Showing papers by "Robin M. Murray published in 1996"

A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders

Abstract: The serotonin transporter (5-HTT) is a candidate locus for aetiological involvement in affective disorders. Biochemical studies in suicides and depressed patients suggest that 5-HT uptake function is frequently reduced in affective illness. Furthermore, 5-HTT is targeted by widely used antidepressant drugs such as fluoxetine. We have performed an association study of a short variant of the 5-HTT-linked polymorphic region (5-HTTLPR), which restricts transcriptional activity of the 5-HTT promoter leading to low functional expression of the 5-HTT, in 454 patients with bipolar or unipolar affective disorder and 570 controls, derived from three European Centres (London, Milan and Wurzburg). In all three centres, the frequency of the low activity allele was higher in patients than in controls (50% vs 45% in London, 45% vs 43% in Milan, 47% vs 40% in Wurzburg). Although these differences were not individually significant, a stratified analysis of all three samples gave a significant overall odds ratio of 1.23 (95% confidence interval 1.02-1.49, P = 0.03). The excess of the homozygous low-activity genotype among the patients was even greater (odds ratio 1.53, 95% confidence interval 1.04-2.23, P = 0.02), suggesting partial recessively of the low-activity allele. Given the functional role of 5-HTT, our findings suggest that 5-HTTLPR-dependent variation in functional 5-HTT expression is a potential genetic susceptibility factor for affective disorders. If this finding is replicated, further work on genetic variants with low 5-HTT activity may facilitate the differential diagnosis of affective disorders, the assessment of suicidal behaviour, and the prediction of good clinical response to antidepressants.

Functional anatomy of inner speech and auditory verbal imagery

Abstract: The neural correlates of inner speech and of auditory verbal imagery were examined in normal volunteers, using positron emission tomography (PET). Subjects were shown single words which they used to generate short, stereotyped sentences without speaking. In an inner speech task, sentences were silently articulated, while in an auditory verbal imagery condition, subjects imagined sentences being spoken to them in an another person's voice. Inner speech was associated with increased activity in the left inferior frontal gyrus. Auditory verbal imagery was associated with increases in the same region, and in the left premotor cortex, the supplementary motor area and the left temporal cortex. The data suggest that the silent articulation of sentences involves activity in an area concerned with speech generation, while imagining speech is associated with additional activity in regions associated with speech perception.

A combined analysis of D22S278 marker alleles in affected sib-pairs: Support for a susceptibility locus for schizophrenia at chromosome 22q12

Abstract: Several groups have reported weak evidence for linkage between schizophrenia and genetic markers located on chromosome 22q using the lod score method of analysis. However these findings involved different genetic markers and methods of analysis, and so were not directly comparable. To resolve this issue we have performed a combined analysis of genotypic data from the marker D22S278 in multiply affected schizophrenic families derived from 11 independent research groups worldwide. This marker was chosen because it showed maximum evidence for linkage in three independent datasets (Vallada et al., Am J Med Genet 60:139-146, 1995; Polymeropoulos et al., Neuropsychiatr Genet 54:93-99, 1994; Lasseter et al., Am J Med Genet, 60:172-173, 1995. Using the affected sib-pair method as implemented by the program ESPA, the combined dataset showed 252 alleles shared compared with 188 alleles not share (chi-square 9.31, 1df, P = 0.001) where parental genotype data was completely known. When sib-pairs for whom parental data was assigned according to probability were included the number of alleles shared was 514.1 compared with 437.8 not shared (chi-square 6.12, 1df, P = 0.006). Similar results were obtained when a likelihood ratio method for sib-pair analysis was used. These results indicate that may be a susceptibility locus for schizophrenia at 22q12.

The neural correlates of inner speech and auditory verbal imagery in schizophrenia: relationship to auditory verbal hallucinations.

Abstract: BACKGROUND Auditory verbal hallucinations are thought to arise from the disordered monitoring of inner speech (thinking in words). We tested the hypothesis that a predisposition to verbal auditory hallucinations would be associated with an abnormal pattern of brain activation during tasks which involved the generation and monitoring of inner speech. METHOD The neural correlates of tasks which engaged inner speech and auditory verbal imagery were examined using positron emission tomography in (a) schizophrenic patients with a strong predisposition to auditory verbal hallucinations (hallucinators), (b) schizophrenic patients with no history of hallucinations (nonhallucinators), and (c) normal controls. RESULTS There were few between-group differences in activation during the inner speech task. However, when imagining sentences spoken in another person's voice, which entails the monitoring of inner speech, hallucinators showed reduced activation in the left middle temporal gyrus and the rostral supplementary motor area, regions which were strongly activated by both normal subjects and nonhallucinators (P < 0.001). Conversely, when nonhallucinators imagined speech, they differed from both hallucinators and controls in showing reduced activation in the right parietal operculum. CONCLUSIONS A predisposition to verbal hallucinations in schizophrenia is associated with a failure to activate areas implicated in the normal monitoring of inner speech, whereas the absence of a history of hallucinations may be linked to reduced activation in an area concerned with verbal prosody.

Psychopathological syndromes in the functional psychoses: associations with course and outcome.

Abstract: The aim of this study was to identify underlying dimensions of psychopathology in a cohort of patients with functional psychosis of recent onset, and to examine their prognostic value. Factor analysis of the psychopathological features of 166 consecutively admitted patients with functional psychosis of recent onset revealed seven psychopathological dimensions, which explained 63% of the variance. Five of these seven syndromes bore differential associations with subsequent treatment and illness course, independent of: (i) associations with DSM-III-R diagnosis; (ii) associations with other prognostic factors; and (iii) associations with the baseline values of outcome variables. The most striking associations were shown for an early and insidious onset syndrome with affective flattening, which predicted a more disabled course of illness on three of four outcome dimensions, and which was more common in males and unmarried individuals. A second syndrome, characterized by bizarre behaviour, inappropriate affect, catatonia, and poor rapport showed similar, slightly less striking, associations with illness course, as well as with poor pre-morbid social functioning. A third syndrome, characterized by positive psychotic symptoms was to a lesser degree associated with poorer outcome, whereas a fourth syndrome distinguished by manic symptomatology predicted a more benign illness course. A fifth syndrome identified by lack of insight predicted more time in hospital and admission under a section of the Mental Health Act during the follow-up period.A further finding was that dimensional representations of psychopathological features were considerably more useful than categorical representations (DSM-III-R and ICD-10) as predictors of illness course and treatment decisions.

The serotonin transporter is a potential susceptibility factor for bipolar affective disorder

Abstract: The serotonin transporter is a strong candidate for aetiological involvement in affective disorders and psychosis. We analysed a VNTR in intron 2 of the human serotonin transporter gene (hSERT) for allelic association with bipolar affective disorder, unipolar depression and schizophrenia. An increased frequency of allele 12 of the VNTR was observed in subjects with bipolar affective disorder (n = 191; chi 2 p = 0.00048 by allele) but not unipolar depression (n = 86; chi 2 p = 0.18, ns) or schizophrenia (n = 129; chi 2 p = 0.08, ns), although a trend towards an excess of allele 12 was observed for the latter. There was also a significant difference in the frequency of allele 12 between bipolar affective disorder and unipolar depression (p = 0.0087). The relative risk for bipolar affective disorder with respect to allele 12 was 1.84 (95% CI 0.97-3.56) for heterozygotes, and 3.10 (95% CI 1.60-6.07) for homozygotes, with evidence for a gene-dosage effect. Because allele 12 is common in the population, the attributable risk is 50.8% (95% CI 14.5%-73.3%). We hypothesize that either the VNTR affects regulation of expression of hSERT at the transcriptional level or it is in linkage disequilibrium with another functional polymorphism in the gene, and this results in an increased risk for the development of bipolar affective disorder.

Additional support for schizophrenia linkage on chromosomes 6 and 8: A multicenter study

Abstract: In response to reported schizophrenia linkage findings on chromosomes 3, 6 and 8, fourteen research groups genotyped 14 microsatellite markers in an unbiased, collaborative (New) sample of 403-567 informative pedigrees per marker, and in the Original sample which produced each finding (the Johns Hopkins University sample of 46-52 informative pedigrees for chromosomes 3 and 8, and the Medical College of Virginia sample of 156-191 informative pedigrees for chromosome 6). Primary planned analyses (New sample) were two-point heterogeneity lod score (lod2) tests (dominant and recessive affected-only models), and multipoint affected sibling pair (ASP) analysis, with a narrow diagnostic model (DSM-IIIR schizophrenia and schizoaffective disorders). Regions with positive results were also analyzed in the Original and Combined samples. There was no evidence for linkage on chromosome 3. For chromosome 6, ASP maximum lod scores (MLS) were 2.19 (New sample, nominal p = 0.001) and 2.68 (Combined sample, p = .0004). For chromosome 8, maximum lod2 scores (tests of linkage with heterogeneity) were 2.22 (New sample, p = .0014) and 3.06 (Combined sample, p = .00018). Results are interpreted as inconclusive but suggestive of linkage in the latter two regions. We discuss possible reasons for failing to achieve a conclusive result in this large sample. Design issues and limitations of this type of collaborative study are discussed, and it is concluded that multicenter follow-up linkage studies of complex disorders can help to direct research efforts toward promising regions.

Psychotic illness in ethnic minorities: clarification from the 1991 census

Abstract: Age and sex-adjusted first admission rates for operationally-defined schizophrenia and other non-affective psychosis in different ethnic groups were calculated over the period 1988-1992 in a defined catchment area in South London. Standardized rates for schizophrenia, corrected for age- and gender-related under-reporting in the 1991 census and a 20% underestimate of the size of the ethnic minority populations in the area, were not only higher in the Afro-Caribbean group (SMR: 3.1; 95% C1:2.0-4.7), but also in the African group (SMR: 4.2; 95% C1: 2.8-6.2). It was further found that higher rates were not specific to schizophrenia. These findings suggest that some common factor associated with ethnic minority membership is important in producing an excess of psychotic illness.

Preferential transmission of the high activity allele of COMT in schizophrenia.

Abstract: Catechol-O-methyl transferase (COMT) metabolizes a variety of catecholamines such as dopamine, adrenaline and noradrenaline. It exists in common high and low activity forms. The low activity form is the result of an amino acid substitution (val-108-met) which reduces the thermostability of the enzyme [Lotta et al. (1994) Biochemistry, 34, 4202-4210]. We have genotyped this polymorphism in 178 trios consisting of Han Chinese schizophrenic subjects and their parents in order to test the hypothesis that the high activity allele is transmitted more often to affected subjects. The data were analysed using the transmission disequilibrium test (TDT), a robust method of detecting linkage in the presence of allelic associations. Of the 131 parents heterozygous at this locus, 80 transmitted the high activity allele (val-108) to affected offspring, while the remaining 51 transmitted the low activity allele (p = 0.005, one-tailed). Combining this result with that of a previous TDT study of the same polymorphism in familial schizophrenia [Kunugi et al. (1996) submitted] gives significant evidence for linkage disequilibrium (p = 0.0015). However, val-108 is frequent in the Han Chinese population, and in the present sample, 239 of the 350 non-transmitted parental alleles were val-108 (68%). It is therefore unlikely that val-108 allele of COMT has a major effect on susceptibility to schizophrenia. Our results suggest that either val-108 is a minor risk factor for schizophrenia, that the COMT gene has additional polymorphisms with greater effect on risk, or that this region of chromosome 22 contains a susceptibility gene which is in linkage disequilibrium with the COMT gene.

Morbid risk of schizophrenia in first-degree relatives of white and African-Caribbean patients with psychosis.

Abstract: BACKGROUND The high rate of schizophrenia among the second-generation African-Caribbean population in Britain has prompted much concern and speculation. Sugarman and Craufurd have reported that the morbid risk in the siblings of second-generation African-Caribbean schizophrenic patients was unusually high compared with that of the siblings of White patients. METHOD We sought to replicate these findings by comparing the morbid risk for schizophrenia in the first-degree relatives of 111 White and 73 African-Caribbean psychotic probands. The latter comprised 35 first-generation (born in the Caribbean) and 38 second-generation (born in Britain) probands. RESULTS The morbid risk for schizophrenia was similar for the parents and siblings of White and first-generation African-Caribbean patients, and for the parents of the second-generation African-Caribbean probands. However, the siblings of second-generation African-Caribbean psychotic probands had a morbid risk for schizophrenia that was seven times that of their White counterparts (P = 0.007); similarly, the siblings of second-generation African-Caribbean schizophrenic probands had a morbid risk for schizophrenia that was four times that of their White counterparts (P = 0.05). CONCLUSIONS These findings replicate those of the earlier report of Sugarman and Craufurd, and suggest either that the second-generation African-Caribbean population in Britain is particularly vulnerable to some environmental risk factors for schizophrenia, or that some environmental factors act selectively on this population in Britain.

Genetic association of the HLA DRB1 gene locus on chromosome 6p21.3 with schizophrenia.

Abstract: Objective : The authors investigated the human leukocyte antigens (HLA) DRB1*04 gene in schizophrenic patients because it is positively associated with rheumatoid arthritis, an autoimmune disease that exhibits a strong negative association with schizophrenia. The HLA DQB1*0602 allele was also studied because of previous reports of genetic association between it and schizophrenia. Maternal HLA was investigated because of the reported association between prenatal influenza and schizophrenia and the central role of HLA molecules in the immune response to viral infections. Method : Polymerase chain reactions and sequence-specific oligonucleotide probes were used to genotype 94 unrelated patients with DSM-III-R schizophrenia, 92 mothers of schizophrenic offspring who were not related either to each other or to the 94 patients, and 177 healthy comparison subjects. Results : The frequency of DRB1*04 alleles was significantly lower in both the schizophrenic patients and the unrelated mothers of schizophrenic offspring than in the healthy comparison subjects. No significant differences were found for DQB1*0602. Conclusions : DRB1*04 alleles may partially account for the genetic predisposition to schizophrenia. The association reported here may be explained by genetic linkage or by an autoimmune pathophysiology for a proportion of schizophrenia cases. Alternatively, it may be that maternal B lymphocytes that do not express the DR4 antigen encoded by DRB1*04 respond to influenza virus by producing antibodies that perturb neurodevelopment, thus underpinning a proportion of schizophrenia cases.

The incidence of mania: time trends in relation to gender and ethnicity

Abstract: In order to investigate conflicting reports about possible changes in the incidence of mania, we established first contact rates for mania in the defined area of Camberwell between 1965 and 1984. There was some evidence for an increase in the first contact rate of mania, especially in females. This rise may be associated with the influx into Camberwell of individuals of Afro-Caribbean origin who showed significantly higher rates than the white group [adjusted rate ratio 3.1; 95% confidence interval (CI) 1.4-6.9] and more often displayed mixed manic and schizophrenic symptomatology (risk ratio 2.2; 95% CI 1.1-4.3). We conclude that the incidence of mania has not decreased and may actually have increased. High rates of mental illness among members of ethnic minorities are not specific to schizophrenia, suggesting that a risk factor common to both manic and schizophrenic illness is more prevalent among these groups.

The neurodevelopmental theory of schizophrenia: evidence concerning structure and neuropsychology.

Abstract: Severe schizophrenics as a group show subtle abnormalities of cerebral structure. Cerebral ventricular enlargement is the best replicated finding, and this tends to be associated with impairment of neuropsychological performance. The idea that these abnormalities have a neurodevelopmental origin gains indirect support from the, admittedly less consistent, evidence of abnormalities of cerebral asymmetry and of neuronal migration in adult schizophrenics, as well as from the better established behavioural, psychomotor, and cognitive impairments reported in preschizophrenic children. However, the relationship between childhood and adult neuropsychological and brain structural findings has not been proven, and we don not know whether only some schizophrenia has a developmental origin, or whether patients differ only in the degree of developmental impairment that they show.

Enhancement of the prolactin response to d-fenfluramine in drug-naive schizophrenic patients.

Abstract: BACKGROUND We wished to investigate central serotonergic function in untreated schizophrenia. METHOD Thirteen drug-naive, DSM-III-R schizophrenic patients were compared with sex, race, age, weight and menstrual phase matched controls. Plasma prolactin and cortisol responses to a specific serotonergic probe, d-fenfluramine, were measured along with BPRS ratings. RESULTS Prolactin responses were enhanced in schizophrenic patients compared to controls (P < 0.05) and were correlated positively with BPRS items for depression, anxiety and guilt. Baseline cortisol was also raised in those with schizophrenia (P < 0.001). CONCLUSIONS Central serotonergic tone may be raised in acute, drug-naive schizophrenia and may be associated with the presence of affective symptomatology.

Age-period-cohort analysis of the incidence of schizophrenia in Scotland

Abstract: Studies examining a possible decline in the incidence of schizophrenia over the last two to three decades have paid little attention to the possible role of birth cohort effects. We collected data on a Scottish national sample of all schizophrenic patients, admitted for the first time between 1966 and 1990 (N = 11348; male = 6301). In an Age-Period-Cohort analysis, a full model, incorporating three factors, had a substantially better fit to the data than other models (especially, an Age-Period model), providing clear evidence of the presence of a cohort effect. After adjustment for the effects of age and period, there was a 55% reduction in the rate of schizophrenia in men and a 39% fall in the number of women over the 50-year birth period from 1923 to 1973. The marked decline in the first admission rates observed in Scotland cannot, however, be attributed entirely to this cohort effect. Rather, a greater proportion of the declining first admission rates (88%) is ascribed to the period effect (i.e. artefactual or causally related cross-sectional effects). Nevertheless, the fact that a birth-cohort effect accounts for part of the declining incidence, suggests that causal environmental factors operating early in life have been diminishing in intensity.

Parasuicide in Camberwell: Ethnic differences

Abstract: Over a 6-month period, this study compared referral rates amongst different ethnic groups to an inner city deliberate self-harm (DSH) team, using native British (in the remainder of this paper referred to as whites) as standard and age-standardized referral ratios as the measure of effect. Indian female rates were 2,6 times those of whites. Amongst United Kingdom born Indian females, (crude) rates were 7.8 times those of United Kingdom born white females. Unemployment was associated with a 9 times increased referral rate amongst whites and a 3 times increased referral rate amongst ethnic minorities, suggesting that ethnicity modifies the association between unemployment and DSH rates. This study suggested that ethnic minority and white DSH differ in important respects; DSH teams serving multicultural communities may need to develop special expertise to meet the needs of minority ethnic groups.

Imaging as a tool in exploring the neurodevelopment and genetics of schizophrenia

Abstract: Neuroimaging has enabled us to address questions about the timing and origin of brain abnormalities in schizophrenia. First episode and longitudinal computed tomography (CT) and magnetic resonance imaging (MRI) studies of schizophrenic patients have shown that the brain abnormalities are present at onset of psychosis and are non-progressive. Such findings support the idea that schizophrenia is a developmental rather than a degenerative condition. Furthermore, the presence of ventriculomegaly and diminished hemispheric asymmetry in familial schizophrenics and in those of their relatives who appear to be transmitting the disorder, implies involvement of the genes controlling neurodevelopment. However, genetic factors do not fully account for the development of schizophrenia; early environmental insults such as obstetric complications are also important and may interact with genetic predisposition. Brain development continues postnatally and profound maturational events also occur in adolescence and early adulthood. Magnetic resonance spectroscopy (MRS) studies allow the investigation of the developmental biochemistry of the living brain and are being used to explore the role of maturational brain events in determining the onset of psychosis.

