The impact of clozapine initiation and cessation on psychiatric hospital admissions and bed days:a mirror image cohort study

BACKGROUND: Clozapine is the most effective medication for the positive symptoms of treatment-refractory schizophrenia. Although clozapine use is associated with fewer admissions, less is known about the impact of clozapine cessation on hospitalisation.AIMS: The aims of this study were to investigate whether clozapine-reduced psychiatric inpatient admissions and bed days, and investigate patient factors associated with these changes from a sample of 1906 people commenced on clozapine.METHODS: All people commencing clozapine during an acute hospitalisation over a 10-year period in Queensland, Australia, were included in this retrospective cohort study. A mirror image design was used to compare psychiatric bed days and hospitalisations 2 years before and after clozapine treatment, and the impact of clozapine continuation or early cessation. Changes in psychiatric bed days and hospitalisations were analysed using linear regression, adjusting for the duration on clozapine, sex, age, indigenous status, country of origin and time to clozapine commencement.RESULTS/OUTCOMES: There was a significant reduction in bed days (29.55 days vs 24.46 days, p &lt; 0.001) and admissions (2.27 vs 1.87 &lt; 0.001) associated with clozapine commencement. This remained significant among clozapine continuers, but not among those with early cessation. Longer duration on clozapine was associated with greater reductions in psychiatric bed days and admissions. Age, sex and time to clozapine commencement, indigeneity and country of origin did not impact outcomes.CONCLUSION/INTERPRETATION: Longer clozapine therapy led to a greater reduction in psychiatric bed days and hospitalisations. Early cessation was associated with a return to pre-clozapine levels of bed days and admissions.</p

Common schizophrenia alleles are enriched in mutation-intolerant genes and maintained by background selection

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 such insight. We report the largest single cohort genome-wide association study of schizophrenia (11,260 cases and 24,542 controls) and through meta-analysis with existing data we identify 50 novel GWAS loci. Using gene-wide association statistics we implicate an additional set of 22 novel associations that map onto a single gene. We show for the first time that the common variant association signal is highly enriched among genes that are intolerant to loss of function mutations and that variants in these genes persist in the population despite the low fecundity associated with the disorder through the process of background selection. Associations point to novel areas of biology (e.g. metabotropic GABA-B signalling and acetyl cholinesterase), reinforce those implicated in earlier GWAS studies (e.g. calcium channel function), converge with earlier rare variants studies (e.g. NRXN1, GABAergic signalling), identify novel overlaps with autism (e.g. RBFOX1, FOXP1, FOXG1), and support early controversial candidate gene hypotheses (e.g. ERBB4 implicating neuregulin signalling). We also demonstrate the involvement of six independent central nervous system functional gene sets in schizophrenia pathophysiology. These findings provide novel 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 are maintained in the population

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

OBJECTIVE: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHODS: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation

Framing the Real: Lefèbvre and NeoRealist Cinematic Space as Practice

In 1945 Roberto Rossellini's Neo-realist Rome, Open City set in motion an approach to cinema and its representation of real life – and by extension real spaces – that was to have international significance in film theory and practice. However, the re-use of the real spaces of the city, and elsewhere, as film sets in Neo-realist film offered (and offers) more than an influential aesthetic and set of cinematic theories. Through Neo-realism, it can be argued that we gain access to a cinematic relational and multidimensional space that is not made from built sets, but by filming the built environment. On the one hand, this space allows us to "notice" the contradictions around us in our cities and, by extension, the societies that have produced those cities, while on the other, allows us to see the spatial practices operative in the production and maintenance of those contradictions. In setting out a template for understanding the spatial practices of Neo-realism through the work of Henri Lefèbvre, this paper opens its films, and those produced today in its wake, to a spatio-political reading of contemporary relevance. We will suggest that the rupturing of divisions between real spaces and the spaces of film locations, as well the blurring of the difference between real life and performed actions for the camera that underlies much of the central importance of Neo-realism, echoes the arguments of Lefèbvre with regard the social production of space. In doing so, we will suggest that film potentially had, and still has, a vital role to play in a critique of contemporary capitalist spatial practices

