Memantine and Cognitive Dysfunction in Bipolar Disorder

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00586066
• Collaborator: Forest Laboratories (Industry)
• Enrollment: 72
• Locations: 3
• Arms: 2
• Actual Duration (Months): 49
• Patients Per Site: 24
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder	Drug: Memantine; Drug: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Memantine and Cognitive Dysfunction in Bipolar Disorder
• Actual Study Start Date: Nov 1, 2005
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 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.	Drug: Placebo; Inactive comparator. Placebo-matching memantine tablet.; Other Names: Sugar pill
Experimental: Memantine Re-purposed Alzheimer's drug to treat cognitive dysfunction associated with bipolar disorder. 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.	Drug: Memantine; 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.; Other Names: Namenda

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars Sinai Department of Psychiatry	Los Angeles	California	United States	90048
2	Asher Depression Center, Northwestern University	Chicago	Illinois	United States	60611
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital
• Forest Laboratories

Investigators

• Principal Investigator: Andrew A. Nierenberg, M.D., Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Andrew A. Nierenberg, MD, Director, Bipolar Clinic and Research Program, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00586066
• Other Study ID Numbers: 2005-p-001651; NCT00645476
• First Posted: Jan 4, 2008
• Last Update Posted: Oct 6, 2017
• Last Verified: Sep 1, 2017

• Keywords provided by Andrew A. Nierenberg, MD, Director, Bipolar Clinic and Research Program, Massachusetts General Hospital: Bipolar disorder; Cognitive dysfunction; Memantine; NMDA antagonist
• Additional relevant MeSH terms: Disease; Bipolar Disorder; Cognitive Dysfunction; Memantine

Study Results

Participant Flow

Recruitment Details	Recruitment began in November 2005 and closed in December 2009.

Arm/Group Title	Memantine	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	48	24
COMPLETED	30	14
NOT COMPLETED	18	10

Baseline Characteristics

Arm/Group Title	Memantine	Placebo	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	48	24	72
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.29 (10.48)	47.33 (7.98)	46.70 (9.54)
Sex: Female, Male (Count of Participants)
Female	24 50%	11 45.8%	35 48.6%
Male	24 50%	13 54.2%	37 51.4%
Region of Enrollment (Count of Participants)
United States	48 100%	24 100%	72 100%

Outcome Measures

1. Primary Outcome

Title	California Verbal Learning Test (CVLT) at Week 12
Description	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

Outcome Measure Data

Analysis Population Description

All Randomized participants with data available at Week 12.

Arm/Group Title	Memantine	Placebo
Arm/Group Description	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.	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.
Measure Participants	26	13
CVLT Trial 1	11.88 (2.659)	11.55 (2.505)
CVLT Trial 5	11.63 (3.645)	11.73 (3.524)
CVLT Short Delay Free Recall	11.79 (3.718)	12.09 (3.477)
CVLT Long Delay Free Recall	14.46 (1.641)	14.55 (1.128)

2. Primary Outcome

Title	California Verbal Learning Test (CVLT) at Week 6
Description	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

Outcome Measure Data

Analysis Population Description

All Randomized participants with data available at Week 6.

Arm/Group Title	Memantine	Placebo
Arm/Group Description	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.	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.
Measure Participants	41	19
CVLT Trial 1	11.55 (3.280)	10.65 (2.849)
CVLT Trial 5	9.15 (3.815)	9.05 (3.316)
CVLT Short Delay Free Recall	11.31 (4.335)	10.24 (4.024)
CVLT Long Delay Free Recall	14.03 (2.732)	13.53 (3.826)

3. Secondary Outcome

Title	Rapid Visual Information Processing Task (RVP)
Description	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

Outcome Measure Data

Analysis Population Description

All randomized participants with data available at the given time-point.

Arm/Group Title	Memantine	Placebo
Arm/Group Description	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.	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.
Measure Participants	48	24
RVPA, Week 6	-1.3997 (5.23534)	-0.6859 (0.96275)
RVPA, Week 12	-0.1508 (1.49027)	-0.6017 (1.00486)
RVPB, Week 6	-2.4440 (7.76338)	-0.2353 (0.74248)
RVPB, Week 12	-1.4833 (4.39216)	-0.2108 (0.59609)

Adverse Events

Time Frame	12 Weeks
Arm/Group Title	Memantine		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Memantine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Memantine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/48 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Memantine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/48 (0%)		2/24 (8.3%)
Gastrointestinal disorders
Gastric reflux	0/48 (0%)		2/24 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.