Ketamine, ECT Pairing Disappoints in Depression

Megan Brooks

May 04, 2017

Administering the anesthetic ketamine in conjunction with a course of electroconvulsive therapy (ECT) does not improve neuropsychological or clinical outcomes in patients with severe depression, according to results of a randomized controlled trial.

"We found no evidence of benefit from adjunctive ketamine given at a dose of 0.5 mg/kg on cognitive and efficacy outcomes," report the authors, led by Ian M. Anderson, MD, of the Neuroscience and Psychiatry Unit, University of Manchester, United Kingdom. "The results do not support the use of adjunctive low-dose ketamine in routine ECT treatment."

The study was published online March 27 in Lancet Psychiatry.

No Impact on Primary Outcome

Animal and preliminary human trials suggesting that the glutamate antagonist ketamine might alleviate the adverse cognitive effects of ECT provided the rationale for the study, the authors explain.

The research team recruited severely depressed patients aged 18 years and older who experienced moderate or severe unipolar or bipolar depressive episodes.

Patients were randomly assigned to receive ketamine (0.5 mg/kg intravenous bolus) or saline adjunctive to the anesthetic (propofol or thiopental) for the duration of their ECT course. There were 33 patients in the ketamine arm and 37 in the saline arm. Patients and the ECT treatment teams were masked to treatment allocation, although anesthetists administering the study medication were not.

Ketamine, when compared with saline, had no benefit on the primary outcome of the Hopkins Verbal Learning Test–Revised delayed verbal recall component (HVLT-R-DR), as determined through analysis after four ECT treatments (difference in means, -0.43 [95% confidence interval (CI), -1.73 to 0.87), the investigators report.

For the primary outcome, "an effect size benefit for ketamine of 0.3 or greater has been excluded with 95% confidence, and an effect size of 0.4 or greater excluded for other key outcomes; this is less than the moderate effect size originally proposed as clinically important," note Dr Anderson and colleagues.

Some studies have suggested that ketamine could accelerate the clinical response to ECT, but there was no evidence of that in this study, the authors say. On average, those who received ketamine achieved remission later than those who received saline, although this observation was not significant. "This is in sharp contrast to the rapid antidepressant effect within hours or days reported when ketamine is given alone," the team notes.

Two patients in the ketamine group had transient psychological effects following ECT treatments that were probably related to ketamine, but there was no evidence of serious tolerability or safety problems with ketamine given at the dose provided in the study.

The smaller-than-planned sample size is the most important limitation of the study, the researchers say, "which resulted in a low power so that we cannot exclude either a small to moderate sized benefit or moderate harm from treatment with adjunctive ketamine."

"Starkly Disappointing"

In an accompanying commentary, Charles Kellner, MD, and Dan Iosifescu, MD, of the Department of Psychiatry, Icahn School of Medicine at Mount Sinai in New York City, note that the research on ketamine use in ECT has been "starkly disappointing so far" and that this new study "adds to the evidence base of adjunctive ketamine use with ECT, and to the disappointment of this pairing."

"At the level of clinical symptoms, ECT is already rapidly acting and effective, such that any added speed or magnitude of antidepressant effects will be hard to detect without very large sample sizes (in excess of 200 patients per group)," they point out.

Dr Kellner and Dr Iosifescu also note that the scientific literature on the combined use of ketamine in ECT comprises more than 130 articles, "but definitive studies are few." Nonetheless, the investigators said it seems "likely that if a powerful augmenting or synergistic effect of ketamine in ECT existed, a strong signal would have emerged by now."

Alexander McGirr, MD, of the Department of Psychiatry, University of British Columbia, in Vancouver, Canada, agrees. The study by Dr Anderson and colleagues was "well conducted and so lends credence to what appears to be an increasingly consistent finding in the literature on ketamine in ECT," he told Medscape Medical News.

The results of this latest trial were included in an updated systematic review and meta-analysis of adjunctive ketamine in ECT by Dr McGirr and colleagues that was published in the British Journal of Psychiatry in April. This analysis also found no evidence to support the use of ketamine over other induction agents in ECT. Results of the recently reported KANECT trial on the use of ketamine with ECT were also negative.

"The question at this stage," said Dr McGirr, "is how ketamine can have such substantial and rapid antidepressant effects when given at a subanesthetic dose in the absence of ECT, whereas it seems to confer little added benefit when combined with ECT. Additional research aimed at this important question has the potential to inform the mechanism of action of this prototype rapid acting antidepressant and possibly optimize augmentation strategies in ECT."

The study was funded by the Efficacy and Mechanism Evaluation Program of the National Institute for Health Research (NIHR). Dr Anderson has received personal fees from Alkermes, Janssen, Lundbeck-Otsuka, and Takeda. The original article contains a complete list of author disclosures. Dr McGirr has disclosed no relevant financial relationships.

Lancet Psychiatry. Published online March 27, 2017. Full text, Commentary


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.