Memantine and Cognitive Dysfunction in Bipolar Disorder

Official Title: “This is a Placebo-controlled Study. It Will Compare the Effects of Memantine With Placebo on Cognitive Dysfunction”

Memantine is a glutamate NMDA receptor antagonist which has shown efficacy in cognitive dysfunction due to moderate to severe Alzheimer disease (Reisberg et al., 2003).

The investigators propose to treat 75 subjects with bipolar disorder with minimal mood symptoms and cognitive dysfunction with memantine or placebo. The 75 subjects will be enrolled at three sites. The same study will be performed at all three sites, with each site functioning independently of the other.

The investigators study will include objective neuropsychological testing of memory and executive functions before and after treatment, as well as ratings of mood symptoms and subjective patient ratings of memory function at every study visit.

The principal aim of this study is to measure the efficacy of memantine on improving memory function in minimally symptomatic subjects with bipolar disorder. The investigators hypothesize that in minimally symptomatic subjects with bipolar disorder memantine will be efficacious in improving cognitive functions, as measured by the difference in neuropsychological test scores at the beginning and at the end of the trial.

Secondary analyses will test the role of memantine in improving residual mood symptoms (depression and mania) in subjects with bipolar disorder.

Demonstrating the role of memantine in reducing cognitive dysfunction in minimally symptomatic subjects with bipolar disorder promises to provide important clinical information, which could lead to improvements in well-being and functional status for large populations of subjects with bipolar disorder.

There will be an optional open label 12-week extension to the study. Subjects will be restarted on memantine similar to the regimen in the first phase of the study. Subjects will meet with the investigators every four weeks (weeks 16, 20, and 24) for assessment as mentioned above. Neuropsychological testing will be repeated at week 24. It is the investigator's belief that this added timeline will better demonstrate any improvements in cognitive function.

Study: MEMANTINE AND COGNITIVE DYSFUNCTION IN BIPOLAR DISORDER The study design involves double-blind, prospective, and longitudinal treatment with flexible doses of memantine or placebo for 12 weeks in minimally symptomatic subjects with bipolar disorder and memory dysfunction. We will use objective neuropsychological testing of memory functions before and after treatment, as well as subjective patient ratings of memory throughout the treatment.

The primary analysis will compare neuropsychological test scores before and after treatment among subjects treated with memantine or placebo.

A minimum of 25 subjects with bipolar disorder will be enrolled. We will enroll subjects with bipolar disorder, diagnosed with the use of the Structured Clinical Interview for DSM-IV-TR Mood Module (SCID Mood Module) (screen visit only). Subjects will have baseline scores on the 17-item Hamilton Depression Rating Scale and on the Young Mania Rating Scale of 10 or lower. Both of these instruments will be administered by trained raters.

Visit Timeline:

Screen: Week -2; Baseline Visit: Week 0; Visit 1Week 4; Visit 2Week 8;Visit 3Week 12

Intervention(s) in this Clinical Trial

• Drug: Memantine
  • Week 0 Memantine 5 mg q.d. Week 1 if mild side effects -continue previous dose Memantine, 5 mg q.d. if well tolerated - Memantine 5 mg b.i.d Weeks 2-3 if well tolerated - Memantine 5 mg b.i.d - if mild side effects - continue Memantine , 5 mg b.i.d. if well tolerated - Memantine 5 mg q.a.m and 10 mg q.p. Week 4-12 if well tolerated - Memantine 5 mg q.a.m and 10 mg q.p.m - if mild side effects - continue Memantine, 5 mg q.a.m and 10 mg q.p.m if well tolerated - Memantine 10 mg b.i.d
• Drug: Placebo
  • Week 0 placebo 5 mg q.d. Week 1 if mild side effects -continue previous dose placebo, 5 mg q.d. if well tolerated - placebo 5 mg b.i.d Weeks 2-3 if well tolerated - placebo 5 mg b.i.d - if mild side effects - continue placebo , 5 mg b.i.d. if well tolerated - placebo 5 mg q.a.m and 10 mg q.p. Week 4-12 if well tolerated - placebo 5 mg q.a.m and 10 mg q.p.m - if mild side effects - continue placebo, 5 mg q.a.m and 10 mg q.p.m if well tolerated - placebo 10 mg b.i.d

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
• Placebo Comparator: 2

Primary Measures

• Validating a strategy for the treatment of cognitive dysfunction, and by furthering our understanding of the relationship between cognitive and mood symptoms in bipolar disorder
  • Time Frame: 2005-2008
    Safety Issue?: Yes

Inclusion Criteria:

Inclusion criteria: the following conditions must be met for patient eligibility:

• DSM-IV diagnostic criteria for any bipolar disorder (type I, type II, and 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 YMRS score of < 10 at screen and baseline visits.
• No acute episodes of depression or mania for the previous 12 weeks.
• MGH Cognitive and Physical Functioning Scale: Cut-off : >15 or
• Everyday Cognition Self-Report Form: Average of all items >1.5 orRBANS:
• <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:

• Subjects 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, 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 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 (e.g., carbonic anhydrase inhibitors, sodium bicarbonate)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Cedars-Sinai Medical Center Other

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00645476

Study ID Number: NAM-MD-31C

ClinicalTrials.gov Identifier: NCT00645476

Health Authority: United States: Institutional Review Board