Targeting metabotropic glutamate receptors for rapid-acting antidepressant drug discovery

ABSTRACT

Introduction

Depression is a highly debilitating psychiatric disorder and a worldwide health issue.

Functional deficits in glutamatergic cortico-limbic areas are hypothesized to play a key role in the pathogenesis of the disease. Consistently, the clinical antidepressant efficacy of the N-Methyl-D-aspartate (NMDA) receptor antagonist ketamine gives hope for a new class of glutamatergic rapid-acting antidepressants. In this context, metabotropic glutamate (mGlu) receptors have received attention as interesting targets for new antidepressants.

Areas covered

The present review summarizes the preclinical evidence supporting the antidepressant effect of the pharmacological modulation of mGlu receptors. Antidepressant properties in animal models of mGlu1 antagonists, mGlu5 negative allosteric modulators (NAMs) and positive allosteric modulators (PAMs), mGlu2/3 agonists, PAMs, orthosteric antagonists and NAMs, mGlu4 and mGlu7 PAMs are reviewed. To date, orthosteric mGlu2/3 antagonists are the most promising compounds in development as antidepressants.

Expert opinion

Although accumulating clinical and preclinical evidence concur to confirm a primary role of glutamate transmission modulation for the induction of a rapid antidepressant effect, very little is still known about the cellular mechanisms involved. More mechanistic studies are required to understand the role of glutamate in depression and the therapeutic potential of drugs directly targeting the glutamate synapse.

KEYWORDS:

• Metabotropic glutamate receptor
• depression
• rapid-acting antidepressant
• glutamate transmission

Article highlights

• Depression is associated with altered homeostatic mechanisms of synaptic plasticity, resulting in destabilization and loss of synaptic connections in glutamatergic brain areas controlling mood and emotion.

• The approval of the non-competitive NMDA receptor antagonist esketamine for treatment-resistant depression gives hope for a new class of rapid-acting antidepressants targeted at the glutamate synapse.

• The variety and functional properties of metabotropic glutamate (mGlu) receptors make them of great interest for the development of new antidepressants.

• mGlu2/3 antagonists showed rapid antidepressant effects in animal models of depression, with no dissociative effects.

• Clinical studies are warranted to demonstrate the safety and efficacy of mGlu receptors modulation in depression.

• The in-depth study of molecular mechanisms underlying the effects of glutamatergic rapid-acting antidepressants is needed for the development of new effective and safe drugs.

Acknowledgments

The author thanks Prof. Maurizio Popoli for his valued comments and suggestions.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

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

Additional information

Funding

The author is supported by Fondazione Cariplo [grant no. 2019-3357].