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Background\udPsychotic experiences (PEs) are associated with an increased risk of future psychotic and non-psychotic mental disorders. The identification of biomarkers of PEs may provide insights regarding the underlying pathophysiology.\ud\udMethods\udThe current study applied targeted lipidomic approaches to compare plasma lipid profiles in participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort who did (n = 206) or did not (n = 206) have PEs when aged approximately 24 years.\ud\udResults\udIn total, 202 lipids including 8 lipid classes were measured by using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Eight lipid clusters were generated. Thirteen individual lipids were nominally significantly higher in the PEs group compared to the control group. After correction for multiple comparisons, 9 lipids comprising 3 lysophosphatidylcholines (LPCs), 2 phosphatidylcholines (PCs) and 4 triacylglycerols (TGs) remained significant. In addition, PEs cases had increased levels of TGs and LPCs with a low double bond count.\ud\udConclusions\udThese findings indicate plasma lipidomic abnormalities in individuals experiencing PEs. The lipidomic profile measures could aid our understanding of the underlying pathophysiological mechanisms.

Highlights • Childhood trauma was associated with increased risk of depression in adulthood. • Prenatal and postnatal stress, indicated by maternal depression and family adversity, were associated with increased exposure to childhood trauma. • Childhood trauma mediated all pathways from pre- and postnatal stress to offspring depression in adulthood, even after accounting for genetic risks., Background There is repeated evidence for a prenatal programming effect for the development of offspring depression. However, examination of environmental influences along this pathway is sparse. This study aimed to investigate the direct and indirect effects of pre- and postnatal stress on offspring depression in adulthood, via increased exposure to childhood trauma. Methods A large longitudinal population-based cohort (N = 3506) was followed up from birth and assessed at 24 years. Diagnosis of depression was derived using the International Classification of Diseases–10th revision (ICD-10). Two separate sources of pre- and postnatal stress were examined – maternal depression and family adversity, and childhood trauma was assessed prospectively across childhood until 17 years. Results Both pre- and postnatal maternal depression and family adversity were associated with offspring depression at 24 years in simple logistic regression models. When all pathways were modelled simultaneously, only childhood trauma was directly associated with offspring depression, and mediated all pathways from both sources of pre- and postnatal stress to offspring depression (7–16% of the total effect mediated). Sensitivity analysis on specific trauma found stronger evidence for a mediated pathway via physical, emotional abuse and peer bullying, compared to emotional neglect, sexual abuse and domestic violence. Conclusions These findings indicate that reducing childhood trauma could be a target to decrease depression in the general population, and the focus should also be on families at high risk of experiencing pre- or postnatal stress, to provide them with better support.

BACKGROUND: Altered functional brain connectivity has been proposed as an intermediate phenotype between genetic risk loci and clinical expression of schizophrenia. Genetic high-risk groups of healthy subjects are particularly suited for the investigation of this proposition because they can be tested in the absence of medication or other secondary effects of schizophrenia. METHODS: Here, we applied dynamic functional connectivity analysis to functional magnetic resonance imaging data to reveal the reconfiguration of brain networks during a cognitive task. We recruited healthy carriers of common risk variants using the recall-by-genotype design. We assessed 197 individuals: 99 individuals (52 female, 47 male) with low polygenic risk scores (schizophrenia risk profile scores [SCZ-PRSs]) and 98 individuals (52 female, 46 male) with high SCZ-PRSs from both tails of the SCZ-PRS distribution from a genotyped population cohort, the Avon Longitudinal Study of Parents and Children (N = 8169). We compared groups both on conventional brain activation profiles, using the general linear model of the experiment, and on the neural flexibility index, which quantifies how frequent a brain region's community affiliation changes over experimental time. RESULTS: Behavioral performance and standard brain activation profiles did not differ significantly between groups. High SCZ-PRS was associated with reduced flexibility index and network modularity across n-back levels. The whole-brain flexibility index and that of the frontoparietal working memory network was associated with n-back performance. We identified a dynamic network phenotype related to high SCZ-PRS. CONCLUSIONS: Such neurophysiological markers can become important for the elucidation of biological mechanisms of schizophrenia and, particularly, the associated cognitive deficit.

