Effects of Low-dose Ketamine as an Adjunct to Propofol-based Anesthesia for Electroconvulsive Therapy

April 26, 2021 updated by: Ferrante Gragasin, University of Alberta

Ketamine has been used successfully as the sole medication for anesthesia in the setting of electroconvulsive therapy (ECT), and has more recently been studied as an adjunct agent in combination with propofol (the most commonly used anesthetic agent) to induce anesthesia for ECT. New literature postulates an anti-depressant effect of ketamine, which in ECT specifically may be helpful with regards to the overall goals of therapy (i.e. ECT indicated for severe or treatment-resistant depression).

Current research focusing on ketamine with respect to its anti-depressant effect suggests it may even represent an alternative to ECT. This study will seek to determine whether ketamine when used in low-doses as an adjunct to propofol-based anesthesia for ECT has anti-depressant effects and whether it influences the characteristics of recovery from anesthesia in the ECT setting (i.e. vital sign parameters such as blood pressure and heart rate, quality of recovery, etc.).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This is a proof-of-concept study to elucidate whether the use of low-dose ketamine as an adjunct to propofol-based anesthesia for electroconvulsive therapy has beneficial anti-depressant effects in a population of adults with major depressive disorder presenting for ECT.

Since thiopental is no longer widely available in North America as an induction agent for anesthesia, other agents have supplanted it for various uses, including for induction of anesthesia for electroconvulsive therapy (ECT). Induction is most commonly achieved using propofol in doses of 0.75 - 1 mg/kg IV bolus.

Propofol as an induction agent for ECT may not be the ideal agent in this setting as its anticonvulsant effects may result in less-than-ideal seizure quality and duration. Ketamine has been studied in the ECT setting but at full induction doses has well-known psychotomimetic and dissociative effects. However, the anti-depressant effects of ketamine, even at low-doses, may have a beneficial effect on depressive symptoms after ECT as compared with propofol alone.

Ketamine also has been used successfully as the sole induction agent for anesthesia in this setting, and has more recently been studied as an adjunct or co-induction agent in combination with propofol. Drawbacks of using ketamine as the sole induction agent are related to its hemodynamic and psychotomimetic effects (e.g. post-treatment hypertension and hallucinogenic activity).

New literature postulates a putative anti-depressant effect of ketamine via the N-Methyl-D-aspartate (NMDA) receptor, which in the ECT setting specifically may be helpful with regards to the overall goals of therapy (i.e. ECT indicated for severe or treatment-resistant depression). Current research focusing on the efficacy of ketamine with respect to anti-depressant effects suggests that ketamine may even represent an alternative to ECT.

As per the investigators' standard practice for ECT, treatment for each patient would be 3 times per week up to a total of 12 treatments (i.e. 4 weeks of treatment). The total study duration for each patient will be not more than 6 weeks. As discussed below, patients will be withdrawn from the study at anytime upon their own request or when the treating psychiatrist feels the clinical improvement is strong enough to justify doing so.

An interim analysis will be completed after the first 14 patients have completed treatment. If after these first 14 patients the investigators find a lower than expected difference in efficacy in favor of the ketamine group, able to achieve alpha error >0.2 and power <80%, all subsequently recruited patients will be randomized to receive either propofol at usual induction doses for ECT (0.75 - 1 mg/kg IV bolus) with placebo (normal saline), or with a slightly higher dose of ketamine of 0.5 mg/kg. Should this turn out to be the case, thirty new patients will be recruited from that point.

Study Type

Interventional

Enrollment (Actual)

48

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Alberta
      • Edmonton, Alberta, Canada, T6G 2B7
        • University of Alberta Hospital
      • Edmonton, Alberta, Canada, T5J 2J7
        • Alberta Hospital Edmonton

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • referred for ECT with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of major depressive disorder
  • considered American Society of Anesthesiologists (ASA) Physical Class I - III
  • baseline MADRS score greater than 24 (i.e. at least moderate to severe depression)
  • a "first" or "new" episode of depression which has lasted not more than 3 months and requires ECT treatment as judged by a psychiatrist

Exclusion Criteria:

  • ASA Class IV or V as judged by the anesthesiologist
  • Any ECT treatment in the previous three months
  • Inability or refusal to provide informed consent
  • A history of allergic reactions, hypersensitivity, or intolerance to anesthetics or their constituents used in the study (ketamine, propofol, egg phosphatide, soybean oil)
  • Anyone taking medications considered contraindicated for ECT or for general anesthesia
  • Presence of any of the following DSM-IV diagnoses: Substance or alcohol dependence at enrolment (except dependence in full remission, and except for caffeine or nicotine dependence), abuse of opiates, amphetamines, barbiturates, cocaine, cannabis, or hallucinogen abuse in the 4 weeks prior to enrolment, pervasive developmental disorder, dementia
  • Significant medical condition that would contraindicate the use of ketamine, propofol or that is untreated and would need urgent attention (as determined by treating physician)
  • Medical conditions that would significantly affect absorption, distribution, metabolism, or excretion of ketamine or propofol
  • Unstable or inadequately treated medical illness (e.g. congestive heart failure, angina pectoris, hypertension) as judged by the investigator
  • Patients with increased risk of laryngospasm (such as active pulmonary infection, upper respiratory infection, asthma), increased intracranial pressure, glaucoma, thyroid disease/hyperthyroidism
  • Any clinically significant deviation from the reference range in clinical laboratory test results as judged by the investigator
  • Pregnancy (or female of child-bearing age not using adequate contraception) or lactation
  • Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Propofol at usual induction doses for ECT (0.75 - 1 mg/kg IV bolus) with placebo (normal saline)
Drug: Placebo
Normal saline administered with usual induction drugs for ECT
Other Names:
  • Normal saline
  • 0.9% NS
Experimental: Ketamine
Propofol at usual induction doses for ECT (0.75 - 1 mg/kg IV bolus) with the addition of low-dose ketamine 0.2 mg/kg (or 0.5 mg/kg - see interim analysis)
Drug: Ketamine
Low dose ketamine 0.2 mg/kg (or 0.5 mg/kg depending on results of interim analysis) administered with usual induction drugs for ECT
Other Names:
  • Ketalar

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of treatments to achieve 50% change (reduction) in Montgomery Ashberg Depression Rating Scale (MADRS)
Time Frame: 6 weeks
Defined a priori as "response". Assessed at baseline, 24 hours after ECT treatments for the duration of the study and then once at 6 weeks.
6 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of treatments to achieve 25% change (reduction) in MADRS
Time Frame: 6 weeks
Defined a priori as "partial response". Assessed at baseline, 24 hours after ECT treatments for the duration of the study and then once at 6 weeks.
6 weeks
Change in Clinical Global Impression - Severity (CGI-S) scores
Time Frame: 6 weeks
Assessed at baseline, 24 hours after ECT treatments for the duration of the study and then once at 6 weeks.
6 weeks
Changes in blood pressure seen during ECT
Time Frame: 4 weeks
Measured during ECT treatments and in the post-ECT recovery room.
4 weeks
Changes in heart rate seen during ECT
Time Frame: 4 weeks
Measured during ECT treatments and in the post-ECT recovery room.
4 weeks
Changes in oxygen saturation seen during ECT
Time Frame: 4 weeks
Measured during ECT treatments and in the post-ECT recovery room.
4 weeks
Changes in respiratory rate seen during ECT
Time Frame: 4 weeks
Measured during ECT treatments and in the post-ECT recovery room.
4 weeks
Changes in times to discharge from post-ECT recovery
Time Frame: 4 weeks
4 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in seizure duration during ECT
Time Frame: 4 weeks
As measured by clinical/visual assessment as well as by EEG.
4 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Alberta

Collaborators

Alberta Health services

Investigators

  • Principal Investigator: Ferrante S Gragasin, MD, PhD, University of Alberta

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2015

Primary Completion (Actual)

May 1, 2019

Study Completion (Actual)

May 1, 2019

Study Registration Dates

First Submitted

October 13, 2015

First Submitted That Met QC Criteria

October 15, 2015

First Posted (Estimate)

October 19, 2015

Study Record Updates

Last Update Posted (Actual)

April 28, 2021

Last Update Submitted That Met QC Criteria

April 26, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PRO00044771

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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