Esketamine Approved by FDA as First Monotherapy for Treatment-Resistent Depression

Esketamine is now the first and only monotherapy for MDD following inadequate response to oral antidepressants.

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The FDA approved a supplemental new drug application for esketamine (Spravato) CIII nasal spray, marking a milestone in the treatment of major depressive disorder (MDD), according to an announcement from Johnson & Johnson.¹ Esketamine is now the first and only monotherapy for adults with MDD with inadequate response to at least 2 oral antidepressants.

This approval comes after a priority review by the FDA, highlighting the therapy’s rapid and superior efficacy compared with placebo. Clinical trial results demonstrated improvement in depressive symptoms at 24 hours and sustained benefits at 4 weeks. The randomized, double-blind, placebo-controlled study that led to this approval showed that 22.5% of patients using esketamine achieved remission by week 4 compared with 7.6% in the placebo group. Also, the treatment's safety profile aligns with existing data from its combined use with oral antidepressants, with no new safety concerns identified.

In 2023, esketamine showed superiority to quetiapine when it exhibited a 54% increased likelihood of patients reaching remission for treatment-resistant depression (TRD) at 8 weeks.² TRD affects nearly one-third of the 21 million adults living with MDD in the US, compromising quality of life and exacerbating economic impact, according to the announcement.¹ Traditional oral antidepressants often require weeks to show results, leaving many patients cycling through multiple treatments without achieving remission. Targeting the glutamate neurotransmitter pathway, the therapy’s mechanism of action aims to address this unmet need with its nonselective, noncompetitive antagonist of the NMDA receptor.

Approved in 77 countries, esketamine is indicated for adults with TRD and depressive symptoms associated with MDD with acute suicidal ideation or behavior when used with or without an oral antidepressant. However, due to potential risks such as sedation, dissociation, and misuse, the treatment is available only through the Risk Evaluation and Mitigation Strategy Program to ensure safe administration in certified health care settings.

MDD is one of the most prevalent psychiatric disorders, with an estimated global impact of 280 million people. TRD, characterized by inadequate response to at least 2 oral antidepressants, contributes significantly to the economic and personal burden of depression. Nearly half of the total costs of MDD are attributable to TRD.

"For more than six years, I've seen firsthand the real-world impact [esketamine] can have on patients' lives," Gregory Mattingly, MD, president of Midwest Research Group and Founding Partner of St. Charles Psychiatric Associates, said in the statement. "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 [esketamine] in as little as 24 hours, through day 28, without the need for a daily oral antidepressant."

Since its initial approval, esketamine has been administered to over 140,000 patients globally, supported by robust clinical and real-world data. Johnson & Johnson stated that the monotherapy approval further cements its position as a leading treatment for TRD, expanding options for health care providers and patients.

References

1. SPRAVATO (esketamine) approved in the U.S. as the first and only monotherapy for adults with treatment-resistant depression. News release. Johnson & Johnson. January 21, 2025. Accessed 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

2. SPRAVATO (esketamine) demonstrates superior efficacy compared to quetiapine extended-release in treatment-resistant major depressive disorder. News release. Johnson & Johnson. October 4, 2023. Accessed Janaury 21, 2025. https://www.jnj.com/media-center/press-releases/spravato-esketamine-demonstrates-superior-efficacy-compared-to-quetiapine-extended-release-in-treatment-resistant-major-depressive-disorder