Ketamine for depression relapse prevention following electroconvulsive therapy: protocol for a randomised pilot trial (the KEEP-WELL trial)

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/DESIGN 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. DISCUSSION 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. TRIAL REGISTRATION 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.