Showing papers by "Robin M. Murray published in 2021"

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia

Abstract: We performed a systematic analysis of blood DNA methylation profiles from 4,483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1,048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.

Social disadvantage, linguistic distance, ethnic minority status and first-episode psychosis: results from the EU-GEI case–control study

Abstract: The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project was funded by grant agreement Health-F2-2010-241909 (Project EU-GEI) from the European Community’s Seventh Framework programme. The Brazilian study was funded by grant 2012-0417-0 from the Sao Paulo Research Foundation. Dr Jongsma is funded by the Economic and Social Research Council (grant ES/S011714/1). Dr Kirkbride is funded by the Wellcome Trust and Royal Society (Grant 101272/Z/13/Z). Dr Jongsma and Professor Jones are funded by the National Institute of Health Research Collaboration of Leadership in Applied Health Research and Care East of England. Professor Rutten is funded by the Netherlands Scientific Organisation (VIDI award number 91718336). Dr Jongsma and Dr Kirkbride are supported by the National Institute for Health Research, University College London Hospital, Biomedical Research Centre.

Daily use of high-potency cannabis is associated with more positive symptoms in first-episode psychosis patients: the EU-GEI case-control study.

Abstract: Background Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients. Method We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses. Results In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score (B = 0.35; 95% CI 0.14–0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B = −0.22; 95% CI −0.37 to −0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use. Conclusions Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.

A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse.

Abstract: The process of stopping antipsychotics may be causally related to relapse, potentially linked to neuroadaptations that persist after cessation, including dopaminergic hypersensitivity. Therefore, the risk of relapse on cessation of antipsychotics may be minimized by more gradual tapering. There is converging evidence that suggests that adaptations to antipsychotic exposure can persist for months or years after stopping the medication-from animal studies, observation of tardive dyskinesia in patients, and the clustering of relapses in this time period after the cessation of antipsychotics. Furthermore, PET imaging demonstrates a hyperbolic relationship between doses of antipsychotic and D2 receptor blockade. We, therefore, suggest that when antipsychotics are reduced, it should be done gradually (over months or years) and in a hyperbolic manner (to reduce D2 blockade "evenly"): ie, reducing by one quarter (or one half) of the most recent dose of antipsychotic, equivalent approximately to a reduction of 5 (or 10) percentage points of its D2 blockade, sequentially (so that reductions become smaller and smaller in size as total dose decreases), at intervals of 3-6 months, titrated to individual tolerance. Some patients may prefer to taper at 10% or less of their most recent dose each month. This process might allow underlying adaptations time to resolve, possibly reducing the risk of relapse on discontinuation. Final doses before complete cessation may need to be as small as 1/40th a therapeutic dose to prevent a large decrease in D2 blockade when stopped. This proposal should be tested in randomized controlled trials.

Jumping to conclusions, general intelligence, and psychosis liability: findings from the multi-centre EU-GEI case-control study.

Abstract: Background The ‘jumping to conclusions’ (JTC) bias is associated with both psychosis and general cognition but their relationship is unclear. In this study, we set out to clarify the relationship between the JTC bias, IQ, psychosis and polygenic liability to schizophrenia and IQ. Methods A total of 817 first episode psychosis patients and 1294 population-based controls completed assessments of general intelligence (IQ), and JTC, and provided blood or saliva samples from which we extracted DNA and computed polygenic risk scores for IQ and schizophrenia. Results The estimated proportion of the total effect of case/control differences on JTC mediated by IQ was 79%. Schizophrenia polygenic risk score was non-significantly associated with a higher number of beads drawn (B = 0.47, 95% CI −0.21 to 1.16, p = 0.17); whereas IQ PRS (B = 0.51, 95% CI 0.25–0.76, p < 0.001) significantly predicted the number of beads drawn, and was thus associated with reduced JTC bias. The JTC was more strongly associated with the higher level of psychotic-like experiences (PLEs) in controls, including after controlling for IQ (B = −1.7, 95% CI −2.8 to −0.5, p = 0.006), but did not relate to delusions in patients. Conclusions Our findings suggest that the JTC reasoning bias in psychosis might not be a specific cognitive deficit but rather a manifestation or consequence, of general cognitive impairment. Whereas, in the general population, the JTC bias is related to PLEs, independent of IQ. The work has the potential to inform interventions targeting cognitive biases in early psychosis.

Predictors of treatment resistant schizophrenia: a systematic review of prospective observational studies.

Abstract: Treatment-resistant schizophrenia, affecting approximately 20–30% of patients with schizophrenia, has a high burden both for patients and healthcare services. There is a need to identify treatment resistance earlier in the course of the illness, in order that effective treatment, such as clozapine, can be offered promptly. We conducted a systemic literature review of prospective longitudinal studies with the aim of identifying predictors of treatment-resistant schizophrenia from the first episode. From the 545 results screened, we identified 12 published studies where data at the first episode was used to predict treatment resistance. Younger age of onset was the most consistent predictor of treatment resistance. We discuss the gaps in the literature and how future prediction models can identify predictors of treatment response more robustly.

Association Between Specific Childhood Adversities and Symptom Dimensions in People With Psychosis: Systematic Review and Meta-Analysis

Abstract: Despite the accepted link between childhood abuse and positive psychotic symptoms, findings between other adversities, such as neglect, and the remaining dimensions in people with psychosis have been inconsistent, with evidence not yet reviewed quantitatively. The aim of this study was to systematically examine quantitatively the association between broadly defined childhood adversity (CA), abuse (sexual/physical/emotional), and neglect (physical/emotional) subtypes, with positive, negative, depressive, manic, and disorganized dimensions in those with psychosis. A search was conducted across EMBASE, MEDLINE, PsychINFO, and Cochrane Libraries using search terms related to psychosis population, CA, and psychopathological dimensions. After reviewing for relevance, data were extracted, synthesized, and meta-analyzed. Forty-seven papers were identified, including 7379 cases across 40 studies examining positive, 37 negative, 20 depressive, 9 disorganized, and 13 manic dimensions. After adjustment for publication bias, general adversity was positively associated with all dimensions (ranging from r = 0.08 to r = 0.24). Most forms of abuse were associated with depressive (ranging from r = 0.16 to r = 0.32), positive (ranging from r = 0.14 to r = 0.16), manic (r = 0.13), and negative dimensions (ranging from r = 0.05 to r = 0.09), while neglect was only associated with negative (r = 0.13) and depressive dimensions (ranging from r = 0.16 to r = 0.20). When heterogeneity was found, it tended to be explained by one specific study. The depressive dimension was influenced by percentage of women (ranging from r = 0.83 to r = 1.36) and poor-quality scores (ranging from r = -0.21 and r = -0.059). Quality was judged as fair overall. Broadly defined adversity and forms of abuse increase transdimensional severity. Being exposed to neglect during childhood seems to be exclusively related to negative and depressive dimensions suggesting specific effects.

The relationship between cannabis and schizophrenia: a genetically informed perspective

Abstract: BACKGROUND AND AIMS While epidemiological studies support a role for heavy, high-potency cannabis use on first-episode psychosis, genetic models of causation suggest reverse causal effects of schizophrenia on cannabis use liability. We estimated the genetic relationship between cannabis use disorder (CUD) and schizophrenia (SCZ) and tested whether liability for CUD is causally associated with increased liability to SCZ while adjusting for tobacco smoking. DESIGN This study used summary statistics from published genome-wide association studies (GWAS). We used genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian randomization to examine genetic relationships between CUD, cannabis ever-use, ever-smoked tobacco regularly, nicotine dependence and SCZ, and to test for a causal relationship between liability to CUD and liability to SCZ. SETTING Genome-wide association studies were published previously as part of international consortia. PARTICIPANTS Sample sizes of the GWAS summary statistics used in this study ranged from 161 405 to 357 806 individuals of European ancestry. MEASUREMENTS Genome-wide summary statistics for CUD and SCZ were the primary measurements, while summary statistics for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence were included as additional variables in the genomic structural equation models and the multivariable Mendelian randomization analyses. FINDINGS Genetic liability to CUD was significantly associated with SCZ [β = 0.29, 95% confidence interval (CI) = 0.11, 0.46, P = 0.001], even when accounting for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence as simultaneous predictors. We found mixed evidence of a causal relationship, with the latent causal variable analysis finding no evidence of causality (genetic causality proportion = -0.08, 95% CI = -0.40, 0.23, P = 0.87) but the multivariable Mendelian randomization analyses suggesting a significant, risk-increasing effect of CUD on liability to SCZ (β = 0.10, 95% CI = 0.02, 0.18, P = 0.02), accounting for the additional risk factors (cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence). CONCLUSIONS Genetic liability for cannabis use disorder appears to be robustly associated with schizophrenia, above and beyond tobacco smoking and cannabis ever-use, with mixed evidence to support a causal relationship between cannabis use disorder and schizophrenia.

