Cost-Effectiveness of Positive Memory Training (PoMeT) for the Treatment of Depression in Schizophrenia.

The Positive Memory Training (PoMeT) trial demonstrated reduced depression symptoms at 3 months for schizophrenia, but its longer-term outcome and cost impacts remain unknown. This study is a within-trial cost-utility analysis with quality-adjusted life years (QALYs) as outcome based on health-related quality of life (HRQoL) measurement and secondary outcome analyses of capability well-being. The incremental cost-effectiveness of PoMeT was compared to Treatment As Usual only (TAU) over 9 months from the 'health and social' care and 'societal' perspectives. Uncertainty was explored using bootstrapping and sensitivity analyses for cost outliers and outcome methods. HRQoL improvement was observed for both PoMeT and TAU at 3 months, but reached statistical significance and was sustained only for TAU. There was no change in capability well-being and no significant group difference in QALYs gained over 9 months. Mean intervention cost was GBP 823. Compared to TAU, PoMeT had significantly higher mental health care costs (+GBP 1251, 95% CI GBP 185 to GBP 2316) during the trial, but 'health and social care' and 'societal' cost differences were non-significant. Compared to the before-trial period, psychiatric medication costs increased significantly in both groups. The probability of PoMeT being cost-effective in the given format over 9 months was <30% and decreased further in sensitivity analyses.. Generalizability remains limited since the before-after cost analysis revealed additional treatment effects also in the TAU group that likely diminished the incremental impacts and cost-effectiveness of PoMeT. It is not clear whether an active post-intervention follow-up could result in sustained longer-term effects and improved cost-effectiveness.

The state of mental health care in China.

Over the past few years there have been considerable changes in China's mental health service system. This review provides an overview of the development of mental health services in China, including epidemiological data on psychiatric disorders, utilisation of mental health services, models of mental health service delivery, mental health resources and workforce, mental health policy framework and financial issues. We consider cultural and social factors including the involvement of family members in patient care, urbanisation and internal migration as well as the application of traditional Chinese medicine, which provides implications for mental health research and practice. Additionally, we also discuss major challenges and conclude by providing some specific recommendations on improving mental health services in China.

Comparison of a theoretically driven cognitive therapy (the Feeling Safe Programme) with befriending for the treatment of persistent persecutory delusions: a parallel, single-blind, randomised controlled trial.

BACKGROUND: There is a large clinical need for improved treatments for patients with persecutory delusions. We aimed to test whether a new theoretically driven cognitive therapy (the Feeling Safe Programme) would lead to large reductions in persecutory delusions, above non-specific effects of therapy. We also aimed to test treatment effect mechanisms. METHODS: We did a parallel, single-blind, randomised controlled trial to test the Feeling Safe Programme against befriending with the same therapists for patients with persistent persecutory delusions in the context of non-affective psychosis diagnoses. Usual care continued throughout the duration of the trial. The trial took place in community mental health services in three UK National Health Service trusts. Participants were included if they were 16 years or older, had persecutory delusions (as defined by Freeman and Garety) for at least 3 months and held with at least 60% conviction, and had a primary diagnosis of non-affective psychosis from the referring clinical team. Patients were randomly assigned to either the Feeling Safe Programme or the befriending programme, using a permuted blocks algorithm with randomly varying block size, stratified by therapist. Trial assessors were masked to group allocation. If an allocation was unmasked then the unmasked assessor was replaced with a new masked assessor. Outcomes were assessed at 0 months, 6 months (primary endpoint), and 12 months. The primary outcome was persecutory delusion conviction, assessed within the Psychotic Symptoms Rating Scale (PSYRATS; rated 0-100%). Outcome analyses were done in the intention-to-treat population. Each intervention was provided individually over 6 months. This trial is registered with the ISRCTN registry, ISRCTN18705064. FINDINGS: From Feb 8, 2016, to July 26, 2019, 130 patients with persecutory delusions (78 [60%] men; 52 [40%] women, mean age 42 years [SD 12·1, range 17-71]; 86% White, 9% Black, 2% Indian; 2·3% Pakistani; 2% other) were recruited. 64 patients were randomly allocated to the Feeling Safe Programme and 66 patients to befriending. Compared with befriending, the Feeling Safe Programme led to significant end of treatment reductions in delusional conviction (-10·69 [95% CI -19·75 to -1·63], p=0·021, Cohen's d=-0·86) and delusion severity (PSYRATS, -2·94 [-4·58 to -1·31], p<0·0001, Cohen's d=-1·20). More adverse events occurred in the befriending group (68 unrelated adverse events reported in 20 [30%] participants) compared with the Feeling Safe group (53 unrelated adverse events reported in 16 [25%] participants). INTERPRETATION: The Feeling Safe Programme led to a significant reduction in persistent persecutory delusions compared with befriending. To our knowledge, these are the largest treatment effects seen for patients with persistent delusions. The principal limitation of our trial was the relatively small sample size when comparing two active treatments, meaning less precision in effect size estimates and lower power to detect moderate treatment differences in secondary outcomes. Further research could be done to determine whether greater effects could be possible by reducing the hypothesised delusion maintenance mechanisms further. The Feeling Safe Programme could become the recommended psychological treatment in clinical services for persecutory delusions. FUNDING: NIHR Research Professorship and NIHR Oxford Health Biomedical Research Centre.

An evaluation of the mental health impact of SARS-CoV-2 on patients, general public and healthcare professionals: A systematic review and meta-analysis.

BACKGROUND: The global impact of COVID-19 pandemic continues to affect the lives of billions of people with recurrent waves. Healthcare systems are struggling to manage pre-existing patient care and recurring covid-19 demands. As a result, we evaluated the mental health impact using systematic review and meta-analysis. METHODS: A comprehensive search was undertaken from April 2020 to 22nd January 2021 using multiple electronic databases. A systematic review protocol was developed and published on PROSPERO registration; CRD42020181481. A random-effects model was used to compute pooled estimates of anxiety, depression, PTSD, insomnia and suicidal thoughts. FINDINGS: Our search yielded 11,295 studies and of those 287 met the inclusion criteria. The meta-analysis of 206 studies revealed minimal differences in prevalence of anxiety, depression, and PTSD among HCPs compared with the public during the pandemic but higher prevalence of suicidal thoughts/ideation or self-harm (11% vs 5.8%) and lower prevalence of wellbeing (28.2% vs 52.6%) among the public compared to HCPs. INTERPRETATION: The pandemic has led to a high mental health burden especially amongst HCPs and higher suicidal ideation and lower wellbeing in general public which warrants further investigation and management globally. These findings highlight an emerging critical public health issue that requires urgent solutions.

Cultural Adaptations in Clinical InteractiONs (CoACtION): a multi-site comparative study to assess what cultural adaptations are made by clinicians in different settings.

Culture influences models of mental illness, help-seeking behaviours and outcomes of interventions. Cultural competency training has been developed to improve clinician practice in addressing these issues. The study aims to identify to what extent culturally competent and informed interactions are used by clinicians in England and how patients experience these interaction. Clinicians and non-white western patients were recruited to complete a questionnaire on culturally adapted practice in 25 areas of England. Clinicians are much more likely to rate their practice as clinically competent whereas patients were more likely to disagree that services were completely culturally competent. Length of time working as clinicians, receipt of specific cultural competence training and a higher percentage of caseload from non-white western backgrounds all increased clinician's perception that their practice was culturally competent. Clinicians recognised the importance of cultural competency but the disparity between their assessment of whether they achieved this and that of patients must be addressed. Ethics approval was obtained via proportionate review from the London - Central Research Ethics Committee (REC Ref no: 17/LO/1962). Study registration: UK Clinical Research Network Portfolio: 36744.

The revised Green et al., Paranoid Thoughts Scale (R-GPTS): psychometric properties, severity ranges, and clinical cut-offs.

