For roughly a third of people with treatment-resistant schizophrenia, even the most effective antipsychotic drug—clozapine—fails to control their symptoms. This trial will test whether adding nine months of cognitive behavioural therapy (CBT) to standard care can improve those stubborn psychotic symptoms, as well as quality of life and personal recovery, in 485 patients across five UK sites. The problem is stark: clozapine is the only antipsychotic proven to work in truly treatment-resistant schizophrenia, yet 30 to 40 percent of patients still respond inadequately. Existing evidence for CBT in this group is limited and inconclusive. Without better options, these individuals face persistent hallucinations, delusions, and social withdrawal that medication alone cannot touch. If CBT proves effective, this trial could change clinical practice by offering a non-drug intervention for a patient group with few alternatives. The researchers will also develop a risk model to identify which patients are most likely to benefit, allowing clinicians to target therapy efficiently. A cost-effectiveness analysis will tell the NHS whether the approach is worth scaling. The primary outcome—symptom severity measured by a standard psychiatric interview—will be assessed over 21 months, giving a clear picture of whether gains are sustained.
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We will test the hypotheses that: 1. In people with a diagnosis of a schizophrenia spectrum disorder who have an inadequate response to or are unable to tolerate clozapine, Cognitive Behavioural Therapy (CBT) plus Treatment As Usual (TAU) will lead to improvement in psychotic symptoms, measured using a psychiatric interview (PANSS), over a 21-month follow-up period compared with TAU alone 2. CBT plus TAU will lead to improved quality of life and user-defined recovery compared to TAU alone 3. CBT plus TAU will lead to a reduction in affective symptoms and negative symptoms compared to TAU alone 4. CBT plus TAU will be cost effective compared to TAU alone 5. It will be possible to develop a risk model that identifies baseline factors that predict good outcome to CBT Background and aim: Clozapine is the only antipsychotic with convincing evidence for efficacy in strictly defined treatment resistant schizophrenia. But even in this category clozapine has limited efficacy, with 30-40% showing an inadequate response to the drug. There is some evidence that cognitive behavioural therapy (CBT) can sometimes produce more improvement, however the evidence is limited. This study plans to evaluate the possible benefits of CBT added to clozapine for 9 months with people with psychosis whose symptoms are considered treatment resistant to clozapine. Method: A parallel group randomised outcome blind evaluation (PROBE) trial comparing the addition of standardised CBT intervention to treatment as usual for people with psychosis who are unable to tolerate or have an inadequate response to clozapine. A total of 485 participants aged between 16 and 65 with a diagnosis on the schizophrenia spectrum or who meet criteria for early intervention in psychosis and who experience persistent symptoms despite an adequate trial of clozapine monotherapy will be recruited from five sites in the UK (Southampton, Manchester, Newcastle, Edinburgh and Glasgow). Analysis: The main analyses will be based on the Intention-to-Treat principle. The primary outcome measure the Positive and Negative Syndrome Scale (PANSS) will be analysed using a linear model that adjusts for pre-specified baseline covariates strongly associated with outcome. Secondary outcomes will be analysed with general linear models and the development of treatment effects over time will be analysed using repeated measures models. The influence of compliance will be addressed via causal or mediation models.
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