Neurocognition and brain functional connectivity in a non-clinical population-based sample with psychotic experiences.

We characterized the neurocognitive profile of communed-based individuals and unaffected siblings of patients with psychosis from Brazil reporting psychotic experiences (PEs). We also analyzed associations between PEs and the intra and inter-functional connectivity (FC) in the Default Mode Network (DMN), the Fronto-Parietal Network (FPN) and the Salience Network (SN) measured by functional magnetic resonance imaging. The combined sample of communed-based individuals and unaffected siblings of patients with psychosis comprised 417 (neurocognition) and 85 (FC) volunteers who were divided as having low (<75th percentile) and high (≥75th percentile) PEs (positive, negative, and depressive dimensions) assessed by the Community Assessment of Psychic Experiences. The neurocognitive profile and the estimated current brief intellectual quotient (IQ) were assessed using the digit symbol (processing speed), arithmetic (working memory), block design (visual learning) and information (verbal learning) subtests of Wechsler Adult Intelligence Scale-third edition. Logistic regression models were performed for neurocognitive analysis. For neuroimaging, we used the CONN toolbox to assess FC between the specified regions, and ROI-to-ROI analysis. In the combined sample, high PEs (all dimensions) were related to lower processing speed performance. High negative PEs were related to poor visual learning performance and lower IQ, while high depressive PEs were associated with poor working memory performance. Those with high negative PEs presented FPN hypoconnectivity between the right and left lateral prefrontal cortex. There were no associations between PEs and the DMN and SN FC. Brazilian individuals with high PEs showed neurocognitive impairments like those living in wealthier countries. Hypoconnectivity in the FPN in a community sample with high PEs is coherent with the hypothesis of functional dysconnectivity in schizophrenia.

Transdiagnostic dimensions of symptoms and experiences associated with immune proteins in the continuity of psychosis.

BACKGROUND: There is limited evidence as to whether the immune protein profile is associated with a particular symptomatology pattern across the psychosis continuum. METHODS: We estimated two bifactor models of general and specific dimensions of psychotic experiences in unaffected siblings of patients (n = 52) and community controls (n = 200), and of psychotic symptoms in first-episode psychosis (FEP) patients (n = 110). We evaluated associations between these transdiagnostic dimensions and trait (TNF-α, IFN-γ), state (IL-6, IL-1ß), and regulatory (TGF-ß, IL-10, IL-4) cytokines. We explored whether schizophrenia genetic liability (schizophrenia polygenic risk score; SZ-PRS) modified the associations. RESULTS: High levels of trait marker IFN-γ were associated with the severity of general psychosis dimension in the unaffected siblings and community controls, expanding to the depressive dimension in siblings and to the manic dimension in FEP. High TNF-α levels were associated with more positive psychotic experiences in unaffected siblings and manic symptoms in FEP. Low levels of state markers IL-6 and IL-1ß were observed in unaffected siblings presenting more depressive experiences. Still, high levels of IL-6 and IL-1ß were associated with the severity of the depressive and negative symptom dimensions at FEP. The severity of transdiagnostic dimension scores across the three groups was associated with lower regulatory cytokines. Exploratory analysis suggested that a high SZ-PRS contributed mostly to associations with psychotic dimensions. CONCLUSIONS: IFN-γ mapped onto the multidimensional expression of psychosis, reinforcing the trait concept. State markers IL-6 and IL-1ß may fluctuate along the spectrum. Dysfunction in the regulatory arm may disinhibit the inflammatory system. Associations with psychotic dimensions may be more prone to SZ-PRS susceptibility.

Lifetime cannabis use and childhood trauma associated with CNR1 genetic variants increase the risk of psychosis: findings from the STREAM study.

