Showing papers by "Robin M. Murray published in 2019"

Non-Genetic Factors in Schizophrenia

Abstract: We review recent developments on risk factors in schizophrenia. The way we think about schizophrenia today is profoundly different from the way this illness was seen in the twentieth century. We now know that the etiology of schizophrenia is multifactorial and reflects an interaction between genetic vulnerability and environmental contributors. Environmental risk factors such as pregnancy and birth complications, childhood trauma, migration, social isolation, urbanicity, and substance abuse, alone and in combination, acting at a number of levels over time, influence the individual’s likelihood to develop the disorder. Environmental risk factors together with the identification of a polygenic risk score for schizophrenia, research on gene–environment interaction and environment–environment interaction have hugely increased our knowledge of the disorder.

A randomised controlled trial of vaporised Δ9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects

Abstract: Access to cannabis and cannabinoid products is increasing worldwide for recreational and medicinal use. Two primary compounds within cannabis plant matter, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are both psychoactive, but only THC is considered intoxicating. There is significant interest in potential therapeutic properties of these cannabinoids and of CBD in particular. Some research has suggested that CBD may ameliorate adverse effects of THC, but this may be dose dependent as other evidence suggests possible potentiating effects of THC by low doses of CBD. We conducted a randomised placebo controlled trial to examine the acute effects of these compounds alone and in combination when administered by vaporisation to frequent and infrequent cannabis users. Participants (n = 36; 31 male) completed 5 drug conditions spaced one week apart, with the following planned contrasts: placebo vs CBD alone (400 mg); THC alone (8 mg) vs THC combined with low (4 mg) or high (400 mg) doses of CBD. Objective (blind observer ratings) and subjective (self-rated) measures of intoxication were the primary outcomes, with additional indices of intoxication examined. CBD showed some intoxicating properties relative to placebo. Low doses of CBD when combined with THC enhanced, while high doses of CBD reduced the intoxicating effects of THC. The enhancement of intoxication by low-dose CBD was particularly prominent in infrequent cannabis users and was consistent across objective and subjective measures. Most effects were significant at p < .0001. These findings are important to consider in terms of recommended proportions of THC and CBD in cannabis plant matter whether used medicinally or recreationally and have implications for novice or less experienced cannabis users. Trial registration: ISRCTN Registry Identifier: ISRCTN24109245.

Cognitive Change in Schizophrenia and Other Psychoses in the Decade Following the First Episode

Abstract: Objective:Schizophrenia is associated with a marked cognitive impairment that is widely believed to remain stable after illness onset. Yet, to date, 10-year prospective studies of cognitive functio...

The Relationship Between Polygenic Risk Scores and Cognition in Schizophrenia.

Abstract: Background Cognitive impairment is a clinically important feature of schizophrenia. Polygenic risk score (PRS) methods have demonstrated genetic overlap between schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), educational attainment (EA), and IQ, but very few studies have examined associations between these PRS and cognitive phenotypes within schizophrenia cases. Methods We combined genetic and cognitive data in 3034 schizophrenia cases from 11 samples using the general intelligence factor g as the primary measure of cognition. We used linear regression to examine the association between cognition and PRS for EA, IQ, schizophrenia, BD, and MDD. The results were then meta-analyzed across all samples. A genome-wide association studies (GWAS) of cognition was conducted in schizophrenia cases. Results PRS for both population IQ (P = 4.39 × 10–28) and EA (P = 1.27 × 10–26) were positively correlated with cognition in those with schizophrenia. In contrast, there was no association between cognition in schizophrenia cases and PRS for schizophrenia (P = .39), BD (P = .51), or MDD (P = .49). No individual variant approached genome-wide significance in the GWAS. Conclusions Cognition in schizophrenia cases is more strongly associated with PRS that index cognitive traits in the general population than PRS for neuropsychiatric disorders. This suggests the mechanisms of cognitive variation within schizophrenia are at least partly independent from those that predispose to schizophrenia diagnosis itself. Our findings indicate that this cognitive variation arises at least in part due to genetic factors shared with cognitive performance in populations and is not solely due to illness or treatment-related factors, although our findings are consistent with important contributions from these factors.

Transdiagnostic dimensions of psychopathology at first episode psychosis: Findings from the multinational EU-GEI study

Abstract: Background The value of the nosological distinction between non-affective and affective psychosis has frequently been challenged. We aimed to investigate the transdiagnostic dimensional structure and associated characteristics of psychopathology at First Episode Psychosis (FEP). Regardless of diagnostic categories, we expected that positive symptoms occurred more frequently in ethnic minority groups and in more densely populated environments, and that negative symptoms were associated with indices of neurodevelopmental impairment. Method This study included 2182 FEP individuals recruited across six countries, as part of the EUropean network of national schizophrenia networks studying Gene–Environment Interactions (EU-GEI) study. Symptom ratings were analysed using multidimensional item response modelling in Mplus to estimate five theory-based models of psychosis. We used multiple regression models to examine demographic and context factors associated with symptom dimensions. Results A bifactor model, composed of one general factor and five specific dimensions of positive, negative, disorganization, manic and depressive symptoms, best-represented associations among ratings of psychotic symptoms. Positive symptoms were more common in ethnic minority groups. Urbanicity was associated with a higher score on the general factor. Men presented with more negative and less depressive symptoms than women. Early age-at-first-contact with psychiatric services was associated with higher scores on negative, disorganized, and manic symptom dimensions. Conclusions Our results suggest that the bifactor model of psychopathology holds across diagnostic categories of non-affective and affective psychosis at FEP, and demographic and context determinants map onto general and specific symptom dimensions. These findings have implications for tailoring symptom-specific treatments and inform research into the mood-psychosis spectrum.

'At risk mental state' clinics for psychosis - an idea whose time has come - and gone!

Abstract: At Risk Mental State (ARMS) clinics are specialised mental health services for young, help-seeking people, thought to be at ultra-high risk of developing psychosis. Their stated purpose is to reduce transitions from the ARMS state to clinical psychotic disorder. Reports of ARMS clinics provide 'evidence-based recommendations' or 'guidance' for the treatment of such individuals, and claim that such clinics prevent the development of psychosis. However, we note that in an area with a very well-developed ARMS clinic (South London), only a very small proportion (4%) of patients with first episode psychosis had previously been seen at this clinic with symptoms of the ARMS. We conclude that the task of reaching sufficient people to make a major contribution to the prevention of psychosis is beyond the power of ARMS clinics. Following the preventative approaches used for many medical disorders (e.g. lung cancer, coronary artery disease), we consider that a more effective way of preventing psychosis will be to adopt a public health approach; this should attempt to decrease exposure to environmental factors such as cannabis use which are known to increase risk of the disorder.

Association of a Schizophrenia-Risk Nonsynonymous Variant With Putamen Volume in Adolescents A Voxelwise and Genome-Wide Association Study

Abstract: Importance Deviation from normal adolescent brain development precedes manifestations of many major psychiatric symptoms. Such altered developmental trajectories in adolescents may be linked to genetic risk for psychopathology. Objective To identify genetic variants associated with adolescent brain structure and explore psychopathologic relevance of such associations. Design, Setting, and Participants Voxelwise genome-wide association study in a cohort of healthy adolescents aged 14 years and validation of the findings using 4 independent samples across the life span with allele-specific expression analysis of top hits. Group comparison of the identified gene-brain association among patients with schizophrenia, unaffected siblings, and healthy control individuals. This was a population-based, multicenter study combined with a clinical sample that included participants from the IMAGEN cohort, Saguenay Youth Study, Three-City Study, and Lieber Institute for Brain Development sample cohorts and UK biobank who were assessed for both brain imaging and genetic sequencing. Clinical samples included patients with schizophrenia and unaffected siblings of patients from the Lieber Institute for Brain Development study. Data were analyzed between October 2015 and April 2018. Main Outcomes and Measures Gray matter volume was assessed by neuroimaging and genetic variants were genotyped by Illumina BeadChip. Results The discovery sample included 1721 adolescents (873 girls [50.7%]), with a mean (SD) age of 14.44 (0.41) years. The replication samples consisted of 8690 healthy adults (4497 women [51.8%]) from 4 independent studies across the life span. A nonsynonymous genetic variant (minor T allele of rs13107325 inSLC39A8, a gene implicated in schizophrenia) was associated with greater gray matter volume of the putamen (variance explained of 4.21% in the left hemisphere; 8.66; 95% CI, 6.59-10.81;P = 5.35 × 10−18; and 4.44% in the right hemisphere;t = 8.90; 95% CI, 6.75-11.19;P = 6.80 × 10−19) and also with a lower gene expression ofSLC39A8specifically in the putamen (t127 = −3.87;P = 1.70 × 10−4). The identified association was validated in samples across the life span but was significantly weakened in both patients with schizophrenia (z = −3.05;P = .002; n = 157) and unaffected siblings (z = −2.08;P = .04; n = 149). Conclusions and Relevance Our results show that a missense mutation in geneSLC39A8is associated with larger gray matter volume in the putamen and that this association is significantly weakened in schizophrenia. These results may suggest a role for aberrant ion transport in the etiology of psychosis and provide a target for preemptive developmental interventions aimed at restoring the functional effect of this mutation.

