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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.

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.

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.

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.

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.

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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