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

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.

Clinical trial registration: ClinicalTrials.gov, NCT02579642.

Conflict of interest statement

CM participated in the Regional Canadian Esketamine Advisory Board Meeting (AB-SK-MB, Feb 13 2019), which provided a clinical review of Esketamine, examined evidence for its use, and reviewed safety protocols. The other authors report no conflicts of interest.

Figures

Figure 1. CONSORT diagram depicting study recruitment. Details about discontinued intervention: * 1 patient was found to be ineligible after enrollment (baseline MADRS † 1 patient withdrew from electroconvulsive therapy. CONSORT = Consolidated Standards of Reporting Trials; ECT = electroconvulsive therapy; MADRS = Montgomery-Asberg Depression Rating Scale.

Figure 2. Reduction of MADRS and CGI-S scores following ECT with or without ketamine. The cumulative data (mean values ± SD) showed no significant difference in the number of ECT sessions required to reduce MADRS scores by (A) 50 or (B) 25% between the ketamine and placebo groups. C) The CGI-S score reduction did not differ significantly between the groups. n=16 for the ketamine group and n=15 for the placebo group. CGI-S = Clinical Global Impression Scale for Severity; ECT = electroconvulsive therapy; MADRS = Montgomery-Asberg Depression Rating Scale; SD = standard deviation.

Figure 3. Reduction of MADRS and CGI-S scores over the duration of ECT sessions. Cumulative data (mean values ± SD) showing the reduction in (A) MADRS scores and (B) CGI-S scores during ECT in the ketamine and placebo groups. n=16 for the ketamine group and n=15 for the placebo group. CGI-S = Clinical Global Impression Scale for Severity; ECT = electroconvulsive therapy; MADRS = Montgomery-Asberg Depression Rating Scale; SD = standard deviation.

Figure 4. Hemodynamic alterations in the ketamine and placebo groups during ECT. A) The cumulative data (mean values ± SD) showed that maximum HR increased significantly in the ketamine group compared to placebo group (* p

Figure 5. Differences in propofol dosing, seizure duration, and maximum respiratory rate between the ketamine and placebo groups during electroconvulsive therapy. A) Cumulative data (mean values ± SD) demonstrating that propofol dosing did not differ significantly in the presence of ketamine 0.2 mg/kg. B) Cumulative data (mean values ± SD) demonstrating a non-significant decrease in propofol requirements in the presence of ketamine 0.5 mg/kg (p = 0.053). The cumulative data (mean values ± SD) also revealed no significant difference in (C) seizure duration or (D) maximum respiratory rate between the ketamine and placebo groups. n=16 for the ketamine group and n=15 for the placebo group. RR = respiratory rate; SD = standard deviation.