Title: For whom is Cognitive Behavioural Therapy (CBT) for psychosis most effective? An IPD meta-analysis of randomised control trials comparing CBT versus standard care and other psychosocial interventions (Cognitive Behaviour Therapy for Psychosis: Individual Modifiers of Patient Response to Treatment)
Funder: Department of Health and Social Care

Abstract: AIMS: Identification of the treatment effect modifiers of CBT in people with diagnoses in the schizophrenia-spectrum to optimise treatment delivery, clinical and cost effectiveness of CBT interventions, and maximise patients’ informed choice of treatment. DESIGN: An individual patient data (IPD) meta-analysis of existing randomised controlled trials (RCT) comparing CBT to standard care and CBT to control psychosocial interventions. POPULATION: People with a diagnosis of a schizophrenia-spectrum disorder. HEALTH TECHNOLOGIES BEING ASSESSED: CBT interventions as defined by the criteria outlined in the updated NICE guideline on prevention and management of schizophrenia in adults (CG 178). OUTCOME MEASURES: The primary outcome will be overall symptom change as measured by valid and reliable clinical assessments of psychotic symptom severity (e.g. total PANSS scores). A range of secondary outcomes have been identified through our review of previous meta-analytic findings, and Patient and Public Involvement activities with service user service users and NHS clinicians (e.g. comorbid anxiety and depression, quality of life, subjectively defined recovery). STRATEGY FOR EVIDENCE SYNTHESIS: We will follow state-of-the-art guidelines for IPD meta-analytic syntheses, and our outputs will comply with the PRISMA-IPD statement. We will update the database and trial registers searches of a recent aggregate data meta-analysis carried out by members of our team (PROSPERO registration number: CRD42013003911). We will obtain relevant IPD through a collaborative network we have been establishing (the CBTp: IMPART Consortium), which comprises the principal investigators/data custodians of RCTs of CBT in patients with schizophrenia worldwide. All investigators contacted prior to the start of the project (N = 14) have joined the Consortium, giving us access to IPD from 4425 patients in 32 trials. We will continue to expand the IPD Consortium over the course of the project with the aim to retrieve all available IPD relevant to the questions examined in this evidence synthesis. Pooled treatment effects and confidence intervals will be estimated using a series of one-step or two-step IPD random-effect meta-analyses. We will then examine, across different outcomes, the effect of potential treatment effect modifiers, including participants’ demographic characteristics (age, gender, ethnicity) and clinical characteristics (specific diagnosis, illness duration, phase of illness, duration of untreated psychosis, initial severity of psychotic symptoms and comorbid affective symptoms), and specific intervention characteristics (measures of therapeutic alliance, number of therapy sessions offered/attended, level of therapists’ training and competence, use of manualised interventions, use of individually tailored formulation-based interventions). This will be done by including treatment by covariate interactions in relevant models. Findings will be interpreted in the light of relevant bias and sensitivity analyses for IPD evidence syntheses. EXPERTISE: Our multidisciplinary team includes researchers with a track record of impactful meta-analytic studies, CBT experts, statisticians with extensive expertise in RCT methodology and IPD meta-analysis, and a service user representative.

Lay abstract: Schizophrenia (a condition characterised by distressing psychotic symptoms, such as unusual beliefs and hearing voices) is associated with distress, impairment and financial costs, and its treatment is amongst the largest challenges for the NHS. The NICE guideline for the prevention and management schizophrenia in adults (CG 178) recommends that treatment options should include effective “talking therapies”, in particular Cognitive Behavioural Therapy (CBT). Previous systematic reviews have shown that CBT is effective in reducing symptoms of psychosis in randomised controlled trials (a type of clinical trial where the treatment patients receive is decided by chance). However, these reviews have also found that the benefits of CBT are highly variable, with some trials showing a clear benefit for CBT but others finding little difference between CBT and other comparison treatments (for example the “standard care” received by patients through mental health services). We suspect that this variation may relate to two factors: 1) The characteristics of the patients who took part in these trials (for example their age, gender, ethnicity, the severity of their mental health difficulties when they started therapy); and 2) The characteristics of the different CBT interventions they received in these trials (for example, how many therapy sessions they were given, and the level of training/experience of the therapists they saw). We believe these patient- and therapy-related factors can help explain why some people found CBT helpful while others didn’t. However, we cannot test this by analysing each trial separately. This is because these trials are too small to show whether some of the factors above improve or reduce the effect of CBT. Similarly, carrying out a new trial will be difficult and expensive given the large number of participants required. The only suitable option is to carry out an “individual patient data meta-analysis”, a type of research where all the raw data from previous trials are pulled together into a single database and re-analysed to answer important questions that are impossible to address accurately in single studies. This will allow us to find out if there are groups of patients who may particularly benefit from CBT and under which conditions CBT works best, but also for which clients CBT might actually be unhelpful under certain circumstances. We have therefore contacted researchers that ran trials of CBT in people with schizophrenia, and established collaborative links with them in order to access their data. The researchers that joined this collaboration prior to the start of the project currently have data for 4425 patients in 32 separate trials, and we will gather even more data throughout the duration of the study. We will then pool these data together and analyse them to find out whether CBT has particularly helpful effects in particular groups of people, and whether certain features of the therapy received by patients can explain why certain people benefit more from CBT while others do not. The results of this project will allow us to make recommendations so that NHS clinicians could offer specific options for treatment to people that are most likely to benefit from specific therapies, improve the training of therapists so that CBT will be delivered more effectively, and also help patients make a more informed choice about the treatment they are offered. Ultimately, this could help decrease the personal and financial burden of schizophrenia by improving chances of recovery and reducing NHS costs.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH