Mechanisms of action and clinical efficacy of NMDA receptor modulators in mood disorders

- Mood disorders are disabling psychiatric disorders associated with adverse psychosocial outcomes.
- Functional imaging studies suggest the occurrence of an imbalance between dorsal and ventral limbic neurocircuitry in mood disorders.
- Current treatment strategies take weeks to achieve symptomatic relief in a number of individuals and yet fail to mitigate symptoms in others.
- NMDA pharmacotherapeutics may offer an alternative treatment strategy by modulating neurotransmission, neurotrophins, and immune function.
- Elucidation of the glutamatergic system interactions with the trophic factors and the immune system will facilitate multimodal therapies.

Although the biogenic amine models have provided meaningful links between clinical phenomena and pharmacological management of mood disorders (MDs), the onset of action of current treatments is slow and a proportion of individuals fail to adequately respond. A growing number of investigations have focused on the glutamatergic system as a viable target. Herein we review the putative role of N-methyl-d-aspartate (NMDA) signaling in the pathophysiology of MDs. Prompting this focus are several lines of evidence: 1) altered glutamate and NMDA receptor (NMDAR) expression and functioning; 2) antidepressant effects of NMDAR signaling blockers; 3) interaction between conventional therapeutic regimens and NMDAR signaling modulators; 4) biochemical evidence of interaction between monoaminergic system and NMDAR signaling; 5) interaction between neurotrophic factors and NMDAR signaling in mood regulation; 6) cross-talk between NMDAR signaling and inflammatory processes; and 7) antidepressant effects of a number of NMDA modulators in recent clinical trials. Altogether, these studies establish a warrant for the refinement of novel compounds that target glutamatergic mechanisms for the treatment of MDs.

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