Risk Factor For Psychosis Research Articles

Cannabinoid receptor CNR1 expression and DNA methylation in human prefrontal cortex, hippocampus and caudate in brain development and schizophrenia

Beyond being one the most widely used psychoactive drugs in the world, cannabis has been identified as an environmental risk factor for psychosis. Though the relationship between cannabis use and psychiatric disorders remains controversial, consistent association between early adolescent cannabis use and the subsequent risk of psychosis suggested adolescence may be a particularly vulnerable period. Previous findings on gene by environment interactions indicated that cannabis use may only increase the risk for psychosis in the subjects who have a specific genetic vulnerability. The type 1 cannabinoid receptor (CB1), encoded by the CNR1 gene, is a key component of the endocannabinoid system. As the primary endocannabinoid receptor in the brain, CB1 is the main molecular target of the endocannabinoid ligand, as well as tetrahydrocannabinol (THC), the principal psychoactive ingredient of cannabis. In this study, we have examined mRNA expression and DNA methylation of CNR1 in human prefrontal cortex (PFC), hippocampus, and caudate samples. The expression of CNR1 is higher in fetal PFC and hippocampus, then drops down dramatically after birth. The lifespan trajectory of CNR1 expression in the DLPFC differentially correlated with age by allelic variation at rs4680, a functional polymorphism in the COMT gene. Compared with COMT methionine158 carriers, Caucasian carriers of the COMT valine158 allele have a stronger negative correlation between the expression of CNR1 in DLPFC and age. In contrast, the methylation level of cg02498983, which is negatively correlated with the expression of CNR1 in PFC, showed the strongest positive correlation with age in PFC of Caucasian carriers of COMT valine158. Additionally, we have observed decreased mRNA expression of CNR1 in the DLPFC of patients with schizophrenia. Further analysis revealed a positive eQTL SNP, rs806368, which predicted the expression of a novel transcript of CNR1 in human DLPFC, hippocampus and caudate. This SNP has been associated with addiction and other psychiatric disorders. THC or ethanol are each significantly associated with dysregulated expression of CNR1 in the PFC of patients with affective disorder, and the expression of CNR1 is significantly upregulated in the PFC of schizophrenia patients who completed suicide. Our results support previous studies that have implicated the endocannabinoid system in the pathology of schizophrenia and provided additional insight into the mechanism of increasing risk for schizophrenia in the adolescent cannabis users.

M22. IGG ANTIBODIES TO TOXOPLASMA GONDII ARE ASSOCIATED WITH INCREASED LONG-TERM RISK FOR PSYCHOSIS IN INDIVIDUALS AT ULTRA-HIGH RISK FOR PSYCHOSIS

BackgroundThe prevalence of antibodies to Toxoplasma gondii, a ubiquitous parasitic protozoan causing the infectious disease toxoplasmosis, is increased in patients with psychotic disorders compared to the general population. We have previously shown that antibody titers for T.gondii correlate with the severity of positive symptoms in young people at ultra-high risk (UHR) for psychosis, suggesting that infection with T. gondii may be relevant to the manifestation of psychosis. However, it is unclear if T. gondii antibodies represent a risk factor for psychosis onset or non-psychotic outcome in UHR individuals. The aim of the present study was to examine whether seropositivity for T.gondii is associated with transition to psychosis and other outcomes in young people at UHR for psychosis.MethodsThe study sample consisted of 96 individuals at UHR for psychosis who were referred to the Personal Assistance and Crisis Evaluation (PACE) clinic in Melbourne, Australia, between 2001 and 2004, consented to optional blood tests for infectious agents and were followed up for up to 10 years after baseline (median (interquartile range) duration of follow-up: 7.15 (3.14 – 7.72) years). Serum IgG antibodies to six viral and parasitic pathogens (Toxoplasma gondii, Herpes Simplex Virus Type 1 and 2, Cytomegalovirus, Epstein Barr Virus, Varicella-Zoster Virus) were measured at baseline. Outcome measures included transition to psychosis, general psychiatric symptomatology and positive psychotic symptoms (BPRS), negative symptoms (SANS), depressive symptoms (HAM-D), anxiety symptoms (HAM-A) and functioning (SOFAS and GAF). Cox proportional hazards regression and linear regression models were used to examine the associations of seropositivity and antibody titers at baseline and transition to psychosis and other outcomes at follow-up.ResultsA total of 17 individuals (17.7%) were seropositive for Toxoplasma gondii at baseline. The rate of transition to psychosis was higher among seropositive (35.7%) compared to seronegative participants (14.6%), although this was not statistically significant (p=0.101). Antibody titers (IgG) for Toxoplasma gondii were significantly higher at baseline in participants who later transitioned to psychosis (1.34 ± 1.36 vs. 0.79 ± 0.73, p=0.027). Seropositivity for T.gondii IgG at baseline significantly predicted transition to psychosis within the follow-up duration (hazard ratio [HR]=3.61, 95%CI 1.08 – 12.00, p=0.036). Toxoplasma IgG at baseline were significantly associated with higher BPRS scores at follow-up in participants who were seropositive at baseline (Beta=6.38, 95%CI 0.43 – 12.34, p=0.038). No significant associations were found between antibodies to other pathogens and outcome, or between antibodies to Toxoplasma gondii and any other outcomes.DiscussionOur findings suggest that the presence of IgG class antibodies for Toxoplasma gondii is associated with a higher risk for psychosis transition in individuals at UHR for psychosis, but not with risk for other long-term outcomes. These observations provide support for the hypothesis that infection with Toxoplasma gondii may be an environmental risk factor for psychosis and suggest that IgG antibodies for Toxoplasma gondii in individuals at UHR for psychosis have prognostic relevance.

