Showing papers by "Robin M. Murray published in 1999"
TL;DR: A substantial genetic contribution to variance in liability was confirmed for the major diagnostic categories except Research Diagnostic Criteria depressive psychosis and unspecified functional psychosis, where familial transmission was confirmed, but the relative contribution of genetic and common environmental factors was unclear.
Abstract: Background Previous twin studies have supported a genetic contribution to the major categories of psychotic disorders, but few of these have employed operational diagnostic criteria, and no such study has been based on a sample that included the full range of functional psychotic disorders. Methods A total of 224 twin probands (106 monozygotic, 118 dizygotic) with a same-sex co-twin and a lifetime history of psychosis was ascertained from the service-based Maudsley Twin Register in London, England. Research Diagnostic Criteria psychotic diagnoses were made on a lifetime-ever basis. Main-lifetime diagnoses of DSM-III-R and International Statistical Classification of Diseases, 10th Revision schizophrenia were also made. Probandwise concordance rates and correlations in liability were calculated, and biometrical model fitting applied. Results A substantial genetic contribution to variance in liability was confirmed for the major diagnostic categories except Research Diagnostic Criteria depressive psychosis and unspecified functional psychosis, where familial transmission was confirmed, but the relative contribution of genetic and common environmental factors was unclear. Heritability estimates for Research Diagnostic Criteria schizophrenia, schizoaffective disorder, mania, DSM-III-R schizophrenia, and International Statistical Classification of Diseases, 10th Revision schizophrenia were all between 82% and 85%. None of the estimates differed significantly from any other. Conclusions Heritability estimates for schizophrenia, schizoaffective disorder, and mania were substantial and similar. Population morbid risk estimates were inferred rather than directly measured, but the results were very similar to those from studies where morbid risks were directly estimated.
777 citations
TL;DR: Individuals born very preterm show an excess of neurocognitive and behavioural problems in adolescence, and more than half have abnormal MRI brain scans.
398 citations
TL;DR: A few specific pregnancy and perinatal factors were associated with the subsequent development of psychotic disorder, particularly schizophrenia, in early adult life.
Abstract: # Prenatal and perinatal risk factors for schizophrenia, affective psychosis, and reactive psychosis of early onset: case-control study {#article-title-2}
Objective: To examine prenatal and perinatal risk factors for subsequent development of schizophrenia and affective and reactive psychosis.
Design: Three population based, case-control studies conducted within a Sweden-wide cohort of all children born during 1973-9.This was done by linking individual data from the Swedish birth register, which represents 99% of all births in Sweden, to the Swedish inpatient register.
Subjects: Patients listed in inpatient register as having been first admitted to hospital aged 15-21years with a main diagnosis of schizophrenia (n=167), affective psychosis (n=198), or reactive psychosis (n=292). For each case, five controls were selected.
Main outcome measures: Risks of schizophrenia and affective and reactive psychosis in relation to pregnancy and perinatal characteristics.
Results: Schizophrenia was positively associated with multiparity (odds ratio 2.0), maternal bleeding during pregnancy (odds ratio 3.5), and birth in late winter (odds ratio 1.4). Affective psychosis was associated with uterine atony (odds ratio 2.2) and late winter birth (odds ratio 1.5). Reactive psychosis was related to multiparity (odds ratio 2.1). An increased risk for schizophrenia was found in boys who were small for their gestational age at birth (odds ratio 3.2), who were number four or more in birth order (odds ratio 3.6), and whose mothers had had bleeding during late pregnancy (odds ratio 4.0).
Conclusions: A few specific pregnancy and perinatal factors were associated with the subsequent development of psychotic disorder, particularly schizophrenia, in early adult life. The association of small size for gestational age and bleeding during pregnancy with increased risk of early onset schizophrenia among males could reflect placental insufficiency.
# Prenatal and perinatal risk factors for early onset schizophrenia, affective psychosis, and reactive psychosis {#article-title-34}
310 citations
TL;DR: It is concluded that some abnormalities of pregnancy and delivery may be associated with development of schizophrenia and the pathophysiology may involve hypoxia and so future studies should focus on the accurate measurement of this exposure.