A greater understanding of why some people are more at risk of developing PTSD is required. We examine the relationship between temperament traits in early childhood and subsequent trauma exposure and risk of PTSD. We used data on 2017 participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). Temperament was measured using the Carey Infant Temperament Scale (average score from ages 6 and 24 months). This provided data on 9 individuals traits, and Easy, Medium, and Difficult temperament clusters. Trauma exposure was measured from 0-17 years, and PTSD at age 23 years using the PTSD Checklist for DSM-V (PCL-5). Regression models were used to estimate associations between temperament and both trauma and PTSD, and to examine mediation (of temperament to PTSD pathway) and interaction (temperament X trauma on PTSD) effects.1178 (58.4%) individuals were exposed to a trauma in childhood and 112 (5.5%) had PTSD. Higher levels of Intensity were associated with a small increase in trauma exposure (ORadjusted1.23, 95% CI 1.12, 1.34; p Higher levels of Activity, Adaptability, Mood and Threshold temperament traits were also associated with trauma exposure. Medium (ORadjusted 1.49, 95% CI 1.21, 1.84; p with increased trauma exposure compared to an Easy cluster, but were notassociated with PTSD. The relationship between trait Intensity and adult PTSD was partially mediated by childhood/adolescent trauma (Indirect ORadjusted 1.08, 95% CI 1.01, 1.16, p = 0.024, proportion mediated 26.2%). There was some evidence that trait Intensity modified the relationship between trauma and PTSD (ORadjusted 1.66, 95% CI 1.07, 2.55, p = 0.023). PTSD in early adulthood is more common in those with intense stimuli responsiveness in childhood. Temperament traits might be useful predictors of trauma exposure and mental health outcomes and offer potential targets for supportive interventions. Journal Pre-proof 3KeywordsPTSD; temperament; trauma; cohort study; ALSPAC.

Summary Background Although studies suggest that concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence for beneficial effects of fatty acid supplementation is scarce. Therefore, in this study, we aimed to determine whether omega-3 and omega-6 fatty acid concentrations are causally related to schizophrenia. Methods We did a two-sample Mendelian randomisation study, using deidentified summary-level data that were publicly available. Exposure-outcome relationships were evaluated using the inverse variance weighted two-sample Mendelian randomisation method using results from genome-wide association studies (GWASs) of fatty acid concentrations and schizophrenia. GWAS results were available for European (fatty acids) and European and Asian (schizophrenia) ancestry samples. Overall age and gender information were not calculable from the summary-level GWAS results. Weighted median, weighted mode, and Mendelian randomisation Egger regression methods were used as sensitivity analyses. To address underlying mechanisms, further analyses were done using single instruments within the FADS gene cluster and ELOVL2 gene locus. FADS gene cluster and ELOVL2 gene causal effects on schizophrenia were calculated by dividing the single nucleotide polymorphism (SNP)-schizophrenia effect estimate by the SNP-fatty acid effect estimate with standard errors derived using the first term from a delta method expansion for the ratio estimate. Multivariable Mendelian randomisation was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins (ie, HDL and LDL), and triglycerides. Findings Mendelian randomisation analyses indicated that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with a lower risk of schizophrenia (eg, inverse variance weighted odds ratio [OR] 0·83 [95% CI 0·75–0·92] for docosahexaenoic acid). By contrast, there was weak evidence that short-chain omega-3 and short-chain omega-6 fatty acids were associated with an increased risk of schizophrenia (eg, inverse variance weighted OR 1·07 [95% CI 0·98–1·18] for α-linolenic acid). Effects were consistent across the sensitivity analyses and the FADS single-SNP analyses, suggesting that long-chain omega-3 and long-chain omega-6 fatty acid concentrations were associated with lower risk of schizophrenia (eg, OR 0·74 [95% CI 0·58–0·96] for docosahexaenoic acid) whereas short-chain omega-3 and short-chain omega-6 fatty acid concentrations were associated with an increased risk of schizophrenia (eg, OR 1·08 [95% CI 1·02–1·15] for α-linolenic acid). By contrast, estimates from the ELOVL2 single-SNP analyses were more imprecise and compatible with both risk-increasing and protective effects for each of the fatty acid measures. Multivariable Mendelian randomisation indicated that the protective effect of docosahexaenoic acid on schizophrenia persisted after conditioning on other lipids, although evidence was slightly weaker (multivariable inverse variance weighted OR 0·84 [95% CI 0·71–1·01]). Interpretation Our results are compatible with the protective effects of long-chain omega-3 and long-chain omega-6 fatty acids on schizophrenia, suggesting that people with schizophrenia might have difficulty converting short-chain polyunsaturated fatty acids to long-chain polyunsaturated fatty acids. Further studies are required to determine whether long-chain polyunsaturated fatty acid supplementation or diet enrichment might help prevent onset of schizophrenia. Funding National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol.

