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BackgroundLow-grade inflammation may occur in association with several mental disorders of early adulthood, though associations with markers of chronic inflammation such as soluble urokinase plasminogen activator receptor (suPAR) are less well-established. We aimed to examine associations between acute and chronic inflammatory markers and mental disorders, as well as psychiatric co-morbidity, in young adults aged 24 years in the Avon Longitudinal Study of Parents and Children.MethodsIncluded were 781 participants (of 4019 who attended at age 24 years) who completed psychiatric assessments and provided plasma samples. Of these, 377 met criteria for psychotic disorder, depressive disorder or generalised anxiety disorder and 404 did not. Plasma concentrations of IFN-γ, IL-6, IL-8, IL-10, TNF-α, CRP, sVCAM1, sICAM1, suPAR and alpha-2-macroglobulin were measured using immunoassays. Logistic regression compared standardised inflammatory marker levels in cases and controls. Negative binomial regression evaluated associations between inflammatory markers and co-morbidity (number of mental disorders). Models were adjusted for sex, body mass index, cigarette smoking, cannabis use and employment status, then additionally for childhood trauma.ResultsFor psychotic disorder, there was evidence for associations with IL-6 (odds ratio[OR] 1.68, 95 %CI 1.20–2.34) and suPAR (OR 1.74, 95 %CI 1.17–2.58). There was weaker evidence for an association between suPAR and depressive disorder (OR 1.31, 95 %CI 1.05–1.62). There was little evidence for associations between inflammatory markers and generalised anxiety disorder. There was weak evidence for an association between suPAR and co-morbidity (β 0.10, 95 %CI 0.01–0.19). There was little evidence for additional confounding by childhood trauma.ConclusionsThere was evidence that 24-year-olds with psychotic disorder had raised plasma IL-6 and suPAR concentrations compared to controls. These findings have implications regarding the role of inflammation in mental disorders in early adulthood.

Background Little is known on whether associations between childhood autistic traits and psychotic experiences persist into adulthood and whether genetic confounding and childhood trauma influence them. Here we investigate the associations between childhood autistic traits and psychotic experiences until young adulthood and assess the influence of schizophrenia polygenic risk and childhood traumatic experiences, using the Avon Longitudinal Study of Parents and Children (ALSPAC) population-based birth cohort. Study design We used a measure of broad autistic traits (autism factor mean score), and four dichotomised measures of autistic traits capturing social communication difficulties (age 7), repetitive behaviours (age 5), sociability (age 3), and pragmatic language (age 9). Psychotic experiences were assessed at ages 18 and 24 using the semi-structured Psychosis-Like Symptoms interview (PLIKSi). Traumatic experiences between ages 5 and 11 were assessed with questionnaires and interviews administered to children and parents at multiple ages. Study results Broad autistic traits, as well as social communication difficulties, were associated with psychotic experiences that were distressing and/or frequent until age 24 (autism factor mean score, n = 3707: OR 1.19, 95%CI 1.01–1.39; social communication difficulties, n = 3384: OR 1.54, 95%CI 0.97–2.45). Childhood trauma mediated a substantial proportion of the identified associations (~28% and 36% respectively, maximum n = 3577). Schizophrenia polygenic risk did not appear to confound the associations. Multiple imputation analyses (maximum n = 13 105) yielded comparable results. Conclusions Childhood trauma may be an important, potentially modifiable pathway between autistic features and later onset of psychotic psychopathology.

AimsEarly intervention in people with an at-risk mental state (ARMS) for psychosis can prevent the onset of psychosis. Clinical guidelines recommend that ARMS are referred to triage services, and then to Early Intervention (EI) teams in secondary care for assessment and treatment. However, little is known about how ARMS patients are identified and managed in UK primary and secondary care. This study explored patients’ and clinicians’ views of ARMS patients’ care pathways. MethodsEleven patients, 20 GPs, 11 clinicians from the triaging Primary Care Liaison Services (PCLS) and 10 EI clinicians were interviewed. Data were analysed thematically.ResultsMost patients said their symptoms started in adolescence with depression and anxiety. Before being referred to EI teams, most patients were referred by their GP to well-being services for talking therapies, which they had not found helpful. Some GPs said secondary care‘s high acceptance thresholds and scarce treatment availability made them reluctant to refer to EI teams. Triage in PCLS was influenced by patients’ risk of self-harm, and formulation of psychotic symptoms; only those without clear evidence of other pathology and not at high risk of self-harm were referred to EI teams, the others being referred to Recovery/Crisis services. Although patients referred to EI teams were offered an assessment, only some EI teams were commissioned to treat ARMS. ConclusionsIndividuals meeting ARMS criteria might not receive early intervention due to high treatment thresholds and limited treatment availability in secondary care, suggesting clinical guidelines are not being met for this patient group.

Social-isolation has been linked to a range of psychiatric issues, but the behavioral component that drives it is not well understood. Here, a GWAS is carried out to identify genetic variants which contribute to Social-isolation behaviors in up to 449,609 participants from the UK Biobank. 17 loci were identified at genome-wide significance, contributing to a 4% SNP heritability estimate. Using the Social-isolation GWAS, polygenic risk scores (PRS) were derived in ALSPAC, an independent, developmental cohort, and used to test for association with friendship quality. At age 18, friendship scores were associated with the Social-isolation PRS, demonstrating that the genetic factors are able to predict related social traits. LD score regression using the GWAS demonstrated genetic correlation with autism spectrum disorder, schizophrenia, and major depressive disorder. However, no evidence of causality was found using a conservative Mendelian randomization approach other than that of autism spectrum disorder on Social-isolation. Our results show that Social-isolation has a small heritable component which may drive those behaviors which is associated genetically with other social traits such as friendship satisfaction as well as psychiatric disorders.

Schizophrenia (SCZ) is associated with structural brain changes, with considerable variation in the extent to which these cortical regions are influenced. We present a novel metric that summarises individual structural variation across the brain, while considering prior effect sizes, established via meta-analysis. We determine individual participant deviation from a within-sample-norm across structural MRI regions of interest (ROIs). For each participant, we weight the normalised deviation of each ROI by the effect size (Cohen’s d) of the difference between SCZ/control for the corresponding ROI from the SCZ Enhancing Neuroimaging Genomics through Meta-Analysis working group. We generate a morphometric risk score (MRS) representing the average of these weighted deviations. We investigate if SCZ-MRS is elevated in a SCZ case/control sample (NCASE = 50; NCONTROL = 125), a replication sample (NCASE = 23; NCONTROL = 20) and a sample of asymptomatic young adults with extreme SCZ polygenic risk (NHIGH-SCZ-PRS = 95; NLOW-SCZ-PRS = 94). SCZ cases had higher SCZ-MRS than healthy controls in both samples (Study 1: β = 0.62, P < 0.001; Study 2: β = 0.81, P = 0.018). The high liability SCZ-PRS group also had a higher SCZ-MRS (Study 3: β = 0.29, P = 0.044). Furthermore, the SCZ-MRS was uniquely associated with SCZ status, but not attention-deficit hyperactivity disorder (ADHD), whereas an ADHD-MRS was linked to ADHD status, but not SCZ. This approach provides a promising solution when considering individual heterogeneity in SCZ-related brain alterations by identifying individual’s patterns of structural brain-wide alterations.

Background: Women who have experienced domestic violence and abuse (DVA) are at increased risk of developing post-traumatic stress disorder (PTSD) and complex PTSD (CPTSD). In 2014-15, we developed a prototype trauma-specific mindfulness-based cognitive therapy curriculum (TS-MBCT) for the treatment of PTSD in a DVA population. This study aimed to refine the prototype TS-MBCT and evaluate the feasibility of conducting a randomised controlled trial (RCT) testing its effectiveness and cost-effectiveness. Methods: Intervention refinement phase was informed by evidence synthesis from a literature review, qualitative interviews with professionals and DVA survivors, and a consensus exercise with experts in trauma and mindfulness. We tested the refined TS-MBCT intervention in an individually randomised parallel group feasibility trial with pre-specified progression criteria, a traffic light system, and embedded process and health economics evaluations. Results: The TS-MBCT intervention consisted of eight group sessions and home practice. We screened 109 women in a DVA agency and recruited 20 (15 TS-MBCT, 5 self-referral to National Health Service (NHS) psychological treatment), with 80% follow-up at 6 months. Our TS-MBCT intervention had 73% uptake, 100% retention, and high acceptability. Participants suggested recruitment via multiple agencies, and additional safety measures. Randomisation into the NHS control arm did not work due to long waiting lists and previous negative experiences. Three self-administered PTSD/CPTSD questionnaires produced differing outcomes thus a clinician administered measure might work better. We met six out of nine feasibility progression criteria at green and three at amber targets demonstrating that it is possible to conduct a full-size RCT of the TS-MBCT intervention after making minor amendments to recruitment and randomisation procedures, the control intervention, primary outcomes measures, and intervention content. At 6 months, none of the PTSD/CPTSD outcomes ruled out a clinically important difference between trial arms indicating that it is reasonable to proceed to a full-size RCT to estimate these outcomes with greater precision. Conclusions: A future RCT of the coMforT TS-MBCT intervention should recruit from multiple DVA agencies, NHS and non-NHS settings, have an active control psychological treatment, use robust randomisation and safety procedures, and clinician-administered measures for PTSD/CPTSD. Trial registration: ISRCTN64458065 11/01/2019, https://www.isrctn.com/ISRCTN64458065?q=64458065&filters=&sort=&offset=1&totalResults=1&page=1&pageSize=10

A trauma-informed approach is a framework for organisational (synonym system) change interventions that address the universal prevalence and impact of trauma. This mixed methods systematic review assessed the effects of trauma-informed approaches on psychological, behavioural, and health outcomes in healthcare providers and adult patients in primary care and community mental healthcare. We searched five databases and grey literature and consulted experts for reports published in January 1990-June 2021. The quantitative descriptive and qualitative framework syntheses were integrated through a line of argument and mapped onto a logic model. We included six non-randomized studies that evaluated eight interventions with varied theoretical development, components, and outcomes. The most common components were budget allocation, workforce development, identification/response to violence and trauma, and evaluation. Evidence for intervention effects was limited and conflicting. Four studies reported improvement in provider readiness and sense of community, while three reported conflicting effects on provider behaviour regarding delivery of trauma-informed care. Four studies reported some improvement in patient readiness for disease management and access to services; however, the evidence for patient satisfaction was conflicting. Two studies found that patients and providers felt safe.While one study reported improvement in patient quality of life and chronic pain, another found no effect on substance use, and three studies reported conflicting effects on mental health. Interventions mechanisms included a package of varied components, tailoring to the organisational needs, capacities, and preferences, staff education and self-care, creating safe environments, shared decision-making. Intervention effects were moderated by contextual (health system values, policies, governance, business models, trauma-informed movement, organisational culture, social determinants of health) and intervention factors (buy-in from all staff, collective learning through conversations, equal attention to staff and patient well-being, sustainable funding). No studies measured adverse events/harm, cost effectiveness, or providers’ health. We need more methodologically robust evaluations of trauma-informed organisational change interventions.A preprint of this article has previously been deposited in the preprint server for health sciences [1].

Background Psychotic experiences emerge from abnormalities in perception and belief formation, and occur more commonly in those experiencing childhood trauma. Yet, which precise aspects of belief formation are atypical in psychosis is not well understood. We used a computational modelling approach to characterise belief-updating in young adults in the general population, examine their relationship with psychotic outcomes and trauma, and the extent to which they mediate the trauma-psychosis relationship.MethodsWe used data from 3,360 individuals from the Avon Longitudinal Study of Parents and Children birth cohort who completed assessments for psychotic outcomes, depression, anxiety, and two belief-updating tasks at age 24, and had data available on traumatic events assessed from birth to late adolescence. Unadjusted and adjusted regression and counterfactual mediation methods were used for the analyses.ResultsBasic behavioural measures of belief-updating (‘draws to decision’ and ‘disconfirmatory updating’) were not associated with psychotic experiences. However, computational modelling revealed an association between increased decision noise with both psychotic experiences and trauma exposure, although ConclusionsThese findings challenge the hypothesis that atypical belief-updating mechanisms (as indexed by the computational models and behavioural measures we employed) underlie the development of psychotic phenomena.

Gamma oscillations (30–90 Hz) have been proposed as a signature of cortical visual information processing, particularly the balance between excitation and inhibition, and as a biomarker of neuropsychiatric diseases. Magnetoencephalography (MEG) provides highly reliable visual-induced gamma oscillation estimates, both at sensor and source level. Recent studies have reported a deficit of visual gamma activity in schizophrenia patients, in medication naive subjects, and high-risk clinical participants, but the genetic contribution to such a deficit has remained unresolved. Here, for the first time, we use a genetic risk score approach to assess the relationship between genetic risk for schizophrenia and visual gamma activity in a population-based sample drawn from a birth cohort. We compared visual gamma activity in a group (N = 104) with a high genetic risk profile score for schizophrenia (SCZ-PRS) to a group with low SCZ-PRS (N = 99). Source-reconstructed V1 activity was extracted using beamformer analysis applied to MEG recordings using individual MRI scans. No group differences were found in the induced gamma peak amplitude or peak frequency. However, a non-parametric statistical contrast of the response spectrum revealed more robust group differences in the amplitude of high-beta/gamma power across the frequency range, suggesting that overall spectral shape carries important biological information beyond the individual frequency peak. Our findings show that changes in gamma band activity correlate with liability to schizophrenia and suggest that the index changes to synaptic function and neuronal firing patterns that are of pathophysiological relevance rather than consequences of the disorder.

BackgroundWe aimed to examine the temporal relationships between traumatic events (TE), post-traumatic stress disorder (PTSD) and non-affective psychotic disorders (NAPD).MethodsA prospective cohort study of 1 965 214 individuals born in Sweden between 1971 and 1990 examining the independent effects of interpersonal and non-interpersonal TE on incidence of PTSD and NAPD using data from linked register data (Psychiatry-Sweden). Mediation analyses tested the hypothesis that PTSD lies on a causal pathway between interpersonal trauma and NAPD.ResultsIncreasing doses of interpersonal and non-interpersonal TE were independently associated with increased risk of NAPD [linear-trend incidence rate ratios (IRR)adjusted = 2.17 [95% confidence interval (CI) 2.02–2.33] and IRRadjusted = 1.27 (95% CI 1.23–1.31), respectively]. These attenuated to a relatively small degree in 5-year time-lagged models. A similar pattern of results was observed for PTSD [linear-trend IRRadjusted = 3.43 (95% CI 3.21–3.66) and IRRadjusted = 1.45 (95% CI 1.39–1.50)]. PTSD was associated with increased risk of NAPD [IRRadjusted = 8.06 (95% CI 7.23–8.99)], which was substantially attenuated in 5-year time-lagged analyses [IRRadjusted = 4.62 (95% CI 3.65–5.87)]. There was little evidence that PTSD diagnosis mediated the relationship between interpersonal TE and NAPD [IRRadjusted = 0.92 (percentile CI 0.80–1.07)].ConclusionDespite the limitations to causal inference inherent in observational designs, the large effect-sizes observed between trauma, PTSD and NAPD in this study, consistent across sensitivity analyses, suggest that trauma may be a component cause of psychotic disorders. However, PTSD diagnosis might not be a good proxy for the likely complex psychological mechanisms mediating this association.

