Title: Research into Antipsychotic Discontinuation And Reduction (RADAR)
Funder: Department of Health and Social Care

Abstract: The problem: Despite modern drug treatment, schizophrenia continues to be a debilitating and costly condition. Many people remain functionally impaired, and suffer substantial physical and mental side-effects from antipsychotic medication. Subsequently, people with schizophrenia are often unhappy with long-term antipsychotic use and tend to have poor adherence. Yet, there is little evidence to inform patients and clinicians in their difficult decision as to whether to continue with long-term antipsychotic medication or try and discontinue. Moreover, there are no guidelines for how to reduce and discontinue antipsychotics, if this is what patients want to do. The inadequacy of research on long-term treatment options for people with schizophrenia has been highlighted by the National Institute for Health and Care Excellence (NICE). Background: Continuous antipsychotic medication is the standard treatment for people with recurrent schizophrenia, but the evidence base has limitations. Notably trials have been mostly short-term, involved abrupt discontinuation of medication, and focused on relapse rather than social functioning as the main outcome. A recent seven year follow-up of a gradual antipsychotic discontinuation programme in people with first episode psychosis conducted in the Netherlands found that those in the discontinuation group had substantially better rates of social recovery, whilst relapses equalled out over time. Meta-analyses suggest antipsychotic discontinuation has similar effects in those with longer term conditions. Aims and Objectives: The overall aim of the research programme is to provide evidence on the outcomes of a supported antipsychotic reduction and discontinuation programme. The specific objectives are: 1) to develop a protocol for a gradual and supported strategy of antipsychotic reduction and discontinuation 2) to design a trial to evaluate this strategy in people with recurrent schizophrenia or related conditions 3) to assess and pilot recruitment techniques for the planned trial in order to maximise and facilitate recruitment 4) to compare the supported strategy of antipsychotic reduction and discontinuation with maintenance antipsychotic treatment in an internal pilot trial 5) to conduct a full, randomised, multi-centre, pragmatic trial with social functioning as the primary outcome and relapse, symptoms, side effects and costs among further outcomes. Research Methods The research programme starts with development and feasibility work which will inform the design and conduct of the trial (WP 1). A methodology group will develop the intervention protocols in an iterative process. The interventions will consist of a flexible and gradual antipsychotic reduction and discontinuation strategy (ADRS), leading to discontinuation where feasible, and maintenance treatment (MT). Monitoring arrangements will be specified to facilitate early intervention if symptoms increase during the course of the trial, and measures for maintaining and assessing adherence to the intervention protocols will be designed. The methodology group will develop aspects of trial design, including new and valid criteria for relapse, since there is no widely-accepted, rigorous definition at present. The group will also formulate precise inclusion and exclusion criteria, considering duration of illness and treatment, risks, ongoing symptoms and substance misuse. A recruitment survey will be conducted to inform the recruitment strategy for the trial. An internal pilot will assess recruitment rates, intervention adherence, assessments and retention up to six months (WP 2). A full randomised controlled trial (RCT) will compare the antipsychotic reduction and discontinuation strategy (ADRS) with maintenance treatment (MT) (WP 3). Both the antipsychotic reduction and discontinuation strategy (ADRS) and maintenance treatment (MT) will be supervised by the participant s usual psychiatrist, with training and support from the research team. The trial will recruit a minimum of 402 participants and follow-up assessments will be conducted at six months, one year and two years. The trial is powered to detect a two point difference in the primary outcome of social functioning as measured by the Groningen Social Disability Scale (GSDS). It will also have 90% power to detect non-inferiority of the Antipsychotic Reduction and Discontinuation Strategy in rates of severe relapse (such as relapse requiring hospitalisation) to within a margin of 10%. Other outcomes include symptoms, quality of life, adverse effects of antipsychotics, adherence and cost effectiveness. A qualitative sub-study using semi-structured interviews will be conducted following the two year follow-up with consenting participants who enrol early. It will assess trial implementation and explore experiences of reducing and discontinuing antipsychotic medication using the trial protocol. Research results and outputs will be disseminated through academic channels, a study website, electronic networking, links with service user and advocacy organisations and a dissemination conference. There will be Patient and Public Involvement (PPI) input at each stage of the programme implemented through a PPI group. Output and impact The research has the potential to fundamentally change clinical practice. It will provide evidence of the effectiveness and safety of an antipsychotic discontinuation strategy which can be implemented in routine practice to support patient choice. If the intervention is successful, it will improve functioning and reduce the considerable burden of adverse effects associated with antipsychotic medication.

Lay abstract: Schizophrenia is a common and costly mental health problem. People with schizophrenia experience distorted thinking, emotions and behaviour as well as social problems. The widely-established treatment is long-term antipsychotic medication, but many people still have difficulties. Antipsychotics can also have dangerous and unpleasant side effects which can put patients off using them. Finding alternatives to long-term drug treatment is a priority for both patients and services. The proposed research aims to test the effects of reducing and discontinuing antipsychotic medication in people with long-term schizophrenia and similar conditions. We want to know whether this approach can help people to function better in their daily lives and improve their social problems. Previous evidence suggests this might be the case. We also want to know how it affects the chances of relapsing. This study will be the first with this group of patients that uses a gradual method of medication reduction, and that follows patients up long-term. The study will start by seeing what the best methods for reducing and discontinuing antipsychotics are. We will talk with experts, service users and carers with relevant experience. We will design a trial to test the effects of the Antipsychotic Reduction and Discontinuation strategy we develop. We will develop new criteria for judging relapse, since there is no widely-accepted and convincing definition at present. In the trial itself, patients who give consent to participate in the research will be assigned at random to one of two treatments. They will either continue on antipsychotic medication at their original dose, or reduce and discontinue antipsychotics in line with the developed Antipsychotic Reduction and Discontinuation strategy. Both types of treatment will be administered by the patients usual psychiatrists. Patients in the Antipsychotic Reduction and Discontinuation strategy group will have their antipsychotic medication gradually reduced, and discontinued if possible, and will receive support to review their progress and monitor symptoms. We aim to enrol a total of more than 400 patients and they will be followed up for two years. At follow-up we will compare patients in the two treatment groups to see how well they are able to manage their daily lives and responsibilities. We will assess rates of relapse in the two groups, and we will compare levels of symptoms, quality of life, side effects and costs. We will interview some of the patients in more detail to explore how they found the antipsychotic reduction programme. We will also see how well the treatments were put into practice. The research programme will provide new evidence on the effects of a gradual programme of antipsychotic reduction and discontinuation, which will support patients and clinicians to make better informed choices about long-term medication.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH