San Francisco—What research led to FDA approval of esketamine nasal spray, in conjunction with an oral antidepressant, for the treatment of depression in adults with treatment-resistant depression?

The study was published online by the American Journal of Psychiatry and was discussed at a briefing held during the annual meeting of the American Psychiatric Association in San Francisco.

Noting that about a third of patients with depression fail to achieve remission despite treatment with multiple antidepressants, an industry-led team conducted a phase III, double-blind, active-controlled, multicenter study at 39 outpatient referral centers. The goal was to compare the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray.

Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. Defined as the primary efficacy endpoint was change from baseline to Day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, as assessed by a mixed-effects model using repeated measures. Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase, the researchers report.

Results indicate that change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at Day 28 (difference of least square means = -4.0; SE = 1.69, 95% CI = -7.31, -0.64). In addition, the authors point out, clinically meaningful improvement was observed in the esketamine-plus-antidepressant arm at earlier time points.

The five most common adverse events—dissociation, nausea, vertigo, dysgeusia, and dizziness—were all observed more frequently in the esketamine-plus-antidepressant arm than in the antidepressant-plus-placebo arm. In fact, the researchers write that 7% and 0.9% of patients in the respective treatment groups discontinued the study drug because of an adverse event, adding that adverse events in the esketamine-plus-antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing.

“Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability,” study authors conclude. “Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.”

“This trial of esketamine was one of the pivotal trials in the FDA’s review of this treatment for patients with treatment resistant depression. Not only was adjunctive esketamine therapy effective, the improvement was evident within the first 24 hours,” explained coauthor Michael Thase, MD, of the Perelman School of Medicine, University of Pennsylvania, MD, one of the study authors. “The novel mechanism of action of esketamine, coupled with the rapidity of benefit, underpin just how important this development is for patients with difficult to treat depression.”

Because of the risk of serious adverse outcomes resulting from sedation and dissociation caused by esketamine, and the potential for abuse and misuse of the drug, the FDA limited its availability only through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy.

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