Esketamine Nasal Spray as Monotherapy for Treatment-Resistant Depression
Objective: Esketamine (ESK) nasal spray is approved in 75 countries for treatment-resistant depression (TRD) in conjunction with an oral antidepressant (OAD). Efficacy and safety of ESK monotherapy versus placebo (PBO) was assessed in this randomized, double-blind, multicenter study (NCT04599855) in adults with TRD.
Methods: Participants with major depressive disorder (per DSM-5) with no psychotic features, IDS-C30 score ≥34, and nonresponse (≤25% improvement) to ≥2 OADs were enrolled. Participants underwent a ≥2 week OAD-free period and were randomly assigned 2:1:1 to receive PBO or fixed-dose ESK (56/84mg) twice weekly for 4 weeks. This analysis included participants with MADRS score ≥28 at screening and baseline, and with ≤25% improvement from screening to baseline. Primary and key secondary endpoints were changes in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to day 28 (D28) and D2 (~24 hours after first dose), respectively.
Results: This analysis examined 378 patients treated with fixed-dose ESK (56mg, n=86; 84mg, n=95) or PBO (n=197). Mean change from baseline in MADRS score at D28 with ESK was superior to PBO (least-squares mean difference [SE]: 56mg: −5.1[1.42]; 84mg: −6.8[1.38]; P < 0.001). At D2, change from baseline in MADRS score for ESK (56mg: p=0.004; 84mg: P=0.006) was also superior to PBO. The most common (≥10%) treatment-emergent adverse events for combined ESK groups were nausea, dissociation, dizziness, and headache.
Conclusion: ESK monotherapy was efficacious versus PBO after 4 weeks of treatment, and as early as 24 hours after first dose, with no new safety concerns.
