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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00789854
• Collaborator: (none)
• Enrollment: 688
• Locations: 106
• Arms: 3
• Duration (Months): 9
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder; Treatment Resistant Depression	Drug: Quetiapine XR; Drug: Lithium carbonate; Drug: SSRI/Venlafaxine	Phase 3

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 688 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Add-on Quetiapine XR+SSRI/Venlafaxine 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; 300 mg once daily (od); Other Names: Seroquel XR ; Drug: SSRI/Venlafaxine; SSRI - doses within label, Venlafaxine dose up to 225 mg/day
Active Comparator: Add-on Lithium+SSRI/Venlafaxine 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; 900 mg once daily (od); Other Names: Quilonum Retard ; Drug: SSRI/Venlafaxine; SSRI - doses within label, Venlafaxine dose up to 225 mg/day
Active Comparator: Monotherapy Quetiapine XR Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Drug: Quetiapine XR; 300 mg once daily (od); Other Names: Seroquel XR

Outcome Measures

Primary Outcome Measures

1. 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) [6 weeks treatment]

   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.

2. 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) [6 weeks of treatment]

   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.

Secondary Outcome Measures

1. Depression Remission; Montgomery-Asberg Depression Rating Scale MADRS ≤10, All Patients [6 weeks of treatment]

   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.

2. Depression Remission; Montgomery-Asberg Depression Rating Scale (MADRS) ≤10, Patients With One Previous Treatment Failure [6 weeks of treatment]

   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.

3. Depression Remission; Montgomery-Asberg Depression Rating Scale (MADRS) ≤10, Patients With Two Previous Treatment Failure [6 weeks of treatment]

   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.

4. Depression Remission; Montgomery-Asberg Depression Rating Scale (MADRS) ≤8 [6 weeks of treatment]

   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.

5. Depression Remission; Montgomery-Asberg Depression Rating Scale (MADRS) ≤12 [6 weeks of treatment]

   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. Response Rate; Montgomery-Asberg Depression Rating Scale (MADRS) Score Reduced ≥ 50%, All Patients [6 week of treatments]

   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

7. Response Rate; Montgomery-Asberg Depression Rating Scale (MADRS) Score Reduced ≥ 50%, Patients With One Previous Treatment Failure [6 weeks of treatment]

   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

8. Response Rate; Montgomery-Asberg Depression Rating Scale (MADRS) Score Reduced ≥ 50%, Patients With Two Previous Treatment Failure [6 weeks of treatment]

   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

9. Responder: Clinical Global Impression Improvement (CGI-I) Item 2, All Patients [6 weeks of treatment]

   Change in global improvement measured by Clinical Global Impression Improvement (CGI-I). Scale from 1-4, where lower value shows a larger improvement.

10. Responder: Clinical Global Impression Improvement (CGI)-I Item 2, Patients With One Previous Treatment Failure [6 weeks of treatment]

    Change in global improvement measured by Clinical Global Impression Improvement (CGI-I). Scale from 1-4, where a lower value shows a larger improvement.

11. Responder: Clinical Global Impression Improvement (CGI-I) Item 2, Patients With Two Previous Treatment Failure [6 weeks of treatment]

    Change in global improvement measured by Clinical Global Impression Improvement (CGI-I). Scale from 1-4, where a lower value shows a larger improvement.

12. Change in Clinical Global Impression Scale (CGI-S), All Patients [6 weeks of treatment]

    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.

13. Change in Clinical Global Impression Scale (CGI-S), Patients With One Previous Treatment Failure [6 weeks of treatment]

    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.

14. Change in Clinical Global Impression Scale (CGI-S), Patients With Two Previous Treatment Failure [6 weeks of treatment]

    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.

15. Change in Beck Depression Inventory (BDI) [6 weeks of treatment]

    Self-rating assessment of depressive symptoms using Beck Depression Inventory (BDI). Scale from 0-63, where a lower value shows a larger improvement.

16. Change in Pain, Measured by Visual Analog Scale (VAS) [6 weeks of treatment]

    Self-rating assessment of pain using a visual analogue scale (VAS). Scale from 0-100, where a lower value shows a larger improvement.

17. Change in Anxiety Measured by Visual Analog Scale (VAS) [6 weeks of treatment]

    Self-rating assessment of anxiety using a visual analogue scale (VAS). Scale from 0-100, where a lower value shows a larger improvement.

18. Change in Anxiety Measured by State-Trait Anxiety Inventory (STAI), State Anxiety Inventory [6 weeks of treatment]

    Self-rating assessment of anxiety measured by STAI, state anxiety inventory (Scale 20-80, where a lower value shows a larger improvement)

19. Change in Anxiety Measured by STAI, Trait Anxiety Inventory [6 weeks of treatment]

    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)

20. Change in Sleep Quality Measured by Montgomery Asberg Depression Rating Scale (MADRS), Item 4 [6 weeks of treatment]

    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)

21. Change in Sleep Quality Measured by Pittsburgh Sleep Quality Index (PSQI) [6 weeks of treatment]

    Self-rated sleeping quality measured by PSQI (Scale 0-21, subscales 0-3, 18 questions, where a lower value shows a larger improvement)

22. Change in Quality of Life Measured by Short-form Health Survey (SF-36), Mental Component [6 weeks of treatment]

    Self rating assessment of quality in life using SF-36, mental component (Scale 0-100, where a higher value shows a larger improvement)

23. Change in Quality of Life Measured by Short-form Health Survey (SF-36), Physical Component [6 weeks of treatment]

    Self rating assessment of quality in life using SF-36, physical component (Scale 0-100, where a higher value shows a larger improvement)

24. Change in Quality of Life Measured by Health Questionnaire EQ-5D as Utility [6 weeks of treatment]

    Self rating assessment of quality in life using EQ-5D utility (Scale 0-100, where a higher value shows a larger improvement)

25. Change in Work Productivity and Activity Impairment: General Health (WPAI:GH) [6 weeks of treatment]

    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)

26. Change in Clinical Global Impression (CGI) Item 4 Efficacy and Safety Combined, All Patients [6 weeks of treatment]

    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).

27. Change in Clinical Global Impression (CGI) Item 4 Efficacy and Safety Combined, Patients With One Previous Treatment Failure [6 weeks of treatment]

    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.

28. Change in Clinical Global Impression (CGI) Item 4 Efficacy and Safety Combined, Patients With Two Previous Treatment Failures [6 week of treatments]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Garran	Australian Capital Territory	Australia
2	Research Site	Brisbane	Queensland	Australia
3	Research Site	Everton Park	Queensland	Australia
4	Research Site	Townsville	Queensland	Australia
5	Research Site	Gilberton	South Australia	Australia
6	Research Site	Clayton	Victoria	Australia
7	Research Site	Frankston	Victoria	Australia
8	Research Site	Heidelberg	Victoria	Australia
9	Research Site	Malvern	Victoria	Australia
10	Research Site	Prahran	Victoria	Australia
11	Research Site	Richmond	Victoria	Australia
12	Research Site	Graz		Austria
13	Research Site	Klagenfurt		Austria
14	Research Site	Salzburg		Austria
15	Research Site	Wels		Austria
16	Research Site	Wiener NEUSTADT		Austria
17	Research Site	Wien		Austria
18	Research Site	Assebroek		Belgium
19	Research Site	Diest		Belgium
20	Research Site	Liege		Belgium
21	Research Site	Tielt		Belgium
22	Research Site	Cerova Koria Village	Veliko Tarnovo	Bulgaria
23	Research Site	Kardjali		Bulgaria
24	Research Site	Pazardjik		Bulgaria
25	Research Site	Pleven		Bulgaria
26	Research Site	Ruse		Bulgaria
27	Research Site	Sofia		Bulgaria
28	Research Site	Varna		Bulgaria
29	Research Site	Esbjerg N		Denmark
30	Research Site	Frederiksberg		Denmark
31	Research Site	Odense		Denmark
32	Research Site	Aachen		Germany
33	Research Site	Achim		Germany
34	Research Site	Augsburg		Germany
35	Research Site	Bad Homburg		Germany
36	Research Site	Bad Honnef		Germany
37	Research Site	Bad Saarow		Germany
38	Research Site	Berlin		Germany
39	Research Site	Bielefeld		Germany
40	Research Site	Bochum		Germany
41	Research Site	Butzbach		Germany
42	Research Site	Chemnitz		Germany
43	Research Site	Dresden		Germany
44	Research Site	Duren		Germany
45	Research Site	Dusseldorf		Germany
46	Research Site	Ellwangen		Germany
47	Research Site	Erbach		Germany
48	Research Site	Gelsenkirchen		Germany
49	Research Site	Gutersloh		Germany
50	Research Site	Halle		Germany
51	Research Site	Hattingen		Germany
52	Research Site	Herborn		Germany
53	Research Site	Kassel		Germany
54	Research Site	Kothen		Germany
55	Research Site	Neu-isenburg		Germany
56	Research Site	Neubrandenburg		Germany
57	Research Site	Nurnberg		Germany
58	Research Site	Oldenburg		Germany
59	Research Site	Ostfildern		Germany
60	Research Site	Schwerin		Germany
61	Research Site	Stuttgart		Germany
62	Research Site	Westerstede		Germany
63	Research Site	Wurzburg		Germany
64	Research Site	Budapest		Hungary
65	Research Site	Gyor		Hungary
66	Research Site	Gyula		Hungary
67	Research Site	Nyiregyhaza		Hungary
68	Research Site	Bressanone	BZ	Italy
69	Research Site	Brunico	BZ	Italy
70	Research Site	Cagliari	CA	Italy
71	Research Site	Pisa	PI	Italy
72	Research Site	Roma	RM	Italy
73	Research Site	Bolzano		Italy
74	Research Site	Catania		Italy
75	Research Site	Napoli		Italy
76	Research Site	Roma		Italy
77	Research Site	Braga		Portugal
78	Research Site	Coimbra		Portugal
79	Research Site	Lisboa		Portugal
80	Research Site	Santarem		Portugal
81	Research Site	Bucharest		Romania
82	Research Site	Craiova		Romania
83	Research Site	Galati		Romania
84	Research Site	Sibiu		Romania
85	Research Site	Bratislava		Slovakia
86	Research Site	Krupina		Slovakia
87	Research Site	Levice		Slovakia
88	Research Site	Liptovsky Mikulas		Slovakia
89	Research Site	Michalovce Stranany		Slovakia
90	Research Site	Presov		Slovakia
91	Research Site	Roznava		Slovakia
92	Research Site	Zilina-bytcica		Slovakia
93	Research Site	Zlate Moravce		Slovakia
94	Research Site	Sama de Langreo	Asturias	Spain
95	Research Site	Salamanca	Castilla Leon	Spain
96	Research Site	Zamora	Castilla Leon	Spain
97	Research Site	Barcelona	Cataluna	Spain
98	Research Site	Vigo	Galicia	Spain
99	Research Site	Addlestone	Surrey	United Kingdom
100	Research Site	Winnick	Warrington	United Kingdom
101	Research Site	Horsham	West Sussex	United Kingdom
102	Research Site	Coventry		United Kingdom
103	Research Site	Glasgow		United Kingdom
104	Research Site	Harrow		United Kingdom
105	Research Site	Hull		United Kingdom
106	Research Site	Winsford		United Kingdom

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Michael Bauer, professor, Germany
• Study Director: Birgit Ekholm, PhD, AstraZeneca MC Sweden

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00789854
• Other Study ID Numbers: D1443L00044
• First Posted: Nov 13, 2008
• Last Update Posted: May 23, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by AstraZeneca: Depression; MDD; TRD
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Quetiapine Fumarate; Lithium Carbonate; Venlafaxine Hydrochloride

Study Results

Participant Flow

Recruitment Details	This was a 3 arm, open-label randomised, rater blinded, parallel group study comparing quetiapine XR monotherapy and augmentation with lithium augmentation in patients with treatment resistant depression, Recruitment period 6 November 2008 to 19 June 2009
Pre-assignment Detail	At visit 1 and 2 (randomisation) the patients should have a Montgomery-Asberg Depression Rating Scale (MADRS) total score above or equal to 25

