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Psychiatry Research Review

Sanjay Gupta, MD
Released: November 18, 2021

Esketamine Treatment Response in Conjunction With an Oral Antidepressant in Patients With Treatment-Resistant Depression Without Early Response

Turkoz T, et al. J Clin Psychiatry. 2021;82:20m13800.

Background
This study evaluated the response to esketamine nasal spray (ESK) plus oral antidepressant in patients with major depressive disorder (DSM-5) and treatment-resistant depression that had not met criteria for response within the first week of treatment.

Methods
The study was a retrospective, pooled post hoc analysis of 518 patients enrolled in 2 double-blind, active-controlled phase III trials that compared ESK plus antidepressant with antidepressant plus placebo. Treatment response was defined as a ≥50% decrease in Montgomery-Åsberg Depression Rating Scale total score and was evaluated at Days 2, 8, and 28. Patients who met response criteria on Day 2 or on Days 2 and 8 were considered to have an early response. Response rates on Day 28 were determined only for patients who did not have an early response to ESK plus antidepressant.

Results
From Day 2 through all subsequent time points, treatment with ESK plus antidepressant improved patient response scores more than antidepressant plus placebo (17.3% vs 9.4%). Among patients who did not achieve a response on Day 2, 54.9% of the patients receiving ESK plus antidepressant achieved a response on Day 28, compared with 44.3% of patients receiving antidepressant plus placebo. Among patients who did not achieve a response on either Day 2 or Day 8, 52.1% of the patients receiving ESK plus antidepressant and 42.4% of patients receiving antidepressant plus placebo achieved a response by Day 28. In both groups of nonresponders, the odds ratio for a response on Day 28 was 1.61 for treatment with ESK plus antidepressant vs 1.56 for treatment with antidepressant plus placebo.

Conclusions
Patients with treatment-resistant depression who do not achieve an early response to esketamine nasal spray can still achieve responses at later time points if the full 4-week induction course is continued.

Clinical Commentary
Intranasal esketamine was approved by the FDA in March 2019 as a rapidly acting therapy for treatment-resistant depression. Esketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist. There have always been questions about nonresponders, just as with any new treatment that is introduced. The patients included in the 2 randomized trials were selected with strict criteria that may not reflect the diversity of patients in real-world clinical settings. This was also a retrospective study, so it has the limitations of that design.

Clinical Insights

  • Patients who do not have a response to esketamine nasal spray on Day 2 or Day 8 can have a response on Day 28, which was significantly higher than in the placebo group.
  • Healthcare professionals should continue esketamine in patients who do not respond by Day 8, as the response can occur by Day 28.
  • Female sex may be a predictor of response on Day 28 if no response has occurred by Day 2 or Day 8.

Summary
In my professional opinion as a healthcare professional who prescribes esketamine, healthcare professionals should continue the 4-week induction treatment with esketamine and an oral antidepressant even in patients who do not have a response after the first week. If there is no response after the first week of starting 56 mg, increase to 84 mg and continue for 4 weeks.

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