Expand section Collapse section. Source: Janssen Inc.: personal communication, 2019 Feb 1). Garay RP, Zarate CA, Jr., Charpeaud T, et al. One author screened the literature search results and reviewed the full text of all potentially relevant studies. 2. Minocycline is a tetracycline antibiotic with potential anti-inflammatory and neuroprotective benefits, and is being investigated in a phase II. 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. Table 2: Summary of Key Efficacy Outcomes From Four of the Phase III Trials. Spravato™ or Esketamine was FDA approved for use in treatment resistant depression on March 5, 2019. The frequency of adverse events in the comparator group was only reported in the TRANSFORM-3 trial as 60%. Regular alerts updated the search until project completion; only citations retrieved before March 13, 2019 were incorporated into the analysis. The recommended starting dose is one or two sprays in each nostril (depending on the patient’s age) on the first day. Conference abstracts and grey literature were included when they provided additional information to that available in the published studies. Authors: Bryanna Nicole Tibensky, Louis de Léséleuc, Christine Perras, Lory Picheca. All the completed phase III trials, with the exception of SUSTAIN 1, included a four-week screening period prior to randomization. In all of the phase III trials, TRD was defined as nonresponse (i.e., 25% or less improvement) to two or more oral antidepressants in the current episode of depression, at a therapeutic dose for at least six weeks in duration. At 21–28 days, esketamine had a g value of g = 0.417 (N = 3, 95% CI: 0.238 to 0.596, p < 0.01). Definitions of treatment resistant depression vary; one accepted definition is lack of response to two or more antidepressants. On May 24, 2019, the Food and Drug Administration approved ruxolitinib for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in adult and pediatric patients 12 years and older. The specific reasons for stopping treatment were not reported. NCT03434041: A study to evaluate the efficacy, pharmacokinetics, safety and tolerability of flexible doses of intranasal esketamine plus an oral antidepressant in adult participants with treatment-resistant depression. CADTH does not have control over the content of such sites. Naurex, Inc, an affiliate of Allergan plc,. If they approve esketamine, on the basis of such inadequate research, it will suggest they are more interested in keeping the drug company happy than keeping the public safe. Plain language summary. Furthermore, there is a lack of evidence comparing intranasal esketamine to current adjunctive strategies for TRD. Adverse events most frequently reported included dizziness, nausea, dissociation, headache, vertigo, sedation, increased blood pressure, dysgeusia (altered sense of taste), hypoesthesia (reduced sense of touch), vomiting, and viral upper respiratory tract infection. Other efficacy outcomes data are summarized in Table 3. Understanding intravenous ketamine infusion therapy. In the induction phase, 198 (25.4%) patients withdrew, and of the 603 patients who entered the optimization and maintenance phase, 120 patients discontinued prior to study completion. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 3. pharmacological treatments. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study. The FDA approved ketamine in 1970. Esketamine also statistically significantly reduced the hazard for relapse for stable remitters (HR 0.49; 95% CI: 0.29 to 0.84, P = 0.003) and for stable responders (HR 0.30; 95% CI: 0.16 to 0.55, P < 0.001). Naurex, Inc, an affiliate of Allergan plc. 2019; Gould TD, Zarate CA, Jr., Thompson SM. According to the FDA, esketamine plus a newly initiated oral antidepressant statistically significantly delayed a relapse event, compared with placebo plus antidepressant, for both stable remitters (i.e., defined as 50% or higher reductions in MADRS score) and stable responders (i.e., defined as a MADRS score of 12 or less).18 The largest differences in relapse time between treatment groups occurred within the first two to four weeks. Hepatic enzyme inhibitors Psilocybin is a mushroom alkaloid that binds to serotonin receptors. Orally administered ketamine has recently been investigated for TRD in a phase I proof-of-concept study.34 In this study, oral ketamine decreased depressive symptoms and was well-tolerated. VTGN's PH94B in Phase 3 clinical trial for treatment of social anxiety disorder was only able to beat placebo by 2 to 12 points on the 100-point LSAS scale. 11 . Serious adverse events in the placebo group were only reported in TRANSFORM-3 (3.1%). Depression and other common mental disorders: global health estimates. ICH GCP - . The U.K. approved the world’s first COVID-19 human challenge trial By Jonathan Lambert February 18, 2021. We should cautiously welcome this new therapeutic option On 5 March 2019 the US Food and Drug Administration approved esketamine nasal spray in conjunction with an oral antidepressant for people with treatment resistant depression. 2019 Mar 6; Janssen Research & Development, LLC. While definitions of so-called “treatment-resistant” depression vary, this generally refers to patients with persistent depression after attempted management with two or more medications. Of these serious adverse events, five were considered related to esketamine — anxiety, delusion, delirium, suicidal ideation, and suicidal attempt. 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. This subpopulation of patients with TRD could benefit from esketamine. The documents include regulatory, safety, effectiveness and quality (chemistry and manufacturing) considerations. 2018-002669-20: A multicentre, double-blind, randomised, placebo - controlled phase II study to assess efficacy, safety and pharmacokinetics of inhaled Esketamine in subjects with treatment-resistant bipolar depression. 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. The information in the summary report is provided for general information only and the contents of the summary report do not constitute medical or other professional advice. 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. In one phase III trial, esketamine plus a newly initiated antidepressant demonstrated a statistically significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) scores relative to placebo plus a newly initiated antidepressant. Summary of Risk Management Plan for esketamine nasal spray. Another examination of Janssen’s FDA application for esketamine finds the drug to be ineffective as an antidepressant, and associated with a host of worrying side effects. MDD is characterized by symptoms of persistent low mood, changes in appetite and sleep, fatigue, loss of motivation, interest or pleasure, or feelings of worthlessness.1 It can also be associated with a substantial loss in productivity, quality of life, and increased mortality from suicide. The increase in C max and AUC values was less than dose-proportional between 28 mg and 56 mg or 84 mg, but it was nearly dose proportional between 56 mg and 84 mg. Interactions. Investigational drugs in recent clinical trials for treatment-resistant depression. a Includes 54 mg and 84 mg doses. The approval of esketamine nasal spray was based, in large part, on efficacy and safety findings from phase 2 and phase 3 studies in patients with TRD (Daly et al., 2018, 2019; Popova et al., 2019; Fedgchin et al., 2019; Wajs et al., 2020; Ochs-Ross et al., 2020). The drug manufacturer also provided input on an earlier draft of this report. 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. PDF | Background: Esketamine nasal spray was recently approved for treatment-resistant depression (TRD). Johnson & Johnson. The appraisal will therefore be paused. The majority of these side effects were mild or moderate in severity and resolved within a few hours of administration. SPRAVATO ® (esketamine) Janssen-Cilag AG. 7.1 Introduction. Thus far, most research has been on ketamine infusions. Just two positive trials formed the basis of the FDA approval: one short-term trial that demonstrated efficacy up to 4 weeks, and -- in an unusual move by the FDA -- … I. NCT02263872: Minocycline as an adjunct for the treatment of depressive symptoms: pilot randomized controlled trial. 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 … James Murrough. Sirukumab and tocilizumab, monoclonal antibodies that bind respectively interleukin-6 and its receptor, are being investigated for TRD in phase II trials. The only drug approved to treat MDD in the past decade is that of Johnson & Johnson's (NYSE:JNJ) esketamine. AXS-05 (Axsome) is a combination of dextromethorphan and bupropion that received Fast Track designation from the FDA for TRD in 2017. CI = confidence interval; Esk = esketamine plus newly initiated oral antidepressant; IND = induction phase; LSM = least squares means; N/A = not applicable; MADRS = Montgomery-Åsberg Depression Rating Scale; PL = placebo nasal spray plus newly initiated oral antidepressant; SD = standard deviation. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services. Furthermore, the overall number of withdrawals in the long-term safety study was quite high, which could introduce bias to the results. NCT03675776: Study of rapastinel as monotherapy in patients with major depressive disorder (MDD). Janssen Research & Development, LLC. Cristea and Naudet also commented that efficacy results were not reported for the 24-week follow-up of the 3001 and 3002 trials. The SBD for is located below.. With subsequent esketamine dosing, the severity of dissociative symptoms appeared to lessen. Esketamine: new therapy for severe depression . The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. 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. Summary. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. 2019 Mar 5; Center for Drug Evalulation and Research. 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. Patten SB, Lee RC. The U.S. Food and Drug Administration (FDA) approved esketamine nasal spray for use in … 2018 Oct 10; Government of Canada. Where SmPC information can be found? Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Source: Janssen Inc.: personal communication, 2019 Feb 1. Al-Harbi KS. NCT02153502: Efficacy, safety, and tolerability study of AVP-786 as an adjunctive therapy in patients with major depressive disorder with an inadequate response to antidepressant treatment. Summary for Treatment of Major Depressive Disorder. Spravato is available as a nasal spray to be used by the patient in a clinic or doctor’s office, under the direct supervision of a healthcare professional. 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. PART VI: SUMMARY OF THE RISK MANAGEMENT PLAN. An intranasal formulation of esketamine, combined with an oral antidepressant, is approved in the USA and the European Union for adults with treatment-resistant depression (TRD). The budget impact is unknown, as the Canadian acquisition cost is not yet available.The budget impact will largely depend on its sequential place in therapy within the context of other treatment options currently on the market for MDD. Priming of the device is not required but a five-minute rest period in-between each device is advised. The copyright and other intellectual property rights in this document are owned by CADTH and its licensors. Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec. Cariprazine is an atypical antipsychotic drug being investigated in a phase III trial for TRD. Overall, these adverse events were less common in elderly patients than in adult patients. NoP = number of patients; NR = not reported; N/A = not applicable. Pakistan Institute of Living and Learning. NCT03097133: A study to evaluate the efficacy and safety of intranasal esketamine in addition to comprehensive standard of care for the rapid reduction of the symptoms of major depressive disorder, including suicidal ideation, in adult participants assessed to be at imminent risk for suicide (Aspire II). Effect of other medicinal products on esketamine. Data sources include IBM Watson Micromedex (updated 3 Mar 2021), Cerner Multum™ (updated 1 Mar 2021), ASHP (updated … There remains an unmet need for a safe and effective treatment of TRD for which esketamine offers the potential to address. Table 1: Summary of Esketamine Phase III Trials — Patient and Trial Characteristics. This is a summary of the risk management plan (RMP) for esketamine nasal spray. 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). In three of the phase III trials, discontinuation of esketamine due to adverse events ranged from 2.6% to 9.5% in the esketamine treatment group and 2.1% to 3.1% in the comparator group. One major limitation of the evidence base presented in this bulletin is that all results were obtained from an FDA briefing report and unpublished conference posters that are not peer-reviewed and may include data gaps. Page 37 ... An important new entry and FDA-approved treatment for MDD in 2019 is the approval of intranasal esketamine. Drug and health product submissions under review (SUR): esketamine hydrochloride. 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. Carhart-Harris RL, Bolstridge M, Rucker J, et al. Esketamine plus a newly initiated oral antidepressant also statistically significantly reduced relapse events and delayed the occurrence of a relapse event. Dissociative symptoms, blood pressure elevations, and sedation were reported to resolve within a few hours but may require patient monitoring shortly after drug administration. No cases of psychosis, or ulcerative or interstitial cystitis, were reported. In SUSTAIN 2 — a longer-term, open-label safety study that followed participants for up to one year — 55 patients reported 68 serious adverse events, with the most common events occurring in greater than two patients including depression, suicidal ideation, suicide attempt, nephritis, anxiety, and gastroenteritis. CADTH has no responsibility for the collection, use, and disclosure of personal information by third-party sites. The FDA requires that the recently approved esketamine be administered only in settings capable of implementing a Risk Evaluation and Mitigation Strategy (REMS). © 2021 Canadian Agency for Drugs and Technologies in Health, https://apps.who.int/iris/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf;jsessionid=073A899990718FDDE11F70671E1D49D1?sequence=1, http://www.io.nihr.ac.uk/report/esketamine-for-treatment-resistant-depression/, https://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id105TA.pdf, https://www.cadth.ca/sites/default/files/pdf/htis/2017/RC0855%20Ketamine%20for%20Resistant%20Depression%20Final.pdf, https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM630970.pdf, https://www.cambridge.org/core/services/aop-cambridge-core/content/view/B1568F88C93EBF4E12820A1BB1755A65/S0924270818000121a.pdf/abstracts_scandinavian_college_of_neuropsychopharmacology_scnp_59th_annual_meeting_11_13_april_2018_aarhus_denmark.pdf, https://clinicaltrials.gov/ct2/show/NCT02497287, https://clinicaltrials.gov/ct2/show/NCT02417064, https://clinicaltrials.gov/ct2/show/NCT02418585, https://clinicaltrials.gov/ct2/show/NCT02422186, https://clinicaltrials.gov/ct2/show/NCT02493868, https://www.jnj.com/janssen-submits-european-marketing-authorisation-application-for-esketamine-nasal-spray-for-treatment-resistant-depression, https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/submissions-under-review.html, https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761.htm, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf, https://www.reuters.com/article/us-johnson-johnson-fda-pricing/jj-prices-ketamine-like-depression-treatment-at-590-885-for-two-doses-idUSKCN1QN2AX, https://clinicaltrials.gov/ct2/show/NCT02782104, https://clinicaltrials.gov/ct2/show/NCT03434041, https://clinicaltrials.gov/ct2/show/NCT03560518, https://clinicaltrials.gov/ct2/show/NCT03675776?term=rapastinel&recrs=a&phase=2&rank=3, https://clinicaltrials.gov/ct2/show/NCT02741791?term=axsome&rank=2, https://clinicaltrials.gov/ct2/show/NCT03738215?term=Cariprazine&cond=%22Depression%22&phase=2&rank=4, https://clinicaltrials.gov/ct2/show/NCT03739203?term=Cariprazine&cond=%22Depression%22&phase=2&rank=5, https://clinicaltrials.gov/ct2/show/NCT01882829, https://clinicaltrials.gov/ct2/show/NCT02153502, https://clinicaltrials.gov/ct2/show/NCT02484456, https://clinicaltrials.gov/ct2/show/NCT03078322?term=AV-101&phase=12&rank=1, https://clinicaltrials.gov/ct2/show/NCT02456948, https://clinicaltrials.gov/ct2/show/NCT02263872, https://clinicaltrials.gov/ct2/show/NCT02660528, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-005206-37, https://clinicaltrials.gov/ct2/show/NCT02805439?term=NCT02805439&rank=1, https://clinicaltrials.gov/ct2/show/NCT03039192, https://clinicaltrials.gov/ct2/show/NCT03097133, https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-002669-20, Randomized, double-blind, active-controlled, multi-centre study, Intervention: Esketamine 56 mg (n = 117) or 84 mg (n = 116) intranasally twice per week, Intervention: Esketamine 56 mg or 84 mg intranasally twice per week (n = 114), Intervention: Esketamine 28 mg, 54 mg, or 84 mg intranasally twice per week (n = 72), Active-controlled, multi-centre study (N = 705), Induction/Optimization Phase: adults (18 to 64 years) with MDD: recurrent or single-episode (≥ 2 years), IDS-C30 ≥ 34, TRD, Intervention: Induction (for direct-entry participants only): esketamine 56 mg or 84 mg intranasally twice per week for 4 weeks, Uncontrolled, open-label, multi-centre study, Intervention: Induction: esketamine 28 (for ≥ 65 years old), 56 mg or 84 mg intranasally twice per week, BPIC-SS Cogstate domains and HVLT-R withdrawal symptoms (assessed by PWC-20), Intervention: Esketamine 56 mg or 84 mg intranasally twice per week, Uncontrolled, open-label, long-term extension study, Patients from ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3005, and ESKETINTRD3006 (US sites only), Intervention: Induction: esketamine 24 mg, 56 mg, or 84 mg intranasally twice per week for 4 weeks, TEAE Blood pressure, heart rate, blood oxygen saturation, ECG, MOAAS score Computerized Cognitive Battery Domain HVLT-R C-SSRS. This is a summary … In animal reproduction studies in rats developmental delays (hypoplasia of skeletal tissues) were noted at 0.3 times the human intramuscular dose of 10 mg/kg. Studies were considered for inclusion if the intervention was esketamine (S-ketamine) and studied for treatment-resistant depression in a phase III trial. d 2-sided P value. Sassano-Higgins S, Baron D, Juarez G, Esmaili N, Gold M. A review of ketamine abuse and diversion. Although esketamine is formulated in a more convenient nasal spray device, it must be administered under direct medical supervision. Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policymakers make well-informed decisions and thereby improve the quality of health care services. f MADRS ≤ 12. 1.What is the summary of product characteristics (SmPC)? 2. Esketamine nasal spray was approved by the European Commission for use in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI), in adult patients with treatment-resistant major depressive disorder (TRD) in December 2019. The dosage regimen used in the completed and ongoing phase III trials is esketamine 28 mg, 56 mg, or 84 mg intranasally twice weekly for four weeks, followed by once weekly for four weeks, then once weekly or once every other week for ongoing maintenance therapy.18,20-24,30,31 As a result, the cost of therapy will vary based on the dose used per session and the number of treatment sessions administered, both of which can differ from patient to patient. Gaynes BN, Dusetzina SB, Ellis AR, et al. Definitions of treatment resistant depression vary; one accepted definition is lack of response to two or more antidepressants. BPIC-SS = bladder pain/interstitial cystitis symptom score; C = clinician rating; CGADR = clinical global assessment of discharge readiness; CGI-S = clinical global impression – severity; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EQ-5D-5L = EuroQol 5-Dimension 5-Levels questionnaire; GAD-7 = Generalized Anxiety Disorder 7-item scale; HVLT-R = Hopkins Verbal Learning Test‒Revised; ID = identification; IDS = Inventory of Depressive Symptomatology; MADRS = Montgomery-Åsberg Depression Rating Scale; MOAAS = Modified Observer's Assessment of Alertness/Sedation scale; PHQ-9 = Patient Health Questionnaire‒9; PWC-20 = Physician Withdrawal Checklist; SDS = Sheehan Disability Scale; TEAE = treatment-emergent adverse events; TRD = treatment-resistant depression. Janssen-Cilag International N.V. 2014-005206-37: A double-blind, placebo-controlled, multicenter study of sirukumab as adjunctive treatment to a monoaminergic antidepressant in adults with major depressive disorder. Cautions currently exist surrounding driving after receiving ketamine, given the potential for dissociative and sedative side effects.18,57 A small, double-blind, randomized phase I study assessed esketamine’s impact on driving performance.59 Healthy patients received single doses of esketamine 84 mg intranasally, oral placebo, and mirtazapine 30 mg orally in a crossover design. Canuso CM, Singh JB, Fedgchin M, et al. About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system. a 50% relapse rate not reached based on Kaplan–Meier estimates. Subject to the aforementioned limitations, the views expressed herein do not necessarily reflect the views of Health Canada, Canada’s provincial or territorial governments, other CADTH funders, or any third-party supplier of information. Users are permitted to make copies of this document for non-commercial purposes only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors. Blood pressure elevations, dissociative symptoms, and sedation occurred more often in the esketamine treatment group. Lam RW, McIntosh D, Wang J, et al. Given the prevalence of dissociation and sedation in the larger phase III trials, the risk for potential accidents and the impact on driving may still be of concern. All previous oral antidepressants to which patients did not respond were discontinued. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH. 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 Spravato™ or Esketamine was FDA approved for use in treatment resistant depression on March 5, 2019. Two (0.3%) deaths occurred in the optimization and maintenance phase of the SUSTAIN 2 trial — one due to acute respiratory and cardiac failure, and the second due to completed suicide (Janssen Inc.: personal communication, 2019 Feb 1). Kennedy SH, Lam RW, McIntyre RS, et al. Brigham and Women's Hospital. At 7–20 days, IN esketamine had a g value of g = 1.018 (N = 4, 95% CI: 0.499 to 1.538, p < 0.01). b Includes 24 mg, 54 mg, and 84 mg doses. One key concern with ketamine is its safety profile, specifically dissociative and cognitive side effects, sedation, elevations in blood pressure, and toxicity to the urinary system.57 With the exception of cognitive dysfunction, these side effects were also reported with intranasal esketamine use (Janssen Inc.: personal communication, 2019 Feb 1). 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 … This is an intra-nasal form of ketamine which was shown to be effective in conjunction with an antidepressant in treating severe and debilitating depression labeled as treatment resistant depression or TRD. 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.
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