Summary Background Young people with psychosis are at high risk of developing cardiometabolic disorders; however, there is no suitable cardiometabolic risk prediction algorithm for this group. We aimed to develop and externally validate a cardiometabolic risk prediction algorithm for young people with psychosis. Methods We developed the Psychosis Metabolic Risk Calculator (PsyMetRiC) to predict up to 6-year risk of incident metabolic syndrome in young people (aged 16–35 years) with psychosis from commonly recorded information at baseline. We developed two PsyMetRiC versions using the forced entry method: a full model (including age, sex, ethnicity, body-mass index, smoking status, prescription of a metabolically active antipsychotic medication, HDL concentration, and triglyceride concentration) and a partial model excluding biochemical results. PsyMetRiC was developed using data from two UK psychosis early intervention services (Jan 1, 2013, to Nov 4, 2020) and externally validated in another UK early intervention service (Jan 1, 2012, to June 3, 2020). A sensitivity analysis was done in UK birth cohort participants (aged 18 years) who were at risk of developing psychosis. Algorithm performance was assessed primarily via discrimination (C statistic) and calibration (calibration plots). We did a decision curve analysis and produced an online data-visualisation app. Findings 651 patients were included in the development samples, 510 in the validation sample, and 505 in the sensitivity analysis sample. PsyMetRiC performed well at internal (full model: C 0·80, 95% CI 0·74–0·86; partial model: 0·79, 0·73–0·84) and external validation (full model: 0·75, 0·69–0·80; and partial model: 0·74, 0·67–0·79). Calibration of the full model was good, but there was evidence of slight miscalibration of the partial model. At a cutoff score of 0·18, in the full model PsyMetRiC improved net benefit by 7·95% (sensitivity 75%, 95% CI 66–82; specificity 74%, 71–78), equivalent to detecting an additional 47% of metabolic syndrome cases. Interpretation We have developed an age-appropriate algorithm to predict the risk of incident metabolic syndrome, a precursor of cardiometabolic morbidity and mortality, in young people with psychosis. PsyMetRiC has the potential to become a valuable resource for early intervention service clinicians and could enable personalised, informed health-care decisions regarding choice of antipsychotic medication and lifestyle interventions. Funding National Institute for Health Research and Wellcome Trust.

Introduction: There is increasing evidence that autistic traits are associated with psychotic experiences. However, the mechanisms underlying such associations are still unknown. In this longitudinal birth cohort study, we examine the relationship between childhood autistic traits and psychotic experiences in adolescence and young adulthood, and the influence of childhood trauma on this association.Methods: We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. We used four dichotomized measures of autistic traits (social communication difficulties at age 7, repetitive behaviour at age 5, sociability at age 3, and pragmatic language at age 9). Psychotic experiences were assessed at ages 18 and 24 using the semi-structured Psychosis-Like Symptoms interview. Traumatic experiences between ages 5 to 11 were assessed with questionnaires and interviews administered to children and parents.Results: The maximum sample with complete data was 3410 for the autistic traits-psychotic experiences analyses and 3327 for the mediation analyses. The corresponding maximum sample sizes for the imputed data analysis were 10,053 and 8121, respectively. Social communication difficulties were associated with psychotic experiences (odds ratio [OR] = 1.43, 95% confidence interval [CI] 1.01–2.02), including those that were distressing and/or frequent (OR = 1.60, 95% CI 1.02–2.52). Childhood trauma mediated approximately 40% of this association. Other autistic traits showed no consistent relationship with psychotic experiences. Results were similar when we adjusted for schizophrenia polygenic risk scores (PRS).Discussion: Childhood social communication difficulties are associated with psychotic experiences by age 24. This association does not appear to be explained by genetic risk as captured by current schizophrenia PRS. The experience of trauma may be an important, potentially modifiable pathway between autistic features and later onset of psychotic psychopathology where interventions could be targeted.

ImportanceEvidence linking parental diagnoses of inflammatory bowel disease (IBD) with offspring autism is inconclusive.ObjectiveTo investigate associations between parental diagnoses of IBD and offspring autism and elucidate their underlying aetiology by conducting four complementary studies.Design, Setting and Participants(1) Nationwide population-based cohort study using Swedish registers to examine associations between parental IBD diagnoses and autism diagnoses in offspring, (2) Linkage disequilibrium (LD)-score regression to estimate the genetic correlation between the phenotypes. (3) Polygenic risk score (PRS) analyses in the Avon Longitudinal Study of Parents and Children (ALSPAC) to investigate associations between maternal genetic liability to IBD and autism factor mean score in offspring. (4) Two-sample Mendelian randomization (MR) to assess bidirectional causal links between genetic liability to IBD and autism.ResultsObservational analyses provided evidence of an association between parental IBD diagnoses and offspring autism diagnosis in mutually adjusted models (maternal: OR= 1.32; 95% CI: 1.25 to 1.40; pPRS= 0.02; 95%CI: 0.003 to 0.05; p= 0.02; R2=0.06; Crohn’s: βPRS= 0.03; 95%CI: 0.01 to 0.05; p= 0.004; R2= 0.06; n= 7357, 50.3% male). MR analyses provided evidence of a potential causal effect of genetic liability for IBD, especially ulcerative colitis, on autism (ORMR= 1.03; 95%CI: 1.01 to 1.06). There was little evidence to suggest a causal effect of genetic liability to autism on risk of IBD, or a genetic correlation between the two conditions.Conclusions and relevanceTriangulating evidence from a nationwide register-based cohort study, genetic correlation, polygenic risk score analyses and MR, we found evidence of a potentially causal link between parental, particularly maternal, diagnoses and genetic liability to IBD and offspring autism. Perinatal immune system dysregulation, micronutrient malabsorption and anaemia may be implicated.

