Clinical Trial of Memantine for Major Depression

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00040261
First received: June 22, 2002
Last updated: March 3, 2008
Last verified: March 2005
  Purpose

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.


Condition Intervention Phase
Depression
Drug: Memantine HCL
Phase 3

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Primary Purpose: Treatment
Official Title: An Investigation of the Antidepressant Efficacy of Memantine, an NMDA Antagonist With Neurotrophic Properties in Major Depression

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment: 112
Study Start Date: June 2002
Estimated Study Completion Date: March 2005
Detailed Description:

Major affective disorders are common, severe, chronic and often a life-threatening illness. Major depression contributes to significant morbidity and mortality. Impairment in physical and social functioning resulting from depression can be just as severe as other chronic medical illnesses. Suicide is the cause of death in 10-20% of individuals with recurrent depressive disorders.

Despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30% to 40% of patients with major depression fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Thus, there is a clear need to develop novel and improved therapeutics for unipolar and bipolar depression. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. Furthermore, a growing body of data suggests that mood disorders are associated with regional volumetric reductions, and cell loss and atrophy. It is thus noteworthy that lamotrigine, which, among other effects reduces glutamate release, has antidepressant effects, and a pilot study has suggested that NMDA antagonists may have antidepressant effects. Together, this data suggests that the glutamatergic system may play a role in the pathophysiology and treatment of depression, and that agents, which more directly reduce glutamatergic neurotransmission, may represent a novel class of antidepressants.

Memantine (Akatinol memantine), an agent that is approved in Germany for dementia syndrome, Parkinson's disease has significant antiglutamatergic and neuroprotective properties, may prove to have antidepressant properties in depressed patients. In this study, we propose to investigate the potential efficacy of memantine, an agent which reduces glutamatergic output via open-channel block of the NMDA receptor-associated ion channel. Most importantly, memantine only blocks the channel during periods of abnormal, excessive activity, and leaves relatively spared normal neurotransmission. This finding is the basis for the minimal side effect profile displayed by memantine.

Patients, ages 18 to 80, with a diagnosis of major depression (without psychotic features), will be randomized to double-blind treatment outpatient study to receive either memantine (5-20mg/day) or placebo for a period of 8 weeks. Following this acute period, patients who fully respond could enter a 16-week continuation phase. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria. Approximately 112 patients with acute major depression will be enrolled in the study.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00040261

Locations
United States, Maryland
National Institute of Mental Health (NIMH)
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
  More Information

Publications:
ClinicalTrials.gov Identifier: NCT00040261     History of Changes
Other Study ID Numbers: 020231, 02-M-0231
Study First Received: June 22, 2002
Last Updated: March 3, 2008
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Antiglutamatergic
Neuroprotective
Unipolar Depression
Treatment
Antidepressant
Depression
Glutamate
Memantine
Pathophysiology
Positron Emission Tomography
Major Depression

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Major
Behavioral Symptoms
Mood Disorders
Mental Disorders
Antidepressive Agents
Memantine
Psychotropic Drugs
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Antiparkinson Agents
Anti-Dyskinesia Agents

ClinicalTrials.gov processed this record on July 28, 2014