Abstract: Several epidemiological studies have reported an association between complications of pregnancy and delivery and schizophrenia, but none have had sufficient power to examine specific complications that, individually, are of low prevalence. We, therefore, performed an individual patient meta-analysis using the raw data from case control studies that used the Lewis-Murray scale. Data were obtained from 12 studies on 700 schizophrenia subjects and 835 controls. There were significant associations between schizophrenia and premature rupture of membranes, gestational age shorter than 37 weeks, and use of resuscitation or incubator. There were associations of borderline significance between schizophrenia and birthweight lower than 2,500 g and forceps delivery. There was no significant interaction between these complications and sex. We conclude that some abnormalities of pregnancy and delivery may be associated with development of schizophrenia. The pathophysiology may involve hypoxia and so future studies should focus on the accurate measurement of this exposure.
295 citations
TL;DR: Poor performance in sports and handicrafts during elementary school, which may indicate a motor coordination deficit, appears to be a risk factor for later schizophrenia.
Abstract: Background We examined whether children who are diagnosed as having schizophrenia in adulthood could be distinguished from their peers on performance in elementary school. Methods We used a case-control study design nested within a population-based birth cohort of all individuals born in Helsinki, Finland, between January 1, 1951, and December 31, 1960. Case ascertainment was from 3 national health care registers. Elementary school records were obtained for 400 children who were diagnosed as having schizophrenia in adulthood and for 408 controls. Results were analyzed for the 4 years of schooling (ages 7-11 years) that were common to all pupils. School subjects were entered into a principal components analysis and produced 3 factors: academic, nonacademic, and behavioral. These factors were compared between cases and controls after adjusting for sex and social group. Eligibility for high school and progression to high school were investigated among cases and controls. Results Cases performed significantly worse than controls only on the nonacademic factor (which loaded sports and handicrafts). There were no differences between the groups on the academic or behavioral factors, and there were no significant clinical correlates of factor scores. Cases were significantly less likely than controls to progress to high school, despite similar eligibility. Conclusions Poor performance in sports and handicrafts during elementary school, which may indicate a motor coordination deficit, appears to be a risk factor for later schizophrenia. Poor academic performance in elementary school was not a risk factor for schizophrenia in this study. Lack of expected progression to high school among cases, despite good academic grades, provides evidence for deteriorating premorbid functional adjustment in schizophrenia.
252 citations
TL;DR: Reduction of the left hippocampal volume was associated with the diagnosis of schizophrenia but was present only in patients with a history of severe PBCs, the earlier the onset of psychosis.
131 citations
TL;DR: The pattern of memory impairment in schizophrenia is more similar in nature to that found in patients with memory dysfunction following mesiotemporal lobe lesions, rather than that associated with focal frontal lobe damage.
113 citations
TL;DR: The results suggest that pathological change in schizophrenia may be expressed at two mutually independent levels of anatomical organization: global change in a grey matter/ventricular system and supra-regionalchange in a frontal-temporal system.
Abstract: At what levels of brain organization might pathological change in schizophrenia be anatomically expressed: global, regional or supraregional? We hypothesised that brain structure reflects a set of supra-regional anatomical systems with common developmental influences. We conducted an exploratory analysis to identify supraregional brain systems and to investigate whether abnormal brain architecture in schizophrenia is manifested within one or more of these systems. Magnetic resonance (MR) images were acquired from 27 patients with schizophrenia and 37 control subjects. After segmentation and registration of each individual MRI dataset in the standard space of Talairach and Tournoux, grey matter and ventricular-cerebrospinal fluid (CSF) maps were automatically parcellated into 104 regions. We used principal components analysis of the multiple regional grey matter and ventricular-CSF measurements, on all 64 subjects, to extract the five main normative supra-regional systems. The first two of these components represented global variation in grey matter and ventricular-CSF regional measures. We interpreted the other three components as representing supra-regional systems comprising: a frontal-parietal system, a frontal-temporal system and a frontal-basal ganglia system. Schizophrenic group mean scores on the first component (global grey matter-ventricular contrast) and fourth component (frontal-temporal system) were significantly reduced compared to controls. These results suggest that pathological change in schizophrenia may be expressed at two mutually independent levels of anatomical organization: global change in a grey matter/ventricular system and supra-regional change in a frontal-temporal system.
112 citations
TL;DR: Attenuation of frontal activation during cognitive task performance in schizophrenia does not represent a fixed deficit in frontal function, but may depend on the specific cognitive demands of the experimental task employed.
107 citations
TL;DR: Quantitative trait analyses in mice suggest a vulnerability locus for physiological alcohol withdrawal severity on a chromosomal segment that harbors the genes encoding the alpha1, alpha6, beta2, and gamma2 subunits of the gamma-aminobutyric acid type-A receptor (GABR).
Abstract: Quantitative trait analyses in mice suggest a vulnerability locus for physiological alcohol withdrawal severity on a chromosomal segment that harbors the genes encoding the α 1 , α 3 , β 2 , and γ 2 subunits of the γ-aminobutyric acid type-A receptor (GABR). We tested whether genetic variation at the human GABA A α6, β2, and γ2 gene cluster on chromosome 5q33 confers vulnerability to alcohol dependence. The genotypes of three nucleotide substitution polymorphisms of the GABRA6, GABRB2, and GABRG2 genes were assessed in 349 German alcohol-dependent subjects and in 182 ethnically matched controls. To eliminate some of the genetic variance, three more homogeneous subgroups of alcoholics were formed by: (1) a history of alcohol withdrawal seizure or delirium (n = 106); (2) a history of parental alcoholism (n = 120); and (3) a comorbidity of dissocial personality disorder (n = 57). We found no evidence that any of the investigated allelic variants confers vulnerability to either alcohol dependence or severe physiological alcohol withdrawal symptoms or familial alcoholism (p > 0.05). The frequency of the T allele of the GABRA6 polymorphism was significantly increased in dissocial alcoholics [f(T) = 0.799] compared with the controls [f(T) = 0.658; p = 0.002; OR(T+) = 7.26]. Taking into account the high a priori risk of false-positive association findings due to multiple testing, further replication studies are necessary to examine the tentative phenotype-genotype relationship of GABRA6 gene variants and dissocial alcoholism.
92 citations
TL;DR: The findings indicate that lack of the normal pattern of frontal and occipital asymmetry is a marker for genetic liability to schizophrenia in families multiply affected with schizophrenia.
TL;DR: The results indicate that the excess of mixed- handedness in schizophrenia may have a genetic basis and there was some evidence for impaired sociability in the mixed-handed schizophrenic patients.
TL;DR: Assessment of whether intensive case management (small case load) reduces hospitalisation and costs compared with standard case management in mild and severe disability and in people of African–Caribbean origin and White Caucasians.
Abstract: Background Case management, particularly in intensive form, has been widely introduced for the treatment of severe mental illness. However, the optimal intensity of case management has not been determined. Aims We aimed to assess whether intensive case management (small case load) reduces hospitalisation and costs compared with standard case management. Method Development and rationale of a large randomised controlled trial comparing intensive case management (case load per worker? 15 patients) with standard case management (case load 30–35 patients) Results Two-year outcome data will be obtained on patients representative of the seriously mentally ill in inner-city mental health services. Conclusions The study planned with 700 patients should be sufficient to detect small differences in the readmission of patients to hospital (10%), the number of days spent in hospital over a two-year period (10 days) and the average weekly cost of care per patient. The sample is large enough to compare the cost-effectiveness of intensive and standard case management in mild and severe disability and in people of African–Caribbean origin and White Caucasians.
TL;DR: Evidence is provided for a role for the GABAA receptor subunit cluster on chromosome 5q33 in susceptibility to the alcohol dependence syndrome and Korsakoff's psychosis.
Abstract: A role for the GABA/benzodiazepine receptor complex in alcohol dependence syndrome has been suggested by several lines of evidence To elucidate the role of GABAA subunits in human alcohol dependence syndrome, we identified polymorphisms in the GABAAbeta2 and GABAAalpha6 receptor subunit genes on 5q33 and assessed their potential contribution in an association study, together with a NciI RFLP at the GABAAgamma2 receptor subunit gene One hundred and eight alcohol-dependent subjects and 54 unrelated controls were recruited from Scotland Two novel genetic markers were identified at the GABAAbeta2 and GABAAalpha6 receptor subunit genes and examined for association with the alcohol dependence syndrome and subgroups of subjects with Korsakoff's psychosis and without Korsakoff's psychosis, together with a NciI RFLP at the GABAAgamma2 receptor subunit gene The chi2 tests demonstrated associations between all alcohol-dependent subjects (not stratified) and the BanI RFLP at the GABAAbeta2 receptor subunit gene (P = 0015), and the AlwNI RFLP at the GABAAalpha6 receptor gene (P = 0013) Significant associations were also found between the alcohol-dependent subjects with Korsakoff's psychosis and the BanI RFLP (P = 0039) and the AlwNI RFLP (P = 0003) Haplotype analysis also provided evidence of association when all alcohol-dependent subjects (P = 0013) and the subjects with Korsakoff's psychosis (P = 0007) were compared with controls Our findings provide evidence for a role for the GABAA receptor subunit cluster on chromosome 5q33 in susceptibility to the alcohol dependence syndrome and Korsakoff's psychosis
TL;DR: This study shows that B&EM patients do not experience significantly more life events than WB patients; however, their perception of these events is clearly different, and significantly more often attributed to racism.
Abstract: Background: Whilst it is commonly believed that black and ethnic minority (BE thus, the Irish (n = 11) had similar scores to the WB while Africans (n = 16) scored like the ACs. Conclusion: Our study shows that BE however, their perception of these events is clearly different, and significantly more often attributed to racism. It is reasonable to suppose that patients may be disinclined to utilise services they believe to be prejudiced against them on the basis of their skin colour, and service providers need to be aware of this in order to create health care services that B&EM patients feel confident to use.
TL;DR: The model is that genetic and/or early environmental factors cause the development of anomalous neural networks that interact in the growing child with inherited schizotypal traits to establish a trajectory towards an increasingly solitary and deviant life style.
TL;DR: A novel, rare one-repeat variant of the DRD4 exon 3 VNTR repeat in Chinese populations, which appears to be absent in Caucasians and is not associated with disease.
Abstract: We have performed a case-control analysis of dopamine D2-like receptor (DRD2, DRD3 and DRD4) gene polymorphisms in 118 Han Chinese cases with bipolar affective disorder and 196 control subjects, and replication analysis in 157 English cases and 143 control subjects. We found association between a functional DRD2 promoter variant (P = 0.03 by allele) and the DRD2 taq1A polymorphism (P = 0.001 by allele) in Chinese bipolar disorder patients. However, this finding was not replicated in the Caucasian subjects, indicating that the significant association we observed in the Chinese population is a false positive finding. An alternative explanation is that these polymorphisms are risk factors in Chinese but not Caucasian populations, a hypothesis which seems unlikely in view of the similarity of the clinical characteristics of bipolar disorder in the two populations. We also report a novel, rare one-repeat variant of the DRD4 exon 3 VNTR repeat in Chinese populations, which appears to be absent in Caucasians and is not associated with disease.
TL;DR: Analysis of clinical characteristics of patients attending a lithium clinic in south London found that Africans were significantly more likely than whites to show exclusively or mainly manic presentations while Afro-Caribbeans were more likely to have had mood-incongruent delusions.
TL;DR: In this paper, the authors tested whether genetic variation at the human GABA(A) alpha6, beta2, and gamma2 gene cluster on chromosome 5q33 confers vulnerability to alcohol dependence.
Abstract: Quantitative trait analyses in mice suggest a vulnerability locus for physiological alcohol withdrawal severity on a chromosomal segment that harbors the genes encoding the alpha1, alpha6, beta2, and gamma2 subunits of the gamma-aminobutyric acid type-A receptor (GABR). We tested whether genetic variation at the human GABA(A) alpha6, beta2, and gamma2 gene cluster on chromosome 5q33 confers vulnerability to alcohol dependence. The genotypes of three nucleotide substitution polymorphisms of the GABRA6, GABRB2, and GABRG2 genes were assessed in 349 German alcohol-dependent subjects and in 182 ethnically matched controls. To eliminate some of the genetic variance, three more homogeneous subgroups of alcoholics were formed by: (1) a history of alcohol withdrawal seizure or delirium (n = 106); (2) a history of parental alcoholism (n = 120); and (3) a comorbidity of dissocial personality disorder (n = 57). We found no evidence that any of the investigated allelic variants confers vulnerability to either alcohol dependence or severe physiological alcohol withdrawal symptoms or familial alcoholism (p > 0.05). The frequency of the T allele of the GABRA6 polymorphism was significantly increased in dissocial alcoholics [f(T) = 0.799] compared with the controls [f(T) = 0.658; p = 0.002; OR(T+) = 7.26]. Taking into account the high a priori risk of false-positive association findings due to multiple testing, further replication studies are necessary to examine the tentative phenotype-genotype relationship of GABRA6 gene variants and dissocial alcoholism.
