Depressive Disorder
Conditions
Keywords
memantine, Namenda, augmentation, add-on, depression, MDD (major depressive disorder), unipolar depression, NMDA, ketamine, uncompetitive NMDA receptor antagonist
Brief summary
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
\- 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.
Interventions
DRUGmemantine
memantine 5mg - 20mg PO daily
DRUGPlacebo
5mg - 20mg PO daily over 8 weeks
Sponsors
Forest Laboratories
University of Massachusetts, Worcester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Montgomery-Asberg Depression Rating Score (MADRS) | Baseline & week 8 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Modified Quick Inventory of Depressive Symptoms Self Report Scale (QIDS-SR) | baseline & week 8 | 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. |
| Hamilton Anxiety Rating Scale (HARS) | baseline & week 8 | 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. |
| Montgomery-Asberg Depression Rating Score (MADRS) | baseline and week 8 | 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. |
Countries
United States
Participant flow
Recruitment details
Study participants were recruited through clinician referral and posted and radio advertising with the majority of patients recruited through clinician referral within our single-site, tertiary-care medical center.
Pre-assignment details
Participants continued on their previously prescribed antidepressant at the same dose throughout the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo comparator : 5mg - 20mg PO daily over 8 weeks | 16 |
| Memantine memantine : memantine 5mg - 20mg PO daily | 15 |
| Total | 31 |
Baseline characteristics
| Characteristic | Memantine | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 15 Participants | 28 Participants |
| Age, Continuous | 54.8 years STANDARD_DEVIATION 6.17 | 49.75 years STANDARD_DEVIATION 11.68 | 52.28 years STANDARD_DEVIATION 8.2 |
| Region of Enrollment United States | 15 participants | 16 participants | 31 participants |
| Sex: Female, Male Female | 8 Participants | 11 Participants | 19 Participants |
| Sex: Female, Male Male | 7 Participants | 5 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 16 | 3 / 15 |
| serious Total, serious adverse events | 1 / 16 | 1 / 15 |
Outcome results
Primary
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.
Time frame: Baseline & week 8
Population: The primary outcome examines a mean change in MADRS scores at baseline \& week 8 through last observation carried forward (LOCF); no values were imputed for missing assessments. The primary data analysis used intent-to-treat measures and computes final study score minus baseline averaged among participants to evaluate treatment group differences.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Montgomery-Asberg Depression Rating Score (MADRS) | -7.25 units on a scale | Standard Deviation 11.14 |
| Memantine | Montgomery-Asberg Depression Rating Score (MADRS) | -7.13 units on a scale | Standard Deviation 6.61 |
Secondary
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.
Time frame: baseline & week 8
Population: Secondary outcome examines a change in mean HARS scores observed at baseline \& week 8 through last observed data carried forward (LOCF);no values were imputed for missing assessments.Efficacy data analysis used intent-to-treat measures \& computes final study score minus baseline averaged among participants to evaluate treatment group differences
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Hamilton Anxiety Rating Scale (HARS) | -4.13 units on a scale | Standard Deviation 5.11 |
| Memantine | Hamilton Anxiety Rating Scale (HARS) | -5.53 units on a scale | Standard Deviation 7.29 |
Secondary
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.
Time frame: baseline & week 8
Population: The secondary outcome examines a change over in mean QID-SR scores at baseline \& week 8 through last observed data carried forward (LOCF); no values were imputed for missing assessments. Data analysis used intent-to-treat measures and computes final study score minus baseline averaged among participants to evaluate treatment group differences.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Modified Quick Inventory of Depressive Symptoms Self Report Scale (QIDS-SR) | -3.69 units on a scale | Standard Deviation 5 |
| Memantine | Modified Quick Inventory of Depressive Symptoms Self Report Scale (QIDS-SR) | -6.47 units on a scale | Standard Deviation 5.25 |
Secondary
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.
Time frame: baseline and week 8
Population: Secondary outcome examines a change in response rates,when 50% change from baseline, \& remission rates, when MADRS scores of 12 or less were observed.Fischer exact tests assessed efficiency in each treatment group. Intent-to-treat rates at baseline minus week 8 through last observed data carried forward (LOCF) were used;no data values were imputed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Montgomery-Asberg Depression Rating Score (MADRS) | -10.75 units on a scale | Standard Deviation 10.46 |
| Memantine | Montgomery-Asberg Depression Rating Score (MADRS) | -7.13 units on a scale | Standard Deviation 6.11 |