Memantine Augmentation of Antidepressants

- Objective

The objective of this study is to evaluate the efficacy and safety of 20 mg of memantine
administered once daily as an augmentation agent for subjects who have been taking
antidepressants for at least 1 month but who have experienced an incomplete or absent
therapeutic response.

- Background

Memantine is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor
antagonist that is approved for the treatment of moderate-to-severe dementia of the
Alzheimer's type. It has been commercially available in 23 countries worldwide since 1982.

There are reports in the published literature that suggest NMDA receptors may be involved in
the etiology of depressive disorders. The NMDA antagonist ketamine has been shown to have
antidepressant effects in a placebo-controlled clinical trial (Berman et al., 2000).
Uncompetitive NMDA receptor antagonists, including memantine, have been shown to exhibit
antidepressant-like activity in animal models of depression (Moryl et al., 1993, Papp and
Moryl 1994). Animal studies also support the possibility that uncompetitive NMDA receptor
antagonists may work synergistically in combination with antidepressants in animal models of
depression (Rogoz et al., 2001). Some authors have hypothesized a role for NMDA receptors in
the therapeutic effects of numerous antidepressants (Skolnick et al., 1996).

- Study Design and Duration

This is a randomized, single site, double-blind, placebo-controlled, parallel-group study in
outpatients. The study consists of an 8-week double-blind treatment period. Approximately 25
patients will be randomized to each treatment group (memantine or placebo) for a total of
approximately 50 patients.

Inclusion Criteria:

- Male or female patients between 18 and 85 years of age at screening.

- Patients must provide written informed consent prior to study entry.

- Patients must meet DSM-IV-TR (Diagnostic and Statistical Manual IV Text Revision)
criteria for Major Depressive Episode of a severity mild, moderate or severe or in
partial remission, as confirmed by the MINI.

- Patients must have a HAM-D (17-item) score of 16 or higher.

- Patients must have been on 1 of the following medications for 4 or more weeks at or
above the listed dose with no psychiatric medication dose changes for the past 25
days:

- 20 mg qD of fluoxetine (Once Daily)

- 50 mg qD of sertraline

- 20 mg qD of paroxetine

- 200 mg qD of fluvoxamine

- 20 mg qD of citalopram

- 10 mg qD of escitalopram

- 150 mg qD of venlafaxine or venlafaxine sustained release

- 300 mg qD of bupropion or bupropion sustained or extended release

- 15 mg qD of mirtazapine

- 60 mg qD of duloxetine

- Participants must agree to keep the dose of their existing antidepressant(s) constant
throughout the 8-week trial.

Exclusion Criteria:

- Diagnosis of bipolar disorder or schizophrenic or schizoaffective disorder.

- History of alcohol or drug abuse or dependence within 6 months of enrollment.

- Patients who have received ECT (Electroconvulsive Therapy) in the past 3 months.

- History of seizures.

- Moderate dementia (MMSE score of 20 or less).

- Active suicidal ideation: endorsing a 3 (most severe score) on QIDS-SR (Quick
Inventory of Depression Symptomatology Self Reports) suicide item OR a score of 2 or
higher for the past week on Suicide Scale items 4 or 5 (current suicidal ideation
moderate or strong or would avoid taking steps to save life).

- Currently taking a mood stabilizer or antipsychotic (except lithium clearly used as an
augmenting agent).

- Patients who, in the opinion of the investigator, might not be suitable for the study.