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      Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial

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          Summary

          Background

          Although clozapine is the treatment of choice for treatment-refractory schizophrenia, 30–40% of patients have an insufficient response, and others are unable to tolerate it. Evidence for any augmentation strategies is scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia.

          Methods

          We did a pragmatic, parallel group, assessor-blinded, randomised controlled trial in community-based and inpatient mental health services in five sites in the UK. Patients with schizophrenia who were unable to tolerate clozapine, or whose symptoms did not respond to the drug, were randomly assigned 1:1 by use of randomised-permuted blocks of size four or six, stratified by centre, to either CBT plus treatment as usual or treatment as usual alone. Research assistants were masked to allocation to protect against rater bias and allegiance bias. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months, which provides a continuous measure of symptoms of schizophrenia; PANSS total was also assessed at the end of treatment (9 months). The primary analysis was by randomised treatment based on intention to treat, for all patients for whom data were available. This study was prospectively registered, number ISRCTN99672552. The trial is closed to accrual.

          Findings

          From Jan 1, 2013, to May 31, 2015, we randomly assigned 487 participants to either CBT and treatment as usual (n=242) or treatment as usual alone (n=245). Analysis included 209 in the CBT group and 216 in the treatment as usual group. No difference occurred in the primary outcome (PANSS total at 21 months, mean difference −0·89, 95% CI −3·32 to 1·55; p=0·48), although the CBT group improved at the end of treatment (PANSS total at 9 months, mean difference −2·40, −4·79 to −0·02; p=0·049). During the trial, 107 (44%) of 242 participants in the CBT arm and 104 (42%) of 245 in the treatment as usual arm had at least one adverse event (odds ratio 1·09, 95% CI 0·81 to 1·46; p=0·58). Only two (1%) of 242 participants in the CBT arm and one (<1%) of 245 in the treatment as usual arm had a trial-related serious adverse event.

          Interpretation

          At 21-month follow-up, CBT did not have a lasting effect on total symptoms of schizophrenia compared with treatment as usual; however, CBT produced statistically, though not clinically, significant improvements on total symptoms by the end of treatment. There was no indication that the addition of CBT to treatment as usual caused adverse effects. The results of this trial do not support a recommendation to routinely offer CBT to all people who meet criteria for clozapine-resistant schizophrenia; however, a pragmatic individual trial might be indicated for some.

          Funding

          National Institute for Health Research Technology Assessment programme.

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          Most cited references21

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

          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.
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            What does the PANSS mean?

            Despite the frequent use of the Positive and Negative Syndrome Scale (PANSS) for rating the symptoms of schizophrenia, the clinical meaning of its total score and of the cut-offs that are used to define treatment response (e.g. at least 20% or 50% reduction of the baseline score) are as yet unclear. We therefore compared the PANSS with simultaneous ratings of Clinical Global Impressions (CGI). PANSS and CGI ratings at baseline (n = 4091), and after one, two, four and six weeks of treatment taken from a pooled database of seven pivotal, multi-center antipsychotic drug trials on olanzapine or amisulpride in patients with exacerbations of schizophrenia were compared using equipercentile linking. Being considered "mildly ill" according to the CGI approximately corresponded to a PANSS total score of 58, "moderately ill" to a PANSS of 75, "markedly ill" to a PANSS of 95 and severely ill to a PANSS of 116. To be "minimally improved" according to the CGI score was associated with a mean percentage PANSS reduction of 19%, 23%, 26% and 28% at weeks 1, 2, 4 and 6, respectively. The corresponding figures for a CGI rating "much improved" were 40%, 45%, 51% and 53%. The results provide a better framework for understanding the clinical meaning of the PANSS total score in drug trials of schizophrenia patients with acute exacerbations. Such studies may ideally use at least a 50% reduction from baseline cut-off to define response rather than lower thresholds. In treatment resistant populations, however, even a small improvement can be important, so that a 25% cut-off might be appropriate.
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              The drug abuse screening test.

              The Drug Abuse Screening Test (DAST) was designed to provide a brief instrument for clinical screening and treatment evaluation research. The 28 self-report items tap various consequences that are combined in a total DAST score to yield a quantitative index of problems related to drug misuse. Measurement properties of the DAST were evaluated using a clinical sample of 256 drug/alcohol abuse clients. The internal consistency reliability estimate was substantial at .92, and a factor analysis of item intercorrelations suggested an unidimensional scale. With respect to response style biases, the DAST was only moderately correlated with social desirability and denial. Concurrent validity was examined by correlating the DAST with background variables, frequency of drug use during the past 12 months, and indices of psychopathology. Although these findings support the usefulness of the DAST for quantifying the extent of drug involvement within a help-seeking population, further validation work is needed in other populations and settings.
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                Author and article information

                Contributors
                Journal
                Lancet Psychiatry
                Lancet Psychiatry
                The Lancet. Psychiatry
                Elsevier
                2215-0366
                2215-0374
                1 August 2018
                August 2018
                : 5
                : 8
                : 633-643
                Affiliations
                [a ]Psychosis Research Unit, Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK
                [b ]Zochonis Building, University of Manchester, Manchester, UK
                [c ]Division of Psychology and Mental Health, Zochonis Building, University of Manchester, Manchester, UK
                [d ]Division of Population Health, Zochonis Building, University of Manchester, Manchester, UK
                [e ]Institute of Health and Wellbeing, University of Glasgow, Gartnavel Royal Hospital, Glasgow, UK
                [f ]Department of Clinical Psychology, School of Health in Social Science, Old Medical School, The University of Edinburgh, Edinburgh, UK
                [g ]Edinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences & Informatics, Nine Edinburgh BioQuarter, The University of Edinburgh, Edinburgh, UK
                [h ]Academic Psychiatry, Northumberland, Tyne and Wear NHS Foundation Trust, Centre for Aging and Vitality, Newcastle General Hospital, Newcastle upon Tyne, UK
                [i ]Centre for Healthcare Randomised Trials, Health Services Research Unit, University of Aberdeen, Aberdeen, UK
                [j ]Institute of Psychology, Health and Society, University of Liverpool, Liverpool, UK
                [k ]School of Psychology, Newcastle University, Newcastle Upon Tyne, UK
                [l ]Early Intervention in Psychosis Service, Northumberland, Tyne and Wear NHS Foundation Trust, Tranwell Unit, Queen Elizabeth Hospital, Gateshead, UK
                [m ]The Centre for Psychiatry, Imperial College London, London, UK
                [n ]University Department of Psychiatry, Academic Centre, University of Southampton, Southampton, UK
                Author notes
                [* ]Correspondence to: Prof Anthony P Morrison, Division of Psychology and Mental Health, University of Manchester, Manchester M13 9PL, UK tony.morrison@ 123456manchester.ac.uk
                [†]

                Members of the FOCUS trial group are listed at the end of the paper

                Article
                S2215-0366(18)30184-6
                10.1016/S2215-0366(18)30184-6
                6063993
                30001930
                4c42aca5-233e-49f8-9d9e-7e4c73c284ce
                © 2018 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND 4.0 license

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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