Adult Bipolar Mania

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00931723
• Collaborator: Quintiles, Inc. (Industry)
• Enrollment: 356
• Locations: 65
• Arms: 2
• Duration (Months): 17
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if lithium 600-1800 mg/day is effective when added to quetiapine fumarate extended release (quetiapine XR or SEROQUEL® XR) 400-800 mg/day in treating acute mania and if so, how it compares with placebo (a non-active capsule, like a sugar pill, that looks like lithium).

Condition or Disease	Intervention/Treatment	Phase
Acute Mania	Drug: Quetiapine fumarate XR; Drug: Lithium; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 356 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: An International, Multicenter, Double-blind, Randomized, Placebo-controlled, Phase IV Study of the Safety and Efficacy of Lithium Versus Placebo as an Add on to SEROQUEL XR (Quetiapine Fumarate) in Adult Patients With Acute Mania
• Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Nov 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Seroquel XR and Lithium	Drug: Quetiapine fumarate XR; Oral treatment, once daily, Day 1 = 300 mg, Day 2 and thereafter 600 mg. Dose might be adjusted as from Day 3 by the discretion of the investigator.; Other Names: Seroquel XR ; Drug: Lithium; Oral treatment, twice daily, Days 1 and 2 = 600 mg/day, Days 3-8 = 900 mg/day. Dose adjustment from day 9 to end of study will be at the discretion of the investigator.
Placebo Comparator: 2 Seroquel XR and placebo	Drug: Quetiapine fumarate XR; Oral treatment, once daily, Day 1 = 300 mg, Day 2 and thereafter 600 mg. Dose might be adjusted as from Day 3 by the discretion of the investigator.; Other Names: Seroquel XR ; Drug: Placebo; Oral treatment twice daily.

Outcome Measures

Primary Outcome Measures

1. Change in the Young Mania Rating Scale (YMRS) Total Score From Baseline to Final Assessment (Day 43) [Change in YMRS total score from baseline to Day 43.]

   The YMRS total score ranges from 0 to 60 where higher scores indicate more severe mania, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in manic symptoms. Total score ≤12 indicates remission (13-19=minimal symptoms; 20-25=mild mania, 26-37=moderate mania, 38-60=severe mania).

Secondary Outcome Measures

1. The Number of Patients With Clinically Significant Response. [43 days (from baseline to Day 43)]

   The number of patients with clinically significant response (defined as ≥50% reduction from baseline to Day 43 in the YMRS total score) was calculated. The YMRS total score ranges from 0 to 60 where higher scores indicate more severe mania, thus, a negative change (or 50% reduction) from baseline indicates a reduction (or improvement) in manic symptoms.

2. Remission [Days 8 to 43]

   The number of patients with clinically significant remission (defined as YMRS total score ≤12) from Days 8 to 43) was calculated. The Young Mania Rating Scale total score ranges from 0 to 60 where higher scores indicate more severe mania, thus, a negative change (or 50% reduction) from baseline indicates a reduction (or improvement) in manic symptoms. Total score ≤12 indicates remission (13-19=minimal symptoms; 20-25=mild mania, 26-37=moderate mania, 38-60=severe mania).

3. Change From Baseline to Day 43 in CGI-BP-S (Clinical Global Impressions for Bipolar Disorder-Severity of Illness) [Change from baseline to Day 43.]

   The CGI-BP-S scale rates the severity of the patient's illness at the time of assessment and is scored from 1 to 7 (1=normal, not ill to 7=very severely ill). Higher CGI-BP-S scores indicate greater illness severity.

4. Change From Baseline to Day 43 in CGI-BP-C (Clinical Global Impressions for Bipolar Disorder-Change From Preceding Phase) [Change from baseline to Day 43]

   The CGI-BP-C scale rates how much the patient's illness has improved or worsened compared to the phase immediately preceding treatment and is scored on a scale from 1 to 8 (1=very much improved to 7=very much worse; 8=not applicable). A missing score will be used when a scale scored as 8 (not applicable). CGI-BP-C scores >4 indicate worsening, while scores <4 indicate improvement.

5. Improvement of Overall Bipolar Illness [Day 43.]

   The number of patients with a CGI-BP-C of "Much" or "Very much" improved in overall bipolar illness assessment at Day 43 was calculated. The CGI-BP-C scale rates how much the patient's illness has improved or worsened compared to the phase immediately preceding treatment and is scored on a scale from 1 to 8 (1=very much improved to 7=very much worse; 8=not applicable). A missing score will be used when a scale scored as 8 (not applicable). CGI-BP-C scores >4 indicate worsening, while scores <4 indicate improvement.

6. Change From Baseline to Day 43 in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score [Change from baseline to Day 43.]

   The MADRS is a 10-item scale that evaluates depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. Higher MADRS scores indicate higher levels of depressive symptoms.

7. Change From Baseline to Day 43 in Positive and Negative Syndrome Scale (PANSS) Total Score [Change from baseline to Day 43]

   The PANSS is a 30-item scale designed to assess various symptoms of schizophrenia and are rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology). The PANSS total score is the sum of all 30 individual-item scores and ranges from 30 to 210.A negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

8. Change From Baseline to Day 43 in PANSS Activation Subscale Score [Change from baseline to Day 43]

   The PANSS is a 30-item scale designed to assess various symptoms of schizophrenia and are rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology). The PANSS activation subscale score for effect on agitation and aggression is the sum of 6 PANSS individual items (ie, hostility, poor impulse control, excitement, uncooperativeness, poor rapport and tension) and ranges from 6 to 42. A negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

9. Change From Baseline to Day 43 in PANSS Positive Subscale Score [Change from baseline to Day 43]

   The PANSS is a 30-item scale designed to assess various symptoms of schizophrenia and are rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology). The PANSS positive subscale score is the sum of the 7 positive item scores (ie, delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution and hostility) and ranges from 7 to 49. A negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

10. Change From Baseline to Day 43 in Each YMRS Item Score No. 1 [Change from baseline to Day 43]

    The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4 (0=normal). This analysis is for Item 1 (Elevated mood) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

11. Change From Baseline to Day 43 in Each YMRS Item Score No. 2 [Change from baseline to Day 43]

    The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4 (0=normal). This analysis is for Item 2 (increased motor activity-energy) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

12. Change From Baseline to Day 43 in Each YMRS Item Score No. 3 [Change from baseline to Day 43]

    The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4 (0=normal). This analysis is for Item 3 (sexual interest) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

13. Change From Baseline to Day 43 in Each YMRS Item Score No. 4 [Change from baseline to Day 43]

    The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4 (0=normal). This analysis is for Item 4 (sleep) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

14. Change From Baseline to Day 43 in Each YMRS Item Score No. 5 [Change from baseline to Day 43]

    The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4 (0=normal). This analysis is for Item 5 (Irritability) which ranges from 0 to 8 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

15. Change From Baseline to Day 43 in Each YMRS Item Score No. 6 [Change from baseline to Day 43]

    The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4 (0=normal). This analysis is for Item 6 (speech-rate and amount) which ranges from 0 to 8 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

16. Change From Baseline to Day 43 in Each YMRS Item Score No. 7 [Change from baseline to Day 43]

    The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4. This analysis is for Item 7 (language-thought disorder) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

17. Change From Baseline to Day 43 in Each YMRS Item Score No. 8 [Change from baseline to Day 43]

    The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4. This analysis is for Item 8 (content) which ranges from 0 to 8 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

18. Change From Baseline to Day 43 in Each YMRS Item Score No. 9 [Change from baseline to Day 43]

    The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4. . This analysis is for Item 9 (disruptive-aggressive behavior) which ranges from 0 to 8 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

19. Change From Baseline to Day 43 in Each YMRS Item Score No. 10 [Change from baseline to Day 43]

    The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4. This analysis is for Item 10 (appearance) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

20. Change From Baseline to Day 43 in Each YMRS Item Score No. 11 [Change from baseline to Day 43]

    The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4. This analysis is for Item 11 (insight) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Provision of informed consent before any study procedures are performed.

• The patient must have a documented clinical diagnosis for bipolar I disorder, including recent episode manic or mixed, and being male of females age 18-65 years, inclusive.

• Patients may be outpatients or inpatients at enrollment visit, but all patients must be inpatients when randomized and remain inpatients until discharged at the discretion of the investigator.

Exclusion Criteria:

• The patient can not have had up to 8 mood episodes during the past 12 months and not been continuously hospitalized for acute bipolar for up to 3 weeks immediately before participating in the study.

• The patient can not have a past diagnosis of stroke or medically documented transient ischemic attacks (TIA) or a history of seizure disorder, except for febrile convulsions.

• The patient must not have received electroconvulsive treatment (ECT) within 90 days before participating in the study and in the doctors judgement pose a current suicidal or homicidal risk.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Cedex		Belgium
2	Research Site	Dendermonde		Belgium
3	Research Site	Montignies-sur-sambre		Belgium
4	Research Site	Overpelt		Belgium
5	Research Site	Tournai		Belgium
6	Research Site	Burgas		Bulgaria
7	Research Site	Cedex		Bulgaria
8	Research Site	Kazanlak		Bulgaria
9	Research Site	Pazardjik		Bulgaria
10	Research Site	Plovdiv		Bulgaria
11	Research Site	Radnevo		Bulgaria
12	Research Site	Sofia		Bulgaria
13	Research Site	Berlin	BE	Germany
14	Research Site	Koln	NW	Germany
15	Research Site	Berlin		Germany
16	Research Site	Cedex		Germany
17	Research Site	Mannheim		Germany
18	Research Site	Munchen		Germany
19	Research Site	Nurnberg		Germany
20	Research Site	Visakhapatnam	Andh Prad	India
21	Research Site	Ahmedabad	Gujarat	India
22	Research Site	Bangalore	Karna	India
23	Research Site	Mangalore	Karna	India
24	Research Site	Manipal	Karna	India
25	Research Site	Nashik	Mahara	India
26	Research Site	Jaipur	Rajasthan	India
27	Research Site	Kanpur	Uttar Prad	India
28	Research Site	Cedex		India
29	Research Site	Bat Yam		Israel
30	Research Site	Beer Ya'acov		Israel
31	Research Site	Cedex		Israel
32	Research Site	Haifa		Israel
33	Research Site	Petach-tikva		Israel
34	Research Site	Tel-hashomer		Israel
35	Research Site	Bydgoszcz		Poland
36	Research Site	Cedex		Poland
37	Research Site	Choroszcz		Poland
38	Research Site	Gorlice		Poland
39	Research Site	Katowice		Poland
40	Research Site	Krakow		Poland
41	Research Site	Lublin		Poland
42	Research Site	Poznan		Poland
43	Research Site	Arkhangelsk		Russian Federation
44	Research Site	Cedex		Russian Federation
45	Research Site	Chita		Russian Federation
46	Research Site	Kazan		Russian Federation
47	Research Site	Moscow		Russian Federation
48	Research Site	Saratov		Russian Federation
49	Research Site	St Petersburg		Russian Federation
50	Research Site	St. Petersburg		Russian Federation
51	Research Site	Voronezh		Russian Federation
52	Research Site	Bloemfontein	Free State	South Africa
53	Research Site	Vereeniging	Free State	South Africa
54	Research Site	Worcester	W Cape	South Africa
55	Research Site	Cape Town		South Africa
56	Research Site	Cedex		South Africa
57	Research Site	Johannesburg		South Africa
58	Research Site	Port Elizabeth		South Africa
59	Research Site	Cedex		Ukraine
60	Research Site	Dnipropetrovsk		Ukraine
61	Research Site	Donetsk		Ukraine
62	Research Site	Kharkov		Ukraine
63	Research Site	Kiev		Ukraine
64	Research Site	Odessa		Ukraine
65	Research Site	Vinnitsia		Ukraine

Sponsors and Collaborators

• AstraZeneca
• Quintiles, Inc.

Investigators

• Study Director: Michael Castiglione, AstraZeneca
• Principal Investigator: Michel Bourin, Professeur, Neurobiologie de l'anxiété et de la dépression Faculté de Médecine

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00931723
• Other Study ID Numbers: D144AC00003
• First Posted: Jul 2, 2009
• Last Update Posted: Apr 19, 2012
• Last Verified: Mar 1, 2012

• Keywords provided by AstraZeneca: Acute Mania; Mania, Adults; Seroquel; Acute Mania in Adult Patients
• Additional relevant MeSH terms: Mania; Bipolar Disorder; Quetiapine Fumarate

Study Results

Participant Flow

Recruitment Details	This multicenter study was conducted between 24 June 2009 and 22 November 2010.
Pre-assignment Detail	The study had an up to 28-day enrollment period (including a washout period lasting 7 to 28 days) and a 6-week double-blind treatment period. Patients were randomized to receive lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day or placebo+quetiapine XR 400 to 800 mg/day.

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Period Title: Overall Study
STARTED	173	183
COMPLETED	147	144
NOT COMPLETED	26	39

Baseline Characteristics

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR	Total
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day	Total of all reporting groups
Overall Participants	173	183	356
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	37.9 (12.71)	38.8 (12.09)	38.3 (12.39)
Sex: Female, Male (Count of Participants)
Female	72 41.6%	62 33.9%	134 37.6%
Male	101 58.4%	121 66.1%	222 62.4%

Outcome Measures

1. Primary Outcome

Title	Change in the Young Mania Rating Scale (YMRS) Total Score From Baseline to Final Assessment (Day 43)
Description	The YMRS total score ranges from 0 to 60 where higher scores indicate more severe mania, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in manic symptoms. Total score ≤12 indicates remission (13-19=minimal symptoms; 20-25=mild mania, 26-37=moderate mania, 38-60=severe mania).
Time Frame	Change in YMRS total score from baseline to Day 43.

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-22.8 (0.706)	-20.1 (0.711)

2. Secondary Outcome

Title	The Number of Patients With Clinically Significant Response.
Description	The number of patients with clinically significant response (defined as ≥50% reduction from baseline to Day 43 in the YMRS total score) was calculated. The YMRS total score ranges from 0 to 60 where higher scores indicate more severe mania, thus, a negative change (or 50% reduction) from baseline indicates a reduction (or improvement) in manic symptoms.
Time Frame	43 days (from baseline to Day 43)

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Number [Participants]	137 79.2%	120 65.6%

3. Secondary Outcome

Title	Remission
Description	The number of patients with clinically significant remission (defined as YMRS total score ≤12) from Days 8 to 43) was calculated. The Young Mania Rating Scale total score ranges from 0 to 60 where higher scores indicate more severe mania, thus, a negative change (or 50% reduction) from baseline indicates a reduction (or improvement) in manic symptoms. Total score ≤12 indicates remission (13-19=minimal symptoms; 20-25=mild mania, 26-37=moderate mania, 38-60=severe mania).
Time Frame	Days 8 to 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Number [Participants]	125 72.3%	105 57.4%

4. Secondary Outcome

Title	Change From Baseline to Day 43 in CGI-BP-S (Clinical Global Impressions for Bipolar Disorder-Severity of Illness)
Description	The CGI-BP-S scale rates the severity of the patient's illness at the time of assessment and is scored from 1 to 7 (1=normal, not ill to 7=very severely ill). Higher CGI-BP-S scores indicate greater illness severity.
Time Frame	Change from baseline to Day 43.

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-2.5 (0.079)	-2.2 (0.080)

5. Secondary Outcome

Title	Change From Baseline to Day 43 in CGI-BP-C (Clinical Global Impressions for Bipolar Disorder-Change From Preceding Phase)
Description	The CGI-BP-C scale rates how much the patient's illness has improved or worsened compared to the phase immediately preceding treatment and is scored on a scale from 1 to 8 (1=very much improved to 7=very much worse; 8=not applicable). A missing score will be used when a scale scored as 8 (not applicable). CGI-BP-C scores >4 indicate worsening, while scores <4 indicate improvement.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	1.7 (0.085)	1.9 (0.086)

6. Secondary Outcome

Title	Improvement of Overall Bipolar Illness
Description	The number of patients with a CGI-BP-C of "Much" or "Very much" improved in overall bipolar illness assessment at Day 43 was calculated. The CGI-BP-C scale rates how much the patient's illness has improved or worsened compared to the phase immediately preceding treatment and is scored on a scale from 1 to 8 (1=very much improved to 7=very much worse; 8=not applicable). A missing score will be used when a scale scored as 8 (not applicable). CGI-BP-C scores >4 indicate worsening, while scores <4 indicate improvement.
Time Frame	Day 43.

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Number [Participants]	134 77.5%	125 68.3%

7. Secondary Outcome

Title	Change From Baseline to Day 43 in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score
Description	The MADRS is a 10-item scale that evaluates depressive symptoms. Each MADRS item is rated on a 0 to 6 scale. Higher MADRS scores indicate higher levels of depressive symptoms.
Time Frame	Change from baseline to Day 43.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-4.8 (0.366)	-4.1 (0.368)

8. Secondary Outcome

Title	Change From Baseline to Day 43 in Positive and Negative Syndrome Scale (PANSS) Total Score
Description	The PANSS is a 30-item scale designed to assess various symptoms of schizophrenia and are rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology). The PANSS total score is the sum of all 30 individual-item scores and ranges from 30 to 210.A negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-19.2 (0.914)	-15.6 (0.914)

9. Secondary Outcome

Title	Change From Baseline to Day 43 in PANSS Activation Subscale Score
Description	The PANSS is a 30-item scale designed to assess various symptoms of schizophrenia and are rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology). The PANSS activation subscale score for effect on agitation and aggression is the sum of 6 PANSS individual items (ie, hostility, poor impulse control, excitement, uncooperativeness, poor rapport and tension) and ranges from 6 to 42. A negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-7.1 (0.281)	-5.9 (0.283)

10. Secondary Outcome

Title	Change From Baseline to Day 43 in PANSS Positive Subscale Score
Description	The PANSS is a 30-item scale designed to assess various symptoms of schizophrenia and are rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology). The PANSS positive subscale score is the sum of the 7 positive item scores (ie, delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution and hostility) and ranges from 7 to 49. A negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-8.1 (0.316)	-7.0 (0.316)

11. Secondary Outcome

Title	Change From Baseline to Day 43 in Each YMRS Item Score No. 1
Description	The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4 (0=normal). This analysis is for Item 1 (Elevated mood) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-1.8 (0.079)	-1.6 (0.080)

12. Secondary Outcome

Title	Change From Baseline to Day 43 in Each YMRS Item Score No. 2
Description	The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4 (0=normal). This analysis is for Item 2 (increased motor activity-energy) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-1.9 (0.071)	-1.7 (0.072)

13. Secondary Outcome

Title	Change From Baseline to Day 43 in Each YMRS Item Score No. 3
Description	The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4 (0=normal). This analysis is for Item 3 (sexual interest) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-1.3 (0.063)	-1.1 (0.064)

14. Secondary Outcome

Title	Change From Baseline to Day 43 in Each YMRS Item Score No. 4
Description	The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4 (0=normal). This analysis is for Item 4 (sleep) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-2.0 (0.085)	-1.8 (0.086)

15. Secondary Outcome

Title	Change From Baseline to Day 43 in Each YMRS Item Score No. 5
Description	The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4 (0=normal). This analysis is for Item 5 (Irritability) which ranges from 0 to 8 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-3.1 (0.109)	-2.8 (0.110)

16. Secondary Outcome

Title	Change From Baseline to Day 43 in Each YMRS Item Score No. 6
Description	The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4 (0=normal). This analysis is for Item 6 (speech-rate and amount) which ranges from 0 to 8 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-3.1 (0.116)	-2.9 (0.118)

17. Secondary Outcome

Title	Change From Baseline to Day 43 in Each YMRS Item Score No. 7
Description	The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4. This analysis is for Item 7 (language-thought disorder) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-1.5 (0.071)	-1.4 (0.072)

18. Secondary Outcome

Title	Change From Baseline to Day 43 in Each YMRS Item Score No. 8
Description	The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4. This analysis is for Item 8 (content) which ranges from 0 to 8 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-3.1 (0.132)	-2.9 (0.133)

19. Secondary Outcome

Title	Change From Baseline to Day 43 in Each YMRS Item Score No. 9
Description	The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4. . This analysis is for Item 9 (disruptive-aggressive behavior) which ranges from 0 to 8 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-2.5 (0.088)	-2.1 (0.089)

20. Secondary Outcome

Title	Change From Baseline to Day 43 in Each YMRS Item Score No. 10
Description	The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4. This analysis is for Item 10 (appearance) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-1.1 (0.057)	-1.0 (0.057)

21. Secondary Outcome

Title	Change From Baseline to Day 43 in Each YMRS Item Score No. 11
Description	The YMRS assesses severity of mania in bipolar disorder. It rates 4 core items from 0 to 8 (0=normal); the other 7 items are rated from 0 to 4. This analysis is for Item 11 (insight) which ranges from 0 to 4 where higher scores indicate more severe symptoms, thus, a negative change (or decrease) from baseline indicates a reduction (or improvement) in symptoms.
Time Frame	Change from baseline to Day 43

Outcome Measure Data

Analysis Population Description

173/176 is modified intent to treat analysis set. The reason why is different from 173/183 is that there is 7 patients excluded from the analysis (1 patient who did not take study drug and 6 patients who did not have post treatment YMRS scores).

Arm/Group Title	Lithium+Quetiapine XR	Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day	Placebo+quetiapine XR 400 to 800 mg/day
Measure Participants	173	176
Least Squares Mean (Standard Error) [Scores on a scale]	-1.4 (0.069)	-1.2 (0.070)

Adverse Events

Arm/Group Title	Lithium+Quetiapine XR		Placebo+Quetiapine XR
Arm/Group Description	Lithium 600 to 1800 mg/day+quetiapine XR 400 to 800 mg/day		Placebo+quetiapine XR 400 to 800 mg/day
All Cause Mortality
	Lithium+Quetiapine XR		Placebo+Quetiapine XR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Lithium+Quetiapine XR		Placebo+Quetiapine XR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/173 (2.3%)		8/183 (4.4%)
Infections and infestations
Gastroenteritis	1/173 (0.6%)		0/183 (0%)
Investigations
No Therapeutic Response	0/173 (0%)		1/183 (0.5%)
Psychiatric disorders
Mania	3/173 (1.7%)		6/183 (3.3%)
Aggression; Hostility	0/173 (0%)		1/183 (0.5%)
Other (Not Including Serious) Adverse Events
	Lithium+Quetiapine XR		Placebo+Quetiapine XR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	106/173 (61.3%)		83/183 (45.4%)
Gastrointestinal disorders
Constipation	16/173 (9.2%)		16/183 (8.7%)
Dry Mouth	14/173 (8.1%)		14/183 (7.7%)
Diarrhoea	8/173 (4.6%)		2/183 (1.1%)
Vomiting	8/173 (4.6%)		0/183 (0%)
Nausea	5/173 (2.9%)		3/183 (1.6%)
General disorders
Pyrexia	10/173 (5.8%)		9/183 (4.9%)
Investigations
Weight Increased	2/173 (1.2%)		5/183 (2.7%)
Metabolism and nutrition disorders
Increased Appetite	4/173 (2.3%)		1/183 (0.5%)
Nervous system disorders
Tremor	27/173 (15.6%)		9/183 (4.9%)
Somnolence	22/173 (12.7%)		10/183 (5.5%)
Dizziness	11/173 (6.4%)		8/183 (4.4%)
Headache	9/173 (5.2%)		11/183 (6%)
Sedation	5/173 (2.9%)		3/183 (1.6%)
Dysarthria	4/173 (2.3%)		2/183 (1.1%)
Psychiatric disorders
Insomnia	11/173 (6.4%)		12/183 (6.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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