive reserve nor the cognitive domains studied were related to functioning, the conditions for mediation were not satisfied. Nevertheless, at 2 years of follow-up, social cognition acted as a mediator between cognitive reserve and functioning. Likewise, social cognition was a mediator between verbal memory and functional outcome. The results of the bootstrap analysis confirmed these significant mediations (95% bootstrapped CI (-10.215 to -0.337) and (-4.731 to -0.605) respectively). CONCLUSIONS: Cognitive reserve and neurocognition are related to functioning, and social cognition mediates in this relationship.

Personalized medicine begins with the phenotype: identifying antipsychotic response phenotypes in a first-episode psychosis cohort.

AIMS: Here, we present a clustering strategy to identify phenotypes of antipsychotic (AP) response by using longitudinal data from patients presenting first-episode psychosis (FEP). METHOD: One hundred and ninety FEP with complete data were selected from the PEPs project. The efficacy was assessed using total PANSS, and adverse effects using total UKU, during one-year follow-up. We used the Klm3D method to cluster longitudinal data. RESULTS: We identified four clusters: cluster A, drug not toxic and beneficial; cluster B, drug beneficial but toxic; cluster C, drug neither toxic nor beneficial; and cluster D, drug toxic and not beneficial. These groups significantly differ in baseline demographics, clinical, and neuropsychological characteristics (PAS, total PANSS, DUP, insight, pIQ, age of onset, cocaine use and family history of mental illness). CONCLUSIONS: The results presented here allow the identification of phenotypes of AP response that differ in well-known simple and classic clinical variables opening the door to clinical prediction and application of personalized medicine.

Differences in the regulation of inflammatory pathways in adolescent- and adult-onset first-episode psychosis.

A precise description of the inflammatory response in first-episode psychosis (FEP) by age of onset does not exist. We explored baseline and 6-month follow-up differences in the pro/anti-inflammatory balance in plasma and peripheral blood mononuclear cells in adolescent-onset FEP (≤ 18 y.o., N = 27) and adult-onset FEP (≥ 25 y.o., N = 43) using non-parametric 1-category ANCOVA, with age group as an independent variable and values of pro- and anti-inflammatory markers at baseline and at follow-up as dependent variables. We used a non-parametric repeated-measures mixed-effects model to explore the baseline/6-month change in pro- and anti-inflammatory markers within adolescent- and adult-onset groups, exploring differential trajectories of change by means of the interaction of time by age-of-onset group. Levels of the nuclear transcription factor (NFκB), a master regulator of the inflammatory and oxido/nitrosative status of cells, were higher in adolescent-onset FEP both at baseline and after 6 months. During follow-up, we found further increases in levels of soluble inflammatory markers (PGE2 and NO2-) only in adolescent-onset FEP. In contrast, in adult-onset FEP, the expression of inducible NO synthase (iNOS), which is also pro-inflammatory, tended to decrease, with no further increase in other pro-inflammatory markers. Significant differences in the direction of change by age-of-onset cohort exist only for NFκB (F = 4.165, df = 2, 70.95, p = 0.019). Our results support the existence of changes in the pro/anti-inflammatory balance in FEP depending on the neurodevelopmental stage at illness onset. These results also suggest that inflammation may be a potential therapeutic target in adolescent-onset FEP.

Cognitive reserve as an outcome predictor: first-episode affective versus non-affective psychosis.

OBJECTIVE: Cognitive reserve (CR) refers to the brain's capacity to cope with pathology in order to minimize the symptoms. CR is associated with different outcomes in severe mental illness. This study aimed to analyze the impact of CR according to the diagnosis of first-episode affective or non-affective psychosis (FEP). METHOD: A total of 247 FEP patients (211 non-affective and 36 affective) and 205 healthy controls were enrolled. To assess CR, common proxies have been integrated (premorbid IQ; education-occupation; leisure activities). The groups were divided into high and low CR. RESULTS: In non-affective patients, those with high CR were older, had higher socioeconomic status (SES), shorter duration of untreated psychosis, and a later age of onset. They also showed greater performance in most cognitive domains. In affective patients, those with a greater CR showed a higher SES, better functioning, and greater verbal memory performance. CONCLUSION: CR plays a differential role in the outcome of psychoses according to the diagnosis. Specifically, in order to address the needs of non-affective patients with low CR, cognitive rehabilitation treatments will need to be 'enriched' by adding pro-cognitive pharmacological agents or using more sophisticated approaches. However, a functional remediation therapy may be of choice for those with an affective psychosis and low CR.

