Comparing Quetiapine XR Monotherapy and Augmentation With Lithium Augmentation in TRD Patients

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the efficacy of Quetiapine extended release (XR) in combination with an selective serotonin reuptake inhibitor (SSRI) or Venlafaxine versus Lithium in combination with an selective serotonin reuptake inhibitor or Venlafaxine versus Quetiapine extended release monotherapy in subjects with treatment resistant depression as assessed by the changes from randomisation to week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. As an independent objective, the primary objective will also be evaluated in two subgroups of patients: (1) patients who were resistant to two previous antidepressant therapies and (2) in the subgroup of patients with one previous failure.

Detailed Description
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The secondary objectives of the study are to compare the effects of the three different treatment regimen as assessed by the following variables and, if applicable, by their changes from randomisation to week 6 (end of study). Additionally the time of onset of therapeutic effect will be assessed by evaluating efficacy data after the first four days (Day 4) of treatment as well as after the first week of treatment (Day 8). These analyses will also be performed in the subgroups of patients with 2 failed previous antidepressants and patients with 1 failure.

Official Title
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A Randomised, 6-week, Multicentre, Open-label, Rater-blinded Parallel Group Study Comparing Quetiapine Extended Release Monotherapy and Augmentation With Lithium Augmentation in Patients With Treatment Resistant Depression

Conditions
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Major Depressive Disorder, Treatment Resistant Depression

