Bipolar Disorder, Mania
Conditions
Brief summary
This study will compare the benefits and side effects of lithium and divalproex in the treatment of older adults with bipolar mania.
Detailed description
This is the first controlled acute treatment study of bipolar disorder in adults 60 years or older with current DSM-IV manic, mixed, or hypomanic episodes. The number of older adults with severe and disabling bipolar disorder is increasing, and information to guide the management of the treatment of the disease is lacking in this population. Guidelines for treatment of younger people with bipolar disorder cannot be used for older people, and there are no safety and efficacy data upon which to base initial treatment decisions for older patients with bipolar mania. Mood stabilizers (lithium and divalproex) are the first-line treatment for bipolar disorder. However, in aged patients physiological changes and comorbid diseases may increase vulnerability to side effects and limit the benefits of the medications. This double-blind study will compare the benefits and side-effects of 9 weeks of treatment with lithium and divalproex in people with bipolar mania. Participants, who may be treated during inpatient hospitalization or as outpatients, will be randomly assigned to receive either lithium or divalproex. During the first 3 weeks of treatment careful titration of lithium and divalproex will be done to reach dose ranges. All other psychotropic medications will be discontinued. Behavioral interventions and/or lorazepam may be added, if necessary. After the first 3 weeks, if symptoms do not improve, risperidone will be added to be taken everyday with the study medication.
Interventions
DRUGLithium (LI)
The starting LI dose will be 150 mg in the morning and evening. The dose of medication will be adjusted to achieve plasma LI level ranges between 0.40 and 0.99 mEq/L (target 0.80 to 0.99 mEq/L).
DRUGDivalproex (DV)
Dosage of DV will be 250 mg in the morning and evening. The dose of medication will be adjusted to achieve plasma DV level ranges between 40 and 99 mcg/mL (target 80 to 99 mcg/ml).
Sponsors
National Institute of Mental Health (NIMH)
Weill Medical College of Cornell University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of DSM-IV Bipolar Disorder, Type I: current manic, mixed, or hypomanic episodes
Exclusion criteria
* Rapid cycling bipolar disorder * History of substance abuse or dependence within last 3 months * Diagnosis of schizophrenia or other chronic psychotic conditions * Acute or unstable medical illness * Documented intolerance to Lithium, Depakote, Risperidone, or Lorazepam * Dementia * Inability to communicate in English
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sedation Score | Day 4, Day 9, Day 15, and then Weekly from Week 3 to Week 9 | The Sedation Item score of the UKU (Norwegian for Committee of Clinical Investigations) Side Effect Rating Scale. A higher value indicates greater severity. Range is 0-3 (not present, mild, moderate, or severe). |
| Young Mania Rating Scale (YMRS) Scores | Day 4, Day 9, Day 15, and then Weekly from Week 3 to Week 9 | The Young Mania Rating Scale is an eleven item interviewer-rated instrument. Four items are scored 0-8, the others 0-4. The total score therefore ranges from 0-60, with higher values reflecting greater severity. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lithium (LI) Participants will receive 9 weeks of treatment with Lithium. The starting Lithium dose will be 150 mg in the morning and evening. | 112 |
| Divalproex (DV) Participants will receive 9 weeks of treatment with Divalproex. The starting Divalproex dose will be 250 mg in the morning and evening. | 112 |
| Total | 224 |
Baseline characteristics
| Characteristic | Lithium (LI) | Divalproex (DV) | Total |
|---|---|---|---|
| Age, Continuous | 67.6 years STANDARD_DEVIATION 6.8 | 68.3 years STANDARD_DEVIATION 6.1 | 68.0 years STANDARD_DEVIATION 6.4 |
| Sedation score | .5 units on a scale STANDARD_DEVIATION 0.7 | .5 units on a scale STANDARD_DEVIATION 0.6 | .5 units on a scale STANDARD_DEVIATION 0.65 |
| Sex: Female, Male Female | 56 Participants | 59 Participants | 115 Participants |
| Sex: Female, Male Male | 56 Participants | 53 Participants | 109 Participants |
| Young Mania Rating Scale | 27.1 units on a scale STANDARD_DEVIATION 7.4 | 25.5 units on a scale STANDARD_DEVIATION 6.1 | 26.3 units on a scale STANDARD_DEVIATION 6.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 112 | 2 / 112 |
| other Total, other adverse events | 69 / 112 | 70 / 112 |
| serious Total, serious adverse events | 24 / 112 | 22 / 112 |
Outcome results
Primary
Sedation Score
The Sedation Item score of the UKU (Norwegian for Committee of Clinical Investigations) Side Effect Rating Scale. A higher value indicates greater severity. Range is 0-3 (not present, mild, moderate, or severe).
Time frame: Day 4, Day 9, Day 15, and then Weekly from Week 3 to Week 9
Population: The number of participants analyzed over the course of the study decreases due to participants missing a visit or dropping from the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lithium (LI) | Sedation Score | Week 3 | 0.5 units on a scale | Standard Deviation 0.7 |
| Lithium (LI) | Sedation Score | Day 4 | 0.5 units on a scale | Standard Deviation 0.7 |
| Lithium (LI) | Sedation Score | Day 9 | 0.6 units on a scale | Standard Deviation 0.7 |
| Lithium (LI) | Sedation Score | Day 15 | 0.4 units on a scale | Standard Deviation 0.6 |
| Lithium (LI) | Sedation Score | Week 4 | 0.5 units on a scale | Standard Deviation 0.7 |
| Lithium (LI) | Sedation Score | Week 5 | 0.5 units on a scale | Standard Deviation 0.7 |
| Lithium (LI) | Sedation Score | Week 6 | 0.5 units on a scale | Standard Deviation 0.7 |
| Lithium (LI) | Sedation Score | Week 7 | 0.4 units on a scale | Standard Deviation 0.6 |
| Lithium (LI) | Sedation Score | Week 8 | 0.4 units on a scale | Standard Deviation 0.6 |
| Lithium (LI) | Sedation Score | Week 9 | 0.4 units on a scale | Standard Deviation 0.6 |
| Divalproex (DV) | Sedation Score | Week 7 | 0.4 units on a scale | Standard Deviation 0.5 |
| Divalproex (DV) | Sedation Score | Week 3 | 0.6 units on a scale | Standard Deviation 0.7 |
| Divalproex (DV) | Sedation Score | Week 5 | 0.4 units on a scale | Standard Deviation 0.6 |
| Divalproex (DV) | Sedation Score | Day 4 | 0.5 units on a scale | Standard Deviation 0.7 |
| Divalproex (DV) | Sedation Score | Week 9 | 0.4 units on a scale | Standard Deviation 0.6 |
| Divalproex (DV) | Sedation Score | Day 9 | 0.6 units on a scale | Standard Deviation 0.6 |
| Divalproex (DV) | Sedation Score | Week 6 | 0.5 units on a scale | Standard Deviation 0.6 |
| Divalproex (DV) | Sedation Score | Day 15 | 0.5 units on a scale | Standard Deviation 0.7 |
| Divalproex (DV) | Sedation Score | Week 8 | 0.3 units on a scale | Standard Deviation 0.5 |
| Divalproex (DV) | Sedation Score | Week 4 | 0.5 units on a scale | Standard Deviation 0.6 |
Primary
Young Mania Rating Scale (YMRS) Scores
The Young Mania Rating Scale is an eleven item interviewer-rated instrument. Four items are scored 0-8, the others 0-4. The total score therefore ranges from 0-60, with higher values reflecting greater severity.
Time frame: Day 4, Day 9, Day 15, and then Weekly from Week 3 to Week 9
Population: The number of participants analyzed over the course of the study decreases due to participants missing a visit or dropping from the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lithium (LI) | Young Mania Rating Scale (YMRS) Scores | Day 15 | 14.3 units on a scale | Standard Deviation 9.3 |
| Lithium (LI) | Young Mania Rating Scale (YMRS) Scores | Week 5 | 7.6 units on a scale | Standard Deviation 5.8 |
| Lithium (LI) | Young Mania Rating Scale (YMRS) Scores | Day 9 | 19.0 units on a scale | Standard Deviation 9.5 |
| Lithium (LI) | Young Mania Rating Scale (YMRS) Scores | Week 6 | 7.2 units on a scale | Standard Deviation 5.4 |
| Lithium (LI) | Young Mania Rating Scale (YMRS) Scores | Week 3 | 12.1 units on a scale | Standard Deviation 8.8 |
| Lithium (LI) | Young Mania Rating Scale (YMRS) Scores | Week 7 | 6.0 units on a scale | Standard Deviation 6 |
| Lithium (LI) | Young Mania Rating Scale (YMRS) Scores | Day 4 | 21.4 units on a scale | Standard Deviation 9.3 |
| Lithium (LI) | Young Mania Rating Scale (YMRS) Scores | Week 4 | 9.4 units on a scale | Standard Deviation 5.9 |
| Lithium (LI) | Young Mania Rating Scale (YMRS) Scores | Week 9 | 6.3 units on a scale | Standard Deviation 6 |
| Lithium (LI) | Young Mania Rating Scale (YMRS) Scores | Week 8 | 6.0 units on a scale | Standard Deviation 5.4 |
| Divalproex (DV) | Young Mania Rating Scale (YMRS) Scores | Week 9 | 6.8 units on a scale | Standard Deviation 5.9 |
| Divalproex (DV) | Young Mania Rating Scale (YMRS) Scores | Day 4 | 19.7 units on a scale | Standard Deviation 7.7 |
| Divalproex (DV) | Young Mania Rating Scale (YMRS) Scores | Day 9 | 16.3 units on a scale | Standard Deviation 8.1 |
| Divalproex (DV) | Young Mania Rating Scale (YMRS) Scores | Day 15 | 15.2 units on a scale | Standard Deviation 8.7 |
| Divalproex (DV) | Young Mania Rating Scale (YMRS) Scores | Week 3 | 13.1 units on a scale | Standard Deviation 9.4 |
| Divalproex (DV) | Young Mania Rating Scale (YMRS) Scores | Week 4 | 9.9 units on a scale | Standard Deviation 7.1 |
| Divalproex (DV) | Young Mania Rating Scale (YMRS) Scores | Week 5 | 9.8 units on a scale | Standard Deviation 7 |
| Divalproex (DV) | Young Mania Rating Scale (YMRS) Scores | Week 6 | 8.2 units on a scale | Standard Deviation 6.5 |
| Divalproex (DV) | Young Mania Rating Scale (YMRS) Scores | Week 7 | 7.0 units on a scale | Standard Deviation 5.9 |
| Divalproex (DV) | Young Mania Rating Scale (YMRS) Scores | Week 8 | 6.7 units on a scale | Standard Deviation 5.8 |