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

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.

Different symptomatic improvement pattern revealed by factor analysis between placebo response and response to Esketamine in treatment resistant depression

“…placebo in patients with treatment‐resistant depression. Details of the study have previously been published 14 . The primary efficacy endpoint was change from baseline in the MADRS total score to the end of 4‐week double blind induction phase.…”

“…During the double‐blind induction phase, patients were randomized to placebo or fixed dose ESK nasal spray (28 mg, 56 mg, or 84 mg) (2:1:1:1; hereafter ESK 28, ESK56, or ESK84, respectively) in addition to oral antidepressant therapy, which continued unchanged from the prospective lead‐in phase. Regarding the late treatment phase and the follow‐up phase (phase 4 and 5), details were described in a previous report 14 . The study protocol and all amendments were approved by the institutional review board (IRB) at each study site (representative of IRB: National Center Hospital, National Center of Neurology and Psychiatry).…”

“…Responders were defined as those who achieved ≥ 50% reduction from baseline in the MADRS total score at the end of DB induction phase (28 days after DB induction), and others were defined as non‐responders 14 . Therefore, the definition of non‐responders at the end of the DB induction phase was different from the definition of non‐responders in the lead‐in phase 14 . In the active drug arms, we treated as one group regardless of active drug doses, because we could not find a relationship between dose and efficacy 14 .…”

Suizidpräventive Effekte von Ketamin und Esketamin

“…Unter Placebo gab es keine Suizide, aber ein Vergleich mit Placebo ist problematisch, denn alle Suizide passierten außerhalb von placebokontrollierten Studienphasen. Nach der Zulassung erschien eine weitere Phase-IIb-Studie von Janssen, in der keine signifikanten Unterschiede zwischen Esketamin und Placebo für Depressivität oder Suizidgedanken gefunden wurden [37]. In den beiden Phase-III-RKS (ASPIRE I + II) [38,39] war die Clinical Global Impression Scale of Severity of Suicidality (CGI-SS-r) das Hauptergebnis für Suizidalität.…”

Time will tell. Reply to “Comments to pharmacological and behavioral divergence of ketamine enantiomers by Jordi Bonaventura et al.” by Chen et al.

“…Although (R)-ketamine seems promising, results from the only study performed to date are inconclusive[ 20 ] and consequently, it is unknown whether (R)-ketamine doses that produce antidepressant effects will also produce dissociation. Importantly, even though FDA-approved, the efficacy of intranasal (S)-ketamine itself requires more long-term systematic studies[ 21 , 22 ].…”