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Period Title: Overall Study
STARTED	228	231	229
COMPLETED	179	196	182
NOT COMPLETED	49	35	47

Baseline Characteristics

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium	Total
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)	Total of all reporting groups
Overall Participants	225	229	221	675
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	47	47	47	47
Sex: Female, Male (Count of Participants)
Female	152 67.6%	162 70.7%	152 68.8%	466 69%
Male	73 32.4%	67 29.3%	69 31.2%	209 31%
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (Number) [Number]
Diagnose code 296.2x Major Depressive Disorder (MD	50 22.2%	36 15.7%	41 18.6%	127 18.8%
Diagnose code 296.3x MDD, Recurrent	175 77.8%	193 84.3%	180 81.4%	548 81.2%
Montgomery-Asberg Depression Rating Scale (MADRS) total score (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	33.74 (5.6)	33.15 (5.34)	32.91 (5.2)	33.32 (5.4)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	75.3 (17.2)	75.2 (17)	76.4 (16.1)	75.8 (16.65)

Outcome Measures

1. Primary Outcome

Title	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)
Description	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.
Time Frame	6 weeks treatment

Outcome Measure Data

Analysis Population Description

Analysis was 'per protocol'. Exclusion reason from analysis: Violation of exclusion/inclusion criteria; Non-compliance regarding prohibited concomitant medication, Total unavailability of MADRS score after randomization, Patient not treated with any dose of study drug after randomization, Non-compliance regarding titration to 300 mg quetiapine/d.

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	180	183	109
Least Squares Mean (Standard Error) [scores on a scale]	-16.2 (0.843)	-17.2 (0.826)	-14.9 (0.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Add-on Quetiapine XR, Add-on Lithium
	Comments	Add-on quetiapine XR was tested versus add-on lithium for non-inferiority. The null hypothesis was that the add-on quetiapine treatment was non-inferior to add-on lithium.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The non-inferiority margin for differences was set to 3 units in the MADRS total score. A power set to 80% and using a Bonferroni-adjusted one-sided alpha* = alpha/3 = 0.0083 yields a planned sample size of 192 patients per study group. With a drop out of 4% a total of 600 randomized patients were required to obtain 192 efficacy evaluable patients per treatment group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.322
	Confidence Interval	() 97.5%; -4.6 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Quetiapine XR Mono, Add-on Lithium
	Comments	Quetiapine XR mono was tested versus add-on lithium for non-inferiority. The null hypothesis was that the quetiapine XR mono treatment was non-inferior to add-on lithium.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The non-inferiority margin for differences was set to 3 units in the MADRS total score. A power set to 80% and using a Bonferroni-adjusted one-sided alpha* = alpha/3 = 0.0083 yields a planned sample size of 192 patients per study group. With a drop out of 4% a total of 600 randomized patients were required to obtain 192 efficacy evaluable patients per treatment group.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.639
	Confidence Interval	() 97.5%; -3.24 to 1.312
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	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)
Description	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.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	225	229	221
Least Squares Mean (Standard Error) [scores on a scale]	-13.9 (0.806)	-15.1 (0.797)	-13.3 (0.801)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Add-on Quetiapine XR, Add-on Lithium
	Comments	The null hypothesis was that the add-on quetiapine XR treatment was not different to the add-on lithium treatment. The power calculation was done for the primary non-inferior analysis. This superiority analysis was only done if the non-inferior analysis was successful.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0489
	Comments	Adjustment for multiplicity was done, alpha = 0.025
	Method	ANCOVA
	Comments	Superiority testing of primary outcome showed no significant difference in the Modified Intention To Treat (ITT) population

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Quetiapine XR Mono, Add-on Lithium
	Comments	The null hypothesis was that the quetiapine XR mono treatment was not different from the add-on lithium treatment. The power calculation was done for the primary non-inferior analysis. This superiority analysis was only done if the non-inferior analysis was successful.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4368
	Comments	Adjustment for multiplicity was done, alpha = 0.025
	Method	ANCOVA
	Comments	Superiority testing of primary outcome showed no significant difference in the Modified Intention To Treat (ITT) population

3. Secondary Outcome

Title	Depression Remission; Montgomery-Asberg Depression Rating Scale MADRS ≤10, All Patients
Description	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.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	225	229	221
Number [Participants]	53 23.6%	73 31.9%	60 27.1%

4. Secondary Outcome

Title	Depression Remission; Montgomery-Asberg Depression Rating Scale (MADRS) ≤10, Patients With One Previous Treatment Failure
Description	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.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	114	117	114
Number [Participants]	22 9.8%	42 18.3%	31 14%

5. Secondary Outcome

Title	Depression Remission; Montgomery-Asberg Depression Rating Scale (MADRS) ≤10, Patients With Two Previous Treatment Failure
Description	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.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	114	114	115
Number [Participants]	31 13.8%	31 13.5%	29 13.1%

6. Secondary Outcome

Title	Depression Remission; Montgomery-Asberg Depression Rating Scale (MADRS) ≤8
Description	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.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	225	229	221
Number [Participants]	35 15.6%	58 25.3%	45 20.4%

7. Secondary Outcome

Title	Depression Remission; Montgomery-Asberg Depression Rating Scale (MADRS) ≤12
Description	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.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	225	229	221
Number [Participants]	67 29.8%	89 38.9%	73 33%

8. Secondary Outcome

Title	Response Rate; Montgomery-Asberg Depression Rating Scale (MADRS) Score Reduced ≥ 50%, All Patients
Description	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
Time Frame	6 week of treatments

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	225	229	221
Number [Participants]	114 50.7%	120 52.4%	102 46.2%

9. Secondary Outcome

Title	Response Rate; Montgomery-Asberg Depression Rating Scale (MADRS) Score Reduced ≥ 50%, Patients With One Previous Treatment Failure
Description	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
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	114	117	114
Number [Participants]	54 24%	65 28.4%	53 24%

10. Secondary Outcome

Title	Response Rate; Montgomery-Asberg Depression Rating Scale (MADRS) Score Reduced ≥ 50%, Patients With Two Previous Treatment Failure
Description	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
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	114	114	115
Number [Participants]	60 26.7%	55 24%	49 22.2%

11. Secondary Outcome

Title	Responder: Clinical Global Impression Improvement (CGI-I) Item 2, All Patients
Description	Change in global improvement measured by Clinical Global Impression Improvement (CGI-I). Scale from 1-4, where lower value shows a larger improvement.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	224	229	220
Mean (Standard Deviation) [scores on a scale]	-1.54 (1.24)	-1.85 (1.34)	-1.58 (1.32)

12. Secondary Outcome

Title	Responder: Clinical Global Impression Improvement (CGI)-I Item 2, Patients With One Previous Treatment Failure
Description	Change in global improvement measured by Clinical Global Impression Improvement (CGI-I). Scale from 1-4, where a lower value shows a larger improvement.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	113	115	111
Mean (Standard Deviation) [scores on a scale]	-1.42 (1.17)	-1.91 (1.31)	-1.62 (1.27)

13. Secondary Outcome

Title	Responder: Clinical Global Impression Improvement (CGI-I) Item 2, Patients With Two Previous Treatment Failure
Description	Change in global improvement measured by Clinical Global Impression Improvement (CGI-I). Scale from 1-4, where a lower value shows a larger improvement.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	111	114	109
Mean (Standard Deviation) [scores on a scale]	-1.67 (1.30)	-1.79 (1.36)	-1.54 (1.38)

14. Secondary Outcome

Title	Change in Clinical Global Impression Scale (CGI-S), All Patients
Description	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.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	224	229	220
Least Squares Mean (Standard Error) [scores on a scale]	-1.43 (0.101)	-1.65 (0.099)	-1.49 (0.1)

15. Secondary Outcome

Title	Change in Clinical Global Impression Scale (CGI-S), Patients With One Previous Treatment Failure
Description	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.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	113	115	111
Least Squares Mean (Standard Error) [scores on a scale]	-1.45 (0.133)	-1.82 (0.13)	-1.59 (0.13)

16. Secondary Outcome

Title	Change in Clinical Global Impression Scale (CGI-S), Patients With Two Previous Treatment Failure
Description	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.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	111	114	109
Least Squares Mean (Standard Error) [scores on a scale]	-1.52 (0.133)	-1.55 (0.131)	-1.45 (0.135)

17. Secondary Outcome

Title	Change in Beck Depression Inventory (BDI)
Description	Self-rating assessment of depressive symptoms using Beck Depression Inventory (BDI). Scale from 0-63, where a lower value shows a larger improvement.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	213	212	205
Least Squares Mean (Standard Error) [scores on a scale]	-11.7 (0.926)	-13.5 (0.921)	-12.2 (0.922)

18. Secondary Outcome

Title	Change in Pain, Measured by Visual Analog Scale (VAS)
Description	Self-rating assessment of pain using a visual analogue scale (VAS). Scale from 0-100, where a lower value shows a larger improvement.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	221	222	218
Least Squares Mean (Standard Error) [scores on a scale]	-9.47 (1.695)	-8.03 (1.681)	-8.3 (1.682)

19. Secondary Outcome

Title	Change in Anxiety Measured by Visual Analog Scale (VAS)
Description	Self-rating assessment of anxiety using a visual analogue scale (VAS). Scale from 0-100, where a lower value shows a larger improvement.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	219	224	218
Least Squares Mean (Standard Error) [scores on a scale]	-21.2 (1.972)	-23.4 (1.947)	-20.6 (1.952)

20. Secondary Outcome

Title	Change in Anxiety Measured by State-Trait Anxiety Inventory (STAI), State Anxiety Inventory
Description	Self-rating assessment of anxiety measured by STAI, state anxiety inventory (Scale 20-80, where a lower value shows a larger improvement)
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	223	227	217
Least Squares Mean (Standard Error) [Scores on a scale]	-0.62 (0.347)	0.014 (0.344)	-0.87 (0.35)

21. Secondary Outcome

Title	Change in Anxiety Measured by STAI, Trait Anxiety Inventory
Description	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)
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	220	220	214
Least Squares Mean (Standard Error) [Scores on a scale]	-1.01 (0.331)	-1.36 (0.328)	-1.39 (0.331)

22. Secondary Outcome

Title	Change in Sleep Quality Measured by Montgomery Asberg Depression Rating Scale (MADRS), Item 4
Description	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)
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	225	229	221
Least Squares Mean (Standard Error) [MADRS item 4 score]	-2.2 (0.108)	-2.4 (0.107)	-1.63 (0.108)

23. Secondary Outcome

Title	Change in Sleep Quality Measured by Pittsburgh Sleep Quality Index (PSQI)
Description	Self-rated sleeping quality measured by PSQI (Scale 0-21, subscales 0-3, 18 questions, where a lower value shows a larger improvement)
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	200	196	185
Least Squares Mean (Standard Error) [Scores on a scale]	-4.77 (0.36)	-4.96 (0.358)	-3.51 (0.364)

24. Secondary Outcome

Title	Change in Quality of Life Measured by Short-form Health Survey (SF-36), Mental Component
Description	Self rating assessment of quality in life using SF-36, mental component (Scale 0-100, where a higher value shows a larger improvement)
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	178	171	174
Least Squares Mean (Standard Error) [Scores on a scale]	9.59 (0.929)	10.77 (0.925)	9.66 (0.932)

25. Secondary Outcome

Title	Change in Quality of Life Measured by Short-form Health Survey (SF-36), Physical Component
Description	Self rating assessment of quality in life using SF-36, physical component (Scale 0-100, where a higher value shows a larger improvement)
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	178	171	174
Least Squares Mean (Standard Error) [Scores on a scale]	5.224 (0.811)	5.065 (0.813)	4.566 (0.817)

26. Secondary Outcome

Title	Change in Quality of Life Measured by Health Questionnaire EQ-5D as Utility
Description	Self rating assessment of quality in life using EQ-5D utility (Scale 0-100, where a higher value shows a larger improvement)
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	220	220	215
Least Squares Mean (Standard Error) [Scores on a scale]	0.184 (0.023)	0.224 (0.023)	0.208 (0.023)

27. Secondary Outcome

Title	Change in Work Productivity and Activity Impairment: General Health (WPAI:GH)
Description	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)
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	31	39	25
Least Squares Mean (Standard Error) [Scores on a scale]	-233 (0.023)	-185 (0.023)	-299 (0.023)

28. Secondary Outcome

Title	Change in Clinical Global Impression (CGI) Item 4 Efficacy and Safety Combined, All Patients
Description	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).
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	225	229	221
Number [Participants]	135 60%	146 63.8%	131 59.3%

29. Secondary Outcome

Title	Change in Clinical Global Impression (CGI) Item 4 Efficacy and Safety Combined, Patients With One Previous Treatment Failure
Description	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.
Time Frame	6 weeks of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	113	115	111
Number [Participants]	67 29.8%	75 32.8%	69 31.2%

30. Secondary Outcome

Title	Change in Clinical Global Impression (CGI) Item 4 Efficacy and Safety Combined, Patients With Two Previous Treatment Failures
Description	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.
Time Frame	6 week of treatments

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine XR Mono	Add-on Quetiapine XR	Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)	Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
Measure Participants	112	114	110
Number [Participants]	68 30.2%	71 31%	62 28.1%

Adverse Events

Arm/Group Title	Quetiapine XR Mono		Add-on Quetiapine XR		Add-on Lithium
Arm/Group Description	Switch from previous treatment with SSRI or venlafaxine to quetiapine XR monotherapy, 300mg tablet once daily (od)		Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with quetiapine XR, 300mg tablet once daily (od)		Selective serotonin reuptake inhibitors (SSRI) or venlafaxine from previous therapy + add-on treatment with lithium, approximately 900mg tablet once daily (od)
All Cause Mortality
	Quetiapine XR Mono		Add-on Quetiapine XR		Add-on Lithium
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Quetiapine XR Mono		Add-on Quetiapine XR		Add-on Lithium
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/228 (2.2%)		5/231 (2.2%)		2/229 (0.9%)
Gastrointestinal disorders
Diarrhoea	0/228 (0%)		1/231 (0.4%)		0/229 (0%)
Hepatobiliary disorders
Cholelithiasis	0/228 (0%)		0/231 (0%)		1/229 (0.4%)
Injury, poisoning and procedural complications
Overdose	1/228 (0.4%)		0/231 (0%)		0/229 (0%)
Psychiatric disorders
Depression	0/228 (0%)		3/231 (1.3%)		1/229 (0.4%)
Affective Disorder	1/228 (0.4%)		0/231 (0%)		0/229 (0%)
Psychotic Disorder	1/228 (0.4%)		0/231 (0%)		0/229 (0%)
Restlessness	1/228 (0.4%)		0/231 (0%)		0/229 (0%)
Suicidal Ideation	1/228 (0.4%)		0/231 (0%)		0/229 (0%)
Mania	0/228 (0%)		1/231 (0.4%)		0/229 (0%)
Other (Not Including Serious) Adverse Events
	Quetiapine XR Mono		Add-on Quetiapine XR		Add-on Lithium
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	93/228 (40.8%)		90/231 (39%)		41/229 (17.9%)
Gastrointestinal disorders
Dry mouth	13/228 (5.7%)		22/231 (9.5%)		6/229 (2.6%)
General disorders
Fatigue	21/228 (9.2%)		13/231 (5.6%)		7/229 (3.1%)
Nervous system disorders
Somnolence	22/228 (9.6%)		20/231 (8.7%)		0/229 (0%)
Sedation	15/228 (6.6%)		11/231 (4.8%)		0/229 (0%)
Tremor	0/228 (0%)		0/231 (0%)		15/229 (6.6%)
Dizziness	11/228 (4.8%)		14/231 (6.1%)		0/229 (0%)
Headache	11/228 (4.8%)		10/231 (4.3%)		13/229 (5.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.