Showing papers by "Robin M. Murray published in 2022"

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Abstract: Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies. A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Abstract: Key Points Question Can common genetic variants be used to differentiate between treatment-resistant schizophrenia (TRS) and other forms of this disorder? Findings Data from this genome-wide association study including 85 490 participants were used to estimate genome-wide single-nucleotide variation effect size differences between individuals with and without TRS, which were compatible with a polygenic model of treatment resistance. Results were used to generate a polygenic risk score, which was significantly associated with TRS status in independent incidence and prevalence samples. Meaning Findings of this study based on common genetic variants indicate that TRS is heritable with a modest but significant single-nucleotide variation–based heritability.

Consensus paper of the WFSBP task force on cannabis, cannabinoids and psychosis

Abstract: Abstract Objectives The liberalisation of cannabis laws, the increasing availability and potency of cannabis has renewed concern about the risk of psychosis with cannabis. Methods The objective of the WFSBP task force was to review the literature about this relationship. Results Converging lines of evidence suggest that exposure to cannabis increases the risk for psychoses ranging from transient psychotic states to chronic recurrent psychosis. The greater the dose, and the earlier the age of exposure, the greater the risk. For some psychosis outcomes, the evidence supports some of the criteria of causality. However, alternate explanations including reverse causality and confounders cannot be conclusively excluded. Furthermore, cannabis is neither necessary nor sufficient to cause psychosis. More likely it is one of the multiple causal components. In those with established psychosis, cannabis has a negative impact on the course and expression of the illness. Emerging evidence also suggests alterations in the endocannabinoid system in psychotic disorders. Conclusions Given that exposure to cannabis and cannabinoids is modifiable, delaying or eliminating exposure to cannabis or cannabinoids, could potentially impact the rates of psychosis related to cannabis, especially in those who are at high risk for developing the disorder.

First Episode Psychosis

Abstract: 1. Introduction 2. Epidemiology 3. Clinical Presentation and Evaluation 4. Investigations 5. Differential Diagnosis and Comorbidity 6. Aetiological Considerations 7. Drug Treatment 8. Psychosocial Treatment 9. Subjective Viewpoint 10. Course of Illness and Outcome 11. Future Developments: The Challenge

Associations Between Canada's Cannabis Legalization and Emergency Department Presentations for Transient Cannabis-Induced Psychosis and Schizophrenia Conditions: Ontario and Alberta, 2015–2019

Abstract: Objective Cannabis legalization in many jurisdictions worldwide has raised concerns that such legislation might increase the burden of transient and persistent psychotic illnesses in society. Our study aimed to address this issue. Methods Drawing upon emergency department (ED) presentations aggregated across Alberta and Ontario, Canada records (April 1, 2015–December 31, 2019), we employed Seasonal Autoregressive Integrated Moving Average (SARIMA) models to assess associations between Canada's cannabis legalization (via the Cannabis Act implemented on October 17, 2018) and weekly ED presentation counts of the following ICD-10-CA-defined target series of cannabis-induced psychosis (F12.5; n = 5832) and schizophrenia and related conditions (“schizophrenia”; F20-F29; n = 211,661), as well as two comparison series of amphetamine-induced psychosis (F15.5; n = 10,829) and alcohol-induced psychosis (F10.5; n = 1,884). Results ED presentations for cannabis-induced psychosis doubled between April 2015 and December 2019. However, across all four SARIMA models, there was no evidence of significant step-function effects associated with cannabis legalization on post-legalization weekly ED counts of: (1) cannabis-induced psychosis [0.34 (95% CI −4.1; 4.8; P = 0.88)]; (2) schizophrenia [24.34 (95% CI −18.3; 67.0; P = 0.26)]; (3) alcohol-induced psychosis [0.61 (95% CI −0.6; 1.8; P = 0.31); or (4) amphetamine-induced psychosis [1.93 (95% CI −2.8; 6.7; P = 0.43)]. Conclusion Implementation of Canada's cannabis legalization framework was not associated with evidence of significant changes in cannabis-induced psychosis or schizophrenia ED presentations. Given the potentially idiosyncratic rollout of Canada's cannabis legalization, further research will be required to establish whether study results generalize to other settings.

Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Abstract: BACKGROUND: Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia (N = 11,095), using a single image analysis protocol. METHODS: We included T1-weighted data from 46 datasets (5,080 affected individuals and 6,015 controls) from the ENIGMA Consortium. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Analyses were also performed with respect to the use of antipsychotic medication and other clinical variables, as well as age and sex. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029). RESULTS: Small average differences between cases and controls were observed for asymmetries in cortical thickness, specifically of the rostral anterior cingulate (d = -0.08, pFDR = 0.047) and the middle temporal gyrus (d = -0.07, pFDR = 0.048), both driven primarily by thinner cortices in the left hemisphere in schizophrenia. These asymmetries were not significantly associated with the use of antipsychotic medication or other clinical variables. Older individuals with schizophrenia showed a stronger average leftward asymmetry of pallidum volume than older controls (d = 0.08, pFDR = 9.0 x 10-3). The multivariate analysis revealed that 7% of the variance across all structural asymmetries was explained by case-control status (F = 1.87, p = 1.25 x 10-5). CONCLUSIONS: Altered trajectories of asymmetrical brain development and/or lifespan asymmetry may contribute to schizophrenia pathophysiology. Small case-control differences of brain macro-structural asymmetry may manifest due to more substantial differences at the molecular, cytoarchitectonic or circuit levels, with functional relevance for lateralized cognitive processes.

Childhood Maltreatment, Educational Attainment, and IQ: Findings From a Multicentric Case-control Study of First-episode Psychosis (EU-GEI).

Abstract: BACKGROUND AND HYPOTHESIS Evidence suggests that childhood maltreatment (ie, childhood abuse and childhood neglect) affects educational attainment and cognition. However, the association between childhood maltreatment and Intelligence Quotient (IQ) seems stronger among controls compared to people with psychosis. We hypothesised that: the association between childhood maltreatment and poor cognition would be stronger among community controls than among people with first-episode of psychosis (FEP); compared to abuse, neglect would show stronger associations with educational attainment and cognition; the association between childhood maltreatment and IQ would be partially accounted for by other risk factors; and the association between childhood maltreatment, educational attainment, and IQ would be stronger among patients with affective psychoses compared to those with nonaffective psychoses. STUDY DESIGN 829 patients with FEP and 1283 community controls from 16 EU-GEI sites were assessed for child maltreatment, education attainment, and IQ. STUDY RESULTS In both the FEP and control group, childhood maltreatment was associated with lower educational attainment. The association between childhood maltreatment and lower IQ was robust to adjustment for confounders only among controls. Whereas childhood neglect was consistently associated with lower attainment and IQ in both groups, childhood abuse was associated with IQ only in controls. Among both patients with affective and nonaffective psychoses, negative associations between childhood maltreatment and educational attainment were observed, but the crude association with IQ was only evident in affective psychoses. CONCLUSIONS Our findings underscore the role of childhood maltreatment in shaping academic outcomes and cognition of people with FEP as well as controls.

Facial Emotion Recognition in Psychosis and Associations With Polygenic Risk for Schizophrenia: Findings From the Multi-Center EU-GEI Case–Control Study

Abstract: Abstract Background and Hypothesis Facial Emotion Recognition is a key domain of social cognition associated with psychotic disorders as a candidate intermediate phenotype. In this study, we set out to investigate global and specific facial emotion recognition deficits in first-episode psychosis, and whether polygenic liability to psychotic disorders is associated with facial emotion recognition. Study Design 828 First Episode Psychosis (FEP) patients and 1308 population-based controls completed assessments of the Degraded Facial Affect Recognition Task (DFAR) and a subsample of 524 FEP and 899 controls provided blood or saliva samples from which we extracted DNA, performed genotyping and computed polygenic risk scores for schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MD). Study Results A worse ability to globally recognize facial emotion expressions was found in patients compared with controls [B= −1.5 (0.6), 95% CI −2.7 to −0.3], with evidence for stronger effects on negative emotions (fear [B = −3.3 (1.1), 95% CI −5.3 to −1.2] and anger [B = −2.3 (1.1), 95% CI −4.6 to −0.1]) than on happiness [B = 0.3 (0.7), 95% CI −1 to 1.7]. Pooling all participants, and controlling for confounds including case/control status, facial anger recognition was associated significantly with Schizophrenia Polygenic Risk Score (SZ PRS) [B = −3.5 (1.7), 95% CI −6.9 to −0.2]. Conclusions Psychosis is associated with impaired recognition of fear and anger, and higher SZ PRS is associated with worse facial anger recognition. Our findings provide evidence that facial emotion recognition of anger might play a role as an intermediate phenotype for psychosis.

Child maltreatment, migration and risk of first-episode psychosis: results from the multinational EU-GEI study.

Abstract: BACKGROUND Child maltreatment (CM) and migrant status are independently associated with psychosis. We examined prevalence of CM by migrant status and tested whether migrant status moderated the association between CM and first-episode psychosis (FEP). We further explored whether differences in CM exposure contributed to variations in the incidence rates of FEP by migrant status. METHODS We included FEP patients aged 18-64 years in 14 European sites and recruited controls representative of the local populations. Migrant status was operationalized according to generation (first/further) and region of origin (Western/non-Western countries). The reference population was composed by individuals of host country's ethnicity. CM was assessed with Childhood Trauma Questionnaire. Prevalence ratios of CM were estimated using Poisson regression. We examined the moderation effect of migrant status on the odds of FEP by CM fitting adjusted logistic regressions with interaction terms. Finally, we calculated the population attributable fractions (PAFs) for CM by migrant status. RESULTS We examined 849 FEP cases and 1142 controls. CM prevalence was higher among migrants, their descendants and migrants of non-Western heritage. Migrant status, classified by generation (likelihood test ratio:χ2 = 11.3, p = 0.004) or by region of origin (likelihood test ratio:χ2 = 11.4, p = 0.003), attenuated the association between CM and FEP. PAFs for CM were higher among all migrant groups compared with the reference populations. CONCLUSIONS The higher exposure to CM, despite a smaller effect on the odds of FEP, accounted for a greater proportion of incident FEP cases among migrants. Policies aimed at reducing CM should consider the increased vulnerability of specific subpopulations.

Epidemiology of Untreated Psychoses in 3 Diverse Settings in the Global South

Abstract: This cohort study investigates if the clinical and demographic profiles of individuals with, and rates of, untreated psychoses vary across diverse settings in the Global South.

Use of multiple polygenic risk scores for distinguishing schizophrenia-spectrum disorder and affective psychosis categories in a first-episode sample; the EU-GEI study