Evidence linking parental inflammatory bowel disease (IBD) with autism in children is inconclusive. We conducted four complementary studies to investigate associations between parental IBD and autism in children, and elucidated their underlying etiology. Conducting a nationwide population-based cohort study using Swedish registers, we found evidence of associations between parental diagnoses of IBD and autism in children. Polygenic risk score analyses of the Avon Longitudinal Study of Parents and Children suggested associations between maternal genetic liability to IBD and autistic traits in children. Two-sample Mendelian randomization analyses provided evidence of a potential causal effect of genetic liability to IBD, especially ulcerative colitis, on autism. Linkage disequilibrium score regression did not indicate a genetic correlation between IBD and autism. Triangulating evidence from these four complementary approaches, we found evidence of a potential causal link between parental, particularly maternal, IBD and autism in children. Perinatal immune dysregulation, micronutrient malabsorption and anemia may be implicated.

Background Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia. Methods and findings We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38–6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36–0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37–2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85–1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant. Conclusions Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance., In a Mendelian randomization study, Benjamin Perry and colleagues investigate the genetic evidence supporting relationships between inflammation, insulin resistance, and schizophrenia., Author summary Why was this study done? Cardiometabolic disorders such as diabetes are up to 30% more common in people with schizophrenia than in the general population, and are among the predominant causes of a 10- to 15-year shortened life expectancy in people with schizophrenia. Insulin resistance, a precursor to diabetes, is sometimes detectable in young adults suffering their first episode of psychosis, which suggests that chronic lifestyle and clinical factors, such as smoking, physical inactivity, and medication side effects may not fully explain the comorbidity. Inflammation has been consistently associated with schizophrenia and cardiometabolic disorders, and so could be a common mechanism for schizophrenia and cardiometabolic disorders. This could help to at least in part explain why people who have schizophrenia also have higher rates of cardiometabolic disorders, over and above the commonly attributed lifestyle/clinical factors. What did the researchers do and find? To examine whether insulin resistance and 7 related cardiometabolic traits causally influence schizophrenia risk or vice versa, we conducted bidirectional, two-sample, uni- and multivariable mendelian randomizsation (MR) analyses. The MR approach uses genetic variants as proxies for modifiable exposures to untangle the problems of reverse causation and unmeasured confounding. To test a hypothesis that inflammation may be a common mechanism for schizophrenia and cardiometabolic disorders, we also examined a subset of genetic variants which were associated with inflammation as well as the cardiometabolic trait. We also used multivariable MR (MVMR) as a sensitivity analysis to adjust for C-reactive protein (CRP), an archetypal inflammatory marker, as a general downstream marker of systemic inflammation. After correction for multiple testing, overall, there was no significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we found evidence that supports a causal relationship of an inflammation-related insulin resistance phenotype with schizophrenia. Evidence for the association of an inflammation-related insulin resistance phenotype with schizophrenia attenuated fully in MVMR analysis after adjusting for CRP, suggesting that these associations may be underpinned by inflammation. What do these findings mean? These results suggest that cardiometabolic traits are unlikely to have a causal role in the pathogenesis of schizophrenia or vice versa. However, our results suggest that inflammation is related to the risk of both schizophrenia and insulin resistance, which may at least partly explain why they commonly occur in clinical practice. Treating or preventing inflammation may be a putative therapeutic option for prevention and/or treatment of both schizophrenia and comorbid insulin resistance. In the future, more research is needed to understand the biological mechanisms underpinning how inflammation may increase the risk of schizophrenia and insulin resistance.

Background: Psychosis and type 2 diabetes mellitus (T2DM) are commonly comorbid and may share pathophysiologic mechanisms. To investigate shared genetic variation and inflammation as potential common mechanisms, we tested: (i) associations between genetic predisposition for T2DM and psychotic experiences and psychotic disorder in young adults; (ii) the association between genetic predisposition for schizophrenia and insulin resistance (IR), a precursor of T2DM; and (iii) whether these associations are mediated by childhood inflammation.Methods: Psychotic experiences (PEs), psychotic disorder and IR were assessed at age 18. Polygenic risk scores (PRS) for T2DM and schizophrenia were derived based on large genome-wide association studies. Associations between PRS and psychotic/IR outcomes were assessed using regression analysis based on 3,768 ALSPAC birth cohort participants with complete data. Inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) measured at age 9 were used in regression and mediation analyses. Results: Genetic predisposition for T2DM was associated with PEs (adjusted OR=1.21; 95% CI, 1.01-1.45) and psychotic disorder (adjusted OR=1.51; 95% CI, 1.04-2.03) at age 18 in a linear dose-response fashion. Genetic predisposition for schizophrenia was weakly associated with IR (adjusted OR=1.10; 95% C.I, 0.99-1.22) at age 18. The association between genetic risk for T2DM and PEs was partly mediated by childhood CRP (p=0.040). Conclusions: Comorbidity between psychosis and T2DM may be partly underpinned by shared genes and inflammation. A summation of minor genetic variation representing lifetime risk for T2DM at conception may predispose individuals to psychosis in adulthood by influencing physiologic changes, such as low-grade inflammation, detectable as early as childhood.

