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Intravenous (IV) ketamine and intranasal (IN) esketamine have been studied as novel alternatives to manage treatment-resistant depression (TRD). The objective of this observational pilot study is to compare the real-world effectiveness and tolerability of IV ketamine and IN esketamine in the management of unipolar TRD.
To compare the effectiveness (primary outcome measure) and tolerability (secondary outcome measure) of racemic ketamine and esketamine in the management of TRD in adults and provide an expert qualitative commentary on the application of IV ketamine and IN esketamine in clinical practice (exploratory objective), focusing on the recruitment process, patient retention, effectiveness, and tolerability of the treatments.
This is a multicenter prospective observational study of naturalistic clinical practice. We expect to recruit 10 patients per treatment arm—IV ketamine or IN esketamine per center (2 centers, total 40 subjects). Patients experiencing moderate to severe TRD and who are candidates for receiving low-dose IV ketamine treatments or IN esketamine as part of their standard-of-care treatments will be recruited. We will measure the effectiveness of each treatment arm by measuring the severity of depression symptoms using the Montgomery and Åsberg Depression Rating Scale; tolerability, side effects, and the appearance of dissociation symptoms using the simplified 6-item version of the Clinician Administered Dissociative Symptom Scale (CADSS-6); and potential for abuse using a Likeability and Craving Questionnaire. Logistic regression will examine odds ratios, number needed to treat for response and remission, number needed to harm, and likelihood to be helped or harmed of each treatment. Covariate analysis will assess the impact of site and demographic variables on treatment efficacy.
This observational trial was approved by the Queen’s University Health Science and Affiliated Teaching Hospital’s Research Ethics Board in February 2021. The two research centers involved have started patient recruitment. Our research center (Providence Care Hospital, Kingston, Ontario) has recruited 9 patients so far. We expect to finalize data gathering by August 2022. The manuscript is expected to be published by December 2022.
We hypothesize that both treatments will have comparable rapid and robust antidepressant effects and similar tolerability profiles in a real-world setting for the management of TRD.
DERR1-10.2196/34711
Racemic ketamine and its enantiomer esketamine have been studied as novel alternatives for treatment-resistant depression (TRD) in major depressive disorder (MDD) and bipolar depression [
Owing to the significant prevalence and overall mental and physical health impact of TRD [
Therefore, our primary objective will be to compare the effectiveness of IV ketamine and IN esketamine to each achieve clinical response and remission based on the changes of depression scores according to the Montgomery and Åsberg Depression Rating Scale (MADRS) from baseline to study end point in patients with MDD experiencing TRD. We will use the clinical response to treatment to calculate the number needed to treat (NNT). Our secondary objective will be to evaluate the tolerability of these treatments by systematically assessing the appearance of the most commonly reported adverse effects. We will calculate the number needed to harm (NNH) and the likelihood of being helped or harmed (LHH) [
This is a multicenter (Providence Care hospital in Kingston, and the Canadian Rapid Treatment Center of Excellence in Toronto, Mississauga, and Ottawa) observational pilot study of naturalistic clinical practice comparing the efficacy and tolerability of IV ketamine and IN esketamine in the management of patients with MDD and those with TRD [
Study design overview. This study involves 4 weeks of acute ketamine treatment. During the acute phase the patients will have up to 2 sessions per week. Baseline MADRS total scores will be measured on the week before the first treatment. Then, MADRS, side effects and CADSS6 will be done up to 24 hours after the second, fourth, sixth and eighth sessions (side effects and CADSS-6 done up to 24 hours after the first session too). Likeability and Craving questionnaire will be done up to 24 hours after the first and eighth, sessions. CADSS: Clinician Administered Dissociative Symptom Scale; IN: intranasal; IV: Intravenous; MADRS: Montgomery and Åsberg Depression Rating Scale; TRD: treatment-resistant depression.
Patients (n=40), aged 18-65 years, with MDD as determined by Diagnostic and Statistical Manual of Mental Disorders, 5th edition, diagnostic criteria and characterized as moderate to severe TRD (baseline MADRS score≥20 and experienced at least 2 failed antidepressant trials of adequate dose and duration [
After obtaining consent to be enrolled in this study, a demographics questionnaire collecting the following information will be completed: age, gender, marital status, living situation, education, employment, health plan or means of accessing either treatment, drug use, and diagnosed medical or psychiatric comorbidities. The aforementioned factors can influence disease and treatment progression in this patient population [
In the clinic, eligible patients will be offered IN esketamine as part of their standard-of-care treatment for TRD initially as an option. If their health insurance coverage cannot cover the costs of IN esketamine, then patients will be offered IV ketamine. We will observe patients undergoing either IV ketamine or IN esketamine treatments and record their vital signs, any potential side effects during and after administration, and changes in severity of depressive symptoms. For the acute phase, both treatments occur up to twice a week over a period of 4 weeks for a total of 6-8 sessions depending on each of the clinical site’s protocols. Patients may choose to continue their treatments beyond this point in the maintenance phase, but they will not be followed up as part of this study. Patients are asked to have no solid foods or liquids (nil per os) 2 hours prior to treatment. Treatment sessions will occur at each of the 2 centers as part of their ongoing clinical services.
