Clinical trial NCT03004521: Lithium Versus Quetiapine in Treatment Resistant Depression
Official title: A Randomised Pragmatic Trial Comparing the Clinical and Cost Effectiveness of Lithium and Quetiapine Augmentation in Treatment Resistant Depression
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Depressive Disorder, Treatment-Resistant
Keywords: Lithium
Quetiapine
Augmentation
Lead sponsor: King's College London
Sponsor class: OTHER
Collaborators: name: University of Oxford
name: Newcastle University
name: Oxford Health NHS Foundation Trust
name: Northumberland, Tyne and Wear NHS Foundation Trust
name: South London and Maudsley NHS Foundation Trust
name: Tees, Esk and Wear Valleys NHS Foundation Trust
name: Sussex Partnership NHS Foundation Trust
name: Avon and Wiltshire Mental Health Partnership NHS Trust
First posted: 2016-12-29
Enrollment: 276
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Longitudinal depressive symptom severity
timeFrame: 52 weeks
measure: Difference in time to all-cause treatment discontinuation
timeFrame: 12 months
Secondary outcomes:
measure: Change in clinician rated depression severity
timeFrame: From baseline to weeks 8 and 52
measure: Response rates
timeFrame: 8 weeks and 52 weeks
measure: Remission rates
timeFrame: 8 and 52 weeks
measure: Health related quality of life
timeFrame: Measured at 8 and 52 weeks
measure: Social functioning
timeFrame: Measured at baseline, 8 and 52 weeks
measure: Adherence to treatment
timeFrame: Measured at weeks 8 and 52
measure: Change in weight in kilograms
timeFrame: Measured at 8 and 52 weeks
measure: Change in diastolic blood pressure
timeFrame: Change from baseline to 8 and 52 weeks
measure: Change in systolic blood pressure
timeFrame: Change from baseline to 8 and 52 weeks
measure: Time to uptake of a new intervention (pharmacological or non-pharmalogical)
timeFrame: 12 months
measure: Time to initiation of treatment
timeFrame: Up to 12 months
measure: CGI Global Improvement
timeFrame: Measured at 8 and 52 weeks
measure: Side effects
timeFrame: Measured at 8 and 52 weeks
measure: Serious Adverse Events
timeFrame: 52 weeks
Other outcomes:
measure: Change in global severity
timeFrame: Measured at 8, 26 and 52 weeks
measure: Global efficacy
timeFrame: Measured at 8, 26 and 52 weeks
measure: Side effects
timeFrame: Measured at 8 and 52 weeks
measure: Physical health changes
timeFrame: Measured at baseline, 8, 26 and 52 weeks
measure: Satisfaction with lithium / quetiapine treatment
timeFrame: Measured at 8, 26 and 52 weeks
measure: Change in self-report manic symptoms
timeFrame: Measured at baseline, 8, 26 and 52 weeks
measure: Change in anxiety symptoms
timeFrame: Measured at baseline, 8, 26 and 52 weeks
measure: Time to prescription
timeFrame: 0-52 weeks
measure: Baseline adherence to antidepressant
timeFrame: Measured at baseline
measure: Change in cognition
timeFrame: Measured at baseline, 8, 26 and 52 weeks
measure: Adherence of clinicians
timeFrame: 0-52 weeks
measure: Proportion of participants having an adequate treatment trial
timeFrame: 0-8 weeks
measure: Number of hospital admissions for depressive episode
timeFrame: 52 weeks
measure: Change in personality measure
timeFrame: Measured at baseline, 8, 26 and 52 weeks
measure: Social functioning
timeFrame: Measured weekly over 12 months
measure: Economic analysis
timeFrame: 52 weeks
measure: Predictors of treatment response
timeFrame: 52 weeks
measure: Longitudinal depression severity until time to all cause treatment discontinuation
timeFrame: 52 weeks
measure: Collection and analysis of biological samples for genetic, cytokine and cortisol analysis
timeFrame: 0-52 weeks
measure: Reliability and validity of the Maudsley VAS
timeFrame: Measured at baseline, 8, 26 and 52 weeks
measure: Discrepancy between the self-rated and clinician-rated version of 16 item IDS
timeFrame: Measured at baseline and 8 weeks
measure: Relationship between quetiapine and lithium serum levels, prescribed dose and depressive symptom severity
timeFrame: 52 weeks
measure: Time to new interventions for depression.
timeFrame: 52 weeks
measure: Number of new interventions for depression
timeFrame: 52 weeks
measure: Patient rated experience of the True Colours weekly monitoring system
timeFrame: 8 / 26 / 52 weeks
measure: Change in cognitive function
timeFrame: Baseline, 8, 26 and 52 weeks
measure: 12. Patient views and experiences of lithium and quetiapine
timeFrame: 52 week visit
Locations:
city: London
country: United Kingdom
facility: Institute of Psychiatry, Psychology and Neuroscience, King's College London
Study officials:
affiliation: Professor of Psychiatry
name: Anothony Cleare
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.