Background Schizophrenia is associated with elevated levels of circulating C-reactive protein (CRP) and other inflammatory markers, but it is unclear whether these associations extend to psychotic symptoms occurring in adolescence in the general population. A symptom-based approach may provide important clues for apparent trans-diagnostic effect of inflammation, which is also associated with depression and other psychiatric disorders. Methods Based on data from 2421 participants from the Avon Longitudinal Study of Parents and Children birth cohort, we examined associations of serum CRP levels assessed around age 16 with ten positive and ten negative symptoms of psychosis assessed using questionnaires around age 17, using both individual symptoms and symptom dimension scores as outcomes. Regression models were adjusted for sex, body mass index, depressive symptoms, substance use, and other potential confounders. Results Most prevalent positive symptoms were paranoid ideation (4.8%), visual (4.3%) and auditory (3.5%) hallucinations. Negative symptoms were more strongly correlated with concurrent depressive symptoms (r=0.51; P, Highlights • We examined psychotic symptoms in adolescents from a population-based birth cohort. • Common positive symptoms were paranoid ideation, visual and auditory hallucinations. • Negative symptoms were correlated with depressive and positive symptoms. • CRP was similarly associated with positive and negative symptom dimension scores. • CRP was specifically associated with auditory hallucinations and anhedonia.

BackgroundTraumatic experiences are associated with a higher risk of psychotic illnesses, but little is known about potentially modifiable mechanisms underlying this relationship. This study aims to examine whether post-traumatic stress disorder (PTSD) symptoms mediate the relationship between trauma and psychotic experiences (PEs).MethodsWe used data from the Avon Longitudinal Study of Parents and Children to examine whether: PTSD symptoms mediate the relationships between (a) childhood trauma and adolescent PEs (study of adolescent PEs; n = 2952), and (b) childhood/adolescent trauma and PEs in early adulthood (study of adult PEs; n = 2492). We examined associations between variables using logistic regression, and mediation using the parametric g-computation formula.ResultsExposure to trauma was associated with increased odds of PEs (adolescent PEs: ORadjusted 1.48, 95% CI 1.23–1.78; adult PEs: ORadjusted 1.57, 95% CI 1.25–1.98) and PTSD symptoms (adolescent PTSD: ORadjusted 1.59, 95% CI 1.31–1.93; adult PTSD: ORadjusted 1.50, 95% CI 1.36–1.65). The association between PTSD symptoms and PE was stronger in adolescence (ORadjusted 4.63, 95% CI 2.34–9.17) than in adulthood (ORadjusted 1.62, 95% CI 0.80–3.25). There was some evidence that PTSD symptoms mediated the relationship between childhood trauma and adolescent PEs (proportion mediated 14%), though evidence of mediation was weaker for adult PEs (proportion mediated 8%).ConclusionsThese findings are consistent with the hypothesis that PTSD symptoms partly mediate the association between trauma exposure and PEs. Targeting PTSD symptoms might help prevent the onset of psychotic outcomes.

BackgroundEarly intervention in people with an at-risk mental state for psychosis can decrease the rates of transition to psychosis. GPs play a key role in the identification of this patient group but very few studies have explored GPs’ awareness of patients who are at risk of psychosis.AimTo explore GPs’ views and experiences of identifying patients with an at-risk mental state for psychosis, and the barriers and facilitators to identification.Design and settingIn-depth semi-structured interviews were held with GPs working in South West England primary care. The interviews were conducted between March and July 2019.MethodA topic guide was used to ensure consistency across interviews. This guide was revised to incorporate a definition of the at-risk mental state for psychosis, as after conducting a few interviews it became clear that some GPs were not familiar with this construct. Interviews were audiorecorded and analysed thematically.ResultsA total of 20 GPs were interviewed. Some GPs were not familiar with the concept of being at risk of developing psychosis, and perceived that they may not have the right skills to identify this patient group. Other barriers related to patients not presenting or disclosing psychotic symptoms, and limitations imposed by scarce resources on the structure and provision of NHS services, such as lack of continuity of care and high thresholds for accessing specialised services.ConclusionIdentifying people at risk of psychosis in primary care is difficult. Provision of GP training, development of policies that support continuity of care, and improved access to specialised services could help improve the identification of this patient group.

