Showing papers by "Robin M. Murray published in 1998"

Attenuated Frontal Activation During a Verbal Fluency Task in Patients With Schizophrenia

Abstract: OBJECTIVE: Functional magnetic resonance imaging was used to study changes in cerebral blood oxygenation in schizophrenic patients during a verbal fluency task. METHOD: Five right-handed male schizophrenic patients and five volunteers matched on demographic variables and verbal fluency performance participated in the study. Echoplanar images were acquired over 5 minutes at 1.5 T while the subjects performed two tasks. The first involved paced silent generation of words beginning with an aurally presented cue letter. This task alternated with paced silent repetition of the aurally presented word “rest.” Generic brain activation maps were constructed from individual images by sinusoidal regression and nonparametric hypothesis testing. Between-group differences in the mean power of experimental response were identified on a voxelwise basis by an analysis of covariance that controlled for between-group differences in stimulus-correlated motion. RESULTS: The comparison group showed significant responses in the...

Pathophysiology of 'positive' thought disorder in schizophrenia

Abstract: BACKGROUND Formal thought disorder is a characteristic feature of psychosis, but little is known of its pathophysiology. We have investigated this in schizophrenia using positron emission tomography (PET). METHOD Regional cerebral blood flow was measured using H2(15)O and PET while six people with schizophrenia were describing a series of 12 ambiguous pictures which elicited different degrees of thought-disordered speech. In a within-subject design, the severity of 'positive' thought disorder was correlated with cerebral blood flow across the 12 scans in each subject. RESULTS Verbal disorganisation (positive thought disorder) was inversely correlated with activity in the inferior frontal, cingulate and left superior temporal cortex, and positively correlated with activity in the parahippocampal/anterior fusiform region bilaterally, and in the body of the right caudate (P < 0.001). The total amount of speech produced (independent of thought disorder) was positively correlated with activity in the left inferior frontal and left superior temporal cortex. CONCLUSIONS The severity of positive thought disorder was inversely correlated with activity in areas implicated in the regulation and monitoring of speech production. Reduced activity in these regions may contribute to the articulation of the linguistic anomalies that characterise positive thought disorder. The positive correlations between positive thought disorder and parahippocampal/anterior fusiform activity may reflect this region's role in the processing of linguistic anomalies.

Risk factors for onset and persistence of psychosis.

Abstract: Clinical practice, training and evaluation of treatment in the functional psychoses continues to be carried out mostly along the traditional line of separation by diagnostic entity. However, the combined evidence from research on risk factors for onset and for persistence of psychotic illness indicates quantitative, but not qualitative, differences between categories of schizophrenia and affective psychosis. “Developmental” factors, such as childhood dysfunction, increased cerebral ventricle size and familial morbid risk of schizophrenia operate preferentially, though not specifically, at that end of the psychopathological spectrum characterised by a preponderance of negative features. On the other hand, “social” factors, such as ethnic group, adverse life events and familial morbid risk of affective disorder have a larger impact at the end associated with predominance of affective features. Heterogeneity in the functional psychoses may thus be best conceived as two discrete effects operating at different ends of a continuous psychopathological spectrum. The use of highly reliable but arbitrary diagnostic categories may introduce serious bias in aetiological and treatment research. Evidence supporting the validity of a model of shared risk factors for continuous characteristics needs to be further elaborated and incorporated into our concepts of psychotic illness.

Quality of parenting and vulnerability to depression: Results from a family study

Abstract: Background. We examined a group of subjects at familial risk of depression and explored the relationship between the perceptions of parents and a history of depression. We also investigated: (a) whether any difference in perceived parenting found between those with and without a past history of depression was an artefact of the depression; and (b) whether the relationship between parenting and depression was explained by neuroticism.Method. We took a sample of first-degree relatives selected from a family study in depression and subdivided them by their history of mental illness on the SADS-L, into those: (a) without a history of mental illness (N=43); and (b) those who had fully recovered from an episode of RDC major depression (N=34). We compared the perceptions of parenting, as measured by the Parental Bonding Instrument (PBI), in these two groups having adjusted for the effect of neuroticism and subsyndromal depressive symptoms. We also had informants report on parenting of their siblings, the latter being subdivided into those with and without a past history of depression.Results. Relatives with a past history of depression showed lower care scores for both mother and father combined compared with the never ill relatives. The presence of a history of depression was associated with a non-significant reduction in the self-report care scores compared to the siblings report. Vulnerable personality (as measured by high neuroticism) and low perceived care were both found to exert independent effects in discriminating between the scores of relatives with and without a history of depression and there was no interaction between them.Conclusion. This study confirmed that low perceived parental care was associated with a past history of depression, that it was not entirely an artefact of having been depressed, and suggested that this association was partially independent of neuroticism.

