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.
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
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
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.
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
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
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.
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
DSM-IV substance abuse or dependence (except nicotine and caffeine) within the past 90
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
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
Judged clinically to be at serious suicidal risk.