Bipolar Disorder
Conditions
Keywords
Bipolar disorder, Cognitive dysfunction, Memantine, NMDA antagonist
Brief summary
The purpose of this study is to see whether memantine improves memory function in participants with bipolar disorder who have minimal symptoms. Secondary analyses will test the role of memantine in improving residual mood symptoms (depression and mania) in participants with bipolar disorder. We hypothesize that in participants with bipolar disorder who have minimal symptoms memantine will be effective in improving cognitive functions, as measured by the difference in neuropsychological test scores at the beginning and at the end of the trial.
Detailed description
A large proportion of participants with bipolar disorder experience significant cognitive dysfunction, even when euthymic, after adequate treatment. The cognitive deficits in asymptomatic patients with bipolar disorder are very important for the participant's psychosocial function. In this population, cognitive deficits have been associated with poor psychosocial functioning, such as inability to hold a job. Memantine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist which has shown efficacy in cognitive dysfunction due to moderate to severe Alzheimer disease. Demonstrating the role of memantine in reducing cognitive dysfunction in minimally symptomatic participants with bipolar disorder promises to provide important clinical information, which could lead to improvements in well-being and functional status for large populations of participants with bipolar disorder.
Interventions
DRUGMemantine
Week 0: 5 mg memantine or placebo once a day (q.d.) Week 1: 5 mg memantine or placebo twice a day (b.i.d.) Week 2-3: 5 mg memantine or placebo once in the morning (q.a.m.)/10 mg once in the evening (q.p.m.) Week 4-12: 10mg Memantine or placebo b.i.d.
DRUGPlacebo
Inactive comparator. Placebo-matching memantine tablet.
Sponsors
Forest Laboratories
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnostic and Statistical Manual-IV (DSM-IV) diagnostic criteria for any bipolar disorder \[type I, type II, and not otherwise specified (NOS)\] (diagnosed with the use of the Structured Clinical Interview for DSM-IV-TR Mood Module (SCID Mood Module) * Written informed consent * Men or women aged 18-65 * A baseline Hamilton-D 17 score of \< 10 at screen and baseline visits. * A baseline Young Mania Rating Scale score of \< 10 at screen and baseline visits. * No acute episodes of depression or mania for the previous 12 weeks. * Massachusetts General Hospital Cognitive and Physical Functioning Scale: Cut-off: \>15 or Everyday Cognition Self-Report Form: Average of all items \>1.5 or Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): \<12 years education, RBANS total scale score of \<85 =12 years education, RBANS total scale score of \<93 \>12 years education, RBANS total scale score of \<100 * Able to read and understand English.
Exclusion criteria
Patients meeting any of the following criteria will be excluded from the study: * Participants with suicidal ideation where outpatient treatment is determined unsafe by the study clinician. These patients will be immediately referred to appropriate clinical treatment. * Pregnant women, nursing mothers, or women of childbearing potential who are not using a medically accepted means of contraception (defined as oral contraceptive pill or implant, condom, diaphragm, spermicide, intrauterine device (IUD), s/p tubal ligation, partner with vasectomy). * Serious or unstable medical illness, including liver impairment, kidney impairment, cardiovascular, hepatic, respiratory, endocrine, neurologic or hematologic disease. * History of seizure disorder, brain injury, any history of known neurological disease \[multiple sclerosis, degenerative disease such as amyotrophic lateral sclerosis (ALS), Parkinson disease and any movement disorders, etc\]. * History or current diagnosis of the following DSM-IV psychiatric illness: organic mental disorder, schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorders not otherwise specified, major depressive disorder, patients with substance dependence disorders, including alcohol, active within the last 12 months. * History of multiple adverse drug reactions. * Patients with mood congruent or mood incongruent psychotic features within the last 12 months. * Clinical or laboratory evidence of hypothyroidism. * Patients who have had an episode of acute depression or mania during the 12 weeks prior to enrollment. * Patients who have had electroconvulsive therapy (ECT) within the 6 months preceding enrollment. * Patients taking drugs which alkalinize the urine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| California Verbal Learning Test (CVLT) at Week 12 | Week 12 | The CVLT is used to measure verbal learning and episodic long-term memory. It assesses learning, short- and long-delayed recall and recognition for a list of 16 shopping items. Subjects are expected to remember a list of words. They are asked to repeat the words remembered 5 times (5 trials). Each of the words correctly remembered, in each trial, is marked as 1 point. The reported data represent the number of correct items for the Trial 1, Trial 5, Short Delay Free Recall, and Long Delay Free Recall. The long-delayed recall is assessed at 20 minutes. The CVLT enables a comprehensive characterization of a participant's memory profile. |
| California Verbal Learning Test (CVLT) at Week 6 | Week 6 | The CVLT is used to measure verbal learning and episodic long-term memory. It assesses learning, short- and long-delayed recall and recognition for a list of 16 shopping items. Subjects are expected to remember a list of words. They are asked to repeat the words remembered 5 times (5 trials). Each of the words correctly remembered, in each trial, is marked as 1 point. The reported data represent the number of correct items for the Trial 1, Trial 5, Short Delay Free Recall, and Long Delay Free Recall. The long-delayed recall is assessed at 20 minutes. The CVLT enables a comprehensive characterization of a participant's memory profile. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rapid Visual Information Processing Task (RVP) | Weeks 6 and 12 | RVP is a sensitive measure of sustained attention. In this test, a white box appears in the center of the screen with digits from 2-9 in a pseudorandom order at a rate of 100 digits per minute. Participants are asked to identify target sequences of three digits and to register responses using the press pad. RVPA is a measure of target sensitivity (i.e., the ability to discriminate between target and distractors). The outcome is defined as a z-score (statistical deviation from normal). A z-score of 0 is average. Higher z-scores represent better than average performance and negative z-scores represent worse than average performance. RVPB is an index of response bias (i.e., the tendency to respond or not respond in general). The outcome is defined as a z-score (statistical deviation from normal). A z-score of 0 is average. Higher z-scores represent a stronger tendency to respond and negative z-scores represent a less than average tendency to respond. |
Countries
United States
Participant flow
Recruitment details
Recruitment began in November 2005 and closed in December 2009.
Participants by arm
| Arm | Count |
|---|---|
| Memantine Memantine 5 mg tablet once per day for 1 week; dose increase if tolerated to memantine 5 mg twice a day, in the morning and the evening in Week 2; dose increase if tolerated to memantine 5 mg in the morning and memantine 10 mg in the evening in Week 3; dose increase if tolerated to memantine 10 mg twice a day, in the morning and the evening Weeks 4 to 12. | 48 |
| Placebo Placebo-matching memantine 5 mg tablet once per day for 1 week; dose increase if tolerated to placebo-matching memantine 5 mg twice a day, in the morning and the evening in Week 2; dose increase if tolerated to placebo-matching memantine 5 mg in the morning and placebo-matching memantine 10 mg in the evening in Week 3; dose increase if tolerated to placebo-matching memantine 10 mg twice a day, in the morning and the evening Weeks 4 to 12. | 24 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Lack of Efficacy | 5 | 3 |
| Overall Study | Lost to Follow-up | 6 | 3 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal of consent | 4 | 2 |
Baseline characteristics
| Characteristic | Memantine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 46.29 years STANDARD_DEVIATION 10.48 | 47.33 years STANDARD_DEVIATION 7.98 | 46.70 years STANDARD_DEVIATION 9.54 |
| Region of Enrollment United States | 48 Participants | 24 Participants | 72 Participants |
| Sex: Female, Male Female | 24 Participants | 11 Participants | 35 Participants |
| Sex: Female, Male Male | 24 Participants | 13 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 48 | 2 / 24 |
| serious Total, serious adverse events | 0 / 48 | 0 / 24 |
Outcome results
Primary
California Verbal Learning Test (CVLT) at Week 12
The CVLT is used to measure verbal learning and episodic long-term memory. It assesses learning, short- and long-delayed recall and recognition for a list of 16 shopping items. Subjects are expected to remember a list of words. They are asked to repeat the words remembered 5 times (5 trials). Each of the words correctly remembered, in each trial, is marked as 1 point. The reported data represent the number of correct items for the Trial 1, Trial 5, Short Delay Free Recall, and Long Delay Free Recall. The long-delayed recall is assessed at 20 minutes. The CVLT enables a comprehensive characterization of a participant's memory profile.
Time frame: Week 12
Population: All Randomized participants with data available at Week 12.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Memantine | California Verbal Learning Test (CVLT) at Week 12 | CVLT Trial 1 | 11.88 correct items | Standard Deviation 2.659 |
| Memantine | California Verbal Learning Test (CVLT) at Week 12 | CVLT Trial 5 | 11.63 correct items | Standard Deviation 3.645 |
| Memantine | California Verbal Learning Test (CVLT) at Week 12 | CVLT Short Delay Free Recall | 11.79 correct items | Standard Deviation 3.718 |
| Memantine | California Verbal Learning Test (CVLT) at Week 12 | CVLT Long Delay Free Recall | 14.46 correct items | Standard Deviation 1.641 |
| Placebo | California Verbal Learning Test (CVLT) at Week 12 | CVLT Long Delay Free Recall | 14.55 correct items | Standard Deviation 1.128 |
| Placebo | California Verbal Learning Test (CVLT) at Week 12 | CVLT Trial 1 | 11.55 correct items | Standard Deviation 2.505 |
| Placebo | California Verbal Learning Test (CVLT) at Week 12 | CVLT Short Delay Free Recall | 12.09 correct items | Standard Deviation 3.477 |
| Placebo | California Verbal Learning Test (CVLT) at Week 12 | CVLT Trial 5 | 11.73 correct items | Standard Deviation 3.524 |
Primary
California Verbal Learning Test (CVLT) at Week 6
The CVLT is used to measure verbal learning and episodic long-term memory. It assesses learning, short- and long-delayed recall and recognition for a list of 16 shopping items. Subjects are expected to remember a list of words. They are asked to repeat the words remembered 5 times (5 trials). Each of the words correctly remembered, in each trial, is marked as 1 point. The reported data represent the number of correct items for the Trial 1, Trial 5, Short Delay Free Recall, and Long Delay Free Recall. The long-delayed recall is assessed at 20 minutes. The CVLT enables a comprehensive characterization of a participant's memory profile.
Time frame: Week 6
Population: All Randomized participants with data available at Week 6.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Memantine | California Verbal Learning Test (CVLT) at Week 6 | CVLT Short Delay Free Recall | 11.31 correct items | Standard Deviation 4.335 |
| Memantine | California Verbal Learning Test (CVLT) at Week 6 | CVLT Trial 5 | 9.15 correct items | Standard Deviation 3.815 |
| Memantine | California Verbal Learning Test (CVLT) at Week 6 | CVLT Long Delay Free Recall | 14.03 correct items | Standard Deviation 2.732 |
| Memantine | California Verbal Learning Test (CVLT) at Week 6 | CVLT Trial 1 | 11.55 correct items | Standard Deviation 3.28 |
| Placebo | California Verbal Learning Test (CVLT) at Week 6 | CVLT Long Delay Free Recall | 13.53 correct items | Standard Deviation 3.826 |
| Placebo | California Verbal Learning Test (CVLT) at Week 6 | CVLT Trial 5 | 9.05 correct items | Standard Deviation 3.316 |
| Placebo | California Verbal Learning Test (CVLT) at Week 6 | CVLT Short Delay Free Recall | 10.24 correct items | Standard Deviation 4.024 |
| Placebo | California Verbal Learning Test (CVLT) at Week 6 | CVLT Trial 1 | 10.65 correct items | Standard Deviation 2.849 |
Secondary
Rapid Visual Information Processing Task (RVP)
RVP is a sensitive measure of sustained attention. In this test, a white box appears in the center of the screen with digits from 2-9 in a pseudorandom order at a rate of 100 digits per minute. Participants are asked to identify target sequences of three digits and to register responses using the press pad. RVPA is a measure of target sensitivity (i.e., the ability to discriminate between target and distractors). The outcome is defined as a z-score (statistical deviation from normal). A z-score of 0 is average. Higher z-scores represent better than average performance and negative z-scores represent worse than average performance. RVPB is an index of response bias (i.e., the tendency to respond or not respond in general). The outcome is defined as a z-score (statistical deviation from normal). A z-score of 0 is average. Higher z-scores represent a stronger tendency to respond and negative z-scores represent a less than average tendency to respond.
Time frame: Weeks 6 and 12
Population: All randomized participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Memantine | Rapid Visual Information Processing Task (RVP) | RVPA, Week 6 | -1.3997 z-score | Standard Deviation 5.23534 |
| Memantine | Rapid Visual Information Processing Task (RVP) | RVPA, Week 12 | -0.1508 z-score | Standard Deviation 1.49027 |
| Memantine | Rapid Visual Information Processing Task (RVP) | RVPB, Week 6 | -2.4440 z-score | Standard Deviation 7.76338 |
| Memantine | Rapid Visual Information Processing Task (RVP) | RVPB, Week 12 | -1.4833 z-score | Standard Deviation 4.39216 |
| Placebo | Rapid Visual Information Processing Task (RVP) | RVPB, Week 12 | -0.2108 z-score | Standard Deviation 0.59609 |
| Placebo | Rapid Visual Information Processing Task (RVP) | RVPA, Week 6 | -0.6859 z-score | Standard Deviation 0.96275 |
| Placebo | Rapid Visual Information Processing Task (RVP) | RVPB, Week 6 | -0.2353 z-score | Standard Deviation 0.74248 |
| Placebo | Rapid Visual Information Processing Task (RVP) | RVPA, Week 12 | -0.6017 z-score | Standard Deviation 1.00486 |