Comparison of Esketamine/Propofol and Methohexital Anesthesia for ECT (Ketofol)

A Prospective Randomized, Double Blind, Controlled, Safety and Non-inferiority Study of Esketamine Plus Propofol Compared to Methohexital Anesthesia for Electroconvulsive Therapy

The current anesthetic drug used as standard for ECT procedure at the Department of Psychiatry and Psychotherapy, Medical University of Vienna, is the barbiturate methohexital (Brevital®). As far as we know, methohexital is the most common anesthetic in the procedure of ECT. Only few heterogeneous randomized controlled trials to directly compare the use of (sole) ketamine and methohexital in ECT with relatively small sample sizes have been conducted so far, showing inconclusive findings: a retrospective comparison of methohexital and switch to ketamine anesthesia in 36 patients showed that ketamine prolonged seizure duration and accelerated posttreatment orientation. Others compared both drugs in terms of recovery and reorientation time showing that reorientation time was faster in the methohexital group (total N=9). Another study showed no difference in any outcome measure (depressive symptom improvement, cognition, adverse events) between both groups (total N=16, N=9 per group). Finally, a comparative investigation (total N=37, N=20 vs. N=17) detected no differences between both anesthetics but a higher systolic blood pressure posttreatment and longer motor seizure duration in the ketamine group. A favorable profile of ketamine in regards to seizure quality has been reported, however in terms of outcome measures methohexital and ketamine were similar (total N=50, N=23 vs. N=27).

The present study is designed as a prospective randomized non-inferiority trial comparing esketamine plus propofol (ratio 1:1, for better readability from now on referred to as "ketofol") to methohexital, the latter being the current standard anesthetic applied for ECT procedure at our department. Patients eligible for ECT will be randomly assigned to receive anesthesia with either ketofol or methohexital for the whole course of the individual ECT series. Group differences will be investigated both in regards to outcomes related to anesthesia, treatment-outcome and seizure quality.

Further, changes in cardiac enzyme levels before and after ECT-treatment and during the entire ECT series will be evaluated and possible group differences will be explored.

As stated above the sole/adjunct administration of ketamine as anesthetic agent for ECT has been associated with better seizure quality, similar antidepressant outcomes and anesthesia-associated events, while there is some evidence suggesting that the use of ketamine might present some advantages to other anesthetics in terms of cognitive side-effects accompanying ECT. Therefore, the aim of the present study will be to establish ketofol as a new standard for anesthesia at our Department.

Study Overview

• Status: Recruiting
• Conditions: Depression; ECT
• Intervention / Treatment: Drug: Methohexital; Drug: Ketofol

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Recruiting
    • Pia Baldinger-Melich
    • Contact: Pia Baldinger-Melich, Assoc.Prof.; Phone Number: +43 1 4040035350; Email: pia.baldinger-melich@meduniwien.ac.at

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• male or female inpatients
• age ≥ 18 years
• ICD-11 diagnosis of severe uni- or bipolar depression (F32.2, F32.2, F33.2, F33.3, F31.4, F31.5)
• Hamilton Depression Rating Scale HAMD17 ≥ 24
• ability to understand and willingness to sign written informed consent document
• negative urine pregnancy test in women
• anesthesiological approval for ECT (Classification of the American Society of Anesthesiologists ASA ≤ 3)
• antidepressant and antipsychotic medication in steady state for at least 7 days prior to first ECT treatment

Exclusion Criteria:

• severe somatic or neurological disease (esp. current or previous history of intracranial hypertension, uncontrolled severe hypertension, bleeds or aneurysm, recent myocardial infarction)
• current or past history of schizophrenia or schizoaffective disorder
• clinical relevant abnormalities on a general physical examination and routine laboratory screening
• pregnancy, breast feeding
• known allergy to the study drugs or compounds of the latter

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Methohexital; Initial dose: methohexital 1 mg/kg (≙ 80 mg methohexital in a subject with 80 kg). If sufficient hypnosis is not achieved with the initial dose further doses of 10 mg methohexital will be administered until sufficient depth of anesthesia according to defined criteria is achieved. Criteria for sufficient depth of anesthesia will be comprised by a) the abolition of the eye-lash reflex b) absence of motor reaction upon inflation of the tourniquet. Maintenance dose: none (The drug combination is injected in order to initiate anesthesia) Route of administration: intravenous Duration: few seconds to initiate anesthesia. The procedure will be repeated for each ECT session.	Drug: Methohexital; anesthesia during ECT
Active Comparator: Ketofol; Esketamine and propofol will be prepared shortly before injection by the nurse anesthetist as follows: 4 ml esketamine 25mg/ml, 6ml NaCl (0,9%), 10ml propofol (10mg/ml). The stability of ketamine-propofol mixtures (undiluted, 50:50 ratio) in one syringe has been documented for up to 3 hours. Initial dose: esketamine 0,5 mg/kg + propofol 0,5 mg/kg (≙ 40 mg esketamine + 40 mg propofol in a subject with 80 kg). If sufficient hypnosis is not achieved with the initial dose further doses of 5mg esketamine and 5 mg propofol will be administered until a sufficient depth of anesthesia is achieved. Maintenance dose: none (The drug combination is injected in order to initiate anesthesia) Route of administration: intravenous Duration: few seconds to initiate anesthesia. The procedure will be repeated for each ECT session	Drug: Ketofol; anesthesia during ECT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
antidepressant effect	• HAMD17 change between baseline and post-ECT in both treatment arms over a series of 8 ECT sessions	4 weeks
recovery time	Mean recovery time over 8 ECT sessions in both treatment arms	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
adverse events	AEs during anesthesia/ECT	4 weeks
concomitant medication	use of concom. medication during intervention to treat AEs	4 weeks
cognition	MMSE, Beck's Depression Inventory (BDI), multiple-choice word test (MWT-B), trail making test (TMT), reaction test (RT), cognitrone (COG), non-verbal learning test (NVLT), verbal learning test (VLT) (Vienna testing system, https://vts.schuhfried.com), compare cognitive outcomes before and after ECT in both treatment arms	4 weeks
time to reorientation	compare time to reorientation in both treatment arms	4 weeks
seizure quality	compare a function of seizure duration, concordance (seizure duration in the electromyogram/seizure duration in the electroencephalogram), midictal amplitude, peak heart rates and interhemispheric coherence in both treatment arms	4 weeks

Collaborators and Investigators

• Sponsor: Medical University of Vienna

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2022
• Primary Completion (Estimated): October 31, 2025
• Study Completion (Estimated): October 31, 2025

Study Registration Dates

• First Submitted: December 6, 2022
• First Submitted That Met QC Criteria: December 16, 2022
• First Posted (Actual): December 19, 2022

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: anesthesia; depression; esketamine; electroconvulsive therapy
• Additional Relevant MeSH Terms: Behavioral Symptoms; Depression; Physiological Effects of Drugs; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Methohexital
• Other Study ID Numbers: BMF22114

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No