O9.3. CANNABIS CONSUMPTION INCREASES RISK OF PSYCHOSIS IN A SUBGROUP OF PATIENTS WITH HIGH PERIPHERAL BLOOD INFLAMMATION

BackgroundAssociations between cannabis use and psychotic outcomes are consistently reported. Increased innate immune markers have also been suggested as risk factors for psychosis; nevertheless, no study has ever tested whether augmented blood inflammation could be a possible biological mechanism underlying the association between cannabis use and psychosis. We investigated: i) which patterns of peripheral blood cytokines (innate and adaptive immune markers) would be associated with the strongest effect on odds of psychosis; and ii) whether the contribution of cannabis use (lifetime use: yes/no; frequency of use: non-users, less than daily use; daily use) on risk of psychosis would vary between subgroups with low- or high-inflammation.MethodsThe Schizophrenia and Other Psychoses Translational Research: Environment and Molecular Biology (STREAM) is an epidemiological and case-sibling-control study, conducted in Ribeirão Preto catchment area (São Paulo, Brazil) between April 2012 and March 2015, which integrates the international multicentre consortium EU-GEI. We recruited 153 first-episode psychosis patients and 256 community-based controls aged between 16–64 years. Participants answered the Cannabis Experience Questionnaire and plasma cytokines (IL-1β, IL-6, TNF-α, IFN-γ, IL-4, IL-10, TGF-β) were measured by Multiplex. We firstly investigated which patterns of peripheral blood innate and adaptive immune markers would contribute to the strongest effect on the odds of psychosis. To do that, the sample was divided into quartiles according to cytokine’s percentile distribution (reference group: minimum value – 25th percentile; lower group: 25th – 50th percentile; middle group: 50th – 75th percentile; and upper group: 75th percentile – maximum value). We next investigated whether the effects of the different patterns of cannabis use (lifetime and frequency of use) on the risk of psychosis would differ between subgroups classified as low- or high-inflammatory, using the median (50th percentile) of each cytokine as the cut-off value. All the binary logistic regression analyses were correct for the effects of confounders (gender, age, ethnicity, years of education, body mass index, tobacco smoking, and recreational drugs).ResultsMore than 60% of the patients were classified as high-inflammatory, whereas in the control group, around the same percentage was classified as low-inflammatory. After adjusting for confounders, we observed a dose-response relationship between the percentile’s distribution of IL-10, IL-6, TNF-α, TGF-β and risk of psychosis, with participants classified in the upper percentile having the highest odds ratio when compared with the reference group. The adjusted odds ratio (adj ORs) and 95% CIs range for each cytokine were the following: IL-10 from 4.68 (2.02–10.85) to 11.86 (5.01–28.11), IL-6 from 3.74 (1.61–8.69) to 9.62 (4.15–22.31); TNF-α from 2.18 (1.01–4.73) to 6.88 (3.12–15.17); TGF-β from 2.17 (1.01–4.67) to 3.20 (1.50–6.80). Lifetime cannabis use only increased risk of psychosis in the high-inflammatory subgroup (adj ORs, 95% CIs: IL10: 4.66, 1.62–13.39; IL-6: 2.75, 1.05–7.21). Daily use increased the risk of psychosis even further, and only in the high-inflammatory but not in the low-inflammatory subgroup (adj OR, 95% CIs: IL-10: 14.09, 2.26–87.93; TNF-α: 6.16, 1.28–29.74; IL-6: 4.68, 1.08–20.36), with the exception of TGF-β, for which the effects were seen in the low-subgroup (adj OR, 95% CI: 5.23, 1.17–23.42).DiscussionThe existence of distinct inflammatory profiles indicates possible biological predisposition facilitating immune activation. This would translate into a higher vulnerability to the effects of cannabis use, especially daily use, on risk of psychosis.

S13. IMPACT OF POLYGENIC AND POLY-ENVIRONMENTAL RISK FACTORS ON A PSYCHOSIS RISK PHENOTYPE EXPLAINED THROUGH BRAIN STRUCTURE

BackgroundWhile single (genetic and environmental) risk factors for psychosis have been studied for their impact on brain structure and function, there is little understanding of how they interact to generate psychosis liability on the neural level. Direct associations between cumulative genetic risk scores and risk phenotypes are often weak, and analyses of G×E interactions are scarce. We developed and tested a multivariate model, in which the effects of cumulative environmental and genetic risk on a dimensional phenotype are mediated by brain structural variation.MethodsIn a data set of 440 non-clinical subjects, we tested a moderated mediation model with an interaction of an environmental (ERS) and a polygenic risk score (PRS) for schizophrenia, impacting on the subclinical psychosis spectrum phenotype schizotypy. We propose this effect to be mediated by grey matter volume variation, derived from voxel-based morphometry. In addition, cognitive function (CF) was considered as a potential moderator.ResultsFirstly, in a whole-brain analysis, we detected a significant interaction effect of PRS×ERS in a cluster (k=910, x/y/z=-4/-50/33, p=0.024 FWE cluster-level corrected) including the left precuneus (Pc, 64%) and posterior cingulate gyrus (pcG, 33%). Secondly, cluster values were extracted and entered into a multivariate moderated mediation model. This model was significant, showing that Pc/pcG volume mediated the impact of a PRS×ERS interaction on positive schizotypy (R2=10.91%, p=4.9×10–5). In predicting Pc/pcG variation (R2=51.69%), neither PRS (b=0.638, p=0.830) nor ERS had a main effect on grey matter variation, but their interaction was significant (b=-3.13, p=0.002): The intensity and direction of the PRS effect is moderated by the level of ERS, with a positive slope for low ERS (i.e., low environmental risk), and a negative slope for high ERS. In predicting positive schizotypy, the direct effects of PRS (b=6.116, p=0.477) and ERS (b=0.006, p=0.068) were not significant. However, we demonstrate an indirect effect through brain structural variation, showing a significant mediation (index=0.223, bootstrapped confidence interval 0.004–0.542). Cluster variation had a significant main effect on positive schizotypy (b=-0.277, p=0.049), but was modulated by the level of cognitive function, with a positive slope for low CF, and a negative slope for high CF, showing a second significant interaction (b=-0.070, p=0.027).DiscussionOur finding is the first to integrate polygenic and poly-environmental markers with MRI parameters to demonstrate that the interaction of these cumulated risk factors leads to the emergence of subclinical symptoms through changes in brain structure. Furthermore, our model confirms cognition as a protective factor, indicating that above-average levels of cognitive function can compensate for dysfunctional processes that arise from altered neurodevelopment. Such compensatory mechanisms are crucial for understanding resilience, explaining high (positive) symptom load in unaffected individuals. Conventional diathesis-stress models propose increased vulnerability specifically to adverse events – our model extends this to suggest an inverted effect for high PRS and low ERS subjects. Under favourable environmental conditions, an increased genetic load might paradoxically result in low psychopathology outcomes or gain of function, supporting the notion of genes associated with schizophrenia as “plasticity genes” rather than simple risk factors. In sum, the present study provides proof for a multivariate model predicting the impact of genetic and environmental risk on a psychosis risk phenotype, extendable to other clinical spectra.

M247. PAST AND ANTICIPATED HUMILIATION MAY CONTRIBUTE TO ANXIETY AND PRONENESS TO PSYCHOSIS EXPERIENCES IN A COMMUNITY SAMPLE

BackgroundChildhood adversity is a risk factor for psychosis. Bullying, abuse, neglect and family conflict can cause biological (e.g. stress hyper-reactivity) and psychological (e.g. negative beliefs about self and perceived threat from others) changes that may lead to psychopathology in adulthood. Past and anticipated humiliation is associated with proneness to persecutory ideation in non-clinical samples. However, whether this is associated with proneness to other positive psychosis symptoms is unclear. This study measured how humiliation is related to hallucination-like experiences (HLE) and intrusive thinking assessed via the Launay-Slade Hallucination Scale Extended and disorganisation assessed via the Schizotypal Personality Questionnaire-Brief Revised, and if increased anxiety mediates this relationship.MethodsThis cross-sectional study recruited a community sample of 92 adults (62% female; Mean [SD] age = 27.3 [10.8]) who completed measures of past/anticipated humiliation, risky family environment, family socioeconomic status, state anxiety and proneness to positive psychotic 1 2020 Congress of the Schizophrenia International Research Society symptoms. Serial mediation tested for direct and indirect relationships among study variables.ResultsWorse past and anticipated humiliation, risky family environments and state anxiety correlated with more severe intrusive thoughts, multisensory HLEs and disorganisation (r range 0.23–0.54). Serial mediation showed that of the historical factors, only past humiliation predicted anticipated humiliation (p < 0.001), which in turn was the only unique predictor of state anxiety (p = 0.004). The relationship then differed for proneness to different positive psychosis symptoms. Only state anxiety was a unique predictor of audio-visual HLEs (p = .03) and intrusive thoughts (p = .01), whereas both past humiliation and anxiety predicted disorganisation and multisensory HLEs (both p < .03).DiscussionAnxious anticipation about potential harm in interpersonal interactions, likely caused by cumulative past humiliation, may increase proneness to positive psychosis experiences through increased difficulty controlling negative emotions and the frequency and content of worrying thoughts and memories.

O10.1. MATERNAL PRENATAL C-REACTIVE PROTEIN, NEURODEVELOPMENT AND OTHER RISK FACTORS FOR PSYCHOSIS IN ADOLESCENT OFFSPRING IN THE NORTHERN FINLAND BIRTH COHORT 1986

BackgroundPrenatal infection is associated with brain structural and functional abnormalities, and may increase risk for psychosis through a direct effect on neurodevelopment. Proinflammatory immune response may be a common mechanism through which various infections exert their harmful effect, but studies of prenatal maternal inflammatory markers and offspring neurodevelopment are scarce. We examined the associations of maternal prenatal C-reactive protein (CRP) levels with psychosis risk factors in adolescent offspring including markers of neurodevelopment and cannabis use.MethodsThis study used a longitudinal birth cohort, the Northern Finland Birth Cohort 1986 (NFBC 1986), followed up to age 16 years (n=6,985/9,432, 76% follow-up). CRP was measured in maternal sera collected in pregnancy. In offspring, school performance was measured at age 7 and 16y; psychotic experiences and cannabis use was measured at age 16. Controlling for offspring sex, maternal education level, maternal body mass index during pregnancy, smoking during pregnancy and alcohol use during pregnancy using regression analysis, we tested associations of CRP with offspring measures. We also tested for mediation, specifically if adolescent cannabis use mediated the associations between maternal CRP and offspring psychotic experiences and school performance.ResultsBased on data from a minimum of 4,153 participants, after controlling for offspring sex, maternal education level, maternal body mass index during pregnancy, smoking during pregnancy and alcohol use during pregnancy, maternal CRP was associated with adolescent neurodevelopmental markers, including psychotic experiences (odds ratio=1.13, 95% CI=1.00–1.29) and academic performance at age 16 years (beta=0.063, SE=0.013, 95% CI=0.037–0.089). Maternal CRP was also associated with adolescent cannabis use (odds ratio=1.27, 95% CI=1.11–1.46). Cannabis use appeared to mediate a small amount of the associations between maternal CRP and both psychotic experiences and academic performance.DiscussionThese results support a neurodevelopmental role for maternal prenatal infection and offspring psychosis but also suggest an indirect effect through increasing risk of exposure to cannabis. Maternal infection and immune activation may impact on brain circuitry involved in impulsivity, increasing behaviours such as cannabis use that are separately associated with psychosis. The results of this study give clues regarding the mechanism of the maternal inflammation – psychosis association and add to our understanding of the complex neurodevelopmental processes predating psychosis.

S174. POLYENVIRONMENTAL AND POLYGENIC RISK SCORES AND THE EMERGENCE OF PSYCHOTIC EXPERIENCES IN CHILDREN AND ADOLESCENTS

BackgroundPsychotic experiences (PE) include subliminal hallucinations and delusions without the characteristic functional impairment that constitutes a psychotic disorder. PE are prevalent during childhood and adolescence and studies show a clear link with higher risk to clinical psychosis and schizophrenia. The persistence and accumulation of psychosocial problems are also well established risk factors, but how they interplay with genetic risk is still unclear, especially during developmental stages. Polygenic risk score to schizophrenia (PRS-SZ) and the polyenviromic risk score (PERS) are two validated measures created to assess the contribution of each factor on the development of such psychopathology. Our aim was to verify if PRS and PERS jointly are able to predict psychotic experiences in a cohort of children and adolescents, considering two time-points.MethodsWe analyzed data from the High Risk Cohort (HRC) for Psychiatric Disorders, composed of 2511 children and adolescents from São Paulo and Porto Alegre. PRS-SZ was calculated using summary statistics from the PGC and corrected for the ten first principal components (PC) of the GWAS. In order to calculate the PERS, we used data corresponding to the nine variables that are consider on the score, being respectively, winter or spring birth, urbanicity, cannabis use, advanced paternal age, obstetric and perinatal complications, physical and sexual abuse, neglect and paternal death, therefore if the person is exposed to one or more enviromic factor the odds ratio corresponding to that factor are added up and divided by all factors considered on the calculation, generating the final score. PE was assessed through the Community Assessment of Psychotic Experiences (CAPE) and a latent variable was generated through confirmatory factor analysis producing a good model fit. The prediction model was performed using different linear regressions where the clinical outcome was the CAPE score and PRS and PERS as independent variables. We performed Spearman’s correlations in order to observe possible correlation between our variables.ResultsOur sample varied from 9 to 18 years old (Mean: 13.49, SD: 1.9, 53.9% male) and a total of 1704 individuals provided available CAPE scores, PRS and PERS. When Spearman’s correlations were performed, we observed a non-significant weak positive correlation between PERS x CAPE (R2 = 0.0118, p = 0.623) and between PRS x CAPE (R2 = 0.0292, p = 0.228) and a non-significant negative correlation between PERS x PRS (R2 = -0.03051, p = 0.207). Lastly, we perform a multiple linear regression and used in the model the ten first PC as covariables and, we observed that with an increase in one unit in the PRS, the model explain positively about 8% of the PE variance (R2 = 0.007986 (F(12;1691) = 2.143, p = 0.01225). When we used the PRS already adjusted by ten first PC in the model, this significance is lost (R2=0.0008381 F(2);1701, p=0.1804 (PC2 and PC8 explaining the most of variance).DiscussionPrevious studies have shown a lack of significant association between PRS-SZ and PE for youth samples. Our results are in line with such results, but also depict a trend direction for those variables. Although all correlations were non-significant statically, they show us their direction as discussed below. The higher PERS, higher the psychotic experience, suggesting known environment risk factors for psychosis play a role in the report of PE as well. The higher PRS, the higher psychotic experience also. On the other hand, we found a negative correlation between PERS and PRS.In addition, PERS and PRS jointly were not able to predict psychotic experience. Although non-significant, our results may shed light on knowledge of disease.

M162. FRONTO-STRIATAL-THALAMIC CIRCUITRY ABNORMALITIES IN WHITE MATTER TRACTS IN INDIVIDUALS WITH 22Q11.2 DELETION SYNDROME

BackgroundCognitive decline is considered a fundamental component in schizophrenia. Abnormalities in fronto-striatal-thalamic (FST) sub-circuits are present in schizophrenia and are associated with cognitive impairments. However, it remains unknown whether abnormalities in FST sub-circuits are present before psychosis onset. This may be elucidated by investigating young adults with 22q11.2 deletion syndrome (22q11DS), of whom 30% will develop schizophrenia in adulthood. In 22q11DS, cognitive decline, most pronounced in Verbal IQ (VIQ), precedes the onset of psychosis and those who develop psychosis diverge more strongly from a typical cognitive trajectory. Based on these findings, studies of young adults with 22q11DS without overt psychosis but with prodromal symptoms may increase our understanding of cognitive manifestations and early pathology in FST sub-circuits in schizophrenia. Here we examined white matter (WM) tracts in FST sub-circuits, especially those involving dorsolateral (DLPFC) and ventrolateral prefrontal cortex (VLPFC), and their associations with VIQ in young adults with 22q11DS with and without prodromal symptoms.MethodsWe compared Fractional Anisotropy (FA), Axial Diffusivity (AD), and Radial Diffusivity (RD) in tracts of the FST sub-circuits in 21 individuals with 22q11DS with prodromal symptoms (age: M=21.43) and 30 individuals without prodromal symptoms (age: M=20.73) to 30 healthy controls (age: M=20.89). Two-tensor tractography was applied to reconstruct WM fiber tracts of the whole brain, followed by applying the White Matter Query Language (WMQL) method to select tracts between striatum and thalamus, with the rostral middle frontal gyrus (rMFG) and inferior frontal gyrus (IFG), representing DLPFC and VLPFC. This yielded four tracts of interest: thalamus-rMFG, thalamus-IFG, striatum-rMFG, and striatum-IFG tracts. Additionally, correlations between the dMRI measures and scores on VIQ were performed.ResultsFA was significantly increased, while RD was significantly decreased in most WM tracts in both 22q11DS groups when compared to healthy controls. In the whole 22q11DS group, VIQ correlated negatively with FA in the right thalamus-IFG tract (r=-0.336, p=.018), while RD correlated positively with VIQ in the right thalamus-IFG tract (r=0.290, p=.043) in individuals with 22q11DS, such that increased FA and decreased RD were associated with a lower VIQ. We followed up on the results in individuals with 22q11DS with prodromal symptoms to determine whether the presence of prodromal symptoms drove the correlations. VIQ correlated significantly with FA (r=-0.491, p=0.024, FDR-adjusted=0.048) and significantly at trend level with RD (r=0.487, p=0.025, FDR-adjusted=0.050) in the right thalamus-IFG tract in individuals with 22q11DS with prodromal symptoms.DiscussionMicrostructural abnormalities in brain WM tracts connecting the thalamus and the striatum with prefrontal cortices are present in young adults with 22q11DS with and without prodromal symptoms compared to healthy controls. These abnormalities are associated with the individuals’ cognitive performance in VIQ in individuals with 22q11DS with prodromal symptoms and therefore emphasize the potential involvement of the FST sub-circuits in schizophrenia. While changes in FST circuitry have been reported in patients with schizophrenia, we observed that changes in FST circuitry are also present in young adults with 22q11DS at risk for but without psychotic symptoms. Our results suggest that psychosis onset in 22q11DS may be associated with a complex pattern of WM alterations. Furthermore, cognitive abnormalities, especially in VIQ, present an important preclinical risk factor for psychosis in 22q11DS.

T226. PSYCHOMETRIC INVESTIGATION OF SELF-REPORTED THOUGHT DISORDER IN NON-CLINICAL SAMPLES

BackgroundSome dimensional models of psychosis predict that clinical phenomena are continuous with non-clinical phenomena. As such, Barrera et al. (2015) developed a self-report questionnaire to measure experiences akin to thought disorder (TD) in non-clinical populations. However, this measure requires further psychometric investigation. The current work seeks to replicate the three-factor structure of responses to the questionnaire that have been reported previously in a non-clinical sample, and to determine whether these responses predict other measures of schizotypal experiences, as well as measures of other personality characteristics (neuroticism and extraversion), and social adversity.MethodsThe 29-item questionnaire was used within an anonymous online survey to collect self-reported TD ratings from samples of 300 university students and 166 people from the general population. The survey also included the Schizotypal Personality Questionnaire (SPQ), neuroticism and extraversion scales from the International Personality Item Pool (IPIP), and the Social Defeat Scale.ResultsOf the self-report TD ratings collected from the student sample, an exploratory minimum rank factor analysis indicated the presence of three factors (Odd Speech, Poor Memory and Monitoring of Speech, and Difficulties with Initiating and Sustaining Conversation), which explained 56.5% of the variance and showed internal consistency (ordinal α ≥ 0.88). Odd Speech and Poor Memory and Monitoring of Speech factor scores showed stronger correlations with scores from the Odd Speech Scale of the SPQ (r ≥ 0.55, p < 0.001) than with other SPQ scale scores and IPIP personality scores. However, Difficulties with Initiating and Sustaining Conversation factor scores correlated strongly with other negative-like symptom scales from the SPQ, as well as with IPIP extraversion scores. A multiple regression analysis showed that, out of the three factors, Poor Memory and Monitoring of Speech scores predicted greater Social Defeat Scale scores independently of SPQ total scores and the IPIP extraversion and neuroticism scores, though the latter was the most important predictor. The results were very similar when the correlation and regression analyses were repeated in the non-student sample from the general population.DiscussionThe findings replicate Barrera et al.’s (2015) work, suggesting that TD-like experiences are multidimensional when measured in non-clinical samples using the self-report questionnaire. Although items intended to capture negative TD-like experiences might reflect introversion, items assessing oddities of speech and speech monitoring may not be entirely accounted for by existing measures of personality and schizotypy. Furthermore, since social defeat is linked to the risk factors of psychosis, some aspects of self-reported TD might prove useful in exploring the mechanisms of developing psychosis. Additional data is currently being collected to further investigate the replicability and generalizability of these findings.

Childhood Trauma in Persons With Schizophrenia and a History of Interpersonal Violence.

BackgroundChildhood trauma is a risk factor for psychosis as well for violent behavior and offending later in life. Childhood trauma comprises subdomains of abuse and neglect that may be differently related to later violence among patients with schizophrenia. The aim of this study was to map the subdomains of childhood trauma associated with violent offending in schizophrenia.MethodsInformation on childhood trauma from predominantly male patients with a DSM-IV diagnosis of schizophrenia and a history of violent offending (interpersonal violence) (SCZ-V, n = 19), schizophrenia patients without a history of violence (SCZ-NV, n = 34), and healthy controls (HC, n = 66) was obtained with the Childhood Trauma Questionnaire (CTQ). Differences between groups in total maltreatment scores and the five subdomains including physical, emotional, and sexual abuse, as well as physical and emotional neglect were analyzed.ResultsSCZ-V had the highest median CTQ scores for all sub-domains. SCZ-V reported significantly higher total CTQ scores than SCZ-NV and HC. SCZ-V had significantly higher scores than HC on all subdomains, and significantly higher than SCZ-NV on physical and emotional neglect. SCZ-NV had higher scores on all domains except sexual abuse compared to HC.ConclusionSCZ-V patients had higher exposure to childhood trauma than SCZ-NV, and both schizophrenia groups had higher exposure than HC. The results suggest that childhood physical and emotional neglect may be of specific importance to later violence in schizophrenia.

Childhood adverse traumatic experiences and schizophrenia

Εpidemiological research during last decades has demonstrated the association of certain environmental variables with psychosis. Ιn parallel with understanding environmental contributors to schizophrenia, identification of those at high risk of psychosis has become a priority. These risk factors include adverse traumatic experiences, such as discrimination, social environment adversities, bullying, emigration and childhood trauma. For many years the possibility of a relationship of adverse traumatic experiences with schizophrenia was minimized in favor of a biological paradigm. However, there is evidence supporting that childhood adversities is one of the most significant environmental risk factors for psychosis, if not the most significant. Studies have demonstrated the validity and the reliability of retrospective reports of adverse traumatic experiences in psychotic patients. The question on the causal relationship between adverse traumatic experiences and psychosis has been raised for many years, but it has not yet been answered. Researchers have focused on the study of dysfunctional cognitive schemes being formed due to childhood adversities and interpreting the world as unfriendly and threatening. According to social defeat hypothesis, the patients do not experience more stressful life events but they experience them as less controllable. Furthermore, researchers study the mediator psychopathology associated directly with adverse traumatic experiences, such as anxiety, mood, dissociative and adaptation disorders, which possibly predispose to psychosis. Cannabis use and childhood adversities may interact to increase the risk of psychotic symptoms in adolescence, according to research findings. Several publications have positively linked the number of traumatic adverse experiences with the severity of mental health and possibly with high risk of psychosis in a dose-response relationship model. Taking note that it is important to have a plausible hypothesis of the biological mechanisms involved with the relationship between adverse traumatic experiences and psychosis, the putative systems being explored are: (1) the hypothalamus-pituitary-adrenal (HPA) axis because it mediates the principal adaptive response to perceived psychological or physiological stress and (2) the dopamine system, which is considered to be important in the development of psychosis. The biological and environmental risk factors are both important in the etiology of psychosis but the effects of some forms of childhood adversity act largely independently of pre-existing genetic liability to increase the risk of psychosis. A supposed differentiation of psychosis associated with adverse traumatic experiences from the classic neurodegenerative model possibly should be considered seriously by the clinician in order to design the best therapeutic plan.

Mechanistic Dissection of Spatially Encoded GPCR Signaling Through High‐throughput CRISPR Screening

Our recent work has overturned the prevailing textbook model for GPCR signaling, which held that GPCR activation at the plasma membrane is responsible for all downstream consequences of signaling. We have demonstrated that receptor/second messenger signaling on internal compartments but not plasma membrane drives all receptor‐dependent transcriptional responses, and the site of receptor activation can dictate how cells “interpret” different ligands, including medically relevant drugs. This phenomenon of functional specialization of signaling based on receptor localization has been gaining significant support in the last few years from us and other groups, yet not much is known about its underlying mechanisms and functional consequences. To begin to address these open questions, we set up a functional genomic screen aimed at identifying factors regulating ß2‐adrenergic receptor (ß2‐AR)‐dependent transcription‐ a location‐biased GPCR signaling response. We combined pooled CRISPR interference libraries targeting all annotated transcripts in the human genome and a novel fluorescent transcriptional reporter for GPCR/cAMP signaling that we have developed with fluorescence‐activated cell sorting and deep sequencing. Through this comprehensive screen, we have identified both known and novel mediators of the GPRC pathway. We are currently defining the biochemical mechanisms and specificity of the new regulators and their contributions to location‐biased receptor signaling, and have intriguing data linking a highly‐penetrant genetic risk factor for psychosis to these pathways.Support or Funding InformationNational Institute of Mental Health [Grant MH10963301]

IMPORTANCE OF SLEEP IN GERIATRIC MENTAL HEALTH: SLEEP RESEARCH IN SCHIZOPHRENIA, COGNITIVE DISORDERS, AND AFFECTIVE DISORDERS

Sleep disturbances are central to many psychiatric disorders and have clear implications for cognition, brain health and aging; though the neurobiological mechanisms connecting sleep and psychopathology are not well understood. Older adults have different sleep architecture as well as increased incidence of insomnia and other sleep disorders, compared to younger adults. Sleep is an important and potentially modifiable risk factor for psychosis, depression, cognitive health, and other important health-related outcomes. Ellen Lee, M.D. will review the literature on sleep abnormalities in older patients with schizophrenia and present data on the links between sleep disturbances, inflammatory biomarkers and other clinical outcomes in adults aged 41-70 years with schizophrenia. Marie Anne Gebara, M.D. will present new data on the relationships between sleep disturbances, fall risk, and depression in older adults. Ruth O'Hara, Ph.D. will present on Slow Wave Sleep and its relationship to affect and cognition. Dilip Jeste, MD, will moderate and lead a discussion of sleep research in the aging population.

Similar psychosis risks in adoptees and immigrants.

There is a consensus that adoptees and immigrants both experience more mental health problems than their peers. The two groups share many risk factors for psychosis, but an increased risk for psychotic illness has only been demonstrated for immigrants. The aim of this review is to describe psychosis risk factors in adoptees, with a focus on difficulties with identity formation, identification with in-groups, attachment to parents, and coping with loss and with discrimination. The literature in these five areas is reviewed as it pertains to adoption and psychosis. There are no clear findings because the relevant studies have not been done, but the literature suggests that adopted children face challenges very similar to those of immigrants to a new country. The immigration field and the adoption field have much to learn from each other. It is recommended that a prevention strategy analogous to increased neighbourhood ethnic density be implemented with adoptees - that they be intentionally exposed from early childhood and throughout adolescence to age peers who share a similar background and with whom they can readily identify. It is also recommended that immigrants be welcomed into their host country with the same open arms as adoptive parents welcome their new children.

Effects of short-term cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis

RationaleStress is a risk factor for psychosis and treatments which mitigate its harmful effects are needed. Cannabidiol (CBD) has antipsychotic and anxiolytic effects.ObjectivesWe investigated whether CBD would normalise the neuroendocrine and anxiety responses to stress in clinical high risk for psychosis (CHR) patients.MethodsThirty-two CHR patients and 26 healthy controls (HC) took part in the Trier Social Stress Test (TSST) and their serum cortisol, anxiety and stress associated with public speaking were estimated. Half of the CHR participants were on 600 mg/day of CBD (CHR-CBD) and half were on placebo (CHR-P) for 1 week.ResultsOne-way analysis of variance (ANOVA) revealed a significant effect of group (HC, CHR-P, CHR-CBD (p = .005) on cortisol reactivity as well as a significant (p = .003) linear decrease. The change in cortisol associated with experimental stress exposure was greatest in HC controls and least in CHR-P patients, with CHR-CBD patients exhibiting an intermediate response. Planned contrasts revealed that the cortisol reactivity was significantly different in HC compared with CHR-P (p = .003), and in HC compared with CHR-CBD (p = .014), but was not different between CHR-P and CHR-CBD (p = .70). Across the participant groups (CHR-P, CHR-CBD and HC), changes in anxiety and experience of public speaking stress (all p’s < .02) were greatest in the CHR-P and least in the HC, with CHR-CBD participants demonstrating an intermediate level of change.ConclusionsOur findings show that it is worthwhile to design further well powered studies which investigate whether CBD may be used to affect cortisol response in clinical high risk for psychosis patients and any effect this may have on symptoms.

Targeting Cognition and Motivation in Coordinated Specialty Care for Early Psychosis: A Grant Report.

In this grant report, we describe our project to expand measurement-based psychiatric care across 6 early psychosis treatment teams in Minnesota, and to provide a neuroscience-informed cognitive training and motivation enhancement program for individuals with early psychosis. This project is part of the NIMH Early Psychosis Intervention Network (EPINET) initiative which seeks to link data from treatment centers nationally that offer evidence-based specialty care to persons experiencing early psychosis. Systematic analyses of pooled data collected in EPINET will help inform methods for early psychosis care, psychosis risk factors, and pre-emptive interventions. As part of the national EPINET, our hub (Early Psychosis Intervention-Minnesota, EPI-MINN), will: (1) provide measurement-based care in coordinated specialty care programs for early psychosis, (2) determine whether a structured feedback report provides benefit to stakeholders—service users, family members, and primary clinicians, and (3) explore whether deficits in cognition and motivated behavior—two domains that significantly impact functioning and overall quality of life in early psychosis—can be addressed as key treatment goals by implementing a 12-week mobile intervention. Using a regression discontinuity design, participants will be randomized to the cognitive training and motivational enhancement intervention or to treatment as usual. The intervention consists of neuroscience-informed, computerized auditory and social cognitive training exercises, as well as a mobile app where participants interact with each other and with a motivational coach. Participants will complete assessments at 4 time points: baseline and post-intervention (i.e., at 6 months), and again at 12 and 18 months to test the long-term effects of the intervention. All assessments and interventions in this project can be completed entirely remotely.

Biological stress response in women at risk of postpartum psychosis: The role of life events and inflammation

BackgroundPostpartum psychosis (PP) is the most severe psychiatric disorder associated with childbirth, and the risk is particularly high in women with a history of bipolar disorder, schizoaffective disorder or in those who have suffered previous episodes of PP. While studies in patients with psychosis not related to the puerperium have demonstrated that abnormalities in stress response are important risk factors for psychosis, it remains unknown whether this is also the case for PP. MethodsThis study includes 30 postpartum women, assessed, on average, at postpartum week 14.8 ± 10.1 either with a current episode of PP (n = 14), or at-risk of PP because of a history of bipolar/schizoaffective disorder but who were well (n = 16), and a group of healthy women (n = 26). Details about recent stressful life events were obtained using the List of Threatening Experiences questionnaire, while perceived stress was evaluated using the Perceived Stress Scale. We estimated hypothalamic-pituitary adrenal (HPA) activity by measuring salivary cortisol at awakening; at 15, 30, and 60 min after awakening; at noon; and at 8 pm. An Area Under the Curve analysis was performed to assess the awakening response (AUCi) and cortisol levels during the day (AUCg). Immune markers, including high sensitivity C-Reactive Protein (hs-CRP) and Interleukin (IL)-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, Tumor Necrosis Factor (TNFa), Vascular Endothelial Growth Factor (VEGF), Interferon gamma (INFγ), Monocyte Chemoattractant Protein 1 (MCP-1), and Epidermal Growth Factor (EGF) were evaluated from peripheral blood samples. ResultsWomen with current PP reported more frequent recent stressful life events, and higher perceived stress than healthy women. They also showed an activation of the stress and immune response, with higher levels of cortisol AUCg and hs-CRP (but not of other inflammatory markers) than healthy controls. Women at-risk of PP who remained well had values on these measures that were intermediate between those of women with a current episode of PP and those of healthy women. Stress measures and markers of stress and immune response explained 78 % of the variance of in group status between PP and healthy women, and 46 % of variance of in group status between women at-risk and healthy women. ConclusionThese findings suggest that an immune-HPA axis dysregulation, together with current stress may represent an important underlying pathophysiological mechanism in the onset of psychosis after childbirth in vulnerable women.

The relationship between childhood trauma, dopamine release and dexamphetamine-induced positive psychotic symptoms: a [11C]-(+)-PHNO PET study

Childhood trauma is a risk factor for psychosis. Amphetamine increases synaptic striatal dopamine levels and can induce positive psychotic symptoms in healthy individuals and patients with schizophrenia. Socio-developmental hypotheses of psychosis propose that childhood trauma and other environmental risk factors sensitize the dopamine system to increase the risk of psychotic symptoms, but this remains to be tested in humans. We used [11C]-(+)-PHNO positron emission tomography to measure striatal dopamine-2/3 receptor (D2/3R) availability and ventral striatal dexamphetamine-induced dopamine release in healthy participants (n = 24). The relationships between dexamphetamine-induced dopamine release, dexamphetamine-induced positive psychotic symptoms using the Positive and Negative Syndrome Scale (PANSS), and childhood trauma using the Childhood Trauma Questionnaire (CTQ) were assessed using linear regression and mediation analyses, with childhood trauma as the independent variable, dexamphetamine-induced dopamine release as the mediator variable, and dexamphetamine-induced symptoms as the dependent variable. There was a significant interaction between childhood trauma and ventral striatal dopamine release in predicting dexamphetamine-induced positive psychotic symptoms (standardized β = 1.83, p = 0.003), but a mediation analysis was not significant (standardized β = −0.18, p = 0.158). There were no significant effects of dopamine release and childhood trauma on change in negative (p = 0.280) or general PANSS symptoms (p = 0.061), and there was no relationship between ventral striatal baseline D2/3R availability and positive symptoms (p = 0.368). This indicates childhood trauma and dopamine release interact to influence the induction of positive psychotic symptoms. This is not consistent with a simple sensitization hypothesis, but suggests that childhood trauma moderates the cognitive response to dopamine release to make psychotic experiences more likely.

Urban remediation: a new recovery-oriented strategy to manage urban stress after first-episode psychosis.

Urban living is a major risk factor for psychosis. Considering worldwide increasing rates of urbanization, new approaches are needed to enhance patients' wellbeing in cities. Recent data suggest that once psychosis has emerged, patients struggle to adapt to urban milieu and that they lose access to city centers, which contributes to isolation and reduced social contacts. While it is acknowledged that there are promising initiatives to improve mental health in cities, concrete therapeutic strategies to help patients with psychosis to better handle urban stress are lacking. We believe that we should no longer wait to develop and test new therapeutic approaches. In this review, we first focus on the role of urban planning, policies, and design, and second on possible novel therapeutic strategies at the individual level. We review how patients with psychosis may experience stress in the urban environment. We then review and describe a set of possible strategies, which could be proposed to patients with the first-episode psychosis. We propose to group these strategies under the umbrella term of 'urban remediation' and discuss how this novel approach could help patients to recover from their first psychotic episode. The concepts developed in this paper are speculative and a lot of work remains to be done before it can be usefully proposed to patients. However, considering the high prevalence of social withdrawal and its detrimental impact on the recovery process, we strongly believe that researchers should invest this new domain to help patients regain access to city centers.

The Maudsley environmental risk score for psychosis.

Risk prediction algorithms have long been used in health research and practice (e.g. prediction of cardiovascular disease and diabetes). However, similar tools have not been developed for mental health. For example, for psychotic disorders, attempts to sum environmental risk are rare, unsystematic and dictated by available data. In light of this, we sought to develop a valid, easy to use measure of the aggregate environmental risk score (ERS) for psychotic disorders. We reviewed the literature to identify well-replicated and validated environmental risk factors for psychosis that combine a significant effect and large-enough prevalence. Pooled estimates of relative risks were taken from the largest available meta-analyses. We devised a method of scoring the level of exposure to each risk factor to estimate ERS. Relative risks were rounded as, due to the heterogeneity of the original studies, risk effects are imprecisely measured. Six risk factors (ethnic minority status, urbanicity, high paternal age, obstetric complications, cannabis use and childhood adversity) were used to generate the ERS. A distribution for different levels of risk based on simulated data showed that most of the population would be at low/moderate risk with a small minority at increased environmental risk for psychosis. This is the first systematic approach to develop an aggregate measure of environmental risk for psychoses in asymptomatic individuals. This can be used as a continuous measure of liability to disease; mostly relevant to areas where the original studies took place. Its predictive ability will improve with the collection of additional, population-specific data.