Antidepressant augmentation using the N-methyl-D-aspartate antagonist memantine: a randomized, double-blind, placebo-controlled trial.
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.


METHODS
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.


BACKGROUND
ClinicalTrials.gov identifier: NCT00344682.
Department of Psychiatry, University of Massachusetts Medical School, 55 Lake Ave North, Worcester, MA 01655 Eric.Smith5@va.gov.
Eric G
EG
Smith
Kristina M
KM
Deligiannidis
Christine M
CM
Ulbricht
Chelsea S
CS
Landolin
Jayendra K
JK
Patel
Anthony J
AJ
Rothschild
D000328:Adult; D000928:Antidepressive Agents / Q000145:classification / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism; D039721:Diagnostic and Statistical Manual of Mental Disorders; D016903:Drug Monitoring; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000009:adverse effects; D011569:Psychiatric Status Rating Scales; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D016896:Treatment Outcome
D000928:Antidepressive Agents; D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D008559:Memantine