Using an experimental medicine model to understand the antidepressant potential of the N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine

A Pringle,Pj Cowen,Sf Mctavish,Lg Cowen,Cj Harmer,E Parsons

doi:10.1177/0269881112446535

Abstract

There is growing interest in the role of the glutamatergic system both in depression and as a novel target for treatments. Preclinical studies suggested that the non-competitive N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine might have antidepressant properties, but a randomised controlled trial failed to support this. A healthy volunteer model of emotional processing was used to assess the neuropsychological profile of action of memantine. Healthy volunteers (n=32) were randomised to receive a single dose of memantine (10 mg) or placebo, and subsequently completed a battery of tasks measuring emotional processing, including facial expression recognition, emotional memory, dot-probe and emotion-potentiated startle tasks, as well as working and verbal memory. Memantine treated volunteers showed an increased emotion-potentiated startle, and a reduced bias for negative items in emotional recognition memory. There were no effects of the drug on any other aspect of emotional or non-emotional information processing. These results suggest that a single dose of memantine produces an early anxiogenic response in the emotion-potentiated startle similar to that seen following a single dose of the selective serotonin reuptake inhibitor, citalopram. However, the overall profile of effects is more limited than that which might be expected in response to a conventional antidepressant.

Highlights

The monoamine hypothesis remains dominant in biological explanations of depression, there is growing interest in the role of the glutamatergic system in the pathophysiology of depression, and in the possible antidepressant effects of glutamatemodifying drugs (Sanacora et al, 2008)
There were no between groups differences in terms of baseline depressive symptoms as measured by the Beck Depression Inventory (BDI), trait anxiety as measured by the State Trait Anxiety Inventory (STAI)
Comparing measurements taking just prior to and five hours after treatment, there was no effect of memantine on depressive symptoms as measured by the BDI or mood and energy as measured by the Befindlichkeits Scale (BFS) or Positive and Negative Affect Scale (PANAS)

Summary

Introduction

The monoamine hypothesis remains dominant in biological explanations of depression, there is growing interest in the role of the glutamatergic system in the pathophysiology of depression, and in the possible antidepressant effects of glutamatemodifying drugs (Sanacora et al, 2008). The high affinity N-methyl-D-aspartic acid (NMDA) receptor antagonist ketamine has been shown to produce a rapid antidepressant response in the treatment of refractory depression (Berman et al, 2000; Zarate et al, 2006a). Such results are compelling and have been suggested to reflect rapid correction of aberrant plasticity mechanisms in depression. The development of new candidate drugs acting at glutamatergic receptors with improved tolerability and side effect profiles is needed to more fully explore this novel avenue for treatment

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