Modulation of Metabotropic Glutamate Receptors as a Strategy to Improve the Efficacy and Safety of Ketamine as an Antidepressant

The NMDA receptor antagonist (S)-ketamine produces rapid and lasting antidepressant effects in patients resistant to traditional treatments, validating the glutamatergic hypothesis of depression proposed over 20 years ago. However, (S)-ketamine also causes side effects that limit its safety. Preclinical studies suggest that low doses of mGlu2 and mGlu5 receptor antagonists can enhance ketamine's therapeutic effects while reducing its side effects. This review examines the synergistic interaction between ketamine and these glutamatergic modulators, the underlying mechanisms, and the role of mGlu2 and mGlu5 receptors in ketamine's antidepressant action.

Study at a glance

Abstract

Since the introduction of the NMDA receptor antagonist (S)-ketamine for depression therapy, it has become evident that the glutamatergic hypothesis of depression, proposed over 20 years ago, was justified and based on solid foundations. A significant breakthrough with this drug is its ability to produce a rapid and relatively long-lasting antidepressant effect in patients who are resistant to traditional depression treatments, both pharmacological and non-pharmacological. However, alongside its beneficial effects, (S)-ketamine can cause several side effects that make it a less safe option. As a result, strategies are being explored to mitigate the risks associated with its use. These strategies include leveraging the shared mechanism of action between ketamine and various modulators of the glutamatergic system. Preclinical studies have shown that low doses of mGlu2 and mGlu5 receptor antagonists can enhance the therapeutic effects of ketamine or its enantiomers without producing the typical side effects associated with ketamine. This review discusses the research on this synergistic effect, the underlying mechanisms, and the role of mGlu2 and mGlu5 receptors in the antidepressant action of ketamine.