Brain changes in schizophrenia. Volumetric MRI study of families multiply affected with schizophrenia--the Maudsley Family Study 5.

Abstract: BACKGROUND Structural brain abnormalities have been reported in schizophrenia. We tested the hypothesis that these abnormalities represented a marker for the genetic liability to schizophrenia in a sample of people with schizophrenia and their relatives from families multiply affected with the disorder. METHOD We compared 31 people with schizophrenia, 57 relatives and 39 unrelated control subjects. Volumetric measurement of brain structures was carried out using stereological principles from three-dimensional reconstructed magnetic resonance images. RESULTS Subjects with schizophrenia had larger lateral ventricles than their relatives and the normal control subjects. Relatives who were 'presumed obligate carriers' had larger left lateral ventricles than other relatives and the control subjects. Subjects with schizophrenia showed smaller whole brain and cerebellar volumes and larger lateral ventricles than their age- and gender-matched unaffected siblings. CONCLUSIONS In families multiply affected with schizophrenia lateral ventricular enlargement distinguishes people with schizophrenia and presumed obligate carriers from other relatives and unrelated control subjects. These changes may be a marker for a genetic liability to schizophrenia.

First episodes of psychosis in Afro-Caribbean and White people. An 18-year follow-up population-based study.

Abstract: BACKGROUND There have been few prospective studies of the long-term outcome of psychosis in people of Afro-Caribbean origin in the UK. METHOD We followed-up a population-based, consecutive series of 34 Afro-Caribbean and 54 White people with psychosis who had been extensively investigated during their first admission in 1973/74. Diagnoses were made by direct interview using the Present State Examination at both first admission and follow-up. RESULTS Ninety-seven percent of the original sample were traced. A slightly greater proportion of the Afro-Caribbean people were assigned to the S+ Catego class (schizophrenia), both on first assessment and at follow-up. No difference was found between the two groups in the consistency of diagnosis over the 18 years or in the proportion of patients considered psychotic but Afro-Caribbean people tended to have fewer negative symptoms at follow-up. There were striking differences between the two groups in their experience of psychiatric care; Afro-Caribbean people were more likely to have been readmitted, to have experienced longer hospitalisations, and to have undergone more involuntary admissions than their White counterparts. CONCLUSIONS Afro-Caribbean people who met clinical and research criteria for schizophrenia had a less satisfactory experience of, and response to, psychiatric care over 18 years than their White counterparts.

Predictors of outcome in schizophrenia.

Abstract: Several factors have been reported to be associated with poor outcome in psychosis. A prospective study was conducted to identify and subsequently assess the relative prognostic value of factors that might assist in the earlier identification of patients likely to have a poor outcome. The results confirmed that certain factors, including male gender, family history of schizophrenia, structural brain abnormalities, absence of adverse life events, and tardive dyskinesia, were indeed associated with poor outcome.

Lack of association between a polymorphism in the promoter region of the dopamine-2 receptor gene and clozapine response.

Abstract: Dopamine receptors are strong candidates for involvement in schizophrenia and are targeted by a wide variety of antipsychotics. We hypothesized that genetic variation in these neurotransmitter receptors may influence clinical response to clozapine, an antipsychotic which displays high affinity for dopamine D2 receptors in the limbic system. To test this hypothesis, we studied a functional polymorphism in the promoter region of the D2 receptor gene (-141C Ins/Del) in a sample of 151 clozapine treated patients of British origin. In addition, the influence of this polymorphism on antipsychotic response in general was investigated on a sample of 146 Han Chinese schizophrenic patients treated with a variety of antipsychotics. No association was found between this polymorphism and clinical response in either of the two samples suggesting that genetic variation in D2 receptors does not play a major role in determining clinical response to antipsychotic treatment.

