FDA Approves Esketamine as First Monotherapy for Treatment-Resistant Depression

Credit: US Food and Drug Administration

The US Food and Drug Administration (FDA) approved esketamine (SPRAVATO) CIII nasal spray as the first monotherapy for adults with treatment-resistant depression (TRD), announced by Johnson & Johnson on January 21, 2025.¹

The approval of this supplemental New Drug Application (sNDA) was based on phase 4 randomized, double-blind, multicenter, placebo-controlled study in which esketamine alone brought a rapid and superior improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) total score at 4 weeks compared with placebo. This decision followed the FDA’s Priority Review on esketamine for treatment-resistant depression.

“For more than six years, I’ve seen firsthand the real-world impact SPRAVATO® can have on patients’ lives,” said Gregory Mattingly, MD, President, Midwest Research Group and Founding Partner St. Charles Psychiatric Associates, in a statement. “Now that it is also available as a monotherapy, healthcare providers have the freedom to further personalize treatment plans based on individual needs, so patients can experience the efficacy of SPRAVATO® in as little as 24 hours, through day 28, without the need for a daily oral antidepressant.”

Approximately 21 million US adults live with major depressive disorder (MDD), and about 1 third of adults do not respond to oral antidepressants alone. Now, adults who do not respond to ≥ 2 oral antidepressants have the option of taking esketamine as a standalone treatment. Esketamine, a non-selective, non-competitive antagonist of the N-methyl-D-aspartate receptor, works by targeting glutamate, although the mechanism by which esketamine creates an antidepressant effect is unknown.

In a post-hoc analysis, esketamine demonstrated meaningful improvements across all MADRS items at day 28. At week 4, 22.5% of patients taking esketamine, compared with 7.6% on placebo, achieved remission with a MADRS total score ≤ 12. ESCAPE-TRD trial, a phase 3b, open-label, single-blind, multicenter, randomized, active control trial, had found esketamine nasal spray was associated with a 54% increased likelihood of patients reaching remission for TRD at 8 weeks compared to the commonly used quetiapine.²

The study showed the safety profile of esketamine as a standalone treatment was consistent with existing clinical and real-world data when used alongside an oral antidepressant.¹ The trials did not identify any new safety concerns. Esketamine is only administered through the SPRAVATO® Risk Evaluation and Mitigation Strategy (REMS) Program since sedation, dissociation, respiratory depression, abuse, and misuse can increase the risk of serious adverse outcomes.

“Treatment-resistant depression can be very complicated, especially for patients who do not respond to oral antidepressants or cannot tolerate them. For too long, healthcare providers have had few options to offer patients much-needed symptom improvement,” said Bill Martin, Ph.D., Global Therapeutic Area Head, Neuroscience, Johnson & Johnson Innovative Medicine, in a statement. “SPRAVATO ® is now available as a standalone treatment, meaning patients may experience improvements in depressive symptoms as early as 24 hours and at 28 days – without the need for daily oral antidepressants.”

References

1. ^{SPRAVATO® (esketamine) approved in the U.S. as the first and only monotherapy for adults with treatment-resistant depression. Johnson & Johnson. January 21, 2025. https://www.jnj.com/media-center/press-releases/spravato-esketamine-approved-in-the-u-s-as-the-first-and-only-monotherapy-for-adults-with-treatment-resistant-depression. Accessed January 21, 2025.}
2. ^{Derman, C. Esketamine Nasal Spray More Likely to Provide Treatment-Resistant Depression Remission than Quetiapine. HCPLive. October 5, 2023. https://www.hcplive.com/view/esketamine-nasal-spray-more-likely-to-provide-treatment-resistant-depression-remission-than-quetiapine. Accessed January 21, 2025.}