Showing papers by "Robin M. Murray published in 2013"

Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment

Abstract: Community-based studies suggest that cannabis products that are high in Δ⁹-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600 mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥ 3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ²=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6 ± 18.9%) compared with the CBD group (-0.4% ± 9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.

The Myth of Schizophrenia as a Progressive Brain Disease

Abstract: Schizophrenia has historically been considered to be a deteriorating disease, a view reinforced by recent MRI findings of progressive brain tissue loss over the early years of illness. On the other hand, the notion that recovery from schizophrenia is possible is increasingly embraced by consumer and family groups. This review critically examines the evidence from longitudinal studies of (1) clinical outcomes, (2) MRI brain volumes, and (3) cognitive functioning. First, the evidence shows that although approximately 25% of people with schizophrenia have a poor long-term outcome, few of these show the incremental loss of function that is characteristic of neurodegenerative illnesses. Second, MRI studies demonstrate subtle developmental abnormalities at first onset of psychosis and then further decreases in brain tissue volumes; however, these latter decreases are explicable by the effects of antipsychotic medication, substance abuse, and other secondary factors. Third, while patients do show cognitive deficits compared with controls, cognitive functioning does not appear to deteriorate over time. The majority of people with schizophrenia have the potential to achieve long-term remission and functional recovery. The fact that some experience deterioration in functioning over time may reflect poor access, or adherence, to treatment, the effects of concurrent conditions, and social and financial impoverishment. Mental health professionals need to join with patients and their families in understanding that schizophrenia is not a malignant disease that inevitably deteriorates over time but rather one from which most people can achieve a substantial degree of recovery.

Serum and gene expression profile of cytokines in first-episode psychosis

Abstract: An inflammatory syndrome has been previously reported in chronic schizophrenia. The aims of this study were to investigate: (1) serum levels and leukocyte gene expression of cytokines in patients with first-episode psychosis and controls; and (2) possible causes of abnormal cytokine levels in first-episode psychosis, testing their association with psychosocial stressors, current nicotine and cannabis use, and duration of antipsychotic treatment. We recruited 24 first-episode psychosis patients and 24 healthy controls matched for age, gender, ethnicity and body mass index. Serum interleukin(IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, Tumour Necrosis Factor- α (TNF-α), Interferon- γ (IFN-γ), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and monocyte chemotactic protein-1 (MCP-1) were analysed in all subjects. Leukocyte gene expression analyses were conducted only for those cytokines that were different between-groups in the serum analyses. Patients had significantly higher serum levels of IL-1α (effect size d=0.6, p=0.03), IL-1β (d=0.4, p=0.01), IL-8 (d=0.6, p=0.01) and TNF-α (d=0.7, p=0.05) and a trend for higher IL-6 serum levels (d=0.3, p=0.09) when compared with controls. Leukocyte m-RNA levels of IL-1α (d=0.6, p=0.04), IL-6 (d=0.7, p=0.01) and TNF-α (d=1.6, p<0.001), but not IL-1β and IL-8, were also significantly higher in patients. A history of childhood trauma was associated with higher TNF-α serum levels (p=0.01), while more recent stressful life-events were associated with higher TNF-α mRNA levels in leukocytes (p=0.002). In conclusion, first-episode psychosis is characterised by a pro-inflammatory state supported, at least in part, by activation of leukocytes. Past and recent stressors contribute to this pro-inflammatory state.

Gender difference in age at onset of schizophrenia: a meta-analysis.

Abstract: BackgroundMost studies reporting the gender difference in age at onset of schizophrenia show an earlier onset in males, but vary considerably in their estimates of the difference. This may be due to variations in study design, setting and diagnostic criteria. In particular, several studies conducted in developing countries have found no difference or a reversed effect whereby females have an earlier onset. The aim of the study was to investigate gender differences in age of onset, and the impact of study design and setting on estimates thereof.MethodStudy methods were a systematic literature search, meta-analysis and meta-regression.ResultsA total of 46 studies with 29218 males and 19402 females fulfilled the inclusion criteria and were entered into a meta-analysis. A random-effects model gave a pooled estimate of the gender difference of 1.07 years (95% confidence interval 0.21–1.93) for age at first admission of schizophrenia, with males having earlier onset. The gender difference in age at onset was not significantly different between developed and developing countries. Studies using Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria showed a significantly greater gender difference in age at onset than studies using International Classification of Diseases (ICD) criteria, the latter showing no difference.ConclusionsThe gender difference in age of onset in schizophrenia is smaller than previously thought, and appears absent in studies using ICD. There is no evidence that the gender difference differs between developed and developing countries.

Self-management intervention for chronic pain in older adults: a randomised controlled trial.

Abstract: This study compared an outpatient pain self-management (PSM) program, using cognitive-behavioural therapy and exercises, with 2 control conditions in 141 chronic pain patients aged > 65 years. Results immediately posttreatment indicated that relative to the Exercise-Attention Control (EAC) group, the PSM group was significantly improved on measures of pain distress, disability, mood, unhelpful pain beliefs, and functional reach. The mean effect size for these gains was 0.52 (range: 0.44-0.68). By 1-month follow-up, relative to the EAC group, the PSM group remained better on most measures. At the 1-month follow-up, relative to a Waiting List (usual care) (WL) group, the PSM group was significantly improved on measures of pain distress, disability, and unhelpful pain beliefs. The mean effect size for these variables was 0.69 (range: 0.56-0.83). Relative to the WL group, the EAC group made no significant gains on any of the measured variables. At 1-month follow-up, the mean proportion of reliably improved cases (across outcome variables) was 41% (range: 16-60%) for the PSM group, twice that of those who met this criterion in the 2 control conditions (and this difference was statistically significant). Similarly, significantly more (44%) of the PSM group (vs 22% and 20% for the control groups) achieved a clinically significant improvement on pain disability. In the short term at least, cognitive-behavioural therapy-based PSM was more effective than exercises and usual care.

Cortical Folding Defects as Markers of Poor Treatment Response in First-Episode Psychosis

Abstract: IMPORTANCE At present, no reliable predictors exist to distinguish future responders from nonresponders to treatment during the first episode of psychosis. Among potential neuroimaging predictors of treatment response, gyrification represents an important marker of the integrity of normal cortical development that may characterize, already at illness onset, a subgroup of patients with particularly poor outcome.

What can we learn about schizophrenia from studying the human model, drug-induced psychosis?

Abstract: When drug-induced psychoses were first identified in the mid-20th century, schizophrenia was considered a discrete disease with a likely genetic cause. Consequently, drug-induced psychoses were not considered central to understanding schizophrenia as they were thought to be phenocopies rather than examples of the illness secondary to a particular known cause. However, now that we know that schizophrenia is a clinical syndrome with multiple component causes, then it is clear that the drug-induced psychoses have much to teach us. This article shows how the major neuropharmacological theories of schizophrenia have their origins in studies of the effects of drugs of abuse. Research into the effects of LSD initiated the serotonergic model; amphetamines the dopamine hypothesis, PCP and ketamine the glutamatergic hypothesis, while most recently the effects of cannabis have provoked interest in the role of endocannabinoids in schizophrenia. None of these models account for the complete picture of schizophrenia; rather the various drug models mimic different aspects of the illness. Determining the different molecular effects of those drugs whose pharmacological effects do and do not mimic the various aspects of schizophrenia has much to teach us concerning the pathogenesis of the illness.

Social Disadvantage: Cause or Consequence of Impending Psychosis?

Abstract: Background: An association between social disadvantage and established psychosis is well documented in the literature, but there remains a lack of data on the social circumstances of patients before they became ill. We investigated whether social disadvantage at, and prior to, first contact with psychiatric services, is associated with psychosis. Method: We collected information on social disadvantage in childhood and adulthood from 278 cases presenting with their first episode of psychosis to the South London and Maudsley National Health Service Foundation Trust and from 226 controls recruited from the local population. Three markers of childhood social disadvantage and 3 markers of disadvantage in adulthood were analyzed. Results: Long term separation from, and death of, a parent before the age of 17 years were both strongly associated with a 2- to 3-fold-increased odds of psychosis. Cases were also significantly more likely to report 2 or more markers of adult social disadvantage than healthy controls (OR = 9.03) at the time of the first presentation with psychosis, independent of a number of confounders. When we repeated these analyses for long-standing adult social disadvantage, we found that the strength of the association decreased but still remained significant for 1 year (OR = 5.67) and 5 years (OR = 2.57) prior to the first contact. Conclusions: Social disadvantage indexes exposure to factors operating prior to onset that increase the risk of psychosis, both during childhood and adulthood.

Temporal Lobe Volume Abnormalities Precede the Prodrome: A Study of Children Presenting Antecedents of Schizophrenia

Abstract: Distributed abnormalities of gray matter (GM) and white matter (WM) volume characterize individuals experiencing their first episode of schizophrenia. Regions of abnormality are present already, albeit less extensively, during the prodromal phase of illness. This study aimed to determine whether putatively at-risk children, aged 9–12 years, who present multiple antecedents of schizophrenia (ASz), display GM and WM volume abnormalities relative to typically developing (TD) children presenting no antecedents. Structural magnetic resonance images were acquired for 20 ASz children and 20 TD children matched on age, sex, and IQ. Whole-brain differences in GM and WM volume were determined using voxel-based morphometry. Relative to the TD group, ASz children showed significantly decreased GM volume in the right middle temporal gyrus (MTG) and increased GM volume in the left superior-middle temporal gyri (P < 0.05, cluster correction). WM volume was significantly increased in ASz children relative to TD children in a cluster encompassing the left inferior parietal lobe, occipital lobe, and superior temporal gyrus. Post-hoc analyses indicated that these abnormalities were not limited to ASz children who self-reported auditory hallucinations on questionnaire. Our findings suggest that children aged 9–12 years who present multiple ASz are characterized by abnormalities of GM and WM volume in the temporal lobes, comprising a subset of the regions affected in first-episode schizophrenia and in the prodromal phase of illness. These preliminary findings indicate that structural brain abnormalities associated with schizophrenia may be detected in putatively at-risk, preprodromal children. Prospective studies following the brain development of at-risk children are needed.

The impact of CACNA1C allelic variation on effective connectivity during emotional processing in bipolar disorder

Abstract: The impact of CACNA1C allelic variation on effective connectivity during emotional processing in bipolar disorder

Increased Risk of Schizophrenia From Additive Interaction Between Infant Motor Developmental Delay and Obstetric Complications: Evidence From a Population-Based Longitudinal Study

Abstract: Objective:Obstetric complications and developmental delay are well-established risk factors for schizophrenia. The authors investigated whether these risk factors interact in an additive manner to further increase risk for schizophrenia. Method:The study population encompassed all individuals born in Helsinki between 1962 and 1969 who had developmental records archived in the Helsinki City Archives. Through linkage between the Finnish Population Register, the Finnish Hospital Discharge Register, and the Child Health Archives, child health cards were traced for 189 individuals who had received a diagnosis of schizophrenia and 189 healthy comparison subjects, individually matched to case subjects on gender and year of birth. Child health cards from the Child Health Archives contain detailed prospective developmental data from birth as well as an indicator of fetal distress, as measured by the Apgar score. Detailed developmental data from the first year of life were extracted. Results:Delayed attainment of m...

Can we identify and treat "schizophrenia light" to prevent true psychotic illness?

Abstract: Better to focus on treating psychosis in non-psychotic disorders In a linked meta-analysis, Stafford and colleagues (doi:10.1136/bmj.f185) provide evidence that cognitive behavioural therapy (CBT) may show some modest benefits in preventing transition to psychosis at 12 months’ follow-up in patients at high risk.1 In doing so, they summarise a huge amount of work on interventions to prevent psychosis. However, this approach assumes that a discrete state of high risk for psychosis exists, an assumption that has increasingly been challenged. Traditionally, phenomena such as delusions and hallucinations (hereafter, psychosis) were thought to be diagnostic indicators of psychotic disorders such as schizophrenia. However, psychotic symptoms are more common than was previously realised. They are present—at various degrees of severity—in about 5% of the general population who are not seeking help; in about 25% of people with (non-psychotic) common mental disorders, such as anxiety and depression; and in around 80% of patients with psychotic disorders.2 Low grade psychotic phenomena in those not seeking help are associated with an increased relative risk—albeit low absolute risk—of later psychotic disorder, and, more surprisingly, also of non-psychotic mental disorder.3 Furthermore, low grade psychotic symptoms in people with common mental disorders predict a poorer prognosis, similar …

A population-level prediction tool for the incidence of first-episode psychosis: translational epidemiology based on cross-sectional data

Abstract: Objectives: Specialist early intervention services (EIS) for people aged 14–35 years with first episodes of psychosis (FEP) have been commissioned throughout England since 2001. A single estimate of population need was used everywhere, but true incidence varies enormously according to sociodemographic factors. We sought to develop a realistically complex, population-based prediction tool for FEP, based on precise estimates of epidemiological risk. Design and participants: Data from 1037 participants in two cross-sectional population-based FEP studies were fitted to several negative binomial regression models to estimate risk coefficients across combinations of different sociodemographic and socioenvironmental factors. We applied these coefficients to the population at-risk of a third, socioeconomically different region to predict expected caseload over 2.5 years, where the observed rates of ICD-10 F10-39 FEP had been concurrently ascertained via EIS. Setting: Empirical population-based epidemiological data from London, Nottingham and Bristol predicted counts in the population at-risk in the East Anglia region of England. Main outcome measures: Observed counts were compared with predicted counts (with 95% prediction intervals (PI)) at EIS and local authority district (LAD) levels in East Anglia to establish the predictive validity of each model. Results: A model with age, sex, ethnicity and population density performed most strongly, predicting 508 FEP participants in EIS in East Anglia (95% PI 459, 559), compared with 522 observed participants. This model predicted correctly in 5/6 EIS and 19/21 LADs. All models performed better than the current gold standard for EIS commissioning in England (716 cases; 95% PI 664–769). Conclusions: We have developed a prediction tool for the incidence of psychotic disorders in England and Wales, made freely available online (http://www.psymaptic.org), to provide healthcare commissioners with accurate forecasts of FEP based on robust epidemiology and anticipated local population need. The initial assessment of some people who do not require subsequent EIS care means additional service resources, not addressed here, will be required.

Improving physical health and reducing substance use in psychosis--randomised control trial (IMPACT RCT): study protocol for a cluster randomised controlled trial.

Abstract: Cardiovascular morbidity and mortality is increased in individuals with severe mental illnesses.

Analysis of multiple phenotypes in genome-wide genetic mapping studies

Abstract: Background: Complex traits may be defined by a range of different criteria. It would result in a loss of information to perform analyses simply on the basis of a final clinical dichotomized affected / unaffected variable. Results: We assess the performance of four alternative approaches for the analysis of multiple phenotypes in genetic association studies. We describe the four methods in detail and discuss their relative theoretical merits and disadvantages. Using simulation we demonstrate that PCA provides the greatest power when applied to both correlated phenotypes and with large numbers of phenotypes. The multivariate approach had low type I error only with independent phenotypes or small numbers of phenotypes. In this study, our application of the four methods to schizophrenia data provides converging evidence of the relative performance of the methods. Conclusions: Via power analysis of simulated data and testing of experimental data, we conclude that PCA, creating one variable based on a linear combination of all the traits, performs optimally. We propose that our comparison will provide insight into the properties of the methods and help researchers to choose appropriate strategy in future experimental studies.

Different rates of first admissions for psychosis in migrant groups in Paris

Abstract: The association between migration and psychosis has been reported in the past decades in many European countries. Despite large-scale migration into France, epidemiological data on the incidence of psychosis in this population are lacking. In this study, we compare the incidence rates of first admission for psychosis among natives and first generation migrants. Two-hundred and fifty-eight patients aged 15+ with first admission for psychosis were identified in the catchment area of the 20th district of Paris between 2005 and 2009. Standardised incidence rates and incidence rate ratios were calculated for migrant and native groups. We found higher rates of admissions for psychosis in the migrant group (IRR 2.9, 95 % CI 0.9–9.8) compared to individuals born in France. Among migrants, incidence was higher in individuals from Sub-Saharan Africa compared to natives (IRR 7.1, CI 95 % 2.3–21.8), whereas the incidence was similar for those from Europe (IRR 1.2, CI 95 % 0.3–5.1) and from North Africa (IRR 1.4, CI 95 % 0.4–5.6). Our findings suggest that Sub-Saharan migrants were identified as the most vulnerable migrant group for developing psychosis in France, but additional work is warranted to confirm these trends.

