Cognitive-behavioural therapy for clozapine-resistant schizophrenia: the FOCUS RCT.

Background: Clozapine (clozaril, Mylan Products Ltd) is a first-choice treatment for people with schizophrenia who have a poor response to standard antipsychotic medication. However, a significant number of patients who trial clozapine have an inadequate response and experience persistent symptoms, called clozapine-resistant schizophrenia (CRS). There is little evidence regarding the clinical effectiveness of pharmacological or psychological interventions for this population.
Objectives: To evaluate the clinical effectiveness and cost-effectiveness of cognitive-behavioural therapy (CBT) for people with CRS and to identify factors predicting outcome.
Design: The Focusing on Clozapine Unresponsive Symptoms (FOCUS) trial was a parallel-group, randomised, outcome-blinded evaluation trial. Randomisation was undertaken using permuted blocks of random size via a web-based platform. Data were analysed on an intention-to-treat (ITT) basis, using random-effects regression adjusted for site, age, sex and baseline symptoms. Cost-effectiveness analyses were carried out to determine whether or not CBT was associated with a greater number of quality-adjusted life-years (QALYs) and higher costs than treatment as usual (TAU).
Setting: Secondary care mental health services in five cities in the UK.
Participants: People with CRS aged ≥ 16 years, with an International Classification of Diseases , Tenth Revision (ICD-10) schizophrenia spectrum diagnoses and who are experiencing psychotic symptoms.
Interventions: Individual CBT included up to 30 hours of therapy delivered over 9 months. The comparator was TAU, which included care co-ordination from secondary care mental health services.
Main Outcome Measures: The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months and the primary secondary outcome was PANSS total score at the end of treatment (9 months post randomisation). The health benefit measure for the economic evaluation was the QALY, estimated from the EuroQol-5 Dimensions, five-level version (EQ-5D-5L), health status measure. Service use was measured to estimate costs.
Results: Participants were allocated to CBT ( n  = 242) or TAU ( n  = 245). There was no significant difference between groups on the prespecified primary outcome [PANSS total score at 21 months was 0.89 points lower in the CBT arm than in the TAU arm, 95% confidence interval (CI) -3.32 to 1.55 points; p  = 0.475], although PANSS total score at the end of treatment (9 months) was significantly lower in the CBT arm (-2.40 points, 95% CI -4.79 to -0.02 points; p  = 0.049). CBT was associated with a net cost of £5378 (95% CI -£13,010 to £23,766) and a net QALY gain of 0.052 (95% CI 0.003 to 0.103 QALYs) compared with TAU. The cost-effectiveness acceptability analysis indicated a low likelihood that CBT was cost-effective, in the primary and sensitivity analyses (probability < 50%). In the CBT arm, 107 participants reported at least one adverse event (AE), whereas 104 participants in the TAU arm reported at least one AE (odds ratio 1.09, 95% CI 0.81 to 1.46; p  = 0.58).
Conclusions: Cognitive-behavioural therapy for CRS was not superior to TAU on the primary outcome of total PANSS symptoms at 21 months, but was superior on total PANSS symptoms at 9 months (end of treatment). CBT was not found to be cost-effective in comparison with TAU. There was no suggestion that the addition of CBT to TAU caused adverse effects. Future work could investigate whether or not specific therapeutic techniques of CBT have value for some CRS individuals, how to identify those who may benefit and how to ensure that effects on symptoms can be sustained.
Trial Registration: Current Controlled Trials ISRCTN99672552.
Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 7. See the NIHR Journals Library website for further project information.
Competing Interests: Anthony P Morrison reports personal fees from the provision of training workshops in cognitive–behavioural therapy (CBT) for psychosis and royalties from books on the topic, outside the submitted work. Andrew Gumley reports grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (grant number 13/15/04) outside the submitted work. Douglas Turkington reports personal fees from Insight–CBT partnership (Insight Healthcare, Newcastle upon Tyne), outside the submitted work. Gemma Shields reports grants from NIHR during the conduct of the study. Graeme MacLennan reports grants from the NIHR HTA programme during the conduct of the study. Hamish J MacLeod reports that he occasionally provides CBT for psychosis workshops and receives fees for this work. John Norrie reports personal fees from the NIHR Editors Board and grants from NIHR HTA General Board Deputy Chairperson, outside the submitted work, and has membership of the HTA Funding Boards Policy Group and Pre-Exposure Prophylaxis Impact Review Panel. Linda Davies reports grants from the NIHR HTA programme during the conduct of the study. Paul French has membership of the HTA prioritisation Panel. Paul Hutton reports that he sits on an Expert Steering Group for Professor Jill Stavert’s Centre for Mental Health and Incapacity Law Rights and Policy at Edinburgh Napier University, and that he is a member of a committee developing National Institute for Health and Care Excellence (NICE) guidelines on supporting decision-making for people who may lack mental capacity. Robert Dudley reports receiving a NIHR Comprehensive Local Research Network Greenshoots award to fund time to support his contribution to the FOCUS (Focusing on Clozapine Unresponsive Symptoms) trial, royalties from Guilford Press and personal fees from Trinity College Dublin, outside the submitted work. Samantha Bowe reports personal fees from Pennine Care NHS Foundation Trust and personal fees from Cheshire & Wirral Partnership NHS Foundation Trust, outside the submitted work. Thomas RE Barnes reports personal fees from Sunovion (Marlborough, MA, USA) and Otsuka (Tokyo, Japan)/Lundbeck (Copenhagen, Denmark), outside the submitted work.