On January 21, 2025, the U.S. Food and Drug Administration approved Spravato (esketamine nasal spray) as monotherapy for adults with treatment-resistant depression (TRD), marking a significant expansion beyond its previous indication as adjunctive therapy. The approval was supported by data from a robust Phase 3b program, including the TRANSFORM-4 study, which demonstrated that esketamine alone significantly improved depressive symptoms compared to placebo over a four-week induction period, followed by sustained benefits during the maintenance phase. Patients showed rapid symptom relief, with notable improvements in mood, suicidal ideation, and functional impairment. This was the first regulatory endorsement for a non-oral monotherapy in TRD, a population historically underserved due to limited efficacy of traditional antidepressants. In conjunction with the label expansion, new clinical guidance published in May 2025 clarified that Spravato may be prescribed without concurrent oral antidepressants, increasing flexibility in clinical decision-making. While safety concerns such as dissociation and sedation remain, these are mitigated by mandatory Risk Evaluation and Mitigation Strategy (REMS) protocols that ensure in-clinic administration and monitoring.

Citation: https://www.businesswire.com/news/home/20250121005733/en/FDA-Approves-Spravato-as-Standalone-Treatment-for-Treatment-Resistant-Depression

Implications: This approval redefines the treatment landscape for TRD, offering clinicians a rapid-acting monotherapy option. It may lead to wider adoption of Spravato in specialty psychiatric settings and simplify regimens for patients unable or unwilling to take multiple medications. Prior authorization and REMS enrollment remain access barriers.