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Cited by 82Treatment of Major DepressionElectroconvulsive Therapy StudiesBipolar Disorder and Treatment

Antidepressant Augmentation Using the N-Methyl-d-Aspartate Antagonist Memantine: A Randomized, Double-Blind, Placebo-Controlled Trial

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Smith, Eric G., Deligiannidis, Kristina M., Ulbricht, Christine M., Landolin, Chelsea S., Patel, Jayendra K., Rothschild, Anthony J.·2013·The Journal of Clinical Psychiatry
DOI 10.4088/jcp.12m08252PMC PMC4000742
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Abstract

OBJECTIVE: Intravenous N-methyl-d-aspartate (NMDA) antagonists have shown promising results in rapidly ameliorating depression symptoms, but placebo-controlled trials of oral NMDA antagonists as monotherapy have not observed efficacy. We conducted a randomized, double-blind, placebo-controlled trial of the NMDA antagonist memantine as an augmentation treatment for patients with DSM-IV major depressive disorder. METHOD: Adult outpatients with major depressive disorder and partial response or nonresponse to their current antidepressant (as indicated by a 17-item Hamilton Depression Rating Scale score of ≥ 16 at baseline) were randomized (from July 2006-December 2011) to add memantine (flexible dose 5-20 mg/d, with all memantine group participants reaching the dose of 20 mg/d) (n = 15) or placebo (n = 16) to their existing treatment for 8 weeks. The primary outcome, change in Montgomery-Asberg Depression Rating Score (MADRS), was evaluated with repeated-measures mixed effects models using last-observation-carried-forward methods. Secondary outcomes included other depression and anxiety rating scales, suicidal and delusional ideation, and other adverse effects. RESULTS: 84% of participants completed the trial, including 93% of participants receiving memantine. Participants receiving memantine did not show a statistically or clinically significant change in MADRS scores compared to placebo, either over the entire study (β = 0.133, favoring placebo, P = .74) or at study completion (week 8 mean [SD] MADRS score change = -7.13 [6.61] [memantine]; -7.25 [11.14] [placebo]; P = .97). A minimal to small effect size (comparing change to baseline variability) favoring placebo was observed (Cohen d = 0.19). Similarly, no substantial effect sizes favoring memantine nor statistically significant between-group differences were observed on secondary efficacy outcomes. CONCLUSIONS: This trial did not detect significant statistical or effect size differences between memantine and placebo augmentation among nonresponders or poor responders to conventional antidepressants. While the small number of participants is a limitation, this study suggests memantine lacks substantial efficacy as an augmentation treatment for major depressive disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00344682.

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  • Memantine, which blocks the NMDAR ion channel at the same site as ketamine, did not produce antidepressant effects in patients with depression.

    “In support, memantine, which blocks the NMDAR ion channel at the same site as ketamine, failed to exert antidepressant effects in patients with depression”

    From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Smith et al., 2013

    The Abstract Conclusions and Discussion report no significant benefit over placebo when memantine was used to augment antidepressants in a small trial of patients with major depressive disorder who had responded poorly to conventional treatment. They do not establish that memantine has no antidepressant effect in patients with depression generally. The copy identifies both drugs as NMDA antagonists but does not say they block the ion channel at the same site. (LLM, conf=0.86)

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Authors
Smith, E. G., Deligiannidis, K. M., Ulbricht, C. M., Landolin, C. S., Patel, J. K., & Rothschild, A. J.
Affiliations
  • University of Massachusetts Chan Medical School (US)
  • UMass Memorial Health Care (US)
Corresponding author
Smith, Eric G.
ORCID
Venue
The Journal of Clinical Psychiatry
Publisher
Physicians Postgraduate Press, Inc
Published
2013-10-15
Volume
74
Issue
10
Pages
966-973
ISSN
0160-6689 (ISSN-L)
DOI
10.4088/jcp.12m08252
PMC
PMC4000742
OpenAlex
W2018922460
Cited by
82
References
27
Citations by year
2026: 1 · 2025: 7 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 8 · 2019: 6 · 2018: 7 · 2017: 7 · 2016: 11 · 2015: 12 · 2014: 5
FWCI
6.87
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
Funders
  • National Institutes of Health (UL1TR000161)
  • National Institute of Mental Health (K23MH097794)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
Keywords
memantine, NMDA receptor antagonists, antidepressant augmentation, major depressive disorder, treatment-resistant depression, antidepressant non-response, antidepressant efficacy
MeSH terms
Adult, Antidepressive Agents, Depression, Major Depressive Disorder, Depressive Disorder, Major, Drug Synergism, Drug Therapy, Combination, Female, Humans, Male, Memantine, Psychiatric Status Rating Scales, Receptors, N-Methyl-D-Aspartate, Treatment Outcome, Drug Monitoring, Excitatory Amino Acid Agonists, Diagnostic and Statistical Manual of Mental Disorders

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