Quetiapine SR and Divalproex Sodium ER in the Treatment of Anxiety in Bipolar Disorder With Panic Disorder and/or GAD

• Sponsor: University of South Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT00579280
• Collaborator: AstraZeneca (Industry)
• Enrollment: 224
• Locations: 3
• Arms: 3
• Duration (Months): 41
• Patients Per Site: 74.7
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

The specific aim of this study is to evaluate the efficacy, tolerability, and safety of quetiapine SR monotherapy and divalproex sodium ER monotherapy in comparison to placebo in the treatment of ambulatory bipolar disorder with co-morbid lifetime panic disorder or generalized anxiety disorder and current at least moderately severe anxiety.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder; Panic Disorder; Generalized Anxiety Disorder	Drug: quetiapine SR; Drug: divalproex sodium ER; Drug: placebo	Phase 4

Detailed Description

This is a randomized, double-blind, placebo controlled, parallel-group, 8-week trial of quetiapine SR monotherapy compared to divalproex sodium ER monotherapy in outpatient subjects with a lifetime bipolar I, II, or not otherwsise specified (NOS) disorder, a lifetime panic or generalized anxiety disorder, and current diagnosis at least moderately severe anxiety symptoms. Approximately 180 subjects will be randomized to obtain 90 subjects who complete the 8-week trial (30 completers per treatment group). This calculation is based on drop out rates in a similar patient population carried out by this group of collaborators. Subjects will be randomized to quetiapine SR or divalproex sodium ER or placebo in a 1:1:1 ratio. No concomitant psychotropic medication will be allowed throughout the study except for prn lorazepam during the first two weeks for the management of affective and anxiety symptoms, prn zolpidem and zaleplon for the management of insomnia and benztropine for the management of extrapyramidal side effects (EPS). Throughout the study, psychiatric scales will be used to assess psychiatric symptoms and the presence of treatment-emergent adverse events will be monitored and recorded.

Study Design

• Study Type: Interventional
• Actual Enrollment: 224 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Study of Quetiapine SR and Divalproex Sodium ER on Anxiety in Bipolar Disorder With at Least Moderately Severe Current Anxiety and Lifetime Panic or Generalized Anxiety Disorder.
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Quetiapine SR Quetiapine SR (Quetiapine Sustained Release)	Drug: quetiapine SR; flexible dosing, 50 mg up to a maximum of 300 mg per day for 8 weeks
Active Comparator: Divalproex Sodium ER Divalproex Sodium ER (Divalproex Sodium Extended Release)	Drug: divalproex sodium ER; Flexible dosing, 500 mg up to a maximum of 3000 mg per day for 8 weeks
Placebo Comparator: Placebo placebo	Drug: placebo; placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the CGI-21 Anxiety [8 weeks (using LOCF Repeated Measures ANOVA)]

   The CGI-21 Anxiety is a 21-point clinician-rated global improvement for anxiety symptoms. Response range: -10 to +10. The higher the score the more improvement. At Baseline all patients have a score of "0" (zero), against which any subsequent improvements or deterioration is assessed. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA). The focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANOVA. Outcomes showing scores above zero indicate that patients did better, i.e. showed improvement on this scale.

Secondary Outcome Measures

1. Change From Baseline on Patient Global Improvement Scale (PGI-21) for Anxiety Symptoms [8 weeks]

   The PGI-21 Anxiety is a 21-point patient-rated global improvement for anxiety symptoms. Response range: -10 to +10. The higher the score the more improvement. At Baseline all patients have a score of "0" (zero), against which any subsequent improvements or deterioration is assessed. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA). The focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANOVA. Outcomes showing scores above zero indicate that patients did better, i.e. showed improvement on this scale.

2. Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores [8 weeks]

   Hamilton Anxiety Scale (HAM-A) measures severity of anxiety symptoms - range of scores is 0-56. A higher score means worse anxiety. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors (labeled "time") and treatment group (labeled "treatment") was the between-subjects factor with 3 levels. The focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale.

3. Change From Baseline in Sheehan Panic Disorder Scale (SPS) [8 weeks]

   Sheehan Panic Disorder Scale (SPS). Range of scores: 0-140. Higher scores indicate greater severity of symptoms. The relative efficacy of quetiapine SR vs. divalproex ER and placebo was tested using a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments for the efficacy variables were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels. The focus in this analysis was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in efficacy measures were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the baseline-to-endpoint LOCF ANCOVA. Outcome results with a "minus" indicate that patients did better, i.e. had a reduction in symptoms on this scale.

4. Change From Baseline on Montgomery Asberg Depression Rating Scale (MADRS) [8 weeks]

   Montgomery Asberg Depression Rating Scale (MADRS) measures severity of depressive symptoms. Range of scores: 0-60. A higher score shows greater severity of depressive symptoms. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels. The central focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in efficacy were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e had a reduction in symptoms on this scale.

5. Change From Baseline in Young Mania Rating Scale (YMRS) [8 weeks]

   Young Mania Rating Scale (YMRS) measures severity of mania / hypomania symptoms. Range of scores: 0-60. A higher score shows worse mania / hypomania. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels. The focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale.

6. Change From Baseline on Clinician Global Impression Scale for Bipolar Disorder (CGI-BP) (Overall Severity) [8 weeks]

   Clinician Global Impression Scale for Bipolar Disorder (CGI-BP) measures the severity of bipolar disorder symptoms overall. Range of response: i1. normal, not ill to 7. very severely ill. A higher score represents greater severity. A last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels was used. The focus was on the "treatment-by-time" effect and whether the trajectory of response differed over time by treatment. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale.

7. Change From Baseline on Rapid Ideas Scale (RISc) [8 weeks]

   Rapid ideas Scale (RISc) measures severity of rapid thoughts. Range of scores is 0-100. A higher score means more severe rapidity of thinking. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels. The focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale.

8. Change From Baseline in Sheehan Irritability Scale (SIS) [8 weeks]

   Sheehan Irritability Scale (SIS) measures severity of anxiety symptoms. Range of scores: 0-70. A higher score shows worse irritability. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels. The focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale.

9. Change From Baseline on Sheehan Disability Scale (SDS) - Total [8 weeks]

   Sheehan Disability Scale (SDS) measures severity of functional impairment or disability. There are 4 scores: 1) Work Disability 2) Social Disability 3) Family Life Disability. Each of these domains is scored 0-10, with a higher score representing greater disability or functional impairment. These 3 domain scores are added to give a Total Disability scale score. Range of response for Total Disability: 0 to 30. A higher score shows greater disability/functional impairment. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA). Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale.

10. Change From Baseline on Sheehan- Suicidality Tracking Scale S-STS (2008 Version With 8 Items) [8 weeks]

    Sheehan - Suicidality Tracking Scale S-STS (2008 version with 8 items) measures severity of a range of suicidality symptoms. Range of scores: 0-32. A higher score represents more severe suicidality. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale..

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subjects must be at least 18 years of age and not older than 65

• Subjects must have lifetime bipolar I, II, or not otherwise specified (NOS) disorder as defined by DSM-IV TR (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision) criteria

• Subjects must have lifetime panic disorder or generalized anxiety disorder (GAD) as defined by DSM-IV, criteria (except clause "does not occur exclusively during a mood disorder" of Criterion F for GAD)

• Subjects' bipolar symptoms must be no more than moderate in severity, defined as a CGI-BP< 4

• Subjects' anxiety symptoms must be at least moderate in severity, defined as a CGI-S > 4

• Subjects must not be receiving regular mood stabilizing, antidepressant, antipsychotic, or anxiolytic medication for at least one week prior to baseline. Patients receiving fluoxetine or depot antipsychotics should be off these medications for at least four weeks prior to baseline

• Subjects or their legally authorized representative must sign the Informed Consent Document after the nature of the trial has been fully explained

• If female, subjects must be: postmenopausal, surgically incapable of childbearing, or practicing medically acceptable effective method(s) of contraception (e.g., hormonal methods, barrier methods, intrauterine device) for at least one month prior to study entry and throughout the study

Exclusion Criteria:

• Subjects who do not have lifetime bipolar disorder by DSM-IV-TR criteria

• Subjects who do not have lifetime panic disorder or generalized anxiety disorder by DSM-IV-TR criteria

• Subjects who are receiving treatment with an anti-manic or mood stabilizing medication (lithium, valproate, carbamazepine, or an antipsychotic), and in the investigators' judgment, require ongoing treatment with that medication

• Subjects whose bipolar symptoms are presently more than moderately severe (CGI-BP>5)

• Subjects whose anxiety symptoms are presently less than moderately severe (CGI-S<3)

• Subjects with clinically significant suicidal or homicidal ideation.

• Subjects with a current DSM-IV TR Axis I diagnosis of delirium, dementia, amnesia, or other cognitive disorders; a DSM-IV TR diagnosis of a substance dependence disorder within the past six months; a lifetime DSM-IV TR psychotic disorder (e.g., schizophrenia or schizoaffective disorder)

• Subjects with serious general medical illnesses including hepatic, renal, respiratory, cardiovascular, endocrine, neurological, or hematological disease as determined by the clinical judgment of the clinical investigator. Subjects with hypo-or hyperthyroidism unless stabilized on thyroid replacement > 3 months

• Subjects with a clinically significant abnormality in their pre-study physical exam, vital signs, EKG, or laboratory tests

• Subjects who are allergic to or who have demonstrated hypersensitivity or intolerance to either of the active study medications

• Women who are pregnant or nursing

• Subjects who have received an experimental drug or used an experimental device within 30 days

• Subjects who have a history of neuroleptic malignant syndrome

• A patient with diabetes mellitus (DM) fulfilling one of the following criteria:

• Unstable DM defined as enrollment glycosylated hemoglobin (HbAlc) >8.5%

• Admitted to hospital for treatment of DM or DM related illness within the past 12 weeks

• Not under physician care for DM

• Physician responsible for patient's DM care has not indicated that the patient's DM is controlled

• Physician responsible for patient's DM care has not approved the patient's participation in the study

• Has not been on the same dose of oral hypoglycemic drug(s) and/or diet for the 4 weeks before randomization. For thiazolidinediones (glitazones) this period should not be less than 8 weeks before randomization

• Taking insulin whose daily dose on one occasion in the past 4 weeks has been more than 10% above or below their mean dose in the preceding 4 weeks Note: If a patient with DM meets one of these criteria, the patient is to be excluded even if the treating physician believes that the patient is stable and can participate in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Palo Alto HCS & Stanford School of Medicine	Palo Alto	California	United States	94304
2	University of South Florida College of Medicine	Tampa	Florida	United States	33613
3	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45267

Sponsors and Collaborators

• University of South Florida
• AstraZeneca

Investigators

• Principal Investigator: David Sheehan, MD, University of South Florida

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of South Florida
• ClinicalTrials.gov Identifier: NCT00579280
• Other Study ID Numbers: AZ 1107
• First Posted: Dec 24, 2007
• Last Update Posted: Jun 11, 2020
• Last Verified: Jul 1, 2012

• Keywords provided by University of South Florida: Randomized; Double-Blind; Placebo-Controlled; Quetiapine; DivalproexSodiumER; Bipolar; Anxiety; Panic; GAD
• Additional relevant MeSH terms: Disease; Anxiety Disorders; Bipolar Disorder; Panic Disorder; Valproic Acid; Quetiapine Fumarate

Study Results

Participant Flow

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo
Arm/Group Description	Quetiapine SR (sustained release)	Divalproex Sodium ER (extended release)	Placebo control
Period Title: Overall Study
STARTED	49	49	51
COMPLETED	47	46	51
NOT COMPLETED	2	3	0

Baseline Characteristics

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo	Total
Arm/Group Description	Quetiapine SR (sustained release)	Divalproex Sodium ER (extended release)	Placebo control	Total of all reporting groups
Overall Participants	49	49	51	149
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	49 100%	49 100%	51 100%	149 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.4 (12.1)	37.5 (12.0)	37.6 (11.6)	38.8 (12.0)
Sex: Female, Male (Count of Participants)
Female	28 57.1%	27 55.1%	33 64.7%	88 59.1%
Male	21 42.9%	22 44.9%	18 35.3%	61 40.9%
Region of Enrollment (participants) [Number]
United States	49 100%	49 100%	51 100%	149 100%
Clinical Global Impression - Severity scale (CGI-S) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5.4 (.5)	5.3 (.6)	5.4 (.6)	5.4 (.6)
Hamilton Anxiety Scale (HAM-A) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	41.4 (12.1)	37.5 (12.0)	37.6 (11.6)	38.8 (12.0)
Sheehan Panic Disorder Scale (SPS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	47.5 (17.8)	42.4 (18.5)	41.8 (19.5)	43.9 (18.7)
Montgomery Asberg Depression Rating Scale (MADRS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	26.4 (8.3)	24.5 (7.3)	25.8 (7.9)	25.6 (7.8)
Young Mania Rating Scale (YMRS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	11.2 (6.1)	12.3 (7.9)	11.2 (5.7)	11.6 (6.6)
Sheehan Disability Scale (SDS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	15.1 (6.8)	12.9 (7.9)	14.8 (7.4)	14.3 (7.4)
Rapid Ideas Scale (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	54.0 (17.3)	52.1 (20.9)	51.7 (19.1)	52.6 (19.1)
Sheehan Irritability Scale (SIS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	48.9 (11.5)	43.2 (16.4)	43.5 (13.9)	45.2 (14.2)
Suicidality Tracking Scale (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.9 (2.6)	1.8 (2.8)	1.0 (1.5)	1.5 (2.3)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the CGI-21 Anxiety
Description	The CGI-21 Anxiety is a 21-point clinician-rated global improvement for anxiety symptoms. Response range: -10 to +10. The higher the score the more improvement. At Baseline all patients have a score of "0" (zero), against which any subsequent improvements or deterioration is assessed. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA). The focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANOVA. Outcomes showing scores above zero indicate that patients did better, i.e. showed improvement on this scale.
Time Frame	8 weeks (using LOCF Repeated Measures ANOVA)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo
Arm/Group Description	Quetiapine SR quetiapine SR: flexible dosing, 50 mg up to a maximum of 300 mg per day for 8 weeks	Divalproex Sodium ER divalproex sodium ER: Flexible dosing, 500 mg up to a maximum of 3000 mg per day for 8 weeks	placebo placebo: placebo
Measure Participants	47	46	51
Least Squares Mean (Standard Error) [score on a scale]	4.9 (0.62)	2.9 (0.63)	3.4 (0.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Quetiapine SR, Divalproex Sodium ER, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.05
	Comments
	Method	ANOVA
	Comments

2. Secondary Outcome

Title	Change From Baseline on Patient Global Improvement Scale (PGI-21) for Anxiety Symptoms
Description	The PGI-21 Anxiety is a 21-point patient-rated global improvement for anxiety symptoms. Response range: -10 to +10. The higher the score the more improvement. At Baseline all patients have a score of "0" (zero), against which any subsequent improvements or deterioration is assessed. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA). The focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANOVA. Outcomes showing scores above zero indicate that patients did better, i.e. showed improvement on this scale.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo
Arm/Group Description	Quetiapine SR quetiapine SR: flexible dosing, 50 mg up to a maximum of 300 mg per day for 8 weeks	Divalproex Sodium ER divalproex sodium ER: Flexible dosing, 500 mg up to a maximum of 3000 mg per day for 8 weeks	placebo placebo: placebo
Measure Participants	47	46	51
Least Squares Mean (Standard Error) [score on a scale]	3.9 (0.68)	1.9 (0.69)	2.3 (0.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Quetiapine SR, Divalproex Sodium ER, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	Change From Baseline in Hamilton Anxiety Scale (HAM-A) Scores
Description	Hamilton Anxiety Scale (HAM-A) measures severity of anxiety symptoms - range of scores is 0-56. A higher score means worse anxiety. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors (labeled "time") and treatment group (labeled "treatment") was the between-subjects factor with 3 levels. The focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo
Arm/Group Description	Quetiapine SR quetiapine SR: flexible dosing, 50 mg up to a maximum of 300 mg per day for 8 weeks	Divalproex Sodium ER divalproex sodium ER: Flexible dosing, 500 mg up to a maximum of 3000 mg per day for 8 weeks	placebo placebo: placebo
Measure Participants	47	46	51
Least Squares Mean (Standard Error) [score on a scale]	-11.7 (1.32)	-6.4 (1.30)	-8.4 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Quetiapine SR, Divalproex Sodium ER, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Change From Baseline in Sheehan Panic Disorder Scale (SPS)
Description	Sheehan Panic Disorder Scale (SPS). Range of scores: 0-140. Higher scores indicate greater severity of symptoms. The relative efficacy of quetiapine SR vs. divalproex ER and placebo was tested using a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments for the efficacy variables were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels. The focus in this analysis was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in efficacy measures were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the baseline-to-endpoint LOCF ANCOVA. Outcome results with a "minus" indicate that patients did better, i.e. had a reduction in symptoms on this scale.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo
Arm/Group Description	Quetiapine SR quetiapine SR: flexible dosing, 50 mg up to a maximum of 300 mg per day for 8 weeks	Divalproex Sodium ER divalproex sodium ER: Flexible dosing, 500 mg up to a maximum of 3000 mg per day for 8 weeks	placebo placebo: placebo
Measure Participants	47	46	51
Least Squares Mean (Standard Error) [score on a scale]	-24.4 (2.9)	-14.8 (2.9)	-18.3 (2.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Quetiapine SR, Divalproex Sodium ER, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.05
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Change From Baseline on Montgomery Asberg Depression Rating Scale (MADRS)
Description	Montgomery Asberg Depression Rating Scale (MADRS) measures severity of depressive symptoms. Range of scores: 0-60. A higher score shows greater severity of depressive symptoms. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels. The central focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in efficacy were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e had a reduction in symptoms on this scale.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo
Arm/Group Description	Quetiapine SR quetiapine SR: flexible dosing, 50 mg up to a maximum of 300 mg per day for 8 weeks	Divalproex Sodium ER divalproex sodium ER: Flexible dosing, 500 mg up to a maximum of 3000 mg per day for 8 weeks	placebo placebo: placebo
Measure Participants	47	46	51
Least Squares Mean (Standard Error) [score on a scale]	-11.5 (1.5)	-5.5 (1.6)	-7.3 (1.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Quetiapine SR, Divalproex Sodium ER, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments

6. Secondary Outcome

Title	Change From Baseline in Young Mania Rating Scale (YMRS)
Description	Young Mania Rating Scale (YMRS) measures severity of mania / hypomania symptoms. Range of scores: 0-60. A higher score shows worse mania / hypomania. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels. The focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo
Arm/Group Description	Quetiapine SR quetiapine SR: flexible dosing, 50 mg up to a maximum of 300 mg per day for 8 weeks	Divalproex Sodium ER divalproex sodium ER: Flexible dosing, 500 mg up to a maximum of 3000 mg per day for 8 weeks	placebo placebo: placebo
Measure Participants	47	46	51
Least Squares Mean (Standard Error) [score on a scale]	-5.4 (1.2)	-4.4 (1.2)	-4.3 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Quetiapine SR, Divalproex Sodium ER, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments

7. Secondary Outcome

Title	Change From Baseline on Clinician Global Impression Scale for Bipolar Disorder (CGI-BP) (Overall Severity)
Description	Clinician Global Impression Scale for Bipolar Disorder (CGI-BP) measures the severity of bipolar disorder symptoms overall. Range of response: i1. normal, not ill to 7. very severely ill. A higher score represents greater severity. A last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels was used. The focus was on the "treatment-by-time" effect and whether the trajectory of response differed over time by treatment. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo
Arm/Group Description	Quetiapine SR quetiapine SR: flexible dosing, 50 mg up to a maximum of 300 mg per day for 8 weeks	Divalproex Sodium ER divalproex sodium ER: Flexible dosing, 500 mg up to a maximum of 3000 mg per day for 8 weeks	placebo placebo: placebo
Measure Participants	47	46	51
Least Squares Mean (Standard Error) [score on a scale]	-1.2 (.16)	-.5 (.17)	-1.0 (.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Quetiapine SR, Divalproex Sodium ER, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Chi-squared
	Comments	Differences in response (70% or greater improvement) and remission (50% or greater improvement) rates between the groups.

8. Secondary Outcome

Title	Change From Baseline on Rapid Ideas Scale (RISc)
Description	Rapid ideas Scale (RISc) measures severity of rapid thoughts. Range of scores is 0-100. A higher score means more severe rapidity of thinking. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels. The focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo
Arm/Group Description	Quetiapine SR quetiapine SR: flexible dosing, 50 mg up to a maximum of 300 mg per day for 8 weeks	Divalproex Sodium ER divalproex sodium ER: Flexible dosing, 500 mg up to a maximum of 3000 mg per day for 8 weeks	placebo placebo: placebo
Measure Participants	47	46	51
Mean (Standard Error) [score on a scale]	-28.9 (3.4)	-19.7 (3.4)	-23.1 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Quetiapine SR, Divalproex Sodium ER, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments

9. Secondary Outcome

Title	Change From Baseline in Sheehan Irritability Scale (SIS)
Description	Sheehan Irritability Scale (SIS) measures severity of anxiety symptoms. Range of scores: 0-70. A higher score shows worse irritability. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels. The focus was on the "treatment-by-time" effect showing whether the trajectory of response differed over time by treatment group. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo
Arm/Group Description	Quetiapine SR quetiapine SR: flexible dosing, 50 mg up to a maximum of 300 mg per day for 8 weeks	Divalproex Sodium ER divalproex sodium ER: Flexible dosing, 500 mg up to a maximum of 3000 mg per day for 8 weeks	placebo placebo: placebo
Measure Participants	47	46	51
Least Squares Mean (Standard Error) [score on a scale]	-29.8 (3.4)	-22.6 (3.4)	-19.4 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Quetiapine SR, Divalproex Sodium ER, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments

10. Secondary Outcome

Title	Change From Baseline on Sheehan Disability Scale (SDS) - Total
Description	Sheehan Disability Scale (SDS) measures severity of functional impairment or disability. There are 4 scores: 1) Work Disability 2) Social Disability 3) Family Life Disability. Each of these domains is scored 0-10, with a higher score representing greater disability or functional impairment. These 3 domain scores are added to give a Total Disability scale score. Range of response for Total Disability: 0 to 30. A higher score shows greater disability/functional impairment. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA). Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo
Arm/Group Description	Quetiapine SR quetiapine SR: flexible dosing, 50 mg up to a maximum of 300 mg per day for 8 weeks	Divalproex Sodium ER divalproex sodium ER: Flexible dosing, 500 mg up to a maximum of 3000 mg per day for 8 weeks	placebo placebo: placebo
Measure Participants	47	46	51
Least Squares Mean (Standard Error) [score on a scale]	-6.5 (1.8)	-3 (1.2)	-5.3 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Quetiapine SR, Divalproex Sodium ER, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments

11. Secondary Outcome

Title	Change From Baseline on Sheehan- Suicidality Tracking Scale S-STS (2008 Version With 8 Items)
Description	Sheehan - Suicidality Tracking Scale S-STS (2008 version with 8 items) measures severity of a range of suicidality symptoms. Range of scores: 0-32. A higher score represents more severe suicidality. The relative efficacy of the 3 treatments was tested with a last-observation-carried forward (LOCF) repeated-measures analysis of variance (ANOVA) in which baseline and each of the 8 weekly assessments were the within subject factors ("time") and treatment group ("treatment") was the between-subjects factor with 3 levels. Also, group differences in baseline-to-endpoint changes in the efficacy measure were tested using LOCF ANCOVA followed by pairwise planned comparisons (t-tests). The least square means shown here are from the LOCF baseline-to-endpoint ANCOVA. Outcome results with a "minus" score indicate that patients did better, i.e. had a reduction in symptoms on this scale..
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Only administered to the last 74 patients enrolled after November 2008

Arm/Group Title	Quetiapine SR	Divalproex Sodium ER	Placebo
Arm/Group Description	Quetiapine SR quetiapine SR: flexible dosing, 50 mg up to a maximum of 300 mg per day for 8 weeks	Divalproex Sodium ER divalproex sodium ER: Flexible dosing, 500 mg up to a maximum of 3000 mg per day for 8 weeks	placebo placebo: placebo
Measure Participants	19	28	27
Mean (Standard Error) [score on a scale]	-.95 (.44)	-.07 (.36)	-.3 (.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Quetiapine SR, Divalproex Sodium ER, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Arm/Group Title	Quetiapine SR		Divalproex Sodium ER		Placebo
Arm/Group Description	Quetiapine SR (sustained release)		Divalproex Sodium ER (extended release)		Placebo control
All Cause Mortality
	Quetiapine SR		Divalproex Sodium ER		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Quetiapine SR		Divalproex Sodium ER		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/49 (2%)		3/49 (6.1%)		2/51 (3.9%)
Cardiac disorders
fainted	0/49 (0%)	0	1/49 (2%)	1	0/51 (0%)	0
Musculoskeletal and connective tissue disorders
back pain	0/49 (0%)	0	0/49 (0%)	0	1/51 (2%)	1
Psychiatric disorders
worsening depression	1/49 (2%)	1	1/49 (2%)	1	1/51 (2%)	1
Skin and subcutaneous tissue disorders
spider bite	0/49 (0%)	0	1/49 (2%)	1	0/51 (0%)	0
Other (Not Including Serious) Adverse Events
	Quetiapine SR		Divalproex Sodium ER		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/49 (49%)		18/49 (36.7%)		17/51 (33.3%)
Gastrointestinal disorders
Dry Mouth	15/49 (30.6%)		3/49 (6.1%)		7/51 (13.7%)
Nausea or Nausea/Vomiting	9/49 (18.4%)		12/49 (24.5%)		14/51 (27.5%)
Increased appetite	7/49 (14.3%)		6/49 (12.2%)		7/51 (13.7%)
Diarrheaa	1/49 (2%)		2/49 (4.1%)		4/51 (7.8%)
Nervous system disorders
Drowsiness/Sleepiness	24/49 (49%)		18/49 (36.7%)		17/51 (33.3%)
Sedation	6/49 (12.2%)		3/49 (6.1%)		3/51 (5.9%)
Headache	4/49 (8.2%)		12/49 (24.5%)		12/51 (23.5%)
Lightheadednessa	4/49 (8.2%)		2/49 (4.1%)		1/51 (2%)
Tiredness	3/49 (6.1%)		1/49 (2%)		3/51 (5.9%)
Dizzinessa	1/49 (2%)		3/49 (6.1%)		1/51 (2%)
Skin and subcutaneous tissue disorders
Tingling	8/49 (16.3%)		1/49 (2%)		1/51 (2%)

Limitations/Caveats

Study was limited to 8 weeks and to patients with bipolar disorder and comorbid panic disorder or generalized anxiety disorder.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.