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

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

Evidence of an epistatic effect between Dysbindin-1 and Neuritin-1 genes on the risk for schizophrenia spectrum disorders.

BACKGROUND: The 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. METHODS: The 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). RESULTS: An 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). DISCUSSION: Our 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.

Cognition and psychopathology in first-episode psychosis: are they related to inflammation?

BACKGROUND: Cognitive deficits are present from the onset of psychosis and are considered a core feature of the disorder. Increasing evidence suggests that cognitive function is associated with inflammatory processes. This study evaluated the association between cognition and inflammatory biomarkers in first-episode psychosis (FEP), in order to identify cognitive phenotypes from inflammatory expression profiles. METHOD: A case-control study of 92 FEP patients and 80 matched controls was used. Neurocognitive assessment, including verbal ability, sustained attention, verbal memory, working memory and executive function, was performed. The expression of pro- and anti-inflammatory mediators of the main intracellular inflammatory pathway was measured in peripheral blood mononuclear cells and plasma. RESULTS: FEP patients performed worse in all cognitive domains compared to controls and had higher expression of pro-inflammatory mediators and lower expression of anti-inflammatory mediators. In the FEP group, cognition and psychopathology were associated with inflammation. Hierarchical regression analysis showed that association between the anti-inflammatory prostaglandin 15d-PGJ2 and sustained attention on one hand, and COX-2 expression and executive function on the other, were statistically significant. CONCLUSIONS: Our study provides evidence for an association between anti-inflammatory biomarkers and cognition in FEP. The identification of a subgroup of patients based on these measures could be useful to guide treatment programmes by providing tools to select a personalized treatment approach, but longitudinal studies are needed before. In the future, establishment of biomarkers linked to cognition would be useful to monitor the course of cognitive impairment, but substantially more data will be required. Determination of IκBα, the inhibitory protein of the pro-inflammatory transcription factor NFκB, could be useful in early phases to assess clinical severity.

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

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

BDNF and NGF Signalling in Early Phases of Psychosis: Relationship With Inflammation and Response to Antipsychotics After 1 Year.

Previous studies have indicated systemic deregulation of the proinflammatory or anti-inflammatory balance in individuals with first-episode psychosis (FEP) that persists 12 months later. To identify potential risk/protective factors and associations with symptom severity, we assessed possible changes in plasma levels of neurotrophins (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) and their receptors in peripheral blood mononuclear cells (PBMCs). Expression of the 2 forms of BDNF receptors (active TrkB-FL and inactiveTrkB-T1) in PBMCs of FEP patients changed over time, TrkB-FL expression increasing by 1 year after diagnosis, while TrkB-T1 expression decreased. The TrkB-FL/TrkB-T1 ratio (hereafter FL/T1 ratio) increased during follow-up in the nonaffective psychosis group only, suggesting different underlying pathophysiological mechanisms in subgroups of FEP patients. Further, the expression of the main NGF receptor, TrkA, generally increased in patients at follow-up. After adjusting for potential confounders, baseline levels of inducible isoforms of nitric oxide synthase, cyclooxygenase, and nuclear transcription factor were significantly associated with the FL/T1 ratio, suggesting that more inflammation is associated with higher values of this ratio. Interestingly, the FL/T1 ratio might have a role as a predictor of functioning, a regression model of functioning at 1 year suggesting that the effect of the FL/T1 ratio at baseline on functioning at 1 year depended on whether patients were treated with antipsychotics. These findings may have translational relevance; specifically, it might be useful to assess the expression of TrkB receptor isoforms before initiating antipsychotic treatment in FEPs.

Movie for the Assessment of Social Cognition (MASC): Spanish validation.

We present the Spanish validation of the "Movie for the Assessment of Social Cognition" instrument (MASC-SP). We recruited 22 adolescents and young adults with Asperger syndrome and 26 participants with typical development. The MASC-SP and three other social cognition instruments (Ekman Pictures of Facial Affect test, Reading the Mind in the Eyes Test, and Happé's Strange Stories) were administered to both groups. Individuals with Asperger syndrome had significantly lower scores in all measures of social cognition. The MASC-SP showed strong correlations with all three measures and relative independence of general cognitive functions. Internal consistency was optimal (0.86) and the test-retest was good. The MASC-SP is an ecologically valid and useful tool for assessing social cognition in the Spanish population.