Around a third to half of patients with depression do not get better after trying two or more antidepressants, and this trial will test whether adding lithium or quetiapine to their existing medication works better over a full year. The problem is that doctors lack clear evidence on which add-on drug to choose for treatment-resistant depression. Current guidelines list both lithium and quetiapine as options, but no large, long-term trial has directly compared them in real-world NHS settings. This study will recruit 276 patients across secondary care mental health services, randomising them to receive either extended-release quetiapine (150–300 mg/day) or lithium (targeting a blood level of 0.6–1.0 mmol/L) alongside their antidepressant. Clinicians will follow a treatment manual but adjust doses as they would in routine practice. If the trial shows one drug is clearly more effective or cheaper over 12 months, it could change NHS prescribing guidelines and spare thousands of patients months of trial-and-error with treatments that do not work. The primary outcomes are depression severity—measured weekly via the Quick Inventory of Depressive Symptomatology—and how long patients stay on the medication. The study also tracks side effects, quality of life, and overall costs, giving commissioners a direct answer on which add-on therapy offers better value for the health service.
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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.
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