SummaryBackgroundThe impact of COVID-19 on mental health is unclear. Evidence from longitudinal studies with pre pandemic data are needed to address (1) how mental health has changed from pre-pandemic levels to during the COVID-19 pandemic and (2), whether there are groups at greater risk of poorer mental health during the pandemic?MethodsWe used data from COVID-19 surveys (completed through April/May 2020), nested within two large longitudinal population cohorts with harmonised measures of mental health: two generations of the Avon Longitudinal Study of Parents and Children (ALPSAC): the index generation ALSPAC-G1 (n= 2850, mean age 28) and the parent’s generation ALSPAC-G0 (n= 3720, mean age = 59) and Generation Scotland: Scottish Family Health Study (GS, (n= 4233, mean age = 59), both with validated pre-pandemic measures of mental health and baseline factors. To answer question 1, we used ALSPAC-G1, which has identical mental health measures before and during the pandemic. Question 2 was addressed using both studies, using pre-pandemic and COVID-19 specific factors to explore associations with depression and anxiety in COVID-19.FindingsIn ALSPAC-G1 there was evidence that anxiety and lower wellbeing, but not depression, had increased in COVID-19 from pre-pandemic assessments. The percentage of individuals with probable anxiety disorder was almost double during COVID-19: 24% (95% CI 23%, 26%) compared to pre-pandemic levels (13%, 95% CI 12%, 14%), with clinically relevant effect sizes. In both ALSPAC and GS, depression and anxiety were greater in younger populations, women, those with pre-existing mental and physical health conditions, those living alone and in socio-economic adversity. We did not detect evidence for elevated risk in key workers or health care workers.InterpretationThese results suggest increases in anxiety and lower wellbeing that may be related to the COVID-19 pandemic and/or its management, particularly in young people. This research highlights that specific groups may be disproportionally at risk of elevated levels of depression and anxiety during COVID-19 and supports recent calls for increasing funds for mental health services.FundingThe UK Medical Research Council (MRC), the Wellcome Trust and University of Bristol.

Copy number variants (CNVs) are associated with psychiatric conditions in clinical populations. The relationship between rare CNV burden and neuropsychiatric traits in young, general populations is underexplored. A total of 6,807 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) were studied. CNVs were inferred from single nucleotide polymorphism-array data using PennCNV. After excluding children with known candidate CNVs for schizophrenia (SCZ), rare (

Highlights • Using CRP data from age 9, 15 and 18 we identified four population subgroups. • The subgroups represent persistently low, persistently high; decreasing; increasing CRP levels. • Increasing CRP levels were associated with moderate/severe depression at age 18., Background Meta-analyses confirm increased circulating C-reactive protein (CRP) levels in depression. Longitudinal studies have linked one-off measurements of CRP at baseline with increased risk of developing depressive symptoms subsequently at follow-up, but studies with repeat CRP measures from the same individuals are scarce. Methods We have examined whether longitudinal patterns of inflammation, based on three CRP measurements from childhood to early-adulthood, are associated with the risk of depression in early-adulthood in the Avon Longitudinal Study of Parents and Children, a prospective birth cohort. Results Using Gaussian mixture modelling of available CRP data from age 9, 15 and 18 years, we identified four population clusters/sub-groups reflecting different longitudinal patterns of CRP: persistently low (N = 463, 29.5%); persistently high (N = 371, 24%); decreasing (N = 360, 23%); increasing (N = 367, 23.5%). The increasing group showed a steep increase in CRP levels between adolescence and early-adulthood. Participants in this group had a higher risk of moderate/severe depression at age 18 years, compared with those with persistently low CRP; adjusted odds ratio (OR) = 3.78 (95% Confidence Interval (CI), 1.46–9.81; p = 0.006). The odds of moderate/severe depression were also increased for the persistently high CRP group, but this was not statistically significant; OR = 2.54 (95% CI, 0.90–7.16). Limitations Repeat CRP measures were available for a subset, who may not be representative of all cohort participants. Conclusions The results suggest that an increasing pattern of inflammation from adolescence to early-adulthood is associated with risk of depression in early-adulthood.

This paper corrects and updates a paper published in BJPsych Open 2018 “Mental Health in UK Biobank” (https://doi.org/10.1192/bjo.2018.12) that was voluntarily retracted following the finding of errors in the coding of the variable for alcohol use disorder. Notably, the percentage of participants reaching threshold for alcohol use disorder on the Alcohol Use Disorder Identification Tool increased from 7% to 21%.BackgroundUK Biobank is a well-characterised cohort of over 500,000 participants that offers unique opportunities to investigate multiple diseases and risk factors. An online mental health questionnaire completed by UK Biobank participants expands the potential for research into mental disorders.MethodsAn expert working group designed the questionnaire, using established measures where possible, and consulting with a service user group regarding acceptability. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and alcohol use disorders.Results157,366 completed online questionnaires were available by August 2017. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was the most common finding in 24% of participants (37,434), with current alcohol use disorder criteria met by 21% (32,602), while other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation.ConclusionsThe questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed due to selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.

Nutritional psychiatry is a growing area of research, with several nutritional factors implicated in the cause of psychiatric ill-health. However, nutritional research is highly complex, with multiple potential factors involved, highly confounded exposures and small effect sizes for individual nutrients. This Personal View considers whether Mendelian randomisation provides a solution to these difficulties, by investigating causality in a low-risk and low-cost way. We reviewed studies using Mendelian randomisation in nutritional psychiatry, along with the potential opportunities and challenges of using this approach for investigating the causal effects of nutritional exposures. Several studies have identified nutritional exposures that are potentially causal by using Mendelian randomisation in psychiatry, offering opportunities for further mechanistic research, intervention development, and replication. The use of Mendelian randomisation as a foundation for intervention development facilitates the best use of resources in an emerging discipline in which opportunities are rich, but resources are often poor.