TL;DR: It is indicated that neither focal frontal nor temporal lobe damage sustained in adult life is a sufficient explanation for the problem-solving deficits found in patients with schizophrenia.
TL;DR: The data are not consistent with ultrarapid metaboliser status being a major cause of failure to respond to typical antipsychotics, and the percentages in the two groups of patients are both within the range for ultrarAPid metabolisers in Caucasian populations.
Abstract: Aims To investigate whether or not there is a correlation between failure to respond to typical antipsychotics and CYP2D6 ultrarapid metaboliser status.
Methods CYP2D6 phenotype (metaboliser status) was assigned following genotyping for gene duplication, as well as for the CYP2D6*3, CYP2D6*4, and CYP2D6*5 null alleles in 235 treatment-refractory patients and 73 nonrefractory patients.
Results Four (1.7%) of the 235 treatment-refractory subjects were positive on the duplication assay, but, of these, two were found to represent duplications of a null allele (CYP2D6*4 ), therefore leaving only two (0.85%) positive for duplication of a wild type allele (ultrarapid metabolisers). Three (4.1%) of the nonrefractory subjects had a genotype consistent with ultrarapid metaboliser status. Fisher’s exact test gave a two-tailed P value of 0.091, i.e. a trend towards an excess of ultrarapid metabolisers in the nonrefractory group, which was in the opposite direction to that predicted by our hypothesis.
Conclusions Although the results show a trend towards an excess of ultrarapid metabolisers in the nonrefractory group, the percentages in the two groups of patients are both within the range for ultrarapid metabolisers in Caucasian populations. Our data are not consistent with ultrarapid metaboliser status being a major cause of failure to respond to typical antipsychotics.
TL;DR: Understanding the inconstancy of hypofrontality in schizophrenia is likely to progress more by theoretically driven experiments that exploit the repeatability of fMRI than by further technological development alone.
Abstract: Comparatively reduced blood flow to frontal brain regions in patients with schizophrenia (hypofrontality) has been frequently observed in the last 25 years. However, there is an inconstant quality to hypofrontality, suggesting either confounded observation of a static (trait-like) abnormality, or that it is a genuinely dynamic (state-like) phenomenon. Possible confounds in functional magnetic resonance imaging (fMRI) studies of hypofrontality are classified. Methods for assessment and correction of stimulus correlated motion (an extracerebral confound) are reviewed in the context of fMRI data acquired from five schizophrenic patients and five comparison subjects during performance of a verbal fluency task. Factorial analysis of these and other data, acquired from the same subjects during a semantic decision task, is used to exclude a number of possible intracerebral confounds. By analogy to the historical controversy concerning the appearance of the planet Saturn viewed through early telescopes, understanding the inconstancy of hypofrontality in schizophrenia is likely to progress more by theoretically driven experiments that exploit the repeatability of fMRI than by further technological development alone. Hum. Brain Mapping 8:86–91, 1999. © 1999 Wiley-Liss, Inc.
TL;DR: It is inferred that inhibition of CYP3A4 in vivo has minimal effects on clozapine metabolism and nefazodone appears to be safe when co-administered with clozAPine.
Abstract: The cytochrome enzyme p4503A4 (CYP3A4) is thought to play a major part in the human metabolism of clozapine. Nefazodone is a potent and specific in-vivo inhibitor of CYP3A4. We co-administered nefazodone and clozapine in six patients and found that mean clozapine levels rose by 4% of baseline and norclozapine levels by 16%. Based on these observations, it is inferred that inhibition of CYP3A4 in vivo has minimal effects on clozapine metabolism. Nefazodone appears to be safe when co-administered with clozapine.
TL;DR: Evidence for linkage between bipolar disorder and three regions on chromosome 18, the pericentromeric region, 18q21, and 18q22-q23, was not significantly increased by analyses that allowed for heterogeneity nor by analysing the subset of pedigrees consistent with paternal transmission.