BackgroundIt is not clear to what extent associations between schizophrenia, cannabis use and cigarette use are due to a shared genetic etiology. We, therefore, examined whether schizophrenia genetic risk associates with longitudinal patterns of cigarette and cannabis use in adolescence and mediating pathways for any association to inform potential reduction strategies.MethodsAssociations between schizophrenia polygenic scores and longitudinal latent classes of cigarette and cannabis use from ages 14 to 19 years were investigated in up to 3925 individuals in the Avon Longitudinal Study of Parents and Children. Mediation models were estimated to assess the potential mediating effects of a range of cognitive, emotional, and behavioral phenotypes.ResultsThe schizophrenia polygenic score, based on single nucleotide polymorphisms meeting a training-set p threshold of 0.05, was associated with late-onset cannabis use (OR = 1.23; 95% CI = 1.08,1.41), but not with cigarette or early-onset cannabis use classes. This association was not mediated through lower IQ, victimization, emotional difficulties, antisocial behavior, impulsivity, or poorer social relationships during childhood. Sensitivity analyses adjusting for genetic liability to cannabis or cigarette use, using polygenic scores excluding the CHRNA5-A3-B4 gene cluster, or basing scores on a 0.5 training-set p threshold, provided results consistent with our main analyses.ConclusionsOur study provides evidence that genetic risk for schizophrenia is associated with patterns of cannabis use during adolescence. Investigation of pathways other than the cognitive, emotional, and behavioral phenotypes examined here is required to identify modifiable targets to reduce the public health burden of cannabis use in the population.

Aims To quantify the relationship between alcohol and violence with increasing age. Methods Data were from The National Longitudinal Study of Adolescent to Adult Health (ADD Health) of 20,386 people representative of the US population. Mean age at the first wave of interviews was 16.2 years, with subsequent interviews mean of 1, 6.3 and 12.9 years later. We used random-effects models and predictive marginal effects of the association between varying quantities of alcohol consumption and violence while controlling for possible confounders. Results Violence was reported by 19.1% of participants at wave I but just 2.1% at wave IV. The random-effects model showed that consuming 1–4 drinks on each occasion was associated with a modest increase in risk of violence in both males (odds ratio (OR) 1.36, 95% CI 1.13–1.63) and females (OR 1.33, 95% CI 1.03–1.72). For consumption of five or more drinks on each occasion, the risk remained similar for females (OR 1.40 (0.99–1.97)) but increased considerably for males (OR 2.41 (1.96–2.95)). Predictive marginal effects models confirmed that violence rates decreased with age. Conclusions Alcohol is most strongly linked to violence among adolescents, so programmes for primary prevention of alcohol-related violence are best targeted towards this age group, particularly males who engage in heavy episodic drinking.

Background Domestic violence and abuse (DVA) is common and destructive to health. Post-traumatic stress disorder (PTSD) is a major mental health consequence of DVA. People who have experienced DVA have specific needs, arising from the repeated and complex nature of the trauma. The National Institute for Health and Care Excellence recommends more research on the effectiveness of psychological interventions for people who have experienced DVA. There is growing evidence that mindfulness-based interventions may help trauma symptoms. Methods Intervention refinement and randomized controlled feasibility trial. A prototype trauma-informed mindfulness-based cognitive therapy (TI-MBCT) intervention will be co-produced following qualitative interviews and consensus exercise with stakeholders. Participants in the feasibility trial will be recruited from DVA agencies in two geographical regions and randomized to receive either TI-MBCT or usual care (self-referral to the Improving Access to Psychological Therapies (IAPT) service). TI-MBCT will be delivered as a group-based eight-week program. It will not be possible to blind the participants or the assessors to the study allocation. The following factors will inform the feasibility of progressing to a fully powered trial: recruitment, retention, intervention fidelity, and the acceptability of the intervention and trial design to participants. We will also test the feasibility of measuring the following participant outcomes before and 6 months post-randomization: PTSD, dissociative symptoms, depression, anxiety, DVA re-victimization, self-compassion, and mother-reported child health. Process evaluation and economic analysis will be embedded within the feasibility trial. Discussion This study will lead to the development of a TI-MBCT intervention for DVA survivors with PTSD and inform the feasibility and design of a fully powered randomized controlled trial (RCT). The full trial will aim to determine the effectiveness and cost-effectiveness of a TI-MBCT intervention in improving the clinically important symptoms of PTSD in DVA survivors. Trial registration ISRCTN, ISRCTN64458065, Registered 11 January 2019.

Background\ud Early life adversity (ELA) is a significant risk factor for mental health disorders. One hypothesised mechanism by which this occurs is via an effect on immune response. In this analysis of epidemiological data, we tested whether ELA was associated with cognitive performance, and if so, whether these effects were influenced by immune function.\ud Methods\ud We investigated the longitudinal relationship between ELA, inflammatory markers, and cognition in data from Avon Longitudinal Study of Parents And Children (ALSPAC; n ~ 5000). ELA was defined in terms of physical/emotional abuse, harsh parenting, or domestic violence before 5 years. Social cognition was measured in terms of theory of mind, and general cognitive ability was measured using IQ. Inflammatory markers included serum C-reactive protein and interleukin-6 levels.\ud Results\ud A significant association was observed between IQ and harsh parenting, whereby children who were physically disciplined had lower IQ scores (accounting for relevant social factors). Both immune markers were associated with variation in cognition, however, neither accounted for the effects of ELA on cognition.\ud Discussion\ud This study highlights the impact of ELA on cognition. In the absence of evidence that these effects are explained by inflammation, other mechanisms by which the effects of ELA are mediated are discussed.

Objective: The negative control design can be used to provide evidence for whether a prenatal exposure-outcome association occurs by in-utero mechanisms. Assortative mating has been suggested to influence results from negative control designs, though how and why has not yet been adequately explained. We aimed to explain why mutual adjustment of maternal and paternal exposure in regression models can account for assortative mating. Study design and setting: We used directed acyclic graphs to show how bias can occur when modelling maternal and paternal effects separately. We empirically tested our claims using a simulation study. We investigated how increasing assortative mating influences the bias of effect estimates obtained from models that do and do not use a mutual adjustment strategy. Results:In models without mutual adjustment, increasing assortative mating lead to increasing bias in effect estimates. The maternal and paternal effect estimates were biased by each other, making the difference between them smaller than the true difference. Mutually adjusted models did not suffer from such bias. Conclusions: Mutual adjustment for maternal and paternal exposure prevents bias from assortative mating influencing the conclusions of a negative control design. We further discuss issues that mutual adjustment may not be able to resolve.

BackgroundPsychotic experiences are reported by 5–10% of young people, although only a minority persist and develop into psychotic disorders. It is unclear what characteristics differentiate those with transient psychotic experiences from those with persistent psychotic experiences that are more likely to be of clinical relevance.AimsTo investigate how longitudinal profiles of psychotic experiences, created from assessments at three different time points, are influenced by early life and co-occurring factors.MethodUsing data from 8045 individuals from a birth cohort study, longitudinal profiles of psychotic experiences based on semi-structured interviews conducted at 12, 18 and 24 years were defined. Environmental, cognitive, psychopathological and genetic determinants of these profiles were investigated, along with concurrent changes in psychopathology and cognition.ResultsFollowing multiple imputations, the distribution of longitudinal profiles of psychotic experiences was none (65.7%), transient (24.1%), low-frequency persistent (8.4%) and high-frequency persistent (1.7%). Individuals with high-frequency persistent psychotic experiences were more likely to report traumatic experiences, other psychopathology, a more externalised locus of control, reduced emotional stability and conscientious personality traits in childhood, compared with those with transient psychotic experiences. These characteristics also differed between those who had any psychotic experiences and those who did not.ConclusionsThese findings indicate that the same risk factors are associated with incidence as with persistence of psychotic experiences. Thus, it might be that the severity of exposure, rather than the presence of specific disease-modifying factors, is most likely to determine whether psychotic experiences are transient or persist, and potentially develop into a clinical disorder over time.

There is controversy about the status of schizoaffective disorder depressive-type (SA-D), particularly whether it should be considered a form of schizophrenia or a distinct disorder. We aimed to determine whether individuals with SA-D differ from individuals with schizophrenia in terms of demographic, premorbid and lifetime clinical characteristics, and genetic liability to schizophrenia, depression and bipolar disorder. Participants were from the CardiffCOGS sample and met ICD-10 criteria for schizophrenia (n=713) or SA-D (n=151). Two samples, Cardiff Affected-sib (n=354) and Cardiff F-series (n=524), were used for replication. For all samples, phenotypic data were ascertained through structured interview, review of medical records, and an ICD-10 diagnosis made by trained researchers. Univariable and multivariable logistic regression models were used to compare individuals with schizophrenia and SA-D for demographic and clinical characteristics, and polygenic risk scores (PRS). In the CardiffCOGS, SA-D, compared to schizophrenia, was associated with female sex, childhood abuse, history of alcohol dependence, higher functioning Global Assessment Scale (GAS) score in worst episode of psychosis, lower functioning GAS score in worst episode of depression, and reduced lifetime severity of disorganised symptoms. Individuals with SA-D had higher depression PRS compared to those with schizophrenia. PRS for schizophrenia and bipolar disorder did not significantly differ between SA-D and schizophrenia. Compared to individuals with schizophrenia, individuals with SA-D had higher rates of environmental and genetic risk factors for depression and a similar genetic liability to schizophrenia. These findings are consistent with SA-D being a sub-type of schizophrenia resulting from elevated liability to both schizophrenia and depression.Key words: Polygenic risk score; depression; psychosis; diagnosis; phenotypes

