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

Abstract

SummaryBackgroundAlthough 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.MethodsWe 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.FindingsFrom 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.InterpretationAt 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.FundingNational Institute for Health Research Technology Assessment programme.

Response rates in patients with schizophrenia and positive symptoms receiving cognitive behavioural therapy: a systematic review and single-group meta-analysis

“…This finding may be explained by the fact that treatment-resistant symptoms are more difficult to treat, and therefore a CBT intervention can bring only a lower improvement compared to that of other patients. A trial on clozapine-resistant patients receiving CBT, published after the date of our search, reported responders’ rates that are slightly higher than the ones that we found (46 and 7% for the 20 and 50% PANSS total reduction of symptoms, respectively) [ 24 ].…”

CBT for schizophrenia: a critical viewpoint

“…The recently published FOCUS trial (Morrison et al, 2018) examined the effectiveness of CBT over a period of 9 months (plus later booster sessions) v. TAU in 487 patients with clozapine-resistant schizophrenia. As well as being very large, this trial was well-conducted, employed randomization by remote allocation and assessor blinding (with measures taken to address accidental breaking), and analysis was by means of a modern equivalent of intention-to-treat (White et al, 2011).…”

“…Hutton and Taylor (2014) meta-analyzed six trials using CBT in individuals at risk of developing psychosis, and found evidence that it was effective in reducing the transition rate at 6, 12, and 18 months [6 months: RR 0.47 (95% CI 0.27-0.82), six studies; 12 months: RR 0.45 (95% CI 0.28-0.73), six studies; 18-24 months: RR 0.41 (95% CI 0.23-0.72), four studies]. This meta-analysis included two large, well-conducted multicenter trials (n = 288, Morrison et al, 2012 andn = 206, van der Gaag et al, 2012); the former failed to find a significant difference in transition frequency but the latter found a significant (55%) reduction.…”

Pharmakotherapie der therapieresistenten Schizophrenie

“…Die Kombination von kognitiver Verhaltenstherapie und antipsychotischer Medikation wurde bisher kaum in einer behandlungsresistenten Population untersucht. In einer großen Studie mit 487 Teilnehmern wurde der Effekt von kognitiver Verhaltenstherapie zusätzlich zur medikamentösen Therapie über einen Zeitraum von fast 2 Jahren untersucht [43]. Eingeschlossen wurden nur Teilnehmer, die sich unter einer Behandlung mit Clozapin nicht ausreichend verbessert hatten oder diese nicht vertragen hatten.…”