Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a double-blind, randomized, placebo-controlled trial

Bipolar Disord. 2012 Feb;14(1):64-70. doi: 10.1111/j.1399-5618.2011.00971.x.


Background: Recent studies indicate that modulation of glutamate neurotransmission is associated with antidepressant response. Lamotrigine, an anticonvulsant which decreases presynaptic glutamate release, has been shown to be effective in the depressive phase of bipolar disorder (BD-D); however, only 40-50% of patients have a full response. This pilot study investigated whether memantine, a low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist approved for Alzheimer's disease, can augment the effects of lamotrigine.

Methods: BD-D outpatients in a major depressive episode on a stable dose of lamotrigine (100 mg or more) were randomized to either memantine (starting dose of 5 mg increased up to 20 mg over four weeks, then 20 mg stable dose from four to eight weeks) or matching pill placebo for eight weeks. Patients were rated on the 17-item Hamilton Depression Rating Scale (HDRS) and other behavioral measures weekly.

Results: The eight-week repeated-measures mixed-effect model for HDRS was not significant for memantine (n = 14) versus placebo (n = 15). Exploratory mixed-effect analyses for the first four weeks, while the memantine dose was being titrated up every week, revealed a significant decrease in HDRS scores from baseline (p = 0.007).

Conclusion: This proof-of-concept study failed to show a statistically significant benefit of memantine augmentation of lamotrigine for patients with BD-D over eight weeks. However, memantine had an antidepressant effect early on in the treatment while its dose was being titrated up. Larger placebo-controlled studies are needed to ascertain optimal timing and dosing for memantine augmentation of lamotrigine in BD-D.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antidepressive Agents / therapeutic use*
  • Antimanic Agents / therapeutic use*
  • Bipolar Disorder / drug therapy*
  • Depression / drug therapy*
  • Dopamine Agents / administration & dosage*
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Glutamic Acid / drug effects
  • Humans
  • Lamotrigine
  • Male
  • Memantine / administration & dosage*
  • Middle Aged
  • Pilot Projects
  • Treatment Outcome
  • Triazines / therapeutic use*


  • Antidepressive Agents
  • Antimanic Agents
  • Dopamine Agents
  • Triazines
  • Glutamic Acid
  • Lamotrigine
  • Memantine