AimsDeficits in social cognition (the ability to recognise and understand emotions, intentions and actions in oneself and in others) have been found in people with post-traumatic stress disorder (PTSD). Few studies so far have examined whether social cognitive ability impacts on PTSD recovery. Here we present a protocol and preliminary data for a study that aims to evaluate whether pre-treatment social cognitive deficits are associated with treatment outcomes following trauma-focused therapy for PTSD.MethodThe protocol was developed after discussion with Patient and Public Involvement (PPI) groups, and a battery of social cognitive tasks was trialled on 20 participants without PTSD. The final protocol was then developed using information and feedback from these preliminary studies. We aim to recruit 60 individuals who are about to start a trauma-focused therapy for PTSD within the two tertiary PTSD services. Social cognition (measured using a variety of tasks including Reading the Mind in the Eyes Task and the Reflective Functioning Questionnaire) and potential confounders (including severity of trauma history, attachment and verbal IQ) are assessed at baseline, prior to the start of therapy. PTSD symptom severity (measured using the PCL-5) and daily functioning (measured using the WSAS) are assessed pre and post-treatment. The primary aim of the study is to examine whether baseline social cognition is associated with the degree of improvement in the PCL-5.ResultSo far 29 participants have been recruited and consented. 6 participants have completed follow-up assessments. The study has been adapted for the COVID-19 pandemic so participants can complete the tasks remotely. Preliminary results show a moderate negative correlation between baseline social cognitive abilities and baseline PTSD symptom severity (Spearman's correlation -0.30) and functional abilities (Spearman's correlation -0.42).ConclusionDevelopment of our study in collaboration with PPI and preliminary testing of measures suggests it is likely that it will be feasible for us to conduct this study in this patient group. Baseline preliminary results show/suggest a moderate correlation between PTSD symptom severity and social cognitive impairment. Our main analyses, when completed, will help to determine whether social cognitive ability is associated with recovery from PTSD.

Highlights • At symptom level, IL-6 is associated with diurnal variation in mood, concentration difficulties, fatigue and sleep disturbances. • These are so-called somatic/neurovegetative symptoms of depression. • At dimension level, IL-6 is associated with both somatic/neurovegetative and psychological symptom dimensions. • Somatic/neurovegetative symptoms could be useful treatment targets and markers of treatment response in clinical trials of anti-inflammatory treatment for depression., Background Low-grade inflammation is associated with depression, but studies of specific symptoms are relatively scarce. Association between inflammatory markers and specific symptoms may provide insights into potential mechanism of inflammation-related depression. Using longitudinal data, we have tested whether childhood serum interleukin 6 (IL-6) and C-reactive protein (CRP) levels are associated with specific depressive symptoms in early adulthood. Methods In the ALSPAC birth cohort, serum IL-6 and CRP levels were assessed at age 9 years and 19 depressive symptoms were assessed at age 18 years. We used modified Poisson generalised linear regression with robust error variance to estimate the risk ratio (RR) and 95% confidence interval (95% CI) for each depressive symptom. In addition, we used confirmatory factor analysis to create two continuous latent variables representing somatic/neurovegetative and psychological dimension scores. Structural equation modelling was used to test the associations between IL-6 and these dimension scores. Results Based on data from 2731 participants, IL-6 was associated with diurnal mood variation, concentration difficulties, fatigue and sleep disturbances. The adjusted RRs for these symptoms at age 18 years for participants in top, compared with bottom, third of IL-6 at age 9 years were 1.75 (95% CI, 1.13–2.69) for diurnal mood variation, 1.50 (95% CI, 1.11–2.02) for concentration difficulties, 1.31 (95% CI, 1.12–1.54) for fatigue, and 1.24 (95% CI, 1.01–1.52) for sleep disturbances. At dimension level, IL-6 was associated with both somatic/neurovegetative (β = 0.059, SE = 0.024, P = 0.013) and psychological (β = 0.056, SE = 0.023, P = 0.016) scores. Conclusions Inflammation is associated with specific symptoms of depression. Associations with so-called somatic/neurovegetative symptoms of depression such as fatigue, sleep disturbances and diurnal mood variation indicate that these symptoms could be useful treatment targets and markers of treatment response in clinical trials of anti-inflammatory treatment for depression.

Contains fulltext : 169834.pdf (Publisher’s version ) (Open Access) Contains fulltext : 169834pos.pdf (Author’s version postprint ) (Open Access) BACKGROUND: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0.0156. FINDINGS: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0.15), amygdala (d=-0.19), caudate (d=-0.11), hippocampus (d=-0.11), putamen (d=-0.14), and intracranial volume (d=-0.10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0.95) and thalamus (p=0.39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (21 years): in the accumbens (Cohen's d=-0.19 vs -0.10), amygdala (d=-0.18 vs -0.14), caudate (d=-0.13 vs -0.07), hippocampus (d=-0.12 vs -0.06), putamen (d=-0.18 vs -0.08), and intracranial volume (d=-0.14 vs 0.01). There was no difference between children and adults for the pallidum (p=0.79) or thalamus (p=0.89). Case-control differences in adults were non-significant (all p>0.03). Psychostimulant medication use (all p>0.15) or symptom scores (all p>0.02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0.5). INTERPRETATION: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING: National Institutes of Health. 10 p.