Background Cognitive impairment in schizophrenia is a major contributor to poor outcomes, yet its causes are poorly understood. Some rare copy number variants (CNVs) are associated with schizophrenia risk and affect cognition in healthy populations, but their contribution to cognitive impairment in schizophrenia has not been investigated. We examined the effect of 12 schizophrenia CNVs on cognition in those with schizophrenia. Methods General cognitive ability was measured using the Measurement and Treatment Research to Improve Cognition in Schizophrenia composite z score in 875 patients with schizophrenia and in a replication sample of 519 patients with schizophrenia using Wechsler Adult Intelligence Scale Full Scale IQ. Using linear regression, we tested for association between cognition and schizophrenia CNV status, covarying for age and sex. In addition, we tested whether CNVs hitting genes in schizophrenia-enriched gene sets (loss-of-function intolerant and synaptic gene sets) were associated with cognitive impairment. Results A total of 23 schizophrenia CNV carriers were identified. Schizophrenia CNV carriers had lower general cognitive ability than nonschizophrenia CNV carriers in discovery (β = −0.66, 95% confidence interval [CI] = −1.31 to −0.01) and replication samples (β = −0.91, 95% CI = −1.71 to −0.11) and after meta-analysis (β = −0.76, 95% CI = −1.26 to −0.25, p = .003). CNVs hitting loss-of-function intolerant genes were associated with lower cognition (β = −0.15, 95% CI = −0.29 to −0.001, p = .048). Conclusions In those with schizophrenia, cognitive ability in schizophrenia CNV carriers is 0.5–1.0 standard deviations below non-CNV carriers, which may have implications for clinical assessment and management. We also demonstrate that rare CNVs hitting genes intolerant to loss-of-function variation lead to more severe cognitive impairment, above and beyond the effect of known schizophrenia CNVs.

Background Urban birth is associated with risk of non-affective psychoses, but the association with subclinical positive and negative symptoms is less clear, despite emerging evidence. Further the extent to which these findings are confounded by polygenic risk scores (PRS) for schizophrenia is also unknown. Methods Using data from the Avon Longitudinal Study of Parents and Children, linked to census geographical indicators, we examined whether various indices of urbanicity at birth were associated with negative and positive psychotic symptoms at age 16 and 18 years, respectively. We used logistic regression models, controlling for child’s ethnicity, maternal age, education, marital status, social class, depressive symptoms, other neighborhood exposures, and, in a subsample of children of white ethnicity (N = 10 283), PRS for schizophrenia. Results Amongst 11 879 adolescents, those born in the most densely populated tertile had greater odds of reporting positive psychotic experiences, after multivariable adjustment (odds ratio [OR]: 1.57, 95% confidence intervals (CIs): 1.14–2.17). Adolescents born in the most socially fragmented neighborhoods had greater odds of negative symptoms, after multivariable adjustment (OR: 1.43, 95% CI: 1.06–1.85). Although we found that greater schizophrenia PRS were associated with an increased risk of being born in more deprived and fragmented (bot not more densely populated areas), these associations were not confounded by PRS. Interpretation Birth into more densely populated and socially fragmented environments increased risk of positive and negative psychotic phenomena in adolescence, respectively, suggesting that different forms of neighborhood social adversity may impinge on different psychopathophysiologies associated with the clinical expression of psychosis.

Objective: Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia. Methods: The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics. Results: The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data. Conclusions: Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia.

Background: Intellectual disability (ID) describes a neurodevelopmental condition involving impaired cognitive and functional ability. Here, we describe a multisource variable of ID using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Methods: The multisource indicator variable for ID was derived from i) IQ scores less than 70 measured at age 8 and at age 15, ii) free text fields from parent reported questionnaires, iii) school reported provision of educational services for individuals with a statement of special educational needs for cognitive impairments, iv) from relevant READ codes contained in GP records, iv) international classification of disease diagnoses contained in electronic hospital records and hospital episode statistics and v) recorded interactions with mental health services for ID contained within the mental health services data set. A case of ID was identified if two or more sources indicated ID. A second indicator, labelled as “probable ID”, was created by relaxing the cut off in IQ scores to be less than 85. An indicator variable for known causes of ID was also created to aid in aetiological studies where ID with a known cause may need to be excluded. Results: 158 of 14,370 participants (1.10%) were indicated as having ID by two or more sources and 449 (3.12%) were indicated as having probable ID when the criteria for IQ scores was relaxed to less than 85. There were 476 participants (3.31%) with 1 or fewer sources of available information on ID; these participants had their multisource variable set to missing. The number of cases of ID with known cause was 31 (0.22% of the cohort, 19.6% of those with ID). Conclusions: The multisource variable of ID can be used in future analyses on ID in ALSPAC children.

Background The association between maternal smoking in pregnancy and offspring intellectual disability (ID) is less well understood than that of smoking and fetal growth restriction. As fetal growth and cognitive development may share similar confounding structures, comparison of the two associations may improve understanding of the causal nature of the association with ID. Furthermore, comparisons of smoking with smokeless tobacco use may aid identification of mechanisms of action. Methods This was a cohort study of all Swedish births between 1999 and 2012 (n = 1 070 013), with prospectively recorded data. We assessed the association between maternal smoking during pregnancy and offspring outcomes ID and born small for gestational age (SGA). Analyses were repeated for snus use in pregnancy. Using a sibling design, we estimated within-family effects that control for shared sibling characteristics. Results Those exposed to maternal smoking in pregnancy had increased odds of ID [odds ratio (OR) = 1.24, 95% confidence interval (CI): 1.16-1.33] and SGA (OR = 2.19, 95% CI: 2.11-2.27) after confounder adjustment. Within-family effects were found for SGA (OR = 1.44, 95% CI: 1.27-1.63) but not ID (OR = 0.92, 95% CI: 0.74-1.14). For snus use, the results for ID were similar to smoking. We found increased odds of offspring SGA among mothers who used snus in pregnancy in sensitivity analyses but not in primary analyses. Conclusions Our findings are consistent with a causal effect of maternal smoking in pregnancy on risk of offspring born SGA but not on risk of ID. We found no evidence for a causal effect of snus use in pregnancy on ID and inconclusive evidence for SGA.

Characterizing patterns of mental phenomena in epidemiological studies of adolescents can provide insight into the latent organization of psychiatric disorders. This avoids the biases of chronicity and selection inherent in clinical samples, guides models of shared aetiology within psychiatric disorders and informs the development and implementation of interventions. We applied Gaussian mixture modelling to measures of mental phenomena from two general population cohorts: the Avon Longitudinal Study of Parents and Children (ALSPAC, n = 3018) and the Neuroscience in Psychiatry Network (NSPN, n = 2023). We defined classes according to their patterns of both positive (e.g. wellbeing and self-esteem) and negative (e.g. depression, anxiety, and psychotic experiences) phenomena. Subsequently, we characterized classes by considering the distribution of diagnoses and sex split across classes. Four well-separated classes were identified within each cohort. Classes primarily differed by overall severity of transdiagnostic distress rather than particular patterns of phenomena akin to diagnoses. Further, as overall severity of distress increased, so did within-class variability, the proportion of individuals with operational psychiatric diagnoses. These results suggest that classes of mental phenomena in the general population of adolescents may not be the same as those found in clinical samples. Classes differentiated only by overall severity support the existence of a general, transdiagnostic mental distress factor and have important implications for intervention.

Exposure to neurodevelopmental adversity and childhood trauma are both independently associated with psychosis. However, there is little research on the mechanism underlying their relationship with each other. The current study investigated both the independent and joint effects of neurodevelopmental adversity and childhood trauma to better understand the etiology of psychosis. A large population-based cohort (N = 3514) followed from birth was assessed on psychotic experiences (PE) at 24 years. Neurodevelopmental adversity included obstetric complications (birth weight, gestational age, in-utero influenza exposure, resuscitation) and developmental impairment (cognitive and motor impairments). Trauma exposure included caregiver and peer inflicted trauma up to 17 years. Multiple regression models tested their independent and interactive effect on PE, and path analysis estimated the indirect effect of neurodevelopmental adversity on PE via trauma. Neurodevelopmental adversity (OR = 1.32, 95%CI: 1.08–1.62) and trauma (OR = 1.97, 95%CI: 1.65–2.36) independently increased the odds of PE. There was also an indirect relationship between neurodevelopmental adversity and PE via increased exposure to childhood trauma (β = 0.01, 95%CI: 0.004–0.024). In particular, peer bullying mediated the association between developmental impairment to PE (β = 0.02, 95%CI: 0.01–0.03). In conclusion, children with neurodevelopmental adversity, in particular those with developmental impairment, are more likely to be exposed to trauma. This new etiological understanding of psychosis suggests that PE may be partially modifiable through reducing exposure to peer bullying, especially in children with developmental impairment.

