Novel Glutamatergic Treatments for Severe Mood Disorders

Abstract

All currently approved antidepressant medications for major depressive disorder (MDD) and bipolar disorder act primarily on the monoaminergic system and have varying affinities for serotonergic, norepinephrine-ergic, and/or dopaminergic receptors. Unfortunately, these drugs are only effective in approximately two-thirds of patients. Glutamate is the major excitatory neurotransmitter in the central nervous system, and the glutamatergic system has been implicated in the pathophysiology of MDD. Here, we review the putative involvement of the glutamate receptor subtypes-N-methyl-D-aspartate (NMDA), α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA), kainate, and the group I, II, and III metabotropic glutamate receptors (mGluRs)-in the development of novel and more effective treatments for MDD as well as preclinical and clinical trials of drugs targeting these receptors. The rapid and robust antidepressant effects of ketamine-an NMDA receptor antagonist-have been consistently replicated in multiple trials. Other glutamatergic drugs have been investigated with varying success. Here, we highlight some of the most interesting results, including: 1) repeated oral, intramuscular, and sublingual ketamine appears to be less robustly effective than intravenous ketamine, but also causes fewer significant adverse effects; 2) the glycine partial agonist GLYX-13 appears to be effective both as monotherapy and adjunctive treatment in the treatment of MDD. An oral analogue, NRX-1074, is currently under investigation; and 3) mGluR modulators targeting mGluR5 have demonstrated convincing preclinical results.

Keywords: N-methyl-D-aspartate (NMDA); antagonist; glutamate; metabotropic positive allosteric modulator; mood disorders; negative allosteric modulator.

Conflict of interest statement

Conflict of Interest

Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA-MH002857-10), by a NARSAD Independent Investigator Award to Carlos A. Zarate, and by a Brain and Behavior Mood Disorders Research Award to Carlos A. Zarate. A patent for the use of ketamine in depression has been awarded that lists Carlos A. Zarate among the inventors; he has assigned his rights on the patent to the U.S. government, but will share a percentage of any royalties that may be received by the government. Minkyung Park and Mark J. Niciu have no conflict of interest to disclose, financial or otherwise.

Figures

Figure 1

Glutamate Receptor Subtypes and Novel Drugs

Figure 2

Hypothesized Mechanisms of Action of Glutamate in Treatment-Resistant Depression (TRD)