4-week course of esketamine nasal spray may still benefit week 1 nonresponders

A 4-week induction course of esketamine nasal spray may still benefit patients with treatment-resistant depression who did not exhibit a response in the first week of treatment.

“With the advent of newer augmentation strategies and rapid-acting antidepressant treatments, expectations for visible results within the first week of treatment have increased,” Ibrahim Turkoz, PhD, of Janssen Research & Development LLC in New Jersey, and colleagues wrote. “Even as many patients may experience clinically meaningful improvement within this timeframe, the time to onset of improvement can be variable for individual patients, as with all antidepressant therapies. Although the literature is not entirely consistent, observable improvement has been reported over time with rapid-acting therapies, suggesting that lack of response within the first week of treatment is not necessarily predictive of future nonresponse.”

The researchers aimed to assess response to esketamine nasal spray (Spravato, Janssen) plus an oral antidepressant at day 28 among patients with major depressive disorder according to DSM-5 criteria and treatment-resistant depression who did not meet response criteria during the first week of treatment. They conducted a pooled post hoc analysis of two phase 3, double-blind, active controlled studies. The studies occurred between August 2015 and February 2018 and compared esketamine nasal spray plus an oral antidepressant (n = 310) with an oral antidepressant plus placebo (n = 208), with data available at day 28 for 518 patients. The researchers defined early treatment response as a 50% or greater decrease in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at day 2 or days 2 and 8. Further, they calculated response rates at day 28 for patients who did not meet early response criteria.

Results showed 17.3% of patients treated with esketamine nasal spray plus an oral antidepressant vs. 9.4% of those treated with an oral antidepressant plus placebo met response criteria starting at day 2 and at all subsequent timepoints, including day 28, at which 58.7% in the esketamine group vs. 45.2% in the placebo group met response criteria. A total of 54.9% of those treated with esketamine nasal spray plus an oral antidepressant vs. 44.3% of the comparison group achieved response at day 28 (P < .01) among day 2 nonresponders, as well as 52.1% vs. 42.4% of day 2 and day 8 nonresponders (P = .01).

Nonresponders at day 2 and at days 2 and 8 had an OR for a response at day 28 of 1.61 (95% CI, 1.09-2.4) with esketamine nasal spray plus oral antidepressant vs. 1.56 (95% CI, 1.04-2.35) with oral antidepressant plus placebo.

“Based on the present findings and provided that the tolerability profile is generally acceptable for individual patients, completion of the full 4-week induction treatment course of esketamine plus an oral antidepressant may be appropriate to optimize treatment effect, even if a full response is not experienced following the first two doses of treatment,” Turkoz and colleagues wrote. “The present analysis provides an important addition to the limited evidence base, suggesting that later response (defined as a 50% improvement from baseline in MADRS total score) may be prevalent among patients with [treatment-resistant depression] receiving treatment with ketamine, or now, esketamine.”