Esketamine Nasal Spray Research Articles

CO151 Estimating the Benefit of Esketamine Nasal Spray Versus Real-World Treatment on Patient-Reported Functional Remission: Results From the Iceberg Study

Treatment resistant depression (TRD) affects 10–30% of patients with major depressive disorder; most patients do not respond to real-world treatments (RWT).1 Esketamine nasal spray (NS), in combination with a selective serotonin or serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI), was recently approved for treatment of TRD. Esketamine NS has demonstrated significant benefit on response and remission versus RWT strategies;2 benefit on daily function remains to be established.

Safety and effectiveness of intranasal esketamine for treatment-resistant depression: a real-world retrospective study.

Aim: There is limited real-world evidence for patients with treatment-resistant depression (TRD) receiving esketamine nasal spray. Methods: This retrospective cohort study used data collected from a psychiatric clinic's EHR system. Results: A total of 171 TRD patients received esketamine July 2019-June 2021. This predominantly female, white population had several mental health comorbidities and high exposure to psychiatric medications. We observed significant reductions (p<0.001) in average PHQ-9 and GAD-7 scores from baseline (PHQ-9: mean: 16.7; SD: 5.8; GAD-7: mean: 12.0; SD: 5.8) to last available treatment (PHQ-9: mean: 12.0; SD: 6.4; GAD-7: mean: 8.7; SD: 5.6). There were no reports of serious adverse events. Conclusion: This study found a significant disease burden for patients with TRD. Esketamine appears to be well tolerated and effective in improving depression and anxiety.

Intranasal esketamine effectively treats treatment-resistant depression in adults regardless of baseline irritability

ObjectiveTo evaluate the impact of baseline irritability on clinical outcomes in adults with treatment-resistant depression (TRD) treated with fixed or flexible doses of esketamine nasal spray plus a newly initiated oral antidepressant (ESK+AD) and to explore whether treatment with ESK affects irritability symptoms over time. MethodsThis was a post hoc analysis of pooled data from two 4-week, double-blind, phase 3 studies: TRANSFORM-1 (NCT02417064) and TRANSFORM-2 (NCT02418585). Adults with TRD (n = 560) were randomly assigned to ESK+AD or placebo nasal spray plus oral antidepressant (AD+PBO). Irritability was assessed with Item 6 of the 7-item Generalized Anxiety Disorder scale at screening and baseline. Changes in depression severity (Montgomery-Åsberg Depression Rating Scale [MADRS] total score) were evaluated by analysis of covariance (ANCOVA) models. Rates of MADRS response (≥50 % decrease from baseline total score) and remission (total score ≤ 12) were examined using multiple logistic regression models. ResultsOf 560 participants with TRD, 52.9 %, 23.2 %, and 23.9 % had high, low, and varying levels of irritability, respectively. No significant interaction between baseline irritability and treatment group was observed for change in MADRS total score, treatment response, or remission at day 28; numerically greater improvement was observed on all outcomes with ESK+AD versus AD+PBO at day 28 regardless of baseline irritability level. Percentages of patients reporting adverse events were similar across the three baseline irritability groups. LimitationsTRANSFORM-1 and TRANSFORM-2 were not designed to prospectively evaluate predetermined irritability outcomes. ConclusionsThese post hoc results support efficacy of ESK+AD in patients with TRD, regardless of baseline irritability. Trial registrationClinicalTrials.gov identifiers: NCT02417064 (TRANSFORM-1), NCT02418585 (TRANSFORM-2).

Characteristics of Real-world Commercially Insured Patients With Treatment-resistant Depression Initiated on Esketamine Nasal Spray or Conventional Therapies in the United States

This study aimed to characterize patients with treatment-resistant depression (TRD) initiating esketamine or conventional therapies. Adults with major depressive disorder (MDD) were selected from the IBM MarketScan Databases. A claims-based algorithm identified patients with evidence of TRD, defined as initiation of a new antidepressant therapy after 2 different antidepressant trials of adequate dose and duration during the most recent major depressive episode. Patients receiving treatment on/after March 5, 2019 (esketamine approval date for TRD), were classified to the esketamine cohort if they newly initiated esketamine (index date) or to the TRD conventional therapies cohorts if they newly initiated electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or pharmacologic therapies (index date was the therapy initiation date, prioritizing ECT, then TMS, then pharmacologic antidepressant therapies). Patient characteristics in the 6 months before therapy initiation were described. The esketamine cohort included 246 patients (mean age, 46.5 years; 63.0% female), and the TRD conventional therapies cohorts included 104,164 patients (mean age, 46.9 years; 74.8% female; 0.4% initiated ECT, 1.2% initiated TMS). During the 6 months preindex, in the esketamine and TRD conventional therapies cohorts, 77.6% and 41.4% received psychotherapy and 82.9% and 34.2% had a psychiatrist visit, respectively. Most patients had outpatient care for MDD in the esketamine (91.9%) and TRD conventional therapies (63.6%) cohorts; 57.3% and 21.0% received care at specialized mental health care settings. MDD was classified as "severe" among 81.3% and 35.1% of patients in the esketamine and TRD conventional therapies cohorts . Preindex mental health-related (MHR) inpatient admissions and emergency department visits were identified in 12.2% and 16.3% of the esketamine cohort and in 8.2% and 10.3% of the TRD conventional therapies cohort. Before therapy initiation, 34.6% and 17.6% of the esketamine and TRD conventional therapies cohorts received ≥3 unique antidepressants. Suicidal ideation or behavior was observed in 8.5% and 3.6% of the esketamine and TRD conventional therapies cohorts pretherapy initiation. Mean monthly all-cause health care costs in the esketamine cohort were $2532 (58.2% MHR); in the TRD conventional therapies cohorts, costs were $1873 (32.4% MHR). Among patients with TRD, those initiating esketamine relative to conventional therapies displayed higher MDD severity, used more MHR inpatient/emergency department services and antidepressant treatments, and incurred higher health care costs 6 months pretherapy initiation. These findings suggest potential benefits of identifying and treating patients with TRD earlier with more effective treatments and should inform payers in consideration of esketamine coverage.

Real-world experience of esketamine use to manage treatment-resistant depression: A multicentric study on safety and effectiveness (REAL-ESK study)

BackgroundTreatment-resistant Depression (TRD) represents a widespread disorder with significant direct and indirect healthcare costs. esketamine, the S-enantiomer of ketamine, has been recently approved for TRD, but real-world studies are needed to prove its efficacy in naturalistic settings. ObjectivesEvaluate the effectiveness and safety of esketamine nasal spray in a clinical sample of patients with TRD from several Italian mental health services. MethodsREAL-ESK study is an observational, retrospective and multicentric study comprising a total of 116 TRD patients treated with esketamine nasal spray. Anamnestic data and psychometric assessment (MADRS, HAMD-21, HAM-A) were collected from medical records at baseline (T0), one month (T1) and three month (T2) follow-ups. ResultsA significant reduction of depressive symptoms was found at T1 and T2 compared to T0. A dramatic increase in clinical response (64.2 %) and remission rates (40.6 %) was detected at T2 compared to T1. No unexpected safety concerns were observed, side effects rates were comparable to those reported in RCTs. No differences in efficacy have been found among patients with and without psychiatric comorbidities. LimitationsThe open design of the study and the absence of a placebo or active comparator group are limitations. The study lacks an inter-rater reliability evaluation of the assessments among the different centres. Side effects evaluation did not involve any specific scale. ConclusionsOur findings support the safety and tolerability of esketamine in a real-world TRD sample. The later response and the non-inferiority in effectiveness in patients with comorbidities represent novel and interesting findings.

Cost-effectiveness of esketamine nasal spray compared to intravenous ketamine for patients with treatment-resistant depression in the US utilizing clinical trial efficacy and real-world effectiveness estimates

ObjectiveThe aim of this study was to estimate the cost-effectiveness of esketamine nasal spray relative to intravenous ketamine for patients with treatment-resistant depression (TRD) in the US. MethodsWe used a Markov model with a 1-month cycle length, and we estimated quality-adjusted life years (QALYs), costs (2020 USD), and incremental cost-effectiveness ratios (ICER) of esketamine relative to ketamine over a 3-year time horizon, from both the healthcare sector and patient perspectives. We ran the model using efficacy estimates from both clinical trial and real-world effectiveness (RWE) data. One-way and probabilistic sensitivity analyses (PSAs) were performed to evaluate the robustness of findings. ResultsOver a 3-year time horizon, the use of esketamine yielded 1.98 QALYs (RWE/clinical trial efficacy), and the use of ketamine yielded 2.03 QALYs (clinical trial efficacy) or 1.99 QALYs (RWE). Esketamine was dominated by ketamine using the healthcare perspective. ICERs were above $150,000/QALY threshold with the patient perspective. Under the healthcare perspective, PSA showed there are no scenarios where esketamine was cost-effective compared to ketamine. With the patient's perspective, the probability that esketamine was cost-effective compared to ketamine was 0.0055 (clinical trial efficacy) and 0.35 (RWE). LimitationsThe data utilized for efficacy have limitations. The time horizon may fail to capture longer-term costs and benefits. ConclusionsIn this decision analytic model evaluating esketamine versus ketamine for TRD, we found esketamine unlikely to be cost-effective under a healthcare sector perspective. Under a patient perspective, esketamine had similar effectiveness and was less costly than ketamine due to insurance coverage.

Longitudinal Course of Adverse Events With Esketamine Nasal Spray: A Post Hoc Analysis of Pooled Data From Phase 3 Trials in Patients With Treatment-Resistant Depression.

Objective: To describe the tolerability of esketamine nasal spray based on the adverse event profile observed during treatment sessions occurring early and later over the course of treatment.Methods: In 2 long-term, phase 3 studies (NCT02493868, October 1, 2015-February 16, 2018; NCT02497287, September 30, 2015-October 28, 2017), patients with treatment-resistant major depressive disorder (per DSM-5) and nonresponse to ≥ 2 oral antidepressants received esketamine nasal spray (56 or 84 mg) twice weekly during a 4-week induction phase, weekly for weeks 5-8, and weekly or every 2 weeks thereafter as maintenance treatment, in conjunction with a new oral antidepressant. A post hoc analysis using descriptive statistics evaluated occurrence (incidence, frequency, severity) and recurrence (incidence and severity) of events of specific interest.Results: In patients treated with esketamine nasal spray plus a newly initiated oral antidepressant (n = 928), spontaneously reported adverse events of dizziness, nausea, sedation, vertigo, and increased blood pressure were more likely to recur after the first week of treatment if they occurred more frequently (twice > once > none) during the first week. The same pattern was observed when these events were assessed by structured instruments. Incidences of dizziness, dissociation, increased blood pressure, nausea, vertigo, and sedation were highest in week 1 of treatment (20.6%, 16.7%, 4.3%, 14.0%, 12.1%, and 3.8%, respectively) and decreased thereafter. Initial occurrences and subsequent recurrences of events were mostly mild or moderate in severity.Conclusions: Adverse events during treatment with esketamine nasal spray plus an oral antidepressant generally become less frequent with ongoing treatment, and the majority are mild or moderate in severity.Trial Registration: ClinicalTrials.gov identifiers: NCT02493868; NCT02497287.

Treatment response to esketamine nasal spray in patients with major depressive disorder and acute suicidal ideation or behavior without evidence of early response: a pooled post hoc analysis of ASPIRE.

To assess the likelihood of attaining response/remission of depressive symptoms with esketamine nasal spray (ESK) plus standard of care (SoC) vs placebo nasal spray (PBO) plus SoC at 4 weeks in patients with major depressive disorder and active suicidal ideation with intent (MDSI) without early response. A post hoc analysis of pooled data from ASPIRE I and ASPIRE II evaluated ESK plus SoC vs PBO plus SoC in adults with MDSI without response (≥50% improvement from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] score) at 24 hours after the first dose or at week 1 after the first two doses (ie, 24-hour and week 1 nonresponders). Response and remission (MADRS score ≤ 12) rates were assessed on day 25. The analysis included 362 patients (n = 182, ESK plus SoC; n = 180, PBO plus SoC). Among 24-hour nonresponders, more patients receiving ESK plus SoC vs PBO plus SoC achieved response (63.9% vs 48.0%, P = .010) and remission (35.1% vs 24.4%, P = .074) at day 25. Odds of response/remission were higher with ESK plus SoC vs PBO plus SoC (response: 1.89, 95% CI, 1.17-3.05; remission: 1.48, 95% CI, 0.93-2.35). Similar findings were observed among week 1 nonresponders for response (48.4% vs 34.5%, P = .075), remission (25.0% vs 13.1%, P = .060), and odds of response/remission (response: 2.03, 95% CI, 1.22-3.40; remission: 1.63, 95% CI, 1.01-2.62). Patients with MDSI not responding within the first week of treatment with ESK plus SoC may still benefit from a full 4-week treatment course.

New antidepressants: New day or false dawn?

The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-ketamine causes rapid onset and sustained antidepressant actions in treatment-resistant patients with major depressive disorder (MDD) and other psychiatric disorders, such as bipolar disorder and post-traumatic stress disorder. (R,S)-ketamine is a racemic mixture consisting of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine), with (S)-enantiomer having greater affinity for the NMDAR. In 2019, an esketamine nasal spray by Johnson & Johnson was approved in the USA and Europe for treatment-resistant depression. In contrast, an increasing number of preclinical studies show that arketamine has greater potency and longer-lasting antidepressant-like effects than esketamine in rodents, despite the lower binding affinity of arketamine for the NMDAR. Importantly, the side effects, i.e., psychotomimetic and dissociative effects and abuse liability, of arketamine are less than those of (R,S)-ketamine and esketamine in animals and humans. An open-label study demonstrated the rapid and sustained antidepressant effects of arketamine in treatment-resistant patients with MDD. A phase 2 clinical trial of arketamine in treatment-resistant patients with MDD is underway. This study was designed to review the brief history of the novel antidepressant arketamine, the molecular mechanisms underlying its antidepressant actions, and future directions.This article is part of the Special Issue on ‘Ketamine and its Metabolites’.

Assessing the meaningful change threshold of Quality of Life in Depression Scale using data from two phase 3 studies of esketamine nasal spray

BackgroundMajor depressive disorder (MDD) directly impacts patients’ lives including symptoms, functioning and health-related quality-of-life (HRQoL). Patient-reported outcomes can capture these impacts, however interpretation of clinical meaningfulness of these measurements are often not readily available. Meaningful change thresholds (MCTs) can be derived for clinical outcome assessments to quantify the change in symptoms that is meaningful to the patient following pharmacologic treatment or other interventions. The objective of this analysis was to determine the within-patient MCT of the self-reported Quality-of-Life in Depression Scale (QLDS) among patients with MDD and active suicidal ideation with intent (MDSI) using an anchor-based approach.MethodsData from 2 randomized phase-3 trials of esketamine nasal spray (ASPIRE I and ASPIRE II) were analyzed. The Montgomery–Åsberg Depression Rating Scale (MADRS) was the primary anchor with three different severity criteria. Other anchor variables utilized were Clinical Global Impression of Severity of Suicidality-revised version, Clinical Global Impression of Imminent Suicide Risk, and EuroQol Visual Analog Scale [EQ-VAS]. Spearman correlation coefficients between the change in QLDS and anchor variables were calculated. The mean change in QLDS score at Day 25 from baseline was calculated based on the categorical change in the anchor. Coefficient yield from linear regression of the mean changes in EQ-VAS and QLDS, and distribution-based approach with ½ SD of change in QLDS were considered.ResultsIn ASPIRE I, mean (SD) improvement in QLDS score among patients with one category improvement in MADRS from baseline to Day 25 was − 8.22 (8.87), − 8.30 (9.01), and − 8.20 (8.92) using severity criteria #1, #2, and #3, respectively. Patients who achieved a 7-point improvement (MCT) in EQ-VAS yielded a mean − 9.69-point improvement in QLDS at Day 25. The ½ SD of change in QLDS was 5.63. Similar results were obtained for ASPIRE II. The MCTs identified using multiple anchors across both trials ranged from − 11.4 to − 6.7 and had an overall mean of − 7.90 (ASPIRE I) and − 7.92 (ASPIRE II). Thus, an 8-point change was recommended as the MCT for QLDS.ConclusionThe recommended MCT will help quantify within-person changes in HRQoL using patient-reported QLDS and determine meaningful treatment benefit in an MDD patient population with acute suicidal ideation or behavior.Trial registration: Name of the registry: ClinicalTrials.gov. Trial registration number: ASPIRE I (NCT03039192), ASPIRE II (NCT03097133). Date of registration: February 01, 2017; March 31, 2017. URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT03039192; https://clinicaltrials.gov/ct2/show/NCT03097133.

CO51 A Real-World Retrospective Study Evaluating Safety, Effectiveness, and Cost of Intranasal Esketamine for Treatment-Resistant Depression

Esketamine nasal spray has garnered interest as a pharmacotherapy for treatment-resistant depression (TRD). However, there is currently limited real-world and long-term evidence for patients with TRD receiving esketamine.

EE51 Cost-Effectiveness of Esketamine Nasal Spray Compared to Intravenous Ketamine for Patients with Treatment-Resistant Depression in the US Utilizing Clinical Trial Efficacy and Real-World Effectiveness Estimates

The aim of our study was to estimate the incremental cost, benefits, and cost-effectiveness of esketamine nasal spray relative to intravenous ketamine for treatment-resistant depression (TRD) in the United States.

Use of Clinical Global Impressions-Severity (CGI-S) to Assess Response to Antidepressant Treatment in Patients with Treatment-Resistant Depression.

BackgroundThis post-hoc analysis evaluated the agreement between Clinical Global Impressions-Severity (CGI-S) score- and Montgomery–Åsberg Depression Rating Scale (MADRS) total score-based assessment of response in patients with treatment-resistant depression (TRD) treated with esketamine nasal spray plus a newly initiated oral antidepressant (ESK-NS + AD).MethodsData were analyzed from a phase 3, randomized, double-blind study (TRANSFORM-2) of flexibly dosed esketamine or placebo nasal spray plus a newly initiated oral-AD in adults with moderate-to-severe TRD. Patients with ≥50% reduction in MADRS from baseline at the end of the 4-week acute treatment phase were defined as responders. For the CGI-S-based assessment of response, patients with ≥2 points decrease from baseline or a CGI-S score of ≤3 (mildly depressed to normal) were considered responders. Cohen’s kappa coefficient was calculated to assess level of agreement between MADRS and CGI-S-based assessments.ResultsAt the end of 4-week treatment, the proportion of responders among all study patients (n=201) was similar when assessed using the MADRS (61%) and CGI-S (62%) methods, with substantial agreement (Cohen’s kappa=0.76; sensitivity=92%; specificity=84%) between both methods. When restricting analysis to ESK-NS + AD-treated patients (n=101) who had a higher response rate (on MADRS: 69%; on CGI-S: 68%), the agreement remained substantial (Cohen’s kappa=0.75; sensitivity=91%; specificity=84%).ConclusionThe CGI-S may be a practical and reliable alternative to the MADRS to assess response to ESK-NS + AD in patients with TRD and can be used in real-world practice to support informed treatment decisions.

ESKALE study, a French real-world study of esketamine nasal spray for patients with treatment-resistant depression

IntroductionEsketamine nasal spray has been developed to treat adults with treatment resistant depression. On Dec.2019, EMA granted a market access approval in this indication.ObjectivesESKALE is a descriptive study of treatment resistant depression patients treated with esketamine in France.MethodsObservational retrospective study. 157 patients are included in 3 cohorts depending on their treatment initiation date. This abstract presents the second interim results of patients treated with esketamine and whom data collection ranges from Oct.2019 and Sept.2021.Results66.7% of patients were females. Average age was 49 years old with 26 patients &gt; 65 years old. Duration of the current depressive episode was 26.0 months (mean). 48.8% of patient have &gt; 1 suicide attempt during whole life. At esketamine initiation, 78.2% patients were clinically perceived to have severe depression with a MADRS score of 32.4 (median) and a PHQ9 score of 19.5 (median). For the overall sample, esketamine was prescribed in median as a 3rd line and for 40.5% of patients after neurostimulation. The majority of the patient started esketamine at 28 mg or 56 mg and increased the dose to 84 mg. After 4 months of treatment, clinical benefits are the following: decrease of MADRS total score -16.5 points (median) corresponding to 58% of responders and a PHQ9 total score decrease of -8.6 points (median). No new safety signal detected.ConclusionsThis second interim analysis describes patients’ profiles and clinical evolution over a longer period and a broader population than the first interim analysis. The conditions of use are consistent with the ones approved by health authorities.DisclosureI (Marie-Alix Codet) works as a full employee at Janssen Cilag

Prediction of Drug–Drug Interactions After Esketamine Intranasal Administration Using a Physiologically Based Pharmacokinetic Model

A physiologically based pharmacokinetic (PBPK) modeling approach for esketamine and its metabolite noresketamine after esketamine intranasal administration was developed to aid the prediction of drug-drug interactions (DDIs) during the clinical development of esketamine nasal spray (SPRAVATO®). This article describes the development of the PBPK model to predict esketamine and noresketamine kinetics after intranasal administration of esketamine and its verification and application in the prediction of prospective DDIs with esketamine using models of index perpetrator and victim drugs. The intranasal PBPK (IN-PBPK) models for esketamine/noresketamine were constructed in Simcyp® v14.1 by combining the oral and intravenous esketamine PBPK models, with the dose divided in the ratio 57.7/42.3. Verification of the model was based on comparing the pharmacokinetics and DDI simulations with observed data in healthy volunteers. The simulated and observed (171 healthy volunteers) plasma pharmacokinetic profiles of intranasal esketamine/noresketamine showed a good match. The relative contributions of different cytochromes P450 (CYPs), mainly CYP3A4 and CYP2B6, involved in esketamine/noresketamine clearance was captured correctly in the IN-PBPK model using the DDI clinical studies of intranasal esketamine with clarithromycin and rifampicin and a published DDI study of oral esketamine with ticlopidine. The induction potential of esketamine toward CYP3A4 was also well captured. Inhibition of intranasal esketamine in the presence of ticlopidine was predicted to be not clinically relevant. Different scenarios tested with esketamine as a CYP3A4 perpetrator of midazolam also predicted the absence of clinically relevant CYP3A4 interactions. This PBPK model of the intranasal route adequately described the pharmacokinetics and DDI of intranasal esketamine/noresketamine with potential perpetrator and victim drugs. This work was used to support regulatory submissions of SPRAVATO®.

Evaluation of Individual Items of the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) in Adults with Treatment-Resistant Depression Treated with Esketamine Nasal Spray Combined with a New Oral Antidepressant.

