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Comparative study of esketamine and racemic ketamine in treatment-resistant depression: Protocol for a non-inferiority clinical trial.

ABSTRACT: INTRODUCTION:The use of ketamine as an option in the treatment of depressive disorder is growing rapidly, supported by numerous clinical trials attesting its efficacy and safety. Esketamine, the S (+) enantiomer of ketamine, is the most widely used form in the anesthetic environment in some countries, and new studies have shown that it may also be effective in depression and with better tolerability. However, no study so far has directly compared esketamine with racemic ketamine. Here we propose a protocol of a clinical trial to evaluate esketamine as a noninferior medication when compared to ketamine in the treatment of patients with treatment-resistant depression. METHODS/DESIGN:This study protocol is for a randomized, controlled, double-blind noninferiority clinical trial. Subjects will be 18 years or older, with major depression characterized as treatment-resistant. Participants will receive a single infusion of either esketamine (0.25?mg/kg) or ketamine (0.5?mg/kg) over 40 minutes. The primary outcome will be the difference in remission rates between the 2 treatment arms at 24 and 72?hours after drug infusion. Secondary outcomes will include other timepoints, measurements of cognition, dissociation, and blood biomarkers. DISCUSSION:A head-to-head study is the best way to evaluate whether the esketamine is in fact comparable to the racemic ketamine in terms of both efficacy and safety, and, if positive, it would be an initial step to increase the access to that type of treatment worldwide. ETHICS AND DISSEMINATION:The study was approved by the local Institutional Review Board (University Hospital Professor Edgard Santos-Federal University of Bahia-Number: 46657415.0.0000.0049). Subjects will only participate after voluntarily agreeing and signing the Informed Consent Form. The study findings will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION:This trial has been registered in the Japan Primary Registries Network (JPRN): UMIN000032355, which is affiliated with the World Health Organization.

SUBMITTER: Correia-Melo FS

PROVIDER: S-EPMC6160185 | biostudies-other | 2018 Sep

REPOSITORIES: biostudies-other

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Comparative study of esketamine and racemic ketamine in treatment-resistant depression: Protocol for a non-inferiority clinical trial.

Correia-Melo Fernanda S FS Leal Gustavo C GC Carvalho Michelle S MS Jesus-Nunes Ana Paula AP Ferreira Carolina B N CBN Vieira Flávia F Magnavita Guilherme G Vale Lucas A S LAS Mello Rodrigo P RP Nakahira Carolina C Argolo Felipe C FC Cardoso Tanise T Souza Cezar D S CDS Fontes Ana Teresa C ATC Ferreira Marcelo B MB Araújo-de-Freitas Lucas L Tuena Marco A MA Echegaray Mariana V F MVF Cavalcanti Diogo E DE Lucchese Ana C AC Bandeira Igor D ID Telles Manuela M Lima Cássio S CS Sampaio Aline S AS Silva Samantha S SS Marback Roberta F RF Del-Porto José A JA Abreu José Neander JN Sarin Luciana M LM Paixão Camilla S CS Carvalho Lucas P LP Machado Paulo R L PRL Turecki Gustavo G Lacerda Acioly L T ALT Quarantini Lucas C LC

Medicine 20180901 38

<h4>Introduction</h4>The use of ketamine as an option in the treatment of depressive disorder is growing rapidly, supported by numerous clinical trials attesting its efficacy and safety. Esketamine, the S (+) enantiomer of ketamine, is the most widely used form in the anesthetic environment in some countries, and new studies have shown that it may also be effective in depression and with better tolerability. However, no study so far has directly compared esketamine with racemic ketamine. Here we ...[more]

PMID: 30235716

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Project description:ObjectiveThe N-methyl-D-aspartate receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD) and bipolar depression. Clinical predictors may identify those more likely to benefit from ketamine within clinically heterogeneous populations.MethodData were analyzed from 4 studies of treatment-resistant inpatients with DSM-IV-TR-diagnosed MDD or bipolar I or II depression. Patients who were currently experiencing a moderate-to-severe major depressive episode were enrolled between November 2004 and March 2013. All subjects received a single subanesthetic (0.5 mg/kg) ketamine infusion over 40 minutes. Patients were analyzed at the 230-minute postinfusion time point (n = 108), at day 1 (n = 82), and at day 7 (n = 71). Univariate Pearson correlations were performed for each variable with percent change from baseline in the 17-item Hamilton Depression Rating Scale (HDRS). Multivariate linear regression was then conducted for statistically significant predictors (P ≤ .05, 2-tailed).ResultsHigher body mass index correlated with greater HDRS improvement at 230 minutes (standardized β = -0.30, P = .004) and at day 1 (standardized β = -0.37, P = .001), but not at day 7 (standardized β = -0.18, P = .10). Family history of an alcohol use disorder in a first-degree relative was associated with greater HDRS improvement at day 1 (standardized β = -0.27, P = .014) and day 7 (standardized β = -0.41, P < .001). No prior history of suicide attempt(s) was associated with greater improvement only at day 7 (standardized β = 0.28, P = .01). The overall statistical model explained 13%, 23%, and 36% of HDRS percent change variance at 230 minutes, day 1, and day 7, respectively.ConclusionsDespite its post hoc nature, this study identified several clinical correlates of ketamine's rapid and durable antidepressant effects. Further investigation of these relationships is critical for individualized treatment of depression.

Project description:IntroductionUp to 40% of orthopaedic injuries in children require a closed reduction, almost always necessitating procedural sedation. Intravenous ketamine is the most commonly used sedative agent. However, intravenous insertion is painful and can be technically difficult in children. We hypothesise that a combination of intranasal dexmedetomidine plus intranasal ketamine (Ketodex) will be non-inferior to intravenous ketamine for effective sedation in children undergoing a closed reduction.Methods and analysisThis is a six-centre, four-arm, adaptive, randomised, blinded, controlled, non-inferiority trial. We will include children 4-17 years with a simple upper limb fracture or dislocation that requires sedation for a closed reduction. Participants will be randomised to receive either intranasal Ketodex (one of three dexmedetomidine and ketamine combinations) or intravenous ketamine. The primary outcome is adequate sedation as measured using the Paediatric Sedation State Scale. Secondary outcomes include length of stay, time to wakening and adverse effects. The results of both per protocol and intention-to-treat analyses will be reported for the primary outcome. All inferential analyses will be undertaken using a response-adaptive Bayesian design. Logistic regression will be used to model the dose-response relationship for the combinations of intranasal Ketodex. Using the Average Length Criterion for Bayesian sample size estimation, a survey-informed non-inferiority margin of 17.8% and priors from historical data, a sample size of 410 participants will be required. Simulations estimate a type II error rate of 0.08 and a type I error rate of 0.047.Ethics and disseminationEthics approval was obtained from Clinical Trials Ontario for London Health Sciences Centre and McMaster Research Ethics Board. Other sites have yet to receive approval from their institutions. Informed consent will be obtained from guardians of all participants in addition to assent from participants. Study data will be submitted for publication regardless of results.Trial registration numberNCT0419525.

Project description:ImportanceThe ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD.ObjectiveTo evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT.Design, setting, and participantsThis secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians.ExposuresEligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks.Main outcomes and measuresAssociation between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses.ResultsAmong the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment.Conclusions and relevanceIn this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.

Project description:BackgroundSuicide is among the top 10 leading causes of death worldwide. Of people who died by suicide, the majority are diagnosed with depression. It is estimated that 25%-60% of people with bipolar depression (BD) will attempt suicide at least once, and 10%-15% will die by suicide. Several treatments, such as lithium, clozapine, electroconvulsive therapy, and cognitive behavioral therapy, have been shown to be effective in treating suicidality. However, these treatments can be difficult to tolerate or may take months to take effect. Ketamine, a glutamate N-methyl-D-aspartate antagonist, has been shown to have rapid antisuicidal effect and antidepressant qualities, and is thus a promising intervention to target acute suicidality in patients with BD. However, the biological mechanism underlying its therapeutic action remains poorly understood. Enhancing our understanding of underlying mechanisms of action for ketamine's effectiveness in reducing suicidality is critical to establishing biological markers of treatment response and developing tailored, personalized interventions for patients with BD.ObjectiveThis is an open-label clinical trial to test the safety and feasibility of repeated ketamine infusions to treat acute suicidality. The primary objective is to test the safety and feasibility of ketamine intervention. The secondary objective is to examine ketamine's potential neurophysiological mechanisms of action by assessing cortical excitation and inhibition to determine potential biomarkers of clinical response. Other objectives are to evaluate the effect of ketamine on acute suicidality and other clinical outcomes, such as depressive symptoms and quality of life, to inform a future larger trial.MethodsThis open-label clinical trial aims to test the safety and feasibility of repeated ketamine infusions in patients with BD for suicidality and to assess ketamine's neurophysiological effects. A sterile form of racemic ketamine hydrochloride will be administered over a 40-minute intravenous infusion 2 times per week on nonconsecutive days for 4 weeks (8 sessions). We will recruit 30 adults (24-65 year olds) over 2 years from an academic psychiatric hospital in Toronto, Canada.ResultsThis study is currently ongoing and actively recruiting participants. So far, 5 participants have completed the trial, 1 is currently in active treatment, and 8 participants are on the waitlist to be screened. We anticipate initial results being available in the fall of 2023. This proposal was presented as a poster presentation at the Research to Reality Global Summit on Psychedelic-Assisted Therapies and Medicine, held in May 2022 in Toronto, Canada.ConclusionsDeveloping effective interventions for acute suicidality in high-risk populations such as those with BD remains a major therapeutic challenge. Ketamine is a promising treatment due to its rapid antidepressant and antisuicidal effects, but its underlying neurophysiological mechanisms of action remain unknown.Trial registrationClinicalTrials.gov NCT05177146; https://clinicaltrials.gov/ct2/show/NCT05177146.International registered report identifier (irrid)DERR1-10.2196/41013.

Project description:IntroductionEpilepsy is a chronic condition requiring consistent follow-up aimed at seizure control, and monitoring of anti-seizure medication (ASM) levels and side effects. Telemedicine (TM) offers invaluable support to patient follow-up, guaranteeing the prompt availability of a team of experts for persons with epilepsy (PWE) widely distributed across the country. Although many health institutions have endorsed the use of TM, robust data on effectiveness, safety and costs of TM applied to epilepsy are lacking. TELEmedicine for EPIlepsy Care (TELE-EPIC) will evaluate the effectiveness of video consultation (VC) via TM compared with usual care (UC) for the monitoring of PWE (TELE-EPIC_RCT). Moreover, TELE-EPIC will apply an innovative Volumetric Absorptive Microsampling (VAMS) device for quantitation of ASM through finger prick blood sampling as an alternative to venipuncture sampling (TELE-EPIC_VAMS).Methods and analysisTELE-EPIC_RCT is a multicentre, open, pragmatic two-arm randomised controlled trial prospectively including adult and paediatric outpatients with established diagnosis of epilepsy consecutively attending the Epilepsy Centres of Bologna and Rome, respectively. The primary outcome is the non-inferiority of VC on seizure control compared with UC after an 18-month follow-up. Secondary outcomes are adherence to treatment, ASM-related adverse events, quality of life, mood disorders, patient and caregiver satisfaction, safety and costs. TELE-EPIC_VAMS is a cross-validation study for blood ASM quantitation through a novel, VAMS-based device, comparing (1) VAMS versus plasma samples (reference standard method); and (2) nurse-collected versus self-collected blood by VAMS device.Ethics and disseminationThe study has been approved by the local ethics committee (349-2019-SPER-AUSLBO). Complete information about the state of project, relevant events and results will be regularly updated on the project's webpage on ClinicalTrials.gov. The project's results and data on the potential impact of TM in epilepsy will be disseminated on social media. A closeout meeting will be convened for the communication and dissemination of the project, highlighting its main achievements and impacts.Trial registration numberNCT04496310.

Project description:A single, subanesthetic dose of (R,S)-ketamine (ketamine) exerts rapid and robust antidepressant effects. Several groups previously reported that (2S,6S;2R,6R)-hydroxynorketamine (HNK) had antidepressant effects in rodents, and that (2R,6R)-HNK increased cortical electroencephalographic gamma power. This exploratory study examined the relationship between ketamine metabolites, clinical response, psychotomimetic symptoms, and gamma power changes in 34 individuals (ages 18-65) with treatment-resistant depression (TRD) who received a single ketamine infusion (0.5 mg/kg) over 40 min. Plasma concentrations of ketamine, norketamine, and HNKs were measured at 40, 80, 120, and 230 min and at 1, 2, and 3 days post-infusion. Linear mixed models evaluated ketamine metabolites as mediators of antidepressant and psychotomimetic effects and their relationship to resting-state whole-brain magnetoencephalography (MEG) gamma power 6-9 h post-infusion. Three salient findings emerged. First, ketamine concentration positively predicted distal antidepressant response at Day 11 post-infusion, and an inverse relationship was observed between (2S,6S;2R,6R)-HNK concentration and antidepressant response at 3 and 7 days post-infusion. Norketamine concentration was not associated with antidepressant response. Second, ketamine, norketamine, and (2S,6S;2R,6R)-HNK concentrations at 40 min were positively associated with contemporaneous psychotomimetic symptoms; post-hoc analysis revealed that ketamine was the predominant contributor. Third, increased (2S,6S;2R,6R)-HNK maximum observed concentration (Cmax) was associated with increased MEG gamma power. While contrary to preclinical observations and our a priori hypotheses, these exploratory results replicate those of a recently published study documenting a relationship between higher (2S,6S;2R,6R)-HNK concentrations and weaker antidepressant response in humans and provide further rationale for studying gamma power changes as potential biomarkers of antidepressant response.

Project description:BackgroundEffective, accessible, and affordable depression treatment is of high importance considering the large personal and economic burden of depression. Internet-based treatment is considered a promising clinical and cost-effective alternative to current routine depression treatment strategies such as face-to-face psychotherapy. However, it is not clear whether research findings translate to routine clinical practice such as primary or specialized mental health care. The E-COMPARED project aims to gain knowledge on the clinical and cost-effectiveness of blended depression treatment compared to treatment-as-usual in routine care.Methods/designE-COMPARED will employ a pragmatic, multinational, randomized controlled, non-inferiority trial in eight European countries. Adults diagnosed with major depressive disorder (MDD) will be recruited in primary care (Germany, Poland, Spain, Sweden, and the United Kingdom) or specialized mental health care (France, The Netherlands, and Switzerland). Regular care for depression is compared to "blended" service delivery combining mobile and Internet technologies with face-to-face treatment in one treatment protocol. Participants will be followed up at 3, 6, and 12 months after baseline to determine clinical improvements in symptoms of depression (primary outcome: Patient Health Questionnaire-9), remission of depression, and cost-effectiveness. Main analyses will be conducted on the pooled data from the eight countries (n = 1200 in total, 150 participants in each country).DiscussionThe E-COMPARED project will provide mental health care stakeholders with evidence-based information and recommendations on the clinical and cost-effectiveness of blended depression treatment.Trial registrationFrance: ClinicalTrials.gov NCT02542891 . Registered on 4 September 2015; Germany: German Clinical Trials Register DRKS00006866 . Registered on 2 December 2014; The Netherlands: Netherlands Trials Register NTR4962 . Registered on 5 January 2015; Poland: ClinicalTrials.Gov NCT02389660 . Registered on 18 February 2015; Spain: ClinicalTrials.gov NCT02361684 . Registered on 8 January 2015; Sweden: ClinicalTrials.gov NCT02449447 . Registered on 30 March 2015; Switzerland: ClinicalTrials.gov NCT02410616 . Registered on 2 April 2015; United Kingdom: ISRCTN registry, ISRCTN12388725 . Registered on 20 March 2015.

Dataset Information

Comparative study of esketamine and racemic ketamine in treatment-resistant depression: Protocol for a non-inferiority clinical trial.

Publications

Comparative study of esketamine and racemic ketamine in treatment-resistant depression: Protocol for a non-inferiority clinical trial.

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