The effect of psychosis associated CACNA1C, and its epistasis with ZNF804A, on brain function.

Abstract: CACNA1C‐rs1006737 and ZNF804A‐rs1344706 polymorphisms are amongst the most robustly associated with schizophrenia (SCZ) and bipolar disorder (BD), and recently with brain phenotypes. As these patients show abnormal verbal fluency (VF) and related brain activation, we asked whether the latter was affected by these polymorphisms (alone and in interaction) – to better understand how they might induce risk. We recently reported effects on functional VF‐related (for ZNF804A‐rs1344706) and structural (for both) connectivity. We genotyped and fMRI‐scanned 54 SCZ, 40 BD and 80 controls during VF. With SPM, we assessed the main effect of CACNA1C‐rs1006737, and its interaction with ZNF804A‐rs1344706, and their interaction with diagnosis, on regional brain activation and functional connectivity (psychophysiological interactions ‐ PPI). Using public data, we reported effects of CACNA1C‐rs1006737 and diagnosis on brain expression. The CACNA1C‐rs1006737 risk allele was associated with increased activation, particularly in the bilateral prefronto‐temporal cortex and thalamus; decreased PPI, especially in the left temporal cortex; and gene expression in white matter and the cerebellum. We also found unprecedented evidence for epistasis (interaction between genetic polymorphisms) in the caudate nucleus, thalamus, and cingulate and temporal cortical activation; and CACNA1C up‐regulation in SCZ and BD parietal cortices. Some effects were dependent on BD/SCZ diagnosis. All imaging results were whole‐brain, voxel‐wise, and familywise‐error corrected. Our results support evidence implicating CACNA1C and ZNF804A in BD and SCZ, adding novel imaging evidence in clinical populations, and of epistasis – which needs further replication. Further scrutiny of the inherent neurobiological mechanisms may disclose their potential as putative drug targets.

The Maudsley environmental risk score for psychosis.

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

Continuity of care and clinical outcomes in the community for people with severe mental illness

Abstract: Background High continuity of care is prized by users of mental health services and lauded in health policy. It is especially important in long-term conditions like schizophrenia. However, it is not routinely measured, and therefore not often evaluated when service reorganisations take place. In addition, the impact of continuity of care on clinical outcomes is unclear.AimsWe set out to examine continuity of care in people with schizophrenia, and to relate this to demographic variables and clinical outcomes. Method Pseudoanonymised community data from 5552 individuals with schizophrenia presenting over 11 years were examined for changes in continuity of care using the numbers of community teams caring for them and the Modified Modified Continuity Index (MMCI). These and demographic variables were related to clinical outcomes measured with the Health of the Nation Outcome Scales (HoNOS). Data were analysed using generalised estimating equations and multivariate marginal models. Results There was a significant decline in MMCI and significant worsening of HoNOS total scores over 11 years. Higher (worse) HoNOS scores were significantly and independently related to older age, later years and both lower MMCI and more teams caring for the individual in each year. Most HoNOS scales contributed to the higher total scores. Conclusions There is evidence of declining continuity of care in this 11-year study of people with schizophrenia, and of an independent effect of this on worse clinical outcomes. We suggest that this is related to reorganisation of services.Declaration of interestNone.

Effect of lifestyle, medication and ethnicity on cardiometabolic risk in the year following the first episode of psychosis: prospective cohort study.

