But first, does it work?

The pivotal Phase 3 study of the drug found that esketamine started reducing depression symptoms within 24 hours. Notably, all 227 participants in the study started a new antidepressant along with either esketamine or a placebo (saline) nasal spray.2

Participants in the esketamine arm of the study saw a 4 point greater reduction in score on the 60-point Montgomery-Asberg Depression Rating Scale than those in the placebo arm at Day 28 of the study. The effect size was 0.3 for esketamine. More than half (52.5%) of the patients in the esketamine arm achieved remission, and 69.3% responded to the treatment compared to 31% and 52%, respectively, of those receiving placebo.

The 4 point improvement was a better result achieved in less time than seen in other studies of U.S. Food and Drug Administration-approved adjunctive medications for treatment-resistant depression, said study co-author Michael E. Thase, MD, staff physician at the Corporal Michael J. Crescenz VAMC in Philadelphia and professor of psychiatry at the University of Pennsylvania Perelman School of Medicine.

“The drugs of greatest comparability, aripiprazole, brexpiprazole and olanzapine had just 2- to 3-point differences at six weeks,” Thase told U.S. Medicine.

“Studies using intravenous ketamine showed a greater difference, so there’s some disappointment that esketamine is not as strong and powerful. Still, it’s better than other comparative options,” he said.

The FDA’s requirement that participants start a new antidepressant coincident with the start of esketamine might also have affected the results. “In studies of other drugs, patients stayed on their previous antidepressant. Based on earlier studies of intravenous and intranasal esketamine using the more conventional designs—in which patients stayed on an ineffective antidepressant—there was reason to expect a larger effect size, on the order of 0.5 or 0.6,” he added.

More participants responded to esketamine than previous adjunctive medications as well, he noted. “A 20% improvement [compared to placebo] is remarkable; other drugs showed only a 10% improvement or less.”

The speed with which esketamine acts is a significant advantage. “What I like best about esketamine is that it shows itself very quickly. If it’s not going to help, you can close it down in two weeks and not wait six or eight weeks as you would with other antidepressants,” Thase noted. The study showed separation between placebo and esketamine within two days.

“The effect of esketamine isn’t as large or quite as fast as IV ketamine, but a form of treatment that doesn’t require an IV is a good thing when you have to gauge and marshal cost and efficacy,” he said. Ketamine does not have FDA approval for treatment of depression, but is increasingly used off-label for that purpose.

Esketamine may not be as effective as its parent, but is it effective enough? While the Phase 3 trial showed positive results, two other trials run by the manufacturer failed to demonstrate a statistically significant separation from placebo. Further, more than 20% of the participants in the successful trial had failed only one class of oral antidepressants prior to the study.

Questions about how truly blinded patients were in the study have also arisen, as the saline nasal spray had none of the signature side effects of esketamine, such as brief dissociation and perceptual disturbances.

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