title: Ketamine for depression relapse prevention following electroconvulsive therapy: protocol for a randomised pilot trial (the KEEP-WELL trial).
abstract: BACKGROUND
  Major depressive disorder is a common debilitating illness that is the second leading contributor to the global burden of disease. Unfortunately, about 30 % of patients do not respond to adequate trials of antidepressants and/or psychotherapies. About 45-60 % of such treatment-resistant patients will remit with electroconvulsive therapy (ECT). However, relapse rates are high following ECT-38 % after 6 months. There is a need for better relapse prevention strategies. One possibility is to use ketamine, a competitive glutamate receptor antagonist used for anaesthesia. A recent paradigm shift in treating depression and understanding its biology has been the finding that ketamine has a robust, rapid-onset, though short-lived, antidepressant effect that is possibly mediated through neuroplastic effects. However, ketamine has not previously been reported on for relapse prevention.
  
  
  METHODS
  The main objective of this study is to conduct a randomised controlled pilot trial (n= 40) of a 4-week course of once-weekly ketamine infusions for relapse prevention following ECT for depression to assess trial procedures that will inform a future definitive trial. Participants with unipolar depression will be recruited prior to commencing ECT and be assessed weekly during the ECT course using the primary clinical outcome, the 24-item Hamilton Rating Scale for Depression (HRSD-24). Those who meet standard response criteria will be invited, on completing ECT, to be randomised in a 1:1 ratio to a course of four once-weekly infusions of ketamine or an active comparator midazolam, which mimics some of the effects of ketamine and may improve blinding over inactive placebo. Participants will be followed up over 6 months using the HRSD-24 to assess for relapse.
  
  
  CONCLUSIONS
  This is the first registered trial (NCT02414932, https://clinicaltrials.gov/ct2/show/NCT02414932) of ketamine for depression relapse prevention, an important possible use of this agent. The primary focus of the pilot trial is on feasibility. However, a 95 % confidence interval will be determined for the difference between ketamine and midazolam groups in 6-month relapse rates to help inform a future definitive trial.
  
  
  BACKGROUND
  https://clinicaltrials.gov/ NCT02414932 Secondary Identifying numbers: EudraCT number: 2014-000339-18 Sponsors' Reference, Sponsor: St. Patrick's Mental Health Services: 05/14 Research Ethics Committee Reference, Joint REC of St James' and Tallaght Hospitals, Dublin: 2014-08-19.
authors.affiliation: Department of Psychiatry and Trinity College Institute of Neuroscience, St. Patrick's University Hospital, James' St., Dublin 8, Ireland.
authors.forename: Martha
authors.initials: M
authors.lastname: Finnegan
authors.affiliation: Trinity College Institute of Neuroscience, Trinity College Dublin, College Green, Dublin 2, Ireland.
authors.forename: Karen
authors.initials: K
authors.lastname: Ryan
authors.affiliation: Department of Psychiatry and Trinity College Institute of Neuroscience, St. Patrick's University Hospital, James' St., Dublin 8, Ireland.
authors.forename: Enda
authors.initials: E
authors.lastname: Shanahan
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, College Green, Dublin 2, Ireland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Harkin
authors.affiliation: Centre for Training and Research in Analysis and Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Leslie
authors.initials: L
authors.lastname: Daly
authors.affiliation: Department of Psychiatry and Trinity College Institute of Neuroscience, St. Patrick's University Hospital, James' St., Dublin 8, Ireland.
authors.forename: Declan M
authors.initials: DM
authors.lastname: McLoughlin
keywords: Depression; Electroconvulsive therapy; Ketamine; Pilot trial; Relapse prevention