Rapid-acting antidepressants targeting modulation of the glutamatergic system: clinical and preclinical evidence and mechanisms

Major depressive disorder (MDD) is a devastating mental illness that affects approximately 20% of the world’s population. It is a major disease that leads to disability and suicide, causing a severe burden among communities. Currently available medications for treating MDD target the monoaminergic systems. The most prescribed medications include selective serotonin reuptake inhibitors and selective norepinephrine reuptake inhibitors. However, these medications have serious drawbacks, such as a delayed onset requiring weeks or months to reach efficacy and drug resistance, as one-third of patients are unresponsive to the medications. Therefore, it is imperative to develop novel therapies with rapid action, high efficacy and few adverse effects. The discovery of the rapid antidepressant effect of ketamine has triggered tremendous enthusiasm for studying new antidepressants that target the glutamatergic system in the central nervous system. Many agents that directly or indirectly modulate the glutamatergic system have been shown to provide rapid and lasting antidepressant action. Among these agents, ketamine, an antagonist of metabotropic glutamate 2/3 receptors, and scopolamine, an unspecific muscarinic acetylcholine receptor antagonist, have been extensively studied. In this review, we discuss the clinical and preclinical evidence supporting the antidepressant efficacy of these agents and the current understanding of the underlying mechanisms.