Intervention / Treatment
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* Drug: Quetiapine XR
* Drug: Lithium carbonate
* Drug: SSRI/Venlafaxine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented clinical diagnosis as confirmed by the M.I.N.I. meeting criteria from the Diagnostic and Statistical Manual of Mental disorders, 4th Edition (DSM-IV) for any of the following:296.2x MDD, Single Episode296.3x MDD, Recurrent Episode Current episode of depression present, at least 42 days prior to enrolment but not more than 18 months MADRS-Score ≥ 25 at enrolment and randomisation Exclusion Criteria: Patients with a DSM-IV Axis I disorder other than MDD within 6 months of randomisation Patients with a diagnosis of DSM-IV Axis II disorder which has a major impact on the patient's current psychiatric status Patients who, in the investigator's judgment pose a current serious suicidal or homicidal risk, or have made a suicide attempt within the past 6 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Add-on Quetiapine XR+SSRI/Venlafaxine<br>Selective serotonin reuptake inhibitors (SSRI) or Venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od). From previous anti-depressant treatment 64% of the patients had SSRI and 35% had Venlafaxine at baseline. | Drug: Quetiapine XR<br>* 300 mg once daily (od)<br>* Other names: Seroquel XR;Drug: SSRI/Venlafaxine<br>* SSRI - doses within label, Venlafaxine dose up to 225 mg/day<br>|
| Active Comparator: Add-on Lithium+SSRI/Venlafaxine<br>Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od). From previous anti-depressant treatment 67% of the patients had SSRI and 33% had Venlafaxine at baseline. | Drug: Lithium carbonate<br>* 900 mg once daily (od)<br>* Other names: Quilonum Retard;Drug: SSRI/Venlafaxine<br>* SSRI - doses within label, Venlafaxine dose up to 225 mg/day<br>|
| Active Comparator: Monotherapy Quetiapine XR<br>Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od) | Drug: Quetiapine XR<br>* 300 mg once daily (od)<br>* Other names: Seroquel XR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Depressive Symptoms Between Randomisation and Week 6 Measured by Change in Montgomery Asberg Depression Rating Scale (MADRS) Total Score (Per Protocol Analysis Set) | Change in LS mean total Montgomery Asberg Depression Rating Scale (MADRS) score from randomisation to end-of-treatment (week 6) (Scale 0-60), lower score indicates a better health status. | 6 weeks treatment | 
| Change in Depressive Symptoms Between Randomisation and Week 6 Measured by Change in Montgomery Asberg Depression Rating Scale (MADRS) Total Score (Modified Intention to Treat Analysis Set) | Change in LS mean total Montgomery Asberg Depression Rating Scale (MADRS) score from randomisation to end-of-treatment (week 6) (Scale 0-60), lower score indicates a better health status. | 6 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Depression Remission; Montgomery-Asberg Depression Rating Scale MADRS ≤10, All Patients | Number of patients in remission, with total Montgomery Asberg Depression Rating Scale (MADRS) score ≤10. MADRS scale has range from 0 to 60, where the lower score indicates the better health status. | 6 weeks of treatment | 
| Depression Remission; Montgomery-Asberg Depression Rating Scale (MADRS) ≤10, Patients With One Previous Treatment Failure | Number of patients in remission with one previous treatment failure and with total Montgomery Asberg Depression Rating Scale (MADRS) score ≤10. MADRS scale has range from 0 to 60, where the lower score indicates the better health status. | 6 weeks of treatment | 
| Depression Remission; Montgomery-Asberg Depression Rating Scale (MADRS) ≤10, Patients With Two Previous Treatment Failure | Number of patients in remission with two previous treatment failure and with total Montgomery Asberg Depression Rating Scale (MADRS) score ≤10. MADRS scale has range from 0 to 60, where the lower score indicates the better health status. | 6 weeks of treatment | 
| Depression Remission; Montgomery-Asberg Depression Rating Scale (MADRS) ≤8 | Number of patients in remission with total Montgomery Asberg Depression Rating Scale (MADRS) score ≤8. MADRS scale has range from 0 to 60, where the lower score indicates the better health status. | 6 weeks of treatment | 
| Depression Remission; Montgomery-Asberg Depression Rating Scale (MADRS) ≤12 | Number of patients in remission with total Montgomery Asberg Depression Rating Scale (MADRS) score ≤12. MADRS scale has range from 0 to 60, where the lower score indicates the better health status. | 6 weeks of treatment | 
| Response Rate; Montgomery-Asberg Depression Rating Scale (MADRS) Score Reduced ≥ 50%, All Patients | Response rate at end of study measured as number of patients with Montgomery Asberg Depression Rating Scale (MADRS) with total score reduction ≥ 50% compared to baseline, the higher number of patients the better | 6 week of treatments | 
| Response Rate; Montgomery-Asberg Depression Rating Scale (MADRS) Score Reduced ≥ 50%, Patients With One Previous Treatment Failure | Response rate at end of study measured as number of patients with Montgomery Asberg Depression Rating Scale (MADRS) with total score reduction ≥ 50% compared to baseline, the higher number of patients the better | 6 weeks of treatment | 
| Response Rate; Montgomery-Asberg Depression Rating Scale (MADRS) Score Reduced ≥ 50%, Patients With Two Previous Treatment Failure | Response rate at end of study measured as number of patients with Montgomery Asberg Depression Rating Scale (MADRS) with total score reduction ≥ 50% compared to baseline, the higher number of patients the better | 6 weeks of treatment | 
| Responder: Clinical Global Impression Improvement (CGI-I) Item 2, All Patients | Change in global improvement measured by Clinical Global Impression Improvement (CGI-I). Scale from 1-4, where lower value shows a larger improvement. | 6 weeks of treatment | 
| Responder: Clinical Global Impression Improvement (CGI)-I Item 2, Patients With One Previous Treatment Failure | Change in global improvement measured by Clinical Global Impression Improvement (CGI-I). Scale from 1-4, where a lower value shows a larger improvement. | 6 weeks of treatment | 
| Responder: Clinical Global Impression Improvement (CGI-I) Item 2, Patients With Two Previous Treatment Failure | Change in global improvement measured by Clinical Global Impression Improvement (CGI-I). Scale from 1-4, where a lower value shows a larger improvement. | 6 weeks of treatment | 
| Change in Clinical Global Impression Scale (CGI-S), All Patients | Change in severity of illness measured by Clinical Global Impression Scale (CGI-S). Scale form 1-7, where a lower value shows a larger improvement. | 6 weeks of treatment | 
| Change in Clinical Global Impression Scale (CGI-S), Patients With One Previous Treatment Failure | Change in severity of illness measured by Clinical Global Impression Scale (CGI-S). Scale from 1-7, where a lower value shows a larger improvement. | 6 weeks of treatment | 
| Change in Clinical Global Impression Scale (CGI-S), Patients With Two Previous Treatment Failure | Change in severity of illness measured by Clinical Global Impression Scale (CGI-S). Scale from 1-7, where a lower value shows a larger improvement. | 6 weeks of treatment | 
| Change in Beck Depression Inventory (BDI) | Self-rating assessment of depressive symptoms using Beck Depression Inventory (BDI). Scale from 0-63, where a lower value shows a larger improvement. | 6 weeks of treatment | 
| Change in Pain, Measured by Visual Analog Scale (VAS) | Self-rating assessment of pain using a visual analogue scale (VAS). Scale from 0-100, where a lower value shows a larger improvement. | 6 weeks of treatment | 
| Change in Anxiety Measured by Visual Analog Scale (VAS) | Self-rating assessment of anxiety using a visual analogue scale (VAS). Scale from 0-100, where a lower value shows a larger improvement. | 6 weeks of treatment | 
| Change in Anxiety Measured by State-Trait Anxiety Inventory (STAI), State Anxiety Inventory | Self-rating assessment of anxiety measured by STAI, state anxiety inventory (Scale 20-80, where a lower value shows a larger improvement) | 6 weeks of treatment | 
| Change in Anxiety Measured by STAI, Trait Anxiety Inventory | Self-rating assessment of anxiety measured by State-Trait Anxiety Inventory (STAI), trait anxiety inventory (Scale 20-80, where a lower value shows a larger improvement) | 6 weeks of treatment | 
| Change in Sleep Quality Measured by Montgomery Asberg Depression Rating Scale (MADRS), Item 4 | Sleeping quality measured by Montgomery-Asberg Depression Rating Scale (MADRS) item 4 (reduced sleep) (Scale 0-6, where a lower value shows a larger improvement) | 6 weeks of treatment | 
| Change in Sleep Quality Measured by Pittsburgh Sleep Quality Index (PSQI) | Self-rated sleeping quality measured by PSQI (Scale 0-21, subscales 0-3, 18 questions, where a lower value shows a larger improvement) | 6 weeks of treatment | 
| Change in Quality of Life Measured by Short-form Health Survey (SF-36), Mental Component | Self rating assessment of quality in life using SF-36, mental component (Scale 0-100, where a higher value shows a larger improvement) | 6 weeks of treatment | 
| Change in Quality of Life Measured by Short-form Health Survey (SF-36), Physical Component | Self rating assessment of quality in life using SF-36, physical component (Scale 0-100, where a higher value shows a larger improvement) | 6 weeks of treatment | 
| Change in Quality of Life Measured by Health Questionnaire EQ-5D as Utility | Self rating assessment of quality in life using EQ-5D utility (Scale 0-100, where a higher value shows a larger improvement) | 6 weeks of treatment | 
| Change in Work Productivity and Activity Impairment: General Health (WPAI:GH) | Self rating assessment of working productivity using WPAI:GH (Scale 0 to number of hours worked during a week multiplied with the salary in Euro, a lower value shows a larger improvement) | 6 weeks of treatment | 
| Change in Clinical Global Impression (CGI) Item 4 Efficacy and Safety Combined, All Patients | The physician has evaluated the therapeutic effect and the side effect combined at end of study. Patients with a 'marked/moderate' therapeutic effect and 'None/Do Not Significantly Interfere' side effect has been added. The higher values show more patients with a treatment effect without any side-effect. The range is from 0 patients to the maximum number of patients in the treatment arm (225, 229 or 221). | 6 weeks of treatment | 
| Change in Clinical Global Impression (CGI) Item 4 Efficacy and Safety Combined, Patients With One Previous Treatment Failure | The physician has evaluated the therapeutic effect and the side effect combined at end of study. Patients with a 'marked/moderate' therapeutic effect and 'None/Do Not Significantly Interfere' side effect has been added. The higher values show more patients with a treatment effect without any side-effect. The range is from 0 patients to the maximum number of patients in the treatment arm. | 6 weeks of treatment | 
| Change in Clinical Global Impression (CGI) Item 4 Efficacy and Safety Combined, Patients With Two Previous Treatment Failures | The physician has evaluated the therapeutic effect and the side effect combined at end of study. Patients with a 'marked/moderate' therapeutic effect and 'None/Do Not Significantly Interfere' side effect has been added. The higher values show more patients with a treatment effect without any side-effect. The range is from 0 patients to the maximum number of patients in the treatment arm. | 6 week of treatments | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Depression, MDD, TRD