Showing papers by "Robin M. Murray published in 1994"

Neurodevelopmental schizophrenia: the rediscovery of dementia praecox

Abstract: Many people with severe schizophrenia have increased cerebral ventricular size and diffuse reduction in cortical volume; recent attention has focused on subtle malformations of the cytoarchitecture in the hippocampus and parahippocampal cortex. Sufferers also show an excess of dermatoglyphic and minor physical abnormalities, and a significant proportion had psychomotor deficits, cognitive or behavioural problems as children. Such findings suggest that the form of schizophrenia most akin to Kraepelin's original description of dementia praecox results from neurodevelopmental impairment. This may have its origin in genetic defects in the control of early brain growth, or in early environmental hazards such as prenatal exposure to maternal influenza or perinatal complications. How foetal or neonatal lesions produce hallucinations and delusions two or three decades later remains a mystery, but maturational changes in the brain may be important.

Volumetric MRI measurements in bipolars compared with schizophrenics and healthy controls.

Abstract: Twenty-six patients with RDC bipolar disorder were compared with a previously reported group of 48 RDC schizophrenics and 34 healthy controls, using volumetric MRI measurements of cerebral, cortical and sulcal volumes. The bipolar group appeared no different from the controls, and both of these groups had significantly larger cerebral and cortical volumes than the schizophrenics. Our previous report of a significantly reduced cortical volume in the schizophrenic group, with a corresponding increase in the volume of sulcal fluid is, therefore, not a generalized feature of psychotic illness but may be more specific to schizophrenia.

Follow‐up of a report of a potential linkage for schizophrenia on chromosome 22q12‐q13.1: Part 2

Abstract: A collaboration involving four groups of investigators (Johns Hopkins University/Massachusetts Institute of Technology; Medical College of Virginia/The Health Research Board, Dublin; Institute of Psychiatry, London/University of Wales, Cardiff; Centre National de la Recherche Scientifique, Paris) was organized to confirm results suggestive of a schizophrenia susceptibility locus on chromosome 22 identified by the JHU/MIT group after a random search of the genome. Diagnostic, laboratory, and analytical reliability exercises were conducted among the groups to ensure uniformity of procedures. Data from genotyping of 3 dinucleotide repeat polymorphisms (at the loci D22S268, IL2RB, D22S307) for a combined replication sample of 256 families, each having 2 or more affected individuals with DNA, were analysed using a complex autosomal dominant model. This study provided no evidence for linkage or heterogeneity for the region 22q12-q13 under this model. We conclude that if this region confers susceptibility to schizophrenia, it must be in only a small proportion of families. Collaborative efforts to obtain large samples must continue to play an important role in the genetic search for clues to complex psychiatric disorders such as schizophrenia

D2 dopamine receptor binding in the basal ganglia of antipsychotic-free schizophrenic patients. An 123I-IBZM single photon emission computerised tomography study.

Abstract: We used SPECT to examine striatal D2 receptor binding in 20 antipsychotic-free DSM-III-R schizophrenic patients and 20 age- and sex-matched normal controls. Dynamic single-slice SPECT, at a slice chosen to include the basal ganglia, began immediately following intravenous injection of 185 MBq of 123I-IBZM. A semiquantitative approach was used to generate indices of specific D2 receptor binding in the basal ganglia. There was no overall elevation of D2 receptor binding between patients and controls. A male sex-specific left lateralised asymmetry of striatal D2 receptor binding was found in the patient group. Age-dependent decline of striatal D2 receptors was confirmed in controls, but not in patients. These results suggest that alterations in striatal D2 receptor distribution and density do occur in schizophrenia, and possibly reflect wider disruptions in prefrontal-striatal-limbic circuits.

