Glutamate Modulators Show Promise, but Questions Remain

March 28, 2017

Progress in using ketamine and other glutamate-modulating agents may be the first major advance in treating major depressive disorder in decades, according to a review published online in Nature Reviews/Drug Discovery.

“The ongoing clinical trial research focusing on the glutamate system may lead to a completely new class of antidepressants that may significantly change the way patients with depression and, in particular, treatment-resistant depression are treated,” said study first author James Murrough, MD, assistant professor of psychiatry and neuroscience at the Icahn School of Medicine at Mount Sinai, New York, New York. “Targeting glutamate receptors could transform care for patients for this devastating disease.”

The review looks at the history, rationale, and efficacy of glutamate-modulating agents for depression and singles out the glutamate N‑methyl-D‑aspartate receptor (NMDAR) antagonist ketamine as a potential rapid-acting antidepressant prototype.

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“Notably, however, there is a near absence of studies of ketamine in depression that examine its safety or efficacy beyond a single treatment adminis­tration,” wrote Dr. Murrough, along with coauthors Chadi G. Abdallah, MD, Yale University, New Haven, Connecticut, and Sanjay J. Mathew, MD, Baylor College of Medicine, Houston, Texas. “This large gap in the literature represents a cru­cial unmet research need and precludes an informed risk–benefit analysis of the clinical use of ketamine for the treatment of depression.”

Until fundamental questions regarding the safety, tolerability, efficacy, dose-response relationships, and therapeutic mechanisms of ketamine and other glutamate-modulating agents are answered, the future of this area of drug development remains unknown, according to the review.

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Currently, no glutamate modulator is approved for depression treatment anywhere in the world.

“An important unknown is the relationship between glutamate modulation and con­ventional pharmacotherapeutic, neurostimulatory, and psychotherapeutic approaches for depression,” researchers wrote, “which may shed light on the strengths and limitations of this pharmacological approach.”

 —Jolynn Tumolo


Murrough JW, Abdallah CG, Mathew SJ. Targeting glutamate signalling in depression: progress and prospects. Nature Reviews/Drug Discovery. 2017 March 17;[Epub ahead of print].

Mount Sinai researchers review progress of treating glutamate signaling in depression [press release]. New York, NY: Mount Sinai Hospital; March 17, 2017.