Title: ATLANTIS: AnTiconvuLsant AugmeNtation Trial In Schizophrenia
Funder: Department of Health and Social Care

Abstract: Schizophrenia is a severe mental illness that affects 1 in 100 people. It is one of the top causes of adult disease burden globally, and the top reason for NHS bed occupancy. Healthcare and other costs for schizophrenia amount to ~100 billion Euros/ year across Europe. The main treatment is with antipsychotic drugs. However, for many patients, these drugs are ineffective at improving their symptoms, which is called treatment resistance. This is a major cause of the extra NHS admissions and healthcare costs. We estimate this affects 1 in 3 patients with schizophrenia._x000D_ _x000D_ Patients and carers identify the need for treatment options for patients where antipsychotics are ineffective as a priority._x000D_ _x000D_ To address this, we aim to investigate a potential new treatment for these patients. This is a drug called valproate, which is taken in addition to antipsychotic treatment. Valproate is not licensed for this purpose, but we conducted a survey across UK NHS trusts, and found that in nearly 20% of patients it is used in this way, costing ~£60 million per year to the NHS. There is some evidence to support this practice, but the evidence is inconclusive. Thus, whilst adding valproate to antipsychotic treatment is widely used, it is unknown if it helps reduce symptoms, improves quality of life or is cost-effective. Therefore, we aim to conduct a study that will answer these questions. _x000D_ _x000D_ People with schizophrenia whose illness has not responded sufficiently despite adequate antipsychotic medication will be randomized to either take a placebo or valproate in addition to their current antipsychotic medication. They and their clinicians will be blinded to the treatment they receive. We will follow them for 1 year to measure their symptoms. We will also measure healthcare costs and quality of life to calculate the overall cost-benefit of valproate treatment. We will conduct further follow-up using patient’s electronic healthcare records to determine long-term outcomes. The study will last for 4.5 years, with a pilot of 18 months duration to assess recruitment rate, tolerability and safety. _x000D_ _x000D_ We have established a patient and carer advisory group that has provided us with valuable guidance on the study design including an assessment of its burden on participants. As the study progresses service user groups at each site will provide ongoing advice including reviewing information sheets and help publicize findings through patient newsletters. We will also present our findings at scientific meetings and in scientific journals._x000D_ _x000D_ If the study determines valproate is beneficial when given to patients with schizophrenia who are not responding well to first-line antipsychotic treatment, it will provide the first evidence-based NHS treatment choice for a large group of people where clozapine is not an option. This has the potential to improve outcomes and save the NHS money. Just as importantly, if we show valproate is not significantly better than placebo, then it would inform a major change in current practice, to stop using valproate, thus reducing exposure to harm and generating savings to the NHS.

Lay abstract: Schizophrenia affects around 1 in 100 people. It has costs of ~100 billion Euros per year across Europe and is the top reason for NHS bed occupancy in the UK. Non-response to first-line antipsychotic (AP) treatment is a major contributor to the illness burden and healthcare costs are estimated to be 3–11 fold higher in patients with treatment resistance than schizophrenia in general._x000D_ _x000D_ Our patient and carer consultation identified the lack of treatment options for patients with non-response to first-line APs as a major unmet need. _x000D_ _x000D_ In practice, clinicians commonly augment AP treatment with an anticonvulsant drug. In a UK wide audit, we found valproate was the most commonly prescribed adjunct to AP treatment, at a cost to the NHS of ~£60 million/year. There have been 26 clinical trials of augmenting an AP with valproate. Meta-analyses, including a recent Cochrane review, show this is potentially effective with a moderate to large effect size. However, the Cochrane review identifies several major limitations: most of the trials are low quality, conducted in very different healthcare settings to the UK, and none has measured quality of life or outcomes beyond 3 months. Thus, there is a need for a high-quality long-term UK study to determine the efficacy and cost-effectiveness of valproate augmentation of first-line AP treatment. _x000D_ _x000D_ To address this, we will conduct a pragmatic 12-month, parallel group, placebo-controlled double-blind randomized controlled trial of augmenting existing AP treatment with valproate in patients (men and women, aged 18–65) who fulfill DSM-V criteria for schizophrenia and have persistent psychotic symptoms despite adequate (non-clozapine) AP treatment. The primary outcome will be psychotic symptom severity after 12 months, measured using the PANSS positive subscale. Our secondary outcome measures will be discontinuation rates, change in clinical global impression scale (CGI), cost-effectiveness and quality of life measures. Cost-effectiveness will be assessed using the PANSS positive subscale, quality-adjusted life years (QALYS) and Client Service Receipt Inventory (CSRI), which covers services and support. There will be an open-label extension beyond 12 months to determine longer-term outcomes and costs using electronic healthcare records. _x000D_ _x000D_ _x000D_ If the study determines that valproate is beneficial and cost-effective, there will be the potential to improve outcomes and reduce healthcare costs for many patients with resistant schizophrenia. Just as importantly, if we show that valproate is not better than placebo, then it will be possible to avoid ineffective treatment with valproate which could save the NHS ~£60 million/year

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH