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An automated virtual reality cognitive therapy (gameChange) has demonstrated its effectiveness to treat agoraphobia in patients with psychosis, especially for high or severe anxious avoidance. Its economic value to the health care system is not yet established. In this study, we aimed to estimate the potential economic value of gameChange for the UK National Health Service (NHS) and establish the maximum cost-effective price per patient. Using data from a randomized controlled trial with 346 patients with psychosis (ISRCTN17308399), we estimated differences in health-related quality of life, health and social care costs, and wider societal costs for patients receiving virtual reality therapy in addition to treatment as usual compared with treatment as usual alone. The maximum cost-effective prices of gameChange were calculated based on UK cost-effectiveness thresholds. The sensitivity of the results to analytical assumptions was tested. Patients allocated to gameChange reported higher quality-adjusted life years (0.008 QALYs, 95% CI -0.010 to 0.026) and lower NHS and social care costs (-£105, 95% CI -£1135 to £924) compared with treatment as usual (£1=US $1.28); however, these differences were not statistically significant. gameChange was estimated to be worth up to £341 per patient from an NHS and social care (NHS and personal social services) perspective or £1967 per patient from a wider societal perspective. In patients with high or severe anxious avoidance, maximum cost-effective prices rose to £877 and £3073 per patient from an NHS and personal social services perspective and societal perspective, respectively. gameChange is a promising, cost-effective intervention for the UK NHS and is particularly valuable for patients with high or severe anxious avoidance. This presents an opportunity to expand cost-effective psychological treatment coverage for a population with significant health needs. ISRCTN Registry ISRCTN17308399; https://www.isrctn.com/ISRCTN17308399. RR2-10.1136/bmjopen-2019-031606.

IntroductionPersecutory delusions are very common in severe mental health disorders such as schizophrenia. Existing treatments often do not work well enough. We developed a face-to-face theory-driven psychological intervention, called Feeling Safe, that produces very large reductions in persistent persecutory delusions. The challenge now is to make Feeling Safe widely available. So, we developed a 6-month supported online version, called Feeling Safer. The aim is an intervention that patients can easily access and use, reduces persecutory delusions and can be supported by a range of mental health professionals in less contact time than face-to-face therapy. Initial proof of concept testing of Feeling Safer was very encouraging. In a randomised controlled trial, we now plan to test whether Feeling Safer is efficacious for patients and can be successfully delivered by any of three different mental health staff groups (peer-support workers, graduate psychologists and cognitive behavioural therapy (CBT) therapists). We will also test whether Feeling Safer works equally across gender, age, ethnicity and cognitive functioning (moderation) and whether Feeling Safer works via the targeted psychological processes (mediation).Methods and analysisThe study design is a multicentre, single-blind (outcome assessor), parallel, four-arm randomised controlled trial; 484 patients with persistent persecutory delusions will be randomised to one of the four conditions (1:1:1:1): Feeling Safer (added to treatment as usual (TAU)) supported by peer-support workers, or Feeling Safer (added to TAU) supported by graduate mental health workers including assistant psychologists, or Feeling Safer (added to TAU) supported by CBT therapists or TAU. Feeling Safer will be provided for 6 months with a staff member. Assessments will be conducted at 0, 3, 6 and 9 months by research assistants blind to group allocation. The primary outcome is severity of persecutory delusions at 6 months rated with the Psychotic Symptoms Rating Scale—Delusions. The secondary outcomes are other psychiatric symptoms (depression, anxiety, insomnia, agoraphobia and paranoia), psychological well-being, recovery, activity and health-related quality of life. Analysis will be conducted under a treatment policy strategy following the intention-to-treat principle, incorporating data from all participants including those who do not complete treatment. Moderation and mediation will be tested. A within-trial cost-effectiveness analysis will be conducted of Feeling Safer compared with TAU.Ethics and disseminationThe trial has received ethical approval from the NHS Health Research Authority (23/LO/0951). Informed consent will be obtained from all participants. A key output will be an open-access publication in a peer-reviewed journal reporting on the clinical effectiveness of a high-quality supported online programme for the treatment of persecutory delusions that has the potential to be used at scale in mental health services.Trial registration numberISRCTN93974770.

Background Adverse events (AEs) are commonly reported in clinical studies using the Medical Dictionary for Regulatory Activities (MedDRA), an international standard for drug safety monitoring. However, the technical language of MedDRA makes it challenging for patients and clinicians to share understanding and therefore to make shared decisions about medical interventions. In this project, people with lived experience of depression and antidepressant treatment worked with clinicians and researchers to co-design an online dictionary of AEs associated with antidepressants, taking into account its ease of use and applicability to real-world settings. Methods Through a pre-defined literature search, we identified MedDRA-coded AEs from randomised controlled trials of antidepressants used in the treatment of depression. In collaboration with the McPin Foundation, four co-design workshops with a lived experience advisory panel (LEAP) and one independent focus group (FG) were conducted to produce user-friendly translations of AE terms. Guiding principles for translation were co-designed with McPin/LEAP members and defined before the finalisation of Clinical Codes (CCs, or non-technical terms to represent specific AE concepts). FG results were thematically analysed using the Framework Method. Results Starting from 522 trials identified by the search, 736 MedDRA-coded AE terms were translated into 187 CCs, which balanced key factors identified as important to the LEAP and FG (namely, breadth, specificity, generalisability, patient-understandability and acceptability). Work with the LEAP showed that a user-friendly language of AEs should aim to mitigate stigma, acknowledge the multiple levels of comprehension in ‘lay’ language and balance the need for semantic accuracy with user-friendliness. Guided by these principles, an online dictionary of AEs was co-designed and made freely available ( https://thesymptomglossary.com ). The digital tool was perceived by the LEAP and FG as a resource which could feasibly improve antidepressant treatment by facilitating the accurate, meaningful expression of preferences about potential harms through a shared decision-making process. Conclusions This dictionary was developed in English around AEs from antidepressants in depression but it can be adapted to different languages and cultural contexts, and can also become a model for other interventions and disorders (i.e., antipsychotics in schizophrenia). Co-designed digital resources may improve the patient experience by helping to deliver personalised information on potential benefits and harms in an evidence-based, preference-sensitive way.

IntroductionMany people with psychosis find the world very frightening. It can be difficult for them to do everyday things—for example, walking down a busy street, travelling on a bus or going to the shops. Sometimes, the fears are so great that individuals rarely leave their homes. gameChange virtual reality therapy is designed to reduce this agoraphobic avoidance. In gameChange, users practise going into computerised immersive versions of ordinary situations. A virtual therapist guides users through the programme. A mental health worker also supports people. People normally do six sessions of gameChange, but now they can do more as headsets can be left with many people. We originally tested gameChange with 346 patients with psychosis. People saw a significant reduction in their fears. People with the most severe problems made the biggest improvements. This led to gameChange receiving National Institute for Health and Care Excellence (NICE) Early Value Assessment (EVA) approval for its use with patients with psychosis who have severe agoraphobic avoidance. NICE EVA approval is conditional on further evidence generation. We aim to carry out a real-world trial of gameChange used in the NHS. The overall aim is to gather evidence on the four essential areas (clinical benefits on agoraphobia, level of engagement and adherence, healthcare resource use, adverse effects) and the two further supporting areas (health-related quality of life, generalisability) identified in the NICE evidence generation plan for gameChange.Methods and analysis200 patients with psychosis and severe agoraphobic avoidance will be randomised (1:1) to receive gameChange in addition to treatment as usual (TAU) or to a waitlist control group receiving TAU. Assessments will be conducted blind to group allocation at baseline, 8 weeks (end of treatment) and 26 weeks (follow-up). The trial will be embedded in services in at least seven National Health Service (NHS) trusts across England. The primary outcome is agoraphobic avoidance at 26 weeks assessed with the Oxford Agoraphobic Avoidance Scale. The secondary clinical outcomes are agoraphobic distress, paranoia and social contacts. There will be tests of moderation of the main clinical outcome. Treatment acceptability, adverse effects and cost-effectiveness will also be assessed. The target estimand is the treatment policy estimand and all primary and secondary analyses will be carried out incorporating data from all participants including those who do not complete treatment.Ethics and disseminationThe trial has received ethical approval from the NHS Health Research Authority and Health and Care Research Wales (25/WA/0081). A key output will be the evidence needed for a NICE guidance update on gameChange and a clear recommendation concerning future routine use in the NHS.Trial registration numberISRCTN79060696.

Introduction Bipolar disorder is a recurrent mental health disorder with a prevalence rate of 1.4%. On average, there can be a delay of 9.5 years from the initial presentation of symptoms to a confirmed diagnosis. Individuals living with bipolar disorder have a reduced life expectancy. There is limited evidence regarding the effectiveness of antidepressants in treating bipolar disorder. The ASCEnD clinical trial will test the clinical and cost‐effectiveness of the aripiprazole/sertraline combination in comparison with quetiapine for the treatment of bipolar depression (individuals who suffer from depressive episodes in bipolar disorder) and will include a nested qualitative study. Methods The qualitative study will use semi‐structured interviews to explore pilot trial participants' and clinicians' perspectives on recruitment procedures, the acceptability of the intervention, the management of bipolar disorder and attitudes to medication combinations. Conclusion Findings will inform recruitment strategies and optimise training for the participating sites in the ASCEnD full trial. They will also help to illuminate the lived experience of people with bipolar disorder and the clinicians who work with people with bipolar disorder. The discussion will explore perspectives on the delay in diagnosis, having a diagnosis, the impact of living with bipolar disorder and attitudes to treatment, including drug combinations. Patient or Public Contribution A Lived Experience Advisory Panel (LEAP) has been convened with the support of the McPin Foundation, which will contribute to the ASCEnD trial and its nested qualitative study to provide input on the design and delivery of the trial and qualitative study, analysis of qualitative data and dissemination of findings.

Background The field of digital mental health has followed an exponential growth trajectory in recent years. While the evidence base has increased significantly, its adoption within health and care services has been slowed by several challenges, including a lack of knowledge from researchers regarding how to navigate the pathway for mandatory regulatory approval. This paper details the steps that a team must take to achieve the required approvals to carry out a research study using a novel digital mental health intervention. We used a randomised controlled trial of a digital mental health intervention called STOP (Successful Treatment of Paranoia) as a worked example. Methods The methods section explains the two main objectives that are required to achieve regulatory approval (MHRA Notification of No Objection) and the detailed steps involved within each, as carried out for the STOP trial. First, the existing safety of digital mental health interventions must be demonstrated. This can refer to literature reviews, any feasibility/pilot safety data, and requires a risk management plan. Second, a detailed plan to further evaluate the safety of the digital mental health intervention is needed. As part of this we describe the STOP study’s development of a framework for categorising adverse events and based on this framework, a tool to collect adverse event data. Results We present literature review results, safety-related feasibility study findings and the full risk management plan for STOP, which addressed 26 possible hazards, and included the 6-point scales developed to quantify the probability and severity of typical risks involved when a psychiatric population receives a digital intervention without the direct support of a therapist. We also present an Adverse Event Category Framework for Digital Therapeutic Devices and the Adverse Events Checklist—which assesses 15 different categories of adverse events—that was constructed from this and used in the STOP trial. Conclusions The example shared in this paper serves as a guide for academics and professionals working in the field of digital mental health. It provides insights into the safety assessment requirements of regulatory bodies when a clinical investigation of a digital mental health intervention is proposed. Methods, scales and tools that could easily be adapted for use in other similar research are presented, with the expectation that these will assist other researchers in the field seeking regulatory approval for digital mental health products.

Background Paranoia, the belief that you are at risk of significant physical or emotional harm from others, is a common difficulty, which causes significant distress and impairment to daily functioning, including in psychosis-spectrum disorders. According to cognitive models of psychosis, paranoia may be partly maintained by cognitive processes, including interpretation biases. Cognitive bias modification for paranoia (CBM-pa) is an intervention targeting the bias towards interpreting ambiguous social scenarios in a way that is personally threatening. This study aims to test the efficacy and safety of a mobile app version of CBM-pa, called STOP (successful treatment of paranoia). Methods The STOP study is a double-blind, superiority, three-arm randomised controlled trial (RCT). People are eligible for the trial if they experience persistent, distressing paranoia, as assessed by the Positive and Negative Syndrome Scales, and show evidence of an interpretation bias towards threat on standardised assessments. Participants are randomised to either STOP (two groups: 6- or 12-session dose) or text-reading control (12 sessions). Treatment as usual will continue for all participants. Sessions are completed weekly and last around 40 min. STOP is completely self-administered with no therapist assistance. STOP involves reading ambiguous social scenarios, all of which could be interpreted in a paranoid way. In each scenario, participants are prompted to consider more helpful alternatives by completing a word and answering a question. Participants are assessed at baseline, after each session, and at 6, 12, 18 and 24 weeks post-randomisation. The primary outcome is the self-reported severity of paranoid symptoms at 24 weeks, measured using the Paranoia Scale. The target sample size is 273 which is powered to detect a 15% symptom reduction on the primary outcome. The secondary outcomes are standardized measures of depression, anxiety and recovery and measures of interpretation bias. Safety is a primary outcome and measured by the Negative Effects Questionnaire and a checklist of adverse events completed fortnightly with researchers. The trial is conducted with the help of a Lived Experience Advisory Panel. Discussion This study will assess STOP’s efficacy and safety. STOP has the potential to be an accessible intervention to complement other treatments for any conditions that involve significant paranoia. Trial registration ISRCTN registry, ISRCTN17754650. Registered on 03/08/2021.  https://doi.org/10.1186/ISRCTN17754650 .

IntroductionThe confidence of young people diagnosed with psychosis is often low. Positive self-beliefs may be few and negative self-beliefs many. A sense of defeat and failure is common. Young people often withdraw from many aspects of everyday life. Psychological well-being is lowered. Psychological techniques can improve self-confidence, but a shortage of therapists means that very few patients ever receive such help. Virtual reality (VR) offers a potential route out of this impasse. By including a virtual coach, treatment can be automated. As such, delivery of effective therapy is no longer reliant on the availability of therapists. With young people with lived experience, we have developed a staff-assisted automated VR therapy to improve positive self-beliefs (Phoenix). The treatment is based on established cognitive behavioural therapy and positive psychology techniques. A case series indicates that this approach may lead to large improvements in positive self-beliefs and psychological well-being. We now aim to conduct the first randomised controlled evaluation of Phoenix VR.Methods and analysis80 patients with psychosis, aged between 16 and 30 years old and with low levels of positive self-beliefs, will be recruited from National Health Service (NHS) secondary care services. They will be randomised (1:1) to the Phoenix VR self-confidence therapy added to treatment as usual or treatment as usual. Assessments will be conducted at 0, 6 (post-treatment) and 12 weeks by a researcher blind to allocation. The primary outcome is positive self-beliefs at 6 weeks rated with the Oxford Positive Self Scale. The secondary outcomes are psychiatric symptoms, activity levels and quality of life. All main analyses will be intention to treat.Ethics and disseminationThe trial has received ethical approval from the NHS Health Research Authority (22/LO/0273). A key output will be a high-quality VR treatment for patients to improve self-confidence and psychological well-being.Trial registration numberISRCTN10250113.

BackgroundPatients diagnosed with psychosis often spend less time than others engaged in exercise and more time sitting down, which likely contributes to poorer physical and mental health.ObjectiveThe aim of this study was to develop a comprehensive framework from the perspective of patients, carers, and staff for understanding what promotes movement and physical activity.MethodsA critical realist approach was taken to design the study. Interviews (n=23) and focus groups (n=12) were conducted with (1) outpatients aged 16 years or older diagnosed with psychosis, and under the care of a mental health team, (2) carers and (3) mental health staff working in the community. Purposive sampling was used to maximise variation in participant characteristics. Data were analysed using reflexive thematic analysis.Findings19 patients (9 women and 10 men, mean age=45·0 (SD=12·2) years, 15 White British, 2 Black African, 1 Pakistani and 1 other ethnic group), 14 carers (11 women and 3 men, mean age=59·9 (SD=12·7) years, 13 White British and 1 Asian) and 18 staff (14 women and 4 men, mean age=38·7 (SD=12·3) years, 15 White British, 1 White other, 1 Asian Bangladeshi and 1 other Asian) participated in the study. Five factors were found to promote movement and physical activity. Patients must be able to find a purpose to moving which is meaningful to them (Factor 1: Purpose). Patients need to have an expectation of the positive consequences of movement and physical activity, which can be influenced by others’ expectations (Factor 2: Predictions). A patient’s current physical (eg, pain) and emotional state (eg, distress about voices) needs to be addressed to allow movement and physical activity (Factor 3: Present state). Movement and physical activity can also be encouraged by the availability of effective and tailored support, provided by engaged and supported people (Factor 4: Provision). Finally, through the identification and interruption of vicious cycles (eg, between inactivity and mood states) more positive cycles can be put in place (Factor 5: Process).Conclusions and clinical implicationsThe 5 P (Purpose, Predictions, Present state, Provision and Process Physical Activity Framework) for understanding movement and physical activity for people diagnosed with psychosis has the potential to inform future research and guide interventions. A checklist is provided for clinicians to help foster change in activity levels.

Background Evidence is conflicting about a causal role of inflammation in psychosis and, specifically, regarding antibodies binding to neuronal membrane targets, especially N-methyl-D-aspartate receptors. NMDAR, LGI1 and GABA-A antibodies were found more prevalent in people with psychosis than in healthy controls. We aim to test whether these antibodies are pathogenic and may cause isolated psychosis. The SINAPPS2 phase IIa double-blinded randomised controlled trial will test the efficacy and safety of immunoglobulin and rituximab treatment versus placebo for patients with acute psychosis symptoms as added to psychiatric standard of care. Methods We will screen approximately 2500 adult patients with acute psychosis to identify 160 with antibody-positive psychosis without co-existing neurological disease and recruit about 80 eligible participants to the trial in the period from September 2017 to September 2021 across the UK. Eligible patients will be randomised 1:1 either to intravenous immunoglobulin (IVIG) followed by rituximab or to placebo infusions of 1% albumin followed by 0.9% sodium chloride, respectively. To detect a time-to-symptomatic-recovery hazard ratio of 0.322 with a power of 80%, 56 participants are needed to complete the trial, allowing for up to 12 participants to drop out of each group. Eligible patients will be randomised and assessed at baseline within 4 weeks of their eligibility confirmation. The treatment will start with IVIG or 1% albumin placebo infusions over 2–4 consecutive days no later than 7 days from baseline. It will continue 4–5 weeks later with a rituximab or sodium chloride placebo infusion and will end 2–3 weeks after this with another rituximab or placebo infusion. The primary outcome is the time to symptomatic recovery defined as symptomatic remission sustained for at least 6 months on the following Positive and Negative Syndrome Scale items: P1, P2, P3, N1, N4, N6, G5 and G9. Participants will be followed for 12 months from the first day of treatment or, where sustained remission begins after the first 6 months, for an additional minimum of 6 months to assess later response. Discussion The SINAPPS2 trial aims to test whether immunotherapy is efficacious and safe in psychosis associated with anti-neuronal membrane antibodies. Trial registration ISRCTN, 11177045. Registered on 2 May 2017. EudraCT, 2016-000118-31. Registered on 22 November 2016. ClinicalTrials.gov, NCT03194815. Registered on 21 June 2017.