Background\ud Cross-sectional studies have reported elevated concentrations of inflammatory markers in psychosis and depression. However, questions regarding temporality and specificity of association, crucial for understanding the potential role of inflammation, remain. \ud \ud Methods\ud Based on 2,224 ALSPAC birth cohort participants, we used regression analyses to test associations of interleukin-6 (IL-6) and C-reactive protein (CRP) levels at age 9 with risks for psychosis (psychotic experiences; negative symptoms; psychotic disorder), and depression (depressive episode; symptom score) at age 24. Regression models were adjusted for sex, ethnicity, social class and body mass index. We tested for linearity (using quadratic terms) and specificity (using bi-variate probit regression) of association, and used multiple imputation to explore the impact of missing data.\ud \ud Results\ud After adjustments, higher IL-6 levels at age 9 were associated with increased risk of psychotic disorder (OR=1.56; 95% C.I., 1.09-2.21 per SD increase in IL-6; OR=1.49; 95% C.I., 1.02-2.18 for the top compared with bottom third of IL-6) and depressive episode (OR=1.14; 95% C.I., 0.99-1.32 per SD increase in IL-6; OR=1.49; 95% C.I., 1.02-2.18 for the top compared with bottom third of IL-6). IL-6 was associated with negative symptoms after adjusting for depression (=0.09; 95% C.I., 0.01-0.22). There was no evidence for outcome-specific associations of IL-6. Childhood CRP was not associated with adult psychosis or depression. \ud \ud Conclusions\ud Evidence for similar, longitudinal, dose-response associations suggest that elevated childhood IL-6 could be a shared risk factor for adult psychosis and depression. The IL-6 pathway may represent a novel target for treatment and prevention of these disorders.

Background: An external locus of control (externality) is associated with poorer psychopathology in individualist cultures, but associations are reported to be weaker in collectivist cultures where an external style is less maladaptive. We investigated the prospective association between externality and psychotic-like experiences (PLE) and depressive symptoms (DS) and compared the strength of associations between a UK and a Japanese cohort.Method: Cross-cultural cohort study of a UK (Avon Longitudinal Study of Parents and Children) and a Japanese cohort (Tokyo Teen Cohort). Externality was assessed using the Children's Nowicki and Strickland Internal, External Scale and DS using the Short Moods and Feelings Questionnaire in both cohorts, PLE were assessed with the Psychosis-Like Experiences Questionnaire (ALSPAC), and the Adolescent Psychotic-Like Symptom Screener (TTC). Associations were investigated using multivariable regression models and bivariate regression models to compare the strength of associations.Results: Mean externality in both childhood and adolescence was higher in ALSPAC than in the TTC. Childhood externality was associated with PLE in late childhood and adolescence in both cohorts and adolescent externality was associated with PLE in young adulthood in the ALSPAC cohort. There was a more mixed pattern of association between externality and DS scores. There was little evidence of any differences in the strength of associations between externality and different psychopathologies, or between cohorts. In ALSPAC adolescent externality and early adult psychopathology were more strongly associated than childhood externality and adolescent and early adult psychopathology. There was no evidence that change in externality between childhood and adolescence was associated with new onset PLE or DS in early adulthood.Conclusion: An external locus of control is associated with poor mental health regardless of cultural context.

ObjectiveAlthough studies suggest that erythrocyte concentrations of omega-3 and omega-6 fatty acids are lower in individuals with schizophrenia, evidence of beneficial effects of omega-3 fatty acid supplementation is limited. This study therefore aimed to determine whether omega-3 and omega-6 fatty acid levels are causally related to schizophrenia.MethodsCausality was evaluated using the inverse variance weighted (IVW) 2-sample Mendelian randomization (MR) method using fatty acid levels and schizophrenia genome-wide association study results. Weighted median, weighted mode, and MR Egger regression methods were used as sensitivity analyses. To address the mechanism, analyses were performed using instruments within the FADS and ELOVL2 genes. Multivariable MR (MVMR) was used to estimate direct effects of omega-3 fatty acids on schizophrenia, independent of omega-6 fatty acids, lipoproteins and triglycerides.ResultsMR analyses indicated that long-chain omega-3 and omega-6 fatty acid levels were associated with lower risk of schizophrenia (docosahexaenoic acid [DHA] ORIVW: 0.83, 95% CI: 0.75-0.92). In contrast, short-chain fatty acids were associated with an increased risk of schizophrenia (alpha-linolenic acid ORIVW: 1.07, 95% CI: 0.98-1.18). Causal effects were consistent across sensitivity and FADS single-SNP analyses. MVMR indicated that the protective effect of DHA on schizophrenia persisted after conditioning on other lipids (ORIVW: 0.84, 95% CI: 0.71-1.01).ConclusionsResults are consistent with protective effects of long-chain omega-3 and omega-6 fatty acids on schizophrenia suggesting that people with schizophrenia may have difficulty converting short-chain to long-chain PUFAs. Long-chain PUFA supplementation or diet enrichment, particularly in higher risk individuals, might help prevent onset of disorder.