Glutamatergic approaches in major depressive disorder: focus on ketamine, memantine and riluzole

The role of glutamate in modulating various mood states is being increasingly recognized and researched. Existing antidepressants have been shown to exert effects on various glutamatergic mechanisms, even if such agents are traditionally classified as working via other mechanisms, such as selective serotonin reuptake inhibitors. The NMDA receptor antagonist ketamine has been investigated in various mood disorders, especially major depressive disorder (MDD). It was found to produce a rapid, robust and persistent antidepressant effect. Although it can produce cognitive, dissociative and perceptual disturbances, these tend to be transient and do not outlast the antidepressant effect. Trials with memantine and riluzole, agents with actions broadly similar to and different from ketamine on the glutamatergic system, are also reviewed in MDD and prospects for future research in the area are discussed. Although preclinical studies are discussed, the main focus of the review is on clinical outcomes.