Depressive Disorder, Treatment-Resistant
Conditions
Keywords
Lithium, Quetiapine, Augmentation
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.
Interventions
DRUGQuetiapine
Quetipatine prescribed in addition to the patient's existing antidepressant treatment.
DRUGLithium
Lithium prescribed in addition to the patient's existing antidepressant treatment.
Sponsors
University of Oxford
Newcastle University
Oxford Health NHS Foundation Trust
Northumberland, Tyne and Wear NHS Foundation Trust
South London and Maudsley NHS Foundation Trust
Tees, Esk and Wear Valleys NHS Foundation Trust
Sussex Partnership NHS Foundation Trust
Avon and Wiltshire Mental Health Partnership NHS Trust
King's College London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 clinician rated depression severity | From baseline to weeks 8 and 52 | MADRS |
| 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. |
| Change in systolic blood pressure | Change from baseline to 8 and 52 weeks | Assessed by measuring blood pressure |
| Response rates | 8 weeks and 52 weeks | Assessed using the MADRS questionnaire |
Other
| Measure | Time frame | Description |
|---|---|---|
| Predictors of treatment response | 52 weeks | Measured using the Maudsley Staging Model, HAM-D, MINI 7, IDS-C and SAPAS questionnaires. |
| Longitudinal depression severity until time to all cause treatment discontinuation | 52 weeks | Measured weekly using the QIDS-SR |
| Collection and analysis of biological samples for genetic, cytokine and cortisol analysis | 0-52 weeks | Blood/hair/saliva samples collected in collaboration with the BRC BioResource |
| Reliability and validity of the Maudsley VAS | Measured at baseline, 8, 26 and 52 weeks | Measured using the Maudsley VAS, validated against the QIDS-SR and MADRS |
| Discrepancy between the self-rated and clinician-rated version of 16 item IDS | Measured at baseline and 8 weeks | Assessed using QIDS and IDS |
| Relationship between quetiapine and lithium serum levels, prescribed dose and depressive symptom severity | 52 weeks | MADRS |
| Time to new interventions for depression. | 52 weeks | Measured using concomitant medication and concomitant therapy questionnaires |
| Number of new interventions for depression | 52 weeks | Measured using concomitant medication and concomitant therapy questionnaires |
| Patient rated experience of the True Colours weekly monitoring system | 8 / 26 / 52 weeks | Qualitative Interview in a subset of participants |
| Change in cognitive function | Baseline, 8, 26 and 52 weeks | THINC-it composite and individual tests scores in a subset of participants |
| Change in global severity | Measured at 8, 26 and 52 weeks | Change in CGI severity score |
| 12. Patient views and experiences of lithium and quetiapine | 52 week visit | Qualitative interviews in a subset of participants |
| Global efficacy | Measured at 8, 26 and 52 weeks | Change in CGI efficacy score |
| Side effects | Measured at 8 and 52 weeks | Frequency of individual items on the PRISE |
| Physical health changes | Measured at baseline, 8, 26 and 52 weeks | Not completed for all participants. Will be reported if there is a sufficient number e.g. blood parameters and waist circumference |
| Satisfaction with lithium / quetiapine treatment | Measured at 8, 26 and 52 weeks | Measured using TSQM subscales |
| Change in self-report manic symptoms | Measured at baseline, 8, 26 and 52 weeks | Measured using the Altman Mania Self Rating Scale |
| Change in anxiety symptoms | Measured at baseline, 8, 26 and 52 weeks | GAD-7 score |
| Time to prescription | 0-52 weeks | First date participant is given a prescription for the treatment |
| Baseline adherence to antidepressant | Measured at baseline | MARS-5 score |
| Change in cognition | Measured at baseline, 8, 26 and 52 weeks | Total DSCT score |
| Adherence of clinicians | 0-52 weeks | Clinician adherence to prescribing and monitoring guidelines |
| Proportion of participants having an adequate treatment trial | 0-8 weeks | Adequate treatment trial as defined in study protocol |
| Number of hospital admissions for depressive episode | 52 weeks | Measured using psychiatric history assessment |
| Change in personality measure | Measured at baseline, 8, 26 and 52 weeks | SAPAS |
| Social functioning | Measured weekly over 12 months | WSAS |
| Economic analysis | 52 weeks | Costs from the NHS and Personal Social Services perspective and from a societal perspective. |
Countries
United Kingdom
Contacts
Primary ContactLindsey Marwood
Outcome results
None listed