This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on https://www.researchprotocols.org, as well as this copyright and license information must be included.
Major depressive disorder is among the most disabling illnesses worldwide, with a lifetime prevalence of 16.2%. Research suggests that 20% to 40% of patients with depression do not respond to pharmacotherapy, developing treatment-resistant depression. Electroconvulsive therapy is the gold standard for treating individuals with treatment-resistant depression, with remission rates of approximately 75% to 90%. However, 10% to 25% of patients do not respond to electroconvulsive therapy, and many are unable to tolerate it due to the side effects. Both groups are considered to be patients who do not respond to electroconvulsive therapy, because both groups continue to exhibit symptoms of severe depression, have a limited number of treatment options available, and are in need of rapid treatment. Ketamine, an N-methyl-D-aspartate receptor antagonist, has been shown to exert rapid antidepressant effects in patients with treatment-resistant depression when administered in subanesthetic doses through 40-minute intravenous infusions. Recently, a ketamine compound, esketamine (Spravato), that is administered through the intranasal route received regulatory approval by the US Food and Drug Administration and Health Canada to treat depression. However, esketamine is challenging to access due to high costs and limited availability. Racemic ketamine (rketamine) is cheap and easy to access; however, the effects in patients who have not responded to electroconvulsive therapy have yet to be understood or tested. This study will use transcranial magnetic stimulation to study mechanisms of human brain cortical physiology at the systemic level to identify neurobiomarkers of response.
The objective of this open-label pilot clinical trial is to test the feasibility and safety of intranasal ketamine in patients who have not responded to electroconvulsive therapy. The primary outcome is to determine the feasibility of a larger randomized controlled trial to test the efficacy of intranasal ketamine for patients who have not responded to electroconvulsive therapy for clinical indicators in unipolar depression. The secondary outcome is to determine the preliminary effects of an intervention on clinical outcomes, such as depressive symptoms, suicidal ideation, and quality of living. The third outcome is to explore neurophysiological changes as measured by transcranial magnetic stimulation electromyography and electroencephalography to measure changes in cortical excitability as potential predictors of clinical response.
A sterile solution of racemic ketamine hydrochloride will be administered twice per week for 4 weeks (8 sessions) intranasally to patients with treatment-resistant depression who did not respond to or could not tolerate an acute course of electroconvulsive therapy. We will recruit 25 adults (24-65 years old) over the course of 2 years from an academic psychiatric hospital in Toronto, Canada.
This study has received ethics approval, and funding has been secured. The study is currently active.
This is the first study to test repeated doses of intranasal rketamine in patients who have not responded to electroconvulsive therapy for depression. Results from this study will (1) inform the development of a larger adequately powered randomized controlled trial to test the efficacy of intranasal ketamine for depression and (2) determine potential neurophysiological markers of clinical response.
Clinical Trials.gov NCT05137938; http://clinicaltrials.gov/ct2/show/NCT05137938
PRR1-10.2196/30163
Depressive disorders remain common, severe, and debilitating, with a lifetime prevalence estimated at 16.2% [
Ketamine, a noncompetitive high-affinity
Although intravenous ketamine has demonstrated rapid antidepressant effects, its delivery method remains challenging because it requires specialized expertise and equipment for administration [
Noninvasive brain stimulation neurophysiological tools, such as transcranial magnetic stimulation (TMS), offer an elegant opportunity to study mechanisms of human cortical physiology at the systemic level. The combination of TMS with a central nervous system pharmacological agent, such as ketamine, provides a platform to explore the neurophysiological impact of ketamine and allows neurophysiological biomarkers of treatment response to be identified. Until recently, only a few studies [
In this study, we aim to assess the safety and feasibility of intranasal rketamine in patients with unipolar depression who did not respond to the acute course of electroconvulsive therapy to inform a larger randomized controlled trial and examine potential neurophysiological biomarkers of response. TMS- electromyography (EMG) and electroencephalography (EEG) paradigms can be used to investigate the impact of ketamine on cortical activities via intracortical facilitation and short-interval cortical inhibition paradigms [
This is an open-label pilot study to assess the feasibility of conducting a randomized controlled trial to test the safety, tolerability, and efficacy of intranasal ketamine in patients with treatment-resistant depression who did not respond or were not able to tolerate a course of acute electroconvulsive therapy.
This study has received Centre for Addiction and Mental Health (CAMH) research ethics board (095-2019) and Health Canada approval. For this pilot trial, all relevant adverse events and all serious adverse events will be reported if they meet applicable reporting requirements. All data monitoring, auditing, and harms reporting will be performed according to CAMH research ethics board and regulatory standards.
Over a period 2 years, we intend to recruit 25 adults aged 24 to 65 years old diagnosed with treatment-resistant depression from one site (CAMH).
Patients will be assessed for eligibility based on inclusion and exclusion criteria.
Inclusion criteria are patients who (1) have a DSM-5 diagnosis of nonpsychotic major depressive disorder, confirmed by the Mini-International Neuropsychiatric Interview; (2) meet criteria for being nonresponsive to electroconvulsive therapy in the current episode (nonresponse is defined as lack of improvement in depressive symptoms after 8 acute sessions of electroconvulsive therapy, confirmed with the Hamilton Rating Scale for Depression (HRSD-24 score >14), and nontolerability is determined by a brain stimulation psychiatrist based on side effects, such as postictal confusion, significant cognitive impairment, severe worsening in anxiety preventing a patient from continuous treatment, or failure to secure intravenous access safely); (3) exhibit moderate to severe symptoms of depression (HRSD-24 score >14); (4) are capable of providing consent; (5) are outpatients; (6) are able to speak and understand English; and (7) are aged 24 to 65 years, inclusive.
Exclusion criteria are patients (1) with a history of a substance use disorder within the past month or lifetime history of ketamine substance use disorder, confirmed by the Mini-International Neuropsychiatric Interview; (2) with concomitant major unstable medical illness (eg, poorly controlled blood pressure; enlarged prostate; unresolved urinary related issues); (3)with a confirmed pregnancy or the intention to become pregnant and breastfeeding during the study (self-report), and female participants of reproductive age must be willing to use a medically acceptable method of birth control that includes highly effective (eg, approved hormonal contraceptives, intrauterine device, tubal ligation), double barrier (eg, male condom with a diaphragm, male condom with cervical cap) methods of contraception, or abstinence if that is the usual and preferred lifestyle of the participant; (4) with cardiac decompensation or heart failure; (5) with a DSM-5 diagnosis of any primary psychotic disorder, bipolar disorder, obsessive-compulsive disorder, or current posttraumatic stress disorder, confirmed by the Mini-International Neuropsychiatric Interview; (6) with a diagnosis of severe personality disorder, assessed during the initial consultation with a physician at the study site prior to study entry; (7) with any significant neurological disorder (eg, a space-occupying brain lesion, a history of stroke, a cerebral aneurysm, a seizure disorder, Parkinson disease, Huntington chorea, multiple sclerosis), assessed through medical history review during the initial consultation with a physician at the study site prior to study entry; (8) with a medical condition, taking medication, or with a laboratory abnormality that could cause a major depressive episode or significant cognitive impairment in the opinion of the investigator; (9) requiring a benzodiazepine with a dose equivalent to lorazepam 2 mg/day or higher; (10) on any anticonvulsant (eg, lamotrigine) or opioid medication due to the potential of these medications to limit the efficacy of ketamine; (11) with the inability to communicate in spoken and written English fluently enough to complete the required study assessments due to a language barrier or a noncorrectable clinically significant sensory impairment (ie, cannot hear or see well enough to complete clinical assessments); (12) with any cognitive or physical impairment which may potentially interfere with intranasal ketamine administration or the patient’s ability to stay in the same place for a 2-hour monitoring supervision, assessed through medical history review during the initial consultation with a physician at the at the study site prior to study entry; (13) with any intracranial implants (eg, aneurysm clips, shunts, cochlear implants) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed given that we will be using TMS-EMG/EEG; (14) with the inability to secure escort to accompany them back home after ketamine sessions; or (15) with any known allergy to ketamine or any component or ingredient of the ketamine preparation.
Participants will be discontinued from the study if they experience clinically significant worsening depression symptoms (50% increase in HDRS-24 scores from baseline on 2 consecutive ratings); require in-patient hospitalization due to the presence of clinically significant suicidal ideation with imminent intent or attempted suicide; develop clinically significant worsening of mood, psychotic, or physical symptoms (assessed by a study physician); miss more than 2 consecutive treatments during the study; develop any medical illness that may be unstable; experience a seizure; become pregnant; or withdraw consent.
We believe recruiting 25 participants over the course of 2 years is feasible. Participants will be recruited through the Temerty Centre for Brain Intervention at CAMH, which treats approximately 150 to 200 patients with depression with electroconvulsive therapy per year. The principal investigator is a staff psychiatrist at the Mood and Anxiety Division, which provides outpatient services for a large population with mood disorders at local and provincial levels. In addition, this protocol has been piloted with 3 patients who were nonresponsive to electroconvulsive therapy, and the patients were able to comply with a protocol of 2 sessions per week for 8 treatment sessions given very close clinical supervision in a trial (unpublished data, Y. Knyahnytska).
Informed consent will be obtained from each individual who agrees to participate in the trial prior to and throughout participation. Patients meeting criteria will be referred to the study coordinator to discuss the study purpose, procedures, potential risks, and rights as research participants. Consent forms describing the study intervention, study procedures, and risks will be given to each participant, and written documentation of informed consent will be required prior to completing the initial screening visit and starting the study intervention. Once consent is obtained, the research personnel will confirm that inclusion and exclusion criteria are met before proceeding with baseline testing. Patients will be informed that they can withdraw from the study at any point. A copy of the information and consent documents will be given to the participants for their records. The informed consent process will be documented, and the form signed before the participant undergoes any study-specific procedures. The rights and welfare of the participants will be protected by emphasizing to them that the quality of their medical care will not be adversely affected if they decline to participate in this study.
Data confidentiality and confidentiality of the identities of the individuals participating in this study will be strictly maintained. Data forms that include identifying information will be kept in locked cabinets. Only the unique ID number assigned by the research coordinator will be used to represent participants during data entry, data transfer, data analysis, or other file management procedures. All information linking their identity will be kept separate from the research records. All information entered into a computer will be stored in a password-protected encrypted file format on a secure server. If any participant withdraws from the study, any research information recorded for or resulting from participation prior to the date that the participant formally withdrew consent will continue to be stored and used (in the manner described above) for research purposes (and will be disclosed by the investigators); however, no new data will be collected. Withdrawing from the study will not have any consequences for the participant. Participants' identities will not be revealed in the publication or presentation of any results from this study.
A sterile form of racemic ketamine hydrochloride will be dispensed through the CAMH pharmacy and will be administered intranasally using an atomizer provided by the pharmacy (MAD300, Teleflex). The CAMH research pharmacy will order the investigational product from the supplier (Sandoz Canada Inc) on behalf of the research team with the study investigator’s authorization and will be responsible for the receipt and responsible destruction of the investigational product. The investigational product will be stored between 15 ºC and 30 ºC, protected from light and heat and discarded within 28 days of initial use.
Intranasal rketamine will be administered twice per week for 4 weeks (8 treatment sessions in total). The dosage schedule will be determined based on participants’ weight, clinical response, and tolerability (
If the first session is tolerated well, and the patient has no side effects, the session 2 dose will be increased to 1 mg/kg (to represent an intravenous dose of 0.75 mg/kg adjusted to 50% bioavailability). If both sessions are tolerated well, session 3 will start on a full therapeutic dose (1.5-1.6 mg/kg to represent intravenous doses of 0.75-1 mg/kg). Participants will have a weekly visit with the study’s medical doctor, and doses will be monitored and adjusted based on tolerability and clinical response; however, they will not exceed 1.6 mg/kg.
All patients will stay on-site for the administration and 2-hour postintervention monitoring period, per consensus guidelines in ketamine administration [
Given the potential risks described below, trained medical personnel will be present during the administration and for the entire duration of the 2-hour monitoring period.
Drug-related risks include (1) psychiatric symptoms such as fatigue, dizziness, anxiety, visual and auditory disturbances, panic attacks, increased irritability, or changes in mood and behavior; (2) medical symptoms such as transient increases in blood pressure and heart rate, an increase in need to urinate, headaches, vision changes, chest pain, shortness of breath, confusion, memory impairment, anaphylaxis; and (3) rare risk of dependency. Ketamine is classified as a schedule I controlled substance due to its potential for abuse and addiction and can be abused in a number of ways, including via injection, snorting, or orally [
A potential risk in clinical assessments is that answering multiple questions can, at times, be distressing. These adverse reactions are primarily brief and transient and rarely have any long-term implications.
The ability of TMS to noninvasively stimulate brain areas presents a significant advance beyond techniques that require the invasive method of direct cortical or transcranial electrical stimulation. Magnetic fields pass through the scalp and skull without the impedance encountered by direct electrical stimulation, permitting enhanced control over the site and intensity of stimulation. In numerous studies [
Given that this trial recruits participants who received at least one electroconvulsive therapy session, and therefore, underwent blood work, electrocardiography, and medical clearance by anesthesia services in accordance with standard clinical procedures, we will use these parameters for this trial. The results will be available for screening and review by the study’s medical doctor prior to the start of treatment. Tests completed within the 6 months prior to screening will be used unless new medical symptoms requiring further investigation emerge, in which case, the tests will be repeated. Blood tests will include complete blood count with differential tests (white blood cells, red blood cells, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red cell distribution width, mean platelet volume, platelet, nucleated red blood cell count, neutrophil count, lymphocyte count, monocyte count, eosinophil count, basophil count) and blood chemistry tests for liver function (alanine aminotransferase, aspartate aminotransferase), kidney function (blood urea nitrogen, creatinine), electrolyte levels (sodium, potassium, chloride, phosphate), and thyroid function (thyroid-stimulating hormone). Electrocardiography results will be reviewed by the study’s medical doctor. Participant blood pressure will also be monitored before, during, and after treatment.
Clinical assessments will include (1) the Mini-International Neuropsychiatric Interview, to assess current and lifetime depression and other psychiatric disorders and to clarify psychiatric inclusion and exclusion criteria; (2) the 24-item Hamilton Rating Scale for Depression [
Demographic information, medical history, concomitant medications, and antidepressant treatment history form information will also be assessed.
Monitoring assessment during treatment sessions will include (1) vital signs collected every 30 minutes during a 2-hour monitoring session (blood pressure, heart rate, and oxygen levels) and (2) behavior changes assessed through observation.
Neurophysiological assessments will include (1) the Transcranial Magnetic Stimulation Adult Safety Screen to assess for potential TMS risk factors; and (2) TMS-EMG/EEG (
EEG will be used to evaluate TMS-induced cortical evoked activity. EEG recordings will be acquired through a 64-channel EEG system [
Baseline participant characteristics will be reported and described using summary statistics—mean and standard deviation for continuous data and number and proportion for categorical data. The primary analysis to determine if there is a statistically significant effect of intranasal ketamine on depressive symptoms will be the paired 1-tailed
CAMH treats approximately 250 new patients with depression each year with electroconvulsive therapy. Assuming 25% to 30% nonresponse or intolerability and that, of these individuals, 20% will be eligible for treatment, we expect to be able to recruit 25 participants over the course of 24 months.
This study has received ethics approval. We have started recruitment for the trial and anticipate having initial results in spring 2022.
To our knowledge, this is the first study to test repeated doses of rketamine delivered intranasally in patients with major depressive disorder who did not respond (either clinically or due to their inability to tolerate) to an acute course of electroconvulsive therapy. The use of neurophysiological tools to assess changes in cortical excitability will provide preliminary data for potential biomarkers of response, which can be further assessed in a larger clinical trial. A lack of control group and small sample size are limitations of the current protocol. However, given that it is a pilot open-label clinical trial, the sample size is sufficient (ie, the goal is not to assess generalizability or statistical significance). The lack of blinding in the control group is a common concern in ketamine trials [
Results will be presented during scientific conferences, in clinical rounds, and publications in relevant journals.
Dosage schedule for intranasal rketamine.
Study visits.
Centre for Addiction and Mental Health
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
electromyography
electroencephalography
γ-aminobutyric acid
N-methyl-D-aspartate
racemic ketamine
transcranial magnetic stimulation
This work was funded in part by the Innovation Fund of Alternative Funding Plan for the Academic Health Sciences Centres in Ontario, Ministry of Health and Long-Term Care.
None declared.