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

Morrison, Anthony P; Pyle, Melissa; Gumley, Andrew; Schwannauer, Matthias; Turkington, Douglas; MacLennan, Graeme; Norrie, John; Hudson, Jemma; Bowe, Samantha E; French, Paul; Byrne, Rory; Syrett, Suzy; Dudley, Robert; McLeod, Hamish J; Griffiths, Helen; Barnes, Thomas R E; Davies, Linda; Kingdon, David; Aydinlar, Suzan; Courtley, James; Douglas-Bailey, Maggie; Graves, Elizabeth; Holden, Natasha; Hutton, Jane; Hutton, Paul; Irving, Susan; Jackson, Clare; Lebert, Toyah; Mander, Helen; McCartney, Laura; Munro-Clark, Trevor; Murphy, Elizabeth Kim; Spanswick, Mairi; Steele, Ann; Tip, Liesbeth; Tully, Sarah


Anthony P Morrison

Melissa Pyle

Andrew Gumley

Matthias Schwannauer

Douglas Turkington

Graeme MacLennan

John Norrie

Jemma Hudson

Samantha E Bowe

Paul French

Rory Byrne

Suzy Syrett

Robert Dudley

Hamish J McLeod

Helen Griffiths

Thomas R E Barnes

Linda Davies

David Kingdon

Suzan Aydinlar

James Courtley

Maggie Douglas-Bailey

Elizabeth Graves

Natasha Holden

Jane Hutton

Susan Irving

Clare Jackson

Toyah Lebert

Helen Mander

Laura McCartney

Trevor Munro-Clark

Elizabeth Kim Murphy

Mairi Spanswick

Ann Steele

Liesbeth Tip

Sarah Tully


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.
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.
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 (


Morrison, A. P., Pyle, M., Gumley, A., Schwannauer, M., Turkington, D., MacLennan, G., …Tully, S. (2018). Cognitive behavioural therapy in clozapine-resistant schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial. Lancet Psychiatry, 5(8), 633-643.

Journal Article Type Article
Acceptance Date May 8, 2018
Online Publication Date Jul 11, 2018
Publication Date 2018-08
Deposit Date Oct 15, 2018
Publicly Available Date Oct 16, 2018
Journal The Lancet Psychiatry
Print ISSN 2215-0366
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 5
Issue 8
Pages 633-643
Keywords Schizophrenia, clozapine, drug treatment, cognitive behavioural therapy, CBT,
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