Abstract: Evidence consistent with the existence of genetic linkage between bipolar disorder and three regions on chromosome 18, the pericentromeric region, 18q21, and 18q22-q23 have been reported. Some analyses indicated greater evidence for linkage in pedigrees in which paternal transmission of disease occurs. We have undertaken linkage analyses using 12 highly polymorphic markers spanning these three regions of interest in a sample of 48 U.K. bipolar pedigrees. The sample comprises predominantly nuclear families and includes 118 subjects with Diagnostic and Statistical Manual of Mental Disorders (DSM IV) bipolar I disorder and 147 subjects with broadly defined phenotype. Our data do not provide support for linkage using either parametric or nonparametric analyses. Evidence for linkage was not significantly increased by analyses that allowed for heterogeneity nor by analysing the subset of pedigrees consistent with paternal transmission.
TL;DR: It is found that children who developed schizophrenia in adulthood performed significantly worse than controls on subjects involving motor co‐ordination, between ages 7 and 9, and are most evident in early and middle childhood.
Abstract: We examined whether children destined to develop schizophrenia in adulthood could be distinguished from their peers on elementary school performance. We used a case–control study design nested within a population-based birth cohort of all individuals born in Helsinki, Finland between 1951 and 1960. Case ascertainment was from three health-care registers, and elementary school records were obtained for 400 children who were diagnosed as suffering from schizophrenia in adulthood and 408 controls. We found that children who developed schizophrenia in adulthood performed significantly worse than controls on subjects involving motor co-ordination (sports and handcrafts), between ages 7 and 9. There were no differences between the groups on academic subjects, but cases were significantly more likely to have been referred to a school psychologist. This study indicates that motor co-ordination deficits are a risk factor for adult schizophrenia, and are most evident in early and middle childhood. Contrary to previous work, we did not find evidence of cognitive impairment preceding schizophrenia, but psychological difficulties are present from an early age in children who later develop the disorder. Copyright © 1999 John Wiley & Sons, Ltd.
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01 Jan 1999
TL;DR: It is necessary to consider the context in which the individual is diagnosed, as well as the individual’s prior medical history, to arrive at a diagnosis and treatment strategy.
Abstract: 1. Introduction 2. Epidemiology 3. Clinical Presentation and Evaluation 4. Investigations 5. Differential Diagnosis and Comorbidity 6. Aetiological Considerations 7. Drug Treatment 8. Psychosocial Treatment 9. Subjective Viewpoint 10. Course of Illness and Outcome 11. Future Developments: The Challenge
01 Jan 1999
TL;DR: The study of populations at unusually high or low risk of a particular disease has a long and productive history in medicine and these populations offer researchers the opportunity to seek particular causal or protective factors.
Abstract: The study of populations at unusually high or low risk of a particular disease has a long and productive history in medicine. These populations offer researchers the opportunity to seek particular causal or protective factors which may be important not only in the population under examination but also more generally. It is for such reasons that epidemiologists are interested in migrants.
TL;DR: Evidence from epidemiological, genetic and neuroimaging studies suggests that schizophrenia is in part a neurodevelopmental disorder, but it is pointed out that this is not the whole story.
01 Jan 1999
TL;DR: It is hypothesised that maternal immunogenetic predisposition interacts with the influenza virus to cause neurodevelopmental lesions which manifest in adulthood as schizophrenia.
Abstract: Disease discordance of 50% in monozygotic twins implicates genetic and environmental factors in the aetiology of schizophrenia. Autoimmune diseases are HLA associated and are thought to occur when a genetically predisposed individual is exposed to an essential, probably viral, environmental trigger. We have reported an excess of autoimmune diseases in the first degree relatives of schizophrenic patients, an excess of second trimester influenza infections in the mothers of schizophrenic patients, and a deficiency of HLA DRB1*O4 alleles in the mothers of schizophrenic patients and in schizophrenic patients themselves. We have therefore hypothesised that maternal immunogenetic predisposition interacts with the influenza virus to cause neurodevelopmental lesions which manifest in adulthood as schizophrenia. Our work raises the possibility of an (immuno)genetic predisposition to schizophrenia at pedigree, maternal, and proband level.