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Clinical Trial
. 2025 May;29(12):1-118.
doi: 10.3310/YQVF5347.

Clinical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant depression in adults: LQD a pragmatic randomised controlled trial

Jess Kerr-Gaffney  1 , Zohra Zenasni  1 , Kimberley Goldsmith  1 , Nahel Yaziji  1 , Huajie Jin  1 , Alessandro Colasanti  2   3 , John Geddes  4 , David Kessler  5 , R Hamish McAllister-Williams  6   7 , Allan H Young  1   8 , Alvaro Barrera  4   9 , Lindsey Marwood  1 , Rachael W Taylor  1 , Helena Tee  1 , Anthony J Cleare  1   8 ; LQD Study Group
Affiliations
Clinical Trial

Clinical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant depression in adults: LQD a pragmatic randomised controlled trial

Jess Kerr-Gaffney et al. Health Technol Assess. 2025 May.

Abstract

Background: Lithium and several atypical antipsychotics are the recommended first-line augmentation options for treatment-resistant depression; however, few studies have compared them directly, and none for longer than 8 weeks. Consequently, there is little evidence-based guidance for clinicians when choosing an augmentation option for patients with treatment-resistant depression.

Objectives: This trial examined whether it is more clinically and cost-effective to prescribe lithium or quetiapine augmentation therapy for patients with treatment-resistant depression over 12 months.

Design: This was a parallel group, multicentre, pragmatic, open-label superiority trial comparing the clinical and cost-effectiveness of lithium versus quetiapine augmentation of antidepressant medication in treatment-resistant depression. Participants were randomised 1 : 1 at baseline to the decision to prescribe either lithium or quetiapine.

Setting: Six National Health Service trusts in England.

Participants: Eligible participants were aged ≥ 18 years, met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for major depressive disorder, scored ≥ 14 on the 17-item Hamilton Depression Rating Scale and whose depression had had an inadequate response to at least two therapeutic antidepressant treatment trials in the current episode, with a current antidepressant treatment at or above the therapeutic dose for ≥ 6 weeks. Patients with a history of psychosis or bipolar disorder were excluded. Patients were judged suitable for either treatment.

Interventions: After randomisation, pre-prescribing safety checks were undertaken as per standard care and trial clinicians decided whether to proceed with prescribing the allocated medication. Trial clinicians received recommendations for titration and dosing in line with current clinical guidelines; however, dosing regimens could be altered according to tolerability and response. Participants were followed up using weekly self-report questionnaires and 8-, 26- and 52-week research visits.

Main outcome measures: The co-primary outcome measures were depressive symptom severity over 52 weeks, measured weekly using the self-rated Quick Inventory of Depressive Symptomatology, and time to all-cause treatment discontinuation of the trial medication. Economic analyses compared costs between the two treatment arms over 52 weeks, from a National Health Service and Personal Social Services perspective, and a societal perspective.

Results: Two hundred and twelve participants were randomised, 107 to quetiapine and 105 to lithium. The quetiapine arm showed a significantly greater reduction in depressive symptoms than the lithium arm over 52 weeks (quetiapine vs. lithium area under the differences curve = -68.36, 95% confidence interval: -129.95 to -6.76, p = 0.0296). Median days to discontinuation did not significantly differ between the two arms (quetiapine = 365.0, interquartile range = 57.0-365.0, lithium = 212.0, interquartile range = 21.0-365.0), p = 0.1196. Quetiapine was more cost effective than lithium. Thirty-two serious adverse events were recorded, only one of which was deemed possibly related to the intervention (lithium).

Limitations: The trial was unblinded, therefore expectancies regarding the trial medications may have influenced the results. Further, there was substantial missing data for some of the secondary outcome measures.

Conclusions: As well as being more cost-effective, quetiapine may be a more clinically effective augmentation option for treatment-resistant depression.

Future work: Examining predictors of treatment response, including clinical, sociodemographic and biological factors, will help establish whether there are additional factors to consider when choosing an augmentation treatment for treatment-resistant depression.

Trial registration: This trial is registered as ISRCTN16387615.

Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/222/02) and is published in full in Health Technology Assessment; Vol. 29, No. 12. See the NIHR Funding and Awards website for further award information.

Keywords: ANTIDEPRESSIVE AGENTS; ANTIPSYCHOTIC AGENTS; DEPRESSION; DEPRESSIVE DISORDER; LITHIUM; MAJOR; QUETIAPINE FUMARATE; RANDOMISED CONTROLLED TRIAL.

Plain language summary

Many people with depression experience limited benefits from initial antidepressant medications and psychological therapies. There is some evidence suggesting that adding another type of medication to an antidepressant might be beneficial for reducing depressive symptoms. Lithium and quetiapine are two of the most commonly used treatments in the National Health Service to add on to antidepressants. This study aimed to test whether adding lithium or adding quetiapine was more effective in reducing symptoms of depression, and whether there were differences in how long patients stayed on the added medications. We also compared the cost of the treatments to the National Health Service and to society (e.g. time off work due to health problems). Adults whose depression had not responded to at least two trials of antidepressants at the recommended dose and duration were eligible to take part. Two hundred and twelve participants were included in the study and had an equal chance of being prescribed either lithium or quetiapine. We assessed participants over 12 months, including weekly assessments of their depression and several visits to the hospital. Over the 12-month study period, we found that adding quetiapine to patients’ antidepressant treatment led to a greater improvement in symptoms of depression than adding lithium. There was no difference in how long the two groups stayed on the medications, or the number of side effects: around 50% of those who started taking lithium and 39% of those who started taking quetiapine stopped taking the medication within 12 months, usually due to side effects. Quetiapine provided a greater benefit for patients at a lower cost than lithium. The results suggest that overall, adding quetiapine may be a better option than adding lithium for those who are still suffering with depression after taking two or more courses of antidepressants.

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