Abstract: Abstract Background Schizophrenia (SZ), bipolar disorder (BD) and depression (D) run in families. This susceptibility is partly due to hundreds or thousands of common genetic variants, each conferring a fractional risk. The cumulative effects of the associated variants can be summarised as a polygenic risk score (PRS). Using data from the EUropean Network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) first episode case–control study, we aimed to test whether PRSs for three major psychiatric disorders (SZ, BD, D) and for intelligent quotient (IQ) as a neurodevelopmental proxy, can discriminate affective psychosis (AP) from schizophrenia-spectrum disorder (SSD). Methods Participants (842 cases, 1284 controls) from 16 European EU-GEI sites were successfully genotyped following standard quality control procedures. The sample was stratified based on genomic ancestry and analyses were done only on the subsample representing the European population (573 cases, 1005 controls). Using PRS for SZ, BD, D, and IQ built from the latest available summary statistics, we performed simple or multinomial logistic regression models adjusted for 10 principal components for the different clinical comparisons. Results In case–control comparisons PRS-SZ, PRS-BD and PRS-D distributed differentially across psychotic subcategories. In case–case comparisons, both PRS-SZ [odds ratio (OR) = 0.7, 95% confidence interval (CI) 0.54–0.92] and PRS-D (OR = 1.31, 95% CI 1.06–1.61) differentiated AP from SSD; and within AP categories, only PRS-SZ differentiated BD from psychotic depression (OR = 2.14, 95% CI 1.23–3.74). Conclusions Combining PRS for severe psychiatric disorders in prediction models for psychosis phenotypes can increase discriminative ability and improve our understanding of these phenotypes. Our results point towards the potential usefulness of PRSs in specific populations such as high-risk or early psychosis phases.

First-Episode Psychosis Patients Who Deteriorated in the Premorbid Period Do Not Have Higher Polygenic Risk Scores Than Others: A Cluster Analysis of EU-GEI Data

Abstract: Abstract Cluster studies identified a subgroup of patients with psychosis whose premorbid adjustment deteriorates before the onset, which may reflect variation in genetic influence. However, other studies reported a complex relationship between distinctive patterns of cannabis use and cognitive and premorbid impairment that is worthy of consideration. We examined whether: (1) premorbid social functioning (PSF) and premorbid academic functioning (PAF) in childhood and adolescence and current intellectual quotient (IQ) define different clusters in 802 first-episode of psychosis (FEP) patients; resulting clusters vary in (2) polygenic risk scores (PRSs) for schizophrenia (SCZ_PRS), bipolar disorder (BD_PRS), major depression (MD_PRS), and IQ (IQ_PRS), and (3) patterns of cannabis use, compared to 1,263 population-based controls. Four transdiagnostic clusters emerged (BIC = 2268.5): (1) high-cognitive-functioning (n = 205), with the highest IQ (Mean = 106.1, 95% CI: 104.3, 107.9) and PAF, but low PSF. (2) Low-cognitive-functioning (n = 223), with the lowest IQ (Mean = 73.9, 95% CI: 72.2, 75.7) and PAF, but normal PSF. (3) Intermediate (n = 224) (Mean_IQ = 80.8, 95% CI: 79.1, 82.5) with low-improving PAF and PSF. 4) Deteriorating (n = 150) (Mean_IQ = 80.6, 95% CI: 78.5, 82.7), with normal-deteriorating PAF and PSF. The PRSs explained 7.9% of between-group membership. FEP had higher SCZ_PRS than controls [F(4,1319) = 20.4, P < .001]. Among the clusters, the deteriorating group had lower SCZ_PRS and was likelier to have used high-potency cannabis daily. Patients with FEP clustered according to their premorbid and cognitive abilities. Pronounced premorbid deterioration was not typical of most FEP, including those more strongly predisposed to schizophrenia, but appeared in a cluster with a history of high-potency cannabis use.

Genetic and psychosocial stressors have independent effects on the level of subclinical psychosis: findings from the multinational EU-GEI study

Abstract: Aims Gene x environment (G×E) interactions, i.e. genetic modulation of the sensitivity to environmental factors and/or environmental control of the gene expression, have not been reliably established regarding aetiology of psychotic disorders. Moreover, recent studies have shown associations between the polygenic risk scores for schizophrenia (PRS-SZ) and some risk factors of psychotic disorders, challenging the traditional gene v. environment dichotomy. In the present article, we studied the role of GxE interaction between psychosocial stressors (childhood trauma, stressful life-events, self-reported discrimination experiences and low social capital) and the PRS-SZ on subclinical psychosis in a population-based sample. Methods Data were drawn from the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study, in which subjects without psychotic disorders were included in six countries. The sample was restricted to European descendant subjects (n = 706). Subclinical dimensions of psychosis (positive, negative, and depressive) were measured by the Community Assessment of Psychic Experiences (CAPE) scale. Associations between the PRS-SZ and the psychosocial stressors were tested. For each dimension, the interactions between genes and environment were assessed using linear models and comparing explained variances of ‘Genetic’ models (solely fitted with PRS-SZ), ‘Environmental’ models (solely fitted with each environmental stressor), ‘Independent’ models (with PRS-SZ and each environmental factor), and ‘Interaction’ models (Independent models plus an interaction term between the PRS-SZ and each environmental factor). Likelihood ration tests (LRT) compared the fit of the different models. Results There were no genes-environment associations. PRS-SZ was associated with positive dimensions (β = 0.092, R2 = 7.50%), and most psychosocial stressors were associated with all three subclinical psychotic dimensions (except social capital and positive dimension). Concerning the positive dimension, Independent models fitted better than Environmental and Genetic models. No significant GxE interaction was observed for any dimension. Conclusions This study in subjects without psychotic disorders suggests that (i) the aetiological continuum hypothesis could concern particularly the positive dimension of subclinical psychosis, (ii) genetic and environmental factors have independent effects on the level of this positive dimension, (iii) and that interactions between genetic and individual environmental factors could not be identified in this sample.

Associations Between Cannabis Use, Polygenic Liability for Schizophrenia, and Cannabis-related Experiences in a Sample of Cannabis Users

Abstract: Abstract Background and Hypothesis Risk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs. Study Design We tested whether measures of cannabis involvement and polygenic risk scores (PRS) for schizophrenia were associated with self-reported cannabis-related experiences in a sample ascertained for alcohol use disorders (AUDs), the Collaborative Study on the Genetics of Alcoholism (COGA). We analyzed 4832 subjects (3128 of European ancestry and 1704 of African ancestry; 42% female; 74% meeting lifetime criteria for an AUD). Study Results Cannabis use disorder (CUD) was prevalent in this analytic sample (70%), with 40% classified as mild, 25% as moderate, and 35% as severe. Polygenic risk for schizophrenia was positively associated with cannabis-related paranoia, feeling depressed or anhedonia, social withdrawal, and cognitive difficulties, even when controlling for duration of daily cannabis use, CUD, and age at first cannabis use. The schizophrenia PRS was most robustly associated with cannabis-related cognitive difficulties (β = 0.22, SE = 0.04, P = 5.2e−7). In an independent replication sample (N = 1446), associations between the schizophrenia PRS and cannabis-related experiences were in the expected direction and not statistically different in magnitude from those in the COGA sample. Conclusions Among individuals who regularly use cannabis, genetic liability for schizophrenia—even in those without clinical features—may increase the likelihood of reporting unusual experiences related to cannabis use.

The effect of antipsychotics on glutamate levels in the anterior cingulate cortex and clinical response: A 1H-MRS study in first-episode psychosis patients

Abstract: Introduction Glutamatergic dysfunction is implicated in the pathophysiology of schizophrenia. It is unclear whether glutamatergic dysfunction predicts response to treatment or if antipsychotic treatment influences glutamate levels. We investigated the effect of antipsychotic treatment on glutamatergic levels in the anterior cingulate cortex (ACC), and whether there is a relationship between baseline glutamatergic levels and clinical response after antipsychotic treatment in people with first episode psychosis (FEP). Materials and methods The sample comprised 25 FEP patients; 22 completed magnetic resonance spectroscopy scans at both timepoints. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Results There was no significant change in glutamate [baseline 13.23 ± 2.33; follow-up 13.89 ± 1.74; t(21) = −1.158, p = 0.260], or Glx levels [baseline 19.64 ± 3.26; follow-up 19.66 ± 2.65; t(21) = −0.034, p = 0.973]. There was no significant association between glutamate or Glx levels at baseline and the change in PANSS positive (Glu r = 0.061, p = 0.777, Glx r = −0.152, p = 0.477), negative (Glu r = 0.144, p = 0.502, Glx r = 0.052, p = 0.811), general (Glu r = 0.110, p = 0.607, Glx r = −0.212, p = 0.320), or total scores (Glu r = 0.078, p = 0.719 Glx r = −0.155, p = 0.470). Conclusion These findings indicate that treatment response is unlikely to be associated with baseline glutamatergic metabolites prior to antipsychotic treatment, and there is no major effect of antipsychotic treatment on glutamatergic metabolites in the ACC.

S0033291721000453jra 3668..3676

Abstract: Background. Perceived discrimination is associated with worse mental health. Few studies have assessed whether perceived discrimination (i) is associated with the risk of psychotic disorders and (ii) contributes to an increased risk among minority ethnic groups relative to the ethnic majority. Methods. We used data from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions Work Package 2, a population-based case−control study of incident psychotic disorders in 17 catchment sites across six countries. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) for the associations between perceived discrimination and psychosis using mixed-effects logistic regression models. We used stratified and mediation analyses to explore differences for minority ethnic groups. Results. Reporting any perceived experience of major discrimination (e.g. unfair treatment by police, not getting hired) was higher in cases than controls (41.8% v. 34.2%). Pervasive experiences of discrimination (≥3 types) were also higher in cases than controls (11.3% v. 5.5%). In fully adjusted models, the odds of psychosis were 1.20 (95% CI 0.91–1.59) for any discrimination and 1.79 (95% CI 1.19–1.59) for pervasive discrimination compared with no discrimination. In stratified analyses, the magnitude of association for pervasive experiences of discrimination appeared stronger for minority ethnic groups (OR = 1.73, 95% CI 1.12–2.68) than the ethnic majority (OR = 1.42, 95% CI 0.65–3.10). In exploratory mediation analysis, pervasive discrimination minimally explained excess risk among minority ethnic groups (5.1%). Conclusions. Pervasive experiences of discrimination are associated with slightly increased odds of psychotic disorders and may minimally help explain excess risk for minority ethnic groups.

Life events and psychosis: case–control study from India, Nigeria, and Trinidad and Tobago

Abstract: Background There is evidence of an association between life events and psychosis in Europe, North America and Australasia, but few studies have examined this association in the rest of the world. Aims To test the association between exposure to life events and psychosis in catchment areas in India, Nigeria, and Trinidad and Tobago. Method We conducted a population-based, matched case–control study of 194 participants in India, Nigeria, and Trinidad and Tobago. Cases were recruited through comprehensive population-based, case-finding strategies. The Harvard Trauma Questionnaire was used to measure life events. The Screening Schedule for Psychosis was used to screen for psychotic symptoms. The association between psychosis and having experienced life events (experienced or witnessed) was estimated by conditional logistic regression. Results There was no overall evidence of an association between psychosis and having experienced or witnessed life events (adjusted odds ratio 1.19, 95% CI 0.62–2.28). We found evidence of effect modification by site (P = 0.002), with stronger evidence of an association in India (adjusted odds ratio 1.56, 95% CI 1.03–2.34), inconclusive evidence in Nigeria (adjusted odds ratio 1.17, 95% CI 0.95–1.45) and evidence of an inverse association in Trinidad and Tobago (adjusted odds ratio 0.66, 95% CI 0.44–0.97). Conclusions This study found no overall evidence of an association between witnessing or experiencing life events and psychotic disorder across three culturally and economically diverse countries. There was preliminary evidence that the association varies between settings.

The Impact of the COVID-19 Pandemic on the Incidence of First Episode Psychosis in South London

Abstract: Aims Transmission of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to a global pandemic. Many studies are underway to ascertain the mental health impact of this seismic event, however no study has investigated its effect on psychosis incidence. We hypothesise that the overall crude incidence rates of first episode psychosis (FEP) will be higher during the pandemic when comparing the same area of South London in defined pre-pandemic and pandemic time periods. Methods Clinical records for all patients aged 18 to 64 years presenting to early intervention in psychosis services in the London boroughs of Southwark and Lambeth between July 1st 2019 to December 31st 2019 (pre-pandemic period) and July 1st 2020 to December 31st 2020 (pandemic period) were extracted from the Clinical Record Interactive Search (CRiS), an online database containing anonymised patient records. All patients were manually screened using the Screening Schedule for Psychosis to confirm FEP, with 104/235 cases meeting criteria for FEP in the pre-pandemic period compared with 158/376 in the pandemic period. Crude, age-standardised, and sex-standardised incidence rates and ratios were calculated for interpretation. Results The crude incidence rate of FEP was significantly higher in the pandemic period (68.3, 95% CI:[57.6 ; 78.9]) than the pre-pandemic period (44.9, 95% CI:[36.3 ; 53.6]). The crude incidence ratio was 1.52 (95% CI:[1.28 ; 1.77]), indicating that the overall crude incidence of FEP in the pandemic period was significantly higher (52%) than in the pre-pandemic period. The directionality and statistical significance of this ratio was unperturbed by standardisation for age (SIR = 1.45, 95% CI[1.23 ; 1.70]) and sex (SIR = 1.56, 95% CI[1.33 ; 1.83]). Conclusion Our results suggest that the COVID-19 pandemic has had a significant impact on the incidence of FEP in the South London boroughs of Southwark and Lambeth. Further research is required to elucidate the factors contributing to this increase to inform targeted interventions and prevent deterioration in at-risk patients.

The long-term effects of a polygenetic predisposition to general cognition on healthy cognitive ageing: evidence from the English Longitudinal Study of Ageing

Abstract: Abstract Background As an accelerated cognitive decline frequently heralds onset of severe neuropathological disorders, understanding the source of individual differences in withstanding the onslaught of cognitive ageing may highlight how best cognitive abilities may be retained into advanced age. Methods Using a population representative sample of 5088 adults aged •50 years from the English Longitudinal Study of Ageing, we investigated relationships of polygenic predisposition to general cognition with a rate of change in cognition during a 10-year follow-up period. Polygenic predisposition was measured with polygenic scores for general cognition (GC-PGS). Cognition was measured employing tests for verbal memory and semantic fluency. Results The average baseline memory score was 11.1 (s.d. = 2.9) and executive function score was 21.5 (s.d. = 5.8). An increase in GC-PGS by one standard deviation (1-s.d.) was associated with a higher baseline verbal memory by an average 0.27 points (95% CI 0.19–0.34, p < 0.001). Similarly, 1-s.d. increase in GC-PGS was associated with a higher semantic fluency score at baseline in the entire sample (β = 0.45, 95% CI 0.27–0.64, p < 0.001). These associations were significant for women and men, and all age groups. Nonetheless, 1-s.d. increase in GC-PGS was not associated with decreases in verbal memory nor semantic fluency during follow-up in the entire sample, as well stratified models by sex and age. Conclusion Although common genetic variants associated with general cognition additively are associated with a stable surplus to cognition in adults, a polygenic predisposition to general cognition is not associated with age-related cognitive decline during a 10-year follow-up.

Effects of Cannabidiol and Delta-9-Tetrahydrocannabinol on Plasma Endocannabinoid Levels in Healthy Volunteers: A Randomized Double-Blind Four-Arm Crossover Study.

Abstract: Background: The effects of cannabis are thought to be mediated by interactions between its constituents and the endocannabinoid system. Delta-9-tetrahydrocannabinol (THC) binds to central cannabinoid receptors, while cannabidiol (CBD) may influence endocannabinoid function without directly acting on cannabinoid receptors. We examined the effects of THC coadministered with different doses of CBD on plasma levels of endocannabinoids in healthy volunteers. Methods: In a randomized, double-blind, four-arm crossover study, healthy volunteers (n=46) inhaled cannabis vapor containing 10 mg THC plus either 0, 10, 20, or 30 mg CBD, in four experimental sessions. The median time between sessions was 14 days (IQR=20). Blood samples were taken precannabis inhalation and at 0-, 5-, 15-, and 90-min postinhalation. Plasma concentrations of THC, CBD, anandamide, 2-arachidonoylglycerol (2-AG), and related noncannabinoid lipids were measured using liquid chromatography-mass spectrometry. Results: Administration of cannabis induced acute increases in plasma concentrations of anandamide (+18.0%, 0.042 ng/mL [95%CI: 0.023-0.062]), and the noncannabinoid ethanolamides, docosatetraenylethanolamide (DEA; +35.8%, 0.012 ng/mL [95%CI: 0.008-0.016]), oleoylethanolamide (+16.1%, 0.184 ng/mL [95%CI: 0.076-0.293]), and N-arachidonoyl-L-serine (+25.1%, 0.011 ng/mL [95%CI: 0.004-0.017]) (p<0.05). CBD had no significant effect on the plasma concentration of anandamide, 2-AG or related noncannabinoid lipids at any of three doses used. Over the four sessions, there were progressive decreases in the preinhalation concentrations of anandamide and DEA, from 0.254 ng/mL [95%CI: 0.223-0.286] to 0.194 ng/mL [95%CI: 0.163-0.226], and from 0.039 ng/mL [95%CI: 0.032-0.045] to 0.027 ng/mL [95%CI: 0.020-0.034] (p<0.05), respectively. Discussion: THC induced acute increases in plasma levels of anandamide and noncannabinoid ethanolamides, but there was no evidence that these effects were influenced by the coadministration of CBD. It is possible that such effects may be evident with higher doses of CBD or after chronic administration. The progressive reduction in pretreatment anandamide and DEA levels across sessions may be related to repeated exposure to THC or participants becoming less anxious about the testing procedure and requires further investigation. The study was registered on clinicaltrials.gov (NCT05170217).

Effects of psychosis-associated genetic markers on brain volumetry: a systematic review of replicated findings and an independent validation

Abstract: Abstract Background Given psychotic illnesses' high heritability and associations with brain structure, numerous neuroimaging-genetics findings have been reported in the last two decades. However, few findings have been replicated. In the present independent sample we aimed to replicate any psychosis-implicated SNPs (single nucleotide polymorphisms), which had previously shown at least two main effects on brain volume. Methods A systematic review for SNPs showing a replicated effect on brain volume yielded 25 studies implicating seven SNPs in five genes. Their effect was then tested in 113 subjects with either schizophrenia, bipolar disorder, ‘at risk mental state’ or healthy state, for whole-brain and region-of-interest (ROI) associations with grey and white matter volume changes, using voxel-based morphometry. Results We found FWER-corrected (Family-wise error rate) (i.e. statistically significant) associations of: (1) CACNA1C-rs769087-A with larger bilateral hippocampus and thalamus white matter, across the whole brain; and (2) CACNA1C-rs769087-A with larger superior frontal gyrus, as ROI. Higher replication concordance with existing literature was found, in decreasing order, for: (1) CACNA1C-rs769087-A, with larger dorsolateral-prefrontal/superior frontal gyrus and hippocampi (both with anatomical and directional concordance); (2) ZNF804A-rs11681373-A, with smaller angular gyrus grey matter and rectus gyri white matter (both with anatomical and directional concordance); and (3) BDNF-rs6265-T with superior frontal and middle cingulate gyri volume change (with anatomical and allelic concordance). Conclusions Most literature findings were not herein replicated. Nevertheless, high degree/likelihood of replication was found for two genome-wide association studies- and one candidate-implicated SNPs, supporting their involvement in psychosis and brain structure.