An update on NMDA antagonists in depression

ABSTRACT

Introduction: Current antidepressant therapies exhibit low therapeutic efficiency and delayed onset of antidepressant action. Thus, the search for better acting agents is a continuous process. One of the primary targets for the development of new antidepressant drugs is the glutamate N-methyl-D-aspartate (NMDA) receptor.

Areas covered: The present review aims to summarize and provide an update on published preclinical data evaluating the antidepressant efficacy of various NMDA antagonists and their mechanisms of action. The review also provides an update on the clinical efficacy of ketamine and esketamine as well as other NMDA receptor antagonists based on published results from clinical studies.

Expert opinion: The recent approval of esketamine by the FDA for the treatment of major depressive disorder (MDD) culminates the almost 30 years of research focused on the NMDA receptor as a target for the development of antidepressants. This action gives hope to patients who do not respond to currently available pharmacotherapy. While knowledge of the mechanism of action of ketamine/esketamine will pave the way for the creation of a new class of antidepressants, recent results have shown that several issues regarding the use of these compounds or other NMDA receptor antagonists must be clarified.

KEYWORDS:

• NMDA receptor
• ketamine
• depression
• antidepressant
• antagonist

Article highlights

• Current antidepressant drugs require chronic treatment and are not effective in about 30% of MDD patients. Thus, novel, fast- and long-acting antidepressants are needed. In the past two decades, several clinical trials have been performed with ketamine. A single dose of ketamine was effective in MDD patients, patients with treatment-resistant depression, and those with suicidal ideations. Despite ketamine’s unique antidepressant potency, its use on a large scale is fraught with serious side effects such as psychotomimetic effects, dissociative properties, and the potential for abuse. However, the question remains, is the development of fast- and long-acting antidepressant drugs without the ketamine-like side effects a possibility?

• In recent years, the antidepressant mechanism of ketamine and properties of its enantiomers (S and R-ketamine) and metabolites (2R,6R-HNK, S-norketamine) have come to light. These compounds all have different mechanisms of action and as such induce a little different behavioral response in many preclinical behavioral paradigms.

• Based on preclinical studies, it is possible that R-ketamine, 2R,6R-HNK, and S-norketamine have antidepressant profiles similar to ketamine but elicit fewer potential side effects. To avoid the discrepancies between studies evaluating the antidepressant-like activity of ketamine or its metabolites it will be desirable to use only animal with depressive-like phenotype since ketamine, its metabolites, or enantiomers will be used in patients with depression and not healthy people.

• Differences between the cellular and molecular effects induced by ketamine, its metabolites, and particular enantiomers raise issues about its final mechanism of action and the contributions of its metabolites and enantiomers either individually or collectively.

• Clinical trials with rapamycin and ketamine support the idea that ketamine effects could be enhanced by drugs with different mechanisms of action from ketamine. These results in some way call into question the involvement of the mTOR kinase in the mechanism of action of ketamine as expounded in several preclinical studies.

2R,6R-HNK antidepressant effects are not NMDAR–dependent but similar to ketamine. 2R,6R-HNK effects are mediated by AMPAR and mGluR2 receptors; however, its precise molecular target is unknown.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript is a patent holder on the use of R-ketamine and S-norketamine in the treatment of depression. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This study was supported by the grant 2015/19/B/NZ4/01890 from the National Science Centre, Poland and the Statutory activity of the Maj Institute of Pharmacology Polish Academy of Sciences in Krakow, Poland.