scholarly journals 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

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Nagahide Takahashi ◽  
Aya Yamada ◽  
Ayako Shiraishi ◽  
Hiroko Shimizu ◽  
Ryosuke Goto ◽  
...  
Keyword(s):  
Nasal Spray ◽  
Japanese Patients ◽  
Controlled Study ◽  
Induction Phase ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Madrs Total Score ◽  
Link Type ◽  
Randomized Clinical Study ◽  
Resistant Depression

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.

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

2020 ◽  
Vol 23 (7) ◽  
pp. 426-433 ◽  
Author(s):  
Michel Nijs ◽  
Ewa Wajs ◽  
Leah Aluisio ◽  
Ibrahim Turkoz ◽  
Ella Daly ◽  
...  
Keyword(s):  
Nasal Spray ◽  
Rating Scale ◽  
Maintenance Phase ◽  
Induction Phase ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Open Label ◽  
Treatment Frequency ◽  
Resistant Depression ◽  
The Impact

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

scholarly journals Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: findings from short-term randomized, controlled trials

2022 ◽  
Author(s):  
Robyn R. Jones ◽  
Marlene P. Freeman ◽  
Susan G. Kornstein ◽  
Kimberly Cooper ◽  
Ella J. Daly ◽  
...  
Keyword(s):  
Nasal Spray ◽  
Repeated Measures ◽  
Rating Scale ◽  
Menopausal Status ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Madrs Total Score ◽  
Randomized Controlled ◽  
Randomized Controlled Studies ◽  
Resistant Depression

AbstractThe objective of this analysis was to determine if there are sex differences with esketamine for treatment-resistant depression (TRD). Post hoc analyses of three randomized, controlled studies of esketamine in patients with TRD (TRANSFORM-1, TRANSFORM-2 [18–64 years], TRANSFORM-3 [≥ 65 years]) were performed. In each 4-week study, adults with TRD were randomized to esketamine or placebo nasal spray, each with a newly initiated oral antidepressant. Change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score was assessed by sex in pooled data from TRANSFORM-1/TRANSFORM-2 and separately in data from TRANSFORM-3 using a mixed-effects model for repeated measures. Use of hormonal therapy was assessed in all women, and menopausal status was assessed in women in TRANSFORM-1/TRANSFORM-2. Altogether, 702 adults (464 women) received ≥ 1 dose of intranasal study drug and antidepressant. Mean MADRS total score (SD) decreased from baseline to day 28, more so among patients treated with esketamine/antidepressant vs. antidepressant/placebo in both women and men: TRANSFORM-1/TRANSFORM-2 women—esketamine/antidepressant -20.3 (13.19) vs. antidepressant/placebo -15.8 (14.67), men—esketamine/antidepressant -18.3 (14.08) vs. antidepressant/placebo -16.0 (14.30); TRANSFORM-3 women—esketamine/antidepressant -9.9 (13.34) vs. antidepressant/placebo -6.9 (9.65), men—esketamine/antidepressant -10.3 (11.96) vs. antidepressant/placebo -5.5 (7.64). There was no significant sex effect or treatment-by-sex interaction (p > 0.35). The most common adverse events in esketamine-treated patients were nausea, dissociation, dizziness, and vertigo, each reported at a rate higher in women than men. The analyses support antidepressant efficacy and overall safety of esketamine nasal spray are similar between women and men with TRD. The TRANSFORM studies are registered at clinicaltrials.gov (identifiers: NCT02417064 (first posted 15 April 2015; last updated 4 May 2020), NCT02418585 (first posted 16 April 2015; last updated 2 June 2020), and NCT02422186 (first posted 21 April 2015; last updated 29 September 2021)).

scholarly journals 142 Withdrawal Symptom Assessment in an Esketamine Safety Study in Patients with Treatment-resistant Depression

CNS Spectrums ◽  
2020 ◽  
Vol 25 (2) ◽  
pp. 290-290
Author(s):  
Leah Aluisio ◽  
Lynn Yieh ◽  
Ewa Wajs ◽  
Allitia DiBernardo ◽  
Andrew Krystal ◽  
...  
Keyword(s):  
Nasal Spray ◽  
Withdrawal Symptoms ◽  
Phase Iii ◽  
Complete Analysis ◽  
Induction Phase ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Open Label ◽  
Receptor Modulation ◽  
Resistant Depression

Abstract:Background:SUSTAIN-2 (NCT02497287) was an open-label, phase III trial evaluating the safety of esketamine (ESK) nasal spray plus a newly initiated oral antidepressant (AD) for up to 1 year in adults with treatment-resistant depression (TRD). ESK is a schedule III drug that acts via glutamate receptor modulation. ESK is rapidly cleared from the plasma, and with intermittent dosing there is no accumulation. Thus, no withdrawal syndrome is expected. The current analysis assessed potential withdrawal symptoms in patients who discontinued ESK after long-term, intermittent use. In the absence of a glutamatergic-specific withdrawal scale, the Physicians Withdrawal Checklist1 (PWC-20) was used. The PWC-20 was designed to assess new or worsening benzodiazepine-like discontinuation symptoms after stopping non-SSRI anxiolytics.Methods:ESK nasal spray was administered two times per week during a 4-week induction phase (IND). Responders entered the optimization/maintenance phase (O/M) where ESK nasal spray was dosed either weekly or every two weeks for up to 48 weeks. Patients entered a 4-week follow up period (F/U) after discontinuation from either phase, during which continuation of the AD was recommended. PWC-20 assessments were conducted at the last ESK dosing (endpoint of IND or O/M) and at weeks 1, 2 and 4 of F/U. Symptoms were rated using a 0-3-point scale (Not present = 0, Mild = 1, Moderate = 2, Severe = 3). To account for worsening of underlying depression, subset calculations were performed for depressive symptoms (PWC-DS: loss of appetite; anxiety or nervousness; irritability; dysphoric mood or depression; insomnia; fatigue, lethargy or lack of energy; restlessness or agitation; headaches; muscle aches or stiffness; weakness; difficulty concentrating or remembering; depersonalization-derealization) and withdrawal symptoms (PWC-WS: nausea and/or vomiting; diarrhea; poor coordination; diaphoresis; tremor or tremulousness; dizziness or light-headedness; increased acuity of sound, smell, or touch; paresthesias).Results:Data on 357 patients entering F/U were included in the analysis (91 completed treatment during the IND phase and 141 were treated during O/M). The mean (SD) PWC-20 total scores (range 0-60) at treatment endpoint, Week 1, 2 and 4 were 7.2 (6.8), 7.5(7.0), 7.4 (7.1) and 7.2 (6.9), respectively. At these same assessment times, mean PWC-WS scores (range 0-24) were 0.9 (1.7), 1.0 (1.7), 1.0 (1.8), and 0.9 (1.8). Mean PWC-DS scores (range 0-36) were 6.3 (5.6), 6.5 (5.7), 6.5 (5.8), and 6.3 (5.7), respectively. Complete analysis of data from the entire SUSTAIN-2 dataset will be presented.Conclusions:No indication of drug-specific withdrawal symptoms was seen after stopping up to 1-year of intermittent treatment with ESK nasal spray for TRD.Funding Acknowledgements:Janssen Research and Development

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