Identification of glucose transporters in Aspergillus nidulans

o characterize the mechanisms involved in glucose transport, in the filamentous fungus Aspergillus nidulans, we have identified four glucose transporter encoding genes hxtB-E. We evaluated the ability of hxtB-E to functionally complement the Saccharomyces cerevisiae EBY.VW4000 strain that is unable to grow on glucose, fructose, mannose or galactose as single carbon source. In S. cerevisiae HxtB-E were targeted to the plasma membrane. The expression of HxtB, HxtC and HxtE was able to restore growth on glucose, fructose, mannose or galactose, indicating that these transporters accept multiple sugars as a substrate through an energy dependent process. A tenfold excess of unlabeled maltose, galactose, fructose, and mannose were able to inhibit glucose uptake to different levels (50 to 80 %) in these s. cerevisiae complemented strains. Moreover, experiments with cyanide-m-chlorophenylhydrazone (CCCP), strongly suggest that hxtB, -C, and –E mediate glucose transport via active proton symport. The A. nidulans ΔhxtB, ΔhxtC or ΔhxtE null mutants showed ~2.5-fold reduction in the affinity for glucose, while ΔhxtB and -C also showed a 2-fold reduction in the capacity for glucose uptake. The ΔhxtD mutant had a 7.8-fold reduction in affinity, but a 3-fold increase in the capacity for glucose uptake. However, only the ΔhxtB mutant strain showed a detectable decreased rate of glucose consumption at low concentrations and an increased resistance to 2-deoxyglucose.The authors would like to thank the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil for financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Resistance through realism : Youth subculture films in 1970s (and 1980s) Britain

This document is the Accepted Manuscript version of the following article: Nathaniel Weiner, ‘Resistance through realism: Youth subculture films in 1970s (and 1980s) Britain’. The final, definitive version of this paper has been published in European Journal of Cultural Studies, November 2015, DOI: https://doi.org/10.1177/1367549415603376. Published by SAGE Publishing.Film scholars have argued that the British social realist films of the late 1950s and early 1960s reflect the concerns articulated by British cultural studies during the same period. This article looks at how the social realist films of the 1970s and early 1980s similarly reflect the concerns of British cultural studies scholarship produced by the University of Birmingham’s Centre for Contemporary Cultural Studies during the 1970s. It argues that the Centre for Contemporary Cultural Studies’ approach to stylised working-class youth subcultures is echoed in the portrayal of youth subcultures in the social realist films Pressure (1976), Bloody Kids (1979), Babylon (1980) and Made in Britain (1982). This article explores the ways in which these films show us both the strengths and weaknesses of the Centre for Contemporary Cultural Studies’ work on subcultures.Peer reviewe

Validation of an algorithm-based definition of treatment resistance in patients with schizophrenia

Large-scale pharmacoepidemiological research on treatment resistance relies on accurate identification of people with treatment-resistant schizophrenia (TRS) based on data that are retrievable from administrative registers. This is usually approached by operationalising clinical treatment guidelines by using prescription and hospital admission information. We examined the accuracy of an algorithm-based definition of TRS based on clozapine prescription and/or meeting algorithm-based eligibility criteria for clozapine against a gold standard definition using case notes. We additionally validated a definition entirely based on clozapine prescription. 139 schizophrenia patients aged 18–65 years were followed for a mean of 5 years after first presentation to psychiatric services in South-London, UK. The diagnostic accuracy of the algorithm-based measure against the gold standard was measured with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). A total of 45 (32.4%) schizophrenia patients met the criteria for the gold standard definition of TRS; applying the algorithm-based definition to the same cohort led to 44 (31.7%) patients fulfilling criteria for TRS with sensitivity, specificity, PPV and NPV of 62.2%, 83.0%, 63.6% and 82.1%, respectively. The definition based on lifetime clozapine prescription had sensitivity, specificity, PPV and NPV of 40.0%, 94.7%, 78.3% and 76.7%, respectively. Although a perfect definition of TRS cannot be derived from available prescription and hospital registers, these results indicate that researchers can confidently use registries to identify individuals with TRS for research and clinical practices

Do schizophrenic patients who managed to get to university have a non-neurodevelopmental form of illness?

Background. Many people who develop schizophrenia have impairments in intellectual and social functioning that are detectable from early childhood. However, some patients do not exhibit such deficits, and this suggests that they may have suffered less neurodevelopmental damage. We hypothesized that the aetiology and form of schizophrenia may differ in such patients. We therefore studied a group of schizophrenic patients who were functioning well enough to enter university prior to illness onset.Methods. The casenotes of 46 university-educated patients and 48 non-university-educated patients were rated on several schedules including the OPCRIT checklist, and the two groups were compared using univariate statistical techniques. Principal components analysis was then performed using data from all patients, and the factor scores for each principal component were compared between groups.Results. Univariate analyses showed the university-educated patients had an excess of depressive symptoms, and a paucity of core schizophrenic symptoms. Four principal components emerged in the principal components analysis: mania, biological depression, schizophrenic symptoms, and a reactive depression. University-educated patients scored significantly higher on the reactive depression principal component, and lower on the schizophrenic symptoms principal component, than the non-university-educated patients.Conclusions. University-educated patients may have a non-developmental subtype of schizophrenia

Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10−8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effec