Title: Aripiprazole/ sertraline combination: Clinical and cost-effectiveness in comparison with quetiapine for the treatment of bipolar depression. An open label randomised controlled trial. (ASCEnD)
Funder: Department of Health and Social Care

Abstract: Bipolar disorder (BP) is diagnosed on the basis of current or previous episodes of abnormal elevated mood (mania or hypomania). It is life-long. It affects more than 1 person in 100, negatively affects people’s lives and places a tremendous strain on caregivers, the NHS and society. It causes earlier than expected death, including by suicide. Depression is common in BP (“bipolar depression”) but it requires different treatment to depression in people who don’t have BP (“unipolar depression”)._x000D_ _x000D_ People with unipolar depression usually improve with a standard antidepressant or talking therapy but only specialist psychological treatments are recommended in BP. These aren’t widely available and haven’t convincingly been shown to treat bipolar depression. Similarly, in BP, antidepressant drugs, when taken by themselves, show no therapeutic value. In light of this, the National Institute of Clinical Excellence (NICE) largely recommends treatment with so called “antipsychotic” drugs, olanzapine (with or without the antidepressant fluoxetine) and quetiapine, and the anti-epilepsy drug lamotrigine. The antipsychotics are often poorly tolerated causing sedation, weight gain, sleep disturbance and diabetes. Lamotrigine is the least effective of the three options and requires the dose to be gradually increased over several weeks for safety reasons. Additional treatment options are needed._x000D_ _x000D_ All three current treatment options are only recommended to be started by psychiatrists. GPs are frustrated by the delays and barriers in obtaining a psychiatrist opinion and treatment. Reducing this delay would reduce the impact of BP on people’s lives and has been identified by the James Lind Alliance (JLA) as a priority for patients. The identification of a drug treatment that is effective and safe enough to be started by GPs fits with this objective. _x000D_ Aripiprazole is an antipsychotic drug that, at the right dose, has fewer side effects than olanzapine or quetiapine. In unipolar depression, it boosts the effectiveness of antidepressants when the two are taken together. A combination of aripiprazole with an antidepressant may be expected to be as effective in bipolar depression as olanzapine with fluoxetine but, importantly, with a reduced burden of side-effects. This combination is starting to be used clinically in this way and a small trial in bipolar depression found some benefit. It is time now for a large trial to see if this combination works. _x000D_ _x000D_ Our plan is to examine the combination of aripiprazole and a standard antidepressant (sertraline) in patients with bipolar depression. We want to understand whether 135 patients who will be prescribed the combination do better than the 135 who will be started on the most widely used recommended treatment, quetiapine. We will follow participants up for 24 weeks to examine any longer-term benefit on depressive symptoms, quality of life and costs._x000D_ _x000D_ If this combination of drugs proves better than quetiapine then we will have met a JLA priority area for better treatments for episodes of illness in bipolar disorder. The treatment could potentially be used in both primary and secondary care. If the combination isn’t better than quetiapine then this will support the argument that antidepressants shouldn’t be used in bipolar depression._x000D_ _x000D_ The study question, design, delivery and dissemination has been, and will continue to be, informed by engagement with the bipolar community.

Lay abstract: This is a prospective, 2-arm, open label, 10 site, superiority, individually randomised, controlled, pragmatic, parallel group, type A open label clinical trial in adults with bipolar disorder who are experiencing a depressive episode. There is a pre-randomisation phase to enable rationalisation of existing medication if needed. The intervention arm is standard of care plus aripiprazole/sertraline combination and the comparator (1:1 randomisation) is standard of care plus quetiapine with primary outcome at 8-12 weeks and secondary outcomes at, and over, 24 weeks. Efficient methods include remote collection of outcome measures of patient rated efficacy, treatment satisfaction and cost-effectiveness._x000D_ _x000D_ Eligibility criteria of current depressive episode of at least moderate severity, bipolar affective disorder, age 18 or over, clinical judgement that alternative pharmacological treatment is indicated, clinical uncertainty about the next step, equipoise between arms, informed consent. Exclusion criteria are previous significant adverse reaction, or recognised contraindication, to trial drugs, planning pregnancy or breast feeding or participation in another interventional trial._x000D_ _x000D_ The primary objective is to test the hypothesis that aripiprazole/sertraline combination is more clinically effective, measured using the Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR), than quetiapine assessed 8-12 weeks after commencement of trial medication. Secondary objectives include comparison of the impact of aripiprazole/sertraline combination vs quetiapine on tolerability, treatment satisfaction, psychosocial functioning, quality of life, costs and incremental cost-effectiveness over 24 weeks. _x000D_ _x000D_ Recruitment will occur via self-referral and from primary and secondary (mental health) NHS services using care register based and opportunistic strategies._x000D_ _x000D_ The internal pilot incorporates a nested qualitative study to explore acceptability and to understand and optimise recruitment strategies. There are clear progression criteria for the trial based on a combination of site opening, recruitment rates, and protocol adherence (fidelity)._x000D_ _x000D_ The primary quantitative analysis will use intention to treat principles, with QIDS-SR reported weekly between weeks 8 to 12 in the two arms analysed as repeated measures, adjusted for baseline. Secondary analyses will include response and remission rates, and, over 24 weeks, will include examination of the trajectories of symptom change and the pattern and cause of drug discontinuation, cost-effectiveness with costs, QALYs/capabilities and incremental cost per QALY calculated, and change in anxiety and hypomanic symptoms. There is no planned interim analysis. Power analysis reveals that 270 participants randomised will provide 90% power using 5% two-sided significance testing._x000D_ _x000D_ The study will run for a total of 48 months. 9 months set-up, 27 months recruitment, 6 months follow-up, 6 months to complete data cleaning, lock, analysis (of quantitative and qualitative data), dissemination and preparation for implementation._x000D_ _x000D_ Patient and Public Involvement and Engagement has been, and will continue to be, integral to the trial design, delivery, and dissemination.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH