SAN FRANCISCO — Patients with treatment-resistant depression saw clinically meaningful and statistically significant improvement in depressive symptoms at days 28 after being switched to esketamine nasal spray plus a newly initiated oral antidepressant, according to phase 3 data released here and simultaneously published in American Journal of Psychiatry.
“Since depression is the world’s greatest public health problem now and the greatest cause of disability in the United States, having novel treatments for patients who don’t respond to standard treatments has been a very exciting and important development,” Michael Thase, MD, professor of psychiatry with Penn Medicine in the University of Pennsylvania Health System, said during a press briefing.
The investigators reported the results from a phase 3, double-blind, active-controlled study examining 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.
Adults with treatment-resistant depression from 39 outpatient referral centers were randomly assigned to treatment with esketamine nasal spray (56 mg or 84 mg twice a week) plus an antidepressant or antidepressant plus placebo nasal spray. Researchers measured the change from baseline to day 28 using the Montgomery-Åsberg Depression Rating Scale (MADRS) score.
Of 435 patients screened, 197 completed the 28-day treatment phase. The investigators found that patients receiving esketamine plus antidepressant had a significantly greater change in MADRS score than those receiving antidepressant plus placebo at day 28 (difference of least square means = 24; 95% CI, 27.31-20.64).
In addition, they observed clinically meaningful improvement in the esketamine plus antidepressant arm at earlier time points. Response was rapid in onset and rose over time during repeated dosing; least square mean between-group differences favored esketamine at 24 hours after dosing (23.3; 95% CI, 25.75-20.85), at day 8 (22.9; 95% CI, 25.17-20.59) at day 15 (22; 95% CI, 24.78-0.82) and at day 22 (23.8; 95% CI, 26.87-20.65).
Post hoc analyses also revealed that the proportion of patients who were responders and in remission generally grew over time during the double-blind treatment phase, with 70 of 101 patients (69.3%) in the esketamine plus antidepressant arm compared with 52 of 100 patients (52%) in the antidepressant plus placebo arm being responders at day 28 (OR = 2.4; 95% CI, 1.3-4.54).
Esketamine nasal spray was also well-tolerated and appeared safe in the sample. Thase and colleagues reported that the five most common adverse events — nausea, vertigo, dysgeusia, dissociation and dizziness — occurred more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm, with 7% and 0.9% of patients in the respective groups discontinuing the drug due to an adverse event. In the esketamine plus antidepressant group, adverse events generally appeared shortly after dosing and resolved by 1.5 hours after dosing, according to the study.
“This is the strongest effect that has been observed in the last 20 years in controlled, double-blind studies,” Thase said.
However, many questions still remain about the use of intranasal esketamine and careful consideration should be paid in applying it into clinical practice, Alan F. Schatzberg, MD, from University of Stanford School of Medicine, wrote in a related commentary.
“Do we have clear evidence of efficacy? Maybe. How strong is the efficacy? Apparently mild. Do we have a real sense of how long and how often to prescribe it? It’s not entirely clear,” Schatzberg wrote. “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.” – by Savannah Demko
Disclosures: Thase reports numerous ties to inductry. Please see the study for his and all other authors’ relevant financial disclosures. Schatzberg reports numerous relevant financial disclosures; please see the commentary.