Neurological Signs at the First Psychotic Episode as Correlates of Long-Term Outcome: Results From the AESOP-10 Study.

Abstract: Minor neurological signs are subtle deficits in sensory integration, motor coordination, and sequencing of complex motor acts present in excess in the early stages of psychosis. Still, it remains unclear whether at least some of these signs represent trait or state markers for psychosis and whether they are markers of long-term disease outcome of clinical utility. We examined the relationship between neurological function at illness onset assessed with the Neurological Evaluation Scale and subsequent illness course in 233 patients from AESOP-10 (Aetiology and Ethnicity in Schizophrenia and Other Psychoses), a 10-year follow-up study of a population-based cohort of individuals recruited at the time of their first episode of psychosis in the United Kingdom. In 56 of these patients, we also explored changes in neurological function over time. We included a group of 172 individuals without psychosis as controls. After 10 years, 147 (63%) patients had developed a non-remitting course of illness, and 86 (37%) a remitting course. Already at first presentation, patients who developed a non-remitting course had significantly more primary, motor coordination, and total signs than both remitting patients and healthy controls. While Motor Coordination signs did not change over time, rates of Primary, Sensory Integration, and Total signs increased, independently of illness course type. These findings suggest that motor coordination problems could be a useful early, quick, and easily detectable marker of subsequent clinical outcome. With other motor abnormalities, a measure of motor incoordination could contribute to the identification of the most vulnerable individuals, who could benefit from targeted and more assertive treatment approaches.

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study.

Abstract: The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

Neuroanatomical abnormalities in first-episode psychosis across independent samples: a multi-centre mega-analysis.

Abstract: Background Neuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples. Methods Structural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons. Results FEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease – gyrus rectus – was negatively correlated with the severity of positive and negative symptoms. Conclusions This study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria.

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Abstract: Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Change in incidence rates for psychosis in different ethnic groups in south London: findings from the Clinical Record Interactive Search-First Episode Psychosis (CRIS-FEP) study.

Abstract: Background A higher incidence of psychotic disorders has been consistently reported among black and other minority ethnic groups, particularly in northern Europe. It is unclear whether these rates have changed over time. Methods We identified all individuals with a first episode psychosis who presented to adult mental health services between 1 May 2010 and 30 April 2012 and who were resident in London boroughs of Lambeth and Southwark. We estimated age-and-gender standardised incidence rates overall and by ethnic group, then compared our findings to those reported in the Aetiology and Ethnicity of Schizophrenia and Other Psychoses (AESOP) study that we carried out in the same catchment area around 10 years earlier. Results From 9109 clinical records we identified 558 patients with first episode psychosis. Compared with AESOP, the overall incidence rates of psychotic disorder in southeast London have increased from 49.4 (95% confidence interval (CI) 43.6–55.3) to 63.1 (95% CI 57.3–69.0) per 100 000 person-years at risk. However, the overall incidence rate ratios (IRR) were reduced in some ethnic groups: for example, IRR (95% CI) for the black Caribbean group reduced from 6.7 (5.4–8.3) to 2.8 (2.1–3.6) and the ‘mixed’ group from 2.7 (1.8–4.2) to 1.4 (0.9–2.1). In the black African group, there was a negligible difference from 4.1 (3.2–5.3) to 3.5 (2.8–4.5). Conclusions We found that incidence rates of psychosis have increased over time, and the IRR varied by the ethnic group. Future studies are needed to investigate more changes over time and determinants of change.

Migration history and risk of psychosis: results from the multinational EU-GEI study.

Abstract: Background Psychosis rates are higher among some migrant groups. We hypothesized that psychosis in migrants is associated with cumulative social disadvantage during different phases of migration. Methods We used data from the EUropean Network of National Schizophrenia Networks studying Gene-Environment Interactions (EU-GEI) case-control study. We defined a set of three indicators of social disadvantage for each phase: pre-migration, migration and post-migration. We examined whether social disadvantage in the pre- and post-migration phases, migration adversities, and mismatch between achievements and expectations differed between first-generation migrants with first-episode psychosis and healthy first-generation migrants, and tested whether this accounted for differences in odds of psychosis in multivariable logistic regression models. Results In total, 249 cases and 219 controls were assessed. Pre-migration (OR 1.61, 95% CI 1.06-2.44, p = 0.027) and post-migration social disadvantages (OR 1.89, 95% CI 1.02-3.51, p = 0.044), along with expectations/achievements mismatch (OR 1.14, 95% CI 1.03-1.26, p = 0.014) were all significantly associated with psychosis. Migration adversities (OR 1.18, 95% CI 0.672-2.06, p = 0.568) were not significantly related to the outcome. Finally, we found a dose-response effect between the number of adversities across all phases and odds of psychosis (⩾6: OR 14.09, 95% CI 2.06-96.47, p = 0.007). Conclusions The cumulative effect of social disadvantages before, during and after migration was associated with increased odds of psychosis in migrants, independently of ethnicity or length of stay in the country of arrival. Public health initiatives that address the social disadvantages that many migrants face during the whole migration process and post-migration psychological support may reduce the excess of psychosis in migrants.

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings

Abstract: Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = –0.45 to –0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = –0.14 to –0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = –0.88 to –0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = –0.13 to –0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = –0.21 to –0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.

Elucidating negative symptoms in the daily life of individuals in the early stages of psychosis

Abstract: Background It remains poorly understood how negative symptoms are experienced in the daily lives of individuals in the early stages of psychosis. We aimed to investigate whether altered affective experience, anhedonia, social anhedonia, and asociality were more pronounced in individuals with an at-risk mental state for psychosis (ARMS) and individuals with first-episode psychosis (FEP) than in controls. Methods We used the experience sampling methodology (ESM) to assess negative symptoms, as they occurred in the daily life of 51 individuals with FEP and 46 ARMS, compared with 53 controls. Results Multilevel linear regression analyses showed no overall evidence for a blunting of affective experience. There was some evidence for anhedonia in FEP but not in ARMS, as shown by a smaller increase of positive affect (BΔat-risk v. FEP = 0.08, p = 0.006) as the pleasantness of activities increased. Against our expectations, no evidence was found for greater social anhedonia in any group. FEP were more often alone (57%) than ARMS (38%) and controls (35%) but appraisals of the social situation did not point to asociality. Conclusions Overall, altered affective experience, anhedonia, social anhedonia and asociality seem to play less of a role in the daily life of individuals in the early stages of psychosis than previously assumed. With the experience of affect and pleasure in daily life being largely intact, changing social situations and appraisals thereof should be further investigated to prevent development or deterioration of negative symptoms.

Lack of support for the genes by early environment interaction hypothesis in the pathogenesis of schizophrenia

Abstract: Ursini et al reported recently that the liability of schizophrenia explained by a polygenic risk score (PRS) derived from the variants most associated with schizophrenia was increased 5-fold in individuals who experienced complications during pregnancy or birth. Follow-up gene expression analysis showed that the genes mapping to the most associated genetic variants are highly expressed in placental tissues. If confirmed, these findings will have major implications in our understanding of the joint effect of genes and environment in the pathogenesis of schizophrenia. We examined the interplay between PRS and obstetric complications (OCs) in 5 independent samples (effective N = 2110). OCs were assessed with the full or modified Lewis-Murray scale, or with birth weight < 2.5 kg as a proxy. In a large cohort we tested whether the pathways from placenta-relevant variants in the original report were associated with case-control status. Unlike in the original study, we did not find significant effect of PRS on the presence of OCs in cases, nor a substantial difference in the association of PRS with case-control status in samples stratified by the presence of OCs. Furthermore, none of the PRS by OCs interactions were significant, nor were any of the biological pathways, examined in the Swedish cohort. Our study could not support the hypothesis of a mediating effect of placenta biology in the pathway from genes to schizophrenia. Methodology differences, in particular the different scales measuring OCs, as well as power constraints for interaction analyses in both studies, may explain this discrepancy.

