Mood disorders are common and debilitating, resulting in a significant public health burden. Current treatments are only partly effective and patients who have failed to respond to trials of existing
antidepressant agents (eg, those who suffer from
treatment-resistant depression [TRD]) require innovative
therapeutics with novel mechanisms of action. Although neuroscience research has elucidated important aspects of the basic mechanisms of
antidepressant action, most
antidepressant drugs target monoaminergic mechanisms identified decades ago.
Glutamate, the major excitatory
neurotransmitter in the central nervous system, and glutamatergic dysfunction has been implicated in
mood disorders. These data provide a rationale for the pursuit of
glutamatergic agents as novel therapeutic agents. Here, we review preclinical and clinical investigations of
glutamatergic agents in
mood disorders with a focus on depression. We begin with discussion of evidence for the rapid
antidepressant effects of
ketamine, followed by studies of the
antidepressant efficacy of the currently marketed drugs
riluzole and
lamotrigine. Promising novel agents currently in development, including
N-methyl-D-aspartate (
NMDA) receptor modulators, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)
propanoic acid (
AMPA) receptor modulators, and drugs with activity at the metabotropic
glutamate (mGlu) receptors are then reviewed. Taken together, both preclinical and clinical evidence exists to support the pursuit of small molecule modulators of the
glutamate system as novel therapeutic agents in
mood disorders. It is hoped that by targeting neural systems outside of the monoamine system, more effective and perhaps faster acting
therapeutics can be developed for patients suffering from these disabling disorders.