Maudsley Hospital

Necropsy brain tissue from normal (control) patients and patients with depression and dementia was examined for activities of various cholinergic components, and these related to the degree of senile plaque formation and extent of intellectual impairment. Choline acetyltransferase and acetylcholinesterase activities decreased significantly as the mean plaque count rose, and in depressed and demented subjects the reduction in choline acetyltransferase activity correlated with the extent of intellectual impairment as measured by a memory information test; muscarinic cholinergic receptor binding activity remained unchanged with increasing senile plaque formation but butyrylcholinesterase activity increased. The results suggest a close relation between changes in the cholinergic system and Alzheimer's dementia, but the precise role of the system in this disease remains to be elucidated.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population. A new GWAS of schizophrenia (11,260 cases and 24,542 controls) and meta-analysis identifies 50 new associated loci and 145 loci in total. The common variant association signal is highly enriched in mutation-intolerant genes and in regions under strong background selection.

Many of the standardized interviews currently used in psychiatry require the interviewer to use expert psychiatric judgements in deciding upon the presence or absence of psychopathology. However, when case definitions are standardized it is customary for clinical judgements to be replaced with rules. The Clinical Interview Schedule was therefore revised, in order to increase standardization, and to make it suitable for use by 'lay' interviewers in assessing minor psychiatric disorder in community, general hospital, occupational and primary care research. Two reliability studies of the revised Clinical Interview Schedule (CIS-R) were conducted in primary health care clinics in London and Santiago, Chile. Both studies compared psychiatrically trained interviewer(s) with lay interviewer(s). Estimates of the reliability of the CIS-R compared favourably with the results of studies of other standardized interviews. In addition, the lay interviewers were as reliable as the psychiatrists and did not show any bias in their use of the CIS-R. Confirmatory factor analysis models were also used to estimate the reliabilities of the CIS-R and self-administered questionnaires and indicated that traditional measures of reliability are probably overestimates.

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

The Severity of Dependence Scale (SDS) was devised to provide a short, easily administered scale which can be used to measure the degree of dependence experienced by users of different types of drugs. The SDS contains five items, all of which are explicitly concerned with psychological components of dependence. These items are specifically concerned with impaired control over drug taking and with preoccupation and anxieties about drug use. The SDS was given to five samples of drug users in London and Sydney. The samples comprised users of heroin and users of cocaine in London, and users of amphetamines and methadone maintenance patients in Sydney. The SDS satisfies a number of criteria which indicate its suitability as a measure of dependence. All SDS items load significantly with a single factor, and the total SDS score was extremely highly correlated with the single factor score. The SDS score is related to behavioural patterns of drug taking that are, in themselves, indicators of dependence, such as dose, frequency of use, duration of use, daily use and degree of contact with other drug users; it also shows criterion validity in that drug users who have sought treatment at specialist and non-specialist agencies for drug problems have higher SDS scores than non-treatment samples. The psychometric properties of the scale were good in all five samples, despite being applied to primary users of different classes of drug, using different recruitment procedures in different cities in different countries.

We describe almost entirely automated procedures for estimation of global, voxel, and cluster-level statistics to test the null hypothesis of zero neuroanatomical difference between two groups of structural magnetic resonance imaging (MRI) data. Theoretical distributions under the null hypothesis are available for 1) global tissue class volumes; 2) standardized linear model [analysis of variance (ANOVA and ANCOVA)] coefficients estimated at each voxel; and 3) an area of spatially connected clusters generated by applying an arbitrary threshold to a two-dimensional (2-D) map of normal statistics at voxel level. We describe novel methods for economically ascertaining probability distributions under the null hypothesis, with fewer assumptions, by permutation of the observed data. Nominal Type I error control by permutation testing is generally excellent; whereas theoretical distributions may be over conservative. Permutation has the additional advantage that it can be used to test any statistic of interest, such as the sum of suprathreshold voxel statistics in a cluster (or cluster mass), regardless of its theoretical tractability under the null hypothesis. These issues are illustrated by application to MRI data acquired from 18 adolescents with hyperkinetic disorder and 16 control subjects matched for age and gender.

BACKGROUND: The Global Assessment of Functioning (GAF) is a quick and simple measure of overall psychological disturbance. However, there is little research on the reliability and validity of this measure in severely mentally ill populations. METHOD: Multidisciplinary keyworkers assessed 103 patients at monthly intervals over a 6-month period. Overall GAF scores were obtained, with additional separate ratings for symptoms and disability. These were compared with changes in antipsychotic medication and support needs over the same period. RESULTS: Satisfactory reliability was obtained for total GAF score and for symptom and disability measures, in spite of raters having only one brief training session. All GAF scores were associated with current support needs of patients. Symptom and disability scores were associated with changes in antipsychotic medication in the previous month. Only symptom score was associated with increases in antipsychotic medication at time of rating. CONCLUSION: GAF proved to be a reliable and, within the limits of the indicators used, a valid measure of psychiatric disturbance in our sample of the severely mentally ill. Differences in relationships between the three GAF scores and medication/support needs indicate the usefulness of obtaining all three scores for monitoring levels and type of psychiatric disturbance in this population.

Oxidative damage has been implicated in the pathology of Parkinson's disease (PD), e.g., rises in the level of the DNA damage product, 8-hydroxy-2'-deoxyguanosine, have been reported. However, many other products result from oxidative DNA damage, and the pattern of products can be diagnostic of the oxidizing species. Gas chromatography/mass spectrometry was used to examine products of oxidation and deamination of all four DNA bases in control and PD brains. Products were detected in all brain regions examined, both normal and PD. Analysis showed that levels of 8-hydroxyguanine (8-OHG) tended to be elevated and levels of 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FAPy guanine) tended to be decreased in PD. The most striking difference was a rise in 8-OHG in PD substantia nigra (p = 0.0002); rises in other base oxidation/deamination products were not evident, showing that elevation in 8-OHG is unlikely to be due to peroxynitrite (ONOO-) or hydroxyl radicals (OH.), or to be a prooxidant effect of treatment with L-Dopa. However, some or all of the rise in 8-OHG could be due to a change in 8-OHG/FAPy guanine ratios rather than to an increase in total oxidative guanine damage.

SUMMARY A controlled investigation comparing a population of 50 temporal lobe epileptics with psychotic episodes with 50 randomly selected temporal lobe epileptics who had never experienced psychotic disturbances, showed that: temporal lobe epilepsy of the dominant hemisphere predisposes to psychotic manifestations; epilepsy of the non‐dominant temporal lobe is associated with manic‐depressive, of the dominant temporal lobe with schizophrenic disturbances; the presence of psychomotor seizures and frequent temporal fits are inversely correlated with psychosis, suggesting that such seizures and psychosis are antithetical manifestations of the same underlying disturbance of cerebral function: epileptic psychoses are fundamentally related to the epileptic process rather than non‐specific psychoses resulting from structural brain damage; in epileptic psychoses periodicity is correlated with minimal chronicity with maximal brain damage. RÉSUMÉ Une étude contrôlée comparant 50 épileptiques présentant une épilepsie du lobe temporal avec épisodes psychotiques et 50 épileptiques pris au hasard présentant une épilepsie du lobe temporal mais n'ayant jamais présenté de troubles psychotiques, a montré que: l'épilepsie du lobe temporal de l'hémisphère dominant prédispose aux manifestations psychotiques. l'épilepsie du lobe temporal de l'hémisphère non dominant s'associe à des troubles maniaco‐dépressifs, celle du lobe temporal de l'hémisphère dominant à des troubles schizophréniques. La présence de crises psycho‐motrices et celle de crises temporales fréquentes sont en corrélation inverse avec les phénomènes psychotiques suggérant que les crises et les psychoses sont des manifestations antithésiques d'un même dysfonctionnement cérébral. Les psychoses épileptiques sont fondamentalement liées au processus épileptique alors que les psychoses non spécifiques résultent d'une lésion organique cérébrale. Les psychoses épileptiques périodiques sont en relation avec une atteinte cérébrale minime, alors que les psychoses épileptiques chroniques sont en relation avec une atteinte cérébrale sévère.

Biopsy material taken from the brain of a patient with CreutzfeldtJakob disease with status spongiosus induced a similar fatal encephalopathy in a chimpanzee 13 months after inoculation.

The place of genetic factors in the aetiology of schizophrenia remains disputed. Several surveys have demonstrated a significantly higher incidence of the disorder in relatives of schizophrenic persons as compared to the general population. Furthermore, the closer the relationship, the higher the incidence of schizophrenia. The studies of Kallmann (1938) and Slater (1953) are especially significant and the research in this area has been thoroughly reviewed by Alanen (1958).

OBJECTIVE: To determine, using a systematic review of case-control studies, whether head injury is a significant risk factor for Alzheimer's disease. We sought to replicate the findings of the meta-analysis of Mortimer et al (1991). METHODS: A predefined inclusion criterion specified case-control studies eligible for inclusion. A comprehensive and systematic search of various electronic databases, up to August 2001, was undertaken. Two independent reviewers screened studies for eligibility. Fifteen case-control studies were identified that met the inclusion criteria, of which seven postdated the study of Mortimer et al. RESULTS: We partially replicated the results of Mortimer et al. The meta-analysis of the seven studies conducted since 1991 did not reach significance. However, analysis of all 15 case-control studies was significant (OR 1.58, 95% CI 1.21 to 2.06), indicating an excess history of head injury in those with Alzheimer's disease. The finding of Mortimer et al that head injury is a risk factor for Alzheimer's disease only in males was replicated. The excess risk of head injury in those with Alzheimer's disease is only found in males (males: OR 2.29, 95% CI 1.47 to 2.06; females: OR 0.91, 95% CI 0.56 to 1.47). CONCLUSIONS: This study provides support for an association between a history of previous head injury and the risk of developing Alzheimer's disease.

BACKGROUND: Unanswered questions from controlled studies of posttraumatic stress disorder concern the value of cognitive restructuring alone without prolonged exposure therapy and whether its combination with prolonged exposure is enhancing. METHODS: In a controlled study, 87 patients with posttraumatic stress disorder of at least 6 months' duration were randomly assigned to have 10 sessions of 1 of 4 treatments: prolonged exposure (imaginal and live) alone; cognitive restructuring alone; combined prolonged exposure and cognitive restructuring; or relaxation without prolonged exposure or cognitive restructuring. RESULTS: Integrity of audiotaped treatment sessions was satisfactory when rated by an assessor unaware of the treatment assignment. Seventy-seven patients completed treatment. The pattern of results was similar regardless of rater, statistical method, measure, occasion, and therapist. Exposure and cognitive restructuring, singly or combined, improved posttraumatic stress disorder markedly on a broad front. Gains continued to 6-month follow-up and were significantly greater than the moderate improvement from relaxation. CONCLUSION: Both prolonged exposure and cognitive restructuring were each therapeutic on their own, were not mutually enhancing when combined, and were each superior to relaxation.

A standardized, semi-structured interview for examining and recording the mental state in elderly subjects is described. It allows the classification of patients by symptom profile and can demonstrate changes in that profile over time. It is believed that good reliability is demonstrated between psychiatric raters both for psychiatric diagnosis made on the basis of the schedule findings and for individual items. The Geriatric Mental State Schedule (GMS) consists mainly of items from the eighth edition of the PSE (Wing et al. 1967), together with additional items from the PSS (Spitzer et al. 1964), and extra sections dealing with disorientation and other cognitive abnormalities. Modifications have been introduced to facilitate interviewing elderly subjects.

Two questions arising in the analysis of functional magnetic resonance imaging (fMRI) data acquired during periodic sensory stimulation are: i) how to measure the experimentally determined effect in fMRI time series; and ii) how to decide whether an apparent effect is significant. Our approach is first to fit a time series regression model, including sine and cosine terms at the (fundamental) frequency of experimental stimulation, by pseudogeneralized least squares (PGLS) at each pixel of an image. Sinusoidal modeling takes account of locally variable hemodynamic delay and dispersion, and PGLS fitting corrects for residual or endogenous autocorrelation in fMRI time series, to yield best unbiased estimates of the amplitudes of the sine and cosine terms at fundamental frequency; from these parameters the authors derive estimates of experimentally determined power and its standard error. Randomization testing is then used to create inferential brain activation maps (BAMs) of pixels significantly activated by the experimental stimulus. The methods are illustrated by application to data acquired from normal human subjects during periodic visual and auditory stimulation.

Glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have been proposed to contribute significantly to the pathophysiology of schizophrenia. In this paper we assess research that has implicated both systems in the aetiology of this disorder. We examine evidence from post-mortem, preclinical, pharmacological and in vivo neuroimaging studies. Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. Converging evidence indicates that genetic and environmental risk factors for schizophrenia underlie disruption of glutamatergic and dopaminergic function. However, while genetic influences may directly underlie glutamatergic dysfunction, few genetic risk variants directly implicate the dopamine system, indicating that aberrant dopamine signalling is likely to be predominantly due to other factors. We discuss the neural circuits through which the two systems interact, and how their disruption may cause psychotic symptoms. We also discuss mechanisms through which existing treatments operate, and how recent research has highlighted opportunities for the development of novel pharmacological therapies. Finally, we consider outstanding questions for the field, including what remains unknown regarding the nature of glutamate and dopamine function in schizophrenia, and what needs to be achieved to make progress in developing new treatments.

