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

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 (100mg or more) were randomized to either memantine (starting dose of 5mg increased up to 20mg over fourweeks, then 20mg stable dose from four to eightweeks) or matching pill placebo for eightweeks. 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 fourweeks, 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 eightweeks. 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.