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 [26]. Both IV ketamine and IN esketamine treatments are administered in accordance with the standards-of-care national clinical guidelines [27-29] and pharmaceutical’s monograph approved by Health Canada [30], respectively. Participants with moderate to severe MDD experiencing TRD who have been assessed and approved to receive these innovative therapies will go through an acute phase of treatment of up to 8 sessions (IV ketamine or IN esketamine) for 4 weeks. After the acute phase, patients may continue their treatments per each center’s clinical protocols and will not be followed as part of this research project. Depression symptom severity will be assessed through the treatment course using the MADRS [31]. Side effects will be recorded through treatment sessions as well, using a checklist of common side effects [32], and we will use the Simplified 6-Item Clinician Administered Dissociative Symptoms Scale (CADSS-6) [33] to assess the severity of dissociative symptoms during treatment (a common side effect in NMDA glutamatergic treatments). Further, potential for abuse of these treatments will be evaluated using a Likeability and Craving Questionnaire (LCQ) (Dr Jennifer Swainson and Dr Jay Wang, University of Alberta, Edmonton). Figure 1 presents a summary of the experimental design.

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 [26,34]) will be assessed to receive IV ketamine or IN esketamine treatment as part of their standard-of-care treatment. Exclusion criteria are reporting any active substance abuse, symptoms of psychosis, diagnosis of bipolar disorder, or personality disorder as the primary diagnosis (as defined by the patient’s psychiatrist or primary care provider), uncontrolled hypertension, previous negative reaction to racemic ketamine or esketamine, and being currently pregnant or breastfeeding. These patients will be consented to be followed through their treatment course, as part of our research study. This is an observational open-label pilot study, which usually requires a minimum sample of 10-12 participants per treatment arm, considering a main study with a power estimate of 90% and CI of 95% [35-40]. Hence, we consider that our sample size (N=40) is sufficient.

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 [41,42]. For instance, socioeconomic differences could promote or hinder the improvement of depression symptoms because of this treatment. Demographic data will be used to stratify our results to better understand their impact on treatment efficacy.

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 [27].

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 [30]. Patients are allowed to start activity as tolerated after administration. Nasal cannula oxygen may be administered if needed using side-stream capnometry monitoring. Pulse, blood pressure, and pulse oximetry are assessed before the start and for 30 minutes after the IN spray of esketamine. Physiological monitoring data are recorded on a standard anesthesia record beginning 5 minutes before treatment. Then, these patients are discharged after a minimum of 2 hours post administration, provided that the vital signs have returned to baseline and that the patient is calm, alert, and oriented [27].

For IV ketamine, patients will start therapy at 0.5 mg/kg [28,29,43]. If the patient has a partial response (defined as a decrease in the MADRS total score of between 25% and <50% of the baseline) after the second week of treatment, the dose will be increased to 0.75 mg/kg for IV ketamine. For IN esketamine, the recommended dose titration by the manufacturer and approved by Health Canada will be followed (i.e., 56 mg on the first treatment and from then on 84 mg per treatment) [44,45]. Further dose modifications can be carried out on an individual level as needed, and an average dose throughout the treatment will be reported to account for these changes.

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 [46]. Logistic regression will be used to calculate odds ratios. Moreover, we will calculate the NNT, the NNH, and the LHH: NNT by considering the response to treatment and NNH by considering the proportion of patients who completed the study versus the dropouts and the adverse effects (side effects checklist and dissociation using the CADSS-6) experienced by the patients. LHH will be calculated as the ratio of NNH and NNT [25]. Linear regression will examine the contribution of treatment arm (IV ketamine versus IN esketamine), site, and patients’ demographic data to account for the influence of these variables to our calculation of effectiveness. Adverse events will be reported in terms of frequency through the treatment course. The data will be compared using a Mann-Whitney U test to determine if there is a significant difference in the response to the 2 treatments (mean depressive scores, mean dissociation scores, and mean LCQ scores). The effect size of each treatment will be calculated using Cohen d [47].

Both IV ketamine and IN esketamine have been shown separately to be effective and potent at managing symptoms of TRD [1-8]. Meta-analytic indirect comparison of these 2 treatments favored IV ketamine, showing that overall, it has a higher response, higher remission rates, and lower dropouts than IN esketamine. Though it is important to mention that phase 3 studies tend to have smaller effect sizes than phase 2 studies [48], and unlike with ketamine, there are phase 3 studies with esketamine, which may impact this analysis [8]. However, IN esketamine has been recently approved for the management of TRD by the FDA and Health Canada [8] and has several features that can make it a more desirable treatment. For instance, its higher affinity for the NMDA receptor means that it can be administered at lower doses than IV ketamine, and IN administration is more convenient and comfortable for patients than IV administration. However, the high cost of IN esketamine treatment may be a significant limiting factor for patients [20,23,49]. Nevertheless, currently, there are no direct comparisons of these 2 treatments in clinical practice, and most of the information that we have about either treatment comes from clinical trials that usually present an overly idealistic version of real-world clinical practice [8,9,13]. Thus, this research study aims to fill this gap through a head-to-head comparison of racemic low-dose IV ketamine with IN esketamine treatment in a multicenter (Providence Care hospital in Kingston and the Canadian Rapid Treatment Center of Excellence in Toronto, Mississauga, and Ottawa) pilot evaluation of naturalistic clinical practice. Hence, through this study, we aim to guide clinical practice in support of either or both treatments in terms of effectiveness and tolerability.

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 [31], we will track the change in the severity of depressive symptoms and compare the effectiveness of these 2 treatments in terms of clinical response and remission from depression and reduction in suicidal ideation. Clinical response results will be taken into account to calculate the NNT [25] for IV ketamine and IN esketamine. Our secondary outcome focuses on the tolerability of IV ketamine and IN esketamine on patients with MDD experiencing TRD. By applying different measurements focusing on side effects (side effects checklist [32]), including dissociation (CADSS-6 [33]) and potential for abuse or craving (LCQ), we will observe the patients through their treatment course to determine the NNH and the LHH [25]. Our exploratory outcomes will focus on the expert commentary of the attending physicians at each of the collaborating research centers with regard to their recruitment process and patient experience through the treatment course. This information and our assessment of the effectiveness and tolerability of these treatments will be used to make a qualitative commentary on the feasibility of implementing IV ketamine and IN esketamine as standard-of-care treatments in naturalistic clinical practice. From this pilot study, we expect that IN esketamine may be less accessible (owing to cost) and thus less feasible for the average person with TRD. We also expect that both treatments will be similar in terms of effectiveness and tolerability; thus, these results will help inform clinical practice in the use of these novel treatments for the management of TRD.

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.