Dietary intake, physical activity and sedentary behaviour patterns in a sample with established psychosis and associations with mental health symptomatology

Abstract: Background People with psychosis experience cardiometabolic comorbidities, including metabolic syndrome, coronary heart disease and diabetes. These physical comorbidities have been linked to diet, inactivity and the effects of the illness itself, including disorganisation, impairments in global function and amotivation associated with negative symptoms of schizophrenia or co-morbid depression. Methods We aimed to describe the dietary intake, physical activity (PA) and sedentary behaviour patterns of a sample of patients with established psychosis participating in the Improving Physical Health and Reducing Substance Use in Severe Mental Illness (IMPaCT) randomised controlled trial, and to explore the relationship between these lifestyle factors and mental health symptomatology. Results A majority of participants had poor dietary quality, low in fruit and vegetables and high in discretionary foods. Only 29.3% completed ⩾150 min of moderate and/or vigorous activity per week and 72.2% spent ⩾6 h per day sitting. Cross-sectional associations between negative symptoms, global function, and PA and sedentary behaviour were observed. Additionally, those with more negative symptoms receiving IMPaCT therapy had fewer positive changes in PA from baseline to 12-month follow-up than those with fewer negative symptoms at baseline. Conclusion These results highlight the need for the development of multidisciplinary lifestyle and exercise interventions to target eating habits, PA and sedentary behaviour, and the need for further research on how to adapt lifestyle interventions to baseline mental status. Negative symptoms in particular may reduce patient's responses to lifestyle interventions.

The Independent Effects of Psychosocial Stressors on Subclinical Psychosis: Findings From the Multinational EU-GEI Study.

Abstract: The influence of psychosocial stressors on psychosis risk has usually been studied in isolation and after the onset of the disorder, potentially ignoring important confounding relationships or the fact that some stressors that may be the consequence of the disorder rather than preexisting. The study of subclinical psychosis could help to address some of these issues. In this study, we investigated whether there was (i) an association between dimensions of subclinical psychosis and several psychosocial stressors including: childhood trauma, self-reported discrimination experiences, low social capital, and stressful life experiences, and (ii) any evidence of environment-environment (ExE) interactions between these factors. Data were drawn from the EUGEI study, in which healthy controls (N = 1497) and siblings of subjects with a psychotic disorder (N = 265) were included in six countries. The association between psychosocial stressors and subclinical psychosis dimensions (positive, negative and depressive dimension as measured by the Community Assessment of Psychic Experiences (CAPE) scale) and possible ExE interactions were assessed using linear regression models. After adjusting for sex, age, ethnicity, country, and control/sibling status, childhood trauma (β for positive dimension: 0.13, negative: 0.49, depressive: 0.26) and stressful life events (positive: 0.08, negative: 0.16, depressive: 0.17) were associated with the three dimensions. Lower social capital was associated with the negative and depression dimensions (negative: 0.26, depressive: 0.13), and self-reported discrimination experiences with the positive dimension (0.06). Our findings are in favor of independent, cumulative and non-specific influences of social adversities in subclinical psychosis in non-clinical populations, without arguments for E × E interactions.

Prevention of psychosis: moving on from the at-risk mental state to universal primary prevention.

Abstract: The value of services for those with the 'At Risk Mental State for Psychosis' (ARMS) continues to be disputed. ARMS services have provided a valuable stimulus to academic research into the transition into psychosis. Furthermore, there is currently a welcome trend to transform such clinics into youth mental health services catering for the broader clientele of young people suffering from anxiety and depression, who already constitute the bulk of those seen at ARMS clinics. However, such services are never likely to make major inroads into preventing psychosis because they only reach a small proportion of those at risk. Evidence from medicine shows that avoiding exposure to factors which increase the risk of disease (e.g. poor nutrition, transmission of infection, tobacco smoking), produces greater public benefit than focussing efforts on individuals with, or about to develop, disease. We consider that the most productive approach for psychosis prevention is avoiding exposure to risk-increasing factors. The best-established risk factors for psychosis are obstetric events, childhood abuse, migration, city living, adverse life events and cannabis use. Some as city living, are likely proxies for an unknown causal factor(s) while preventing others such as childhood abuse is currently beyond our powers. The risk factor for psychosis which is most readily open to this approach is the use of cannabis. Therefore, as an initial step towards a strategy for universal primary prevention, we advocate public health campaigns to educate young people about the harms of regular use of high potency cannabis.

Synergistic effects of childhood adversity and polygenic risk in first-episode psychosis: the EU-GEI study

Abstract: A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to the number of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing polygenic vulnerability. Here, we investigated, in the largest sample of first-episode psychosis (FEP) cases to date, whether childhood adversity and high polygenic risk scores for schizophrenia (SZ-PRS) combine synergistically to increase the risk of psychosis, over and above the effect of each alone. We assigned a schizophrenia-polygenic risk score (SZ-PRS), calculated from the Psychiatric Genomics Consortium (PGC2), to all participants in a sample of 384 FEP patients and 690 controls from the case–control component of the EU-GEI study. Only participants of European ancestry were included in the study. A history of childhood adversity was collected using the Childhood Trauma Questionnaire (CTQ). Synergistic effects were estimated using the interaction contrast ratio (ICR) [odds ratio (OR)exposure and PRS − ORexposure − ORPRS + 1] with adjustment for potential confounders. There was some evidence that the combined effect of childhood adversities and polygenic risk was greater than the sum of each alone, as indicated by an ICR greater than zero [i.e. ICR 1.28, 95% confidence interval (CI) −1.29 to 3.85]. Examining subtypes of childhood adversities, the strongest synergetic effect was observed for physical abuse (ICR 6.25, 95% CI −6.25 to 20.88). Our findings suggest possible synergistic effects of genetic liability and childhood adversity experiences in the onset of FEP, but larger samples are needed to increase precision of estimates.

Structural Covariance of Cortical Gyrification at Illness Onset in Treatment Resistance: A Longitudinal Study of First-Episode Psychoses.

Abstract: Treatment resistance (TR) in patients with first-episode psychosis (FEP) is a major cause of disability and functional impairment, yet mechanisms underlying this severe disorder are poorly understood. As one view is that TR has neurodevelopmental roots, we investigated whether its emergence relates to disruptions in synchronized cortical maturation quantified using gyrification-based connectomes. Seventy patients with FEP evaluated at their first presentation to psychiatric services were followed up using clinical records for 4 years; of these, 17 (24.3%) met the definition of TR and 53 (75.7%) remained non-TR at 4 years. Structural MRI images were obtained within 5 weeks from first exposure to antipsychotics. Local gyrification indices were computed for 148 contiguous cortical regions using FreeSurfer; each subject's contribution to group-based structural covariance was quantified using a jack-knife procedure, providing a single deviation matrix for each subject. The latter was used to derive topological properties that were compared between TR and non-TR patients using a Functional Data Analysis approach. Compared to the non-TR patients, TR patients showed a significant reduction in small-worldness (Hedges's g = 2.09, P < .001) and a reduced clustering coefficient (Hedges's g = 1.07, P < .001) with increased length (Hedges's g = -2.17, P < .001), indicating a disruption in the organizing principles of cortical folding. The positive symptom burden was higher in patients with more pronounced small-worldness (r = .41, P = .001) across the entire sample. The trajectory of synchronized cortical development inferred from baseline MRI-based structural covariance highlights the possibility of identifying patients at high-risk of TR prospectively, based on individualized gyrification-based connectomes.

Age-dependent genetic variants associated with longitudinal changes in brain structure across the lifespan

Abstract: Human brain structure changes throughout our lives. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental, and neurodegenerative diseases. Here, we identified common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal MRI data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene-set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and ageing.