Life events before psychotic episodes: do clinical and social variables affect the relationship?

Abstract: We have previously used data from the Camberwell Collaborative Psychosis Study to demonstrate a strong relationship between life events and subsequent episodes of schizophrenic, manic and depressive psychoses. In the current paper, we confirmed the robustness of this relationship, which was not vitiated by controlling for clinical and social variables. Thus, the event-onset association was not affected by the type of onset or the number of previous episodes. The influences of social variables, such as social class, ethnicity and marital status, did not seriously diminish the importance of events, although there may be a role for other forms of social disadvantage as reflected in these variables.

Relationship of birth season to clinical features, family history, and obstetric complications in schizophrenia

Abstract: Birth in late winter and spring has been consistently shown to be a risk factor of schizophrenia. The relationship of late winter/spring birth to clinical characteristics and other putative risk factors, such as family history and obstetric complications, may provide clues to etiology. Data relating to season of birth, clinical features, family history, and obstetric complications were analyzed for 192 patients with schizophrenia as defined by Research Diagnostic Criteria (including schizoaffective disorder). There was no significant association of season of birth with any of the psychopathological dimensions nor was there a significant association with obstetric variables or family history. However, winter-born schizophrenic patients who had a negative family history were more likely to have a history of obstetric complications. These findings suggest that obstetric complications associated with schizophrenia are perhaps the result of some seasonal risk factors important in those without a family history of the disorder.

Prenatal Exposure to Influenza and Increased Cerebrospinal Fluid Spaces in Schizophrenia

Abstract: Several epidemiological studies have suggested that maternal exposure to influenza during midgestation is a risk factor for schizophrenia. In exploring the possible pathogenic mechanism, we examined the relationship between computed tomography structural brain measures in 83 schizophrenia patients and 113 controls and also their risk of maternal exposure to influenza. Four brain measures of the cerebrospinal fluid (CSF) spaces (lateral ventricle, maximum third ventricle, sulcal fluid, and sylvian fissure) were investigated in relation to the risk exposure level. In schizophrenia patients, these measures, in particular sylvian fissures, were found to increase with higher levels of risk exposure to influenza during the susceptible period (i.e., midgestation); no such effect was found in controls. These results indicate that risk for midgestational influenza exposure is associated with generalized enlargement of the CSF spaces, especially in the region of the temporal lobe. The findings suggest that certain morphological abnormalities of the brain frequently reported in schizophrenia patients may be partly attributable to antenatal exposure to influenza.

Perinatal Complications and Schizophrenia Data from the maternal and Child Health Handbook in Japan

Abstract: A number of studies have shown that schizophrenics have increased obstetric complications compared with controls, but conflicting negative results have also been reported. Similarly, some studies found that obstetric complications were more frequently observed among male or nonfamilial schizophrenics than their female or familial schizophrenic counterparts, but others reported negative or inverse results. Since 1948 in Japan, every pregnant woman has been assigned a Maternal and Child Health Handbook in which obstetricians have been obliged to fill in obstetric data. In the current study, perinatal complications assessed using the scale of Parnas et al. (1982), based on information from the maternal and child health handbook were compared between DSM-III-R-diagnosed schizophrenics (N = 59), their healthy siblings (N = 31), and controls (N = 108). We found that female schizophrenics had experienced significantly more perinatal complications than siblings and controls. We could not detect any significant association between perinatal complications and family history.