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

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Of the 202 patients randomized in the DB induction phase (esketamine [<jats:italic>n</jats:italic> = 122] or placebo [<jats:italic>n</jats:italic> = 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.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Efficacy of esketamine plus oral AD in Japanese TRD patients was not established; further investigation is warranted. All esketamine doses were safe and tolerated.</jats:p> </jats:sec><jats:sec> <jats:title>Trial registration</jats:title> <jats:p><jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://clinicaltrials.gov">ClinicalTrials.gov</jats:ext-link> Identifier: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT02918318?term=02918318&draw=2&rank=1">NCT02918318</jats:ext-link>. Registered: 28 September 2016.</jats:p> </jats:sec>