SPRAVATO™ may harm your baby. If you take a nasal corticosteroid or nasal decongestant medicine, take these medicines at least 1 hour before taking SPRAVATO™. Approximately optimal one-parameter boundaries for group sequential trials. 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The study was conducted in accordance with ethical principles of the Declaration of Helsinki,16 Good Clinical Practices, and applicable regulatory requirements. Patients who were lost to follow-up or discontinued treatment after randomization were included in the analysis. 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). Adverse events (AEs) and other safety assessments, including clinical laboratory tests, physical examination, electrocardiography, Columbia Suicide Severity Rating Scale, 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 (, 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.  et al. During the 4-week screening and observation phase, nonresponse to the ongoing oral antidepressant treatment was assessed prospectively in eligible patients. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. Like ketamine, esketamine can produce hallucinations and out-of-body experiences in high doses. 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). Kaplan-Meier Estimates of Time to Relapse for Stable Remitters by Dosing Frequency in the Maintenance Phase, eFigure 2. 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. There is a pregnancy registry for women who are exposed to SPRAVATO™. 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.  I, Lafer  DR. Obtained funding: Hough, Divacka, Drevets. 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. Meaning  There has been no studies to directly compare the efficacy of Ketamine vs Esketamine; and, there may never be one due to the off-patent status of Ketamine.  LC, Presented at the 9th Biennial Conference of the International Society for Affective Disorders (ISAD) and the Houston Mood Disorders Conference; September 21, 2018; Houston, Texas. Dr Norris was compensated for her work. 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. 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. 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). If you miss a SPRAVATO™ treatment, your healthcare provider may change your dose and treatment schedule. Collectively, across all sites participating in the trial, the response rate was between 53% and 69% during the first month of treatment.  KA. 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. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. 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). 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. The reason esketamine is so effective, explains Kaplin, is that it’s delivered not only through a different receptor, but via an ion channel — a much faster route to deliver a signal down the neuron highway of the brain. Bell said his center has a high success rate with suicidal patients. Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial. All Rights Reserved. Privacy Policy| What are the long-term effects of esketamine nasal spray in patients with treatment-resistant depression?  DJ, Carpenter Your healthcare provider will tell you how much SPRAVATO™ you will take and when you will take it. In addition, a web-based prescreening tool was developed to assist sites in identifying appropriate study candidates. Not a cure. Results favored the esketamine gp but statistical significance for the primary endpoint was missed; median unbiased estimate of the difference in MADRS score from day 1 (baseline) to day 28 for esketamine vs. placebo gp: -3.6, 95% CI: -7.20, 0.07; one-sided p=0.029.  RF, Mulsant 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). A Long-term Safety Study of Intranasal Esketamine in Treatment-resistant Depression (SUSTAIN-3). Walker Quiz Ref IDAdverse 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. Esketamine is made from a drug called ketamine, an anesthetic that has also been used for many years to treat depression. A history (lifetime) of ketamine use disorder was exclusionary. JAMA Psychiatry. Time to Relapse and Number of Patients Who Remained Relapse Free in the Maintenance Phase, Table 3. Ein Narkotikum macht Karriere: Esketamin, in der Drogenszene auch als „Special K“ bekannt, scheint neueren Daten zufolge in Form eines Nasensprays bei therapieresistenter Depression zu wirken. 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). The dosage of antidepressant throughout the maintenance phase remained unchanged from the induction phase. The most common cause of censoring participants was based on being relapse free at study end (see Table 2 legend). 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. 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. Dr Baum is an employee of Janssen. Trial Registration  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. 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. Intravenous Ketamine has been shown to have over 70% success rate in the treatment of major depression. Infusion therapies available through ketamine clinics across the United States report a high success rate of 60% to 70% treating Treatment Resistant Depression as well as Major Depression with risk of suicide [1][3][5][6]. 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.  EJ, Singh Quiz Ref IDOverall, 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).  HA, Haskett Funding/Support: This study was funded by Janssen Research & Development LLC.  JB, Tohen  CA 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). 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. But even when we give multiple infusions over, say, a two-week period, a lot of patients will relapse in about 18 days," says William V. Bobo, M.D., M.P.H., a psychiatrist specializing in the evaluation and treatment of depression at Mayo Clinic's campus in Minnesota. 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. Findings  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. No deaths were reported during the study. 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. Mean (±SE) Blood Pressure Over Time in the Maintenance Phase for Stable Remitters and Stable Responders, eFigure 4. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. 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.  TP, Get free access to newly published articles. To date, it has only been shown to be effective when taken in combination with an oral antidepressant. Ninety-nine sites randomized patients. New Orleans, LA, (May 21, 2019) — The Janssen Pharmaceutical Companies of Johnson & Johnson presented a new cost-efficiency analysis at the International Society for Pharmacoeconomics and Outcomes Research Annual Meeting (ISPOR 2019) that illustrates the value of SPRAVATO™ (esketamine) CIII nasal spray for treatment-resistant depression (TRD), for patients, U.S. payers, and … The 20-item Physician Withdrawal Checklist23 was administered to assess for potential withdrawal symptoms after cessation of intranasal study medication. Consequently, scientists aren’t exactly certain how esketamine reduces depression. Follow your SPRAVATO™ treatment schedule exactly as your healthcare provider tells you to. Remission rate (MADRS total score ≤12) at day 28 was 52.5% and 31.0% for the esketamine and placebo groups, respectively. Response Rates: In the TRANSFORM-1 and TRANSFORM-2 trials with participants between 18 to 64 years of age, 53.1% to 69.3% of patients who received esketamine in combination with a new oral antidepressant were stable responders (i.e., defined as 50% or higher reductions in MADRS depression severity scores) by day 28. Zarate The most common treatment-emergent adverse events (>10%) reported in the esketamine group were metallic taste, nausea, vertigo, dizziness, headache, drowsiness, dissociation, blurred vision, paraesthesia (tingling sensation) and anxiety. Esketamine is the S-enantiomer of ketamine, an FDA-approved anaesthetic, known to cause dissociation and, occasionally, hallucinations.  FW, It may also be effective at lifting severe symptoms of depression, such as suicidal ideation. 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. Your healthcare provider will decide when you are ready to leave the healthcare setting. Results   JB, Fedgchin Definition of treatment-resistant depression in the Medicare population. Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS). Currently available antidepressants target the monoamine neurotransmitter systems—predominantly serot…  et al. Terms of Use| Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. 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). The median number of patients per site was 2 (range, 1-25). For these reasons, esketamine is not considered a first-line treatment option for depression. 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.