The Safety, Clinical, and Neurophysiological Effects of Intranasal Ketamine in Patients Who Do Not Respond to Electroconvulsive Therapy: Protocol for a Pilot, Open-Label Clinical Trial
Yuliya Knyahnytska, D. Blumberger, Tyler S Kaster, Daphne Voineskos, Alisson Trevizol, Reza Zomorrodi
JMIR Research Protocols May 10, 2021 DOI: 10.2196/30163 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Open-label pilot clinical trial (clinical protocol) Randomized Peer reviewed |
|---|---|
| Sample size | 25 |
| Population | Adults aged 24-65 with treatment-resistant unipolar depression who did not respond to or could not tolerate an acute course of electroconvulsive therapy, recruited from an academic psychiatric hospital in Toronto, Canada |
| Dose | sterile solution of racemic ketamine hydrochloride administered intranasally twice per week for 4 weeks (8 sessions); specific milligram dose not stated |
| Duration | 4-week intervention (8 sessions); recruitment over 2 years |
| Measures | feasibility of a larger randomized controlled trial (primary); depressive symptoms, suicidal ideation, quality of living (secondary); transcranial magnetic stimulation electromyography and electroencephalography measures of cortical excitability (exploratory) |
| Topics | Esketamine Ketamine |
| Registration | NCT05137938 |
| Key findings | The authors propose that repeated intranasal racemic ketamine may be a feasible and safe option for patients with treatment-resistant depression who have not responded to or cannot tolerate electroconvulsive therapy, and that transcranial magnetic stimulation measures of cortical excitability may serve as predictors of clinical response. No efficacy results are reported; the trial is ongoing. |
Abstract
Background: 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.
Objective: 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.
Methods: 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.
Results: This study has received ethics approval, and funding has been secured. The study is currently active.
Conclusions: 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.
Trial Registration: Clinical Trials.gov NCT05137938; http://clinicaltrials.gov/ct2/show/NCT05137938 International Registered Report Identifier (IRRID) PRR1-10.2196/30163
Comparable studies
Other non-randomized and open-label trials on ketamine, most cited first.