Condition category
Mental and Behavioural Disorders
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Major depressive disorder (MDD), often referred to as depression, is one of the most common mental health conditions in the world. The symptoms of MDD can vary greatly from person to person, but they generally include low mood, problems with sleeping and/or eating, and a general loss of interest in life. Treatment often relies heavily on antidepressant medications, which work by increasing the activity and levels of a group of chemicals in the brain (neurotransmitters). However, around 30-50% of patients fail to respond adequately to the first or second antidepressant they take (treatment resistant depression). Sufferers of treatment resistant depression have been found to take longer to recover and are often hit harder by the depressive symptoms. A possible option for treating treatment resistant depression is by adding an additional antidepressant medication to those they already take. Lithium and quetiapine are drugs usually used for treating conditions such as bipolar disorder, however there is evidence that they can be effective in the treatment of treatment resistant depression, however little is known about whether this is effective in the long-term. The aim of this study is to find out whether lithium or quetiapine is more effective and cost-effective at treating patients with treatment resistant depression over one year.

Who can participate?
Adults with resistant depression who have been taking the same antidepressants for at least four weeks.

What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group are given lithium carbonate to take as well as any antidepressant medication they are already taking. At the start of the study, participants are started on 400 mg to take every night, which can be increased or decreased to find the best possible dose for that particular patient. Those in the second group are given quetiapine to take as well as any antidepressant medication they are already taking. Participants are started on a dose of 50mg per day for the first two days, increasing to 150mg per day on the third day, up to 300mg per day by week two. The dosage can be adjusted within the range of 150mg-300mg per day as required. Throughout the 52 weeks of the study, participants in both groups complete a questionnaire online about how bad their depressive symptoms are. In addition, at the start of the study and then again at 8, 26 and 52 weeks, participants in both groups complete a number of questionnaires in order to assess their levels of mood and general health.

What are the possible benefits and risks of participating?
Participants may benefit from an improvement to their depressive symptoms in the long term from the drug treatment they are assigned to. Risks of taking part are small, although some patients may experience side-effects from the medication.

Where is the study run from?
1. King's College London (UK)
2. University of Oxford (UK)
3. Newcastle University (UK)

When is the study starting and how long is it expected to run for?
May 2016 to May 2020

Who is funding the study?
National Institute for Health Research (UK)

Who is the main contact?
Professor Anthony Cleare

Trial website

Contact information



Primary contact

Prof Anthony Cleare


Contact details

King's College London
Institute of Psychiatry
Psychology and Neuroscience
103 Denmark Hill
United Kingdom
+44 20 7848 0783

Additional identifiers

EudraCT number

2016-001637-27 number

Protocol/serial number


Study information

Scientific title

A randomised pragmatic trial comparing the clinical and cost effectiveness of Lithium and Quetiapine augmentation in treatment resistant Depression



Study hypothesis

The aim of this study is to assess whether it is more clinically and cost-effective to augment an antidepressant with lithium or quetiapine for patients with treatment resistant depression.

Ethics approval

East of England - Cambridge South Research Ethics Committee, 20/09/2016, ref: 16/EE/0318

Study design

Multi-centre randomised pragmatic randomised parallel trial

Primary study design


Secondary study design

Randomised parallel trial

Trial setting


Trial type


Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet


Major depressive disorder (MDD)


Each Participant will be randomised 1:1 to lithium or quetiapine add on, after their eligibility has been confirmed. Randomisation will be stratified by recruiting centre and TRD severity (failure of two or failure of three or more antidepressant treatments) with the block size randomly varying. Randomisation will not be blinded.

In both arms, the guidance will be to trial at least 8 weeks of treatment, and to keep the dose of existing antidepressant treatment unchanged and above minimal therapeutic dosage during that time. We propose a pragmatic trial that reflects real world UK clinical practice, in which add-on therapy for TRD is given initially for an acute phase of treatment, leading to a decision point regarding continuation of the therapy and/or the addition of other therapies, depending on response. The two treatment arms for both acute and continuation phases of treatment will be as follows:

Lithium arm: Lithium carbonate, added on the current antidepressant. Acute phase treatment includes dose titration as per standard BNF protocol starting at 400 mg/day taken at night and flexible dose adjustment thereafter aiming for an optimal therapeutic plasma level of 0.6-1.0 mmol/l (Bauer, Pfennig, et al., 2013; Taylor et al., 2015). Blood monitoring will be performed as per Maudsley Prescribing Guidelines, including standard lithium plasma level testing frequency during the acute phase (1 week, 3 weeks and 8 weeks). Continuation phase will continue to aim for a plasma level of 0.6-1.0 mmol/l with 3 monthly plasma level testing.

Quetiapine arm: quetiapine fumarate (quetiapine XR), taken once daily before bedtime. Dose titrated upwards using a standard BNF dose titration protocol of 50 mg on days 1 and 2 and 150 mg on day 3, aiming for a dose of 300 mg/day by week 2 if tolerated. Thereafter, flexible dosing will be followed in the range 150-300 mg/day according to tolerance during the acute phase (as per Bauer et al 2013). Fully flexible dosing during the continuation phase (manufacturer guidance suggests lowest dose to control symptoms should be used in 50-300 mg/day range). In elderly patients (>65 years old), the dose titration protocol will be modified according to the SmPC and best practice as follows: 50 mg/day on Days 1-3, increasing to 100 mg/day on Day 4, 150 mg/day on Day 8 and 300 mg/day on Day 22 of treatment if required during the acute phase. Continuation phase will be as per younger adults (lowest dose to control symptoms in 50-300 mg/day range).

Participants in both groups are followed up at 8, 26 and 52 weeks.

