Lithium Versus Quetiapine in Treatment Resistant Depression

Phase 4

• Conditions: Depressive Disorder, Treatment-Resistant
• Interventions: Drug: Lithium; Drug: Quetiapine

• Registration Number: NCT03004521
• Lead Sponsor: King's College London

Brief Summary

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.

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 Timeline

• Study Start: 2016-11
• Study First Submitted: 2016-11-17
• Study First Submitted QC: 2016-12-22
• Study First Posted: 2016-12-29
• Status Verified: 2021-03
• Last Update Submitted: 2021-03-03
• Last Update Posted: 2021-03-05
• Primary Completion: 2021-04
• Study Completion: 2021-08

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 276

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Lithium	Lithium	Lithium will be prescribed to patients in this arm as an augmenter on top of a patient's existing antidepressant treatment.
Quetiapine	Quetiapine	Quetiapine will be prescribed to patients in this arm as an augmenter on top of a patient's existing antidepressant treatment.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Institute of Psychiatry, Psychology and Neuroscience, King's College London; 🇬🇧 London, United Kingdom