Purpose To investigate the longitudinal associations between social cognitive ability an external locus of control (externality) and adolescent psychopathology. Methods 7058 participants from a prospective population-based cohort provided data on externality, social communication, and emotion perception between 7 and 16 years and psychotic experiences and depressive symptoms at 12 and 18 years. Bivariate probit modelling was used to investigate associations between these risk factors and psychopathological outcomes. Results Externality was associated with psychopathology at 12 (psychotic experiences OR 1.23 95% CI 1.14, 1.33; depression OR 1.12 95% CI 1.02, 1.22) and 18 years (psychotic experiences OR 1.38 95% CI 1.23, 1.55; depression OR 1.40 95% CI 1.28, 1.52). Poor social communication was associated with depression at both ages (12 years OR 1.22 95% CI 1.11, 1.34; 18 years OR 1.21 95% CI 1.10, 1.33) and marginally associated with psychotic experiences. There was marginal evidence of a larger association between externality and psychotic experiences at 12 years (p = 0.06) and between social communication and depression at 12 years (p = 0.03). Conclusions Externality was more strongly associated with psychotic experiences. At 18 years change in externality, between 8 and 16 years were associated with a larger increase in the risk of depression. Poor social communication was more strongly associated with depression. Electronic supplementary material The online version of this article (doi:10.1007/s00127-017-1359-z) contains supplementary material, which is available to authorized users.

Background Early life adversity (ELA), including physical abuse or neglect and emotional abuse or neglect, is a significant risk factor for schizophrenia. Changes in cognitive function, and in particular social cognition, are also associated with this disorder. In psychosis, ELA and cognitive deficits have, separately, been associated with an increased immune response. In this study we sought to determine whether ELA’s might affect cognitive performance and if so, whether these affects were mediated via an impact on immune response. Methods We investigated the relationship between ELA, immune response and cognition in the Avon Longitudinal study of parents and children (ALSPAC; n~5,000). ELA was defined in terms of the experience of physical abuse or neglect, emotional abuse or neglect, witnessing domestic violence, and harsh parenting before the age of 5 years. Social cognition was defined in terms of performance on theory of mind while general cognitive ability was defined in terms of IQ. Immune function was measured using C-reactive protein and Interleukin-6. Analysis was run both for the full sample and for individuals presenting with a history of psychotic symptoms at age 12. Results Early life adversity was associated with poorer performance on a range of both general and social cognitive measures. Increased immune activation was associated with cognitive performance, but was not observed to mediate the effects of ELA on cognition. Comparable findings were observed in children presenting with and without psychotic symptoms. Discussion While increased immune response has been associated with both early life adversity and cognitive impairment, this response was not observed to mediate the relationship between these two variables. Alternative hypothesis for the mechanism by which ELA may result in poorer cognitive performance, including attachment related effects, will be discussed.

Background Some childhood speech and language impairments precede psychosis but it is not clear whether they also precede adolescent psychotic experiences and whether this association is specific to psychotic experiences. Methods Pragmatic language and expressive speech and language (parent-assessed using the Children's Communication Checklist) at age 9 and psychotic experiences and depression at ages 12 and 18 were investigated in 7659 participants from the Avon Longitudinal Study of Parents and Children. Associations were investigated using multivariate modelling. Results Poorer pragmatic language at 9 years was associated with psychotic experiences at both ages (12 years OR 1.22, 95% CI 1.11, 1.34; 18 years OR 1.25, 95% CI 1.10, 1.41) but only with depression at 18 years (OR 1.10, 95% CI 1.00, 1.22). Poorer expressive speech and language ability was not associated with psychotic experiences or depression at either age. There was evidence that pragmatic language was specifically associated with psychotic experiences at age 12 but no evidence that the strength of any of the associations changed over time. Conclusions Deficits in pragmatic language precede early and late adolescent psychotic experiences and early adolescent depression. Interventions aimed at helping children improve pragmatic language skills may reduce the incidence of adolescent psychopathology and associated psychological disorder and dysfunction later in life.

Background International studies indicate that the median prevalence of psychotic experiences in children is 7%. It has been proposed that environmental stress during pregnancy may affect the neurodevelopment of the foetus and lead to a vulnerability in the child to later stressors and psychopathology. Aim In this study we explore the relationship between environmental stress during pregnancy and psychotic experiences in children in the general population at 12 years. Methods We analysed a birth cohort of 5038 children from the Avon Longitudinal Study of Parents and Children. Environmental stress was measured as life event exposure. Data on life events were collected on women during their pregnancy, whilst psychotic experiences in the offspring were assessed at age 12. Results There was a weak association between maternal exposure to life events and psychotic experiences at twelve years (crude OR 1.10 95% CI 1.02–1.18) per quartile of life event score. This association was not reduced after adjustment for socio-economic status, family history of schizophrenia, maternal education or birth weight but after adjustment for maternal anxiety and depression and smoking in early pregnancy there was no longer any evidence for an association (OR 1.01 95% CI 0.93–1.10). Conclusion This study provides some evidence to suggest that stressful life events may affect child psychotic experiences through effects on maternal psychopathology, and possibly physiology, during pregnancy.