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


CONCLUSIONS
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.


BACKGROUND
Current Controlled Trials: ISRCTN14689382 (assigned 30/07/2012); EudraCT Number: 2011-005476-41.
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. liam.trevithick@newcastle.ac.uk.|Northumberland Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK. liam.trevithick@newcastle.ac.uk.
Liam
L
Trevithick
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. hamish.mcallister-williams@newcastle.ac.uk.|Northumberland Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK. hamish.mcallister-williams@newcastle.ac.uk.
R Hamish
RH
McAllister-Williams
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. andrew.blamire@newcastle.ac.uk.
Andrew
A
Blamire
Leeds and York Partnership NHS Foundation Trust, Leeds, UK. t.branton@nhs.net.
Tim
T
Branton
Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK. rossclark@doctors.org.uk.
Ross
R
Clark
Neuroscience and Psychiatry Unit, The University of Manchester and Manchester Academic Health Science Centre, Room G809, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. darragh.downey@manchester.ac.uk.
Darragh
D
Downey
Biostatistics Group, The University of Manchester, Manchester, UK. graham.dunn@manchester.ac.uk.
Graham
G
Dunn
Alpha Hospital, Sheffield, UK. amee100@doctors.org.uk.
Andrew
A
Easton
Neuroscience and Psychiatry Unit, The University of Manchester and Manchester Academic Health Science Centre, Room G809, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. rebecca.elliot@manchester.ac.uk.
Rebecca
R
Elliott
Biomedical Optics Research Laboratory, University College London, London, UK. celwell@medphys.ucl.ac.uk.
Clare
C
Ellwell
Pennine Care NHS Foundation Trust, Stockport, UK. Katherine.hayden@nhs.net.
Katherine
K
Hayden
Biostatistics Group, The University of Manchester, Manchester, UK. fiona.holland@manchester.ac.uk.
Fiona
F
Holland
Lancashire Care NHS Foundation Trust/ The University of Manchester, Preston, UK. salman.karim@manchester.ac.uk.
Salman
S
Karim
Neuroscience and Psychiatry Unit, The University of Manchester and Manchester Academic Health Science Centre, Room G809, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. jo.e.lowe@manchester.ac.uk.
Jo
J
Lowe
School of Psychiatry, University of New South Wales, Sydney, Australia. colleen.loo@unsw.edu.au.
Colleen
C
Loo
Tees, Esk and Wear Valley NTW NHS Foundation Trust, Darlington, UK. rajesh.nair1@nhs.net.
Rajesh
R
Nair
Northumberland Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK. tim.oakley@ntw.nhs.uk.
Timothy
T
Oakley
Derbyshire Healthcare NHS Foundation Trust, Derby, UK. Antony.Prakash@derbyshcft.nhs.uk.
Antony
A
Prakash
Manchester Mental Health and Social Care Trust, Manchester, UK. parveen.sharma@mhsc.nhs.uk.
Parveen K
PK
Sharma
Imaging Science and Biomedical Imaging Institute, The University of Manchester, Manchester, UK. steve.williams@manchester.ac.uk.
Stephen R
SR
Williams
Neuroscience and Psychiatry Unit, The University of Manchester and Manchester Academic Health Science Centre, Room G809, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. ian.anderson@manchester.ac.uk.
Ian M
IM
Anderson
D000293:Adolescent; D000328:Adult; D000368:Aged; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D003131:Combined Modality Therapy; D003865:Major Depressive Disorder / Q000523:psychology / Q000628:therapy*; D061218:Depressive Disorder, Treatment-Resistant / Q000628:therapy; D004311:Double-Blind Method; D004565:Electroconvulsive Therapy / Q000009:adverse effects / Q000379:methods*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D056344:Executive Function / Q000502:physiology; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use*; D061212:Memory, Episodic; D011939:Mental Recall / Q000502:physiology; D008875:Middle Aged; D019265:Spectroscopy, Near-Infrared; D016896:Treatment Outcome; D055815:Young Adult
D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine