Advancing past ketamine: emerging glutamatergic compounds for the treatment of depression

Glutamatergic neuroplasticity is framed as a core mechanism in depression, and NMDA-related drugs are treated as a path to rapid antidepressant effects. The review explains how ketamine and its S-enantiomer esketamine (the established NMDA receptor antagonist example) set a precedent for other rapid-acting antidepressant drugs targeting glutamatergic synapses. Beyond ketamine and esketamine, the review focuses on glutamatergic compounds with meaningful clinical trial data, including arketamine and esmethadone, as well as nitrous oxide, alongside other glutamate receptor modulators. Preclinical-only molecules and isolated case reports are discussed only briefly. Overall, the argument is that targeting glutamatergic modulation could improve clinical outcomes and reduce the burden of depression by enabling faster therapeutic effects, while also highlighting that mechanistic and efficacy questions remain.