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Esketamine targets glutamate, the most abundant neurotransmitters in the brain.
Esketamine (Spravato CIII; Janssen Pharmaceuticals) received FDA approval, becoming the first and only monotherapy to treat adults with treatment-resistant depression (TRD) who had inadequate responses to at least 2 oral antidepressants. The monotherapy met its primary end point at 4 weeks, leading to improvements in depressive symptoms in as little as 24 hours.
TRD accounts for approximately 30% of all cases of major depressive disorder (MDD), which affects an estimated 21 million adults in the United States alone. When patients with MDD fail to respond to 2 oral medications, it is considered TRD. TRD has a significant impact on patients’ quality of life and is associated with high financial burdens. Due to limited treatment options, patients must cycle through multiple oral medications and wait 4 to 6 weeks for potential relief. By the third oral antidepressant, an estimated 86% of patients do not achieve remission.1,2
Esketamine is a nasal spray that was originally approved by the FDA in 2019 in combination with an oral antidepressant for TRD, available only at a certified doctor’s office or clinic. It is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate receptor and targets a pathway in the brain that affects glutamate. However, its underlying mechanism of action as an antidepressant is unknown.2,3
The 2025 approval as a monotherapy is supported by data from the randomized, double-blind, multicenter, placebo-controlled study (NCT04599855) in which esketamine alone showed rapid and robust improvements in Montgomery-Asberg Depression Rating Scale (MADRS) total score compared with placebo.4
The trial randomized enrolled participants to receive 56 mg and 84 mg of esketamine or placebo nasal spray. At day 28, esketamine was associated with numerical improvements across all 10 MADRS items. At week 4, 22.5% of patients receiving esketamine achieved remission compared with 7.6% of patients taking placebo (MADRS total score ≤ 12). The safety profile was consistent with esketamine as a combination therapy and there were no new concerns.2
However, due to adverse outcomes from sedation, dissociation, respiratory depression, abuse, and misuse, esketamine is only available through the Spravato Risk Evaluation and Mitigation Strategy Program.2
“For more than 6 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 press release. “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 [esketamine] in as little as 24 hours, through day 28, without the need for a daily oral antidepressant.”2