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Glutamatergic Modulators in Depression

Henter, Ioline D., MA; de Sousa, Rafael Teixeira, MD, PhD; Zarate, Carlos A. Jr., MD

doi: 10.1097/HRP.0000000000000183

Learning objective After participating in this activity, learners should be better able to evaluate the evidence supporting the antidepressant effects of glutamatergic modulators.

Both preclinical and clinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders such as bipolar depression and major depressive disorder. In particular, rapid reductions in depressive symptoms have been noted in response to subanesthetic doses of the glutamatergic modulator ketamine in subjects with major depressive disorder or bipolar depression. These results have prompted the repurposing or development of other glutamatergic modulators, both as monotherapy or adjunctive to other therapies. Here, we highlight the evidence supporting the antidepressant effects of various glutamatergic modulators, including (1) broad glutamatergic modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine [Nuedexta], AVP-786, nitrous oxide [N2O], AZD6765), (2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (CP-101,606/traxoprodil, MK-0657 [CERC-301]), (3) glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and (4) metabotropic glutamate receptor modulators (AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819 [RG1578]).

From the Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD.

Supported by the National Institute of Mental Health Intramural Research Program grant nos. IRP-NIMH-NIH and ZIA-MH002857, a NARSAD Independent Investigator grant (Dr. Zarate), and a Brain & Behavior Mood Disorders Research Award (Dr. Zarate).

Original manuscript received 29 March 2017, accepted for publication subject to revision 20 June 2017; revised manuscripts received 13 July and 15 August 2017.

Correspondence: Carlos A. Zarate Jr., MD, Experimental Therapeutics and Pathophysiology Branch, NIMH-NIH, 10 Center Dr., Bldg. 10 CRC, Unit 7 Southeast, Room 7–5342, Bethesda, MD 20892. Email:

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