Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data

Michel Nijs, Ewa Wajs, Leah Aluisio, Ibrahim Turkoz, Ella Daly, Adam Janik, Stephane Borentain, Jaskaran B Singh, Allitia DiBernardo, Frank Wiegand, Michel Nijs, Ewa Wajs, Leah Aluisio, Ibrahim Turkoz, Ella Daly, Adam Janik, Stephane Borentain, Jaskaran B Singh, Allitia DiBernardo, Frank Wiegand

Abstract

Background: Esketamine nasal spray was recently approved for treatment-resistant depression. The current analysis evaluated the impact of symptom-based treatment frequency changes during esketamine treatment on clinical outcomes.

Methods: This is a post-hoc analysis of an open-label, long-term (up to 1 year) study of esketamine in patients with treatment-resistant depression (SUSTAIN 2). During a 4-week induction phase, 778 patients self-administered esketamine twice weekly plus a new oral antidepressant daily. In responders (≥50% reduction in Montgomery-Åsberg Depression Rating Scale total score from baseline), esketamine treatment frequency was thereafter decreased during an optimization/maintenance phase to weekly for 4 weeks and then adjusted to the lowest frequency (weekly or every other week) that maintained remission (Montgomery-Åsberg Depression Rating Scale ≤ 12) based on a study-defined algorithm. The relationship between treatment frequency and symptom response, based on clinically meaningful change in Clinical Global Impression-Severity score, was subsequently evaluated 4 weeks after treatment frequency adjustments in the optimization/maintenance phase.

Results: Among 580 responders treated with weekly esketamine for the first 4 weeks in the optimization/maintenance phase (per protocol), 26% continued to improve, 50% maintained clinical benefit, and 24% worsened. Thereafter, when treatment frequency could be reduced from weekly to every other week, 19% further improved, 49% maintained benefit, and 32% worsened. For patients no longer in remission after treatment frequency reduction, an increase (every other week to weekly) resulted in 47% improved, 43% remained unchanged, and 10% worsened.

Conclusions: These findings support individualization of esketamine nasal spray treatment frequency to optimize treatment response in real-world clinical practice.

Trial registration: ClinicalTrials.gov identifier: NCT02497287.

Keywords: Esketamine; dosing; s-ketamine; treatment-resistant depression.

© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.

Figures

Figure 1.
Figure 1.
Study design: esketamine nasal spray treatment frequency. Abbreviations: AD, antidepressant; EOW, every other week; MADRS, Montgomery-Åsberg Depression Rating Scale. Note: Downward arrow indicates potential change in treatment frequency.
Figure 2.
Figure 2.
Patient flow based on frequency of treatment with esketamine nasal spray. The bars represent the number of patients: treatment frequency, light blue bar, twice weekly; orange bars, once weekly (QW); blue bars, every other week (EOW); dark green, study completers; light green, patients who had discontinued by study end. During the 4-week induction period, study drug was administered twice weekly.
Figure 3.
Figure 3.
Change in Clinical Global Impression–Severity (CGI-S) score 4 weeks after change in treatment frequency (pooled and by switch analysis). (a) Change in CGI-S after reducing the treatment frequency to 4 weeks of weekly treatment. (b) Change in CGI-S after reducing the treatment frequency to 4 weeks of every-other-week (EOW) treatment (pooled analysis). (c) Change in CGI-S after increasing the treatment frequency to 4 weeks of weekly treatment (pooled analysis). Note: Denominator for the pooled analysis is the number of times patients changed treatment frequency.
Figure 4.
Figure 4.
Change in Patient Health Questionnaire–9 Item Depression Module (PHQ-9) score 4 weeks after change in treatment frequency (pooled analysis). (a) Change in PHQ-9 after reducing the treatment frequency to 4 weeks of weekly treatment. (b) Change in PHQ-9 after reducing the treatment frequency to 4 weeks of every-other-week (EOW) treatment. (c) Change in PHQ-9 after increasing the treatment frequency to 4 weeks of weekly treatment. Note: Denominator is the number of times patients changed treatment frequency.

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