Targeting metabotropic glutamate receptors for the treatment of depression and other stress-related disorders

The discovery of robust antidepressant effects of ketamine in refractory patients has led to increasing focus on agents targeting glutamatergic signaling as potential novel antidepressant strategy. Among the agents targeting the glutamatergic system, compounds acting at metabotropic glutamate (mGlu) receptors are among the most promising agents under studies for depressive disorders. Further, the receptor diversity, distinct distribution in the CNS, and ability to modulate the glutamatergic neurotransmission in the brain areas implicated in mood disorders make them an exciting target for stress-related disorders. In preclinical models, antidepressant and anxiolytic effects of mGlu5 negative allosteric modulators (NAMs) have been reported. Interestingly, mGlu2/3 receptor antagonists show fast and sustained antidepressant-like effects similar to that of ketamine in rodents. Excitingly, they can also induce antidepressant effects in the animal models of treatment-resistant depression and are devoid of the side-effects associated with ketamine. Unfortunately, clinical trials of both mGlu5 and mGlu2/3 receptor NAMs have been inconclusive, and additional trials using other compounds with suitable preclinical and clinical properties are needed. Although group III mGlu receptors have gained less attention, mGlu7 receptor ligands have been shown to induce antidepressant-like effects in rodents. Collectively, compounds targeting mGlu receptors provide an alternative approach to fill the outstanding clinical need for safer and more efficacious antidepressants. This article is part of the special Issue on Glutamate Receptors - mGluRs.

Automated summary

Compounds targeting mGlu receptors show promise as potential novel antidepressant strategies, with mGlu5 negative allosteric modulators and mGlu2/3 receptor antagonists demonstrating antidepressant effects in preclinical models. Despite inconclusive clinical trials, these compounds offer an exciting alternative for the development of safer and more efficacious antidepressants.