Cognitive behavioural therapy in Clozapine-Resistant Schizophrenia (FOCUS): an assessor-blinded, randomised controlled trial

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 limited. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for Clozapine Resistant Schizophrenia (CRS). Methods:We conducted a pragmatic, parallel group, randomised controlled trial in community based and inpatient mental health services in five sites in the United Kingdom. Randomisation was 1:1 using randomly permuted blocks of size four or six, stratified by centre to either CBT plus treatment as usual (TAU) or TAU. 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 end of treatment (9 months). Outcomes were analysed using intention-to-treat mixed effects linear regression adjusted for site, age, sex and baseline PANSS. This study was prospectively registered as International Standard Randomised Controlled Trial number: ISRCTN99672552. Findings:We randomised 487 participants (CBT+TAU 242, TAU 245) between January 2013, and May 2015. There was no difference in the primary outcome (PANSS total at 21 months, mean difference -0·89, 95% CI -3·32 to 1·55; p = 0·48), although there was an improvement in the CBT group at end of treatment (PANSS total at 9 months, mean difference -2·40, 95% CI -4·79 to -0̏·02; p = 0·049). During the trial, 107 participants in the CBT arm and 104 participants in the TAU arm experienced at least one adverse event (odds ratio 1.09, 95% CI 0.81 to 1.46; p=0.58). Only 2 participants in the CBT arm and one in the TAU arm experienced a trial-related serious adverse event. Interpretation:At 21 month follow-up, there was no lasting effect on total symptoms of schizophrenia compared with TAU, although CBT produced statistically, though not clinically, significant improvements on total symptoms by end of treatment. There was no suggestion that the addition of CBT to TAU caused adverse effects. The results of this trial do not support a recommendation to routinely offer CBT to all people who meet criteria for CRS; however, a pragmatic individual trial may be indicated for some individuals.Funding:NIHR Health Technology Assessment programme (10/101/02).