For IV ketamine, an indwelling catheter placed in the nondominant arm is used. This treatment is administered at a subanesthetic dose: 0.5 mg/kg up to 1 mg/kg (depending on the level of response of the patient to the treatment) over 40 minutes. Administration is carried out with the patient in bed rest, and then the patient is asked to remain in bed for 30 minutes after administration before starting activity as tolerated. Nasal cannula oxygen may be administered if needed using side-stream capnometry monitoring. Pulse, blood pressure, pulse oximetry, and electrocardiography are assessed before the start and through the treatment with IV ketamine. Physiological monitoring data are recorded on a standard anesthesia record beginning 5 minutes before treatment. These patients are discharged after a minimum of 30 minutes post administration, provided that the vital signs have returned to baseline and that the patient is calm, alert, and oriented [
IN esketamine is administered as a spray that delivers a 14-mg dose per spray per nostril (28 mg total per device), which the patients self-administer under the supervision of a health care provider. Depending on the response of the patient to the treatment and their clinician’s decision, they may self-administer up to 84 mg of IN esketamine, by using up to 3 devices, waiting 5 minutes between each 28-mg dose, per the esketamine product monograph [
For IV ketamine, patients will start therapy at 0.5 mg/kg [
Effectiveness and tolerability of the ketamine treatments will be determined through assessment scales (MADRS, side effects checklist, CADSS-6, and LCQ) by a trained interviewer, over the phone, through videoconference, or in person when possible. We will inform the patient about the potential risks associated with a phone or videoconference assessment and obtain consent to continue before starting each assessment. Treatment effectiveness will be assessed using the MADRS [
The effectiveness of racemic ketamine and IN esketamine in improving the depression scores will be determined from baseline to the study end point (completion of the treatment course) using the MADRS in patients with an episode of MDD and TRD. Response to treatment will be defined as a minimum reduction of 50% in their baseline depression score. We will calculate the number NNT for response and remission [
We will determine the tolerability of racemic ketamine and esketamine by calculating the NNH and the LHH [
We will gather expert commentary from the attending physicians implementing IV ketamine and IN esketamine treatment at their respective collaborating research centers. We will focus on the recruitment process and overall patient experience (each researcher is asked to keep a systematic record of their recruitment process and patient retention). Then, with this information and the assessment of the effectiveness and tolerability of these treatments, we will make a qualitative commentary on the feasibility of implementing IV ketamine and IN esketamine as standard-of-care treatments in naturalistic clinical practice.
All components of this study were approved by the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board. To protect their privacy, participants will be given an anonymous and unique code that was used to identify their data through all the assessment measures and data processing and for all purposes of knowledge dissemination (including but not limited to peer-reviewed publications, scientific presentations, grant proposals, and reports). Assessment data will be stored in secured and password-protected laptops for 5 years after the study completion date, and hard copies of consent forms and participants identifying data will be stored on site in secured lockers and destroyed 5 years after study completion. The research team will safeguard the privacy of the participants to the extent permitted by the applicable laws and duty to report. Grounds for breaching confidentiality will include immediate physical risk to the self or others, elder abuse, and child abuse and neglect.
The collected data will be analyzed by applying descriptive statistics: mean, median, SD, maximum, and minimum scores for primary and secondary outcome measures and patients’ demographics data. To assess treatment efficacy, changes in depression symptoms as measured with the MADRS with either IV ketamine or IN esketamine treatment and will be tracked and compared over time (1 month of the acute phase) using within-subjects repeated measures ANOVA for each treatment arm. Further, we will calculate the response to treatment as the proportion of patients who reached a minimum reduction of 50% from their baseline depression score by study end point and the remission from depression as the proportion of patients who reported a MADRS total score equal or less than 10 at the study end point [
Since this observational trial was approved by the Queen’s University Health Science and Affiliated Teaching Hospitals Research Ethics Board in February 2021, we began offering patients the opportunity to participate in this study in March 2021 at the Mood Disorders Services in Providence Care Hospital, Kingston. Thus far, we have recruited 9 patients, and we expect to finalize data gathering from the 2 centers by August 2022 and analyze the findings by October 2022 at which point, we will begin our process of knowledge dissemination (including but not limited to peer-reviewed publications, scientific presentations, grant proposals, and reports). The manuscript is expected to be published by December 2022.
Both IV ketamine and IN esketamine have been shown separately to be effective and potent at managing symptoms of TRD [
The two main strengths of this study are that it observes the effectiveness and tolerability of these novel treatments in naturalistic clinical practice, and that both treatments are administered in the same 4 clinics and under similar conditions. Naturalistic clinical administration of IV ketamine and IN esketamine would allow us to better understand how these innovative therapies behave in a real-world setting and with the challenges of administering these treatments in clinical practice, such as scheduling conflicts, managing side effects, and modifying dosing schedules in accordance with symptom improvement and side effects, among others. Further, by having both treatments in the same clinical setting, with minimal changes other than the administration route, we hope to minimize external factors that could confound the effect of the treatments.
Our primary outcome focuses on determining the effectiveness of IV ketamine and IN esketamine on symptoms of depression in patients with MDD experiencing TRD. By applying the MADRS [
The main limitations in this study are associated with the challenges of real-world clinical practice. We foresee that scheduling conflicts with the patients’ treatment sessions may cause alterations in the acute regimen, and some patients may choose to stop the treatment abruptly. Further, the significant cost and still scarce insurance coverage for IN esketamine treatment means that only some patients will be able to opt to receive this treatment. As a result, we may have biases in the demographics of patients who are able to receive either treatment—this will be analyzed at the end of the study. Another limitation is that owing to COVID-19 restrictions, we have resorted to carrying out the assessment scales over the phone. This represents an important limitation, as a key part of understanding the patients’ mental state is through their body language and their appearance. Furthermore, we are not able to carry out the assessment promptly after the treatment sessions and usually have to wait till the patient gets to their home. This represents a problem, especially for side effect–tracking (including dissociation), as the patient is asked to remember their state several hours after the treatment.
In terms of future direction, as this is a pilot study, we are planning to expand this study to include a comparison with other standard-of-care treatments for MDD and TRD. Further, we are planning to carry out a longer-term follow-up assessment of these patients—for 6 months and 1 year—to further assess the extent of the benefit of these innovative treatments. We will also expand the follow-up assessment to both patients who have continued with routine maintenance and those who have slowly tapered their sessions and may no longer be taking the medication. Through this future study, we could help determine effective ways to apply these treatments in clinical practice to achieve long-lasting results and better understand the potential benefits of these treatments over the long term.
IV ketamine and IN esketamine are novel, rapid-acting, promising treatments for TRD; hence, we aim to understand whether these treatments are comparable in terms of effectiveness and tolerability in naturalistic clinical practice. We hypothesize that owing to the chemical similarity of these two compounds, they would have comparable effects; thus, we hope to inform clinical practice in support of either or both treatments.
Side Effects Checklist.
Likeability & Craving Questionnaire.
Simplified 6-Item Clinician Administered Dissociative Symptoms Scale
US Food and Drug Administration
intranasal
intravenous
Likeability and Craving Questionnaire
likelihood to be helped or harmed
Montgomery and Åsberg Depression Rating Scale
major depressive disorder
N-methyl-D-aspartate
number needed to harm
number needed to treat
response rate
treatment resistant depression
The design and development of this research project would not have been possible without the exceptional support of my supervisor, Dr Gustavo Vázquez. I would like to thank Dr Emily Hawken for her continuous support and guidance in the review of this paper. I extend a special thanks to our collaborators Dr Joshua Rosenblat and Dr Jennifer Swainson for their expertise and support in bringing this project to this stage.
GG acquired the data and drafted and critically reviewed the manuscript. JR collaborated in the multicenter study, was the principal investigator at the external site, and critically reviewed the manuscript. EH and GV conceptualized and designed the study and critically reviewed the manuscript. JS collaborated in the multicenter study, was the principal investigator at the external site, designed the assessment scale for Likeability and Craving of Ketamine/Esketamine, and critically reviewed the study.
GV has received consulting and speaking honoraria from AbbVie, Allergan, CANMAT, Elea/Phoenix, Eurofarma, Gador, Janssen, Lundbeck, NeonMind Biosciences, Tecnofarma, Raffo, Otsuka, Psicofarma, and Sunovion, and research grants from CAN-BIND, CIHR, PCH and Queen’s University. JR has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from Janssen, Allergan, Lundbeck, Sunovion and COMPASS. He is the Chief Medical and Scientific Officer of Braxia Scientific and the medical director of Braxia Health (formerly known as Canadian Rapid Treatment Centre of Excellence). JS has received honoraria from AbbVie, Bausch Health, Lundbeck, Otsuka, CCRN, Janssen, Eisai, Sunovion, and is a medical advisor for the Newly Institute. The authors have no further conflicts to declare.