Much of the literature on the family of the schizophrenic patient has suggested that a number of common features are present in the personalities of the parents, and that these are significant in the aetiology of the illness. Most studies have been con cerned with the parent-child relationship and only a few with the adult patient and his parents. Tietze's description of mothers as generally over-anxious, obsessional, and domineering is typical (Tietze, 1949); and Fromm-Reichmann (1948) coined the term schizophrenogenic to describe such women. The more systematic work has indicated a high frequency of domineering and over-solicitous be haviour among mothers (Mark, 1953; Freeman and Grayson, 1955; Gerard and Siegel, 1950; Kohn and Clausen, 1956). Two studies, however, have pro duced negative evidence (Neilsen, 1954; Hotchkiss, Carmen, Ogilby, and Wiesenfeld, 1955) and the second of these was the only one in which the behaviour of the mother and patient was directly observed. Even if differences exist between the mothers of schizophrenics and other mothers, this need not be of aetiological importance. The possibility must first be excluded that behaviour such as over protectiveness may be the result of the patient's unusual behaviour influencing the parents (Kasanin, Knight, and Sage, 1934). Once an illness has developed in one member of a family, a heightened level of tension is probably common. Once estab lished, tense relationships in turn may have an important effect on the later stages of the illness. Some evidence that family relationships can in fluence the course of schizophrenia was provided by a previous study, which showed that re-admission of long-stay patients was related to the type of living group to which they returned (Brown, Carstairs, and Topping, 1958; Brown, 1959). Patients who lived with wives and parents showed a higher re-admission rate than those going to brothers, sisters, or more distant kin, or in lodgings. There was evidence that the risk of deterioration in clinical condition was increased when prolonged contact with close rela tiv s in the house was unavoidable?when, for example, both patient and mother were unemployed. Results could not be explained entirely by the length or past severity of illness or by differences in clinical condition at the time of discharge; and it was concluded that it might not always be best for the schizophrenic patient to return to the close emo tional ties of affection or hostility often found in parental and marital homes. These close emotional ties are not, of course, confi ed to households of any particular kinship, c tegory. It was therefore decided to continue the work by studying the relationships within each home to which discharged patients returned. The majority of patients in this second study were short-stay schizophrenics, and a different survey method was used. Patients and their families were interviewed at the time of discharge and during the year, if the patient was re-admitted, as well as at the end of the follow-up period. In this way the difficulties inherent in the previous exploratory survey, which relied on one interview at the time of follow-up, were avoided. In particular, since patients and families were seen at discharge, predictions could be made about outcome which were not influenced by knowledge of the later course of the illness; and the clinical condition of patients (assessed at the time of discharge) could be controlled in testing the pre dictions. The two hypotheses were:

Reviews The Study of Behavior. Q-Technique and its Methodology (see record 1954-06810-000) by William Stephenson. The reviewer notes that this book does not, as the title implies, deal with behaviour, at least, not in the sense that the term is usually understood by psychologists; it deals essentially with techniques of obtaining self-ratings and ratings of others, called Q-sorts by Stephenson, and with techniques of correlating persons and factor analyzing the resulting tables of correlations, called Q-techniques by Stephenson. It constitutes, therefore, a summary and detailed statement of work carried on intermittently by Stephenson since 1935, and well known in its main aspects to statistically-minded psychologists. Those who have followed this work, and the many controversies to which it has given rise, will turn to this book in anticipation of finding a detailed discussion of the main points, together with an empirical proof of the effectiveness of the methods suggested. The reviewer notes that a great deal of the argument is difficult to follow because of Stephenson's somewhat explosive and disjointed manner of writing. In summary, there is much that is ingenious, interesting, and suggestive in this book, but it cannot be recommended to anyone not thoroughly familiar with the field and able to discount the more unorthodox and less acceptable parts of the argument. (PsycINFO Database Record (c) 2006 APA, all rights reserved)

A technique for assessing in vivo fiber connectivity in the human brain is presented. The method utilizes a novel connectivity algorithm that operates in three spatial dimensions and uses estimates of fiber tract orientation and tissue anisotropy, obtained from diffusion tensor magnetic resonance imaging, to establish the pathways of fiber tracts. Sample in vivo connectivity images from healthy human brain are presented that demonstrate connections in the white matter tracts. White matter connectivity information is potentially of interest in the study of a range of neurological, psychiatric, and developmental disorders and shows promise for following the natural history of disease.