Study protocol for a randomised pragmatic trial comparing the clinical and cost effectiveness of lithium and quetiapine augmentation in treatment resistant depression (the LQD study)

L Marwood, R Taylor, K Goldsmith, R Romeo, R Holland, A Pickles, J Hutchinson, D Dietch, A Cipriani, R Nair, M-J Attenburrow, A H Young, J Geddes, R H McAllister-Williams, A J Cleare, L Marwood, R Taylor, K Goldsmith, R Romeo, R Holland, A Pickles, J Hutchinson, D Dietch, A Cipriani, R Nair, M-J Attenburrow, A H Young, J Geddes, R H McAllister-Williams, A J Cleare

Abstract

Background: Approximately 30-50% of patients with major depressive disorder can be classed as treatment resistant, widely defined as a failure to respond to two or more adequate trials of antidepressants in the current episode. Treatment resistant depression is associated with a poorer prognosis and higher mortality rates. One treatment option is to augment an existing antidepressant with a second agent. Lithium and the atypical antipsychotic quetiapine are two such add-on therapies and are currently recommended as first line options for treatment resistant depression. However, whilst neither treatment has been established as superior to the other in short-term studies, they have yet to be compared head-to-head in longer term studies, or with a superiority design in this patient group.

Methods: The Lithium versus Quetiapine in Depression (LQD) study is a parallel group, multi-centre, pragmatic, open-label, patient randomised clinical trial designed to address this gap in knowledge. The study will compare the clinical and cost effectiveness of the decision to prescribe lithium or quetiapine add-on therapy to antidepressant medication for patients with treatment resistant depression. Patients will be randomised 1:1 and followed up over 12 months, with the hypothesis being that quetiapine will be superior to lithium. The primary outcomes will be: (1) time to all-cause treatment discontinuation over one year, and (2) self-rated depression symptoms rated weekly for one year via the Quick Inventory of Depressive Symptomatology. Other outcomes will include between group differences in response and remission rates, quality of life, social functioning, cost-effectiveness and the frequency of serious adverse events and side effects.

Discussion: The trial aims to help shape the treatment pathway for patients with treatment resistant depression, by determining whether the decision to prescribe quetiapine is superior to lithium. Strengths of the study include its pragmatic superiority design, broad inclusion criteria (external validity) and longer follow up than previous studies.

Trial registration: ISRCTN registry: ISRCTN16387615 , registered 28 February 2016. ClinicalTrials.gov: NCT03004521 , registered 17 November 2016.

Keywords: Augmentation; Lithium; Longitudinal; Multi-centre; Open-label; Pragmatic; Quetiapine; Randomised clinical trial; Superiority design; Treatment resistant depression.

Conflict of interest statement

Consent for publication

Not applicable.

Competing interests

AJC has in the last three years received honoraria for speaking from Astra Zeneca (AZ) and Lundbeck, honoraria for consulting from Allergan and Livanova and research grant support from Lundbeck.

AHY has given paid lectures and sits on advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders; is lead investigator for the Embolden Study (AZ), BCI Neuroplasticity study, and Aripiprazole Mania Study and investigator initiated studies from AZ, Eli Lilly, Lundbeck, and Wyeth; and has received grant funding from the National Institute of Mental Health (USA); Canadian Institutes of Health Research (Canada); National Alliance for Research on Schizophrenia and Depression (USA); Stanley Medical Research Institute (USA); Medical Research Council (UK); Wellcome Trust (UK); Royal College of Physicians (Edinburgh); British Medical Association (UK); University of British Columbia-Vancouver General Hospital Foundation (Canada); Western Economic Diversification Canada (Canada); Canadian Cardiovascular Society Depression Research Fund (Canada); Michael Smith Foundation for Health Research (Canada); and NIHR (UK).

In the last 3 years RHMW has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, Liva Nova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion.

RHMW, AHY and AJC all undertake clinical work within tertiary level specialist affective disorders services.

In 2015 AC was expert witness for a patent issue about quetiapine extended release.

AJC and AHY acknowledge support by the NIHR Biomedical Research Council (BRC). JG is an NIHR Senior Investigator and MJA and AC acknowledge support from the NIHR Oxford cognitive health Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

All other authors declare that they have no competing interests. All authors will have full access to the final trial dataset.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Flow Chart of Trial Procedures

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