Study protocol for the randomised controlled trial: Ketamine augmentation of ECT to improve outcomes in depression (Ketamine-ECT study)

Trevithick et al. BMC Psychiatry (2015) 15:257 DOI 10.1186/s12888-015-0641-4 STUDY PROTOCOL Open Access Study protocol for the randomised controlled trial: Ketamine augmentation of ECT to improve outcomes in depression (Ketamine-ECT study) Liam Trevithick1,2, R. Hamish McAllister-Williams1,2, Andrew Blamire3, Tim Branton4, Ross Clark5, Darragh Downey6, Graham Dunn7, Andrew Easton8, Rebecca Elliott6, Clare Ellwell9, Katherine Hayden10, Fiona Holland7, Salman Karim11, Jo Lowe6, Colleen Loo12, Rajesh Nair13, Timothy Oakley2, Antony Prakash14, Parveen K Sharma15, Stephen R. Williams16 and Ian M. Anderson6* Abstract Background: There is a robust empirical evidence base supporting the acute efficacy of electroconvulsive therapy (ECT) for severe and treatment resistant depression. However, a major limitation, probably contributing to its declining use, is that ECT is associated with impairment in cognition, notably in anterograde and retrograde memory and executive function. Preclinical and preliminary human data suggests that ketamine, used either as the sole anaesthetic agent or in addition to other anaesthetics, may reduce or prevent cognitive impairment following ECT. A putative hypothesis is that ketamine, through antagonising glutamate receptors, protects from excess excitatory neurotransmitter stimulation during ECT. The primary aim of the ketamine-ECT study is to investigate whether adjunctive ketamine can attenuate the cognitive impairment caused by ECT. Its secondary aim is to examine if ketamine increases the speed of clinical improvement with ECT. Methods/Design: The ketamine ECT study is a multi-site randomised, placebo-controlled, double blind trial. It was originally planned to recruit 160 moderately to severely depressed patients who had been clinically prescribed ECT. This recruitment target was subsequently revised to 100 patients due to recruitment difficulties. Patients will be randomly allocated on a 1:1 basis to receive either adjunctive ketamine or saline in addition to standard anaesthesia for ECT. The primary neuropsychological outcome measure is anterograde verbal memory (Hopkins Verbal Learning Test-Revised delayed recall task) after 4 ECT treatments. Secondary cognitive outcomes include verbal fluency, autobiographical memory, visuospatial memory and digit span. Efficacy is assessed using observer and self-report efficacy measures of depressive symptomatology. The effects of ECT and ketamine on cortical activity during cognitive tasks will be studied in a sub-sample using functional near-infrared spectroscopy (fNIRS). (Continued on next page) * Correspondence: 6 Neuroscience and Psychiatry Unit, The University of Manchester and Manchester Academic Health Science Centre, Room G809, Stopford Building, Oxford Road, Manchester M13 9PT, UK Full list of author information is available at the end of the article © 2015 Trevithick et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Trevithick et al. BMC Psychiatry (2015) 15:257 Page 2 of 11 (Continued from previous page) Discussion: The ketamine-ECT study aims to establish whether or not adjunctive ketamine used together with standard anaesthesia for ECT will significantly reduce the adverse cognitive effects observed after ECT. Potential efficacy benefits of increased speed of symptom improvement and a reduction in the number of ECT treatments required will also be assessed, as will safety and tolerability of adjunctive ketamine. This study will provide important evidence as to whether adjunctive ketamine is routinely indicated for ECT given for depression in routine NHS clinical practice. Trial Registration: Current Controlled Trials: ISRCTN14689382 (assigned 30/07/2012); EudraCT Number: 2011005476-41 Keywords: Ketamine, Major Depressive Episode, Electroconvulsive therapy, Memory, Cognition, Efficacy Background Depression is a leading cause of disability worldwide with unipolar depression ranked 9th in the world and 3rd in Europe amongst causes of health-related disability 2000–2012 [1] and at any one time around 3 % of the UK population meet the criteria for major depression [2]. Effective treatment remains a major problem in depression; in the largest study to date examining patient outcomes in major depression, the STAR*D study, only a quarter to a third of patients remitted after the first antidepressant and a about third had still failed to remit after 4 drug interventions [3]. The National Institute for Health and Clinical Excellence (NICE) recommends electroconvulsive therapy (ECT) as a treatment option for patients with severe depression that is life threatening or those with moderate or severe depression who have not responded to multiple drug treatments and psychological treatment [4]. ECT has been demonstrated to have greater efficacy than pharmacotherapy (effect size, ES -0.8) [5] and achieves remission rates of about 50 % in patients who have failed to respond to drug treatments [6]. It has equal efficacy in both unipolar and bipolar depressed patients [7]. Despite the robust evidence base demonstrating the efficacy of ECT, the number of patients being treated with it has fallen dramatically in recent decades. In England over a 3 month period in 2006, an estimated 1250 patients received ECT compared with over double that number in 1999 [8]. The reduction in ECT usage may be a consequence of concerns about a poor riskbenefit balance due to adverse cognitive side effects [9]. ECT treatment is associated with significant objective impairments in cognitive function, the largest effect being on verbal delayed recall, but also with significant impairment in all tests of anterograde memory, executive function and processing speed [10]. Following the end of ECT treatment there is a rapid reversal of deficits, with moderate to large improvements above baseline in most measures after 1–2 weeks [10]. However, one study showed enduring deficits in spatial recognition memory one month after end of treatment [11]. There is uncertainty as to the magnitude and persistence of retrograde amnesia following ECT [12], though a systematic review suggested that 29–55 % of patients reported persistent and often distressing loss of important past memories after ECT [13]. It has been reported that there is an association between subjective memory impairment and objective autobiographical memory impairment immediately after ECT course as well as 6 months later [14]. A surve (...truncated)