A systematic review and meta-analysis of randomized controlled trials of adjunctive ketamine in electroconvulsive therapy: Efficacy and tolerability

McGirr, Alexander; Berlim, Marcelo T.; Bond, David J.; Neufeld, Nicholas H.; Chan, Peter; Yatham, Lakshmi N.; Lam, Raymond W.

doi:10.1016/j.jpsychires.2015.01.003

Cited by 96 publications

(46 citation statements)

References 44 publications

(93 reference statements)

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“…In contrast to the meta-analysis by McGirr et al 52 we did not find a significant increase in AEs or confusion, although 6% (n = 2/33) of ketamine patients experienced transient psychological reactions that were probably attributable to ketamine. Other studies found that ketamine alone, or at higher doses than used in this study, may be associated with slower reorientation and more AEs 48,49,163 (although this appears to be attenuated when ketamine is used with propofol 163,164 ).…”

Section: Neuropsychological Outcomescontrasting

confidence: 99%

“…The lack of effect of adjunctive ketamine on efficacy is consistent with a meta-analysis of five small studies with differing methodology 52 that showed no pooled benefit. Pooling this study with the largest other study, which also used a ketamine dose of 0.5 mg/kg and was the only one reporting a full course of ECT, 51 there is no significant difference between ketamine and placebo in rates of response or remission or in continuous measures of depression either after 1 week or at the end of treatment (see Table 27).…”

supporting

confidence: 76%

“…When continuous measures were pooled a moderate to large advantage of ketamine was reported in one study, 41 but no benefit was found for response, remission or continuous measures in another. 52 The latter meta-analysis also reported higher rates of confusion/disorientation/ prolonged delirium with ketamine than with placebo. At present, the small heterogeneous studies of ketamine administered with ECT, either as the sole anaesthetic agent or alongside a conventional anaesthetic, emphasise the need for further, larger-scale trials.…”

Section: Background and Objectivesmentioning

confidence: 88%

“…) and the data from studies using higher doses of ketamine with ECT, 52 or as a pharmacological treatment, 165 do not suggest an efficacy benefit.…”

mentioning

confidence: 98%

“…As discussed in Chapter 1 the results to date have been patchy and inconclusive (see also McGirr et al 52 ). Pooling the results of this study together with those of Loo et al, 51 which used ultra-brief RUL ECT and the same outcome measures, there is currently no evidence for a cognitive benefit of low-dose ketamine augmentation of ECT; the 95% CIs exclude more than a small-to-moderate advantage of ketamine for most measures (Table 27).…”

mentioning

confidence: 99%

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Randomised controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study)

et al. 2017

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BackgroundElectroconvulsive therapy (ECT) is the most effective acute treatment for severe depression, but there are concerns about its adverse cognitive effects. ECT may impair cognition through stimulation of glutamate receptors, and preliminary evidence has suggested that ketamine, a glutamate antagonist, may alleviate these effects. Ketamine has been shown to have a rapid, but temporary, antidepressant effect after a single infusion.ObjectiveTo determine the efficacy and safety of adjunctive low-dose ketamine to reduce cognitive impairments caused by ECT and, secondarily, to improve symptomatic outcome.DesignMulticentre, two-arm, parallel-group, patient-randomised, placebo-controlled superiority trial.SettingEleven ECT suites based in seven NHS trusts in the north of England.ParticipantsSeverely depressed hospitalised patients or outpatients who received ECT as part of their usual clinical care.InterventionsPatients were randomised to ketamine (0.5 mg/kg) or saline as an adjunct to their anaesthetic for their ECT course in a 1 : 1 ratio.Main outcome measuresThe primary outcome was delayed verbal recall on the Hopkins Verbal Learning Task – Revised (HVLT-R) after four ECT treatments (mid-ECT), analysed using a Gaussian repeated measures model. Secondary outcomes included autobiographical, working and visual memory and verbal fluency, symptoms and quality of life; assessments occurred at mid-ECT, end of treatment and 1 and 4 months after the last ECT. Neuropsychological function was compared with that of healthy control subjects and a functional near-infrared spectroscopy (fNIRS) substudy investigated prefrontal cortex function. A patient survey of study participation was carried out.ResultsSeventy-nine severely depressed patients were randomised to ketamine (0.5 mg/kg) or saline as an adjunct to their anaesthetic for their ECT course; the modified intention-to-treat sample included 70 patients. Compared with saline, adjunctive ketamine had no significant effect on HVLT-R delayed recall [treatment effect difference –0.43, 95% confidence interval (CI) –1.73 to 0.87], other neuropsychological outcomes, improvement in depression [difference in Montgomery–Åsberg Depression Rating Scale (MADRS) score of 0.44, 95% CI –1.03 to 1.91], the number of ECT treatments to remission (MADRS score of ≤ 10: 0.83, 95% CI –3.2 to 4.9), anxiety symptoms or quality of life. By the end of ECT treatment, 37% (saline 35%, ketamine 39%) of patients had remitted. Tolerability was similar in the two treatment arms; two patients had isolated transient psychological effects attributable to ketamine. Preliminary fNIRS analysis found that patients had blunted prefrontal cortical haemodynamic responses compared with control subjects during a verbal fluency task at baseline; this was further diminished at mid-ECT without modulation by ketamine. Greater haemodynamic responsivity to ECT appeared to be associated with a better clinical response. The majority of patients surveyed reported a positive experience of study participation.ConclusionsThe results of the study do not support the use of adjunctive ketamine in routine ECT treatment in the NHS. Although no evidence of benefit was found for ketamine, moderate benefits or harms cannot be excluded, as recruitment was < 50% of that planned, limiting the power of the clinical trial. Low numbers also meant that in the fNIRS substudy the effect of ketamine could not be assessed and the other findings must be viewed as preliminary. Included patients were younger than those not included and had only limited cognitive impairment with ECT, limiting generalisation to more cognitively compromised patients. fNIRS appeared to be a potentially feasible portable brain imaging technology in severely ill patients and further research is warranted to investigate its clinical utility.Trial registrationCurrent Controlled Trials ISRCTN14689382.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

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Section: Neuropsychological Outcomescontrasting

confidence: 99%

supporting

confidence: 76%

Section: Background and Objectivesmentioning

confidence: 88%

“…) and the data from studies using higher doses of ketamine with ECT, 52 or as a pharmacological treatment, 165 do not suggest an efficacy benefit.…”

mentioning

confidence: 98%

mentioning

confidence: 99%

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Randomised controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study)

et al. 2017

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Ketamine for Treatment-Resistant Unipolar and Bipolar Major Depression: Critical Review and Implications for Clinical Practice

et al. 2016

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There is an urgent need for more rapidly effective pharmacotherapies for major depressive disorder and bipolar disorder (BP) that are efficacious and tolerable for depressed patients who respond poorly to conventional treatments. Multiple controlled trials have now demonstrated a rapid, nonsustained antidepressive response to a single intravenous infusion of ketamine. Early controlled studies of intranasal or serial infusion therapy appear promising. The effective dose for depression is lower than the typical anesthetic doses, and side-effects are generally mild and transient. The data investigating the adjunctive use of concurrent ketamine in the course of electroconvulsive therapy (ECT) for depression do not suggest efficacy or tolerability. The therapeutic potential of ketamine has stimulated considerable excitement among clinicians, patients, and industry, and has led to the increasing use of ketamine as an off-label substitute for ECT and other antidepressive treatments. This clinical review of ketamine will assess the evidence-based use of ketamine and initial clinical implications of further development of a potentially novel treatment for rapid reduction of symptoms in depressed patients.

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Ketamine: Its Safety, Tolerability, and Impact on Neurocognition

Rybakowski

Permoda-Osip

Bartkowska-Śniatkowska

2016

Ketamine for Treatment-Resistant Depression

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A systematic review and meta-analysis of randomized controlled trials of adjunctive ketamine in electroconvulsive therapy: Efficacy and tolerability

Cited by 96 publications

References 44 publications

Randomised controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study)

Randomised controlled trial of ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT study)

Ketamine for Treatment-Resistant Unipolar and Bipolar Major Depression: Critical Review and Implications for Clinical Practice

Ketamine: Its Safety, Tolerability, and Impact on Neurocognition

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