title: Ketamine augmentation of electroconvulsive therapy to improve neuropsychological and clinical outcomes in depression (Ketamine-ECT): a multicentre, double-blind, randomised, parallel-group, superiority trial.
abstract: The use of electroconvulsive therapy (ECT) is limited by concerns about its cognitive adverse effects. Preliminary evidence suggests that administering the glutamate antagonist ketamine with ECT might alleviate cognitive adverse effects and accelerate symptomatic improvement; we tested this in a randomised trial of low-dose ketamine.
  
  
  
  In this multicentre, randomised, parallel-group study in 11 ECT suites serving inpatient and outpatient care settings in seven National Health Service trusts in the North of England, we recruited severely depressed patients, who were diagnosed as having unipolar or bipolar depressive episodes defined as moderate or severe by DSM-IV criteria, aged at least 18 years, and were able and willing to provide written consent to participate in the study. Patients were randomly assigned (1:1) to ketamine (0·5 mg/kg intravenous bolus) or saline adjunctive to the anaesthetic for the duration of their ECT course. Patients and assessment and ECT treatment teams were masked to treatment allocation, although anaesthetists administering the study medication were not. We analysed the primary outcome, Hopkins Verbal Learning Test-Revised delayed verbal recall (HVLT-R-DR) after four ECT treatments, using a Gaussian repeated measures model in all patients receiving the first ECT treatment. In the same population, safety was assessed by adverse effect monitoring. This trial was registered with International Standard Randomised Controlled Trial Number, number ISRCTN14689382.
  
  
  
  Between early December, 2012, and mid-June, 2015, 628 patients were screened for eligibility, of whom 79 were randomly assigned to treatment (40 in the ketamine group vs 39 in the saline group). 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]). 15 (45%) of 33 ketamine-treated patients compared with 10 (27%) of 37 patients receiving saline experienced at least one adverse event which included two (6%) of 33 patients who had ketamine-attributable transient psychological effects. Psychiatric adverse events were the most common in both groups (six [27%] of 22 adverse events in the ketamine group vs seven [54%] of 13 in the saline group).
  
  
  
  No 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.
  
  
  
  National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme, an MRC and NIHR partnership.
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address: ian.anderson@manchester.ac.uk.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Anderson
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Blamire
authors.affiliation: Leeds and York Partnership NHS Foundation Trust, Leeds, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Branton
authors.affiliation: Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Clark
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Darragh
authors.initials: D
authors.lastname: Downey
authors.affiliation: Centre for Biostatistics, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Dunn
authors.affiliation: Nuffield Health, Leeds, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Easton
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Elliott
authors.affiliation: Biomedical Optics Research Laboratory, University College London, London, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Elwell
authors.affiliation: Pennine Care NHS Foundation Trust, Stockport, UK.
authors.forename: Katherine
authors.initials: K
authors.lastname: Hayden
authors.affiliation: Centre for Biostatistics, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Holland
authors.affiliation: Lancashire Care NHS Foundation Trust & University of Manchester, Preston, UK.
authors.forename: Salman
authors.initials: S
authors.lastname: Karim
authors.affiliation: School of Psychiatry, University of New South Wales, Black Dog Institute & St George Hospital, Sydney, NSW, Australia.
authors.forename: Colleen
authors.initials: C
authors.lastname: Loo
authors.affiliation: Neuroscience and Psychiatry Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Jo
authors.initials: J
authors.lastname: Lowe
authors.affiliation: Tees, Esk and Wear Valley NHS Foundation Trust, Darlington, UK.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Nair
authors.affiliation: Northumberland Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Oakley
authors.affiliation: Derbyshire Healthcare NHS Foundation Trust, Derby, UK.
authors.forename: Antony
authors.initials: A
authors.lastname: Prakash
authors.affiliation: Manchester Mental Health and Social Care Trust, Manchester, UK.
authors.forename: Parveen K
authors.initials: PK
authors.lastname: Sharma
authors.affiliation: Centre for Imaging Science, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Williams
authors.affiliation: Northumberland Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK; Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: R Hamish
authors.initials: RH
authors.lastname: McAllister-Williams
mesh_terms: D000328:Adult; D000368:Aged; D001714:Bipolar Disorder / Q000523:psychology / Q000628:therapy*; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D003131:Combined Modality Therapy; D015897:Comorbidity; D004311:Double-Blind Method; D004565:Electroconvulsive Therapy / Q000009:adverse effects / Q000379:methods*; D004739:England; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine