Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders

Abstract

Mood disorders are common, chronic, recurrent mental illnesses that affect the lives of millions of individuals worldwide. There is growing evidence that the glutamatergic system is central to the treatment, and potentially the neurobiology of these disorders. Abnormal function of the glutamatergic system has been implicated in the pathophysiology of many psychiatric and neurological disorders. Glutamatergic abnormalities have been reported in plasma, serum, cerebrospinal fluid and brain tissue of individuals afflicted with mood disorders. There is mounting evidence of alterations in NMDA (N-methyl-D-aspartate) and AMPA/KA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate) receptor function in mood disorders, and several studies have found differences related to NMDA receptor expression and binding affinities between individuals with and without mood disorders. Therapeutics used in the treatment of mood disorders affect many facets of the glutamatergic system. These include both antidepressants and mood stabilizers such as lithium, valproate and lamotrigine. Several agents that act on the glutamatergic system have been explored as potential treatments in mood disorders. These include inhibitors of glutamate release (such as lamotrigine and riluzole), partial NMDA antagonists (for example, D-cycloserine) and NMDA antagonists (such as memantine and ketamine). Ketamine has been shown to have anxiolytic and antidepressant effects in animal models of anxiety and depression as well as antidepressant effects in humans. A double-blind placebo-controlled crossover study found that a single intravenous dose of ketamine resulted in rapid and significant antidepressant effects in patients with treatment-resistant major depressive disorder within 2 hours, an effect that remained significant for 7 days. Other agents that affect the glutamatergic system are also being explored as potential novel therapeutics. These include AMPA potentiators, subunit selective NMDA receptor subunit 2B (NR2B) antagonists, glial glutamate transporter enhancers, group I metabotropic receptor modulators and presynaptic packaging and glutamate-release inhibitors.