Major depressive disorder (MDD) Mental and Behavioural Disorders Major depressive disorder (MDD)
Conditions
Interventions
Interventions as of 22/11/2016:
Each participant will be randomised 1:1 to lithium or quetiapine add on therapy, after their eligibility has been confirmed. Randomisation will be stratified by recruit
Sponsors
King’s College London, and South London and Maudsley NHS Foundation Trust
Eligibility
Sex/Gender
All
Age
18 Years to 100 Years
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 15/12/2017: 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. Inclusion criteria as of 22/11/2016: 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 =30mg/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 for =6 weeks 7. Provision of written, informed consent. Original inclusion criteria: 1. Under the care of a GP and/or adult mental health services 2. Current episode of depression meeting DSM-V criteria for major depressive disorder (MDD) – single or recurrent episode 3. Score 14 or over on the 17-item Hamilton Depression Rating Scale (HAMD) 4. Aged 18 years or older 5. Meet criteria for treatment resistant depression: 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 =30mg/day, tricyclic antidepressant =125mg/day, and as guided by the Maudsley Prescribing Guidelines or BNF for any other antidepressant 6. Current antidepressant treatment has remained unchanged for =4 weeks 7. Provision of written, informed consent
Exclusion criteria
Exclusion criteria: Exclusion criteria as of 15/12/2017: 1. Diagnosis of bipolar disorder (defined as meeting DSM-5 criteria 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. Exclusion criteria as of 22/11/2016: 1. Diagnosis of bipolar disorder (defined as meeting DSM-5 criteria 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. Use of lithium or quetiapine during current episode 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 inhibit
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary outcome measures as of 22/11/2016: 1. Depression severity is measured weekly using the self-rated Quick-Inventory of Depressive Symptomatology (QIDS-SR), over 52 weeks. 2. Time to all cause discontinuation is measured using patient medical notes and patient self-report to determine the time between first prescription and discontinuation over 52 weeks Original primary outcome measure: Longitudinal depressive symptom severity, as measured using the Quick Inventory of Depressive Symptoms self rated (QIDS-SR) questionnaire, assessed weekly via the True Colours system (www.truecolours.nhs.uk) over 52 weeks. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary outcome measures as of 14/11/2018: 1. Change in depression severity measured using the clinician rated Montgomery-Åsberg Depression Rating Scale, MADRS, at baseline, week 8 and week 52 2. Response rates measured by the MADRS at 8 and 52 weeks 3. Remission rates measured using the MADRS at 8 and 52 weeks 4. Health-related quality of life measured using the EuroQol-5D at 8 and 52 weeks 5. Social functioning measured using the Work & Social Adjustment Scale score at baseline, 8 and 52 weeks 6. Adherence to treatment measured using the MARS-5 at weeks 8 and 52 7. Change in weight measured in kilograms by a researcher at baseline, 8 and 52 weeks 8. Change in diastolic blood pressure measured in mmHg by the researcher at baseline, 8 and 52 weeks 9. Change in systolic blood pressure measured in mmHg by the researcher at baseline, 8 and 52 weeks 10. Time to uptake of a new intervention for depression (pharmacological or non-pharmacological) measured by patient self-report up to 52 weeks 11. Time to initiation of treatment measured by patient self-report up to 52 weeks 12. Global improvement measured using the CGI at 8 and 52 weeks 13. Side Effects, measured using the PRISE at 8 and 52 weeks 14. Serious Adverse Events – the number of SAEs measured by reviewing medical notes, patient self-report and patient interview up to 52 weeks Tertiary outcomes 1. Global severity measured using the CGI at 8, 26 and 52 weeks 2. Global efficacy measured using the CGI at 8, 26 and 52 weeks 3. Side effects measured using the PRISE at 8, 26, and 52 weeks 4. Side Effects measured using the three FIBSER subscales: Frequency, Intensity, and Burden at 8 and 52 weeks 5. Physical health changes measured using continuous blood parameters measured in appropriate units and waist circumference in cm measured at baseline, 8, 26 and 52 weeks (these measures will not be completed for all participants; and will be reported if they are completed for a sufficient number) 6. Satisfaction with lith | — |
Countries
England, United Kingdom
Contacts
Public ContactAnthony Cleare
Outcome results
None listed