Memantine Augmentation of Antidepressants

Study Overview
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Brief Summary
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This study is evaluating the efficacy and safety of the drug memantine (trade name NAMENDA) as an augmentation agent for the treatment of depression in people who are not fully responding to antidepressant medications.

Detailed Description
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- 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.

Official Title
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A Randomized Double-Blind Pilot Study of Memantine Augmentation in Antidepressant Nonresponders or Incomplete Responders

Conditions
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Depressive Disorder

Intervention / Treatment
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* Drug: memantine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: memantine<br>memantine (5-20mg a day) | Drug: memantine<br>* memantine 5mg - 20mg PO daily<br>* Other names: Namenda;|
| Placebo Comparator: Placebo<br>placebo (5-20mg a day) | Drug: Placebo<br>* 5mg - 20mg PO daily over 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery-Asberg Depression Rating Score (MADRS) | Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. Scores 0 to 6 indicate symptoms absent; 7 to 19 indicates mild depression; 30 to 34 defines moderate; 35 to 60 indicates severe depression. Changes in MADRS score was a primary measure. | Baseline & week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Quick Inventory of Depressive Symptoms Self Report Scale (QIDS-SR) | The 16 item Quick Inventory of Depressive Symptomatology (QIDS-SR16) (Rush et al. 2003) is designed to assess the severity of depressive symptoms, with higher scores representing more severe forms of depression. When complete, the QIDS are scored by summing responses to obtain a total score ranging from 0 to 27. Either appetite increase or decrease, but not both, are used to calculate the total score. Weight increase or decrease, but not both, are used to calculate the total score. Scores 0-5 indicate no severity of depression; 6-10 is mild; 11-15 is moderate; 16-20 is severe; 21-27 is very severe levels of depression. Participants were evaluated at baseline and at weeks 1, 2, 3, 4, 6 & 8. | baseline & week 8 | 
| Hamilton Anxiety Rating Scale (HARS) | Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. Scores > 30 indicate severe anxiety. | baseline & week 8 | 
| Montgomery-Asberg Depression Rating Score (MADRS) | Higher MADRS score indicates more severe depression, and each item yields a score of 0 to 6 on 10 items. The overall score ranges from 0 to 60. Scores 0 to 6 indicate symptoms absent; 7 to 19 indicates mild depression; 30 to 34 defines moderate; 35 to 60 indicates severe depression. Changes in response rate and remission rate were assessed for secondary measures. | baseline and week 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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memantine, Namenda, augmentation, add-on, depression, MDD (major depressive disorder), unipolar depression, NMDA, ketamine, uncompetitive NMDA receptor antagonist