Stress-sensitivity (SS) is considered a psychobiological trait possibly resulting from the interaction of genetic and environmental factors (GxE). This study examined whether the interaction of SS-related genetic markers with interview-based dimensions of childhood adversity predicted longitudinal trajectories of low versus high SS. Participants were nonclinically-ascertained young adults comprising normative and elevated scores on schizotypy. SS trajectories were defined in a previous report based on three prospective assessments (23.5, 25, 28 years-old) of both retrospective (Perceived Stress Scale; PSS) and momentary (Experience Sampling Methodology; ESM) stress ratings. A total of n = 177 and n = 165 participants with PSS and ESM stress-sensitivity trajectories, respectively, as well as genetic data, were included in the study. GxE effects between a SS Polygenic Risk Score (PRS-SS) and a Genetic Risk Score of the Hypothalamic Pituitary Adrenal axis (GRS-HPA) with childhood adversity dimensions (Intrafamilial Adversity, Threat and Deprivation) on SS trajectories were examined. Threat was the most consistent predictor of persistently high SS. PRS-SS moderated the association of Threat with high-PSS. GRS-HPA moderated the effects of all adversity dimensions on high-PSS. The interaction of PRS-SS with Deprivation and GRS-HPA with Intrafamilial Adversity predicted trajectories of momentary social stress, but the effects were driven by those with lower genetic susceptibility. Genetic-HPA-axis moderates the effects of all adversity dimensions on persistent SS trajectories, as well as PRS-SS and Threat, particularly for retrospective stress measure. The findings highlight the complex interplay between GxE factors and suggest that PSS may better capture SS trait. Including biologically-meaningful GRS indexing SS and adversity dimensions in future studies using comprehensive stress measures would enhance our knowledge on high SS susceptibility and its relationship with diverse psychopathological outcomes.

Here we report on the results of an experimental study investigating "who?" emerges as a leader in the context of male group cooperation and "how?" they do that. The study was designed based on the iterated Public Goods Game, played face-to-face in groups composed of four male strangers. The game involved interactions both with and without communication to allow the assessment of individual cooperative strategies, leadership potential, and individual features of positive nonverbal expressiveness during interactions. Along with the individual behavioural characteristics we have addressed personality traits (the Big Five) and an oxytocin receptor gene polymorphism (OXTR: SNP rs53576; A/G) as putative markers of individual sociability. Our results revealed that emergent leaders most often employed the strategy of unconditional cooperation ("altruism") and were characterized by enhanced positive facial expressiveness and extraversion compared to non-leaders. However, a fraction of emergent leaders (25%) turned out to be occasional free-riders ("cheaters"). Their distinctive features were the highest scores on extraversion, exaggerated activity in negotiations, and over-expression of positive nonverbal elements. Given the high efficiency of leaders-cheaters' behaviour, we consider this result as the evidence for supernormal stimuli functioning in humans. Moreover, leaders-cheaters were characterized by a specific allelic frequency of OXTR rs53576 (heterozygosity: AG). The homozygous GG variant of this SNP is argued to be associated with prosociality, and the AA, on the contrary, with poor sociability. The heterozygous variant (AG) probably is a compromise that enables its carriers to successfully combine high social skills with antisocial behavior (free-riding). This finding supports existing evidence on the role of OXTR rs53576 in human social behaviour.

Background: Bipolar disorder (BD) is a recurrent chronic psychiatric disorder. Evidence indicates that many individuals with BD exhibit high serum levels of inflammation and oxidative stress markers, which are further associated with mood symptoms and cognitive dysfunction. Due to the crosstalk between the periphery and central nervous system in BD, the disruption of the blood-brain barrier (BBB) has been proposed as a key mechanism of the pathophysiology of the disorder. This study aimed to investigate claudin-5 expression – a major protein of the BBB – in the brain of an animal model of mania induced by d-amphetamine (AMPH) and evaluate the effects of treatment with lithium. Results: AMPH-injected animals exhibited increased overall activity in the open field test. In the serum, TBARS levels were augmented in the lithium-treated groups, regardless of AMPH injection, while TNFα was not detected. In the brain, TBARS and TNFα did not differ between groups but were positively and strongly correlated in the ST of AMPH-injected rats. Contrary to the primary hypothesis, AMPH and lithium injections did not affect brain claudin-5 protein levels.Conclusions: This is one of the first attempts to investigate the effects of AMPH on BBB integrity. Although no evidence of BBB disruption was found in the current study, our results provide evidence and rationale for future research to elucidate the importance of such alteration in BD.

Objective Evidence has suggested that immune imbalance is involved with bipolar disorder (BD); however, its precise mechanism is poorly understood. This study investigated whether biochemical changes in the serum from BD patients could modulate the phenotype of cultured macrophages. Methods Eighteen subjects with BD and five healthy individuals were included in this study. The human monocyte cell line U-937 was activated with phorbol 12-myristate 13-acetate (PMA) and polarization was induced with RPMI-1640 media supplemented with 10% serum from each patient for 24 hours. Gene expression of selected M1 and M2 markers was assessed by quantitative PCR. Results Macrophages exposed to serum of manic and depressive BD patients displayed an increase of interleukin-1β (6.40±3.47 and 9.04±5.84 vs. 0.23±0.11; p<0.05) and tumor necrosis factor-α (2.23±0.91 and 2.03±0.45 vs. 0.62±0.24; p=0.002 and p=0.004, respectively) compared to euthymic group (there was no difference between euthymic and controls). In parallel, U-937 macrophages treated with serum of patients in acute episode displayed a down-regulation of CXCL9 (0.29±0.20 vs. 1.86±1.61; p=0.006) and CXCL10 expression (0.36±0.15 and 0.86±0.24 vs. 1.83±0.88; p<0.000 and p=0.04) compared to the euthymia group. Conclusion Our results are consistent with previous studies showing that changes in peripheral blood markers could modulate M1/M2 polarization in BD. The evidence of macrophages as source of inflammatory cytokines might be helpful to unravel how the mononuclear phagocyte system is involved in the etiology of BD.

IntroductionEvidence has shown that some patients with bipolar disorder have a relatively accurate sense of their cognitive abilities, whereas others may overreported or underreported cognitive difficulties, which causes a discrepancy in this measures.ObjectivesTo investigate concordance and discrepancy between subjective and objective cognitive measures, as well as to identify factors that could influence this discrepancy.MethodsPatients who met DSM IV-TR criteria for bipolar disorder in partial or full remission (HDRS-17 score ≤ 12; YMRS score ≤ 7) were recruited from outpatient clinic at Barcelona and Porto Alegre. Objective cognitive assessment was performed by the Letter-Number Sequencing (LNS-WAIS III). Cognitive Complaints in Bipolar Disorder Rating Scale (COBRA) was used as a subjective cognitive measure.ResultsWere included 179 patients. We found a concordance between COBRA and LNS in 62 cases, and discrepancy in 117 cases (Fig. 1). The incongruent group (COBRA–and LNS + ) have less years of study (8.10 ± 4.01) than the incongruent group (COBRA+ and LNS–) (13.44 ± 4.05, P = 0.001), and than congruent group (COBRA–and NLS–) (13.75 ± 4.04, P = 0.003). Finally, the congruent group (COBRA+ and LNS + ) was the group with higher functioning impairment.ConclusionsA few number of false-negative cases were detected, suggesting that COBRA can be used as a screening instrument. A special attention should be provided for subjects with a few years of study, because possibly these subjects presents more difficulty in express its cognitive difficulties.Disclosure of interestThe authors have not supplied their declaration of competing interest.

OBJECTIVE:The interaction of single nucleotide polymorphisms with both distal and proximal environmental factors across the extended psychosis phenotype is understudied. This study examined (i) the interaction of relevant SNPs with both early-life adversity and proximal (momentary) stress on psychotic experiences (PEs) in an extended psychosis sample; and (ii) differences between early-psychosis and non-clinical groups for these interactions.METHODS:Two hundred and forty-two non-clinical and 96 early-psychosis participants were prompted randomly eight times daily for 1 week to complete assessments of current experiences, including PEs and stress. Participants also reported on childhood trauma and were genotyped for 10 SNPs on COMT, RGS4, BDNF, FKBP5, and OXTR genes.RESULTS:Unlike genetic variants, distal and proximal stressors were associated with PEs in both samples and were more strongly associated with PEs in the early-psychosis than in the non-clinical group. The RGS4 TA and FKBP5 CATT haplotypes interacted with distal stress, whereas the A allele of OXTR (rs2254298) interacted with proximal stress, increasing momentary levels of PEs in the early-psychosis group. No interactions emerged with COMT or BDNF variants.CONCLUSION:Individual differences in relevant stress-regulation systems interact with both distal and proximal psychosocial stressors in shaping the daily-life manifestation of PEs across the psychosis continuum.

Data describing bipolar disorder in older adults people are scarce, particularly with regard to functional status. This observational, comparative study assessed psychosocial functioning in 33 euthymic older adults with bipolar disorder compared with 30 healthy controls. In addition, we evaluated the association between clinical variables and poor functioning in the patient group. The mean age of the group was 68.70 years. Patients with bipolar disorder experienced poorer psychosocial functioning (19.15 ± 11.36) than healthy controls (5.17 ± 3.72; p = 0.0001), as assessed using the Functioning Assessment Short Test. Significant differences between the groups were found for specific domains of functioning: autonomy, occupational functioning, cognitive functioning, financial issues, and interpersonal relationships (p = 0.0001, respectively). The largest variation was observed in overall functioning (Cohen's d = 0.63). The number of previous hospitalizations was strongly associated with poor overall functioning (F = 7.217, p = 0.002). Older patients with bipolar disorder had a greater functional impairment than the healthy control group. Implementation of novel rehabilitation models is critical to help patients manage their illness.

IntroductionFamily psycho-education is an essential part of the treatment for people with severe mental illness (SMI), however this relevant intervention is underutilized. Shortened variations of family psycho-education have been described in attempts to make it more attractive, efficient, and feasible.Objectives/aimsConsidering the lack of manualized intervention for families in Brazil, our study comes up with a proposal to implement and to evaluate the feasibility of brief family psycho-education program (BFPP) during inpatient psychiatric treatment.MethodsAn extensive review using a combination of the words: “family psychoeducation”; “severe mental illness”; “schizophrenia”; “bipolar disorder” was conducted in PubMed/Medline with the aim to select reports of multifamily group psycho-educational programs. Studies involving adults with severe mental illness published until March 2016 were included.ResultsAfter the review of literature and meeting with experts in SMI, the BFPP was developed collaboratively by bipolar disorders’ team at Hospital de Clínicas de Porto Alegre (HCPA). The standard BFPP consists of four sessions: (1) causes, symptoms, course, prognosis and stigma of severe mental disorder; (2) treatment; (3) community resources, communication skills and importance of healthy and regular habits; and (4) problem-solving strategies: preventing relapses and establishing plans for crisis. Each session will occur weekly, lasting 90 min, with 8–12 caregivers. The patients did not attend the group.ConclusionWe purposed a standard, brief, cheap and simple intervention to apply. We believe that BFPP is highly suitable for caregivers of patients with SMI. We hope that this program demonstrates feasibility among participants and become a useful and effective intervention.Disclosure of interestThe authors have not supplied their declaration of competing interest.

OBJECTIVES:Depressive symptoms are associated with worse outcomes in patients with bipolar disorder (BD). However, scarce data are available regarding neurocognitive profiles across different areas of functioning among BD patients with moderate and severe depression. Our objective was to assess cognition and global functioning in a group of patients with bipolar depression.METHODS:Data were available for 100 patients with bipolar depression (78% female) and 70 controls (64% female) paired by age and education level. Cognitive function was assessed with a neuropsychological test battery. Functioning was assessed with the Functioning Assessment Short Test.RESULTS:In patients, severe depression was associated with poorer cognitive performance on measures of executive function. Patients with severe depression showed worse global functioning than those with moderate depression (z = 2.54, p = 0.011). In patients with severe depression, lower global functioning was associated with lower scores in working memory (r = -0.200, p = 0.010), and executive function (r = -0.210, p = 0.007; and r = 0.293, p < 0.001).CONCLUSION:Our findings suggest cognitive impairment and global functioning impairment are associated with the severity of depressive symptoms in bipolar depression. Intensive treatment of depressive symptoms in patients with BD is crucial to improve cognitive functioning and, consequently, functional outcomes.

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. (C) 2015 Elsevier Masson SAS. All rights reserved.

Introduction:Recent studies have suggested that functional impairment in bipolar disorder may be strongly associated with residual depressive symptoms. However, there is a notable disparity between functional recovery and symptomatic recovery. This study was carried out to investigate clinical factors as potential predictors on functional impairment in a well defined euthymic bipolar sample.Methods:Seventy-one patients were recruited from the Bipolar Disorder Program at the Clinic Hospital of Barcelona. A Structured Clinical Interview for DSM-IV-TR, HAM-D and YMRS were used to diagnostic assessment and euthymia criteria. The Functioning Assessment Short Test (FAST) was employed to assess functional impairment. The FAST is a reliable and valid, interview-administered scale, rapid and easy to apply (3-6 min). It consists of 24 items which allow to assess six specific areas of functioning such as autonomy, occupational functioning, cognitive functioning, financial issues, interpersonal relationships, and leisure time.Results:The sample comprised 36 (51%) men, aged 48±13.56 years. Several clinical variables were associated with poor functioning on a linear regression model, such as age, depressive symptoms, number of previous mixed episodes and number of previous hospitalizations. This model explained 44% of the variance (F=12.54, df=58, p< 0.001).Discussion:In this study, specific clinical and socio-demographic characteristics were identified as predictors of functional impairment in remitted bipolar patients. Poor functioning was identified in patients with older age and more severe illness course.

One of the main lines of our group focuses On the research Of genetic and biological risk factors involved in functional psychosis (schizophrenia and bipolar disorder). Our studies are based on case-control, family and twin designs and are conducted in close collaboration with clinical and basic research groups from other Spanish and European Institutions. Recent results coming from the molecular genetics analyses have been focused on: i) the identification of genetic variability on chromosome 1q in relation to the syndromal definition of functional psychoses, ii) the identification of the interleukin-1 cluster, on chromosome 2q13, as a shared genetic risk factor for both schizophrenia and bipolar disorder, iii) the relationship between this genomic area and functional and morphological brain changes observed by neuroimaging techniques in both disorders, iv) the identification of CNVs related to the risk for psychoses and v) the role of the dysbindin gene in neurocognitive profiles and premorbid adjustment in early onset psychoses. Our results from the studies based on prenatal markers of brain instability have contributed to the identification of three congenital dermatoglyphic risk factors in schizophrenia including low ab-ridge count, presence of ridge dissociations and presence of abnormal palmar flexion creases. Gene-environmental interactions have also been explored in schizophrenia and healthy relatives involving the Val158Met polymorphism in COMT gene and cannabis used these studies have provided evidence of synergism between the Val allele and exposure to cannabis in the causation of psychosis. New projects based oil epigenetics are currently conducted ill our group ill Order to understand the genetic complexity of functional psychoses.

The Reeler heterozygous mice (reln+/−) are haplodeficient in the gene (reln) encoding for the reelin glycoprotein (RELN) and display reductions in brain/peripheral RELN similar to autistic or schizophrenic patients. Cytoarchitectonic alterations of the reln+/− brain may be subtle, and are difficult to demonstrate by current histological approaches. We analyzed the number and topological organization of the Purkinje neurons (PNs) in five vermal lobules – central (II–III), culmen (IV–V), tuber (VIIb), uvula (IX), and nodulus (X) – that process different types of afferent functional inputs in reln+/+ and reln+/− adult mice (P60) of both sexes (n = 24). Animals were crossed with L7GFP mice so that the GFP-tagged PNs could be directly identified in cryosections. Digital images from these sections were processed with different open source software for quantitative topological and statistical analyses. Diversity indices calculated were: maximum caliper, density, area of soma, dispersion along the XZ axis, and dispersion along the YZ axis. We demonstrate: i. reduction in density of PNs in reln+/− males (14.37%) and reln+/− females (17.73%) compared to reln+/+ males; ii. that reln+/− males have larger PNs than other genotypes, and females (irrespective of the reln genetic background) have smaller PNs than reln+/+ males; iii. PNs are more chaotically arranged along the YZ axis in reln+/− males than in reln+/+ males and, except in central lobulus, reln+/− females. Therefore, image processing and statistics reveal previously unforeseen gender and genotype-related structural differences in cerebellum that may be clues for the definition of novel biomarkers in human psychiatric disorders.

Objective: A functional polymorphism in the catechol‐o‐methyltransferase gene (COMT Val158Met) may moderate the psychosis‐inducing effects of cannabis. In order to extend this finding to dynamic effects in the flow of daily life, a momentary assessment study of psychotic symptoms in response to cannabis use was conducted.Method: The experience sampling technique was used to collect data on cannabis use and occurrence of symptoms in daily life in patients with a psychotic disorder (n = 31) and healthy controls (n = 25).Results: Carriers of the COMT Val158Met Val allele, but not subjects with the Met/Met genotype, showed an increase in hallucinations after cannabis exposure, conditional on prior evidence of psychometric psychosis liability.Conclusion: The findings confirm that in people with psychometric evidence of psychosis liability, COMT Val158Met genotype moderates the association between cannabis and psychotic phenomena in the flow of daily life.

Gene-environment interactions involving the catechol-O-methyltransferase Val(158)Met polymorphism (COMT(Val158Met)) have been implicated in the causation of psychosis. Evidence from general population studies suggests that Met/Met subjects are sensitive to stress, a trait associated with psychosis. We hypothesized that the Met allele would moderate the effects of stress on negative affect (NA) in controls, and on NA and psychosis in patients with a psychotic disorder. Thirty-one patients with a psychotic disorder and comorbid cannabis misuse and 25 healthy cannabis users were studied with the experience sampling method (ESM), a structured diary technique assessing current context and emotional and psychotic experiences in daily life. A significant interaction between COMT(Val158Met) genotype and ESM stress in the model of NA was found for patients (interaction chi(2) = 7.4, P = 0.02), but not for controls (interaction chi(2) = 3.8, P = 0.15). In the model of ESM psychosis, a significant interaction between COMT(Val158Met) genotype and ESM stress was also apparent (interaction chi(2) = 11.6, P < 0.01), with Met/Met patients showing the largest increase in psychotic experiences as well as NA in reaction to ESM stress. The findings suggest that the COMT(Val158Met) polymorphism moderates affective and psychotic responses to stress in patients with psychosis, providing evidence for gene-environment interaction mechanisms in the formation of psychotic symptoms.