Ketamine and ECT: better alone than together?
Authors: Charles H Kellner, Dan V Iosifescu
Journal: The Lancet Psychiatry (2017)

An exciting therapeutic advance in the treatment of severe mood disorders has been the discovery that the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine, a widely used anaesthetic agent, results in a rapid antidepressant effect in some patients with treatment-resistant unipolar or bipolar depression (with onset of this effect within 24 hours, lasting about 7 days after a single administration).1Murrough JW Iosifescu DV Chang LC et al.Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.Am J Psychiatry. 2013; 170: 1134-1142Crossref PubMed Scopus (808) Google Scholar, 2Zarate Jr, CA Brutsche NE Ibrahim L et al.Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial.Biol Psychiatry. 2012; 71: 939-946Summary Full Text Full Text PDF PubMed Scopus (588) Google Scholar However, the early adoption and enthusiasm surrounding the clinical use of ketamine in treatment-resistant depression greatly exceed its empirical support. The clinical enthusiasm is tempered by concerns that ketamine's antidepressant activity is short lived and by uncertainty regarding long-term safety in repeated administrations, with unknown risks for long-term cognitive side-effects, psychotic symptoms, and substance abuse.3Schwartz J Murrough JW Iosifescu DV Ketamine for treatment-resistant depression: recent developments and clinical applications.Evid Based Ment Health. 2016; 19: 35-38Crossref PubMed Scopus (87) Google Scholar Given the need for anaesthesia during electroconvulsive therapy (ECT) and the excitement about ketamine's acute effects in reducing depressive symptoms, combining the two therapies seemed a logical next step. However, the research on ketamine use in ECT has been starkly disappointing so far. The study by Ian Anderson and colleagues in The Lancet Psychiatry4Anderson IM Blamire A Branton T et al.Ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT): a multicentre, double-blind, randomised, parallel-group, superiority trial.Lancet Psychiatry. 2017; (published online March 27.)http://dx.doi.org/10.1016/S2215-0366(17)30077-9PubMed Google Scholar adds to the evidence base of adjunctive ketamine use with ECT, and to the disappointment of this pairing. Ketamine has been used successfully as an alternative stand-alone anaesthetic in ECT for decades. Typically, it is a third-line or fourth-line choice (after methohexital or thiopental, propofol, or etomidate), indicated when ECT-induced seizures have become short or difficult to elicit. In this context, it is a good ECT anaesthetic agent, with modest seizure-enhancing properties and a reasonable tolerability profile, albeit including some increased hypertension, tachycardia and occasional dissociative symptoms during the recovery period. This use involves bolus dosing in the range of 1–2 mg/kg. When it became apparent from basic science and clinical investigations that low-dose ketamine has multiple, complex effects on cognition and mood,1Murrough JW Iosifescu DV Chang LC et al.Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.Am J Psychiatry. 2013; 170: 1134-1142Crossref PubMed Scopus (808) Google Scholar, 2Zarate Jr, CA Brutsche NE Ibrahim L et al.Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial.Biol Psychiatry. 2012; 71: 939-946Summary Full Text Full Text PDF PubMed Scopus (588) Google Scholar, 5Murrough JW Burdick KE Levitch CF et al.Neurocognitive effects of ketamine and association with antidepressant response in individuals with treatment-resistant depression: a randomized controlled trial.Neuropsychopharmacology. 2015; 40: 1084-1090Crossref PubMed Scopus (105) Google Scholar researchers began to study its use as adjunctive treatment in ECT, that is, so-called cutting the induction anaesthetic with small doses of ketamine. It has been combined with various agents, including barbiturates and etomidate, but probably most commonly with propofol, a combination referred to in the anesthesia literature as ketofol. The ketamine doses used in this combination are typically in the range used in stand-alone ketamine infusions (0·5 mg/kg), but the administration is as a bolus, not a slow infusion over 45 minutes. Additionally, a few patients have been given low-dose ketamine infusions before ECT with standard anaesthetics. Ketamine might enhance (or accelerate) the antidepressant efficacy of ECT by the above-mentioned potentiation of the therapeutic seizure, or it might have intrinsic additive antidepressant properties. The antidepressant mechanism of ketamine is considered to be triggered by the acute, short-term surge in synaptic glutamate and GABA concentrations;6Milak MS Proper CJ Mulhern ST et al.A pilot in vivo proton magnetic resonance spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder.Mol Psychiatry. 2016; 21: 320-327Crossref PubMed Scopus (99) Google Scholar these concentrations are in turn responsible for the downstream effects on multiple signalling pathways.7Duman RS Li N Liu RJ Duric V Aghajanian G Signaling pathways underlying the rapid antidepressant actions of ketamine.Neuropharmacology. 2012; 62: 35-41Crossref PubMed Scopus (413) Google Scholar However, ECT also acutely increases glutamate and GABA concentrations,8Biedermann S Weber-Fahr W Zheng L et al.Increase of hippocampal glutamate after electroconvulsive treatment: a quantitative proton MR spectroscopy study at 9·4 T in an animal model of depression.World J Biol Psychiatry. 2012; 13: 447-457Crossref PubMed Scopus (20) Google Scholar and it is unclear that additional increases are possible or desirable. 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). One meta-analysis,9Li DJ Wang FC Chu CS et al.Significant treatment effect of add-on ketamine anesthesia in electroconvulsive therapy in depressive patients: a meta-analysis.Eur Neuropsychopharmacol. 2017; 27: 29-41Summary Full Text Full Text PDF PubMed Scopus (37) Google Scholar which analysed data from about 400 patients, concluded that ECT might have a modest effect in enhancing antidepressant efficacy.9Li DJ Wang FC Chu CS et al.Significant treatment effect of add-on ketamine anesthesia in electroconvulsive therapy in depressive patients: a meta-analysis.Eur Neuropsychopharmacol. 2017; 27: 29-41Summary Full Text Full Text PDF PubMed Scopus (37) Google Scholar Whether the benefit outweighs the increased side-effect burden is not yet clear. Although clinical trials of intravenous ketamine have most frequently used a 0·5 mg/kg dose,1Murrough JW Iosifescu DV Chang LC et al.Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.Am J Psychiatry. 2013; 170: 1134-1142Crossref PubMed Scopus (808) Google Scholar, 2Zarate Jr, CA Brutsche NE Ibrahim L et al.Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial.Biol Psychiatry. 2012; 71: 939-946Summary Full Text Full Text PDF PubMed Scopus (588) Google Scholar the optimal antidepressant dose of ketamine is still unknown (an NIMH-funded dose-finding multicentre study is expected to report results in 2017: ClinicalTrials.gov, number NCT01920555). The uncertain dose and the unknown effects of combining ketamine with other anaesthetic agents with respect to antidepressant effects further complicate the interpretation of ketamine augmentation of ECT in clinical studies. Anderson and colleagues4Anderson IM Blamire A Branton T et al.Ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT): a multicentre, double-blind, randomised, parallel-group, superiority trial.Lancet Psychiatry. 2017; (published online March 27.)http://dx.doi.org/10.1016/S2215-0366(17)30077-9PubMed Google Scholar reported that ketamine (mean 5·17, SD 2·92), when compared with saline (5·54, 3·42), had no benefit on the primary outcome (HVLT-R-DR; difference in means −0·43, 95%CI −1·73 to 0·87). Ketamine might improve the cognitive tolerability profile of ECT, but this too is uncertain. Assessing the cognitive effects of ECT is fraught with difficulty, with challenging choices related to the most relevant cognitive domains to target, optimal neuropsychological instruments, and timepoints of assessments. We do know that most of the cognitive effects of ECT dissipate within days to weeks after the end of treatment and that retrograde autobiographical memory, the issue of greatest concern to patients, is remarkably difficult to measure accurately.10Semkovska M McLoughlin DM Objective cognitive performance associated with electroconvulsive therapy for depression: a systematic review and meta-analysis.Biol Psychiatry. 2010; 68: 568-577Summary Full Text Full Text PDF PubMed Scopus (451) Google Scholar The benign cognitive profile of ECT used in the Ketamine-ECT study (predominantly with bilateral electrode placement, a type of ECT typically associated with more cognitive effects)11Kumar S Mulsant BH Liu AY Blumberger DM Daskalakis ZJ Rajji TK Systematic review of cognitive effects of electroconvulsive therapy in late-life depression.Am J Geriatr Psychiatry. 2016; 24: 547-565Summary Full Text Full Text PDF PubMed Scopus (43) Google Scholar is reassuring, despite not shedding much light on whether ketamine has some protective effect. The scientific literature on the combined use of ketamine in ECT comprises over 130 articles, but definitive studies are few. As for many clinical questions in psychiatry, and medicine in general, an adequately powered and well-designed study to test both the cognitive and antidepressant effects of ketamine in conjunction with ECT remains elusive and unlikely to receive funding support. Can the numerous small studies and case series take the place of such a definitive study when subjected to meta-analysis? Probably not, but it seems likely that if a powerful augmenting or synergistic effect of ketamine in ECT existed, a strong signal would have emerged by now. Anderson and colleagues state that their results excluded greater than a small to moderate benefit with 95% confidence. However, in our opinion, even a small-to-moderate benefit is worth pursuing. ECT remains the gold standard of antidepressant treatment and is essential for a large subgroup of patients who are seriously ill and resistant to treatment.12Kellner CH Greenberg RM Murrough JW Bryson EO Briggs MC Pasculli RM ECT in treatment-resistant depression.Am J Psychiatry. 2012; 169: 1238-1244Crossref PubMed Scopus (162) Google Scholar Improving the efficacy and tolerability profile of ECT, even incrementally, remains a worthy research goal. CHK reports grant support from NIMH, honoraria from UpToDate, North Shore-LIJ Health System, and Psychiatric Times and royalties from Cambridge University Press. Over the past five years DVI has been a consultant for Avanir, Axome, CNS Response, INSYS Therapeutics, Lundbeck, Otsuka, Servier, Sunovion and has received research support through the Icahn School of Medicine at Mount Sinai from Alkermes, Astra Zeneca, Brainsway, Euthymics, Neosync, Roche, and Shire. The Icahn School of Medicine at Mount Sinai is named on a licensed patent on ketamine for the treatment of depression. Icahn School of Medicine at Mount Sinai could potentially benefit if ketamine were to gain approval for the treatment of depression. Ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT): a multicentre, double-blind, randomised, parallel-group, superiority trialNo evidence of benefit for ketamine was found although the sample size used was small; however, the results excluded greater than a small to moderate benefit with 95% confidence. The results do not support the use of adjunctive low-dose ketamine in routine ECT treatment. Full-Text PDF Open Access