BACKGROUND: The Green et al., Paranoid Thoughts Scale (GPTS) - comprising two 16-item scales assessing ideas of reference (Part A) and ideas of persecution (Part B) - was developed over a decade ago. Our aim was to conduct the first large-scale psychometric evaluation. METHODS: In total, 10 551 individuals provided GPTS data. Four hundred and twenty-two patients with psychosis and 805 non-clinical individuals completed GPTS Parts A and B. An additional 1743 patients with psychosis and 7581 non-clinical individuals completed GPTS Part B. Factor analysis, item response theory, and receiver operating characteristic analyses were conducted. RESULTS: The original two-factor structure of the GPTS had an inadequate model fit: Part A did not form a unidimensional scale and multiple items were locally dependant. A Revised-GPTS (R-GPTS) was formed, comprising eight-item ideas of reference and 10-item ideas of persecution subscales, which had an excellent model fit. All items in the new Reference (a = 2.09-3.67) and Persecution (a = 2.37-4.38) scales were strongly discriminative of shifts in paranoia and had high reliability across the spectrum of severity (a > 0.90). The R-GPTS score ranges are: average (Reference: 0-9; Persecution: 0-4); elevated (Reference: 10-15; Persecution: 5-10); moderately severe (Reference: 16-20; Persecution:11-17); severe (Reference: 21-24; Persecution: 18-27); and very severe (Reference: 25+; Persecution: 28+). Recommended cut-offs on the persecution scale are 11 to discriminate clinical levels of persecutory ideation and 18 for a likely persecutory delusion. CONCLUSIONS: The psychometric evaluation indicated a need to improve the GPTS. The R-GPTS is a more precise measure, has excellent psychometric properties, and is recommended for future studies of paranoia.

Positive memory training for the treatment of depression in schizophrenia: A randomised controlled trial.

BACKGROUND: Around half of people diagnosed with schizophrenia suffer from co-morbid depression, yet there are no evidence-based psychological treatments to target this presentation. METHOD: Participants were aged 18-65 years old, had a clinical diagnosis of schizophrenia or schizoaffective disorder and at least a mild level of depression. Participants were randomly assigned (1:1) to receive PoMeT or treatment as usual. PoMeT was delivered in up to 12 individual sessions within 3 months. We stratified randomisation by site and by severity of depression using randomised-permuted blocks. Assessments were carried out at baseline, 3-month, 6-month and 9-month by assessors who were blind to treatment allocation. The primary outcome was reduction in the symptoms of depression at 3-month, 6-month and 9-month as measured by the BDI-II. Analysis was by intention-to-treat with linear mixed-effects models. The trial was registered with the ISRCTN registry number 99485756. RESULTS: One hundred participants were randomly assigned to either PoMeT (n = 49) or treatment as usual (n = 51). The reduction in BDI-II total score at 3 months was significantly greater for PoMeT than for treatment as usual (mean difference = 4.33, SE = 2.00, 95% CI 0.38 to 8.23; p = 0.03). DISCUSSION: To our knowledge this is, to date, the largest powered randomised controlled trial focused on the psychological treatment of depression in people diagnosed with schizophrenia. Results indicate that a brief targeted intervention can reduce the symptoms of depression in the group. The main limitation of the study is the lack of an active control group which may contribute to an inflated treatment effect.

D-cycloserine augmentation of cognitive behavioral therapy for delusions: A randomized clinical trial.

OBJECTIVE: D-cycloserine (DCS) promotes consolidation of extinction learning. This study extends earlier work by examining whether DCS can enhance cognitive behavioral therapy (CBT) for delusions. METHODS: Adults reporting moderate or greater delusions were randomly assigned to receive 50 mg of DCS or placebo prior to 10 weekly CBT sessions. The primary outcome was change in severity of delusions measured with the Psychotic Symptom Rating Scale delusion subscale (PSYRATS-D). Secondary outcomes included persistence of response at 3 and 6 month follow-up and the effects of DCS on memory consolidation and cognitive flexibility. Fifty-eight participants were randomized and 44 completed the trial. RESULTS: The DCS and placebo groups did not differ in change from baseline to end of CBT on PSYRATS-D, nor did DCS improve memory consolidation or cognitive flexibility compared to placebo. However, at the 3 month follow-up visit (week 24), 47% of participants who completed treatment with DCS reported a 20% or greater decrease on PSYRATS-D compared to 15% in the placebo group (p = .04). Change in distress across CBT sessions interacted with treatment group to predict change from baseline to week 24 in PSYRATS-D total score (p = .03) such that response at week 24 was greatest in DCS-treated participants who experienced a decrease in distress during CBT sessions. CONCLUSIONS: DCS augmentation of CBT did not improve delusions compared to placebo during treatment; however, DCS was associated with a higher response rate at 3-month follow-up. DCS may produce a delayed therapeutic effect, associated with successful CBT sessions, but this finding requires replication.

Results of a prospective, mixed methods study to assess feasibility, acceptability and effectiveness of TRIumPH (Treatment and Recovery In PsycHosis): an integrated care pathway for psychosis, compared to usual treatment.

OBJECTIVES: To evaluate whether a newly developed care pathway, Treatment and Recovery In PsycHosis (TRIumPH), is feasible, acceptable and effective in meeting National Institute of Health and Care Excellence (NICE) quality standards in a timely manner. METHODS: This is a pragmatic, non-randomised, prospective, mixed methods study comparing an implementation (TRIumPH) and comparator site (not implementing TRIumPH) across three cohorts to assess feasibility, acceptability and effectiveness of the integrated pathway. SETTING: Early intervention in psychosis (EIP) services at two National Health Service organisations in South of England. PARTICIPANTS: All patients accepted into EIP services between 1 June 2014 and 31 May 2017 were each followed up for 1 year within their respective cohorts. METHODOLOGY: Quantitative data consisted of routinely collected clinical data retrieved from patient records to assess whether the implementation of TRIumPH achieved better concordance to NICE standards. These included time to access services, physical health assessments, clinical outcomes based timeliness of delivery and acute data. The controlled trial has evaluated the effect of TRIumPH (Intervention) with Care As Usual (Comparator). Qualitative measures consisted of questionnaires, interviews and focus groups to assess acceptability and satisfaction. Outcome measures were compared within the baseline, year 1 and year 2 cohorts and between the two sites. Quantitative data were statistically analysed by comparing means and proportions. RESULTS: Time to assessment improved in the implementation site and remained within the target in comparator site. Meeting of quality standards increased substantially in the implementation site but was more variable and reached lower levels in the comparator site especially for physical health standards. Cognitive therapy for psychosis, family intervention and carer and employment support were all offered to a greater extent in the implementation site and uptake increased over the period. CONCLUSIONS: Pathway implementation generally led to greater improvements in achievement of access and quality standards compared with comparator site. TRIAL REGISTRATION NUMBER: UK Clinical Research Network Portfolio (19187).

Health and Social Care Diversity Among Individuals with Longstanding Physical and Psychological Health Problems: Pooled Repeated Cross Sectional Analyses.

This paper examines differences in health-and-social care utilisation for individuals with physical and/or mental health problems. Logistic regression models are used to determine disparity in the percentage of General Household/Lifestyle Survey participants with physical compared to mental health problems receiving disability benefits or health care services between 2000 and 2011. Our findings of a relative underutilisation of secondary health care combined with a relative overutilization of out-of-work benefits by individuals with mental health problems is novel to the field of rehabilitative health care. These results provide evidence for the previously suspected disparity in health care utilisation of individuals with mental health problems and indicate problems in labour force integration. The findings support the political call for a 'parity of esteem', which, in Britain, was enshrined in the Health and Social Care Act of 2012.

The Dunn Worry Questionnaire and the Paranoia Worries Questionnaire: new assessments of worry.

BACKGROUND: The cognitive process of worry, which keeps negative thoughts in mind and elaborates the content, contributes to the occurrence of many mental health disorders. Our principal aim was to develop a straightforward measure of general problematic worry suitable for research and clinical treatment. Our secondary aim was to develop a measure of problematic worry specifically concerning paranoid fears. METHODS: An item pool concerning worry in the past month was evaluated in 250 non-clinical individuals and 50 patients with psychosis in a worry treatment trial. Exploratory factor analysis and item response theory (IRT) informed the selection of scale items. IRT analyses were repeated with the scales administered to 273 non-clinical individuals, 79 patients with psychosis and 93 patients with social anxiety disorder. Other clinical measures were administered to assess concurrent validity. Test-retest reliability was assessed with 75 participants. Sensitivity to change was assessed with 43 patients with psychosis. RESULTS: A 10-item general worry scale (Dunn Worry Questionnaire; DWQ) and a five-item paranoia worry scale (Paranoia Worries Questionnaire; PWQ) were developed. All items were highly discriminative (DWQ a = 1.98-5.03; PWQ a = 4.10-10.7), indicating small increases in latent worry lead to a high probability of item endorsement. The DWQ was highly informative across a wide range of the worry distribution, whilst the PWQ had greatest precision at clinical levels of paranoia worry. The scales demonstrated excellent internal reliability, test-retest reliability, concurrent validity and sensitivity to change. CONCLUSIONS: The new measures of general problematic worry and worry about paranoid fears have excellent psychometric properties.

Refractory depression - mechanisms and efficacy of radically open dialectical behaviour therapy (RefraMED): findings of a randomised trial on benefits and harms.

BACKGROUND: Individuals with depression often do not respond to medication or psychotherapy. Radically open dialectical behaviour therapy (RO DBT) is a new treatment targeting overcontrolled personality, common in refractory depression. AIMS: To compare RO DBT plus treatment as usual (TAU) for refractory depression with TAU alone (trial registration: ISRCTN 85784627). METHOD: RO DBT comprised 29 therapy sessions and 27 skills classes over 6 months. Our completed randomised trial evaluated RO DBT for refractory depression over 18 months in three British secondary care centres. Of 250 adult participants, we randomised 162 (65%) to RO DBT. The primary outcome was the Hamilton Rating Scale for Depression (HRSD), assessed masked and analysed by treatment allocated. RESULTS: After 7 months, immediately following therapy, RO DBT had significantly reduced depressive symptoms by 5.40 points on the HRSD relative to TAU (95% CI 0.94-9.85). After 12 months (primary end-point), the difference of 2.15 points on the HRSD in favour of RO DBT was not significant (95% CI -2.28 to 6.59); nor was that of 1.69 points on the HRSD at 18 months (95% CI -2.84 to 6.22). Throughout RO DBT participants reported significantly better psychological flexibility and emotional coping than controls. However, they reported eight possible serious adverse reactions compared with none in the control group. CONCLUSIONS: The RO DBT group reported significantly lower HRSD scores than the control group after 7 months, but not thereafter. The imbalance in serious adverse reactions was probably because of the controls' limited opportunities to report these.

Refractory depression - cost-effectiveness of radically open dialectical behaviour therapy: findings of economic evaluation of RefraMED trial.

BACKGROUND: Refractory depression is a major contributor to the economic burden of depression. Radically open dialectical behaviour therapy (RO DBT) is an unevaluated new treatment targeting overcontrolled personality, common in refractory depression, but it is not yet known whether the additional expense of RO DBT is good value for money.AimsTo estimate the cost-effectiveness of RO DBT plus treatment as usual (TAU) compared with TAU alone in people with refractory depression (trial registration: ISRCTN85784627). METHOD: We undertook a cost-effectiveness analysis alongside a randomised trial evaluating RO DBT plus TAU versus TAU alone for refractory depression in three UK secondary care centres. Our economic evaluation, 12 months after randomisation, adopted the perspective of the UK National Health Service (NHS) and personal social services. It evaluated cost-effectiveness by comparing the net cost of RO DBT with the net gain in quality-adjusted life-years (QALYs), estimated using the EQ-5D-3L measure of health-related quality of life. RESULTS: The additional cost of RO DBT plus TAU compared with TAU alone was £7048 and was associated with a difference of 0.032 QALYs, yielding an incremental cost-effectiveness ratio (ICER) of £220 250 per QALY. This ICER was well above the National Institute for Health and Care Excellence (NICE) upper threshold of £30 000 per QALY. A cost-effectiveness acceptability curve indicated that RO DBT had a zero probability of being cost-effective compared with TAU at the NICE £30 000 threshold. CONCLUSIONS: In its current resource-intensive form, RO DBT is not a cost-effective use of resources in the UK NHS.Declaration of interestR.H. is co-owner and director of Radically Open Ltd, the RO DBT training and dissemination company. D.K. reports grants outside the submitted work from the National Institute for Health Research (NIHR). T.L. receives royalties from New Harbinger Publishing for sales of RO DBT treatment manuals, speaking fees from Radically Open Ltd, and a grant outside the submitted work from the Medical Research Council. He was co-director of Radically Open Ltd between November 2014 and May 2015 and is married to Erica Smith-Lynch, the principal shareholder and one of two directors of Radically Open Ltd. H.O'M. reports personal fees outside the submitted work from the Charlie Waller Institute and Improving Access to Psychological Therapy. S.R. provides RO DBT supervision through her company S C Rushbrook Ltd. I.R. reports grants outside the submitted work from NIHR and Health & Care Research Wales. M. Stanton reports personal fees outside the submitted work from British Isles DBT Training, Stanton Psychological Services Ltd and Taylor & Francis. M. Swales reports personal fees outside the submitted work from British Isles DBT Training, Guilford Press, Oxford University Press and Taylor & Francis. B.W. was co-director of Radically Open Ltd between November 2014 and February 2015.

Outcome-based providing and commissioning: pathways and standards.

Aims and methodImplementation of evidence-based psychosocial interventions in accordance with National Institute of Health and Care Excellence guidelines and quality standards has been incomplete. This project involved allocation of adults under mental health services to six guideline categories, completion of a clinician- and patient-rated outcome measure, and individual assessment against clinical standards. RESULTS: In the first 3 months of the project, 5048 patients were allocated to a pathway and 3734 (73%) were assessed against at least one of the relevant standards. All were assessed using the Health of the Nation Outcome Scales (91-93% of scales completed) and 1866 (36%) completed the patient-rated outcome measure, DIALOG.Clinical implicationsClinicians will allocate patients to pathways, complete outcome measures and assess against standards, providing data to guide practice, service design and costing of mental health systems with supporting technology to assist data entry and presentation. This has the potential to provide much improved and readily accessible information about individual outcomes and standards for people with mental health problems and those working with them. It could also provide a method for payment for services which directly support good clinical practice.Declaration of interestNone.

Care programme approach - time to move beyond?

The Care Programme Approach (CPA) has been instrumental in embedding principles of holistic collaborative assessment and management into mental health care. Initially, its implementation was assisted by targeting those at greatest need. However dichotomising patients into more and less severe is now considered unhelpful and has been demonstrated to be unreliable. Division of patients into severe and not severe categories is no more logical than such a division of patients with physical health problems. CPA principles are now applied to all patients in mental health services and practice needs to move to individualised care, focusing on meeting quality standards and achieving positive outcomes. A system based on evidence-based clinical pathways and reliable measures of severity and need should replace the current approach.Declaration of interestNone.

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.

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 scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia. METHODS: We 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. FINDINGS: From 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. INTERPRETATION: At 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. FUNDING: National Institute for Health Research Technology Assessment programme.