A Phase 4 interventional study of Ketamine and ECT in Treatment Resistant Depression and Ketamine, sponsored by University of Saskatchewan. Recruiting at 1 site in Canada. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-01-23.
Sponsored by University of Saskatchewan · Phase 4, Interventional, and Treatment
To determine if an high intensity ketamine with ECT rescue (HIKER) approach for treatment resistant depression will: 1) reduce patient suffering by hastening disease remission, 2) have fewer side effects, 3) reduce the need for ECT, and 4) be preferred by most patients. Half of participants will be randomized to the HIKER arm and receive high intensity ketamine treatment for eight consecutive days, and the other half will be assigned to the ECT with ketamine anesthesia (EAST) arm and receive 8 ECT treatments (2-3 treatment/week)
Major depressive disorder (MDD) is a common psychiatric illness that will affect at least 15% of the population. The burden of MDD is staggering, considered by the World Health Organization to be the leading cause of disability in developed countries for people aged 15-44.
Oral antidepressant therapy for MDD is notoriously ineffective. At least 3 weeks of treatment is usually required to achieve response rates that rarely exceed 40% (only 10% better than placebo); furthermore, treatment can be complicated by serious side effects serious (e.g. falls, weight gain) including increased suicidality. Up to 15% of patients will eventually be diagnosed as having treatment-resistant depressions (TRD), defined as the failure to respond to at least two antidepressants from different pharmacologic classes after adequate treatment duration at therapeutic dosages. The gold standard therapy for TRD is electroconvulsive therapy (ECT) with general anaesthesia (GA), which produces rapid antidepressant effects after only a few sessions. Propofol is the traditional anaesthetic agent used in GA for ECT, although recently this research group showed that ECT with ketamine as the primary anaesthetic produced faster depression remission compared to ECT with propofol.
Despite its efficacy, ECT is associated with considerable problems. More than 10% of patients will experience amnesia and confusion, which can persist for weeks. These cognitive side effects limit the frequency of ECT treatments to two or three times per week. There is also a risk of rare but devastating cardiorespiratory adverse events, at least part of which can be attributed to the need to induce chemical paralysis (for safety) and administer opioids (for pain control) during ECT with GA. Lastly, ECT requires specialized psychiatric expertise, dedicated resources, specially trained nurses, and an anaesthesiologist - requirements that are both costly and not readily available in many settings.
In contrast to ECT, daily short-acting anaesthesia, including ketamine, is well tolerated. A recent study found that only three treatments of intravenous ketamine produced a greater early improvement in depression scores compared to ECT under non-ketamine-based GA. This suggests a possibility of achieving early disease remission in TRD with ketamine-only infusions while avoiding the safety risks and treatment delays associated with ECT under GA.
The efficacy, feasibility, and improved side-effect profile of frequent successive ketamine treatments suggest it may be the preferred treatment for TRD compared to ECT with ketamine-based GA. There may, however, be a small subgroup of TRD patients who do not respond to ketamine alone and require ECT, although with a daily treatment regimen, ketamine non-responders could be quickly identified and given a standard course of ECT. The researchers propose that a treatment protocol of daily High Intensity Ketamine with ECT Rescue (HIKER) will be superior to ECT Therapy with ketamine anesthesia standard therapy (EAST) in facilitating early disease remission, while at the same time yielding similar overall remission rates by allowing ketamine non-responders to be quickly identified and given ECT.
472 studies on the registry are indexed under Depressive Disorder, Treatment-Resistant; 151 are open to participants now.
This study's planned enrollment of 62 is above the median of 51 across 397 interventional studies indexed under Depressive Disorder, Treatment-Resistant.
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Exclusion Criteria:
Patients in the HIKER arm will receive a single dose of ketamine 0.50 mg/kg, which is enough to achieve a full anaesthetic effect (i.e., unconsciousness mimicking the GA regimen above), on 8 successive weekdays.
Drug: Ketamine
Patients in the EAST arm will initially receive intravenous ketamine 0.75 mg/kg, remifentanil 1 mcg/kg (to reduce discomfort), and succinylcholine 0.75 mg/kg (for safety). Based on patients' anaesthetic response, the attending anaesthesiologist is given the freedom to vary the dose of remifentanil and succinylcholine as well as administer propofol to achieve safe and acceptable anaesthetic conditions. As per the Saskatoon Health Region's care standard, patients in the EAST arm will receive eight ECT sessions (on a bi/triweekly schedule) delivered by the attending psychiatrist with either unilateral or bilateral electrode placement and monitoring of seizure threshold by the half-age method.
Drug: Ketamine · Procedure: ECT
IV Ketamine 0.50 mg/kg
Also known as: Ketalar
ECT with unilateral or bilateral electrode placement and monitoring of seizure threshold by the half-age method
Number of treatments required to reach disease remission
The primary outcome is number of treatments required to reach disease remission, as defined by a reduction of MADRS score to under 10
Time frame: From date of randomization until the date of disease remission or after 8 treatments, assessed up to 4 weeks
Rate of rescue ECT in the HIKER arm
Percent of patients in the HIKER arm who do not achieve a 25% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) after the third treatment.
Time frame: From date of randomization up to 6 days
Suicidal ideation
Suicidal ideation as measured by the Columbia Suicide Severity Rating Scale
Time frame: From date of randomization until the date of disease remission or after 8 treatments and at 30 days following last treatment, assessed up to 8 weeks
Cognitive Impairment
Cognitive Impairment as measured by Mini-Mental State Exam (MMSE)
Time frame: MMSE will be assessed at baseline, final treatment, and 30 day post-treatment follow-up
Self- and clinician rated improvement
Patients will rate their condition on the patient-rated clinical global impression - improvement scale (PGI-I)
Time frame: From date of randomization until the date of disease remission or after 8 treatments and at 30 days following last treatment, assessed up to 8 weeks
Patient satisfaction with treatment
Satisfaction with treatment will be assessed by the 2-item treatment satisfaction questionnaire for medication-version II (TSQM-GS-II).
Time frame: From date of randomization until the date of disease remission or after 8 treatments and at 30 days following last treatment, assessed up to 8 weeks
Plan to share: No
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Depressive Disorder, Treatment-Resistant →