Novel glutamatergic drugs for the treatment of mood disorders

Abstract

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.

Keywords: AMPA; NMDA; glutamate; ketamine; major depressive disorder; mood disorders.

Figure 1

Molecular targets of glutamatergic drugs for mood disorders. Notes: Sites of action and regulation for glutamate neurotransmission are shown, and drugs that target each specific site/mechanism are indicated. The specific locations depicted here are representative, though ionotropic and metabotropic glutamate receptors may be located on both presynaptic and postsynaptic cells. Numbers indicate the following targets: (1) NMDAR; (2) AMPAR; (3) Group I mGluR; (4) Group II mGluR; (5) Group III mGluR; (6) Glycine site of NMDAR; (7) Na⁺ Channel; (8) Ca⁺⁺ Channel; (9) K⁺ Channel. Abbreviations: AMPAR, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid receptor; EAAT, excitatory amino acid transporter; Gln, glutamine; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartate receptor; MTEP, 3-((2-methyl-4-thiazolyl)ethynyl)pyridine; PHCCC, (−)-N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide; EMCMQM, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate; Glu, glutamate; ACPC, 1-aminocyclo-propanecarboxylic acid.