Bipolar Disorder, Schizophrenia
Conditions
Keywords
Mania, Manic-depressive, Psychotic disorder
Brief summary
This study will determine the effectiveness of three different drug therapies in treating the symptoms of mania.
Detailed description
Mania is a serious condition characterized by extreme excitement, mental and physical hyperactivity, insomnia, and disconnected thoughts. Symptoms of mania are common in patients with schizophrenia or bipolar disorder. When associated with these conditions, mania reaches psychotic proportions and often includes hallucinations, paranoia, and feelings of omnipotence. Such symptoms may put individuals with mania and those around them at risk for physical harm. Drug therapies that can safely and effectively treat symptoms of mania are needed. This study will compare three drug combinations in their ability to treat symptoms of mania in people with schizophrenia or bipolar I disorder. This study will comprise a 12-week acute phase and a 14-week continuation phase. While the acute phase is the primary component of this study, the continuation phase will provide extended data on the characteristics and course of responders to the initial treatment combinations. Results from the continuation phase will be reported elsewhere. In the acute phase, participants will be randomly assigned to receive one of three treatments: divalproex-extended release (DV-ER) and lithium, DV-ER and quetiapine, or DV-ER and placebo. Participants will receive their intervention for 12 weeks. Participants will have weekly study visits for the first 4 weeks of the acute phase; biweekly study visits will occur for the following 8 weeks. After the acute phase, participants who have not responded to their drug regimen will complete their participation in the study. Participants whose symptoms of mania have decreased will be offered enrollment in the 14-week continuation phase, during which time participants will continue the drug regimen they began in the acute phase. Participants will have biweekly study visits in the continuation phase. During each study visit in both phases, participants will be interviewed about their mania symptoms. Mania, depression, quality of life, and overall functioning scales will assess participants at study entry, at the end of the acute phase, and at the end of the continuation phase. Participants over 50 years of age will have an electrocardiogram (EKG) at study entry to determine cardiac function.
Interventions
DRUGDivalproex-extended release (DVP-ER)
Divalproex ER will be given in 250 mg or 500 mg tablets. Dosing is once a day, every day, for the duration of study participation, either 12 or 26 weeks.
DRUGLithium
Extended release lithium will be provided in 300 mg capsules. Participants will be dosed to a therapeutic blood level of lithium from 0.8 to 1.2 mcg/L.
DRUGQuetiapine
Quetiapine will be dosed to efficacy, provided in 50 mg, 100 mg, 200 mg, or 300 mg pills.
Sponsors
National Institute of Mental Health (NIMH)
Palo Alto Veterans Institute for Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of bipolar I disorder or schizophrenia * Experiencing symptoms of mania at study entry * Able to speak and understand English * Willing and able to comply with all study requirements
Exclusion criteria
* History of partial response or nonresponse to any of the drugs or drug combinations given in this study * History of intolerance to DVP, DVP-ER, lithium, or quetiapine * Disorders that would contraindicate the use of DV, DV-ER, lithium, or quetiapine * Use of antidepressants within 1 month prior to study entry * Use of fluoxetine within 3 months prior to study entry * Impaired cardiac function, as evidenced by abnormal EKG in participants 50 or over * Unstable medical illness within 2 months prior to study entry * At risk for suicide * Substance abuse or dependence within 1 month prior to study entry * Pregnancy, breastfeeding, or plans to become pregnant during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Symptoms of Mania, as Measured by Young Mania Rating Scale | Week 12 | Symptoms of mania, as measured by Young Mania Rating Scale. The scale is eleven-item multiple choice diagnostic questionnaire (range 0-60), which psychiatrists use to measure the severity of manic episodes in children and young adults. Typically, 20 is the minimum score required for mania. Higher scores represent increased severity of mania symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Rating Scale for Depression (HAM-D,17) | Week 12 | The Hamilton Rating Scale for Depression is a multiple item questionnaire used to provide an indication of depression, and as a guide to evaluate recovery. The questionnaire is designed for adults and is used to rate the severity of their depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. The 17-item Likert-type scale (range 0-50) includes eight questions with a 5-point scale (ranging from 0=not present to 4=severe) and nine items scored from 0 to 2. Higher scores indicate increased depression severity. The total sum of these 17 answers is used to arrive at the final score: normal (0-7), mild (8-13), moderate (14-18), severe (19-22), or very severe (\>=23). |
| Clinical Global Impression Scale for Bipolar Disorder (CGI-BD) | Week 12 | The Clinical Global Impression (CGI) rating scale was modified by Spearing and colleagues (1997) for use in bipolar disorder. CGI scales are measures of symptom severity, treatment response and the efficacy of treatments in treatment studies of patients with mental disorders. The revised CGI-Bipolar Version (CGI-BP) is effective in rating severity of manic and depressive episodes and the degree of change from the immediately preceding phase and from the worst phase of illness. The CGI-BP is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal, not ill) to 7 (very severely ill). Each component of the CGI is rated separately; the instrument does not yield a global score. Only severity of illness scores are reported. Increased scores represent increased illness severity |
| Global Assessment of Functioning | Week 12 | The Global Assessment of Functioning (GAF) is a numeric scale used by mental health clinicians and physicians to rate subjectively the social, occupational, and psychological functioning of an individual, e.g., how well one is meeting various problems-in-living. Scores range from 100 (extremely high functioning) to 1 (severely impaired). |
| Social and Occupational Functioning Assessment Scale (SOFAS) | Week 12 | The Social and Occupational Functioning Assessment Scale (SOFAS) provides a rating of global social and occupational function independent of clinical symptoms. SOFAS is provided in the Diagnostic and Statistical Manual (DSM-IV) as an Axis V measure. The SOFAS is a global rating of current functioning, which is scored positively on a scale from 0 to 100. Higher scores represent higher levels of functioning. This instrument is a one-item rating of consumer functioning. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| DVP + Placebo Participants will receive divalproex ER at a therapeutic dose, plus placebo
Divalproex-extended release (DVP-ER): Divalproex ER will be given in 250 mg or 500 mg tablets. Dosing is once a day, every day, for the duration of study participation, either 12 or 26 weeks. | 24 |
| DVP + Quetiapine Participants will receive divalproex ER at a therapeutic dose, plus quetiapine up to 800 mg
Divalproex-extended release (DVP-ER): Divalproex ER will be given in 250 mg or 500 mg tablets. Dosing is once a day, every day, for the duration of study participation, either 12 or 26 weeks.
Quetiapine: Quetiapine will be dosed to efficacy, provided in 50 mg, 100 mg, 200 mg, or 300 mg pills. | 26 |
| DVP + Lithium Participants will receive divalproex ER at a therapeutic dose, plus lithium at a therapeutic blood level
Divalproex-extended release (DVP-ER): Divalproex ER will be given in 250 mg or 500 mg tablets. Dosing is once a day, every day, for the duration of study participation, either 12 or 26 weeks.
Lithium: Extended release lithium will be provided in 300 mg capsules. Participants will be dosed to a therapeutic blood level of lithium from 0.8 to 1.2 mcg/L. | 25 |
| Total | 75 |
Baseline characteristics
| Characteristic | DVP + Placebo | DVP + Quetiapine | DVP + Lithium | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 26 Participants | 25 Participants | 75 Participants |
| Age, Continuous | 39.5 years STANDARD_DEVIATION 11.6 | 33.1 years STANDARD_DEVIATION 9.8 | 34.9 years STANDARD_DEVIATION 9 | 35.6 years STANDARD_DEVIATION 10.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 25 Participants | 21 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Mean Number of Lifetime Episodes of Depression | 3.4 episodes of depression STANDARD_DEVIATION 1 | 3.5 episodes of depression STANDARD_DEVIATION 1.3 | 3.7 episodes of depression STANDARD_DEVIATION 0.9 | 3.5 episodes of depression STANDARD_DEVIATION 1.1 |
| Region of Enrollment United States | 24 participants | 26 participants | 25 participants | 75 participants |
| Sex: Female, Male Female | 10 Participants | 16 Participants | 12 Participants | 38 Participants |
| Sex: Female, Male Male | 14 Participants | 10 Participants | 13 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 24 | 1 / 26 | 1 / 25 |
| serious Total, serious adverse events | 0 / 24 | 0 / 26 | 0 / 25 |
Outcome results
Primary
Symptoms of Mania, as Measured by Young Mania Rating Scale
Symptoms of mania, as measured by Young Mania Rating Scale. The scale is eleven-item multiple choice diagnostic questionnaire (range 0-60), which psychiatrists use to measure the severity of manic episodes in children and young adults. Typically, 20 is the minimum score required for mania. Higher scores represent increased severity of mania symptoms.
Time frame: Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DVP + Placebo | Symptoms of Mania, as Measured by Young Mania Rating Scale | 5.7 units on a scale | Standard Deviation 5.5 |
| DVP + Quetiapine | Symptoms of Mania, as Measured by Young Mania Rating Scale | 11.1 units on a scale | Standard Deviation 7.8 |
| DVP + Lithium | Symptoms of Mania, as Measured by Young Mania Rating Scale | 10.0 units on a scale | Standard Deviation 6.9 |
Secondary
Clinical Global Impression Scale for Bipolar Disorder (CGI-BD)
The Clinical Global Impression (CGI) rating scale was modified by Spearing and colleagues (1997) for use in bipolar disorder. CGI scales are measures of symptom severity, treatment response and the efficacy of treatments in treatment studies of patients with mental disorders. The revised CGI-Bipolar Version (CGI-BP) is effective in rating severity of manic and depressive episodes and the degree of change from the immediately preceding phase and from the worst phase of illness. The CGI-BP is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal, not ill) to 7 (very severely ill). Each component of the CGI is rated separately; the instrument does not yield a global score. Only severity of illness scores are reported. Increased scores represent increased illness severity
Time frame: Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DVP + Placebo | Clinical Global Impression Scale for Bipolar Disorder (CGI-BD) | 1.58 units on a scale | Standard Deviation 1.02 |
| DVP + Quetiapine | Clinical Global Impression Scale for Bipolar Disorder (CGI-BD) | 2.54 units on a scale | Standard Deviation 1.33 |
| DVP + Lithium | Clinical Global Impression Scale for Bipolar Disorder (CGI-BD) | 2.32 units on a scale | Standard Deviation 1.35 |
Secondary
Global Assessment of Functioning
The Global Assessment of Functioning (GAF) is a numeric scale used by mental health clinicians and physicians to rate subjectively the social, occupational, and psychological functioning of an individual, e.g., how well one is meeting various problems-in-living. Scores range from 100 (extremely high functioning) to 1 (severely impaired).
Time frame: Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DVP + Placebo | Global Assessment of Functioning | 68.3 units on a scale | Standard Deviation 13.4 |
| DVP + Quetiapine | Global Assessment of Functioning | 62.3 units on a scale | Standard Deviation 11.1 |
| DVP + Lithium | Global Assessment of Functioning | 60.8 units on a scale | Standard Deviation 10.4 |
Secondary
Hamilton Rating Scale for Depression (HAM-D,17)
The Hamilton Rating Scale for Depression is a multiple item questionnaire used to provide an indication of depression, and as a guide to evaluate recovery. The questionnaire is designed for adults and is used to rate the severity of their depression by probing mood, feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms. The 17-item Likert-type scale (range 0-50) includes eight questions with a 5-point scale (ranging from 0=not present to 4=severe) and nine items scored from 0 to 2. Higher scores indicate increased depression severity. The total sum of these 17 answers is used to arrive at the final score: normal (0-7), mild (8-13), moderate (14-18), severe (19-22), or very severe (\>=23).
Time frame: Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DVP + Placebo | Hamilton Rating Scale for Depression (HAM-D,17) | 13.2 units on a scale | Standard Deviation 11.6 |
| DVP + Quetiapine | Hamilton Rating Scale for Depression (HAM-D,17) | 18.3 units on a scale | Standard Deviation 9.2 |
| DVP + Lithium | Hamilton Rating Scale for Depression (HAM-D,17) | 18.8 units on a scale | Standard Deviation 11 |
Secondary
Social and Occupational Functioning Assessment Scale (SOFAS)
The Social and Occupational Functioning Assessment Scale (SOFAS) provides a rating of global social and occupational function independent of clinical symptoms. SOFAS is provided in the Diagnostic and Statistical Manual (DSM-IV) as an Axis V measure. The SOFAS is a global rating of current functioning, which is scored positively on a scale from 0 to 100. Higher scores represent higher levels of functioning. This instrument is a one-item rating of consumer functioning.
Time frame: Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| DVP + Placebo | Social and Occupational Functioning Assessment Scale (SOFAS) | 68.2 units on a scale | Standard Deviation 13.7 |
| DVP + Quetiapine | Social and Occupational Functioning Assessment Scale (SOFAS) | 62.1 units on a scale | Standard Deviation 11.9 |
| DVP + Lithium | Social and Occupational Functioning Assessment Scale (SOFAS) | 59.8 units on a scale | Standard Deviation 11.8 |