Obstetric complications and familial morbid risk of psychiatric disorders.

Abstract: Obstetric complications (OCs) have been found to occur in higher frequency in patients with schizophrenia. One explanation for this finding is that the genes that contribute to the schizophrenia phenotype also influence the likelihood to experience OCs. If this were true, morbid risk of psychiatric illness should be higher in the first-degree relatives of both schizophrenic and control probands exposed to OCs, compared to probands not exposed to OCs. We set out to test this hypothesis. Information on OCs, blind to family history of psychiatric disorder, was collected retrospectively through maternal interview in 151 psychotic patients and 100 controls. Family history (FH) in relatives of cases (n = 600) and controls (n = 461) was assessed with the FH-RDC and through personal interviews. Tests for associations between family history and OCs were conducted using Cox proportional hazard regression. In the cases, familial morbid risk of affective disorder was greater in those with a history of OCs (hazard ratio (HR) = 1.9, P = 0.007). Analyses examining individual complications revealed associations between FH of affective disorder and pre-eclampsia (HR = 2.9, P = 0.003) and FH of affective disorder and breech presentation (HR = 2.8, P = 0.02), especially when family history in the relatives was confined to affective illness in the mother (HR pre-eclampsia = 4.4, P = 0.009; HR breech-presentation = 4.2, P = 0.008). In controls, affective illness in the mother was not only associated with breech presentation (HR = 7.0, P = 0.01) and pre-eclampsia (HR = 4.4, P = 0.03) but also with other complications. Familial morbid risk of schizophrenia and related psychoses was not associated with OCs. The positive associations between OCs and familial morbid risk of affective disorder suggest that the factors that contribute to familial aggregation of affective symptoms in psychotic patients also influence the likelihood to experience OCs. Although the proportion of OCs that could be attributed to these factors was very small, part of the relationship between family history of affective disorder and psychosis may be mediated by OCs.

Minor physical anomalies in familial and sporadic schizophrenia: the Maudsley family study.

Abstract: OBJECTIVES—(1) To test the hypothesis that minor physical anomalies are increased in patients with schizophrenia and (2) to investigate differences in the prevalence of minor physical anomalies in patients with familial and sporadic schizophrenia and their first degree relatives. METHODS—A weighted Waldrop assessment was carried out on 214 subjects in five groups: schizophrenic patients from multiply affected families; first degree relatives of these familial schizophrenic patients; sporadic schizophrenic patients; first degree relatives of these sporadic schizophrenic patients, and normal controls. Broad and narrow criteria for abnormality were defined based on the distribution of minor physical anomalies in the control group. RESULTS—(1) The total schizophrenic group did not have a significant increase in minor physical anomalies using a narrow criterion of abnormality, but did when a broader criterion was used. (2) A significant increase in the proportion of subjects with an abnormally high number of minor physical abnormalities was shown in the group of sporadic schizophrenic patients (uncorrected p<0.01). Separate analyses for males and females showed a significant increase in the male sporadic group (uncorrected p<0.05), and a smaller non-significant increase in the female sporadic group. Neither the familial schizophrenic group nor either group of first degree relatives showed any significant increases in the proportion of patients with high abnormality scores. CONCLUSION—This work supports prenatal developmental abnormality as a mechanism for sporadic, but not familial, schizophrenia.

Neonatal origins of schizophrenia

Abstract: Schizophrenia is not an illness which impinges much upon the daily practice of paediatricians or, indeed, child psychiatrists, as only a tiny proportion of diagnosed cases (< 5%) arise before the age of 16 years.1 Schizophrenia is one of the few chronic diseases which arise principally during late adolescence and early adulthood, normally the healthiest period of life. There is increasing evidence, however, that neurodevelopmental factors, acting in utero and in early childhood, are important in determining the risk for later schizophrenia.2 3 #### Key messages There is no doubt that genetic factors are involved in the aetiology of schizophrenia.4 First degree relatives of patients have a morbid risk of developing schizophrenia which is eight to 10 times higher than the risk in the general population; this risk rises to approximately 50% in the identical twins of schizophrenics. Now that a neurodevelopmental aetiological model is considered most likely, genes that control early development have come under particular suspicion. Unfortunately, in spite of an intensive effort to locate and identify susceptibility genes for schizophrenia, none has yet been found.5 The fact that the monozygotic concordance rate for schizophrenia is only 50% indicates that environmental factors must also be involved, and simple additive models suggest that between …

The dexamethasone suppression test in schizophrenia

Abstract: Background. Cortisol non-suppression following the dexamethasone suppression test (DST) has been found to a variable extent in schizophrenia. The aetiology is unclear but may be related to depression or negative symptoms. Methods. The DST was administered to 64 patients with DSM-IV schizophrenia. All patients were screened for DSM-IV major depression and rated on the Hamilton Rating Scale for Depression (HRSD), Scale for Assessment of Negative Symptoms (SANS) and the Brief Psychiatric Rating Scale (BPRS). Results. DSM-IV criteria for major depression was fulfilled by 36% of the patients and 42% of patients had a history of parasuicide. Four patients had undetectable levels of dexamethasone and were excluded from the endocrine analyses. Only one remaining patient had a cortisol level above the cut-off point (>138 nmol/l), indicating escape from dexamethasone suppression. The post-dexamethasone cortisol level correlated significantly with HRSD and BPRS scores but not with the SANS. The SANS and HRSD scores were not correlated, but they were independently correlated with the BPRS score. Conclusions. In contrast to some other work, rates of dexamethasone non-suppression were very low; together with the high rates of depression, this suggests that depression in schizophrenia may have a different neuroendocrine profile from major depressive disorders. Failure to measure dexamethasone levels can be misleading.

Abnormal 5-HT1D receptor function in major depression : a neuropharmacological challenge study using sumatriptan

Abstract: Background. Sumatriptan, a specific agonist at 5-HT 1D receptors, stimulates release of growth hormone (GH) and inhibits release of prolactin (PRL). Methods. We gave sumatriptan (6mg subcutaneously) to 11 patients with unipolar major depression and 11 control subjects matched for age, sex, weight and menstrual cycle phase. Serum GH and PRL were measured at 0, 15, 30, 45, 60 and 90 min after injection. Results. The maximal rise in GH was significantly reduced in the depressed patients, with 60% showing no increase over baseline compared with 18% of controls. There were no significant differences in PRL responses. Conclusions. These results suggest reduced sensitivity of 5-HT 1D receptors in major depression. Our results and those of studies investigating 5-HT 1A receptors imply that both 5-HT 1A and 5-HT 1D autoreceptors may show reduced function in major depression.

Co-administration of citalopram and clozapine: effect on plasma clozapine levels

Abstract: Antidepressants are frequently used in the treatment of depressive symptoms associated with schizophrenia. In patients taking clozapine, choice of antidepressant is complicated by additive pharmacodynamic effects and by pharmacokinetic interactions. We predicted that citalopram would not elevate plasma clozapine levels when the two drugs were co-administered because it does not inhibit the relevant enzyme systems. In this preliminary study of five patients given citalopram and clozapine there was no overall change in mean clozapine levels. Based on this limited evidence, citalopram might be the antidepressant of choice in patients taking clozapine.

Family history as a predictor of poor long-term outcome in depression.

Abstract: BACKGROUND We investigated whether family history had prognostic significance in depression in a study which addressed some of the methodological shortcomings of previous studies. METHOD We collected family history data on a consecutive series of 89 patients admitted with RDC major depression, blind to the outcome of the proband. This comprised 116, 283 and 120 first-degree relatives examined with the SADS-L, FH-RDC and case note data, respectively. The outcome of 74 of these probands (83%), previously categorised into four operationally defined groups, was then examined. RESULTS A positive family history of severe psychiatric illness (i.e. a relative with a history of either a psychosis, hospitalised depression or suicide) was associated with poor outcome in the proband. This association persisted after controlling for variable family size, age structure and gender. As family history was correlated with neither Kendell's neurotic/psychotic index nor the proband's neuroticism score, an individual with high scores an all three would have a greatly increased chance of having a poor outcome. CONCLUSIONS A family history of severe psychiatric illness in a first-degree relative may be useful as one of the vulnerability factors for predicting poor long-term outcome in depression.