Abstract: Background The first episode of psychosis is a critical period in the emergence of cardiometabolic risk. Aims We set out to explore the influence of individual and lifestyle factors on cardiometabolic outcomes in early psychosis. Method This was a prospective cohort study of 293 UK adults presenting with first-episode psychosis investigating the influence of sociodemographics, lifestyle (physical activity, sedentary behaviour, nutrition, smoking, alcohol, substance use) and medication on cardiometabolic outcomes over the following 12 months. Results Rates of obesity and glucose dysregulation rose from 17.8% and 12%, respectively, at baseline to 23.7% and 23.7% at 1 year. Little change was seen over time in the 76.8% tobacco smoking rate or the quarter who were sedentary for over 10 h daily. We found no association between lifestyle at baseline or type of antipsychotic medication prescribed with either baseline or 1-year cardiometabolic outcomes. Median haemoglobin A1c (HbA1c) rose by 3.3 mmol/mol in participants from Black and minority ethnic (BME) groups, with little change observed in their White counterparts. At 12 months, one-third of those with BME heritage exceeded the threshold for prediabetes (HbA1c >39 mmol/mol). Conclusions Unhealthy lifestyle choices are prevalent in early psychosis and cardiometabolic risk worsens over the next year, creating an important window for prevention. We found no evidence, however, that preventative strategies should be preferentially directed based on lifestyle habits. Further work is needed to determine whether clinical strategies should allow for differential patterns of emergence of cardiometabolic risk in people of different ethnicities.

De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes.

Abstract: Recent studies have demonstrated genetic differences between monozygotic (MZ) twins. To test the hypothesis that early post-twinning mutational events associate with phenotypic discordance, we investigated a cohort of 13 twin pairs (n = 26) discordant for various clinical phenotypes using whole-exome sequencing and screened for copy number variation (CNV). We identified a de novo variant in PLCB1, a gene involved in the hydrolysis of lipid phosphorus in milk from dairy cows, associated with lactase non-persistence, and a variant in the mitochondrial complex I gene MT-ND5 associated with amyotrophic lateral sclerosis (ALS). We also found somatic variants in multiple genes (TMEM225B, KBTBD3, TUBGCP4, TFIP11) in another MZ twin pair discordant for ALS. Based on the assumption that discordance between twins could be explained by a common variant with variable penetrance or expressivity, we screened the twin samples for known pathogenic variants that are shared and identified a rare deletion overlapping ARHGAP11B, in the twin pair manifesting with either schizotypal personality disorder or schizophrenia. Parent–offspring trio analysis was implemented for two twin pairs to assess potential association of variants of parental origin with susceptibility to disease. We identified a de novo variant in RASD2 shared by 8-year-old male twins with a suspected diagnosis of autism spectrum disorder (ASD) manifesting as different traits. A de novo CNV duplication was also identified in these twins overlapping CD38, a gene previously implicated in ASD. In twins discordant for Tourette’s syndrome, a paternally inherited stop loss variant was detected in AADAC, a known candidate gene for the disorder.

Neuropsychological function at first episode in treatment-resistant psychosis: findings from the ÆSOP-10 study.

Abstract: BACKGROUND: Neuropsychological investigations can help untangle the aetiological and phenomenological heterogeneity of schizophrenia but have scarcely been employed in the context of treatment-resistant (TR) schizophrenia. No population-based study has examined neuropsychological function in the first-episode of TR psychosis. METHODS: We report baseline neuropsychological findings from a longitudinal, population-based study of first-episode psychosis, which followed up cases from index admission to 10 years. At the 10-year follow up patients were classified as treatment responsive or TR after reconstructing their entire case histories. Of 145 cases with neuropsychological data at baseline, 113 were classified as treatment responsive, and 32 as TR at the 10-year follow-up. RESULTS: Compared with 257 community controls, both case groups showed baseline deficits in three composite neuropsychological scores, derived from principal component analysis: verbal intelligence and fluency, visuospatial ability and executive function, and verbal memory and learning (p values⩽0.001). Compared with treatment responders, TR cases showed deficits in verbal intelligence and fluency, both in the extended psychosis sample (t = -2.32; p = 0.022) and in the schizophrenia diagnostic subgroup (t = -2.49; p = 0.017). Similar relative deficits in the TR cases emerged in sub-/sensitivity analyses excluding patients with delayed-onset treatment resistance (p values<0.01-0.001) and those born outside the UK (p values<0.05). CONCLUSIONS: Verbal intelligence and fluency are impaired in patients with TR psychosis compared with those who respond to treatment. This differential is already detectable - at a group level - at the first illness episode, supporting the conceptualisation of TR psychosis as a severe, pathogenically distinct variant, embedded in aberrant neurodevelopmental processes.

