Clinical and cost-effectiveness of lithium versus quetiapine augmentation for treatment-resistant depression in adults: LQD a pragmatic randomised controlled trial
File(s)
Published version
Author(s)
Type
Journal Article
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.
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.
Date Issued
2025-05-01
Date Acceptance
2025-04-01
Citation
Health Technology Assessment, 2025, 29 (12), pp.1-118
ISSN
1366-5278
Publisher
NIHR Journals Library
Start Page
1
End Page
118
Journal / Book Title
Health Technology Assessment
Volume
29
Issue
12
Copyright Statement
Copyright © 2025 Kerr-Gaffney et al. This work was produced by Kerr-Gaffney et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.
License URL
Identifier
10.3310/YQVF5347
Subjects
LQD Study Group
Humans
Lithium
Antipsychotic Agents
Antidepressive Agents
Drug Therapy, Combination
Quality-Adjusted Life Years
Adult
Aged
Middle Aged
England
Female
Male
Depressive Disorder, Treatment-Resistant
Quetiapine Fumarate
Cost-Effectiveness Analysis
Publication Status
Published
Date Publish Online
2025-05-01