Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study
Comprehensive Overview
Published in the American Journal of Psychiatry in 2019, this study asked whether esketamine nasal spray, a rapid-acting drug related to the anesthetic ketamine, could help patients with treatment-resistant depression who had already failed multiple antidepressants, and whether it could do so faster than conventional treatment. Researchers conducted a phase 3, randomized, double-blind, active-controlled trial at 39 outpatient centers, enrolling adults with moderate to severe depression and a documented history of nonresponse to at least two antidepressants in their current depressive episode. After confirming nonresponse to a prospectively monitored antidepressant, 227 patients were randomly assigned to switch to either flexibly dosed esketamine nasal spray, given twice weekly, combined with a newly started oral antidepressant, or a placebo nasal spray combined with the same newly started oral antidepressant, which served as the active comparator rather than a true do-nothing control. The primary outcome was the change in depression severity, measured with the clinician-rated Montgomery-Åsberg Depression Rating Scale, from baseline to day 28, with MADRS assessments performed by independent raters unaware of study details to reduce bias. The topline result was that esketamine plus antidepressant produced a significantly greater reduction in depression severity than antidepressant alone by day 28.
Outcomes and Implications
The most important finding was that patients receiving esketamine plus antidepressant showed a significantly greater reduction in depression scores by day 28 than those receiving antidepressant plus placebo, a difference of 4.0 points on the depression rating scale, and this benefit was already apparent 24 hours after just a single dose. At day 28, 69.3% of patients in the esketamine group were classified as responders, meaning at least a 50% reduction in depression severity, compared with 52.0% in the comparator group, and 52.5% achieved full remission compared with 31.0% on antidepressant alone, translating to a number needed to treat of 6 for response and 5 for remission. Esketamine's side effects were distinct but manageable: dissociation, nausea, vertigo, altered taste, and dizziness were the most common, occurring mostly during and shortly after dosing sessions and typically resolving within 1.5 hours, and only 7% of esketamine-treated patients discontinued the study because of an adverse event, compared with under 1% in the comparator group. No deaths were considered related to the study drug, and there was no evidence of treatment-emergent suicidal behavior in either group. The authors note that the antidepressant-alone comparator group responded better than typically seen in past trials, which may have narrowed the observed treatment difference. They conclude that current options for treatment-resistant depression remain limited, and that esketamine nasal spray, working through a novel mechanism distinct from standard antidepressants, offers a rapidly acting, effective, and reasonably well-tolerated option for this difficult-to-treat population.