The U.S. Food and Drug Administration (FDA) has approved esketamine (Spravato) nasal spray as the first monotherapy for adults with treatment-resistant depression, marking a significant advancement in therapeutic options for patients who have not responded to conventional oral antidepressants.
In the clinical trial supporting its approval, esketamine demonstrated superior efficacy to placebo in reducing Montgomery-Åsberg Depression Rating Scale (MADRS) total scores. At week 4, 22.5% of patients receiving esketamine achieved remission (MADRS total score ≤12), compared with 7.6% of patients in the placebo group.
The randomized, double-blind, multicenter, placebo-controlled study showed onset of action as early as 24 hours, with sustained improvement through day 28. Post-hoc analysis revealed numerical improvements across all 10 MADRS items at day 28.
"Treatment-resistant depression can be very complicated, especially for patients who do not respond to oral antidepressants or cannot tolerate them," said Bill Martin, PhD, Global Therapeutic Area Head of Neuroscience at Johnson & Johnson Innovative Medicine. "[Esketamine] 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."
Current epidemiological data indicate that approximately 21 million adults in the United States have experienced at least one major depressive episode, with approximately one-third not responding to treatment with oral antidepressants. This new indication expands therapeutic options for the estimated one-third of adults with major depressive disorder who have treatment-resistant depression, defined as inadequate response to two oral medications. Research indicates that after trying a third oral antidepressant, approximately 86% of patients do not achieve remission, underscoring the importance of alternative therapeutic approaches.
"For more than six years, I've seen firsthand the real-world impact [esketamine] can have on patients' lives. Now that it is also available as a monotherapy, health-care providers have the freedom to further personalize treatment plans based on individual needs," remarked Gregory Mattingly, MD, President of Midwest Research Group and Founding Partner of St. Charles Psychiatric Associates.
The safety profile of esketamine monotherapy remained consistent with previous clinical and real-world data when used in combination with oral antidepressants, with no new safety concerns identified. Due to risks of sedation, dissociation, respiratory depression, and potential for abuse and misuse, esketamine remains available only through the SPRAVATO Risk Evaluation and Mitigation Strategy Program.
The medication, which targets glutamate, the brain's most abundant excitatory neurotransmitter, has been administered to more than 140,000 patients worldwide and is currently approved in 77 countries. While its exact antidepressant mechanism remains unknown, esketamine acts as a nonselective, noncompetitive antagonist of the N-methyl-D-aspartate receptor.
The FDA granted Priority Review status to the supplemental New Drug Application, reflecting the significant unmet medical need in this patient population.
Reference
Johnson & Johnson. SPRAVATO® approved in the U.S. as the first and only monotherapy for adults with treatment-resistant depression [news release]. Titusville, NJ: Johnson & Johnson; January 21, 2025.
