The effectiveness of Lithium plus Quetiapine COMBination versus LithIum versus QuetiapiNe monothErapy in the maintenance treatment of bipolaR disorder: the COMBINER trial.

Background: Bipolar disorder (BD) is a severe mood disorder characterised by episodes of hypomania / mania and depression. Maintenance treatment is critical to reducing the number of mood episodes experienced over a person’s lifetime. Lithium is recommended as the first line maintenance treatment, but antipsychotics are often prescribed instead of or in addition to lithium.

Combination treatment could be more effective, but tolerability is more of an issue. Currently there is a lack of good quality evidence to help clinicians and patients make choices about whether lithium, an antipsychotic, or a combination of both is best in maintenance treatment.

Research question, aims and objectives: Our aim is to answer the research question: What is the clinical and cost-effectiveness of lithium plus quetiapine vs. lithium vs. quetiapine in the maintenance treatment of BD?

Primary objective: To evaluate whether a combination of lithium and quetiapine increases time to next mood episode (a measure of relapse/symptoms) over 24 months in comparison to lithium or quetiapine in the maintenance treatment of BD. Secondary objectives: To evaluate in the maintenance treatment of BD:

A] the effectiveness of lithium vs quetiapine on time to new mood episode over 24 months. B] the effectiveness of lithium plus quetiapine vs lithium vs quetiapine on health related quality of life (QoL), functioning, and other important outcomes at 12 and 24 months. C] the cost-effectiveness of lithium plus quetiapine vs lithium vs quetiapine

Methods: We will carry out a pragmatic, observer-blind, multi-centre, 3-arm RCT comparing lithium plus quetiapine vs lithium vs quetiapine in the maintenance treatment of BD over 24 months. 303 participants will be recruited, meaning 101 participants will be randomised to each trial arm. A 9-month internal pilot will assess recruitment per month per centre, and adherence to medication.

Participants will be recruited from mental health Trusts across England. The target population is adults with BD in whom pharmacological maintenance treatment is clinically indicated. The primary outcome is time to new mood episode, assessed by a 3 monthly researcher administered Longitudinal Interval Follow-up Evaluation.

Secondary outcomes are health-related QoL, functioning, side effects, patient acceptability, hospitalisation, service utilisation, adherence, occupational and educational outcomes, comorbid mental conditions, physical health, suicidal ideation, use of emergency medication at 12 and 24 months and time to stopping allocated treatment. The analysis will be on an intention to treat basis and compare time to new mood episode during follow-up between the 3 arms.

A health economic trial-based analysis of the cost-effectiveness of lithium plus quetiapine vs lithium vs quetiapine will be undertaken. Timelines for delivery: 68 months.

Anticipated impact and dissemination: The study will provide definitive evidence on the clinical and cost-effectiveness of lithium and quetiapine combination therapy vs lithium vs quetiapine monotherapies in the maintenance treatment of BD. Trial results will be disseminated via open access publications, conferences, public engagement events, blogs, Bipolar UK, clinical workshops, and CPD to reach prescriber networks.

Study findings will inform the NICE and BAP guidelines for the treatment of BD and could improve longer terms outcomes of people with BD, reducing costs for the individual, the NHS and society.