Esketamine CIII Nasal Spray: First and Only Monotherapy for Treatment-Resistant Depression

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The US Food and Drug Administration (FDA) has approved the Johnson & Johnson supplemental New Drug Application (sNDA) for esketamine (Spravato) CIII nasal spray, the first and only monotherapy for adults with treatment-resistant depression, defined as inadequate response to at least 2 oral antidepressants. Spravato reduces symptoms of depression in as little as 24 hours and reduces the time to relapse for patients who stay on treatment.¹

"Today's announcement of the FDA approval for intranasal esketamine (Spravato) as monotherapy for patients with treatment resistant depression is a big win for these depressed patients who have already failed 2 monotherapy oral antidepressant trials. It allows for esketamine to be used as soon as it is clinically deemed appropriate without the need for a more complex treatment with another antidepressant," said Psychiatric Times Editor in Chief, John J. Miller, MD. "This is significant as esketamine as monotherapy in the clinical trial submitted to the FDA achieved remission in 15% more patients than placebo at 28 days, and demonstrated an improvement in depressive symptoms as early as 24 hours following the first intranasal dose. Hence patients can receive a rapidly acting antidepressant as a monotherapy to begin treatment while other additional treatment options are being considered."

Following FDA Priority Review, this approval is supported by positive results from the randomized, double-blind, multicenter, placebo-controlled study in which only Spravato showed a rapid and superior improvement in Montgomery-Asberg Depression Rating Scale (MADRS) total score compared with placebo. In a post-hoc analysis, Spravato demonstrated numerical improvements across all 10 MADRS items at day 28.² By week 4, 7.6% of patients taking placebo and 22.5% of patients taking Spravato achieved remission (MADRS total score ≤ 12).³ Spravato’s safety profile as a standalone treatment was consistent with the existing body of clinical and real-world data when used in conjunction with an oral antidepressant. No new safety concerns were identified.

"For more than 6 years, I have seen firsthand the real-world impact Spravato can have on patients' lives," said Gregory Mattingly, MD, president of the Midwest Research Group and Founding Partner, St. Charles Psychiatric Associates. "Now that it is also available as a monotherapy, health care 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."

Spravato is only available through the Spravato Risk Evaluation and Mitigation Strategy (REMS) Program due to the potential risks of serious adverse events resulting from sedation, dissociation, respiratory depression, abuse, and misuse. The REMS ensures safe and appropriate use.

"Treatment-resistant depression can be very complicated, especially for patients who do not respond to oral antidepressants or cannot tolerate them. For too long, health care providers have had few options to offer patients much-needed symptom improvement," said Bill Martin, PhD, global therapeutic area head of Neuroscience at Johnson & Johnson Innovative Medicine. "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."

The mechanism by which esketamine exerts its antidepressant effect is unknown. The FDA approved first approved Spravato in 2019 as the first nonmonoamine molecule for the treatment of major depressive disorder. Its putative mechanism of action is antagonizing the N-methyl-_D-aspartate–glutamate receptor (NMDA-GR), beginning a cascade of molecular events that ultimately increases the mammalian target of rapamycin, a well-established molecule that orchestrates synaptogenesis and neuroplasticity as soon as 4 hours after NMDA-GR antagonism.⁴

References

1. SPRAVATO® (esketamine) approved in the U.S. as the first and only monotherapy for adults with treatment-resistant depression. News release. January 21, 2025. https://www.investor.jnj.com/news/news-details/2025/SPRAVATO-esketamine-approved-in-the-U.S.-as-the-first-and-only-monotherapy-for-adults-with-treatment-resistant-depression/default.aspx

2. Data on File. Titusville, NJ: Janssen Pharmaceuticals, Inc.

3. Janik A, Qiu X, Lane R, et al. SPRAVATO (esketamine nasal spray) as a monotherapy for treatment-resistant depression (TRD). American Society of Psychopharmacology Annual Meeting; May 28-31, 2024. Poster W80.

4. Miller JJ. Psychopharmacology innovations. Psychiatric Times. 2024;41(12).