ObjectiveThe objective of this study was to determine which symptoms measured by the Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) improve in those treated with esketamine nasal spray in combination with oral antidepressant (AD) compared with those treated with placebo plus AD for adult patients with treatment-resistant depression (TRD). These results complement the interpretation of PHQ-9 and MADRS total scores.MethodsThe TRANSFORM 2 study evaluated the efficacy and safety of esketamine nasal spray in combination with AD. This post-hoc analysis used PHQ-9 and MADRS data to evaluate symptom changes. The total scores change and proportions of individual item change scores on the PHQ-9 and MADRS were evaluated at days 15 and 28; analysis of variance was used to test differences on total scores. Generalized estimation equations of logistic regression models were used to estimate the likelihood of improvement on instrument items.ResultsThe mean total score reduction of the PHQ-9, indicating improvement, was greater in the esketamine plus AD arm compared with placebo plus AD at day 15 (− 1.8; p = 0.045) and day 28 (− 2.8; p = 0.006). Proportions of those who improved (≥ 1 point on a 4-point scale and ≥ 2 points on a 7-point scale for the PHQ-9 and MADRS, respectively) was greater in the esketamine plus AD group compared with the placebo plus AD group across all items. The odds of improving for those in the esketamine plus AD group compared with the placebo plus AD group were over two times greater on the PHQ-9 items: “Little interest/pleasure in things” (OR 2.252, 95% CI 1.165–4.355); “Feeling down, depressed, or hopeless” (OR 2.767, 95% CI 1.400–5.470); and “Feeling tired or having little energy” (OR 2.171, 95% CI 1.153–4.087). The mean reduction in total scores on the MADRS, indicating improvement, was numerically greater at day 15 (− 2.0; p = 0.189) and statistically significantly greater at day 28 (− 4.4; p = 0.017) in the esketamine plus AD arm compared with placebo plus AD. The odds of improving for those in the esketamine plus AD group compared with the placebo plus AD group were over two times greater on the MADRS items measuring “Apparent sadness” (OR 2.007, 95% CI 1.096–3.674); and “Inability to feel” (OR 2.099, 95% CI 1.180–3.735).ConclusionImprovement in mean total scores in those treated with esketamine plus AD compared with placebo plus AD are important results to confirm efficacy. The odds of improving in those treated with esketamine plus AD was at least two times greater than with placebo plus AD on three patient- and two clinician-reported individual symptoms of TRD. These findings provide patient-relevant quantification of the esketamine plus AD treatment benefit, adding understanding as to which symptoms are most improved with treatment.Trial RegistrationClinicalTrials.gov identifier: NCT02418585; first posted 16 April 2015.

Long-term Safety and Efficacy of Esketamine Nasal Spray Plus an Oral Antidepressant in Patients with Treatment-resistant Depression- an Asian Sub-group Analysis from the SUSTAIN-2 Study.

ObjectiveTo evaluate the long-term safety and efficacy of intranasal esketamine in patients with treatment-resistant depression from the Asian subgroup of the SUSTAIN-2 study.MethodsSUSTAIN-2 was a phase 3, open-label, single-arm, multicenter study comprising a 4-week screening, 4-week induction, 48-week optimization/maintenance, and 4-week follow-up (upon esketamine discontinuation) phase. Patients with treatment-resistant depression received esketamine plus an oral antidepressant during the treatment period.ResultsThe incidence of ≥ 1 serious treatment-emergent adverse event (TEAE) among the 78 subjects from the Asian subgroup (Taiwan 33, Korea 26, Malaysia 19) was 11.5% (n = 9); with no fatal TEAE. 13 Asian patients (16.7%) discontinued esketamine due to TEAEs. The most common TEAEs were dizziness (37.2%), nausea (29.5%), dissociation (28.2%), and headache (21.8%). Most TEAEs were mild to moderate in severity, transient and resolved on the same day. Upon discontinuation of esketamine, no trend in withdrawal symptoms was observed to associate long-term use of esketamine with withdrawal syndrome. There were no reports of drug seeking, abuse, or overdose. Improvements in symptoms, functioning and quality of life, occurred during in the induction phase and were generally maintained through the optimization/maintenance phases of the study.ConclusionThe safety and efficacy of esketamine in the Asian subgroup was generally consistent with the total SUSTAIN-2 population. There was no new safety signal and no indication of a high potential for abuse with the long-term (up to one year) use of esketamine in the Asian subgroup. Most of the benefits of esketamine occurred early during the induction phase.

Esketamine nasal spray in patients with treatment-resistant depression: the real-world experience in the French cohort early-access programme

Objective To present the first real-world data of patients with treatment-resistant depression (TRD) treated with esketamine through a French cohort Temporary Authorisation for Use (ATUc) programme. Methods In 2019, the French Health Authorities exceptionally granted the first ATUc in psychiatry for TRD patients. Clinical characteristics, safety and efficacy data were reported by physicians. The ATUc ended ∼6 months after initiation. Results The cohort (n = 66; median age 53.0 years; 62.1% female; 78.8% with severe major depressive episodes; resistance to a mean of 4.2 previous antidepressants) received esketamine treatment for a median of 30 days. Among 46 analysed patients, 22 (47.8%) achieved response (Montgomery–Åsberg Depression Rating Scale [MADRS] total score reduction ≥50.0%) and 17 (37.0%) achieved remission (MADRS total score of ≤12) at least once at a median of 18.5 (2.0–77.0) and 21.0 (2.0–46.0) days after initiation, respectively. By Week 4, patients had a 31.6% probability of achieving remission (Kaplan–Meier method). Sedation, somnolence, dizziness, hypertension, anxiety and dissociation were the most frequently reported (>10.0%) adverse events. No new safety signals were identified. Conclusions Patient characteristics of this cohort demonstrate high-level treatment resistance. The safety and efficacy of esketamine in patients with TRD in real‐world clinical practice were consistent with Phase 3 trials. Key points Patients with treatment-resistant depression (TRD) exceptionally received esketamine nasal spray ahead of its launch through a French cohort Temporary Authorisation for Use (ATUc) programme. The clinical characteristics of 66 adult patients with TRD included in this cohort demonstrated a high-level of resistance to conventional treatments at the time of treatment request prior to esketamine initiation. No new safety signals were observed with esketamine initiation during the ATUc period compared with the Phase 3 clinical trials. The safety and efficacy of esketamine in the real world remain consistent with that established in Phase 3 clinical trials. The data collected during this ATUc also provide the first real-world data on the management and practical use of esketamine in a hospital setting in France.

US budget impact analysis of esketamine nasal spray in major depressive disorder with acute suicidal ideation/behavior.

Background: Esketamine nasal spray plus an oral antidepressant is approved in adults with major depressive disorder with acute suicidal ideation or behavior (MDSI). Methods: A budget impact analysis from a US payer perspective was performed with a hypothetical 1-million-member plan, using pharmacy and medical costs associated with adding esketamine plus an oral antidepressant to usual care. Results: Estimated annual total healthcare costs of managing patients with MDSI increased from $32,988,247 without esketamine to $34,161,188 in Year 3 with esketamine (primarily due to medical costs). The per-member-per-month incremental costs were $0.02, $0.06 and $0.10 in Years 1, 2 and 3, respectively. Conclusion: Incorporation of esketamine results in a modest estimated impact on the annual budget over a 3-year time horizon.

Relationship Between Dissociation and Antidepressant Effects of Esketamine Nasal Spray in Patients With Treatment-Resistant Depression.

BackgroundIn this post-hoc analysis, data from 2 positive, pivotal, phase 3 trials of esketamine nasal spray (ESK) in treatment-resistant depression (TRD)—short-term study (TRANSFORM-2) and maintenance study (SUSTAIN-1)—were analyzed to evaluate the relationship between dissociation and antidepressant effects of ESK.MethodsAnalysis by responder status, correlation analysis, and mediation analysis were performed to assess the relationships between peak Clinician Administered Dissociative States Scale (CADSS) scores after first (day 1) and last (day 25) ESK dose and change in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores at the first (day 2) and last assessments (day 28) in TRANSFORM-2 and peak CADSS after first maintenance ESK dose and time to relapse in SUSTAIN-1 (only for mediation analysis).ResultsIn TRANSFORM-2, the percentage of responders (>50% reduction in MADRS) at day 2 and day 28 did not significantly differ between patients who did vs did not manifest significant dissociation (peak CADSS scores >4 or ≤4, respectively) following the first ESK dose. Spearman correlation coefficients between dissociation and depression improvement were nonsignificant and close to zero. CADSS scores did not significantly mediate the reduction in MADRS at day 2 or 28 in TRANSFORM-2 or the time to depression relapse in SUSTAIN-1. The mean difference in MADRS between ESK and active-control arms persisted beyond day 2 without significant change across time, although the mean peak CADSS scores significantly decreased across consecutive doses and fewer patients experienced significant dissociation after the last ESK dose compared with the first.ConclusionWithin the dose range tested, the dissociative and antidepressant effects of ESK were not significantly correlated.Trial registrationNCT02417064 (TRANSFORM-1); NCT02418585(TRANSFORM-2); NCT02493868 (SUSTAIN-1)