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Quetiapine XR for Cognitive and Functional Disability in Clinically Stable Patients With Bipolar Disorder

Primary Purpose

Bipolar Disorder, Cognitive Impairment

Status

Terminated

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Quetiapine XR

Placebo

About this trial

This is an interventional treatment trial for Bipolar Disorder focused on measuring Cognition, attention, bipolar, disability

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Provision of written informed consent
A primary diagnosis of Bipolar disorder type 1 or 2, with a definite history of manic or hypomanic episodes by Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition (DSM-IV).
Females and/or males aged 18-65 years.
Female patients of childbearing potential must be using a reliable method of contraception and have a negative urine human chorionic gonadotropin (HCG) test at enrolment.
Able to understand and comply with the requirements of the study.
YMDRS score <13.
MADRS score <19.
Currently receiving medication therapy with lithium, valproate, or lamotrigine or any combination thereof. (preference given to lithium and/or valproate).
Clinically stable for 4 weeks prior to study entry, confirmed at week 2.

Exclusion criteria:

Intolerance of quetiapine
Change in mood stabilizer medication or dose in the last 4 weeks, change in antidepressant medication or dose in the last two months.
Current treatment with carbamazepine, stimulants, atomoxetine, or another antipsychotic
Current treatment with norepinephrine reuptake inhibiting antidepressants (Milnacipran, bupropion, paroxetine, duloxetine, venlafaxine, all MAOI's, all TCAs)
Current pregnancy or lactation
Active Anorexia nervosa or Bulimia nervosa in the past six months
History of non-affective psychotic disorders (including schizoaffective disorder)
Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others
Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days preceding enrolment including but not limited to: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir, ritonavir, fluvoxamine and saquinavir
Use of any of the following cytochrome P450 inducers in the 14 days preceding enrollment including but not limited to: phenytoin, carbamazepine, barbiturates, rifampin, St. John's Wort, and glucocorticoids
Administration of a depot antipsychotic injection within one dosing interval (for the depot) before randomisation
Active Substance/ alcohol abuse or dependence in the past three months before enrollment ( except for caffeine or nicotine dependence), as defined by DSM-IV criteria Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment
Unstable or inadequately treated medical illness (e.g. diabetes, angina pectoris, hyperlipidemia, hypertension) as judged by the investigator
Involvement in the planning and conduct of the study
Previous enrolment or randomisation of treatment in the present study.
Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements
A patient with Diabetes Mellitus (DM) fulfilling one of the following criteria:
- Unstable DM defined as enrollment glycosylated hemoglobin (HbA1c) >8.5%.
- Admitted to hospital for treatment of DM or DM related illness in past 12 weeks.
- Not under physician care for DM
- Physician responsible for patient's DM care has not indicated that patient's DM is controlled.
- Physician responsible for patient's DM care has not approved patient's participation in the study
- Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to randomization. For thiazolidinediones (glitazones) this period should not be less than 8 Weeks.
- 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 diabetic patient 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.
An absolute neutrophil count (ANC) of < 1.5 x 10^9 per liter

Sites / Locations

Emory University School of Medicine
Duke University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm Description

Quetiapine XR 200-400 mg/day

Placebo one pill per day matching 200, 300, or 400 mg

Outcomes

Primary Outcome Measures

The Continuous Performance Test-Identical Pairs Version

The Continuous Performance Test, Identical Pairs version (CPT-IP) is a cognitive test that requires a subject to respond whenever two identical stimuli appear in a row within a sequence of 150 rapidly flashed trials. The outcome is measured as d' (detection signal) and is dimensionless. Among healthy adult men and women, d' scores ranged from 3.07-4.57 (Chen et al. Schizophrenia Bulletin, 1998; 24(1):163-174). The higher the value the better the performance. The d' is calculated by averaging the d' scores from three trials.

Secondary Outcome Measures

Brief Assessment of Cognition for Affective Disorders (BAC-A)

This is a series of neurocognitive tests and includes brief assessments of attention, motor speed, working memory, verbal memory, reasoning and problem solving, verbal fluency, affective interference, and emotion inhibition. The total BAC-A score is represented by a composite T-score which is dimensionless. This is computed by adding up the scores for each trial of a test domain (e.g. verbal memory) within the cognitive battery. Each test domain total is then inputted into a proprietary BAC-A calculator which determines the composite T-scores. A higher score indicates better performance. A study of 404 healthy adults demonstrated a mean composite score of 50 with a standard deviation of 10 (Keefe et al. Schizophrenia Bulletin. 2008; 102: 108-115).

Full Information

NCT ID

NCT00746421

First Posted

September 3, 2008

Last Updated

March 31, 2014

Sponsor

Emory University

Collaborators

Duke University, University of Toronto

1. Study Identification

Unique Protocol Identification Number

NCT00746421

Brief Title

Quetiapine XR for Cognitive and Functional Disability in Clinically Stable Patients With Bipolar Disorder

Official Title

Phase IV Study of Quetiapine XR Aimed at Disability and Cognitive Impairments.

Study Type

Interventional

2. Study Status

Record Verification Date

March 2014

Overall Recruitment Status

Terminated

Why Stopped

Sponsor withdrew funding

Study Start Date

January 2010 (undefined)

Primary Completion Date

April 2012 (Actual)

Study Completion Date

April 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Emory University

Collaborators

Duke University, University of Toronto

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Quetiapine has been reported to have beneficial cognitive effects in several randomized controlled trials in schizophrenia. It has not yet been studied in bipolar disorder, but promising results from the use of extended release quetiapine for the maintenance treatment of bipolar disorder suggests that its cognitive benefits could be detected. Moreover, quetiapine has been shown to have direct beneficial effects on performance-based measures of social competence in schizophrenia and to improve quality of life (QoL) in bipolar depression. The investigators propose to study quetiapine augmentation of mood stabilizer monotherapy in clinically stable patients with bipolar disorder. This will be a randomized, placebo controlled trial, with attentional impairments as the primary outcome and other cognitive performance variables and measures of social and everyday living skills, as well as subjective QoL, as the secondary outcomes.

Detailed Description

In contrast to previous conceptions of bipolar disorder as an illness where cognitive impairments were limited to manic and depressed episodes, it has become clear that cognitive impairments are common in clinically stable bipolar patients. Quetiapine has been reported to have beneficial cognitive effects in several randomized controlled trials in schizophrenia. It has not yet been studied in bipolar disorder, but promising results from the use of extended release quetiapine for the maintenance treatment of bipolar disorder suggests that its cognitive benefits could be detected. Moreover, quetiapine has been shown to have direct beneficial effects on performance-based measures of social competence in schizophrenia and to improve quality of life (QoL) in bipolar depression. We propose to study quetiapine augmentation of mood stabilizer monotherapy in clinically stable patients with bipolar disorder. This will be a randomized, placebo controlled trial, with attentional impairments as the primary outcome and other cognitive performance variables and measures of social and everyday living skills, as well as subjective QoL, as the secondary outcomes. An additional possible benefit of quetiapine treatment, and one that is directly relevant to neuropsychological performance, is that of increased activity of cortical norepinephrine (NE). Thus, in studies of cognitive enhancement with quetiapine, examination of cortical NE neet occupancy will be of substantial interest. General Background: This will be a three site study which will include Emory University (Coordinating site), Duke University, and University of Toronto. We choose to have three sites so that the difficult task of recruiting clinically stable patients with bipolar can be accomplished quickly and the study can be completed within a two-year time frame. Subjects: We will recruit 100 patients for this study. Fifty percent of them will receive active treatment with quetiapine XR. All participants will meet diagnostic criteria for bipolar I and II disorder and have medical record-based evidence of at least one previous manic or mixed episode. They will be clinically stable, as evidence by meeting criteria for low scores on both the Young Mania Rating Scale (YMRS) and the Montgomery-Asberg Depression rating scale (MADRS). They will also be receiving therapy with mood stabilizers, either lithium or an approved mood stabilizing agent. Visit Schedule: This is a 10 week study with a six-week active treatment protocol. All interested patients who meet study entry criteria will be screened for stability four and two weeks prior to the baseline assessment. Patients will also be re-assessed for stability at baseline. Patients who fail to meet entry criteria at baseline can come back for a second screening after 2 and 4 weeks. Throughout treatment, medication adjustments will be limited to changes of less than 25% during this time period. Assessments: Cognitive assessments will be performed at baseline, week 2 and week 6 of active treatment. Clinical Assessments will be performed at screening and rescreening, baseline, weeks 2 and 6. Biological Measures: Bloods for NE net occupancy will be drawn at baseline, week 2, and week 6. Serum levels of quetiapine at all three assessments will also be examined. Cognitive Assessments: We will focus our cognitive assessment on the types of cognitive impairments previously reported in bipolar disorder. Our focus will be on attention, episodic memory, processing speed, and working memory. This same instrumentation has proven able to detect sedation as well, so that we can use the results of our assessment to identify any potential adverse sedation effects.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Bipolar Disorder, Cognitive Impairment

Keywords

Cognition, attention, bipolar, disability

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

32 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

Quetiapine XR 200-400 mg/day

Arm Title

Arm Type

Placebo Comparator

Arm Description

Placebo one pill per day matching 200, 300, or 400 mg

Intervention Type

Drug

Intervention Name(s)

Quetiapine XR

Other Intervention Name(s)

Seroquel XR

Intervention Description

oral doses, 200 mg, 300 mg, 400 mg

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

200mg, 300mg or 400mg

Primary Outcome Measure Information:

Title

The Continuous Performance Test-Identical Pairs Version

Description

Time Frame

6 weeks

Secondary Outcome Measure Information:

Title

Brief Assessment of Cognition for Affective Disorders (BAC-A)

Description

Time Frame

6 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: Provision of written informed consent A primary diagnosis of Bipolar disorder type 1 or 2, with a definite history of manic or hypomanic episodes by Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition (DSM-IV). Females and/or males aged 18-65 years. Female patients of childbearing potential must be using a reliable method of contraception and have a negative urine human chorionic gonadotropin (HCG) test at enrolment. Able to understand and comply with the requirements of the study. YMDRS score <13. MADRS score <19. Currently receiving medication therapy with lithium, valproate, or lamotrigine or any combination thereof. (preference given to lithium and/or valproate). Clinically stable for 4 weeks prior to study entry, confirmed at week 2. Exclusion criteria: Intolerance of quetiapine Change in mood stabilizer medication or dose in the last 4 weeks, change in antidepressant medication or dose in the last two months. Current treatment with carbamazepine, stimulants, atomoxetine, or another antipsychotic Current treatment with norepinephrine reuptake inhibiting antidepressants (Milnacipran, bupropion, paroxetine, duloxetine, venlafaxine, all MAOI's, all TCAs) Current pregnancy or lactation Active Anorexia nervosa or Bulimia nervosa in the past six months History of non-affective psychotic disorders (including schizoaffective disorder) Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days preceding enrolment including but not limited to: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir, ritonavir, fluvoxamine and saquinavir Use of any of the following cytochrome P450 inducers in the 14 days preceding enrollment including but not limited to: phenytoin, carbamazepine, barbiturates, rifampin, St. John's Wort, and glucocorticoids Administration of a depot antipsychotic injection within one dosing interval (for the depot) before randomisation Active Substance/ alcohol abuse or dependence in the past three months before enrollment ( except for caffeine or nicotine dependence), as defined by DSM-IV criteria Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment Unstable or inadequately treated medical illness (e.g. diabetes, angina pectoris, hyperlipidemia, hypertension) as judged by the investigator Involvement in the planning and conduct of the study Previous enrolment or randomisation of treatment in the present study. Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements A patient with Diabetes Mellitus (DM) fulfilling one of the following criteria: Unstable DM defined as enrollment glycosylated hemoglobin (HbA1c) >8.5%. Admitted to hospital for treatment of DM or DM related illness in past 12 weeks. Not under physician care for DM Physician responsible for patient's DM care has not indicated that patient's DM is controlled. Physician responsible for patient's DM care has not approved patient's participation in the study Has not been on the same dose of oral hypoglycaemic drug(s) and/or diet for the 4 weeks prior to randomization. For thiazolidinediones (glitazones) this period should not be less than 8 Weeks. 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 diabetic patient 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. An absolute neutrophil count (ANC) of < 1.5 x 10^9 per liter

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jeffrey J Rakofsky, MD

Organizational Affiliation

Emory University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Emory University School of Medicine

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Duke University

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

12. IPD Sharing Statement

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Quetiapine XR for Cognitive and Functional Disability in Clinically Stable Patients With Bipolar Disorder

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