FDA Expands Approval of Esketamine for Depression

The FDA approved esketamine (Spravato) nasal spray as monotherapy for adults with treatment-resistant depression who had an inadequate response to at least two oral antidepressants, maker Johnson & Johnson announced on Tuesday.

Used under the supervision of a healthcare provider, esketamine was first approved in 2019 for use alongside an oral antidepressant for treatment-resistant depression, and then received an additional indication in 2020 for adults with major depressive disorder plus acute suicidal ideation or behavior, in conjunction with an oral antidepressant. The drug acts as a non-selective, non-competitive antagonist of the NMDA receptor and works by targeting glutamate in the brain.

While it is estimated that 21 million U.S. adults are living with major depressive disorder, roughly a third won’t respond to oral antidepressants alone.

“Patients often cycle through multiple oral medications, waiting 4-6 weeks for potential relief,” said Johnson & Johnson in a statement. “After trying their third oral antidepressant, approximately 86% of patients do not achieve remission.”

In the 379-participant double-blind trial underpinning the new indication, participants who received one of two strengths of esketamine had a significantly greater improvement in average Montgomery-Åsberg Depression Rating Scale (MADRS) total score compared with placebo by day 28, with least-square mean differences of -5.1 with the 56-mg dose and -6.8 with the 84-mg dose.

In a post-hoc analysis, esketamine yielded numerical improvements across all 10 MADRS items by day 28. At week 4, 7.6% of patients taking placebo and 22.5% of patients on treatment achieved remission, defined as a MADRS total score of 12 or less.

“For more than 6 years, I’ve seen firsthand the real-world impact Spravato can have on patients’ lives,” said trial investigator Gregory Mattingly, MD, president of the Midwest Research Group and founding partner of St. Charles Psychiatric Associates in Missouri, 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.”

Mattingly previously told MedPage Today this allows patients who haven’t benefited from standard antidepressants “to ‘unchain’ themselves from [these treatments] that have often provided little benefit but are often associated with unwanted side effects.”

The esketamine label carries a boxed warning for the risks of sedation, dissociation, respiratory depression, abuse and misuse, and suicidal thoughts and behaviors.

The most common adverse events (occurring in at least 5% of patients) included dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, vomiting, feelings of drunkenness, and headache.

Esketamine should not be used in patients who are breastfeeding; those with aneurysmal vascular disease, arteriovenous malformation, or a history of brain bleeds; and those who are allergic to any of its ingredients.

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