Memantine Augmentation of Antidepressants

• ClinicalTrials.gov Identifier: NCT00344682
• Recruitment Status: Completed
• First Posted: June 27, 2006
• Results First Posted: November 25, 2013
• Last Update Posted: July 11, 2018
• Sponsor: University of Massachusetts, Worcester
• Collaborator: Forest Laboratories
• Information provided by (Responsible Party): University of Massachusetts, Worcester

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Depressive Disorder	Drug: memantine; Drug: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Double-Blind Pilot Study of Memantine Augmentation in Antidepressant Nonresponders or Incomplete Responders
• Study Start Date: June 2006
• Actual Primary Completion Date: December 2011
• Actual Study Completion Date: December 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: memantine; memantine (5-20mg a day)	Drug: memantine; memantine 5mg - 20mg PO daily; Other Name: Namenda
Placebo Comparator: Placebo; placebo (5-20mg a day)	Drug: Placebo; 5mg - 20mg PO daily over 8 weeks

Outcome Measures

Primary Outcome Measures :

1. Montgomery-Asberg Depression Rating Score (MADRS) [ Time Frame: 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 Outcome Measures :

1. Modified Quick Inventory of Depressive Symptoms Self Report Scale (QIDS-SR) [ Time Frame: 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.
2. Hamilton Anxiety Rating Scale (HARS) [ Time Frame: 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.
3. Montgomery-Asberg Depression Rating Score (MADRS) [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Massachusetts

Center for Psychopharmacologic Research and Treatment (University of Massachusetts Medical School)

Worcester, Massachusetts, United States, 01605

Sponsors and Collaborators

University of Massachusetts, Worcester

Forest Laboratories

Investigators

• Principal Investigator: Kristina M Deligiannidis, M.D.; University of Massachusetts, Worcester

More Information

Additional Information:

Center for Psychopharmacologic Research and Treatment 

Publications:

Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000 Feb 15;47(4):351-4.

Moryl E, Danysz W, Quack G. Potential antidepressive properties of amantadine, memantine and bifemelane. Pharmacol Toxicol. 1993 Jun;72(6):394-7.

Oquendo MA, Baca-Garcia E, Kartachov A, Khait V, Campbell CE, Richards M, Sackeim HA, Prudic J, Mann JJ. A computer algorithm for calculating the adequacy of antidepressant treatment in unipolar and bipolar depression. J Clin Psychiatry. 2003 Jul;64(7):825-33.

Papp M, Moryl E. Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Eur J Pharmacol. 1994 Sep 22;263(1-2):1-7.

Rogóz Z, Skuza G, Kuśmider M, Wójcikowski J, Kot M, Daniel WA. Synergistic effect of imipramine and amantadine in the forced swimming test in rats. Behavioral and pharmacokinetic studies. Pol J Pharmacol. 2004 Mar-Apr;56(2):179-85.

Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R. Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry. 1996 Jan;29(1):23-6. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A. Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder. Cochrane Database Syst Rev. 2021 Sep 12;9:CD011612. doi: 10.1002/14651858.CD011612.pub3. Review.

Smith EG, Deligiannidis KM, Ulbricht CM, Landolin CS, Patel JK, Rothschild AJ. Antidepressant augmentation using the N-methyl-D-aspartate antagonist memantine: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2013 Oct;74(10):966-73. doi: 10.4088/JCP.12m08252.

• Responsible Party: University of Massachusetts, Worcester
• ClinicalTrials.gov Identifier: NCT00344682
• Other Study ID Numbers: NAM-MD-34
• First Posted: June 27, 2006
• Results First Posted: November 25, 2013
• Last Update Posted: July 11, 2018
• Last Verified: June 2018

Keywords provided by University of Massachusetts, Worcester:

memantine; Namenda; augmentation; add-on; depression; MDD (major depressive disorder); unipolar depression; NMDA; ketamine; uncompetitive NMDA receptor antagonist

Additional relevant MeSH terms:

Depressive Disorder; Depression; Mood Disorders; Mental Disorders; Behavioral Symptoms; Memantine; Antiparkinson Agents; Anti-Dyskinesia Agents; Dopamine Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents