Clinical trial NCT01935115: Comparing Ketamine and Propofol Anesthesia for Electroconvulsive Therapy
Official title: A Prospective Randomized Double Blinded Control Trial Using Ketamine or Propofol Anesthesia for Electroconvulsive Therapy: Improving Treatment-Resistant Depression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Treatment Resistant Depression
Keywords: Depression
MDD
Treatment Resistant Depression
Electroconvulsive Therapy
ECT
Ketamine
Propofol
NMDA
Lead sponsor: University of Saskatchewan
Sponsor class: OTHER
Collaborators: name: Saskatoon Health Region
name: Royal University Hospital Foundation
name: Schulman Research Award
First posted: 2013-09-04
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: 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.
timeFrame: After 8 treatments or completion of therapy for an expected average of 4 weeks
Secondary outcomes:
measure: Change in CADSS (Clinician Administered Dissociative States Scale)
timeFrame: 30 minutes after each ECT session and one day after each ECT session for an expected average of 4 weeks
measure: Change in ALS-18 (Affective Lability Scale)
timeFrame: 30 days after final ECT session for an expected average duration of 2 months
measure: Change in ECT energy settings and seizure quality
timeFrame: Within 30 minutes of each treatment for an expected average of 4 weeks
measure: Hemodynamic instability and respiratory complications
timeFrame: 1 hour after each ECT for an expected average of 4 weeks
measure: Time to discharge
timeFrame: 1 hour after each treatment for an expected average of 4 weeks
measure: Change in MADRS score
timeFrame: 24 hours after each treatment and 30 days after final treatment for an expected average of 2 months
measure: The number of ECT sessions required to achieve depression remission (MADRS ≤10)
timeFrame: Number of ECT treatments to achieve depression remission (MADRS) or completion of therapy up to 4 weeks
measure: The proportion of depressed patients (MADRS > 20) at 30 days after the last ECT session
timeFrame: 30 days after the last ECT session, up to 60 days after ECT initiation.
measure: Change in systolic blood pressure
timeFrame: During ECT, up to 8 treatments or 4 weeks
Other outcomes:
Locations:
city: Saskatoon
country: Canada
facility: Royal University Hospital
state: Saskatchewan
Study officials:
affiliation: University of Saskatchewan
name: Jonathan Gamble, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug;63(8):856-64. doi: 10.1001/archpsyc.63.8.856.
citation: Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000 Feb 15;47(4):351-4. doi: 10.1016/s0006-3223(99)00230-9.
citation: Zarate CA Jr, Brutsche NE, Ibrahim L, Franco-Chaves J, Diazgranados N, Cravchik A, Selter J, Marquardt CA, Liberty V, Luckenbaugh DA. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012 Jun 1;71(11):939-46. doi: 10.1016/j.biopsych.2011.12.010. Epub 2012 Jan 31.
citation: Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, Kammerer WA, Quezado Z, Luckenbaugh DA, Salvadore G, Machado-Vieira R, Manji HK, Zarate CA Jr. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010 Aug;67(8):793-802. doi: 10.1001/archgenpsychiatry.2010.90.
citation: Okamoto N, Nakai T, Sakamoto K, Nagafusa Y, Higuchi T, Nishikawa T. Rapid antidepressant effect of ketamine anesthesia during electroconvulsive therapy of treatment-resistant depression: comparing ketamine and propofol anesthesia. J ECT. 2010 Sep;26(3):223-7. doi: 10.1097/YCT.0b013e3181c3b0aa.
citation: Wang X, Chen Y, Zhou X, Liu F, Zhang T, Zhang C. Effects of propofol and ketamine as combined anesthesia for electroconvulsive therapy in patients with depressive disorder. J ECT. 2012 Jun;28(2):128-32. doi: 10.1097/YCT.0b013e31824d1d02.
citation: Gamble JJ, Bi H, Bowen R, Weisgerber G, Sanjanwala R, Prasad R, Balbuena L. Ketamine-based anesthesia improves electroconvulsive therapy outcomes: a randomized-controlled study. Can J Anaesth. 2018 Jun;65(6):636-646. doi: 10.1007/s12630-018-1088-0. Epub 2018 Feb 21.