This study used data for those patients who had been undergoing treatment with esketamine nasal spray plus an oral antidepressant for 16 weeks and who, after meeting criteria for either stable remission (primary analysis) or stable response (secondary analysis), were randomized (separately) to continue treatment with esketamine nasal spray plus an oral antidepressant or to discontinue treatment with esketamine and switch to placebo nasal spray and continue use of the oral antidepressant. Stable remission was defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of 12 or lower for 3 or more of the last 4 weeks of the optimization phase, with up to 1 excursion (MADRS total score >12) or 1 missing MADRS assessment permitted at week 13 or 14 only. Stable response was defined as 50% or greater reduction in MADRS total score from baseline in the last 2 weeks of the optimization phase, but without achieving stable remission criteria. Patients who were lost to follow-up or discontinued treatment after randomization were included in the analysis.
aOne patient with stable response was incorrectly randomized in the group with stable remission.
bOne patient who did not meet stable remission or stable response criteria at the end of the optimization phase was incorrectly randomized in the group with stable response.
One patient who achieved stable response was incorrectly randomized as a patient who achieved stable remission at the end of the optimization phase. One patient did not meet stable remission or stable response criteria and was incorrectly randomized as a patient with stable response. The most common cause of censoring participants was based on being relapse free at study end (see Table 2 legend). Vertical lines indicate censored observations.
eAppendix 1. List of Institutional Review Boards and Independent Ethics Committees
eAppendix 2. Patient Inclusion and Exclusion Criteria
eAppendix 3. Columbia Suicide Severity Rating Scale (C-SSRS) Item Descriptions
eTable 1. Time-to-Relapse and Number (%) of Stable Remitters That Remained Relapse Free (Based on Stable Remission Defined as MADRS Total Score ≤10) in the Maintenance Phase
eFigure 1. Kaplan-Meier Estimates of Time to Relapse for Stable Remitters by Dosing Frequency in the Maintenance Phase
eFigure 2. Mean (±SE) in MADRS Total Score Over Time LOCF During the Induction, Optimization, and Maintenance Phases
eFigure 3. Mean (±SE) Blood Pressure Over Time in the Maintenance Phase for Stable Remitters and Stable Responders
eFigure 4. Mean (±SE) CADSS Total Score Over Time During the Induction, Optimization, and Maintenance Phases for Stable Remitters and Stable Responders
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Daly EJ, Trivedi MH, Janik A, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. Published online June 05, 2019. doi:10.1001/jamapsychiatry.2019.1189
What are the long-term effects of esketamine nasal spray in patients with treatment-resistant depression?
Of the 297 adults with treatment-resistant depression who were randomized in the maintenance phase of this clinical trial, those who continued treatment with intermittently administered esketamine nasal spray plus an oral antidepressant had a significantly delayed time to relapse vs those treated with oral antidepressant plus placebo nasal spray after 16 weeks of initial treatment with esketamine and an antidepressant.
Continued treatment with esketamine nasal spray plus an antidepressant can sustain antidepressant effects among patients with treatment-resistant depression to a greater extent than an oral antidepressant alone.
Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.
To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.
Design, Setting, and Participants
In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase.
Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group.
Main Outcomes and Measures
Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.
Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo.
Conclusions and Relevance
For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo.
ClinicalTrials.gov identifier: NCT02493868
Depression is the leading cause of disability worldwide and is associated with a 10-year reduction in life expectancy.1,2 Achieving and maintaining remission, the goals of treatment for this recurrent disease, improves functioning, reduces suicide risk, and leads to greater clinical stability.3 Patients who have not responded to at least 2 different antidepressants in the current depressive episode are considered to have treatment-resistant depression (TRD).4 Patients with treatment-resistant major depressive disorder (MDD) experience relapse at a higher rate than do those with treatment-responsive MDD. Even when patients with TRD respond to treatment, the overall relapse rate while continuing treatment with the same antidepressant is high after 2 (65%; within 3.1 months) and 3 failed trials (71.1%; within 3.3 months).3 There is a substantial unmet need for effective treatments that can sustain antidepressant benefits for the population with TRD.
Several short-term studies5-12 with racemic ketamine and a stereoisomer, esketamine, have demonstrated efficacy for TRD. In contrast to available data about short-term antidepressant effects of esketamine and ketamine,13,14 little is known about maintaining antidepressant effects in the long term. We report the findings of, to our knowledge, the first controlled maintenance study of esketamine that evaluated whether continued use of intermittently administered esketamine nasal spray plus an oral antidepressant can sustain antidepressant effects among patients with TRD to a greater extent than an oral antidepressant alone.
Patients were enrolled directly or were transferred into this study after achieving treatment response (≥50% reduction from baseline in Montgomery-Åsberg Depression Rating Scale [MADRS] total score) to esketamine nasal spray in 1 of 2 short-term double-blind, active-controlled studies (1 fixed dose and 1 flexible dose), with all patients meeting identical entrance criteria (reported elsewhere12,15. Participants were outpatients who were in treatment or referred to a variety of academic and nonacademic clinic settings across the United States, Canada, and Europe. Enrolled patients were approached by their treating physician or responded to institutional review board– or independent ethics committee–approved patient recruitment materials. In addition, a web-based prescreening tool was developed to assist sites in identifying appropriate study candidates.
The trial protocol can be found in Supplement 1. Institutional review boards and independent ethics committees (eAppendix 1 in Supplement 2) approved the study protocol and amendments. The study was conducted in accordance with ethical principles of the Declaration of Helsinki,16 Good Clinical Practices, and applicable regulatory requirements. All patients provided written informed consent before entering the study.
Eligible patients (aged 18-64 years) had recurrent or single-episode (≥2 years) MDD (DSM-5),17 a total score of 34 or higher on the Clinician-Rated Inventory of Depressive Symptomatology,18 and a total MADRS score of 28 or higher, indicating moderate to severe depression. At screening, all patients were nonresponders to at least 1, but no more than 5, antidepressants in the current depressive episode, with nonresponse to a different oral antidepressant confirmed by 4 weeks or more of observed treatment during the prospective screening phase.12 Key exclusion criteria were history of psychotic disorder, suicidal behavior within the prior year, current or recent homicidal or suicidal ideation or intent, diagnosis of MDD with psychotic features, and moderate or severe substance or alcohol use disorder within 6 months. A history (lifetime) of ketamine use disorder was exclusionary. (A full list of the inclusion and exclusion criteria is presented in eAppendix 2 in Supplement 2.) Urine drug screening (eg, barbiturates, methadone, opiates, cocaine, cannabinoids, phencyclidine, and amphetamine or methamphetamine) was conducted intermittently before dosing throughout the study.
This double-blind, randomized clinical trial (A Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Adult Participants With Treatment-Resistant Depression [SUSTAIN-1]) used a randomized withdrawal design and was conducted from October 6, 2015, to February 15, 2018. Ninety-nine sites randomized patients.
The study consisted of up to 5 phases: (1) a 4-week screening and prospective observation phase (direct-entry patients only); (2) a 4-week open-label induction phase (direct-entry patients only); (3) a 12-week optimization phase (open-label, direct-entry patients or double-blind, transfer-entry patients); (4) a maintenance phase (double-blind, randomized withdrawal, event driven, variable duration); and (5) a 2-week posttreatment follow-up phase. The study continued until the requisite number of relapses occurred, specified by a preplanned interim analysis (described below).
During the 4-week screening and observation phase, nonresponse to the ongoing oral antidepressant treatment was assessed prospectively in eligible patients. Those with nonresponse at the end of this phase discontinued use of the prior antidepressant(s), with the option of a 3-week or less taper period. In the induction phase, patients received esketamine nasal spray (56 or 84 mg, flexibly dosed) twice weekly plus a new oral antidepressant (duloxetine, escitalopram, sertraline, or extended-release venlafaxine) administered daily.
Transfer-entry and direct-entry patients who achieved treatment response at the end of the induction phase (ie, ≥50% reduction in MADRS score from baseline) entered a 12-week optimization phase during which study drug dosages at the end of the induction phase remained fixed but the frequency of intranasal dosing was reduced to once weekly for 4 weeks then individualized to weekly or every 2 weeks based on the severity of depressive symptoms. To preserve the blinding, transfer-entry patients continued treatment assignment (esketamine or placebo) from the induction phase.
At week 16 of the optimization phase, esketamine-treated direct-entry (open-label treatment) and transfer-entry patients (double-blind treatment) who had achieved stable remission (primary analysis set; defined as MADRS score ≤12 for ≥3 of the last 4 weeks, with 1 excursion [MADRS score >12] or 1 missing MADRS assessment permitted at week 13 or 14 only) and patients with stable response (secondary analysis set; defined as ≥50% reduction in MADRS score from baseline in the last 2 weeks of the optimization phase but without achieving remission) continued into the maintenance phase. Because patients with treatment resistance who achieve remission reportedly have lower relapse rates compared with those who respond but do not experience remission,3 the prespecified primary analysis was conducted using the analysis of patients who achieved stable remission. However, those who met the less conservative criteria for stable response (but not stable remission) were also evaluated because a reduction in MADRS score from baseline of 50% or more for 2 weeks in this patient population is considered as clinically meaningful. Patients who achieved stable remission and those who achieved stable response (without remission) were separately randomized 1:1 according to a computer-generated schedule to continue esketamine treatment or discontinue esketamine treatment and switch to placebo nasal spray, each in addition to oral antidepressant treatment. The dosage of antidepressant throughout the maintenance phase remained unchanged from the induction phase. Randomization was balanced using randomly permuted blocks and stratified by country.
Transfer-entry patients who were assigned to the antidepressant and placebo group in the short-term studies and achieved stable remission or stable response continued the same treatment in the maintenance phase and were included in safety, but not efficacy, analyses of this study. Treatment administration frequency during the maintenance phase was based on an algorithm using the MADRS score and was reevaluated every 4 weeks, with nasal spray treatment self-administered either once weekly or every 2 weeks.
Patients who met the criteria for experiencing relapse could proceed into a long-term safety study of esketamine nasal spray.19 Otherwise, patients continued to a 2-week posttreatment follow-up phase after their participation in the maintenance phase ended.
Esketamine and placebo were provided in nasal spray devices, each containing 200 μL of solution per device (ie, 2 sprays). Each device contained 32.28 mg of esketamine hydrochloride (28 mg of esketamine base) or placebo. The placebo solution contained a bittering agent (denatonium benzoate) to simulate the taste of esketamine solution and maintain the blinding.
Independent, blinded, remote raters performed MADRS assessments throughout the study (weeks 1, 2, and 4 of the screening and observation phase and weekly during the induction, optimization, maintenance, and follow-up phases).
Adverse events (AEs) and other safety assessments, including clinical laboratory tests, physical examination, electrocardiography, Columbia Suicide Severity Rating Scale20 (C-SSRS) (with 0 indicating no suicidal ideation or behavior; 1-5, suicidal ideation; and 6-10, suicidal behavior; item descriptions in eAppendix 3 in Supplement 2) were monitored throughout the study. Vital signs, the Clinician-Administered Dissociative States Scale21 (CADSS), and the Brief Psychiatric Rating Scale22 (4-item positive symptom subscale) were assessed at baseline and all treatment administration visits (before dosing and at 40 minutes, 1 hour [vital signs only], and 1.5 hours after dosing).
The 20-item Physician Withdrawal Checklist23 was administered to assess for potential withdrawal symptoms after cessation of intranasal study medication. Cognitive testing was performed before dosing to assess for a potential effect on cognition; these data will be reported in a separate article.
On the basis of assumptions (accrual period and rate, maximum study duration, and dropout rate), 211 patients who achieved stable remission needed to be randomized (1:1 ratio) to obtain 84 relapses, providing 90% power to detect a hazard ratio (HR) of 0.49 at a 2-sided α of .05 for a fixed-sample design to detect superiority of esketamine and antidepressant over antidepressant and placebo in delaying relapse. A 2-stage group-sequential design was implemented for the analysis set of patients who achieved stable remission, and an independent data-monitoring committee performed a prespecified interim analysis after 31 relapses to assess early efficacy.
The interim analysis on patients who achieved stable remission did not show superiority of esketamine and antidepressant over antidepressant and placebo (at a 2-sided significance level of .0097, log-rank test); therefore, the study continued, and the number of relapses in patients who achieved stable remission was reestimated to 59 relapses in total with an adjusted significance level of .046 (2-sided) for the final efficacy analysis (based on the Wang-Tsiatis boundary α-spending function24), ensuring a conditional power of 90% or higher after the interim analysis.
Cumulative distribution of time to relapse during the maintenance phase among patients who achieved stable remission (primary efficacy end point) and those who achieved stable response without remission (secondary end point) was estimated by the Kaplan-Meier method. Relapse was defined as a MADRS total score of 22 or higher for 2 consecutive assessments separated by 5 to 15 days or hospitalization for worsening depression, suicide attempt, suicide prevention or completed suicide, or another clinically relevant event suggestive of relapse (assessed by a relapse adjudication committee).
The between-group difference in time to relapse was analyzed using a log-rank test (weighted combination [interim and final analyses] for patients who achieved stable remission because of conducting an interim analysis). The estimated HRs and 95% CIs were based on weighted estimates for patients who achieved stable remission and on a Cox proportional hazards regression model with treatment as a factor for patients who achieved stable response. A similar post hoc analysis was performed combining the analysis set of patients who achieved stable remission and the analysis set of patients who achieved stable response.
A total of 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) were randomized in the maintenance phase of the study. A CONSORT diagram is presented in Figure 1. The median number of patients per site was 2 (range, 1-25). The treatment groups were comparable based on demographic and baseline clinical characteristics (Table 1). Median exposure to intranasal esketamine during the maintenance phase was 17.7 weeks among patients who achieved stable remission and 19.4 weeks among patients who achieved stable response. Median exposure to placebo during the maintenance phase was 10.2 weeks among patients who achieved stable remission and 10.1 weeks among those who achieved stable response.
Of the 90 patients who achieved stable remission in the esketamine and antidepressant group, 40 (44.4%) received 56 mg of esketamine on day 1 of the maintenance phase and 50 (55.6%) received 84 mg, with 62 (68.9%) receiving treatment every 2 weeks for most of the maintenance phase. A greater proportion of the 62 patients who achieved stable response in the esketamine and antidepressant group received the higher esketamine dose in the maintenance phase (56 mg: n = 20 [32.3%]; 84 mg: n = 42 [67.7%]), with 34 (54.8%) receiving treatment once weekly most of the time.
Overall, among patients who achieved stable remission, 24 patients (26.7%) in the esketamine and antidepressant group and 39 patients (45.3%) in the antidepressant and placebo group experienced a relapse event during the maintenance phase; among the patients who achieved stable response (but not remission), 16 patients (25.8%) in the esketamine and antidepressant group and 34 patients (57.6%) in the antidepressant and placebo group experienced relapse (Table 2). Continued treatment with esketamine and antidepressant significantly delayed relapse compared with treatment with antidepressant and placebo (patients who achieved stable remission: HR, 0.49; 95% CI, 0.29-0.84; P = .003, number needed to treat [NNT], 6; patients who achieved stable response: HR, 0.30; 95% CI, 0.16-0.55: P < .001, NNT, 4). According to HR estimates, treatment with esketamine and antidepressant decreased relapse risk by 51% among patients who achieved stable remission and by 70% among patients who achieved stable response compared with antidepressant and placebo (Figure 2). In addition, in a post hoc analysis, esketamine and antidepressant delayed relapse compared with antidepressant and placebo among patients who achieved stable remission and patients who achieved stable response combined (HR, 0.38; 95% CI, 0.26-0.57; P < .001). In a post hoc sensitivity analysis for the primary end point, using a MADRS score cutoff of 10 for remission, the between-group difference remained statistically significant (2-sided P = .005) (eTable 1 in Supplement 2). Time to relapse for patients who achieved stable remission was also assessed by study entry (direct vs transfer). The HRs were 0.49 (95% CI, 0.27-0.90) for direct-entry patients and 0.45 (95% CI, 0.17-1.18) for transfer-entry patients.
Given the low median number of patients per site (2; range, 1-25), to further evaluate the effect of site on the estimation of treatment effect (ie, HR), a post hoc sensitivity analysis was performed using a Cox proportional hazards regression model by excluding one site at a time. On the basis of this analysis, the HR was estimated to range from 0.42 to 0.57, which is consistent with the overall HR of 0.47 (unweighted).
Nineteen of the 39 relapses in patients who achieved stable remission and who were switched to placebo nasal spray occurred in the first month after discontinuation of esketamine treatment (6 by week 2 and the remainder by week 4), with 11 of these 19 early relapses occurring in patients who had required weekly treatment administration in the last 4 weeks of the optimization phase before randomization (eFigure 1 in Supplement 2).
After completing induction and optimization treatment (16 weeks total), in patients who achieved stable remission and those who achieved stable response, there was separation in MADRS total scores between patients randomized to continue vs discontinue esketamine treatment, each in the presence of antidepressant therapy, with MADRS total scores being lower over time for esketamine-treated patients. This separation was maintained in both patients who achieved stable remission and those who achieved stable response. Mean MADRS total score over time using last observation carried forward data during the induction, optimization, and maintenance phases is presented in eFigure 2 in Supplement 2.
The 5 most common AEs reported in the esketamine and antidepressant group during the maintenance phase were dysgeusia, vertigo, dissociation, somnolence, and dizziness (Table 3). Most AEs were mild to moderate, observed after dosing, and generally resolved in the same day. No cases of respiratory depression or interstitial cystitis were observed.
No deaths were reported during the study. Serious AEs considered by the investigator as related to study drug were reported for 6 patients in the esketamine and antidepressant group (autonomic nervous system imbalance, disorientation, hypothermia, lacunar stroke [ie, ischemic lesion, day 1, 6 hours after dosing], sedation, simple partial seizures [day 5, 45 minutes after dosing; no seizure history], and suicidal ideation) during the induction phase. No serious AEs considered as related to esketamine were reported during the optimization or maintenance phases.
Seven patients experienced 1 or more AEs during the maintenance phase, leading to discontinuation of the intranasal study drug; 4 (2.6%) of 152 were in the esketamine and antidepressant group (worsening depression, 3 patients; anxiety and confusional state [transient], 1 patient) and 3 (2.1%) of 145 were in the antidepressant and placebo group (worsening depression for each).
Transient blood pressure increases were observed with esketamine on treatment days; the maximum value was reached at 40 minutes after the start of administration in most cases and typically returned to the predose range by 1.5 hours after administration (eFigure 3 in Supplement 2). Few patients experienced treatment-emergent transient hypertension, defined as a systolic blood pressure of 180 mm Hg or higher and/or a diastolic blood pressure of 110 mm Hg or higher (ie, systolic hypertension: 1 [0.7%] esketamine-treated patient and 0 antidepressant- and placebo-treated patients; diastolic hypertension: 2 [1.3%] esketamine-treated patients and 0 antidepressant-and placebo-treated patients) during the maintenance phase. No clinically significant change in electrocardiographic findings was observed during the study.
Most direct-entry patients (362 [85.4%]) had baseline C-SSRS scores of 0, indicating no suicidal ideation or behavior. Of those patients treated with esketamine and oral antidepressant who reported no suicidal ideation or behavior at baseline, 42 (11.6%) had a higher postbaseline score (maximum C-SSRS score of 1 [n = 35], 2 [n = 3], 3 [n = 2], 5 [n = 1], and 8 [n = 1]) during the open-label induction phase; 22 (5.7%) (direct- and transfer-entry patients) had a higher postbaseline score (maximum C-SSRS score of 1 [n = 17], 2 [n = 3], and 3 [n = 2]) in the optimization phase; and 3 (2.4%) had a higher postbaseline score (maximum C-SSRS score of 1 [n = 2] and 4 [n = 1]) compared with 6 patients (4.5%) receiving antidepressant and placebo (maximum C-SSRS score of 1 [n = 6]) in the maintenance phase. On the basis of the C-SSRS, there were no reports of suicidal behavior in the optimization or maintenance phases. None of the patients who experienced relapse had a significant elevation in C-SSRS score (ie, the most severe postbaseline score was 2 for patients who experienced relapse in the esketamine and antidepressant group and 3 for patients who experienced relapse in the antidepressant and placebo group).
Present-state dissociative symptoms, as measured by CADSS (eFigure 4 in Supplement 2), began shortly after the start of esketamine treatment, peaked at 40 minutes, and generally resolved by 1.5 hours. The magnitude of symptoms attenuated with repeated administrations over time in the induction phase, with a relatively low magnitude reported in the optimization and maintenance phase. No symptoms or AEs of psychosis were observed.
Of note, 1 patient received 1 dose of ketamine (10 mg intravenously) during the study for the treatment of an AE of nephrolithiasis, but no AEs were reported by any participant related to use or abuse of ketamine. No evidence of a distinct withdrawal syndrome was observed during the 2 weeks after cessation of esketamine nasal spray as assessed by the 20-item Physician Withdrawal Checklist.
In this first study, to our knowledge, of esketamine nasal spray for relapse prevention in patients with TRD, continued treatment with esketamine and an antidepressant demonstrated clinically meaningful and statistically significant superiority compared with antidepressant and placebo in delaying relapse in patients who had achieved stable remission or stable response after 16 weeks of treatment with esketamine and an antidepressant. No major difference in efficacy was seen by direct- or transferred-entry status.
One concern often cited in interpretation of randomized withdrawal studies is that the increased rate of depression observed after switching to placebo is a pharmacologic consequence of antidepressant withdrawal.26 A high relapse rate early in the withdrawal period could indicate a possible withdrawal or rebound effect. In this study, although there were a high number of relapses in the first month in those switched to placebo nasal spray, it is unlikely that a pharmacologic withdrawal effect contributed given that the decrease in esketamine plasma concentrations is rapid for the initial 2 to 4 hours and more gradual thereafter (mean terminal half-life, 7-12 hours), with steady state never reached with intermittent dosing. Moreover, this high rate of early relapse is similar to that observed after cessation of electroconvulsive therapy.27 There are no known rebound effects after electroconvulsive therapy discontinuation. The high rates of early relapse after esketamine discontinuation and those observed by Rush et al3 for patients in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study at level 3 or 4 (ie, who had failed 2 and 3 prior antidepressant treatments, respectively) more likely reflect a greater vulnerability to relapse among patients with TRD during maintenance treatment with an antidepressant alone.
In recognition of interindividual variability, the MADRS-based treatment algorithm individualized dosing frequency to the lowest frequency that maintained remission or response. Dosing frequency was reduced to once every 2 weeks if the patient had achieved remission (ie, MADRS score ≤12), whereas those unable to achieve or maintain remission were assigned to a weekly dosing frequency. Of note, more than half of the patients who experienced relapse during the first month after discontinuation of esketamine treatment required weekly dosing to sustain remission, reflecting the higher vulnerability in this subpopulation. Taken together, the evidence suggests that relapses seen in the first weeks after discontinuing esketamine treatment are likely attributable to more vulnerable patients and not a withdrawal or rebound phenomenon.
No new or unexpected safety concern was observed in this long-term study of esketamine nasal spray administered weekly or every 2 weeks. Results were consistent with previous findings from completed short-term (4-week) phase 2 and 3 studies.10,12,15
Study limitations include the fact that esketamine has known transient dissociative and sedative effects that are difficult to blind; these symptoms could have biased the staff who observed treatment administration. To ensure unbiased efficacy evaluation, independent, remote, blinded MADRS raters assessed treatment response throughout this study. In addition, a post hoc analysis assessed participants randomized to discontinue intranasal esketamine treatment who subsequently experienced relapse in the first 4 weeks of the maintenance phase (n = 19). A sensitivity analysis, performed by censoring the patients who experienced relapse and showed a clear change in CADSS score before and after randomization (n = 3), resulted in an HR of 0.50 (95% CI, 0.30-0.84) with a 2-sided P = .008 (consistent with the primary analysis), based on an unweighted Cox proportional hazards regression model and log rank test.
This study demonstrated that, after 16 weeks of initial treatment, continued treatment with esketamine plus antidepressant leads to significant, clinically meaningful superiority compared with an antidepressant plus placebo for relapse prevention among patients with TRD and provides further safety data supporting a positive benefit-risk ratio of long-term treatment.
Accepted for Publication: March 25, 2019.
Published Online: June 5, 2019. doi:10.1001/jamapsychiatry.2019.1189
Open Access: This article is published under the JN-OA license and is free to read on the day of publication.
Corresponding Author: Ella J. Daly, MD, Department of Neuroscience, Janssen Research and Development LLC, 1125 Trenton-Harbourton Rd, Titusville, NJ 08560 (firstname.lastname@example.org).
Author Contributions: Drs Drevets and Singh contributed equally to the work as senior authors. Dr Daly had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Daly, Trivedi, Janik, Lane, Lim, Duca, Hough, Thase, Shelton, Manji, Drevets, Singh.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Daly, X. Li, Lane, Lim, Duca, Hough, Thase, Zajecka, Manji, Singh.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Zhang, X. Li, Lane, Lim.
Obtained funding: Hough, Divacka, Drevets.
Administrative, technical, or material support: H. Li, Zajecka, Bitter, Shelton, Molero.
Supervision: Daly, Janik, Hough, Thase, Blier, Manji, Drevets, Singh.
Conflict of Interest Disclosures: Drs Daly, Janik, H. Li, Zhang, X. Li, Lim, Hough, Manji, Drevets, and Singh and Mss Lane and Duca are employees of Janssen Research & Development LLC and hold company equity. Dr Manji reports holding a patent, which is assigned to Icahn School of Medicine at Mount Sinai, Yale University, and the National Institutes of Health; no financial benefit was received from this patent. Dr Trivedi reports consulting for or serving on the advisory board of Alkeremes Inc, Akili Interactive, Allergan Pharmaceuticals, Arcadia Pharmaceuticals, Avanir Pharmaceuticals, Brintellix Global, Bristol Myers Squibb, Caudex, Cerecor, Forest Pharmaceuticals, Global Medical Education Inc, Health Research Associates, Insys, Johnson & Johnson Pharmaceutical Research & Development, Lilly Research Laboratories, Lundbeck Research USA, Medscape, Merck & Co Inc, Mitsubishi Pharma, MSI Methylation Sciences–Pamlab Inc, Navitor, Otsuka America Pharmaceutical Inc, One Carbon Therapeutics, Otsuka America Pharmaceutical Inc, Pfizer Inc, and Takeda Global Research; receiving royalties from Janssen Research and Development LLC; having author agreements with Janssen Asia Pacific and the Oxford University Press; and receiving grants from the Agency for Healthcare Research and Quality, the Cancer Prevention and Research Institute of Texas, the National Institute of Mental Health, National Institute of Drug Abuse, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Advancing Translational Sciences, Johnson & Johnson, and the Patient-Centered Outcomes Research Institute (PCORI). Dr Thase reports serving as an advisor or consultant for Acadia, Akilii, Alkermes, Allergan (Forest, Naurex), AstraZeneca, Axome, Cerecor, Eli Lilly and Company, Fabre-Kramer, Gerson Lehrman Group, Guidepoint Global, Johnson & Johnson, Janssen, Lundbeck, MedAvante, Merck & Co, moksha8, Nestlé (PamLab), Novartis, Otsuka, Pfizer, Shire, Sunovion, and Takeda; receiving grant support from Acadia, the Agency for Healthcare Research and Quality, Alkermes, Allergan (Forest), Avanir, Axome, Intracellular, Janssen, the National Institute of Mental Health, Otsuka, PCORI, and Takeda; and receiving royalties from American Psychiatric Press, Guilford Publications, Herald House, and W.W. Norton & Company Inc. Dr Zajecka reports consulting for or serving on the advisory board of Avanir (Depression Data Safety Monitoring Board), Alkermes, ElMindA, Forest, Naurex, Lundbeck, PamLab/Nestle, Shire, and Takeda and receiving grant or research support from Actavis, Alkermes, Allergan, AstraZeneca, Axesome, Cyberonics, ElMindA, Forest, the Cheryl T. Herman Foundation, Hoffman-LaRoche, Janssen, Johnson & Johnson, Lundbeck, Naurex, Neuralstem, Otsuka, the National Institutes of Health, Shire, Taisho, and Takeda. Dr Divacka reports receiving research grants from Axovant, Lundbeck, Servier, and Janssen. Dr Fagiolini reports serving as a consultant and/or a speaker and/or has received research grants from Allergan, Angelini, Generici DOC, Lundbeck, Italfarmaco, Janssen, Mylan, Otsuka, Pfizer, Recordati, Roche, and Sanofi Aventis. Dr Cubała reports serving as a consultant and/or receiving research grants from Alkermes, Allergan, Auspex Pharmaceuticals, Biogen, BMS, Cephalon, Ferrier, Forest Laboratories, GedeonRichter, GW Pharmaceuticals, Janssen, KCR, Eli Lilly and Company, Lundbeck, Minerva, the National Institutes of Health, NeuroCog, Orion, Otsuka, Sanofi, and Servier and serving as a consultant for GW Pharmaceuticals, Janssen, KCR, Quintiles, Roche, and Sanofi. Dr Bitter reports serving as a consultant to and/or speaker for Angelini, Gedeon Richter, Janssen/Janssen-Cilag, Eli Lilly and Company, Lundbeck, Pierre Fabre, and Servier. Dr Blier reports serving a consultant and/or receiving research grants from Allergan, Bristol Myers Squibb, Janssen, Lundbeck, Meda-Valeant, Otsuka, Pfizer, Pierre Fabre Médicaments, Sunovion, and Takeda. Dr Shelton reports serving as a consultant to Acadia Pharmaceuticals, Allergan Inc, Cerecor Inc, Clintara LLC, Janssen Pharmaceutica, Lundbeck A/S, Medtronic Inc, MSI Methylation Sciences Inc, Naurex Inc, Nestle’ Health, Pfizer Inc, and Takeda Pharmaceuticals and receiving grant support from Acadia Pharmaceuticals, Alkermes Inc, Allergan Inc, Assurex Health, Avanir Pharmaceuticals, Cerecor Inc, Genomind, Intracellular Therapies, Janssen Pharmaceutica, Otsuka Pharmaceuticals, Nestle’ Health, Novartis Inc, and Takeda Pharmaceuticals. Dr Molero reports receiving research grants from the Ministry of Education (Spain), the Government of Navarra (Spain), the Spanish Foundation of Psychiatry and Mental Health, and AstraZeneca; serving as a clinical consultant for MedAvante-ProPhase; and has receiving lecture honoraria from and/or consulting for Scienta, AB-Biotics, Novumed, and Janssen. Dr Winokur reported serving as a consultant to Alkermes and to Janssen. No other disclosures were reported.
Funding/Support: This study was funded by Janssen Research & Development LLC.
Role of the Funder/Sponsor: Employees of Janssen Research & Development LLC were involved in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Meeting Presentations: This study was presented at the American Society of Clinical Psychopharmacology 2018 Annual Meeting; May 30, 2018; Miami, Florida; 31st European College of Neuropsychopharmacology Congress; October 7, 2018; Barcelona, Spain; US Psych Congress; October 26, 2018; Orlando, Florida; and the German Association for Psychiatry, Psychotherapy and Psychosomatics e.V. 2018 Congress; November 30, 2018; Berlin, Germany.
Data Sharing Statement: See Supplement 3.
Additional Contributions: The following investigators participated in the study: Belgium: Geert De Bruecker, Sven Estercam, Stefaan Geerts, and Hans van den Ameele; Brazil: Rodolfo Campos, Norton Sateg Castro, Gerardo de Araujo Filho, Clarissa Gama, Hamilton Grabowski, Jacson Hubner, Acioly Lacerda, Ricardo Moreno, Gustavo Ottoni, Cintia Perico, Fabio Lopes Rocha, Sandra Ruschel, and Fabio Souza; Canada: Pierre Blier and Arun Ravindran; Czech Republic: Martin Anders, Ilona Divacka, Erik Herman, Marta Holanova, Lubos Janu, Bronislav Kobeda, Oto Markovic, Alexander Nawka, Simona Papezova, Dita Protopopova, and Zdenek Solle; Estonia: Anu Arold; France: Mocrane Abbar, Helene Denizot, Philippe Desbonnet, Raphael Gaillard, and Nemat Jaafari, Germany: Malek Bajbouj, Ralf Bodenschatz, Nadine Dreimüller, and Jana Thomsen; Hungary: István Bitter, László Csekey, Sándor Fekete, Gábor Feller, Ede Frecska, Janos Kalman, Agnes Kertesz, Zsuzsanna Kiss, Tamas Kurimay, Zoltan Makkos, Erzsebet Payer, and Gyorgy Szekeres; Italy: Eugenio Aguglia, Andrea Fagiolini, Giuseppe Maina, and Gabriele Sani; Mexico: Gabriel Alejo, Mario Caceres, Vicente Escaname, Erasmo Saucedo, Juan Luis Vazquez, and Sergio Villasenor; Poland: Hanna Badzio-Jagiello, Agnieszka Bijakowska, Wiesław J. Cubała, Marek Domanski, Mieczyslaw Janiszewski, Ireneusz Kaczorowski, Bartosz Loza, Dariusz Malicki, Tomasz Markowski, Mariusz Perucki, Agata Szulc, Napoleon Waszkiewicz, Adam Wichniak, and Marcin Wojnar; Slovakia: Zuzana Janikova, Abdul Shinwari, and Livia Vavrusova; Spain: Patricio Molero, Francisco Montańes, Angel Luis Montejo, Diego Jose Palao, Jose Maria Pelayo, Josep Antoni Ramos, Salvador Ros, Joan Salva, Pedro Manual Sanchez, and Eduard Vieta; Sweden: Peter Bosson, Anders Luts, Maria Markevind, and Miranda Michaneck; Turkey: Cengiz Akkaya, Umut Mert Aksoy, Sibel Cakir, Serdar Suleyman Can, Sel Demet, Nesrin Dilbaz, Mehmet Cagdas Eker, Atila Erol, Huseyin Gulec, Oguz Karamustafalioglu, Elvan Ozalp, Meram Can Saka, Lut Tamam, Halil Ibrahim Tas, Brahim Taymur, and Tuba Yilman; United States: Alabama: Richard Shelton; Arkansas: Paul Wylie; California: Jason Bermak, Jesse Carr, Daniel Chueh, Corinna Gamez, Vishaal Mehra, Michael Plopper, and David Walling; Connecticut: Andrew Winokur; Florida: Morteza Nadjafi, Sonia Rente, Elias Sarkis, Kelley Yokum, and Jose Zaglul; Georgia: Robert Riesenberg; Illinois: Angelos Halaris, Andrew Kim, Mark Lerman, Cosme Lozano, Brett Plyler, Jeffrey Ross, John Sonnenberg, and John Zajecka; Kansas: Matthew Macaluso and Mikel Thomas; Louisiana: Kashinath Yadalam; Maryland: Alan Jonas, Adam Kaplin, and Robert Litman; Massachusetts: Gregory Labun, Irina Mezhebovsky, Mohammed Munir, Anthony Rothschild, Daniel Rutrick, and James Whalen; Michigan: Joel Young; Missouri: Howard Ilivicky; New York: Michael Liebowitz and Matthew Milak; North Carolina: James Barker; Oklahoma: Courtney Nixon; Pennsylvania: Sanjay Chandragiri, Shivkumar Hatti, and Michael Thase; Rhode Isalnd: Linda Carpenter; Texas: Rayan Al Jurdi, Michael Downing, Andrew Klymiuk, Divyansu Patel, Asim Shah, and Madhukar Trivedi; Virginia: Anita Clayton; Wisconsin: Cary Kohlenberg. Sandra Norris, PharmD, Norris Communications Group LLC, supported by Janssen Research and Development LLC, provided medical writing assistance. Ellen Baum, PhD, Janssen Global Services LLC, provided additional editorial support and was not compensated. Dr Norris was compensated for her work. Dr Baum is an employee of Janssen. We thank the study patients for their participation in this study.
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