Comparing Ketamine and Propofol Anesthesia for Electroconvulsive Therapy

Study Overview
=================
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.

Official Title
-----------------
A Prospective Randomized Double Blinded Control Trial Using Ketamine or Propofol Anesthesia for Electroconvulsive Therapy: Improving Treatment-Resistant Depression

Conditions
-----------------
Treatment Resistant Depression

Intervention / Treatment
-----------------
* Drug: Propofol
* Drug: Ketamine


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Propofol<br>The control group will receive propofol 1 mg/kg and remifentanil 1 mcg/kg intravenously | Drug: Propofol<br>* Propofol anesthesia for ECT<br>* Other names: Diprivan;|
| Experimental: Ketamine<br>Study group will receive ketamine 0.75 mg/kg and remifentanil 1 mcg/kg intravenously | Drug: Ketamine<br>* Ketamine anesthesia for ECT<br>* Other names: Ketalar;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | After 8 treatments or completion of therapy for an expected average of 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in CADSS (Clinician Administered Dissociative States Scale) | 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. | 30 minutes after each ECT session and one day after each ECT session for an expected average of 4 weeks | 
| Change in ALS-18 (Affective Lability Scale) | A baseline ALS-18 score will be obtained. 30 days after completion of therapy, another score will be collected. | 30 days after final ECT session for an expected average duration of 2 months | 
| Change in ECT energy settings and seizure quality | We will document energy settings used by the psychiatrist as well as duration and quality of seizures achieved. | Within 30 minutes of each treatment for an expected average of 4 weeks | 
| Hemodynamic instability and respiratory complications | 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. | 1 hour after each ECT for an expected average of 4 weeks | 
| Time to discharge | Total time spend in the post-anesthetic recovery unit will be recorded. | 1 hour after each treatment for an expected average of 4 weeks | 
| Change in MADRS score | 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. | 24 hours after each treatment and 30 days after final treatment for an expected average of 2 months | 
| The number of ECT sessions required to achieve depression remission (MADRS ≤10) | 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. | Number of ECT treatments to achieve depression remission (MADRS) or completion of therapy up to 4 weeks | 
| The proportion of depressed patients (MADRS > 20) at 30 days after the last ECT session | 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. | 30 days after the last ECT session, up to 60 days after ECT initiation. | 
| Change in systolic blood pressure | 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) | During ECT, up to 8 treatments or 4 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Depression, MDD, Treatment Resistant Depression, Electroconvulsive Therapy, ECT, Ketamine, Propofol, NMDA