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 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 Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1)

2019 ◽  
Vol 22 (10) ◽  
pp. 616-630 ◽  
Author(s):  
Maggie Fedgchin ◽  
Madhukar Trivedi ◽  
Ella J Daly ◽  
Rama Melkote ◽  
Rosanne Lane ◽  
...  
Keyword(s):  
Nasal Spray ◽  
Rating Scale ◽  
Statistical Significance ◽  
Statistical Testing ◽  
Fixed Dose ◽  
P Value ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Double Blind ◽  
Resistant Depression

Abstract Background About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression. Methods This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested. Results Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: –3.2 [–6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was –4.1 [–7.67, –0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache. Conclusions Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression. Trial Registration ClinicalTrials.gov identifier: NCT02417064

scholarly journals The Neurostimulation of the Brain in Depression Trial: Protocol for a Randomized Controlled Trial of Transcranial Direct Current Stimulation in Treatment-Resistant Depression (Preprint)

2020 ◽  
Author(s):  
Raheem Suleman ◽  
Benjamin V Tucker ◽  
Serdar M Dursun ◽  
Michael L Demas
Keyword(s):  
Side Effects ◽  
Adverse Events ◽  
Rating Scale ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
University Of Alberta ◽  
Randomized Controlled ◽  
Resistant Depression ◽  
Double Blinded ◽  
The Brain

BACKGROUND Major depressive disorder (MDD) is the second highest cause of disability worldwide. Standard treatments for MDD include medicine and talk therapy; however, approximately 1 in 5 Canadians fail to respond to these approaches and must consider alternatives. Transcranial direct current stimulation (tDCS) is a safe, noninvasive method that uses electrical stimulation to change the activation pattern of different brain regions. By targeting those regions known to be affected in MDD, tDCS may be useful in ameliorating treatment-resistant depression. OBJECTIVE The objective of the Neurostimulation of the Brain in Depression trial is to compare the effectiveness of active versus sham tDCS in treating patients with ultraresistant MDD. The primary outcome will be the improvement in depressive symptoms, as measured by the change on the Mongtomery-Asberg Depression Rating Scale. Secondary outcomes will include changes in the Quick Inventory of Depressive Symptomatology Scale (subjective assessment), the World Health Organization Disability Assessment Schedule 2.0 (functional assessment), and the Screen for Cognitive Impairment in Psychiatry (cognitive assessment). Adverse events will be captured using the Young Mania Rating Scale; tDCS Adverse Events Questionnaire; Frequency, Intensity, and Burden of Side Effects Rating Scale; and Patient-Rated Inventory of Side Effects Scale. A parallel component of the study will involve assaying for baseline language function and the effect of treatment on language using an exploratory acoustic and semantic corpus analysis on recorded interviews. Participant accuracy and response latency on an auditory lexical decision task will also be evaluated. METHODS We will recruit inpatients and outpatients in the city of Edmonton, Alberta, and will deliver the study interventions at the Grey Nuns and University of Alberta Hospitals. Written informed consent will be obtained from all participants before enrollment. Eligible participants will be randomly assigned, in a double-blinded fashion, to receive active or sham tDCS, and they will continue receiving their usual pharmacotherapy and psychotherapy throughout the trial. In both groups, participants will receive 30 weekday stimulation sessions, each session being 30 minutes in length, with the anode over the left dorsolateral prefrontal cortex and the cathode over the right. Participants in the active group will be stimulated at 2 mA throughout, whereas the sham group will receive only a brief period of stimulation to mimic skin sensations felt in the active group. Measurements will be conducted at regular points throughout the trial and 30 days after trial completion. RESULTS The trial has been approved by the University of Alberta Research Ethics Board and is scheduled to commence in June 2021. The target sample size is 60 participants. CONCLUSIONS This is a protocol for a multicenter, double-blinded, randomized controlled superiority trial comparing active versus sham tDCS in patients with treatment-resistant MDD. CLINICALTRIAL ClinicalTrials.gov NCT04159012; http://clinicaltrials.gov/ct2/show/NCT04159012. INTERNATIONAL REGISTERED REPORT PRR1-10.2196/22805

scholarly journals Prevalence and Impact of Treatment-Resistant Depression in Latin America: a Prospective, Observational Study

2021 ◽  
Author(s):  
Bernardo Soares ◽  
Gabriela Kanevsky ◽  
Chei Tung Teng ◽  
Rodrigo Pérez-Esparza ◽  
Gerardo Garcia Bonetto ◽  
...  
Keyword(s):  
Latin America ◽  
Observational Study ◽  
Latin American ◽  
Prospective Observational Study ◽  
Rating Scale ◽  
Fisher Exact Test ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Work Impairment ◽  
Resistant Depression

AbstractApproximately one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD). The TRAL study will evaluate the prevalence and impact of TRD among patients with MDD in four Latin American countries. In this multicenter, prospective, observational study, patients with MDD were recruited from 33 reference sites in Mexico, Colombia, Brazil, and Argentina. Patients were assessed for TRD, defined as failure to respond to ≥ 2 antidepressant medications of adequate dose and duration. Demographics, previous/current treatments, depressive symptoms, functioning, healthcare resource utilization, and work impairment were also collected and evaluated using descriptive statistics, chi-square test, Fisher exact test, t-test for independent samples, or the Mann–Whitney nonparametric test, as appropriate. 1475 patients with MDD were included in the analysis (mean age, 45.6 years; 78% women); 89% were receiving relevant psychiatric treatment. 429 patients met criteria for TRD, and a numerically higher proportion of patients with TRD was present in public versus private sites of care (31% vs 27%). The mean Montgomery-Asberg Depression Rating Scale score was 25.0 among all MDD patients and was significantly higher for patients with TRD versus non-TRD (29.4 vs 23.3; P < 0.0001). Patients with TRD, versus those with non-TRD, were significantly more likely to be older, have a longer disease duration, have more comorbidities, be symptomatic, have a higher median number of psychiatric consultations, and report greater work impairment. Patients with TRD have a disproportionate burden of disease compared to those with non-TRD. Appropriate treatment for TRD is a substantial unmet need in Latin America. https://www.ClinicalTrials.gov identifier NCT03207282, 07/02/2017.

scholarly journals Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial

2018 ◽  
Vol 49 (4) ◽  
pp. 655-663 ◽  
Author(s):  
Fernanda Palhano-Fontes ◽  
Dayanna Barreto ◽  
Heloisa Onias ◽  
Katia C. Andrade ◽  
Morgana M. Novaes ◽  
...  
Keyword(s):  
Rating Scale ◽  
Remission Rate ◽  
Controlled Trial ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Open Label ◽  
Double Blind ◽  
Therapeutic Value ◽  
Antidepressant Effects ◽  
Resistant Depression

AbstractBackgroundRecent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression.MethodsTo test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing.ResultsWe observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 (p= 0.04), and at D7 (p< 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen'sd= 0.84; D2: Cohen'sd= 0.84; D7: Cohen'sd= 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64%v.27%;p= 0.04). Remission rate showed a trend toward significance at D7 (36%v.7%,p= 0.054).ConclusionsTo our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. This study is registered athttp://clinicaltrials.gov(NCT02914769).

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