Low-dose ketamine does not improve the speed of recovery from depression in electroconvulsive therapy: a randomized controlled trial

This randomized, double-blind, placebo-controlled study investigated the efficacy of using low-dose ketamine (35mg/70kg) as an anaesthetic adjunct to propofol during electroconvulsive therapy (ECT) for treating patients with depression (MDD). Adding ketamine did not alter the antidepressant efficacy or the hemodynamics of electroconvulsive therapy, although it may help reduce the dose requirements of propofol anaesthesia.

Abstract

Objective: Electroconvulsive therapy (ECT) is a well-established therapeutic intervention for major depressive disorder. Recent literature has shown that the anesthetic agent ketamine has some antidepressant properties at low doses and may be an alternative therapy for treatment-resistant major depressive disorder. We hypothesized that the use of low-dose ketamine as an anesthetic adjunct in ECT would more rapidly improve depression while maintaining hemodynamic stability than ECT with propofol alone.

Methods: Institutional ethics approval was obtained, and the use of ketamine in this study was approved by Health Canada. This is a randomized, double-blinded, placebo-controlled trial that involved ketamine administration at 0.5 mg/kg IV in addition to propofol anesthesia for ECT. The primary outcome was the number of ECT treatments required to achieve a 50% reduction in the Montgomery-Asberg Depression Rating Scale (MADRS). Secondary outcomes included the number of ECT treatments required to achieve a 25% reduction in MADRS score, as well as any differences in the Clinical Global Impression Scale for Severity, hemodynamic variables, and seizure duration. Adverse events were recorded for safety assessment.

Results: A total of 45 patients completed the study. No difference was found between groups with respect to the primary or secondary outcomes. The ketamine group showed a trend towards a decreased dose of propofol required to achieve adequate anesthesia. No adverse events were reported.

Conclusion: Low-dose ketamine does not improve psychiatric outcomes in the setting of propofol-based anesthesia for ECT. Specifically, ketamine did not reduce the number of ECT sessions necessary to achieve a 50 or 25% reduction in MADRS scores. Reassuringly, the fact that no differences in hemodynamic variables or unexpected adverse events occurred suggests that low-dose ketamine may be safely used in this setting should clinical indications warrant its use.”

Authors: Adrianna J. Woolsey,  Jalal A. Nanji, Chantal Moreau, Sudhakar Sivapalan, Stephane L. Bourque, Alfonso Ceccherini-Nelli & Ferrante S. Gragasin

Summary

Introduction

Electroconvulsive therapy (ECT) is an effective treatment modality for a variety of psychiatric disorders, including major depressive disorder. However, propofol, a potent antiepileptic agent, may decrease the efficacy of ECT as a depression treatment.

Ketamine is a general anesthetic agent with dissociative properties, and has been used successfully as the sole anesthesia induction agent in ECT. At low doses, ketamine may improve ECT depression treatment by potentially improving seizure activity elicited by ECT or by improving depression in its own right.

Study design

A double-blind, placebo-controlled, randomized trial was conducted in adult patients with major depressive disorder undergoing ECT. Ketamine was administered at a dose of 0.2 mg/kg, and an interim analysis was performed to determine if a difference was detected.

Subjects

Adults between 18 and 70 years of age referred for ECT with a DSM-5 diagnosis of major depressive disorder were included if they had a baseline MADRS score of 4 24.

Patients who have a history of allergic reactions, hypersensitivity, or intolerance to anesthetics or their constituents used in the study, a history of substance or alcohol dependence, abuse of opiates, amphetamines, barbiturates, cocaine, cannabis, or hallucinogens, a pervasive developmental disorder, or dementia, or inability to provide informed consent are excluded from participation.

Randomization and blinding

Allocation concealment was achieved using the sequentially-numbered, opaque, sealed envelope method. The study coordinator, treating psychiatrist, anesthesiologist, and patients were all blinded to treatment allocation.

Study medication

The research pharmacy prepared ketamine in syringes labelled with patient identifiers, and the ECT anesthesiologist administered the entire study drug syringe followed immediately by propofol and succinylcholine to achieve adequate anesthesia for the ECT treatment.

Procedures

In the index course of ECT, patients received the study drug at each of their treatments. A maximum of 12 treatments were performed, and a REDCap secure online database was used for data collection and management.

Outcomes

Data was collected on heart rate, blood pressure, oxygen saturation, respiratory rate, temperature, and seizure duration during ECT sessions. Adverse events were also collected during ECT sessions and inpatient hospitalization.

Statistical analysis

Based on estimates that a single ECT treatment will help less than 10% of patients with treatment-resistant major depressive disorder, 14 subjects per group are needed for a study with 80% power.

The final analyses were performed on psychiatric data using an independent samples t-test and Levene’s test, and hemodynamic and seizure data were analyzed using an independent samples I-test.

Screening and randomization

48 patients provided informed consent for study enrollment. 45 patients completed the study and were included in the final analyses.

The first 14 patients received either ketamine at 0.2 mg/kg or an equivalent volume of saline, and the subsequent 31 patients received ketamine at 0.5 mg/kg or placebo.

Psychiatric endpoints

At interim analysis, no significant differences in primary or secondary psychiatric outcomes were noted between the ketamine and placebo groups. In the final analyses, there were no significant differences in the number of ECT sessions required to achieve a 25% reduction in MADRS or in the CGI-S score between groups.

Non-psychiatric endpoints

The maximum heart rate and mean arterial pressure were higher in the ketamine group than the placebo group, but did not differ significantly when normalized to the patient’s baseline pre-ECT values.

Propofol dose was similar between the ketamine and placebo groups, with a trend towards a lower dose in the ketamine group. Seizure duration and maximum post-ECT respiratory rate were similar.

Discussion

In this randomized controlled trial, low-dose ketamine did not improve depression scores or reduce seizure duration compared to placebo.

Ketamine has been used in depression treatment in numerous randomized controlled trials, with inconsistent evidence of improvement in psychiatric outcomes and some evidence of potential for increased harm. Our study differs from previous trials in that we started with the lowest dose of ketamine reported to improve depression, performed an interim analysis, and then increased the dose. We also allowed the treating anesthesiologist to select the propofol dose, thus enhancing the authenticity of the clinical scenario.

Although our results do not suggest that ketamine improves psychiatric outcomes with ECT, it was well tolerated and had no unexpected adverse events. The patients achieved maximal recovery after an index course of ECT plus ketamine.

Ketamine may have similar antidepressant mechanisms to ECT, including increased cerebral blood flow and metabolic rate, breakdown of the blood brain barrier, and upregulation of brain-derived neurotrophic factor. Ketamine may also not be relevant in this situation because of its N-methyl-D-aspartate receptor antagonism.

Ketamine may improve depression by creating a dissociative experience similar to taking ayahuasca. However, ketamine may have little benefit when administered as part of a general anesthetic technique.

The anesthesiologist was unaware of the treatment allocation, but could still control the dose of propofol. The results indicate that the propofol doses were appropriately titrated to effect, and there was no difference in seizure duration or hemodynamic effects in these patients. Based on our results, low-dose ketamine may reduce propofol requirements and thus theoretically increase seizure duration, but it is reassuring that low-dose ketamine is a safe addition to the anesthetic regimen for ECT.

Our study has some limitations, such as a small sample size and no post-treatment cognitive testing. However, meaningful information can still be conveyed regarding psychiatric endpoints and recovery time after ECT.

Low-dose ketamine did not improve depression compared to placebo, and did not affect hemodynamic parameters or seizure duration. It may be considered for use in certain clinical contexts for ECT treatment.

Study details

Compounds studied
Ketamine

Topics studied
Depression

Study characteristics
Placebo-Controlled Double-Blind Randomized

Participants
45