Treatment Resistant Depression
Conditions
Keywords
Depression, MDD, Treatment Resistant Depression, Electroconvulsive Therapy, ECT, Ketamine, Propofol, NMDA
Brief summary
To determine the effect of ketamine, compared to propofol, when used an an anesthetic agent for electroconvulsive therapy (ECT) in the treatment of major depressive disorder (MDD). We hypothesize that ketamine, compared to propofol, will improve the the symptoms of MDD when used as the anesthetic agent to facilitate ECT. Additionally, we hypothesize the dissociative and cardiovascular effects of ketamine will be minimal.
Detailed description
Treatment resistant depression is a common and disabling condition. The delayed onset of action and side effects exhibited by oral antidepressants are significant limitations. An alternative and well-established therapy is electroconvulsive therapy (ECT). ECT has rapid antidepressant effect beginning with the completion of the first session. Nevertheless, like oral medications, patients treated with ECT can develop treatment resistance or failure to respond. There is great need for a novel approach to treatment-resistant depression; one that that is safe, has rapid onset, and is sustained. Pharmaceutical agents with rapid antidepressant effects are a new and promising paradigm in the research for treatment of MDD. A potential therapeutic target is glutamate based signal transmission because glutamate transmission is abnormally regulated in the limbic/cortical areas of many depressed people. Glutamatergic modulating agents, in particular ketamine, have been shown to induce rapid antidepressant effects both in both preclinical models and humans. Additionally, ketamine has been shown to have persistent antidepressive effect. Presently worldwide, propofol is one of the most commonly used anesthetic agents for ECT. There are 2 main disadvantages to this practice. First, propofol has no antidepressive effect. Second, propofol is a potent anticonvulsant that may worsen the quality of the ECT induced seizures. A recent open-label trial compared ketamine to propofol for anesthesia during ECT and demonstrated a significant improvement of depression in the ketamine arm. Ketamine is routinely used to provide safe general anesthesia as well as procedural sedation, analgesia, and amnesia. The combination of the intrinsic antidepressant effects of ketamine with electroconvulsive therapy is a promising concept in clinical research. This study will include planned interim analysis to ensure patients safety. This analysis will be performed by a statistician who is blinded to group allocation after 20 and after 40 patients. An independent safety committee will informed of the results of the interim analysis including side effects and complications and will have the option to adjust the drug dosage or to discontinue the trial.
Interventions
DRUGPropofol
Propofol anesthesia for ECT
DRUGKetamine
Ketamine anesthesia for ECT
Sponsors
Saskatoon Health Region
Royal University Hospital Foundation
Schulman Research Award
University of Saskatchewan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Fulfill the diagnostic criteria for major depression according to the Diagnostic and Statistical Manual of Mental Disorders (most recent edition) * Failure to respond to at least 2 adequate drug therapies for the current depression episode * MADRS score of 20 or above (moderate - severe * ASA physical status classification I to III
Exclusion criteria
* Inability to obtain informed consent * ASA physical status classification IV * Complication by any serious physical diseases such as cardiovascular disease (including untreated HTN), respiratory disease, cerebrovascular disease, intracranial HTN (including glaucoma), or seizures * Presence of foreign body (including pacemaker) * Pregnancy * Allergies to anesthetics used in study Includes: a) Ketamine b) Propofol c) Eggs d) Egg products e) Soybeans f) Soy products
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The primary outcome is defined as the number of ECT treatments required to reach a 50% reduction in baseline MADRS (Montgomery-Asberg Depression Scale) score. | After 8 treatments or completion of therapy for an expected average of 4 weeks | Standard of care for ECT in the Saskatoon Health Region are biweekly sessions for a total of 8 treatments. Occasionally, a patient meets early remission and may not require the full 8 treatments and may be eligible for early withdrawal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in ALS-18 (Affective Lability Scale) | 30 days after final ECT session for an expected average duration of 2 months | A baseline ALS-18 score will be obtained. 30 days after completion of therapy, another score will be collected. |
| Change in ECT energy settings and seizure quality | Within 30 minutes of each treatment for an expected average of 4 weeks | We will document energy settings used by the psychiatrist as well as duration and quality of seizures achieved. |
| Hemodynamic instability and respiratory complications | 1 hour after each ECT for an expected average of 4 weeks | Any hemodynamic or respiratory instability requiring unanticipated intervention will be recorded as well as the treatment for the event recorded. Type of intervention will also be documented. |
| Time to discharge | 1 hour after each treatment for an expected average of 4 weeks | Total time spend in the post-anesthetic recovery unit will be recorded. |
| Change in CADSS (Clinician Administered Dissociative States Scale) | 30 minutes after each ECT session and one day after each ECT session for an expected average of 4 weeks | The CADSS is used to assess states of clinical dissociation; a potential side effect of ketamine. A baseline CADSS will be obtained one day prior to start of ECT. Additional scores will be assessed 30 minutes after each therapy as well as one day post-therapy on the ward. |
| The number of ECT sessions required to achieve depression remission (MADRS ≤10) | Number of ECT treatments to achieve depression remission (MADRS) or completion of therapy up to 4 weeks | Standard of care for ECT in the Saskatoon Health Region are biweekly sessions for a total of 8 treatments. Occasionally, a patient meets early remission and may not require the full 8 treatments and may be eligible for early withdrawal. |
| The proportion of depressed patients (MADRS > 20) at 30 days after the last ECT session | 30 days after the last ECT session, up to 60 days after ECT initiation. | The proportion of patients in each group who have severe depression 30 days after their last ECT session. This is a measure of longer term efficacy of treatment effect. |
| Change in systolic blood pressure | During ECT, up to 8 treatments or 4 weeks | Increases or decreases in baseline systolic blood pressure at any point during the anesthetic care will be categorically recorded as minimal change (20 - 50 mm Hg from baseline) and significant change (more than 50 mm Hg from baseline) |
| Change in MADRS score | 24 hours after each treatment and 30 days after final treatment for an expected average of 2 months | A baseline MADRS score will be conducted one day prior to ECT. Additional scores will be obtained one day after each ECT session. A final MADRS score will be assessed 30 days after completion of ECT. |
Countries
Canada
Outcome results
None listed