Lithium Versus Quetiapine in Treatment Resistant Depression (LQD)

A Randomised Pragmatic Trial Comparing the Clinical and Cost Effectiveness of Lithium and Quetiapine Augmentation in Treatment Resistant Depression

LQD is a multicentre randomised clinical trial comparing the clinical and cost effectiveness of lithium versus quetiapine when used as add-on therapies to antidepressant medication for patients with treatment resistant depression. The Lithium versus Quetiapine in Depression (LQD) study will assess patients over 12 months to establish which (if any) treatment is more likely to improve TRD over a long duration of time. Professor Anthony Cleare is the Chief Investigator and recruitment began in November 2016.

Study Overview

• Status: Recruiting
• Conditions: Depressive Disorder, Treatment-Resistant
• Intervention / Treatment: Drug: Lithium; Drug: Quetiapine

Detailed Description

This 12 month parallel group, multi-centre, patient randomised, pragmatic, open label trial is comparing the clinical and cost-effectiveness of the decision to prescribe lithium versus quetiapine add-on treatment to antidepressant medication. There will be two parallel groups: 1) Quetiapine add-on to existing antidepressant medication; 2) Lithium add-on to existing antidepressant medication. 276 patients will be randomised 1:1 at baseline to the decision to prescribe either lithium or quetiapine, and treatment will then be undertaken by clinicians on a real world basis. All patients, regardless of their treatment status, will be followed up in the trial for one year. This is a superiority design whereby we hypothesise that quetiapine will be superior to lithium in terms of time to treatment discontinuation and average symptom burden (QIDS-SR) over 12 months.

• Study Type: Interventional
• Enrollment (Anticipated): 276
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Lindsey Marwood; Email: LQDstudy@kcl.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, SE5 8AF
    • Recruiting
    • Institute of Psychiatry, Psychology and Neuroscience, King's College London
    • Contact: Helena Tee; Email: helena.tee@kcl.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Under the care of a GP and/or adult mental health services
2. Current episode of depression meeting DSM-5 criteria for major depressive disorder (MDD) - single or recurrent episode 3.17-item HAM-D score ≥ 14 - this cut-off reflects a pragmatic minimum severity of depression as also chosen in comparable studies such as STAR*D (Rush et al 2006, Trivedi et al 2006)

4.Any gender and aged 18 years or over 5.Meet criteria for treatment resistant depression (Fekadu et al., 2009a; Cleare et al., 2015): 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 ≥15mg/day, tricyclic antidepressant ≥125mg/day, and dosage as guided by the national Maudsley Prescribing Guidelines or BNF for any other antidepressant. Please note, relapse whilst on an antidepressant also counts as a failed treatment trial 6.Current antidepressant treatment has remained unchanged and at, or above, a therapeutic dose for ≥6 weeks 7.Provision of written, informed consent.

Exclusion Criteria:

1. Diagnosis of bipolar disorder (defined as meeting DSM-5 criteria for bipolar 1 or bipolar 2) on the MINI 7.0 (as recommended treatments are different for bipolar depression)
2. Diagnosis of current psychosis (as recommended treatments are different for current psychosis - antidepressants plus antipsychotics is the first-line treatment recommendation (NiCE, 2009; Cleare et al., 2015)
3. Adequate use of lithium or quetiapine during the current episode. An adequate dose of lithium is defined as the patient taking lithium for at least 4 weeks at an adequate dose (leading to a documented plasma concentration of >0.4mmol/L) and for quetiapine, prescription in the range of 150-300mg/d for 4 weeks or longer. Or, if the patient has taken an inadequate dose of lithium or quetiapine in the current episode, the patient and clinician are not willing to re-prescribe/take the medication.
4. Ongoing use of another atypical antipsychotic (discontinuation will be required before study entry i.e. any time prior to randomisation)
5. Known contraindication to use of either lithium or quetiapine: known hypersensitivity of lithium or quetiapine or any of their excipients; severe renal insufficiency / impairment; untreated hypothyroidism; severe cardiac disease / insufficiency; low sodium levels e.g. dehydrated patients or those on low sodium diets; Addison's disease; Brugada syndrome or family history of Brugada syndrome; the rare hereditary inborn errors of metabolism galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption; concomitant administration of cytochrome P450 3A4 inhibitors; or congenital QT prolongation.
6. We will not recruit any individual who is currently participating in a clinical trial of an investigational medical product (CTIMP).
7. Insufficient degree of comprehension or attention to be able to engage in trial procedures.
8. We will exclude women who are pregnant, actively trying for pregnancy, or currently breastfeeding. This will be based on verbal report of the subject. Otherwise the management will be as appropriate according to standard clinical practice within the context of a pragmatic, open trial, for example adequate contraceptive precautions decided on the clinical judgement of the prescriber.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Lithium; Lithium will be prescribed to patients in this arm as an augmenter on top of a patient's existing antidepressant treatment.	Drug: Lithium; Lithium prescribed in addition to the patient's existing antidepressant treatment.
Experimental: Quetiapine; Quetiapine will be prescribed to patients in this arm as an augmenter on top of a patient's existing antidepressant treatment.	Drug: Quetiapine; Quetipatine prescribed in addition to the patient's existing antidepressant treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Longitudinal depressive symptom severity	QIDS-SR	52 weeks
Difference in time to all-cause treatment discontinuation	The difference in the time at which patients stop taking the medication for any reason between the two treatment arms.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in clinician rated depression severity	MADRS	From baseline to weeks 8 and 52
Response rates	Assessed using the MADRS questionnaire	8 weeks and 52 weeks
Remission rates	Assessed using the MADRS questionnaire	8 and 52 weeks
Health related quality of life	Assessed using the EuroQol-5D questionnaire	Measured at 8 and 52 weeks
Social functioning	Measured using the WSAS self rated questionnaire	Measured at baseline, 8 and 52 weeks
Adherence to treatment	Assessed using the MARS-5 questionnaire	Measured at weeks 8 and 52
Change in weight in kilograms	Assessed by weighing participants	Measured at 8 and 52 weeks
Change in diastolic blood pressure	Assessed by measuring blood pressure	Change from baseline to 8 and 52 weeks
Change in systolic blood pressure	Assessed by measuring blood pressure	Change from baseline to 8 and 52 weeks
Time to uptake of a new intervention (pharmacological or non-pharmalogical)	Assessed by recording all pharmacological and non-pharmacological interventions	12 months
Time to initiation of treatment	Assessed using treatment initiation form	Up to 12 months
CGI Global Improvement	CGI	Measured at 8 and 52 weeks
Side effects	PRISE total score	Measured at 8 and 52 weeks
Serious Adverse Events	Serious adverse events will be monitored and reported throughout the patient's participation in the trial.	52 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in global severity	Change in CGI severity score	Measured at 8, 26 and 52 weeks
Global efficacy	Change in CGI efficacy score	Measured at 8, 26 and 52 weeks
Side effects	Frequency of individual items on the PRISE	Measured at 8 and 52 weeks
Physical health changes	Not completed for all participants. Will be reported if there is a sufficient number e.g. blood parameters and waist circumference	Measured at baseline, 8, 26 and 52 weeks
Satisfaction with lithium / quetiapine treatment	Measured using TSQM subscales	Measured at 8, 26 and 52 weeks
Change in self-report manic symptoms	Measured using the Altman Mania Self Rating Scale	Measured at baseline, 8, 26 and 52 weeks
Change in anxiety symptoms	GAD-7 score	Measured at baseline, 8, 26 and 52 weeks
Time to prescription	First date participant is given a prescription for the treatment	0-52 weeks
Baseline adherence to antidepressant	MARS-5 score	Measured at baseline
Change in cognition	Total DSCT score	Measured at baseline, 8, 26 and 52 weeks
Adherence of clinicians	Clinician adherence to prescribing and monitoring guidelines	0-52 weeks
Proportion of participants having an adequate treatment trial	Adequate treatment trial as defined in study protocol	0-8 weeks
Number of hospital admissions for depressive episode	Measured using psychiatric history assessment	52 weeks
Change in personality measure	SAPAS	Measured at baseline, 8, 26 and 52 weeks
Social functioning	WSAS	Measured weekly over 12 months
Economic analysis	Costs from the NHS and Personal Social Services perspective and from a societal perspective.	52 weeks
Predictors of treatment response	Measured using the Maudsley Staging Model, HAM-D, MINI 7, IDS-C and SAPAS questionnaires.	52 weeks
Longitudinal depression severity until time to all cause treatment discontinuation	Measured weekly using the QIDS-SR	52 weeks
Collection and analysis of biological samples for genetic, cytokine and cortisol analysis	Blood/hair/saliva samples collected in collaboration with the BRC BioResource	0-52 weeks
Reliability and validity of the Maudsley VAS	Measured using the Maudsley VAS, validated against the QIDS-SR and MADRS	Measured at baseline, 8, 26 and 52 weeks
Discrepancy between the self-rated and clinician-rated version of 16 item IDS	Assessed using QIDS and IDS	Measured at baseline and 8 weeks
Relationship between quetiapine and lithium serum levels, prescribed dose and depressive symptom severity	MADRS	52 weeks
Time to new interventions for depression.	Measured using concomitant medication and concomitant therapy questionnaires	52 weeks
Number of new interventions for depression	Measured using concomitant medication and concomitant therapy questionnaires	52 weeks
Patient rated experience of the True Colours weekly monitoring system	Qualitative Interview in a subset of participants	8 / 26 / 52 weeks
Change in cognitive function	THINC-it composite and individual tests scores in a subset of participants	Baseline, 8, 26 and 52 weeks
12. Patient views and experiences of lithium and quetiapine	Qualitative interviews in a subset of participants	52 week visit

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: University of Oxford; Newcastle University; South London and Maudsley NHS Foundation Trust; Sussex Partnership NHS Foundation Trust; Oxford Health NHS Foundation Trust; Northumberland, Tyne and Wear NHS Foundation Trust; Avon and Wiltshire Mental Health Partnership NHS Trust; Tees, Esk and Wear Valleys NHS Foundation Trust
• Investigators: Principal Investigator: Anothony Cleare, Professor of Psychiatry

Publications and helpful links

General Publications

• Marwood L, Taylor R, Goldsmith K, Romeo R, Holland R, Pickles A, Hutchinson J, Dietch D, Cipriani A, Nair R, Attenburrow MJ, Young AH, Geddes J, McAllister-Williams RH, Cleare AJ. 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). BMC Psychiatry. 2017 Jun 26;17(1):231. doi: 10.1186/s12888-017-1393-0.

Helpful Links

• Study website link

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Anticipated): April 1, 2021
• Study Completion (Anticipated): August 1, 2021

Study Registration Dates

• First Submitted: November 17, 2016
• First Submitted That Met QC Criteria: December 22, 2016
• First Posted (Estimate): December 29, 2016

Study Record Updates

• Last Update Posted (Actual): March 5, 2021
• Last Update Submitted That Met QC Criteria: March 3, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Augmentation; Quetiapine; Lithium
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Physiological Effects of Drugs; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Quetiapine Fumarate
• Other Study ID Numbers: HTA 14/222/02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: The decision to share IPD to other researchers will be made by the CI on a case by case basis.