Efficacy and safety of fixed doses of intranasal Esketamine as an add-on therapy to Oral antidepressants in Japanese patients with treatment-resistant depression: a phase 2b randomized clinical study

Nagahide Takahashi, Aya Yamada, Ayako Shiraishi, Hiroko Shimizu, Ryosuke Goto, Yushin Tominaga, Nagahide Takahashi, Aya Yamada, Ayako Shiraishi, Hiroko Shimizu, Ryosuke Goto, Yushin Tominaga

Abstract

Background: Esketamine nasal spray (Spravato) in conjunction with oral antidepressants (ADs) is approved in the European Union, United States, and other markets for treatment-resistant depression (TRD). Efficacy, safety, and tolerability of esketamine nasal spray in Japanese patients with TRD needs to be assessed.

Methods: This Phase 2b, randomized, double-blind (DB), placebo-controlled study was conducted in adult Japanese patients with TRD meeting the Diagnostic and Statistical Manual of Mental Disorders (fifth edition) criteria of major depressive disorder with nonresponse to ≥ 1 but < 5 different ADs in the current episode at screening. Patients were treated with a new oral AD for 6 weeks (prospective lead-in phase); nonresponders were randomized (2:1:1:1) to placebo or esketamine (28-, 56-, or 84-mg) nasal spray along with the continued use of AD for 4 weeks (DB induction phase). Responders (≥50% reduction from baseline in the Montgomery-Asberg Depression Rating Scale [MADRS] total score) from the DB induction phase continued into the 24-week posttreatment phase and patients who relapsed could participate in a 4-week open-label (OL) second induction (flexibly-dosed esketamine). The primary efficacy endpoint, change from baseline in the MADRS total score at Day 28 in the DB induction phase, was based on mixed-effects model using repeated measures pairwise comparisons using a Dunnett adjustment.

Results: Of the 202 patients randomized in the DB induction phase (esketamine [n = 122] or placebo [n = 80]), the MADRS total scores decreased from baseline to Day 28 of the DB induction phase (- 15.2, - 14.5, - 15.1, and - 15.3 for esketamine 28 mg, 56 mg, 84 mg, and placebo groups, respectively), indicating an improvement in depressive symptoms; however, the difference between the esketamine and placebo groups was not statistically significant. The most common treatment-emergent adverse events during the DB induction phase in the combined esketamine group (incidences ranging from 12.3 to 41.0%) were blood pressure increased, dissociation, dizziness, somnolence, nausea, hypoaesthesia, vertigo, and headache; the incidence of each of these events was > 2-fold higher than the corresponding incidence in the placebo group.

Conclusions: Efficacy of esketamine plus oral AD in Japanese TRD patients was not established; further investigation is warranted. All esketamine doses were safe and tolerated.

Trial registration: ClinicalTrials.gov Identifier: NCT02918318 . Registered: 28 September 2016.

Keywords: Add-on therapy; Efficacy; Esketamine; N-methyl-D-aspartate receptor antagonist; Nasal spray; Safety; Treatment-resistant depression.

Conflict of interest statement

The authors report conflicts of interest in this work. AY, AS, HS, RG, and YT are full time employees of Janssen Pharmaceutical K.K., Tokyo, Japan. NT is a contract Study Responsible Physician of Janssen Pharmaceutical K.K., Tokyo, Japan.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Patient Disposition. Notes: In the DB follow-up phase and posttreatment phase, the dose groups are the ones randomized during the DB induction phase. *The patients received only oral AD medication during the DB follow-up phase, posttreatment phase, and OL follow-up phase. Abbreviations: AD = antidepressant; AE = adverse event; COM = completed; DB = double-blind; Esk = esketamine; Flex = flexible; LFU = lost to follow-up; LOE = loss of efficacy; N = number of patients; NC = noncompliance; OL = open-label; OTH = other reason for withdrawal; PLO = placebo; WBP = withdrawal by patient; WDDB = withdrawal from DB induction phase; WDDBFU = withdrawal from DB follow-up phase; WDOL = withdrawal from OL induction phase; WDOLFU = withdrawal from OL follow-up phase; WDPT = withdrawal from posttreatment phase
Fig. 2
Fig. 2
Mean Change in MADRS Total Score Over Time Observed Case MMRM; DB Induction Phase. Abbreviations: DB = double-blind; Esk = esketamine; MADRS = Montgomery-Asberg Depression Rating Scale; MMRM = mixed-model for repeated measures; SE = standard error
Fig. 3
Fig. 3
CGI-S Score Over Time; DB Induction Phase. Abbreviations: CGI-S=Clinical Global Impression-Severity; DB = double-blind; Esk = esketamine

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