Effect of DISC1 on the P300 Waveform in Psychosis

Abstract: INTRODUCTION: Abnormalities in the neurophysiological measures P300 amplitude and latency constitute endophenotypes for psychosis. Disrupted-in-Schizophrenia-1 (DISC1) has been proposed as a promising susceptibility gene for schizophrenia, and a previous study has suggested that it is associated with P300 deficits in schizophrenia. METHODS: We examined the role of variation in DISC1 polymorphisms on the P300 endophenotype in a large sample of patients with schizophrenia or psychotic bipolar disorder (n = 149), their unaffected relatives (n = 130), and unrelated healthy controls (n = 208) using linear regression and haplotype analysis. RESULTS: Significant associations between P300 amplitude and latency and DISC1 polymorphisms/haplotypes were found. Those homozygous for the A allele of single-nucleotide polymorphism (SNP) rs821597 displayed significantly reduced P300 amplitudes in comparison with homozygous for the G allele (P = .009) and the heterozygous group (P = .018). Haplotype analysis showed a significant association for DISC1 haplotypes (rs3738401|rs6675281|rs821597|rs821616|rs967244|rs980989) and P300 latency. Haplotype GCGTCG and ACGTTT were associated with shorter latencies. DISCUSSION: The P300 waveform appears to be modulated by variation in individual SNPs and haplotypes of DISC1. Because DISC1 is involved in neurodevelopment, one hypothesis is that disruption in neural connectivity impairs cognitive processes illustrated by P300 deficits observed in this sample.

Gender differences in neuropsychological performance across psychotic disorders--a multi-centre population based case-control study.

Abstract: Background Patients with schizophrenia and other psychoses exhibit a wide range of neuropsychological deficits. An unresolved question concerns whether there are gender differences in cognitive performance. Methods Data were derived from a multi-centre population based case-control study of patients with first-episode psychosis. A neuropsychological test battery was administered to patients with a diagnosis of schizophrenia or schizoaffective disorder (N=70, 36% females), bipolar/mania (N=34, 60% females), depressive psychosis (N=36, 58% females) and healthy controls (N=148, 55% females). Generalized and specific cognitive deficits were compared. Results There was strong evidence for disorder-specific gender differences in neuropsychological performance. Males and females with schizophrenia showed similar pervasive neuropsychological impairments. In psychotic depressive disorder females performed worse than males across neuropsychological measures. Differences in neuropsychological performance between males and females with bipolar/manic disorder were restricted to language functions. Symptom severity did not contribute to the observed gender differences. Conclusions Early in the course of psychotic illness, gender related factors appear to moderate the severity of cognitive deficits in depressive psychosis and bipolar/mania patients.

Risk variant of oligodendrocyte lineage transcription factor 2 is associated with reduced white matter integrity

Abstract: The oligodendrocyte lineage transcription factor 2 (OLIG2) regulates the genesis of oligodendrocytes, the brain cells responsible for axonal myelination. Although it has been associated with psychiatric and neurological disorders, the impact of this gene on white matter integrity has never been investigated in humans. Using diffusion tensor imaging, we examined the effect of a single nucleotide polymorphism (rs1059004) in OLIG2 previously associated with reduced gene expression, and with psychiatric disorders on fractional anisotropy in 78 healthy subjects. We found that the risk allele (A) was associated with reduced white matter integrity in the corona radiata bilaterally. This is consistent with evidence that it is a schizophrenia susceptibility gene, and suggests that it may confer increased risk through an effect on neuroanatomical connectivity.

Unemployment, ethnicity and psychosis

Abstract: Unemployment is common in people with psycho-sis (1) This is clearly true once the illness hasbegun, where it mainly represents the difficulty ofreturning to work in the context of persistentsymptoms, self-stigmatisation and employerprejudice However, high rates of unemploymentare also seen before the identified onset of psycho-sis (2) This has usually been interpreted as aconsequence of postulated prodromal symptoms orneurodevelopmental impairment (3, 4), but there isno a priori reason why unemployment should nothave true aetiological effects It is acknowledged toBoydell J, Bebbington P, Bhavsar V, Kravariti E, van Os J, MurrayRM, Dutta R Unemployment, ethnicity and psychosisObjective: This study describes the incidence of psychosis inunemployed people and determines whether unemployment has agreater impact on the development of psychosis amongst Blackminority groups than White groupsMethod: Patients with a first diagnosis ofResearch Diagnostic Criteriapsychosis, in a defined area of London from 1998 to 2004, wereidentified Crude and standardised incidence rates of psychosisamongst unemployed people for each ethnic group were calculatedPoisson regression modelling tested for interactions betweenunemployment and ethnicityResults: Hundred cases occurred amongst employed people and 78cases occurred amongst the unemployed people When standardised tothe employed White population of the area, White unemployed peoplehad a standardised incidence ratio (SIR) of 117 (95% CI 64–197),Black Caribbean people had a SIR of 601(95% CI 393–88) and BlackAfrican people had a SIR of 407 (95% CI 258–611) There was nointeraction however between ethnicity and unemployment (Likelihoodratio test P =054)Conclusion: Rates of psychosis are high amongst unemployed peoplein south London and extremely high amongst Black Caribbean andBlack African unemployed people There was no evidence howeverthat the minority groups were particularly sensitive to the stresses,limitations or meaning of unemployment

Substantial genetic link between IQ and working memory: implications for molecular genetic studies on schizophrenia. the European twin study of schizophrenia (EUTwinsS).

Abstract: While evidence is accumulating to support specific neurocognitive deficits as putative endophenotypes for schizophrenia, the heritability of these deficits in healthy subjects and whether they share common genetic influences, is not well established. In the present study, 529 healthy adult twins from two centers within the European Twin Study Network on Schizophrenia (EUTwinsS) were assessed on two domains that are consistently found to be particularly compromised in schizophrenia. Specifically, Intellectual Quotient Score (IQ) and the Letter–Number Sequencing Test (LNS), a measure of working memory, were measured in all twins. Latent variable components were explored through structural equation modeling, and common genetic underpinnings were examined using bivariate analyses. Results showed that the phenotypic correlation between IQ and working memory was almost entirely attributed to shared genetic variance (95.5%). We discuss the potential use of a combined measure of IQ and working memory to improve the power of molecular studies in detecting the genetic mechanisms underlying schizophrenia. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.

Meta‐analytic approaches to determine gender differences in the age‐incidence characteristics of schizophrenia and related psychoses

Abstract: A recent systematic review and meta-analysis of the incidence and prevalence of schizophrenia and other psychoses in England investigated the variation in the rates of psychotic disorders. However, some of the questions of interest, and the data collected to answer these, could not be adequately addressed using established meta-analysis techniques. We developed a novel statistical method, which makes combined use of fractional polynomials and meta-regression. This was used to quantify the evidence of gender differences and a secondary peak onset in women, where the outcome of interest is the incidence of schizophrenia. Statistically significant and epidemiologically important effects were obtained using our methods. Our analysis is based on data from four studies that provide 50 incidence rates, stratified by age and gender. We describe several variations of our method, in particular those that might be used where more data is available, and provide guidance for assessing the model fit. Copyright © 2013 John Wiley & Sons, Ltd.

Association between the 2-bp deletion polymorphism in the duplicated version of the alpha7 nicotinic receptor gene and P50 sensory gating

Abstract: There is considerable evidence implicating the 15q13.3 region in neuropsychiatric disorders, with the α7 nicotinic receptor gene CHRNA7 the most plausible candidate. This region has multiple duplications and many copy number variants (CNVs). A common CNV involves a partial duplication of CHRNA7 (CHRFAM7A), which occurs in either orientation. We examined the distribution of these alternative genomic arrangements in a large cohort of psychiatric patients, their relatives and controls using the 2-bp deletion polymorphism as a marker for the orientation of CHRFAM7A. We investigated three common alleles for association with psychosis and with the P50 sensory gating deficit, which is strongly associated with psychosis and strongly linked to 15q13.3. We found significant within-family association with P50 (empirical P=0.004), which is robust to population stratification. Most of the effect came from the 2-bp deletion allele, which tags the variant of CHRFAM7A in the same orientation as CHRNA7. This allele is associated with the presence of the P50 sensory gating deficit (empirical P=0.0006). Tests comparing within-family and between-family components of association suggest considerable population stratification in the sample. We found no evidence for association with psychosis, but this may reflect lower power using this phenotype. Four out of six previous association studies found association of different psychiatric phenotypes with the same 2-bp deletion allele.

Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function

Abstract: The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation.