Bipolar Disorder
Conditions
Keywords
Depression
Brief summary
This study will compare triple and double drug regimens in the treatment of patients with depression, hypomania, or mania.
Detailed description
Early studies have shown lithium to produce a high percentage of satisfactory clinical response in patients with bipolar disorders. These studies, however, do not include lithium-refractory subgroups, such as bipolar II disorder patients. When the wide spectrum of bipolar disorders is considered, the lithium response rate decreases significantly. More broadly effective regimens are needed. Participants in this study will be randomly assigned to receive either lithium plus divalproex or lithium, divalproex, and lamotrigine for 7 months. Symptoms of depression and mania will be assessed with scales and patient questionnaires.
Interventions
DRUGLithium
Lithium monotherapy was initiated at 450 mg once daily and titrated slowly over three weeks to a minimum blood level of 0.5 milliequivalent /L (mEq/L).
DRUGLamotrigine
Patients were assigned in a one to one ratio to adjunctive lamotrigine versus placebo after stratification for illness type (bipolar I versus bipolar II), historical response to lithium (response versus non-response), and length of current exposure to combination treatment with lithium and divalproex (\< 2 months versus ≥ 2 months). During Phase 2, patients were continued on the same doses of lithium and divalproex as during the open-label treatment phase and equal capsules of double-blind lamotrigine or matching placebo were gradually added per a structured dosing schedule up to a minimum dose of 150 mg and a maximum dose of 200 mg per day.
DRUGDivalproex
Divalproex was then initiated at 250 mg twice daily and increased slowly over five weeks to a minimum blood level of 50 μg/mL.
DRUGPlacebo
Patients were assigned in a one to one ratio to adjunctive lamotrigine versus placebo after stratification for illness type (bipolar I versus bipolar II), historical response to lithium (response versus non-response), and length of current exposure to combination treatment with lithium and divalproex (\< 2 months versus ≥ 2 months). During Phase 2, patients were continued on the same doses of lithium and divalproex as during the open-label treatment phase and equal capsules of double-blind lamotrigine or matching placebo were gradually added per a structured dosing schedule up to a minimum dose of 150 mg and a maximum dose of 200 mg per day.
Sponsors
National Institute of Mental Health (NIMH)
University Hospitals Cleveland Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Bipolar I or II Disorder * Meet criteria for rapid cycling, defined as four or more episodes over the past 12 months * Meet criteria for a major depressive episode
Exclusion criteria
* History of intolerability of lithium, divalproex, or lamotrigine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Patients Who Experience a Marked and Persistent Bimodal Response | Baseline and Week 28 | A marked bimodal response is defined by the following three conditions over four consecutive weeks while on triple therapy and after three weeks of ltg: 1. Montgomery Asberg Depression Rating Scale (MADRS) total score of \<= 19 2. Young Mania Rating Scale (YMRS) total score of \<= 12.5 3. Global Assessment Scale (GAS) score \>= 51 The MADRS measures the severity of a subject's depression symptoms with a possible total score ranging from 0 - 60, with higher scores indicating more severe depression. The YMRS measures the severity of a subject's manic symptoms with a possible total score ranging from 0 - 60, with higher scores indicating more severe mania. The GAS measures a used to rate subjectively the social, occupational, and psychological functioning of a subject and ranges in score from 0-100, with a higher score indicating better social, occupational, and psychological functioning. |
Participant flow
Recruitment details
The study was conducted by the Mood Disorders Program at Case Western Reserve University/University Hospitals Case Medical Center (Cleveland, OH, USA) from August 2002 to June 2007.
Participants by arm
| Arm | Count |
|---|---|
| Lithium + Divalproex + Lamotrigine Divalproex : Divalproex was then initiated at 250 mg twice daily and increased slowly over five weeks to a minimum blood level of 50 μg/mL.
Lamotrigine : Patients were assigned in a one to one ratio to adjunctive lamotrigine versus placebo after stratification for illness type (bipolar I versus bipolar II), historical response to lithium (response versus non-response), and length of current exposure to combination treatment with lithium and divalproex (\< 2 months versus ≥ 2 months). During Phase 2, patients were continued on the same doses of lithium and divalproex as during the open-label treatment phase and equal capsules of double-blind lamotrigine or matching placebo were gradually added per a structured dosing schedule up to a minimum dose of 150 mg and a maximum.
dose of 200 mg per day.
Lithium : Lithium monotherapy was initiated at 450 mg once daily and titrated slowly over three weeks to a minimum blood level of 0.5 mEq/L. | 23 |
| Lithium + Divalproex + Placebo Divalproex : Divalproex was then initiated at 250 mg twice daily and increased slowly over five weeks to a minimum blood level of 50 μg/mL.
Lithium : Lithium monotherapy was initiated at 450 mg once daily and titrated slowly over three weeks to a minimum blood level of 0.5 mEq/L. | 26 |
| Total | 49 |
Baseline characteristics
| Characteristic | Lithium + Divalproex + Placebo | Total | Lithium + Divalproex + Lamotrigine |
|---|---|---|---|
| Age, Continuous | 43.0 years STANDARD_DEVIATION 9.6 | 37.9 years STANDARD_DEVIATION 11.1 | 35.7 years STANDARD_DEVIATION 11 |
| Bipolar Subtype Bipolar I disorder | 16 participants | 27 participants | 11 participants |
| Bipolar Subtype Bipolar II disorder | 10 participants | 22 participants | 12 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 45 Participants | 21 Participants |
| Sex: Female, Male Female | 15 Participants | 27 Participants | 12 Participants |
| Sex: Female, Male Male | 11 Participants | 22 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 23 | 1 / 26 |
| serious Total, serious adverse events | 0 / 23 | 0 / 26 |
Outcome results
Primary
The Proportion of Patients Who Experience a Marked and Persistent Bimodal Response
A marked bimodal response is defined by the following three conditions over four consecutive weeks while on triple therapy and after three weeks of ltg: 1. Montgomery Asberg Depression Rating Scale (MADRS) total score of \<= 19 2. Young Mania Rating Scale (YMRS) total score of \<= 12.5 3. Global Assessment Scale (GAS) score \>= 51 The MADRS measures the severity of a subject's depression symptoms with a possible total score ranging from 0 - 60, with higher scores indicating more severe depression. The YMRS measures the severity of a subject's manic symptoms with a possible total score ranging from 0 - 60, with higher scores indicating more severe mania. The GAS measures a used to rate subjectively the social, occupational, and psychological functioning of a subject and ranges in score from 0-100, with a higher score indicating better social, occupational, and psychological functioning.
Time frame: Baseline and Week 28
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lithium + Divalproex + Lamotrigine | The Proportion of Patients Who Experience a Marked and Persistent Bimodal Response | 7 participants |
| Lithium + Divalproex + Placebo | The Proportion of Patients Who Experience a Marked and Persistent Bimodal Response | 8 participants |