Bipolar I Disorder, Bipolar II Disorder
Conditions
Brief summary
The purpose of this study is to compare which of the two mood stabilizers (drugs that help to steady/stabilize mood in patients with bipolar disorder (BD)), lithium and divalproex, is more effective in patients with bipolar disorder over 26 weeks. The study will also compare if lithium or divalproex used alone versus lithium or divalproex used with quetiapine versus lithium or divalproex used with lamotrigine is more effective when symptoms of depression develop.
Detailed description
This open methods advancement study will randomize BD patients with clinically significant symptoms to treatment with one of two mood stabilizers (MS), lithium \[Li\] or divalproex \[Div\]. Those who develop protocol defined depression will then be randomized to a MS alone, MS + quetiapine \[QTP\] or MS + lamotrigine \[LTG\]. A SMART strategy employs a rule for adding new treatments based on each patient's current illness state and response during the trial, mimicking the adaptive nature of treatment selection which occurs in clinical settings, but in a controlled way which allows application of causal inference. By using early indices of response to dynamically alter treatment decisions to improve outcome, SMART eliminates unmeasured confounders associated with treatment decisions that are not randomized, as occurs in data mining exercises and in other non-randomized decisions in studies which randomize one variable at baseline. This sequential adaptive design represents a methodological innovation in bipolar trial history which will have particular implications for effectiveness studies. Specific Aim A.1: Assess the feasibility of a SMART design in the conduct of an effectiveness study over 26 weeks in patients with BD (bipolar disorder). Aim A.2 Compare the effectiveness of Li to Div as a primary component of treatment for BD over 26 weeks. Aim A.3: Assess the effectiveness of MS + QTP and MS + LTG versus MS in subjects who develop depression. A4. Exploratory Aims: 1.Determine the effects of ethnicity, language facility, education and stress as moderators of treatment outcomes; 2. Explore the use of novel statistical methodologies to more informatively characterize illness trajectories in response to the interventions. In the aggregate these aims also will clarify whether the SMART confirms results provided by traditional, single point randomized controlled trials (RCTs).
Interventions
DRUGLithium
Therapeutic dosage as indicated by participants condition with blood levels. LI will be dosed to attain Li of ≥0.5mEq/L (milliequivalents per liter).
DRUGDivalproex
DV will be dosed to attain DV levels of ≥45mg/L.
DRUGLamotrigine
LM will be incrementally dosed up to 400 mg/day, or, in combination with DV, 200 mg/day. Dosage may be reduced for adverse effects to one half of the target dose.
DRUGQuetiapine
QT will be started at 50 mg/day and titrated up to 300 mg as tolerated. QT will be discontinued if not tolerated at 100mg/day and the patient will be treated according to guidelines.
Sponsors
National Institute of Mental Health (NIMH)
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* DSM-IV TR (Diagnostic and Statistical Manual Edition IV Text Revision) diagnosis BD I or II as assessed by MINI PLUS (Mini International Neuropsychiatric Interview PLUS) * Male or female ≥ 18 years old * Currently symptomatic with a CGI-BP-S ≥3 for mania/hypomania &/or depression for ≥ 2 weeks * One of the following indicators of recent active illness: a depressive or manic or hypomanic or mixed episode in the past 12 months * If female of child bearing age must use effective birth control.
Exclusion criteria
* Unwilling or unable to comply with study requirements * Renal impairment (serum creatinine \> 1.5 mg/dL) * If maintained on thyroid medication must be euthyroid for at least 1 month before Visit 1 * Patients who have had intolerable side effects to QTP, Li, Div, or LTG * Patients whose clinical status requires inpatient care * Drug/alcohol dependence within the past 30 days * Pregnancy as determined by serum pregnancy test or breastfeeding * History of poor response to Li at a serum Li of ≥ 0.5 mEq/L (milliequivalents per Liter) or Div at a serum level of ≥ 45 mg/dL for at least 2 weeks.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Bipolar Inventory of Symptoms Scale (BISS) | Change from Baseline to 26 weeks | The BISS uses a structured interview to assess the full spectrum of symptoms associated with all primary clinical states in bipolar disorder, yielding a total severity, a depression, a mania, as well as dimensional scale scores. There are 42 items; each item is rated on a 0-4 scale. The BISS is a clinician-rated instrument. The Scale is rated as follows: 0 Not at all 1. Slight 2. Mild 3. Moderate 4. Severe Each of the 42 items is rated separately, with a score, based on the most recent 7 day period. The mean score is calculated from the total score, giving an overall score out of 4, where 0 is slight and 4 is the most severe symptoms. A negative score indicated an improvement from baseline to 26 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Global Assessment of Functioning | Change from Baseline to 26 weeks | The Clinical Global Impression-Severity Scale (CGI-S) is used to assess global illness severity The CGI-S score change is measured from baseline to 26 weeks and is rated on a 7-point scale. The scale is read as follows: 1. very much improved since the initiation of treatment 2. much improved 3. minimally improved 4. no change from baseline (the initiation of treatment) 5. minimally worse 6. much worse 7. very much worse since the initiation of treatment The score is calculated as a mean of all items, where 1 indicates improvement from inititation of visit, and 7 indicates the condition to be much worse since the inititation of treatment. A negative score indicates a change from worse to better. |
| Baseline Randomization Percentage of Bipolar Types | Baseline | Percentages of Type I and Type II Bipolar Disorder included in Randomization groups |
| Demographic in Randomization 1 Group | Baseline | Baseline demographic percentages of subject randomized to either Divalproex or Lithium at the first randomization |
Countries
United States
Participant flow
Pre-assignment details
After a washout period of up to 1 week, subjects will be openly randomized to treatment with Lithium (Li) or Divalproex (Div) for 2 weeks. Subjects who become intolerant to lithium or divalproex at any point will be crossed over to the other mood stabilizer and continued in the study, or terminate early.
Participants by arm
| Arm | Count |
|---|---|
| Randomization to Divalproex Subjects randomized to Divalproex at Randomization 1. Demographics were only tracked in the Randomization 1 phase. | 59 |
| Randomization to Lithium Subjects randomized to Lithium at Randomization 1. Demographics were only tracked in the Randomization 1 phase. | 53 |
| Total | 112 |
Baseline characteristics
| Characteristic | Total | Randomization to Divalproex | Randomization to Lithium |
|---|---|---|---|
| Age, Customized Subjects over 18 years old | 112 Participants | 59 Participants | 53 Participants |
| Race/Ethnicity, Customized Overall Total African American | 15 Participants | 8 Participants | 7 Participants |
| Race/Ethnicity, Customized Overall Total Asian/Asian American | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Overall Total Hispanic | 34 Participants | 15 Participants | 19 Participants |
| Race/Ethnicity, Customized Overall Total Other | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Overall Total White (non Hispanic) | 59 Participants | 33 Participants | 26 Participants |
| Region of Enrollment United States | 112 Participants | 59 Participants | 53 Participants |
| Sex: Female, Male Female | 69 Participants | 37 Participants | 32 Participants |
| Sex: Female, Male Male | 43 Participants | 22 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 59 | 15 / 53 |
| serious Total, serious adverse events | 1 / 59 | 1 / 53 |
Outcome results
Primary
Bipolar Inventory of Symptoms Scale (BISS)
The BISS uses a structured interview to assess the full spectrum of symptoms associated with all primary clinical states in bipolar disorder, yielding a total severity, a depression, a mania, as well as dimensional scale scores. There are 42 items; each item is rated on a 0-4 scale. The BISS is a clinician-rated instrument. The Scale is rated as follows: 0 Not at all 1. Slight 2. Mild 3. Moderate 4. Severe Each of the 42 items is rated separately, with a score, based on the most recent 7 day period. The mean score is calculated from the total score, giving an overall score out of 4, where 0 is slight and 4 is the most severe symptoms. A negative score indicated an improvement from baseline to 26 weeks.
Time frame: Change from Baseline to 26 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Divalproex After Randomization 1 | Bipolar Inventory of Symptoms Scale (BISS) | Depression | -0.71 calculated mean scale score |
| Divalproex After Randomization 1 | Bipolar Inventory of Symptoms Scale (BISS) | Irritability | -0.50 calculated mean scale score |
| Divalproex After Randomization 1 | Bipolar Inventory of Symptoms Scale (BISS) | Mania | -0.31 calculated mean scale score |
| Divalproex After Randomization 1 | Bipolar Inventory of Symptoms Scale (BISS) | Anxiety | -0.49 calculated mean scale score |
| Divalproex After Randomization 1 | Bipolar Inventory of Symptoms Scale (BISS) | Psychosis | -0.14 calculated mean scale score |
| Lithium After Randomization 1 | Bipolar Inventory of Symptoms Scale (BISS) | Depression | -0.20 calculated mean scale score |
| Lithium After Randomization 1 | Bipolar Inventory of Symptoms Scale (BISS) | Psychosis | -0.25 calculated mean scale score |
| Lithium After Randomization 1 | Bipolar Inventory of Symptoms Scale (BISS) | Irritability | -0.39 calculated mean scale score |
| Lithium After Randomization 1 | Bipolar Inventory of Symptoms Scale (BISS) | Anxiety | -0.51 calculated mean scale score |
| Lithium After Randomization 1 | Bipolar Inventory of Symptoms Scale (BISS) | Mania | -0.41 calculated mean scale score |
| Divalproex or Lithium Monotherapy | Bipolar Inventory of Symptoms Scale (BISS) | Depression | -0.18 calculated mean scale score |
| Divalproex or Lithium Monotherapy | Bipolar Inventory of Symptoms Scale (BISS) | Psychosis | -0.27 calculated mean scale score |
| Divalproex or Lithium Monotherapy | Bipolar Inventory of Symptoms Scale (BISS) | Mania | 0.15 calculated mean scale score |
| Divalproex or Lithium Monotherapy | Bipolar Inventory of Symptoms Scale (BISS) | Irritability | -0.27 calculated mean scale score |
| Divalproex or Lithium Monotherapy | Bipolar Inventory of Symptoms Scale (BISS) | Anxiety | 0.16 calculated mean scale score |
| Lithium or Divalproex Plus Quetiapine | Bipolar Inventory of Symptoms Scale (BISS) | Irritability | -0.66 calculated mean scale score |
| Lithium or Divalproex Plus Quetiapine | Bipolar Inventory of Symptoms Scale (BISS) | Psychosis | -0.14 calculated mean scale score |
| Lithium or Divalproex Plus Quetiapine | Bipolar Inventory of Symptoms Scale (BISS) | Mania | -0.38 calculated mean scale score |
| Lithium or Divalproex Plus Quetiapine | Bipolar Inventory of Symptoms Scale (BISS) | Anxiety | -0.72 calculated mean scale score |
| Lithium or Divalproex Plus Quetiapine | Bipolar Inventory of Symptoms Scale (BISS) | Depression | -0.61 calculated mean scale score |
| Lithium or Divalproex Plus Lamotrigine | Bipolar Inventory of Symptoms Scale (BISS) | Psychosis | -0.16 calculated mean scale score |
| Lithium or Divalproex Plus Lamotrigine | Bipolar Inventory of Symptoms Scale (BISS) | Depression | -0.95 calculated mean scale score |
| Lithium or Divalproex Plus Lamotrigine | Bipolar Inventory of Symptoms Scale (BISS) | Irritability | -0.96 calculated mean scale score |
| Lithium or Divalproex Plus Lamotrigine | Bipolar Inventory of Symptoms Scale (BISS) | Anxiety | -0.93 calculated mean scale score |
| Lithium or Divalproex Plus Lamotrigine | Bipolar Inventory of Symptoms Scale (BISS) | Mania | -0.85 calculated mean scale score |
Secondary
Baseline Randomization Percentage of Bipolar Types
Percentages of Type I and Type II Bipolar Disorder included in Randomization groups
Time frame: Baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Divalproex After Randomization 1 | Baseline Randomization Percentage of Bipolar Types | 70 percentage of participants |
| Lithium After Randomization 1 | Baseline Randomization Percentage of Bipolar Types | 74.1 percentage of participants |
| Divalproex or Lithium Monotherapy | Baseline Randomization Percentage of Bipolar Types | 30 percentage of participants |
| Lithium or Divalproex Plus Quetiapine | Baseline Randomization Percentage of Bipolar Types | 25.9 percentage of participants |
Secondary
Demographic in Randomization 1 Group
Baseline demographic percentages of subject randomized to either Divalproex or Lithium at the first randomization
Time frame: Baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Divalproex After Randomization 1 | Demographic in Randomization 1 Group | Single never married | 27.1 percentage of subjects |
| Divalproex After Randomization 1 | Demographic in Randomization 1 Group | Married | 55.9 percentage of subjects |
| Divalproex After Randomization 1 | Demographic in Randomization 1 Group | Disrupted Marriage | 17.0 percentage of subjects |
| Lithium After Randomization 1 | Demographic in Randomization 1 Group | Single never married | 33.3 percentage of subjects |
| Lithium After Randomization 1 | Demographic in Randomization 1 Group | Married | 37.0 percentage of subjects |
| Lithium After Randomization 1 | Demographic in Randomization 1 Group | Disrupted Marriage | 29.6 percentage of subjects |
Secondary
Global Assessment of Functioning
The Clinical Global Impression-Severity Scale (CGI-S) is used to assess global illness severity The CGI-S score change is measured from baseline to 26 weeks and is rated on a 7-point scale. The scale is read as follows: 1. very much improved since the initiation of treatment 2. much improved 3. minimally improved 4. no change from baseline (the initiation of treatment) 5. minimally worse 6. much worse 7. very much worse since the initiation of treatment The score is calculated as a mean of all items, where 1 indicates improvement from inititation of visit, and 7 indicates the condition to be much worse since the inititation of treatment. A negative score indicates a change from worse to better.
Time frame: Change from Baseline to 26 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Divalproex After Randomization 1 | Global Assessment of Functioning | CGI-Depression | -1.11 calculated mean scale score |
| Divalproex After Randomization 1 | Global Assessment of Functioning | CGI-Overall | -1.28 calculated mean scale score |
| Divalproex After Randomization 1 | Global Assessment of Functioning | CGI-Mania | -0.69 calculated mean scale score |
| Lithium After Randomization 1 | Global Assessment of Functioning | CGI-Mania | -1.12 calculated mean scale score |
| Lithium After Randomization 1 | Global Assessment of Functioning | CGI-Depression | -0.32 calculated mean scale score |
| Lithium After Randomization 1 | Global Assessment of Functioning | CGI-Overall | -0.55 calculated mean scale score |
| Divalproex or Lithium Monotherapy | Global Assessment of Functioning | CGI-Mania | -0.19 calculated mean scale score |
| Divalproex or Lithium Monotherapy | Global Assessment of Functioning | CGI-Depression | -0.09 calculated mean scale score |
| Divalproex or Lithium Monotherapy | Global Assessment of Functioning | CGI-Overall | -0.11 calculated mean scale score |
| Lithium or Divalproex Plus Quetiapine | Global Assessment of Functioning | CGI-Depression | -0.99 calculated mean scale score |
| Lithium or Divalproex Plus Quetiapine | Global Assessment of Functioning | CGI-Overall | -0.99 calculated mean scale score |
| Lithium or Divalproex Plus Quetiapine | Global Assessment of Functioning | CGI-Mania | -0.71 calculated mean scale score |
| Lithium or Divalproex Plus Lamotrigine | Global Assessment of Functioning | CGI-Mania | -1.81 calculated mean scale score |
| Lithium or Divalproex Plus Lamotrigine | Global Assessment of Functioning | CGI-Depression | -1.24 calculated mean scale score |
| Lithium or Divalproex Plus Lamotrigine | Global Assessment of Functioning | CGI-Overall | -1.64 calculated mean scale score |