Skip to main content

Esketamine Nasal Spray Prevents Relapse of Treatment-Resistant Depression

June 14, 2019

By Will Boggs MD

NEW YORK—Esketamine nasal spray, added to oral antidepressant treatment, helps to prevent relapse in patients with treatment-resistant depression, according to results from the SUSTAIN-1 randomized trial.

"Esketamine nasal spray is the first approved antidepressant in decades with a new mechanism of action," Dr. Ella J. Daly from Janssen Research and Development, in Titusville, New Jersey, told Reuters Health by email. "Given that approximately one-third of patients with major depressive disorder (MDD) do not respond to currently available antidepressants, it is important to have new treatment options for patients with treatment resistant depression."

Several short-term studies have demonstrated efficacy of racemic ketamine and its stereoisomer esketamine for treatment-resistant depression, but little is known about whether it maintains its antidepressant effects in the long term.

Dr. Daly and colleagues assessed the efficacy of esketamine nasal spray plus an oral antidepressant versus an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with treatment-related depression (TRD) who achieved stable remission on esketamine nasal spray and the oral antidepressant. Patients were randomized to continue esketamine nasal spray or switch to placebo after week 16.

Among 176 patients (59%) with stable remission, 24 (26.7%) of the 90 randomized to esketamine and 39 of the 86 (45.3%) randomized to placebo experienced a relapse event during the maintenance phase (P=0.003), the researchers report in JAMA Psychiatry, online June 5.

Similarly, among 121 patients (41%) who achieved a stable response but not remission, 16 esketamine patients (25.8%) and 34 placebo patients (57.6%) experienced relapse during the maintenance phase (P<0.001).

This corresponded to decreases in relapse risk of 51% among patients who achieved stable remission and 70% among patients who achieved stable response.

Most relapses among patients who achieved stable remission and were switched to placebo (19/39) occurred in the first month after discontinuation of esketamine treatment, and 11 of these 19 early relapses occurred in patients who had required weekly treatment administration in the last four weeks of the optimization phase before randomization.

Adverse events were much more common in the esketamine group than in the placebo group, but most were mild to moderate, observed after dosing, and generally resolved in the same day.

"The data from this SUSTAIN-1 study and the recently published short-term Transform 2 study provide evidence of clinically meaningful short- and long-term efficacy when esketamine is used in combination with a newly initiated oral antidepressant in this difficult-to-treat population," Dr. Daly concluded.

Dr. Kenji Hashimoto from Chiba University Center for Forensic Mental Health, in Chiba, Japan, who has studied the antidepressant effects of ketamine and its two enantiomers, told Reuters Health by email, "Since there are no maintenance antidepressant drugs for TRD, it is noteworthy that esketamine nasal spray is the only FDA-approved drug for TRD. However, the efficacy of esketamine nasal spray was not potent because only 2 of 5 phase 3 trials were positive."

"Importantly, it seems that intravenous (IV) racemic ketamine (off-label in USA) may have more potent antidepressant actions than esketamine nasal spray since racemic ketamine has equal amount of arketamine (the R-enantiomer of ketamine) and esketamine," he said.

"Because of the risk of serious adverse outcomes resulting from sedation and dissociation caused by esketamine administration, and the potential for abuse and misuse of the drug, it is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS)," Dr. Hashimoto explained.

He also disclosed that he has been working with Perception Neuroscience in New York to develop arketamine "as a novel antidepressant without the side effects of ketamine and esketamine."

Janssen funded the study and employed more than half of the authors of the new report.


JAMA Psychiatry 2019.

(c) Copyright Thomson Reuters 2019. Click For Restrictions -

Back to Top