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

Abstract

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.

Cognitive function after electroconvulsive therapy for depression: relationship to clinical response

“…The neuropsychological assessment consisted of tests involving verbal and visual memory, attention and verbal fluency/executive function (Anderson et al, 2017a(Anderson et al, , 2017b with the key outcomes reported here.…”

A review of ketamine’s role in ECT and non-ECT settings

“… 9 When combined with barbiturates such as thiopental, ketamine has not been shown to be effective in reducing depressive symptoms, likely due to the effects of barbiturates in attenuating seizures as a result of their anticonvulsant properties. 7 , 11 , 15 , 16 Ketamine may have a role as an adjunctive agent to a non-barbiturate anesthetic, or as a sole anesthetic to accelerate response in the severely ill and those at risk of suicide. While iv ketamine remains the main route of administration, a few studies have demonstrated promising results in non-ECT settings when using alternate routes, notably intranasal.…”

“…It is important to note that most of these adverse effects are transient in nature, and subside shortly after completion of an ECT session. 7 , 15 , 18 Therefore, an individual risk–benefit analysis should be considered.…”

“…In contrast, a few RCTs have not found ketamine to be superior to other anesthetics in depressive symptom reduction or improved cognition, 15 – 17 , 19 , 20 even if the seizure duration was prolonged with ketamine. 11 The effect of ketamine on seizure duration varied between studies, with some demonstrating no difference between ketamine and controls.…”

Effects of ketamine in electroconvulsive therapy for major depressive disorder: meta-analysis of randomised controlled trials

“…Studies with multiple ECT sessions (≥2 times) were excluded. [33][34][35][36][37][38][39][40][41][42][43][44][45][46] Observational studies, conference articles, case report/ series and meta-analyses and systematic reviews were excluded. Moreover, multiple-intervention studies, including ECT combined with acupuncture or Chinese herbal medicine, were excluded.…”