Protocol Number: 02-M-0231

Title:

An Investigation of the Antidepressant Efficacy of Memantine, an NMDA Antagonist with Neurotrophic Properties in Major Depression

Number:

02-M-0231

Summary:

The purpose of this study is to determine the safety and effectiveness of the drug memantine for treating major depression.

Major depression is a serious public health concern that contributes to significant morbidity and mortality. Despite the availability of a wide range of antidepressant drugs, a proportion of patients with major depression fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Recent studies suggest that the glutamatergic system may play a role in the pathophysiology and treatment of depression. Memantine and other agents which reduce glutamatergic neurotransmission may represent a novel class of antidepressants.

The study consists of three phases. In Phase 1, participants will be tapered off all psychiatric medications over a 2-week washout period. In Phase 2, participants will be randomly assigned to receive either memantine or placebo (an inactive pill) three times a day for 8 weeks. Participants who do not respond to the treatment after 8 weeks will be taken off the study and offered standard treatment. Weekly psychiatric evaluations will evaluate treatment response. During Phase 2, participants who respond well to treatment will enter Phase 3, a 16-week continuation phase of either memantine or placebo. Interviews will be conducted every other week in the first month , then monthly thereafter.

Participants will have a physical examination, neuropsychological tests, and eye blink tests at baseline and at the end of the study. Pulse, blood pressure, and blood samples will be taken throughout the study. Participants will undergo an electrocardiogram as well as positron emission tomography (PET) and magnetic resonance imaging (MRI) scans of the brain.

Sponsoring Institute:

National Institute of Mental Health (NIMH)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

Subjects may be included in the study only if they meet all of the following criteria:

Male or female subjects, 18 to 80 years of age.

Female subjects of childbearing potential must be using a medically accepted means of contraception.

Each subject must have a level of understanding sufficient to agree to all tests and examinations required by the protocol.

Subjects must be considered reliable.

Each subject must understand the nature of the study and must sign an informed consent document.

Subjects must fulfill the criteria for major depression, recurrent without psychotic features as defined in DSM-IV based on clinical assessment and confirmed by structured diagnostic interview SCID-P.

Subjects must have an initial score at Visit 1 and Visit 2 of at least 22 on the MADRS.

Subjects must not have a decrease in the total score of MADRS of greater than 20 % during washout (between Visits 1 and 2).

Current major depressive episode of at least 4 weeks duration.

EXCLUSION CRITERIA:

Subjects will be excluded from the study for any of the following reasons:

Lack of response to more than 2 antidepressants (adequate dose and duration).

Participation in a clinical trial of another investigational drug within 1 month (30 days) prior to study entry (Visit 1).

Female subjects who are either pregnant or nursing.

Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease), endocrinologic, neurologic, immunologic, or hematologic disease.

Subjects with uncorrected hypothyroidism or hyperthyroidism.

Subjects with one or more seizures without a clear and resolved etiology.

Documented history of hypersensitivity or intolerance to amantadine or prior treatment with memantine.

DSM-IV substance abuse or dependence (except nicotine and caffeine) within the past 90 days.

Treatment with an injectable depot neuroleptic within less than one dosing interval between depot neuroleptic injections prior to Visit 2.

Treatment with a reversible monoamine oxidase inhibitor, guanethidine, or guanadrel within 1 week prior to Visit 2.

Treatment with fluoxetine within 6 weeks prior to Visit 2.

Treatment with any other concomitant medication with primarily CNS activity.

Treatment with clozapine within 4 weeks prior to Visit 2.

Treatment with amitriptyline (elavil) within 4 weeks prior to Visit 2 since amitriptyline and similar TCAs may manifest a mild NMDA receptor antagonism, as demonstrated in electrophysiological studies.

Treatment with the anticonvulsants carbamazepine (tegretol, carbatrol, tegretol XR and similar derivatives), gabapentin (neurontin) or felbamate (felbatol) within 4 weeks prior to Visit 2 because these drugs may interfere with NMDA receptor function.

Treatment with electroconvulsive therapy (ECT) within 3 months (90 days) prior to Visit 2.

Current diagnosis of schizophrenia or other psychotic or bipolar disorder as defined in the DSM-IV.

Judged clinically to be at serious suicidal risk.

Special Instructions: Currently Not Provided

Keywords:

Antiglutamatergic

Neuroprotective

Unipolar Depression

Treatment

Antidepressant

Depression

Glutamate

Memantine

Pathophysiology

Positron Emission Tomography

Recruitment Keywords:

Depression

Major Depression

Unipolar Depression

Conditions:

Depression

Investigational Drug(s):

Memantine HCL

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Altamura CA, Mauri MC, Ferrara A, Moro AR, D'Andrea G, Zamberlan F Plasma and platelet excitatory amino acids in psychiatric disorders Am J Psychiatry 1993 Nov;150(11):1731-3 PMID: 8214185

Auer DP, Putz B, Kraft E, Lipinski B, Schill J, Holsboer F Reduced glutamate in the anterior cingulate cortex in depression: an in vivoproton magnetic resonance spectroscopy studyBiol Psychiatry 2000 Feb 15;47(4):305-13PMID: 10686265

Ambrozi L, Danielczyk W Treatment of impaired cerebral function in psychogeriatric patients withmemantine--results of a phase II double-blind study Pharmacopsychiatry 1988 May;21(3):144-6 PMID: 3406051

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