This safety study also reported that, regardless of age, cognitive functioning (e.g., memory, processing speed) remained stable throughout treatment. Nasal administration of esketamine-a promising new antidepressant [abstract]. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. This subpopulation of patients with TRD could benefit from esketamine. Janssen submits European Marketing Authorisation Application for esketamine nasal spray for treatment-resistant depression. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. But “esketamine inhaler therapy” was a different animal altogether: a lower dose designed to minimize these effects, and thus be suitable for long-term use. The FDA approved ketamine in 1970. Esketamine is the S-enantiomer of racemic ketamine and is being developed as a nasal spray device for potential therapeutic use in patients with TRD. Esketamine Plus an Oral Antidepressant for RelapsePrevention in Treatment-resistant Depression Sustenance of Esketamine Treatment Response With Repeated Doses at Intervals Determined by Symptom Severity(SUSTAIN-1) ProtocolESKETINTRD3003; Phase 3 AMENDMENT 4 JNJ-54135419(esketamine) *Janssen Research & Development is a global organization that operates … 2019; Canadian Rapid Treatment Center of Excellence. Treatment-resistant depression: therapeutic trends, challenges, and future directions. 1.What is the summary of product characteristics (SmPC)? Spravato contains the active substance esketamine. In the U.S. it costs more than £25,000 to treat one patient for a year with esketamine. The specific reasons for stopping treatment were not reported. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. pharmacological treatments. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211243Orig1s000TOC.cfm, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211243s004lbl.pdf Grand challenges in global mental health. This could present a challenge for patients, as it would require repeat visits to the physician’s office on a bi-weekly basis. Thus far, most research has been on ketamine infusions. Esketamine for treatment-resistant depression has now been rescheduled into the work programme and is due to be discussed at committee on Wednesday 5 August 2020. CANMAT advises this strategy may be best employed for patients in their first antidepressant trial and therefore may not be the optimal strategy for TRD (i.e., failed two or more antidepressants). The FDA reports six deaths with esketamine during the development program; however, five of these deaths occurred after the drug was stopped.18 Three of these deaths were due to completed suicide, and three were due to one of following: a motor vehicle accident, sudden death, and a heart attack. In comparison, 38.9% to 52% of patients who received placebo with a newly initiated antidepressant were stable responders. A total of five phase III trials evaluated the efficacy and safety of esketamine nasal spray in combination with a newly initiated oral antidepressant for patients with TRD; four were randomized, double-blind, active-controlled trials21-24 and one was an open-label safety study.20 There are an additional two phase III trials currently ongoing to further assess the efficacy and long-term safety of esketamine in this patient population.30,31 Details of these trials are summarized in Table 1. First, the scope test described above was included only in the panel-sample survey; the clinical-trial sample was too small for this additional test. How is Spravato used? The appraisal will therefore be paused. Regular alerts updated the search until project completion; only citations retrieved before March 13, 2019 were incorporated into the analysis. TRD presents an even greater burden, with an increased risk for subsequent relapses and suicide.8,9 Patients with TRD are also twice as likely to be hospitalized, incurring additional medical costs.8,10 Risk factors for TRD may include old age, high stress levels, concomitant psychiatric disorders, and a history of medication nonadherence.6. Of note, the FDA grants a Breakthrough Therapy designation for drugs intended to treat a serious or life-threatening disease and where initial clinical data suggests that the drug may demonstrate substantial improvement over current therapies.28, The Canadian cost of esketamine is unavailable, as this product is not marketed in the country. Other efficacy outcomes data are summarized in Table 3. J&J prices ketamine-like depression treatment at $590-$885 for two doses. The reports contain a summary of the quality, safety and efficacy of approved new chemicals and biologics, and HSA's benefit-risk assessment for the approvals. TRD is a more challenging depressive disorder to treat, with few strong recommendations in clinical practice guidelines. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/211243Orig1s004ltr.pdf, https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211243s003lbl.pdf (CADTH issues in emerging health technologies; issue 176). Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 1. disease burden and principles of care. 3. The manufacturer has filed for regulatory approval in Canada and the European Union for adults with TRD (defined as MDD patients who have not responded adequately to at least two different antidepressants of adequate dose and duration in the current depressive episode) based on five, phase III clinical trials (Janssen Inc., Toronto, ON: personal communication, 2019 Feb 1).20-25 Health Canada is currently reviewing esketamine as a priority submission.26, In the US, the FDA has recently approved the marketing of esketamine nasal spray under the trade name Spravato, in conjunction with an oral antidepressant, “for the treatment of depression in adults who have tried other antidepressant medicines but have not benefited from them (treatment-resistant depression)”.27 It also received Breakthrough Therapy designation in 2016 from the FDA for MDD with imminent risk for suicide; this indication is not currently approved. As studies of emerging treatments utilize diverse definitions of TRD, it can be difficult to translate research findings into practical guidelines. Boucherville (QC): Angita Pharma Inc.; 2019 Jan 11: Domany Y, Bleich-Cohen M, Tarrasch R, et al. It is being investigated in a phase II trial for TRD. Topic update: this appraisal has not been defined as therapeutically critical. Whiteford HA, Degenhardt L, Rehm J, et al. Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. Authors: Bryanna Nicole Tibensky, Louis de Léséleuc, Christine Perras, Lory Picheca. Esketamine is approximately three to four times more potent than R-ketamine, potentially translating into lower doses with fewer side effects compared with previously studied ketamine infusions.7,16,17 Esketamine’s antidepressant effects are not mediated by known mood-modulating pathways such as the monoamine, gamma-aminobutyric acid (GABA), or opioid axes. 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. Because of the trial design and choice of comparator, this evidence cannot be used to assess how esketamine compares with other options available to patients with TRD, such as adjunctive therapy. The majority of patient information, labels, approval letters, reviews, and other information are available for drug products approved since 1998. MADRS is a clinician-rated scale consisting of 10 domains (i.e., apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), for a total possible score of 60. However, the generalizability of these results to chronic esketamine use is limited. c Due to pre-defined statistical testing sequence, since the esketamine 84 mg group was non-significant, the esketamine 54 mg group could not be evaluated. Carhart-Harris RL, Bolstridge M, Rucker J, et al. A very good summary of @eturnermd1’s recent Lancet Psychiatry ... the USA’s Food and Drug Administration approved Spravato (esketamine), on the basis of just one efficacy study. 2018 Oct 10; Government of Canada. In trials with elderly patients (i.e., TRANSFORM-3, SUSTAIN 2), additional exclusion criteria included a Mini-Mental State Examination score of less than 25, neurodegenerative disorders, or clinically significant cardiovascular disorders. As study results have not yet been fully published, the data were obtained from conference poster presentations and an FDA briefing report (Janssen Inc.: personal communication, 2019 Feb 1).18 An ongoing, open-label extension study is evaluating the safety of esketamine over five years following the completion of the earlier phase III efficacy trials; no results have been posted to date.30. Dissociation symptoms are a prominent side effect known to be associated with esketamine. NCT03738215: Efficacy, safety and tolerability of cariprazine as an adjunctive treatment to antidepressant therapy (ADT) in patients with major depressive disorder (MDD) who have had an inadequate response to antidepressants alone. The Investigator’s Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that … Definition of treatment-resistant depression in the medicare population. Janssen Research & Development, LLC. Reviews that appear to be created by parties with a vested interest in the medication will not be published. Furthermore, the mean difference between treatment groups was statistically significant for almost all the time points throughout the 28 days of treatment. Patients were specifically excluded from any of the five studies if they had MDD with psychotic features, had previously demonstrated nonresponse to ketamine in the current depressive episode, had a history of suicidal ideations in the past six months, or had a history of a substance or alcohol use disorder. Language Assistance Available: Español | 繁體中文 | Tiếng Việt | 한국어 | Tagalog | Русский | العربية | Kreyòl Ayisyen | Français | Polski | Português | Italiano | Deutsch | 日本語 | فارسی | English, U.S. Department of Health and Human Services, Approval Date(s) and History, Letters, Labels, Reviews for NDA 211243, Instructions for Downloading Viewers and Players, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243lbl.pdf While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. a 50% relapse rate not reached based on Kaplan–Meier estimates. Results of a double-blind, randomized phase II trial comparing esketamine 84 mg with placebo twice weekly demonstrated statistically significant improvements in suicidal thoughts within four hours; however, these effects were not sustained at 24 hrs.54 Similarly, esketamine statistically significantly improved depressive symptoms at four hours and approximately 24 hours; however, these effects were not sustained at day 25. National Institute of Mental Health (NIMH). NCT02418585: A study to evaluate the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus an oral antidepressant in adult participants with treatment-resistant depression (TRANSFORM-2). Esketamine is a form of ketamine. The use of this document outside of Canada is done so at the user’s own risk. The approval of esketamine marks a new approach to treating serious mood problems, experts said. Presented at 59th Annual Meeting of Scandinavian College of Neuropsychopharmacology; 2018 Apr 11-13; Aarhus, Denmark. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH. SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites. Cristea and Naudet also commented that efficacy results were not reported for the 24-week follow-up of the 3001 and 3002 trials. It has not yet been approved in any country but is under priority review at Health Canada and recently received FDA approval. The recommended starting dose is one or two sprays in each nostril (depending on the patient’s age) on the first day. In the active-controlled studies, patients were randomized to receive either esketamine nasal spray plus a newly initiated oral antidepressant or placebo nasal spray plus a newly initiated oral antidepressant. Contact requests@cadth.ca with inquiries about this notice or legal matters relating to CADTH services. Drug and health product review and approval Regulatory decision summaries of drugs and health products Understand the decisions to approve or not approve the sale of … This summary report and its contents are made available on an “as is” basis and the Health Sciences Authority makes no warranty of any kind, whether express or implied. Depression and other common mental disorders: global health estimates. On 17.10.19 the European Medicines Agency (EMA) issued a ‘positive opinion’ recommending the granting of marketing authorisation for esketamine for depression in adults and sent it to the European Commission, which has 67 days to make a final … Major depressive disorder (MDD) is a common and debilitating condition; on an annual basis, it is estimated that nearly 14 million Americans will have at least one episode of MDD. For the majority of patients with MDD, available medications, psychotherapy, and alternative therapies (e.g., electroconvulsive therapy, transmagnetic stimulation) are effective at relieving symptoms and achieving disease remission. Garay RP, Zarate CA, Jr., Charpeaud T, et al. Esketamine (Spravato), which the FDA approved in March, is given as a nasal spray. c Approximately two-thirds of patients received esketamine 84 mg and one-third received esketamine 54 mg.18 ICH GCP. Avanir Pharmaceuticals. Psilocybin is a mushroom alkaloid that binds to serotonin receptors. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/211243Orig1s003ltr.pdf, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/211243Orig1s002ltr.pdf, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211243s001lbl.pdf