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
BMC Psychiatry October 31, 2021 DOI: 10.1186/s12888-021-03538-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled Double-blind Open-label Peer reviewed |
|---|---|
| Sample size | 202 |
| Population | Adult Japanese patients with treatment-resistant depression |
| Interventions | Esketamine nasal spray Oral antidepressant |
| Dose | 28 mg, 56 mg, 84 mg |
| Duration | 4-week double-blind induction phase, with a 24-week posttreatment phase and optional 4-week open-label second induction |
| Topics | Depression Esketamine |
| Keywords | N-methyl-d-aspartate receptor antagonist Nasal spray Add-on therapy Efficacy |
| Citations | 56 |
| Registration | NCT02918318 |
| Key findings | Esketamine nasal spray added to an oral antidepressant did not significantly reduce depressive symptoms compared to placebo plus antidepressant in Japanese patients with treatment-resistant depression. |
Abstract
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.