Age at onset, sex, and familial psychiatric morbidity in schizophrenia. Camberwell collaborative psychosis study

Abstract: BACKGROUND Although a genetic component in schizophrenia is well established, it is likely that the contribution of genetic factors is not constant for all cases. Several recent studies have found that the relatives of female or early onset schizophrenic patients have an increased risk of schizophrenia, compared to relatives of male or late onset cases. These hypotheses are tested in the current study. METHOD A family study design was employed; the probands were 195 patients with functional psychosis admitted to three south London hospitals, diagnosed using Research Diagnostic Criteria (RDC), and assessed using the Present State Examination (PSE). Information on their relatives was obtained by personal interview of the mother of the proband, and from medical records. Psychiatric diagnoses were made using Family History-Research Diagnostic Criteria (FH-RDC), blind to proband information. RESULTS There was a tendency for homotypia in the form of psychosis within families. The lifetime risk of schizophrenia in the first degree relatives of schizophrenic probands, and the risk of bipolar disorder in the first degree relatives of bipolar probands, were 5-10 times higher than reported population risks. Relatives of female and early onset (< 22 years) schizophrenic probands had higher risk of schizophrenia than relatives of male and late onset schizophrenic probands. However, this effect was compensated in part by an excess of non-schizophrenic psychoses in the relatives of male probands. CONCLUSIONS These results suggest a high familial, possibly genetic, loading in female and early onset schizophrenia, but do not resolve the question of heterogeneity within schizophrenia.

Low birth weight and schizophrenia.

Abstract: BACKGROUND Low birth weight has been postulated to be a risk factor for schizophrenia. METHOD Obstetric history, premorbid adjustment, and cognitive function during admission were assessed in 167 patients with DSM-III schizophrenia or affective psychosis. RESULTS A birth weight of less than 2500 g was significantly more common in patients with schizophrenia than in those with affective psychosis. Schizophrenic patients as a group had significantly lower mean birth weight, a finding which was particularly marked after controlling for sociodemographic confounders. In schizophrenic men, lower birth weight was highly significantly correlated with poorer premorbid social and cognitive ability, and with impairment of adult cognitive function. CONCLUSIONS Neurodevelopmental impairment may cause poor foetal growth, and schizophrenia in adult life.

The relationship of schizophrenic births to 16 infectious diseases.

Abstract: BACKGROUND Recently, several investigators have reported an association between influenza epidemics and increased birth rates of 'preschizophrenic' individuals some four to six months later Here we examine whether maternal exposure to other infectious diseases can also predispose the foetus to later schizophrenia METHOD Two independent sets of dates of birth of first admission schizophrenic patients, born between 1938 and 1965 in England and Wales, were obtained from the Mental Health Enquiry in England and Wales Data on the number of deaths per month from 16 infectious diseases between 1937 and 1965 in England and Wales were also collected We used a Poisson regression model to examine the relationship between deaths from infectious diseases and schizophrenic births RESULTS In the two separate data sets, increased national deaths from bronchopneumonia preceded, by three and five months respectively, increased numbers of schizophrenic births We did not find any other significant associations between schizophrenic births and any of the other 15 infectious diseases CONCLUSIONS The association between deaths from bronchopneumonia and increased schizophrenic births some months later may be a reflection of the fact that bronchopneumonia deaths increase markedly during influenza epidemics

Fractal analysis of the boundary between white matter and cerebral cortex in magnetic resonance images: a controlled study of schizophrenic and manic-depressive patients

Abstract: This paper reports development of a computerized (‘box-counting’) method for estimation of fractal dimension (FD) of the magnetic resonance image (MRI) boundary between cerebral cortex and white matter; and the application of this method to MRIs of 39 schizophrenics (SZs), 23 manic-depressives (MDs) and 31 controls (CONs). Mean FD across all diagnostic groups was 1·402; 95% confidence interval (CI) 1·399 to 1·406. Mean FD was greater in boundaries extracted from manic-depressive patients than in boundaries extracted from controls (difference between MD and CON mean FDs = 0·008; 95% CI −0·002 to +0·018); and less in schizophrenics than in controls (difference between SZ and CON mean FDs = −0·003; 95% CI −0·011 to +0·005). Mean FD was positively correlated with subcortical volume and anterior cerebral volume, and negatively correlated with sulcal cerebrospinal fluid volume. Significant differences in mean FD between diagnostic groups were demonstrated by analysis of covariance (ANCOVA; P < 0·01), with age and volumetric measures of brain size as covariates; and manic-depressive boundaries were shown to have significantly greater values for residual FD (after controlling for effects of brain size) than boundaries extracted from controls (t test; P < 0·05). It is proposed that FD is a useful measure of clinically relevant differences in the complexity of MRI boundaries.

Prenatal exposure to influenza and the development of schizophrenia : is the effect confined to females ?