Intervention type



Phase IV

Drug names

1. Lithium carbonate
2. Quetiapine extended release

Primary outcome measures

Longitudinal depressive symptom severity, as measured using the Quick Inventory of Depressive Symptoms self rated (QIDS-SR) questionnaire, assessed weekly via the True Colours system ( over 52 weeks.

Secondary outcome measures

1. Costs of each treatment arm, measured using the Client Service Receipt Inventory (modified for treatment resistant depression) at baseline, 8, 26, and 52 weeks
2. Observer-rated depressive symptoms measured at baseline, 8, 26, and 52 weeks using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS) and Clinician rated Quick-Inventory of Depressive Symptomatology (QIDS-CR). Outcomes including, proportion of time over 12 months when patients were free from depressive symptoms (QIDS-SR≤5), response rates (≥50% reduction in HAM-D) and remission rates (HAM-D ≤7).
3. Time before other medication added for depression
4. Amount of concomitant treatment (medication and/or non-pharmacological) over 12 months
5. Withdrawal from quetiapine or lithium due to adverse effects
6. Social functioning, measured weekly via the True Colours system using the Work and Social Adjustment Schedule)
7. Health-related quality of life measured using the EuroQol-5D health index completed weekly via the True Colours system
8. Adherence to treatment, using weekly True Colours self report and a modified version of the Medical Adherence Report Scale for treatment resistant depression.
9. Side effects and acceptability of treatment, measured at baseline, 8, 26, and 52 weeks using the UKU Side Effect Rating Scale.
10. Serious Adverse Events including deliberate self-harm and suicidal behaviour
11. Death (all cause and cause-specific including suicide)
12. Physical health (weight, ECG, blood pressure and blood parameters) at baseline, 8, 26, and 52 weeks
13. Global outcome, measured using the Clinical Global Impressions scale (CGI) at 0, 8, 26, and 52 weeks
14. Manic symptoms, assessed using the Altman Mania Self Rating Scale at baseline, 8, 26, and 52 weeks
15. Anxiety symptoms, assessed using the Zung Anxiety Scale at baseline, 8, 26, and 52 weeks
16 New intervention (admission, psychological or drug treatment) for depressive episode by 52 weeks

Overall trial start date


Overall trial end date


Reason abandoned


Participant inclusion criteria

1. Under the care of a GP and/or adult mental health services
2. Current episode of depression meeting DSM-V criteria for major depressive disorder (MDD) – single or recurrent episode
3. Score 14 or over on the 17-item Hamilton Depression Rating Scale (HAMD)
4. Aged 18 years or older
5. Meet criteria for treatment resistant depression: current episode has not responded to at least two antidepressants given for at least 6 weeks at minimum therapeutic dose defined as fluoxetine ≥20mg/day, paroxetine ≥20mg/day, sertraline ≥50mg/day, citalopram ≥20mg/day, escitalopram ≥10mg/day, venlafaxine ≥75mg/day, duloxetine ≥60 mg/day, mirtazapine ≥30mg/day, tricyclic antidepressant ≥125mg/day, and as guided by the Maudsley Prescribing Guidelines or BNF for any other antidepressant
6. Current antidepressant treatment has remained unchanged for ≥4 weeks
7. Provision of written, informed consent

Participant type


Age group




Target number of participants


Participant exclusion criteria

1. Diagnosis of bipolar disorder
2. Diagnosis of current psychosis
3. Below age of 18
4. Use of lithium or quetiapine during current episode
5. Ongoing use of another atypical antipsychotic (discontinuation will be required before study entry)
6. Contraindication to use of either lithium or quetiapine. To this end, all patients will have a physical examination, ECG and blood test assessments as per the standard lithium workup. In addition, clinical concerns about the risk of overdose being sufficient to contra-indicate the prescription of lithium in the judgement of the treating clinician would be an exclusion
7. Being in another treatment trial
8. Insufficient degree of comprehension or attention to be able to engage in trial procedures.
9. Pregnant women, those actively trying for pregnancy and those who are breastfeeding

Recruitment start date


Recruitment end date



Countries of recruitment

United Kingdom

Trial participating centre

King's College London
Centre for Affective Disorders Institute of Psychiatry, Psychology and Neuroscience 103 Denmark Hill
United Kingdom

Trial participating centre

University of Oxford
Department of Psychiatry Warneford Hospital Warneford Lane
United Kingdom

Trial participating centre

Newcastle University
Institute of Neuroscience, Wolfson Research Centre Campus for Ageing and Vitality
Newcastle upon Tyne
United Kingdom

Sponsor information


King’s College London, and South London and Maudsley NHS Foundation Trust

Sponsor details

King’s Health Partners Clinical Trials Office
F16 Guy’s Tower
Guy’s Hospital
Great Maze Pond
United Kingdom

Sponsor type




Funder type


Funder name

National Institute for Health Research

Alternative name(s)


Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government


United Kingdom

Results and Publications

Publication and dissemination plan

1. Planned publication of study results in open access, peer-reviewed journals
2. Presentation of findings at National and International conferences
3. Dissemination of reports for patient literature, linking with relevant patient organisations to do this, and aiming to present the findings at relevant patient and user group meetings
4. Publication of a full account of the research will be published in the NIHR HTA Journal

IPD Sharing plan:
Access to participant level data will be judged by the Chief Investigator on a case by case basis. All trial data will be stored in line with the Medicines for Human Use (Clinical Trials) Amended Regulations 2006 and the Data Protection Act and archived in line with the Medicines for Human Use (Clinical Trials) Amended Regulations 2006 as defined in the Kings Health Partners Clinical Trials Office Archiving SOP.

Intention to publish date


Participant level data

Not expected to be available

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

10/10/2016: Ethics approval information and EudraCT number added. The recruitment start date has been updated from 01/07/2016 to 03/11/2016