OBJECTIVES: Gene-environment interactions increase the risk of psychosis. The objective of this study was to investigate gene-gene and gene-environment interactions in psychosis, including single nucleotide variants (SNVs) of dopamine-2 receptor (D2R), N-methyl-d-aspartate receptor (NMDAR), and cannabinoid receptor type 1 (CB1R), lifetime cannabis use, and childhood trauma. METHODS: Twenty-three SNVs of genes encoding D2R (DRD2: rs1799978, rs7131056, rs6275), NMDAR (GRIN1: rs4880213, rs11146020; GRIN2A: rs1420040, rs11866328; GRIN2B: rs890, rs2098469, rs7298664), and CB1R (CNR1: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898) were genotyped in 143 first-episode psychosis patients (FEPp) and 286 community-based controls by Illumina HumanCoreExome-24 BeadChip. Gene-gene and gene-environment associations were assessed using nonparametric Multifactor Dimensionality Reduction software. RESULTS: Single-locus analyses among the 23 SNVs for psychosis and gene-gene interactions were not significant (p > 0.05 for all comparisons); however, both environmental risk factors showed an association with psychosis (p < 0.001). Moreover, gene-environment interactions were significant for an SNV in CNR1 and cannabis use. The best-performing model was the combination of CNR1 rs12720071 and lifetime cannabis use (p < 0.001), suggesting an increased risk of psychosis. CONCLUSION: Our study supports the hypothesis of gene-environment interactions for psychosis involving T-allele carriers of CNR1 SNVs, childhood trauma, and cannabis use.

Lifetime cannabis use and childhood trauma increase risk of psychosis in carriers of CNR1 genetic variants: findings from the STREAM study

Objectives: Gene-environment interactions increase the risk of psychosis. The objective of this study was to investigate gene-gene and gene-environment interactions in psychosis, including single nucleotide variants (SNVs) of dopamine-2 receptor (D2R), N-methyl-d-aspartate receptor (NMDAR), and cannabinoid receptor type 1 (CB1R), lifetime cannabis use, and childhood trauma. Methods: Twenty-three SNVs of genes encoding D2R (DRD2: rs1799978, rs7131056, rs6275), NMDAR (GRIN1: rs4880213, rs11146020; GRIN2A: rs1420040, rs11866328; GRIN2B: rs890, rs2098469, rs7298664), and CB1R (CNR1: rs806380, rs806379, rs1049353, rs6454674, rs1535255, rs2023239, rs12720071, rs6928499, rs806374, rs7766029, rs806378, rs10485170, rs9450898) were genotyped in 143 first-episode psychosis patients (FEPp) and 286 community-based controls by Illumina HumanCoreExome-24 BeadChip. Gene-gene and gene-environment associations were assessed using nonparametric Multifactor Dimensionality Reduction software. Results: Single-locus analyses among the 23 SNVs for psychosis and gene-gene interactions were not significant (p > 0.05 for all comparisons); however, both environmental risk factors showed an association with psychosis (p < 0.001). Moreover, gene-environment interactions were significant for an SNV in CNR1 and cannabis use. The best-performing model was the combination of CNR1 rs12720071 and lifetime cannabis use (p < 0.001), suggesting an increased risk of psychosis. Conclusion: Our study supports the hypothesis of gene-environment interactions for psychosis involving T-allele carriers of CNR1 SNVs, childhood trauma, and cannabis use.

Increased blood neutrophil extracellular traps (NETs) associated with early life stress: translational findings in recent-onset schizophrenia and rodent model.

Higher levels of interleukin (IL)-6 and elevated neutrophil counts are consistently reported in the blood of patients with schizophrenia. Stressors during childhood and/or adolescence are major socioenvironmental risk factors for schizophrenia and may contribute to immune dysregulation. Previous studies using blood cytokines to stratify patients with schizophrenia suggest that only a subset presents a low-grade inflammatory state. However, these studies have not addressed whether environmental factors such as childhood maltreatment contributed to identifying inflammatory clusters. Moreover, a neutrophil-related mechanism (Neutrophil Extracellular Traps; NETs) central to both the initiation and chronicity of autoimmune and inflammatory diseases has never been investigated in psychiatry. Elevated NETs in schizophrenia may predispose patients to inflammatory and autoimmune diseases resulting in reduced life expectancy. We, therefore, investigated NETs as a novel mechanism and biological target in early schizophrenia and their role together with IL-6 and childhood maltreatment in identifying cluster subgroups. We found increased NETs in the plasma of patients with early schizophrenia (n = 78) compared to both their unaffected siblings (n = 25) and community controls (n = 78), irrespective of sex, body mass index, psychoactive drug use, or tobacco smoking. Increased NETs in patients were unrelated to antipsychotic treatment, which was further tested in vitro using fresh neutrophils. By applying unsupervised two-step clustering analysis, we integrated values of NETs, IL-6, and childhood maltreatment scores. We identified two main clusters; childhood maltreatment scores and NETs were the most important variables contributing to cluster separation (high-CL1 and low-CL2), while IL-6 was the least contributor. Patients allocated in the high-CL1 (61.5%) had significantly higher childhood maltreatment scores, NETs, and IL-6 levels than the remaining groups (patients low-CL2, siblings, and controls high-CL1 and low-CL2). We complemented these findings with a rat model based on stress exposure during adolescence that results in several schizophrenia-like changes in adulthood. We found that adolescent stressed rats had higher NETs and IL-6 levels in serum compared to non-stressed rats with a tendency to produce more NETs from the bone marrow. Altogether, this study brings a novel cellular-based mechanism in schizophrenia that, combined with early-stress, could be useful to identify subgroups for more personalised treatments.

Early Schizophrenia and Bipolar Disorder Patients Display Reduced Neural Prepulse Inhibition.

BACKGROUND: Altered sensorimotor gating has been demonstrated by Prepulse Inhibition (PPI) tests in patients with psychosis. Recent advances in signal processing methods allow assessment of neural PPI through electroencephalogram (EEG) recording during acoustic startle response measures (classic muscular PPI). Simultaneous measurements of muscular (eye-blink) and neural gating phenomena during PPI test may help to better understand sensorial processing dysfunctions in psychosis. In this study, we aimed to assess simultaneously muscular and neural PPI in early bipolar disorder and schizophrenia patients. METHOD: Participants were recruited from a population-based case-control study of first episode psychosis. PPI was measured using electromyography (EMG) and EEG in pulse alone and prepulse + pulse with intervals of 30, 60, and 120 ms in early bipolar disorder (n = 18) and schizophrenia (n = 11) patients. As control group, 15 socio-economically matched healthy subjects were recruited. All subjects were evaluated with Rating Scale, Hamilton Rating Scale for Depression, and Young Mania Rating Scale questionnaires at recruitment and just before PPI test. Wilcoxon ranked sum tests were used to compare PPI test results between groups. RESULTS: In comparison to healthy participants, neural PPI was significantly reduced in PPI 30 and PPI60 among bipolar and schizophrenia patients, while muscular PPI was reduced in PPI60 and PPI120 intervals only among patients with schizophrenia. CONCLUSION: The combination of muscular and neural PPI evaluations suggested distinct impairment patterns among schizophrenia and bipolar disorder patients. Simultaneous recording may contribute with novel information in sensory gating investigations.

The relationship of childhood trauma and DNA methylation of NMDA receptor genes in first-episode schizophrenia.

Aim: We investigated GRIN1, GRIN2A, GRIN2B and LINE-1 DNA methylation in first-episode schizophrenia patients, their nonaffected siblings and age- and sex-matched controls testing for associations between DNA methylation and exposition to childhood trauma. Materials & methods: The Childhood Trauma Questionnaire evaluated the history of childhood trauma. Genomic DNA was bisulfite converted and pyrosequencing was employed to quantify DNA methylation. Results:GRIN2A, GRIN2B and LINE-1 DNA methylation was not associated with childhood trauma in patients, siblings and controls. Siblings with childhood trauma had hypermethylation at CpG1 of GRIN1 compared with siblings without trauma. Conclusion: Childhood trauma may influence GRIN1 methylation in subjects with liability to psychosis, but not in frank schizophrenia or controls.

Lay abstract Schizophrenia results from a combination of genetic and environmental influences. We investigated how some changes in genes can be silenced by a process named DNA methylation and may be linked to schizophrenia. For this reason, we hypothesized that childhood trauma, an environmental risk factor, would be associated with DNA methylation in schizophrenia patients compared with their unaffected siblings and controls. Our research has shown that altered blood DNA methylation of one candidate gene for psychiatric disorders may be associated with childhood trauma in the unaffected siblings of schizophrenia patients, but not in frank schizophrenia or controls. We believe that this gene plays an important role in helping identify vulnerable as well as resilient individuals to schizophrenia disorder.

Plasma prevalence of anti-N-methyl-d-aspartate receptor IgG antibodies in early stages of psychosis.

We investigated the feasibility of including plasma anti-NMDAR antibody screening in the assessment of first-episode psychosis patients in an early intervention programme in the Southern hemisphere. Anti-NMDAR IgG antibodies were assessed by ELISA in 166 patients (64.0% men), 166 matched population-based controls and 76 patients' siblings (30.3% men). Fisher's exact test and ANOVA were performed. Positive anti-NMDAR antibody patients were more often observed in bipolar disorder (10.0%) than schizophrenia (2.4%) or psychotic depression (3.1%), although no significant differences were observed. Our results are not conclusive regarding the inclusion of plasma anti-NMDAR IgG antibodies in differential diagnostic protocols for psychosis.

The independent and combined effects of cannabis use and systemic inflammation during the early stages of psychosis: exploring the two-hit hypothesis.

BACKGROUND: Cannabis consumption is a modifiable risk factor associated with psychosis, but not all cannabis users develop psychosis. Animal studies suggest that an antecedent active immune system interacts with subsequent cannabis exposure and moderates the cannabis-psychosis association, supporting the two-hit hypothesis. The clinical investigations are few, and it is unclear if the immune system is a biological candidate moderating the cannabis-psychosis association or whether cannabis increases inflammation, which in turn, augments psychosis likelihood. METHODS: We explored the mediating and moderating role of blood inflammation using PROCESS macro. We used data from a cross-sectional study, including 153 first-episode psychosis patients and 256 community-based controls. Participants answered the Cannabis Experience Questionnaire (cannabis frequency, age of onset, and duration), and plasma cytokines were measured [interleukin (IL)-1ß, IL-6, IL-4, IL-10, tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ), transforming growth factor-ß (TGF-ß); multiplex]. We computed an inflammatory composite score (ICS) to represent the systemic inflammatory state. Confounders included sex, age, ethnicity, educational level, body mass index, tobacco smoking, lifetime use of other drugs, and antipsychotic treatment. RESULTS: Mediation: Cannabis consumption was not associated with increased inflammation, thus not supporting a mediating effect of inflammation. Moderation: Daily use and age of onset <17 interacted significantly with the ICS to increase the odds of psychosis beyond their individual effects and were only associated with psychosis among those scoring medium-high in the ICS. CONCLUSIONS: Immune dysregulation might be part of the pathophysiology of psychosis, not explained by cannabis use or other confounders. We provide the first and initial evidence that immune dysregulation modifies the cannabis-psychosis association, in line with a two-hit hypothesis.

Family environment and depressive episode are associated with relapse after first-episode psychosis.

WHAT IS KNOWN ON THE SUBJECT?: Relapse rates are high among patients who have experienced first-episode psychosis (FEP). Psychotic relapses are associated with worse quality of life and poorer functionality of the FEP patient. The use of psychoactive substances, non-adherence to drug treatment, and high expressed emotion (EE) are notable predictors of relapse after the FEP. Although some studies have suggested that psychotic relapse may be associated with a family environment with high levels of emotional over-involvement (EOI), this finding is still inconsistent across different cultures. EE specific components must be evaluated and interpreted according to the context of cultural norms. There is a scarcity of studies on the role of depression in the occurrence of relapses after the FEP, and the results remain uncertain. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: This study explored the predictors of psychotic relapses in Brazilian patients who experienced FEP. Our results indicate that 29.2% of the patients relapsed after the FEP. Patients diagnosed with depression and high-EOI in the family environment were predictors of psychotic relapses in this population. This study expands knowledge about the cultural specificity of EOI and the role of depression in psychotic relapse. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Nursing professionals must consider the implications of the family environment and depression in the course of psychosis. Family interventions and the appropriate treatment of depression are important for improving the prognosis of FEP patients. ABSTRACT: Introduction Psychotic relapse may be associated with relatives' high emotional over-involvement (EOI) and with a diagnosis of major depressive episode (MDE) among first-episode psychosis (FEP) patients, but the results are still inconsistent across different cultures. Aim Evaluate the predictors of relapse in FEP patients. Method Prospective cohort study with 6-month follow-up conducted with 65 dyads of patients and relatives from an early intervention unit in Brazil. At the baseline interview, relatives answered to a sociodemographic data form and to the Family Questionnaire. Patients provided sociodemographic and clinical data and answered the Measurement of Treatment Adherence; the Alcohol, Smoking and Substance Involvement Screening Test; the Severity of Dependence Scale to assess cannabis dependence, and the MDE module of the Mini-International Neuropsychiatric Interview. Psychotic relapses were evaluated using items from the Brief Psychiatric Rating Scale. The data were analysed using multiple logistic regression. Results 29.2% of the patients presented at least one psychotic relapse. High-EOI and MDE were predictors of psychotic relapses. Discussion Our findings expand the knowledge about the cultural specificity of EOI and the role of depression in psychotic relapse. Implications for practice Family nursing interventions and the appropriate treatment of MDE must be considered in the care of FEP patients.

Early-life stress effects on BDNF DNA methylation in first-episode psychosis and in rats reared in isolation.

Stressful events during early-life are risk factors for psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is implicated in psychosis pathophysiology and deficits in BDNF mRNA in animal models of psychiatric disease are reported. DNA methylation can control gene expression and may be influenced by environmental factors such as early-life stress. We investigated BDNF methylation in first-episode psychosis (FEP) patients (n = 58), their unaffected siblings (n = 29) and community-based controls (n = 59), each of whom completed the Childhood Trauma Questionnaire (CTQ); BDNF methylation was also tested in male Wistar rats housed isolated or grouped from weaning. DNA was extracted from human blood and rat brain (prefrontal cortex and hippocampus), bisulphite-converted and the methylation of equivalent sequences within BDNF exon IV determined by pyrosequencing. BDNF methylation did not differ significantly between diagnostic groups; however, individuals who had experienced trauma presented higher levels of methylation. We found association between the mean BDNF methylation and total CTQ score in FEP, as well as between individual CpG sites and subtypes of trauma. No significant correlations were found for controls or siblings with child trauma. These results were independent of age, gender, body mass index, BDNF genotype or LINE-1, a measure of global methylation, which showed no significant association with trauma. Isolation rearing resulted in increased BDNF methylation in both brain regions compared to group-housed animals, a correlate of previously reported changes in gene expression. Our results suggest that childhood maltreatment may result in increased BDNF methylation, providing a mechanism underlying the association between early-life stress and psychosis.

Plasma amino acids profile in first-episode psychosis, unaffected siblings and community-based controls.

Investigations of plasma amino acids in early psychosis and their unaffected siblings are rare. We measured plasma amino acids involved in the co-activation of dopaminergic, GABAergic, glutamatergic, and serotoninergic neurotransmitters in first-episode psychosis (FEP) patients (n = 166), unaffected siblings (n = 76), and community-based controls (n = 166) included in a cross-sectional study. Plasma levels of glutamic acid (GLU), glutamine, glycine, proline (PRO), tryptophan (TRP), tyrosine, serine and GABA were quantified by gas-chromatography-mass spectrometry. We used the generalized linear model adjusted by sex, age, and body mass index for group comparison and paired t-test for FEP-Sibling pairs. FEP had reduced GABA plasma levels compared to siblings and controls (p < 0.05 for both). Siblings had lower GLU, Glx and PRO (p < 0.05 for all) but increased TRP compared to patients and controls (p < 0.05 for both). FEP patients with longer duration of pharmacological treatment and medicated only with antipsychotics had increased GLU compared to FEP with shorter periods, or with those treated with a combination of medications (p < 0.05 for both). Finally, FEP patients treated only with antipsychotics presented higher Glx compared to those with mixed medications (p = 0.026). Our study suggests that FEP have low a GABA plasma profile. Unaffected siblings may be a possible risk group for metabolic abnormalities.

Epigenetic-mediated N-methyl-D-aspartate receptor changes in the brain of isolated reared rats.

Aim: We investigated: Grin1, Grin2a, Grin2b DNA methylation; NR1 and NR2 mRNA/protein in the prefrontal cortex (PFC); and hippocampus of male Wistar rats exposed to isolation rearing. Materials & methods: Animals were kept isolated or grouped (n = 10/group) from weaning for 10 weeks. Tissues were dissected for RNA/DNA extraction and N-methyl-D-aspartate receptor subunits were analyzed using quantitative reverse transcription (RT)-PCR, ELISA and pyrosequencing. Results: Isolated-reared animals had: decreased mRNA in PFC for all markers, increased NR1 protein in hippocampus and hypermethylation of Grin1 in PFC and Grin2b in hippocampus, compared with grouped rats. Associations between mRNA/protein and DNA methylation were found for both brain areas. Conclusion: This study indicates that epigenetic DNA methylation may underlie N-methyl-D-aspartate receptor mRNA/protein expression alterations caused by isolation rearing.

Predictors of Expressed Emotion in First Episode Psychosis.

This article evaluated the predictors of EE and its components, EOI and CC, in relatives of first episode psychosis patients (FEP) in Brazil. Cross-sectional observational study conducted with 82 dyads of FEP patients and their relatives. Data collection instruments: sociodemographic and clinical data questionnaire, Family Questionnaire, Zarit Burden Interview and Morisky Medication Adherence Scale. Logistic and linear regression models were used. Our results indicate that patient's age, relative's sex, daily time spent together, and family burden were predictors of EE and its components. Our findings may be helpful in planning nursing interventions to reduce EE and prevent psychotic relapses.

Validation of the Portuguese version of the Community Assessment of Psychic Experiences and characterization of psychotic experiences in a Brazilian sample.

OBJECTIVE: We investigated: i) the reliability and validity of a Brazilian version of the Community Assessment of Psychic Experiences (CAPE), developed to detect and characterize psychotic experiences in the general population; and ii) the association between psychotic experiences, childhood adversity, and cannabis use in a population-based sample. METHODS: We performed factorial analyses and generalized linear models with CAPE scores as the dependent variable in a sample composed of 217 first-episode psychosis patients, 104 unaffected biological siblings, and 319 non-psychotic population-based participants. RESULTS: After removing seven items from its positive dimension and two items from its negative dimension, a 33-item Brazilian version of the CAPE showed acceptable adjustment indices (confirmatory fit index = 0.895; goodness of fit index = 0.822; parsimony goodness of fit index = 0.761; root mean square error of approximation [RMSEA] = 0.055, p [RMSEA ≤ 0.05] = 0.04) and internal consistency in all its dimensions (> 0.70). Childhood adversity was associated with higher scores in all three dimensions, as well as with total score. Lifetime cannabis use was associated with higher scores only in the positive dimension. CONCLUSION: The proposed Brazilian version of the CAPE corroborates the tridimensional approach for assessing psychosis-proneness, and the frequency and severity of psychotic manifestations are distributed as a spectrum in the general population.

Cytokine profile in first-episode psychosis, unaffected siblings and community-based controls: the effects of familial liability and childhood maltreatment.

BACKGROUND: Inflammation is a possible biological mechanism underlying the association between childhood maltreatment and psychosis. Previous investigations on this regard were mainly conducted on chronic schizophrenia and lacked control for confounders. We aim to investigate the role of familial liability, childhood maltreatment and recent stress in determining cytokine abnormalities at the onset of psychosis. METHODS: We recruited 114 first-episode psychosis (FEP) patients, 57 unaffected biological siblings of FEP patients, and 251 community-based controls. Plasma cytokines (IL-1ß, IL-6, TNF-α, IFN-γ, IL-4, IL-10 and TGF-ß) were measured and differences across the groups analysed after adjusting for potential confounders. RESULTS: FEP had a higher pro- and anti-inflammatory cytokine profile (IL-1ß, IL-6, TNF-α, IL-10 and TGF-ß), which was not observed in unaffected siblings. Siblings presented decreased IL-1ß when compared with patients and controls. Childhood maltreatment was associated with higher levels of TGF-ß in both patients and siblings when compared with controls. Physical childhood abuse was associated with increased levels of TGF-ß in FEP patients but with decreased levels in controls. Other childhood maltreatment subtypes or recent stressors did not affect cytokine levels in any of the groups. CONCLUSIONS: Normal or reduced cytokines in siblings represent possibly a protective factor and suggest that the identified inflammatory profile in FEP can be a real pathophysiological component of psychosis. Experience of childhood maltreatment may contribute as long-term immune priming for the TGF-ß pathway, and increased levels of this cytokine in both patients and siblings exposed to childhood maltreatment point to a possible biological candidate of familial risk for psychosis.

Effect of changes to the formal curriculum on medical students' motivation towards learning: a prospective cohort study.

BACKGROUND: One of the factors known to influence performance in the learning process is student motivation. In turn, students' motivation can be regulated by a large number of variables relating to the individual (such as sex, age and socioeconomic status) or to aspects of the academic life. OBJECTIVE: The primary aim of this study was to evaluate the influence of curriculum changes involving reduction in content overload and increased early exposure to clinical settings, on motivation towards learning among Year 1 medical students. Secondarily, the aim was to ascertain whether this influence on motivation remained stable until the undergraduate program ended (Year 6). DESIGN AND SETTING: Prospective study on two student cohorts at a Brazilian state-owned university. METHODS: Two consecutive student cohorts were assessed: one with a traditional curriculum (n = 87) and the other with a reformed curriculum (n = 63), at the same medical school. Participants in both cohorts gave responses on four scales in Years 1 and 6: the Academic Motivation Scale, containing subscales for autonomous and controlled motivation, and lack of motivation towards learning; Beck's Anxiety and Depression Inventories; Spielberger's State-Trait Anxiety Inventory; and the Social Adjustment Scale. In Year 6, 68% of the initial sample (66 students with the traditional curriculum and 36 with the reformed curriculum) was reassessed. RESULTS: No differences between Year 1 cohorts were found regarding demographic and social background, social adjustment, depression or anxiety. Students with the reformed curriculum scored significantly higher regarding autonomous and controlled motivation than those with the traditional curriculum. Comparison between Year 6 and Year 1 showed increases in controlled motivation only for the traditional curriculum cohort. CONCLUSION: Curriculum changes were associated with increased motivation towards learning in Year 1, which persisted until Year 6.

Urbanicity and risk of first-episode psychosis: incidence study in Brazil.

We estimated the incidence of first-episode psychosis over a 3-year period in a Brazilian catchment area comprising the region's main city, Ribeirão Preto (1 425 306 persons-years at risk), and 25 other municipalities with a total of 1 646 556 persons-years at risk. The incidence rates were estimated and adjusted by gender and age, using the direct standardisation method to the world population as reference. The incidence of psychosis was higher in the younger groups, men, and among Black and minority ethnic Brazilians. Psychosis incidence was lower in Ribeirão Preto (16.69/100 000 person-years at risk; 95% CI 15.68-17.70) compared with the average incidence in the remaining municipalities (21.25/100 000 person-years at risk; 95% CI 20.20-22.31), which have lower population density, suggesting a distinct role for urbanicity in the incidence of first-episode psychosis in low- and middle-income countries.