Liberal Acceptance Bias, Momentary Aberrant Salience, and Psychosis: An Experimental Experience Sampling Study.

Abstract: Cognitive models of psychosis posit that reasoning biases are an important mechanism contributing to the formation of psychotic symptoms, in part through transforming anomalous experiences of aberrant salience into frank psychotic symptoms. This study aimed to investigate the interplay of liberal acceptance (LA) bias, which is a specific type of reasoning bias, and momentary aberrant salience in the development of paranoid and psychotic experiences in daily life in first-episode psychosis patients (FEP), at-risk mental state participants (ARMS), and controls. We used a novel experimental Experience Sampling Methodology (eESM) task for measuring LA bias (ie, decisions based on low probability estimates) and ESM measures of momentary aberrant salience and paranoid and psychotic experiences in 51 FEP, 46 ARMS, and 53 controls. We found evidence that LA bias was more likely to occur in FEP than in controls. Further, LA bias was associated with psychotic and paranoid experiences (all P < .007) and modified the association between momentary aberrant salience and psychotic experiences (χ2(df) = 7.4(2), P = .025) in ARMS, such that momentary salience was associated with more intense psychotic experiences in the presence of LA bias in ARMS, but not in FEP and controls. Our findings suggest that LA bias may be central for anomalous experiences such as momentary aberrant salience to increase intensity of psychotic experiences in at-risk individuals. Further, LA bias appears to be more likely to be present, but not directly linked to current intensity of psychotic experiences, in treated FEP. Novel eESM tasks open new avenues for targeting psychological processes under real-world conditions.

Jumping to conclusions at first onset of psychosis predicts longer admissions, more compulsory admissions and police involvement over the next 4 years: the GAP study.

Abstract: Background Jumping to conclusions (JTC), which is the proneness to require less information before forming beliefs or making a decision, has been related to formation and maintenance of delusions. Using data from the National Institute of Health Research Biomedical Research Centre Genetics and Psychosis (GAP) case-control study of first-episode psychosis (FEP), we set out to test whether the presence of JTC would predict poor clinical outcome at 4 years. Methods One-hundred and twenty-three FEP patients were assessed with the Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF) and the probabilistic reasoning 'Beads' Task at the time of recruitment. The sample was split into two groups based on the presence of JTC bias. Follow-up data over an average of 4 years were obtained concerning clinical course and outcomes (remission, intervention of police, use of involuntary treatment - the Mental Health Act (MHA) - and inpatient days). Results FEP who presented JTC at baseline were more likely during the follow-up period to be detained under the MHA [adjusted OR 15.62, 95% confidence interval (CI) 2.92-83.54, p = 0.001], require intervention by the police (adjusted OR 14.95, 95% CI 2.68-83.34, p = 0.002) and have longer admissions (adjusted IRR = 5.03, 95% CI 1.91-13.24, p = 0.001). These associations were not accounted for by socio-demographic variables, IQ and symptom dimensions. Conclusions JTC in FEP is associated with poorer outcome as indicated and defined by more compulsion police intervention and longer periods of admission. Our findings raise the question of whether the implementation of specific interventions to reduce JTC, such as Metacognition Training, may be a useful addition in early psychosis intervention programmes.

Verbal Fluency Is Affected by Altered Brain Lateralization in Adults Who Were Born Very Preterm

Abstract: Language difficulties have been reported in children and adolescents who were born very preterm ( Rest and Hard > Rest conditions, compared to controls, in superior temporal gyrus (STG), insula, thalamus, and sensorimotor cortex, particularly in the right hemisphere. At the whole-group level, decreased hemodynamic response suppression in the right sensorimotor cortex was associated with worse on-line performance on the hard letter trials. Increased left-laterality in the AF was present alongside increased right hemispheric hemodynamic response suppression in controls. When only right-handed participants were considered, decreased hemodynamic response suppression in the right STG during hard letter trials was related to weaker left and right FAT white matter integrity in the preterm group only. These results show that verbal fluency is affected by altered functional lateralization in adults who were born very preterm.