The FDA has recently approved esketamine nasal spray as the first monotherapy for adults with treatment-resistant depression. In clinical trials, esketamine demonstrated superior efficacy compared to a placebo, with 22.5% of patients achieving remission at week 4. The agent targets glutamate, the brain's most abundant excitatory neurotransmitter. This approval marks a significant advancement in therapeutic options for patients who have not responded to conventional oral antidepressants.