Title: A randomised pragmatic trial comparing the clinical and cost effectiveness of lithium and quetiapine augmentation in treatment resistant depression.
Funder: Department of Health and Social Care

Abstract: BACKGROUND: Around 30-50% of patients with major depressive disorder fail to respond to first and second line treatments for depression, commonly described as treatment resistant depression. One treatment option for these patients is augmenting an antidepressant with a second agent, for example lithium or an atypical antipsychotic (such as quetiapine, aripiprazole, olanzapine and risperidone). OBJECTIVE: To determine whether it is more clinically or cost-effective to augment an antidepressant with lithium or quetiapine for patients with treatment resistant depression over one year. DESIGN: One-year, multi-centre, randomised, parallel group, open-label, pragmatic trial. SETTING: Participants will be recruited from secondary care adult mental health services (supplemented by recruitment from primary care and community adverts). PARTICIPANTS: 276 patients with treatment resistant depression, defined as a failure to respond adequately to at least two antidepressants given at a therapeutic dose and for an adequate duration as defined in the Maudsley Prescribing Guidelines, as it is at this point that add-on therapy is usually considered and where there is currently clinical equipoise. INTERVENTIONS: Participants will be randomised 1:1 to receive extended release quetiapine (150-300 mg/day) or lithium (plasma level 0.6-1.0 mmol/l) as add-on to existing antidepressant. Treatment will then be undertaken by clinicians on a real world basis, guided by a treatment manual detailing optimal, evidence based treatment protocols. Long term outcome will be assessed at 12 months. OUTCOMES: Clinical effectiveness will be compared between the two treatment arms longitudinally over 1 year and a detailed economic analysis untaken. Main outcomes will be assessed weekly by self -report; other outcomes assessed at 0, 8, 26 and 52 weeks. The primary outcomes will be depression severity, analysed using the Quick Inventory of Depressive Symptomatology measured weekly and time to study medication discontinuation. Other outcomes include response/remission rates; use of other treatment; adverse events; costs; function; quality of life; adherence; global outcome; and other psychiatric symptoms. OUTPUTS: The findings of this study will be published in peer reviewed journals, presented at conferences, and a range of summaries produced to a variety of audiences to increase reach and impact.

Lay abstract: BACKGROUND: There is currently uncertainty about how best to treat patients whose depression has not shown a good response to initial antidepressant treatments (“treatment resistant depression” – TRD). This is a major problem as perhaps half of patients do not respond fully to antidepressants alone. There are several effective options for treating TRD, including medication or psychological therapies. However, few good studies have compared these treatments directly with one another. Furthermore, most studies have been short-term (i.e. 6-8 weeks) and have not assessed the longer-term effects of these treatments. This is a problem because, not only do patients with TRD experience a longer and more difficult condition to treat in the first place, they also have higher rates of relapse in the 12 months or so after responding. Thus, it is not enough to look only at the short term effects. A common option for patients and their doctor is to prescribe a different type of medication in addition to an antidepressant (“augmentation”, or “add-on” treatment). For many years, lithium has been a standard first line add-on treatment. We now know that some newer antipsychotics are also effective add-on treatments for TRD, usually in doses lower than those used for psychosis. One of these, the extended release version of quetiapine, is now licenced for TRD in the UK. We propose to compare the long term effects of lithium and quetiapine head to head over 12 months to see which medication is most clinically and cost-effective for patients with TRD. METHOD AND TREATMENTS: We will invite people with depression whose condition has not improved sufficiently despite a full course (at least 6 weeks) of at least two different antidepressant treatments. 276 patients will receive add-on treatment with either quetiapine or lithium chosen at random. They and their doctors will know which treatment they are on. Treatment will be guided by current best practice, including dosing and monitoring and will be prescribed by patients’ existing clinicians. Patients will be monitored by trial researchers for 12 months, even if they discontinue the initial treatment, as it is important that we know what happens in real life when these treatments are used and when they are stopped. To be suitable for the study, patients must be aged 18 or over, meet DSM criteria for a current major depressive episode and have at least moderate depression severity (a score of 14 or above on the 17 item Hamilton Depression Rating Scale). Participants must not have a diagnosis of bipolar disorder or current psychosis. They must not be pregnant, trying to get pregnant or breastfeeding. This will be a multi-site study with hubs in London, Newcastle and Oxford, with the lead centre being King’s College London. ANALYSIS: We will measure how effective the treatments are in terms of depressive symptoms, quality of life, side effects and whether any other treatments were needed. Many of the measures can be done at home by text message or e-mail (“True Colours”) – this system has worked well in previous studies and is liked by patients. True Colours’ ease of use allows weekly self-ratings and thus gives a more complete picture of long-term symptom control with the two treatments. We will also estimate the costs associated with each treatment. DISSEMINATION OF RESULTS: Results will be published in open-access, peer-reviewed academic journals and presented at conferences. We also aim to disseminate the findings in the wider press and directly to patient groups. Patients will benefit from the study by knowing which (if any) treatment is more likely to improve their condition over a longer duration of time than is currently known. The NHS will also benefit through cost effectiveness analysis which we will conduct. The results of the study could help advise future clinical guidelines by determining which treatment is more effective.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH