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".