Abstract: The question of whether prenatal exposure to influenza epidemics is associated with an increased risk of later schizophrenia remains controversial. The authors examined this relationship, using data on the dates of birth and gender of 3,827 schizophrenic patients born in England and Wales between 1938 and 1965 and first admitted to hospitals in the 1980s, the numbers of live births between 1938 and 1965, and the numbers of deaths attributed to influenza between 1937 and 1965. The analysis showed that females, but not males, exposed to influenza epidemics 5 months before birth had a significantly greater rate of adult schizophrenia.

The subtyping of schizophrenia in men and women: a latent class analysis.

Abstract: SYNOPSIS Latent class analysis on an epidemiologically based series of 447 first contact patients with a broad diagnosis of schizophrenia revealed evidence for two subtypes: a' neurodevelopmental' type characterized by early onset, poor pre-morbid social adjustment, restricted affect and a male: female ratio of 7:3; and a ' paranoid' type characterized by later onset, persecutory delusions and an almost equal sex ratio. A third 'schizoaffective' subtype, whose existence was less clear cut, was almost entirely confined to females and characterized by dysphoria and persecutory delusions, and had negligible familial risk of schizophrenia. The aetiological, biological and clinical significance of this typology remains to be tested.

Cerebral ventricle dimensions as risk factors for schizophrenia and affective psychosis: an epidemiological approach to analysis.

Abstract: A case-control study was undertaken of volumetric computerized tomographic scan measures in 216 consecutive admissions for functional psychosis and 67 healthy community controls. Odds ratio analysis demonstrated significant linear trends in the association between increasing lateral and third ventricle volumes, and both RDC schizophrenia (N = 121) and schizo-affective disorder (N = 41); cases were consistently associated with larger volumes than controls. There was an association between larger third, but not lateral, ventricle size in affective psychoses (N = 54). These associations were statistically independent of intracranial volume, sex, social class and ethnicity, factors which were significantly associated with ventricular measures in the controls. There was no evidence of a threshold corresponding to the notion of normal versus enlarged ventricles. Within the schizophrenia group, there were no large or significant associations between ventricle dimensions and age at onset, duration of illness or pre-morbid social functioning. Neither obstetric complications nor a family history of schizophrenia or other psychiatric illness was associated with large ventricles in these cases.

Which patients with non-affective functional psychosis are not admitted at first psychiatric contact?

Abstract: BACKGROUND We wished to explore the sociodemographic and clinical characteristics associated with admission to hospital in patients with a non-organic non-affective psychosis. METHOD Subjects were 484 first-contact patients with a non-affective functional psychosis from an inner-city catchment area over 20 years from the mid-1960s. Sociodemographic and clinical characteristics associated with admission to hospital were analysed. RESULTS Around 20% of patients were not admitted, and the proportion did not change significantly over the years. Ethnicity, sex, and marital and employment status did not predict admission. Factors associated with admission included police involvement, and violence to self or others. A diagnosis of schizoaffective disorder, and persecutory delusions, auditory hallucinations, and bizarre behaviour were all more common in patients admitted to hospital. CONCLUSIONS The study indicates biases which might arise in research based exclusively on patients admitted to hospital.

The influence of life events on the subsequent course of psychotic illness: A prospective follow-up of the Camberwell Collaborative Psychosis Study

Abstract: Fifty-nine psychotic patients with acute onset of illness, who had been interviewed about their experience of stressful life events before the episode, were followed up for an average of 42 months. Thirty patients (51%) had experienced a stressful life event in the 3 months immediately before onset (EV +), 29 had not (EV −).In patients with an RDC diagnosis of affective disorder or unspecified functional psychosis, the presence of stressful life events was associated subsequently with milder symptom severity, less time spent in hospital, more treatment for depressive symptoms and less for psychotic symptoms. In schizophrenia, differences were less apparent, but patients with event associated episodes had less need of anti-psychotic maintenance medication over the follow-up period and tended to have spent more time in complete remission. EV + schizophrenic subjects also had higher morbid risk for schizophrenia in their first degree relatives, and tended to be female and to have less typical symptoms than EV − schizophrenic patients.

Failure to find linkage between a functional polymorphism in the dopamine D4 receptor gene and schizophrenia.

Abstract: We report the results of a linkage study in 24 families multiply affected with schizophrenia using a polymorphic DNA sequence encoding the third cytoplasmic loop of the dopamine D4 receptor. Two-point LOD score analyses with a range of single gene models ranging from near dominant to near recessive revealed no evidence for linkage. In addition, we examined the data by non-parametric sib-pair analysis and found no excess sharing of alleles between affected sib-pairs. We therefore conclude that mutations within the dopamine D4 receptor gene do not have a major aetiological role in schizophrenia in our collection of pedigrees

No evidence of association between dopamine D4 receptor variants and bipolar affective disorder

Abstract: Disturbance in the dopamine neurotransmitter system has been implicated in the pathogenesis of affective disorder. In this study, we examine the possibility that functional variants of the recently cloned dopamine D4 receptor gene contribute to the genetic component of manic depression. The polymorphism, a 48 bp tandem repeat coding for part of the third cytoplasmic loop, was detected using a PCR based method. In a first sample of 57 patients and 59 controls, we found allele 7 to be in excess in the patients. In contrast, allele 3 was less frequent in patients. A second, larger sample of 90 patients and 91 controls was utilized to test these hypotheses. Data from the two samples were then pooled together for further analyses. We calculated the power of our samples, and if the frequency of 7 repeat allele obtained from sample 1 is true, i.e., 25% (28/114) for patients and 14% (16/118) for controls, then the power of the combined sample is 62% at 5% (two-tailed) significance level. However, both observations were not replicated; we therefore conclude that variations in this repeat at the DRD4 gene do not contribute to the genetic component of manic depression. © 1994 Wiley-Liss, Inc.

Twin concordance for congenital and adult-onset psychosis: a preliminary study of the validity of a novel classification of schizophrenia.

Abstract: As a test of the hypothesis that the psychoses can be divided into congenital and adult-onset forms, we applied operational criteria for these two disorders to the case summaries of 24 monozygotic and 33 dizygotic schizophrenic twin pairs. Our results indicate that the reliability and validity of this novel classification are comparable with the best of the existing systems and support further investigation of the hypothesis.

Genetic mapping of 14 short tandem repeat polymorphisms on human chromosome 22.

Abstract: We have constructed a linkage map of 14 short tandem repeat polymorphisms (11 with heterozygosity > 70%) on the long arm of human chromosome 22 using 23 non-CEPH pedigrees. Twelve of the markers could be positioned uniquely with a likelihood of at least 1,000:1, and distributed at an average distance of 6.62 cM (range 1.5-16.1 cM). The sex-combined map covers a total of 79.6 cM, the female map 93.2 cM and the male map 64.6 cM. Based on comparisons between physical maps and other genetic maps, we estimate that our map covers 70%-80% of the chromosome. The map integrates markers from previous genetic maps and uniquely positions one marker (D22S307). Data from physical mapping on the location of four genetic markers correlates well with our linkage map, and provides information on an additional marker (D22S315). This map will facilitate high resolution mapping of additional polymorphic loci and disease genes on chromosome 22, and act as a reference for building and verifying physical maps.

Growth hormone responses to Pyridostigmine in schizophrenia: Evidence for cholinergic dysfunction

Abstract: The hypothesis that increased central cholinergic neurotransmitter function may be present in schizophrenic illness and may underlie negative symptoms was tested using a neuroendocrine challenge approach. The cholinergic challenge used was the anticholinesterase pyridostigmine, thought to cause the release of growth hormone (GH) from the anterior pituitary by diminishing inhibitory somatostatin tone. Eleven patients, six neuroleptic-naive and five neuroleptic-free, satisfying DSM-III-R criteria for schizophrenia and 11 matched controls took part. Subjects received pyridostigmine (120 mg orally) and blood was sampled at 0, 60, 90, 120, and 180 min for GH estimation. Peak GH responses were significantly increased in the schizophrenic group compared to controls. There was no relationship between individual peak GH values and negative symptom ratings (Scale for the Assessment of Negative Symptoms). Neither could a relationship be established between other aspects of psychopathology or dyskinesias and GH responses. An increased pyridostigmine/GH response is also found in affective disorders and could be related to nonspecific symptoms common to all these diagnostic groups. This study suggests that schizophrenia may be associated with increased cholinergic neurotransmitter function but the relationship between this cholinergic dysfunction and schizophrenia may involve psychopathology not specific to schizophrenia.