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Lithium Versus Quetiapine in Treatment Resistant Depression (LQD)

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ClinicalTrials.gov Identifier: NCT03004521
Recruitment Status : Recruiting
First Posted : December 29, 2016
Last Update Posted : December 21, 2017
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Depressive Disorder, Treatment-Resistant Drug: Quetiapine Drug: Lithium Phase 4

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  (Clinical Trial)
Estimated Enrollment : 276 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomised Pragmatic Trial Comparing the Clinical and Cost Effectiveness of Lithium and Quetiapine Augmentation in Treatment Resistant Depression
Actual Study Start Date : November 2016
Estimated Primary Completion Date : July 2020
Estimated Study Completion Date : July 2020

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Longitudinal depressive symptom severity [ Time Frame: 52 weeks ]
    QIDS-SR

  2. Difference in time to all-cause treatment discontinuation [ Time Frame: 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 :
  1. Change in clinician rated depression severity [ Time Frame: From baseline to weeks 8 and 52 ]
    MADRS

  2. Response rates [ Time Frame: 8 weeks and 52 weeks ]
    Assessed using the MADRS questionnaire

  3. Remission rates [ Time Frame: 8 and 52 weeks ]
    Assessed using the MADRS questionnaire

  4. Health related quality of life [ Time Frame: Measured at 8 and 52 weeks ]
    Assessed using the EuroQol-5D questionnaire

  5. Social functioning [ Time Frame: Measured at baseline, 8 and 52 weeks ]
    Measured using the WSAS self rated questionnaire

  6. Adherence to treatment [ Time Frame: Measured at weeks 8 and 52 ]
    Assessed using the MARS-5 questionnaire

  7. Change in weight in kilograms [ Time Frame: Measured at 8 and 52 weeks ]
    Assessed by weighing participants

  8. Change in diastolic blood pressure [ Time Frame: Change from baseline to 8 and 52 weeks ]
    Assessed by measuring blood pressure

  9. Change in systolic blood pressure [ Time Frame: Change from baseline to 8 and 52 weeks ]
    Assessed by measuring blood pressure

  10. Time to uptake of a new intervention (pharmacological or non-pharmalogical) [ Time Frame: 12 months ]
    Assessed by recording all pharmacological and non-pharmacological interventions

  11. Time to initiation of treatment [ Time Frame: Up to 12 months ]
    Assessed using treatment initiation form

  12. CGI Global Improvement [ Time Frame: Measured at 8 and 52 weeks ]
    CGI

  13. Side effects [ Time Frame: Measured at 8 and 52 weeks ]
    PRISE total score

  14. Serious Adverse Events [ Time Frame: 52 weeks ]
    Serious adverse events will be monitored and reported throughout the patient's participation in the trial.


Other Outcome Measures:
  1. Change in global severity [ Time Frame: Measured at 8, 26 and 52 weeks ]
    Change in CGI severity score

  2. Global efficacy [ Time Frame: Measured at 8, 26 and 52 weeks ]
    Change in CGI efficacy score

  3. Side effects [ Time Frame: Measured at 8 and 52 weeks ]
    Frequency of individual items on the PRISE

  4. Physical health changes [ Time Frame: 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

  5. Satisfaction with lithium / quetiapine treatment [ Time Frame: Measured at 8, 26 and 52 weeks ]
    Measured using TSQM subscales

  6. Change in self-report manic symptoms [ Time Frame: Measured at baseline, 8, 26 and 52 weeks ]
    Measured using the Altman Mania Self Rating Scale

  7. Change in anxiety symptoms [ Time Frame: Measured at baseline, 8, 26 and 52 weeks ]
    GAD-7 score

  8. Time to prescription [ Time Frame: 0-52 weeks ]
    First date participant is given a prescription for the treatment

  9. Baseline adherence to antidepressant [ Time Frame: Measured at baseline ]
    MARS-5 score

  10. Change in cognition [ Time Frame: Measured at baseline, 8, 26 and 52 weeks ]
    Total DSCT score

  11. Adherence of clinicians [ Time Frame: 0-52 weeks ]
    Clinician adherence to prescribing and monitoring guidelines

  12. Proportion of participants having an adequate treatment trial [ Time Frame: 0-8 weeks ]
    Adequate treatment trial as defined in study protocol

  13. Number of hospital admissions for depressive episode [ Time Frame: 52 weeks ]
    Measured using psychiatric history assessment

  14. Change in personality measure [ Time Frame: Measured at baseline, 8, 26 and 52 weeks ]
    SAPAS

  15. Social functioning [ Time Frame: Measured weekly over 12 months ]
    WSAS

  16. Economic analysis [ Time Frame: 52 weeks ]
    Costs from the NHS and Personal Social Services perspective and from a societal perspective.

  17. Predictors of treatment response [ Time Frame: 52 weeks ]
    Measured using the Maudsley Staging Model, HAM-D, MINI 7, IDS-C and SAPAS questionnaires.

  18. Longitudinal depression severity until time to all cause treatment discontinuation [ Time Frame: 52 weeks ]
    Measured weekly using the QIDS-SR

  19. Collection and analysis of biological samples for genetic, cytokine and cortisol analysis [ Time Frame: 0-52 weeks ]
    Blood/hair/saliva samples collected in collaboration with the BRC BioResource

  20. Reliability and validity of the Maudsley VAS [ Time Frame: Measured at baseline, 8, 26 and 52 weeks ]
    Measured using the Maudsley VAS, validated against the QIDS-SR and MADRS

  21. Discrepancy between the self-rated and clinician-rated version of 16 item IDS [ Time Frame: Measured at baseline and 8 weeks ]
    Assessed using QIDS and IDS

  22. Relationship between quetiapine and lithium serum levels, prescribed dose and depressive symptom severity [ Time Frame: 52 weeks ]
    MADRS

  23. Time to new interventions for depression. [ Time Frame: 52 weeks ]
    Measured using concomitant medication and concomitant therapy questionnaires

  24. Number of new interventions for depression [ Time Frame: 52 weeks ]
    Measured using concomitant medication and concomitant therapy questionnaires

  25. Patient rated experience of the True Colours weekly monitoring system [ Time Frame: 8 / 26 / 52 weeks ]
    Qualitative Interview in a subset of participants

  26. Change in cognitive function [ Time Frame: Baseline, 8, 26 and 52 weeks ]
    THINC-it composite and individual tests scores in a subset of participants



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03004521


Contacts
Contact: Lindsey Marwood lindsey.marwood@kcl.ac.uk

Locations
United Kingdom
Institute of Psychiatry, Psychology and Neuroscience, King's College London Recruiting
London, United Kingdom, SE5 8AF
Contact: Lindsey Marwood       lindsey.marwood@kcl.ac.uk   
Sponsors and Collaborators
King's College London
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
Investigators
Principal Investigator: Anothony Cleare Professor of Psychiatry

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: King's College London
ClinicalTrials.gov Identifier: NCT03004521     History of Changes
Other Study ID Numbers: HTA 14/222/02
First Posted: December 29, 2016    Key Record Dates
Last Update Posted: December 21, 2017
Last Verified: December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: The decision to share IPD to other researchers will be made by the CI on a case by case basis.

Keywords provided by King's College London:
Lithium
Quetiapine
Augmentation

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Treatment-Resistant
Behavioral Symptoms
Mood Disorders
Mental Disorders
Antidepressive Agents
Lithium Carbonate
Quetiapine Fumarate
Psychotropic Drugs
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimanic Agents