Bipolar Disorder
Conditions
Keywords
Bipolar disorder, Comparative effectiveness trial, Lithium, Quetiapine
Brief summary
The purpose of this study is to compare the effectiveness of lithium and quetiapine for the treatment of individuals with bipolar disorder.
Detailed description
Mood stabilizers, medications that prevent future mood episodes, are the foundation for treatment of bipolar disorder. While all published bipolar disorder treatment guidelines recommend that pharmacotherapy should include mood stabilizers for long-term maintenance treatment, no randomized comparative effectiveness studies have examined the real-world advantages and disadvantages of the newer second generation antipsychotic (SGA) mood stabilizers compared to the classic mood stabilizers, such as lithium (Li). No studies have looked at the effectiveness of SGAs compared to mood stabilizers when used in the context of other medications required to manage bipolar patients, since bipolar disorder patients take a median of 3 medications for optimal outcomes. Quetiapine (QTP) is the most extensively studied, broadly efficacious and the most widely prescribed SGA for bipolar disorder. The classic mood stabilizer Li has the largest evidence base for treating bipolar disorder, but has been largely supplanted by the SGAs. Thus, this study compares symptomatic benefits and adverse effect burden between a QTP foundation with adjunctive personalized treatments (QTP+APT) and a mood stabilizer foundation consisting of Li with APT (Li+APT). APT will include any other medication needed with the following exceptions: the QTP+APT cannot receive Li and the Li+APT group cannot receive an antipsychotic. If, however, participants clinically require a switch to, or the addition of any other SGA or mood stabilizer, then those medications can be added as a rescue strategy that will be carefully recorded. Consistent with an effectiveness trial, participants will be able to continue in the study if they require a rescue treatment. The specific plan is a randomized, open, two arm, comparative effectiveness study of QTP+APT vs. Li+APT treatment for 6 months across 10 sites. In summary, this comparative effectiveness study compares fundamentally different acute and continuation treatments for bipolar disorder. The investigators address the key question of whether to use a prototypical mood stabilizing SGA (i.e., QTP) or the classical mood stabilizer Li as the foundational treatment in the context of other necessary adjunctive personalized treatments (APT).
Interventions
DRUGLithium
600-900mg per day over 6 months
DRUGQuetiapine
100-800mg a day over 6 months
Sponsors
Agency for Healthcare Research and Quality (AHRQ)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 68 Years
Healthy volunteers
No
Inclusion criteria
1. Meets DSM-IV criteria for BD I or II, which is the primary focus of treatment 2. Able to give written informed consent 3. Age \> to 18 years and \< 68 years 4. Women of child bearing potential must agree to use adequate contraception (e.g. oral contraceptives, intrauterine device, barrier methods, or total abstinence from intercourse; Depo Provera is acceptable if it is started 3 months prior to enrollment), inform their doctor at the earliest possible time of their plans to conceive, and to understand the risks of lithium and other study treatments to the fetus and infant 5. Currently symptomatic, as defined as a Clinical Global Impression - Bipolar Disorder Overall Severity (CGI-BP-S) score of at least 3 (mild) 6. If currently taking an SGA, participants would be required to be willing to either discontinue or switch to QTP 7. Willing to be randomized to either QTP+APT or Li+APT.
Exclusion criteria
1. Unwilling or unable to comply with study requirements 2. If maintained on thyroid medication must be euthyroid for at least 1 month before Visit 1 3. Patients who have had intolerable side effects with QTP or Li 4. Patients whose clinical status requires inpatient care 5. Drug/alcohol dependence within the past 30 days 6. Pregnancy as determined by urine pregnancy test or breastfeeding 7. History of nonresponse to Li at a serum level of ≥ 1.0 mEq/L ≥ 8 weeks 8. History of nonresponse to QTP at doses of at least 600 mg ≥ 8 weeks.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression-Efficacy Index (CGI-EI) | Average 6 month score minus Average baseline score | The CGI-EI integrates benefits and harms and yields a score that can be compared across interventions. It is made up of 2 subscales: therapeutic effects and side effects. Each rating is on a scale from 1 to 4. To combine these two subscales into the CGI-EI we report as our primary outcome, we subtracted the side effects subscale from the therapeutic effects subscale. Thus, the CGI-EI we report ranges the integers from -3 to +3 (i.e. possible scores are -3,-2,-1,0,1,2,3). A score of -3 is the most burdensome side effect score (4) and the least therapeutic effect score (1) and a score of +3 is the least burdensome side effect score (1) and the highest therapeutic effect score (4). Higher CGI-EI signifies better outcome (minimal side effects, maximal therapeutic effect). Lower CGI-EI signifies worse outcome (maximal side effects, minimal therapeutic effect).To compute CGI-EI score, we subtract the side effect score from the therapeutic effect score. |
| Necessary Clinical Adjustments | 6 Months | Necessary Clinical Adjustment (NCA): The Medication Recommendation Tracking Form was developed and successfully implemented in a previous study to capture recommended medication changes at each study visit 17. Clinicians record dosage changes, missed doses, new medications added or discontinued, and specify the reason for each change. Any change in psychotropic medications, or medications used to treat side effects, is coded along with the reason for the change. NCAs include those changes made for lack of effectiveness or intolerance, but not changes for planned dose titrations. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Risk of Cardiovascular Disease - Framingham Risk Score | Average baseline score minus Average 6 month score | The Framingham risk score captures the classic risk factors for cardiovascular disease, including age, sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, and smoking. The Framingham risk score is used as a simple predictive tool to determine 10-year (short term) risk for developing cardiovascular disease (CHD), with higher scores indicating higher risk. Established benchmarks exist for scores from 0 to 25--though it can exceed this value--that are meant to translate to the probability of developing heart disease. |
| Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT) | Average baseline score minus Average 6-month score | The LIFE-RIFT asses the extent to which psychopathology has impacted current functioning in work, household chores, interpersonal relationships with partner, family, and friends, recreational activities, and life, satisfaction, leisure activities and social relationships. Summary scores can range from 4 to 20, with higher scores indicating greater functional impairment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Li + APT Study participants will take lithium in addition to any other medications recommended by the study physician.
Lithium: 600-1200mg per day over 6 months | 240 |
| QTP + APT Study participants will take quetiapine in addition to any other medications recommended by the study physician.
Quetiapine: 100-800mg a day over 6 months | 242 |
| Total | 482 |
Baseline characteristics
| Characteristic | Li + APT | QTP + APT | Total |
|---|---|---|---|
| Age, Continuous | 38.6 Years STANDARD_DEVIATION 12.1 | 39.1 Years STANDARD_DEVIATION 12.2 | 38.9 Years STANDARD_DEVIATION 12.1 |
| Region of Enrollment United States | 240 participants | 242 participants | 482 participants |
| Sex: Female, Male Female | 140 Participants | 143 Participants | 283 Participants |
| Sex: Female, Male Male | 100 Participants | 99 Participants | 199 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 210 / 240 | 221 / 242 |
| serious Total, serious adverse events | 36 / 240 | 27 / 242 |
Outcome results
Primary
Clinical Global Impression-Efficacy Index (CGI-EI)
The CGI-EI integrates benefits and harms and yields a score that can be compared across interventions. It is made up of 2 subscales: therapeutic effects and side effects. Each rating is on a scale from 1 to 4. To combine these two subscales into the CGI-EI we report as our primary outcome, we subtracted the side effects subscale from the therapeutic effects subscale. Thus, the CGI-EI we report ranges the integers from -3 to +3 (i.e. possible scores are -3,-2,-1,0,1,2,3). A score of -3 is the most burdensome side effect score (4) and the least therapeutic effect score (1) and a score of +3 is the least burdensome side effect score (1) and the highest therapeutic effect score (4). Higher CGI-EI signifies better outcome (minimal side effects, maximal therapeutic effect). Lower CGI-EI signifies worse outcome (maximal side effects, minimal therapeutic effect).To compute CGI-EI score, we subtract the side effect score from the therapeutic effect score.
Time frame: Average 6 month score minus Average baseline score
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Li + APT | Clinical Global Impression-Efficacy Index (CGI-EI) | 1.58 Units on the scale |
| QTP + APT | Clinical Global Impression-Efficacy Index (CGI-EI) | 1.52 Units on the scale |
Comparison: For the first co-primary aim, mixed-effects linear regression analyses compared the two intervention groups on the repeated assessments of the CGI-EI over 6 months.p-value: 0.59Mixed Models Analysis
Primary
Necessary Clinical Adjustments
Necessary Clinical Adjustment (NCA): The Medication Recommendation Tracking Form was developed and successfully implemented in a previous study to capture recommended medication changes at each study visit 17. Clinicians record dosage changes, missed doses, new medications added or discontinued, and specify the reason for each change. Any change in psychotropic medications, or medications used to treat side effects, is coded along with the reason for the change. NCAs include those changes made for lack of effectiveness or intolerance, but not changes for planned dose titrations.
Time frame: 6 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Li + APT | Necessary Clinical Adjustments | .8 Mean NCAs per month | Standard Deviation 0.8 |
| QTP + APT | Necessary Clinical Adjustments | .9 Mean NCAs per month | Standard Deviation 1 |
Comparison: For the second co-primary, patient monthly rates of NCAs (determined by dividing total number of NCAs during follow-up by the length of follow-up - to account for attrition and resulting differential exposure time) for treatment groups were compared using a Wilcoxon rank-sum test.p-value: 0.118Wilcoxon (Mann-Whitney)
Secondary
Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT)
The LIFE-RIFT asses the extent to which psychopathology has impacted current functioning in work, household chores, interpersonal relationships with partner, family, and friends, recreational activities, and life, satisfaction, leisure activities and social relationships. Summary scores can range from 4 to 20, with higher scores indicating greater functional impairment.
Time frame: Average baseline score minus Average 6-month score
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Li + APT | Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT) | -3.74 units on a scale |
| QTP + APT | Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT) | -3.61 units on a scale |
Comparison: Mixed-effects linear regression analyses compared the two intervention groups on the repeated assessment of the LIFE-RIFT over 6 monthsp-value: 0.7Mixed Models Analysis
Secondary
Risk of Cardiovascular Disease - Framingham Risk Score
The Framingham risk score captures the classic risk factors for cardiovascular disease, including age, sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, and smoking. The Framingham risk score is used as a simple predictive tool to determine 10-year (short term) risk for developing cardiovascular disease (CHD), with higher scores indicating higher risk. Established benchmarks exist for scores from 0 to 25--though it can exceed this value--that are meant to translate to the probability of developing heart disease.
Time frame: Average baseline score minus Average 6 month score
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Li + APT | Risk of Cardiovascular Disease - Framingham Risk Score | -0.26 units on a scale |
| QTP + APT | Risk of Cardiovascular Disease - Framingham Risk Score | 0.17 units on a scale |
Comparison: Mixed-effects linear regression analyses compared the two intervention groups on the repeated collection of measures relevant to calculation of the Framingham Risk Score over 6 monthsp-value: 0.11Mixed Models Analysis