Esketamine nasal spray a new kid on the block for treatment-resistant depression
Esketamine nasal spray effectively and rapidly improves depressive symptoms in patients with treatment-resistant depression, making it the first antidepressant to be approved by the US FDA in a new drug class.
The pivotal phase III study showed rapid separation in the Montgomery-Åsberg Depression Rating Scale (MADRS) score within 24 hours for esketamine plus antidepressant compared with antidepressant alone, which was sustained up to 28 days. [Am J Psychiatry 2019;176:428-438]
“There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition,” said Dr Tiffany Farchione, acting director of the FDA’s Division of Psychiatry Products in an FDA statement. The only other drug that is FDA-approved for treatment-resistant depression is a fixed-dose combination of olanzapine/fluoxetine. [N Engl J Med 2019;doi:10.1056/NEJMp1903305]
“Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability,” the researchers pointed out.
Esketamine is an S-enantiomer of ketamine purportedly more potent than its “R” counterpart as a NMDA receptor antagonist.
“The novel mechanism of action of esketamine, coupled with the rapidity of benefit, underpin just how important this development is [in addressing an unmet medical need] for patients with difficult to treat depression,” said study co-author Dr Michael Thase from Perelman School of Medicine, University of Pennsylvania in Philadelphia, Pennsylvania, US.
“Not only was adjunctive esketamine therapy effective, the improvement was evident within the first 24 hours,” highlighted Thase.
In the phase III, double-blind, pivotal study, 197 adults with treatment-resistant depression* who were randomized to receive esketamine nasal spray (either 56 or 84 mg twice weekly) or placebo, both in addition to a newly initiated oral antidepressant (SNRI or SSRI)**.
Improvement in depressive symptoms, as indicated by the least-square (LS) mean change in MADRS score, was greater in the esketamine plus antidepressant group compared with the antidepressant-alone group (mean change from baseline, -21.4 vs -17.0, difference in LS means, -4.0; p=0.02).
The onset of response was rapid, with a between-group difference in LS means of -3.3 in favour of esketamine within 24 hours after dosing, which according to the authors was “a clinically meaningful treatment difference” based on existing literature. The benefit with esketamine persisted throughout the study course, with a statistically significant difference between groups at 28 days (p=0.02).
Furthermore, the improvement in MADRS score with esketamine remained across subgroups, regardless of region, age, sex, baseline severity, functional impairment, number of previous treatment failures, and class of oral antidepressant used (SSRIs or SNRIs).
In terms of safety, dizziness, dysgeusia, vertigo, dissociation symptoms, and nausea were the five most commonly reported treatment-emergent adverse events, and all occurred at a higher rate in the esketamine plus antidepressant group (incidence range, 20.9–26.1 percent).
“Most adverse events were of mild or moderate severity and were transient, with onset shortly after dosing and resolution by 1.5 hours after dosing,” observed the researchers.
More questions than answers
However, Dr Alan Schatzberg from Stanford University School of Medicine, Stanford, California, US raised concerns about the drug’s abusability in an accompanying commentary. “There are more questions than answers with intranasal esketamine, and care should be exercised in its application in clinical practice.” [Am J Psychiatry 2019;176:422-424]
“Do we have a real sense of how long and how often to prescribe it? It’s not entirely clear. If patients lose response, should we increase the frequency of administration? This could be problematic. Can coming off the drug be problematic? Data suggest that it could be an issue,” he raised. “[These] questions need to be considered in the context of what ketamine is—an anaesthetic agent that has been abused in this country and elsewhere in various formulations.”
“Only time will tell how useful it will be. Still, the agent could be helpful to many patients with refractory depression, and efforts to develop rapidly acting agents for severely depressed patients need to be applauded,” wrote Schatzberg.
In view of its potential for abuse, Farchione stated, “[T]he drug will only be available through a restricted distribution system [REMS***] and it must be administered in a certified medical office where the health care provider can monitor the patient."