Treatment-resistant depression (TRD), afflicting 30% of 21 million U.S. MDD cases, gains a standalone warrior: FDA’s January 21, 2025, approval of esketamine (Spravato) CIII nasal spray as monotherapy for adults failing two oral antidepressants. Johnson & Johnson’s sNDA, via Priority Review, leverages a 379-patient trial where 56-84 mg doses halved Montgomery-Åsberg Depression Rating Scale (MADRS) scores by Day 28 versus placebo (-5.1/-6.8 least-square means), with 22.5% remission (MADRS ≤12) versus 7.6%—effects kicking in at 24 hours.
Glutamate-modulating esketamine fosters synaptic plasticity sans serotonin reliance, outpacing quetiapine in remission odds; post-hoc analyses show gains across all MADRS items. Administered twice weekly (84 mg induction, tapering to 56 mg) under REMS supervision in certified settings, it mitigates dissociation risks while enabling self-dosing post-monitoring.
This expands 2019’s adjunctive nod, slashing relapse time and empowering 24-hour breakthroughs—15% remission edge over placebo—amid hesitancy; contraindicated in aneurysmal disease or breastfeeding. As CNS depressant interactions warrant caution, Spravato’s toolkit integration could halve TRD’s $100 billion burden, illuminating paths for glutamate therapies.
