A randomized, crossover comparison of ketamine and electroconvulsive therapy for treatment of major depressive episodes: a Canadian biomarker integration network in depression (CAN-BIND) study protocol.

BACKGROUND: Recent evidence underscores the utility of rapid-acting antidepressant interventions, such as ketamine, in alleviating symptoms of major depressive episodes (MDE). However, to date, there have been limited head-to-head comparisons of intravenous (IV) ketamine infusions with other antidepressant treatment strategies in large randomized trials. This study protocol describes an ongoing multi-centre, prospective, randomized, crossover, non-inferiority trial comparing acute treatment of individuals meeting diagnostic criteria for a major depressive episode (MDE) with ketamine and electroconvulsive therapy (ECT) on efficacy, speed of therapeutic effects, side effects, and health care resource utilization. A secondary aim is to compare a 6-month maintenance strategy for ketamine responders to standard of care ECT maintenance. Finally, through the measurement of clinical, cognitive, neuroimaging, and molecular markers we aim to establish predictors and moderators of treatment response as well as treatment-elicited effects on these outcomes. METHODS: Across four participating Canadian institutions, 240 patients with major depressive disorder or bipolar disorder experiencing a MDE are randomized (1:1) to a course of ECT or racemic IV ketamine (0.5 mg/kg) administered 3 times/week for 3 or 4 weeks. Non-responders (< 50% improvement in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) crossover to receive the alternate treatment. Responders during the randomization or crossover phases then enter the 6-month maintenance phase during which time they receive clinical assessments at identical intervals regardless of treatment arm. ECT maintenance follows standard of care while ketamine maintenance involves: weekly infusions for 1 month, then bi-weekly infusions for 2 months, and finally monthly infusions for 3 months (returning to bi-weekly in case of relapse). The primary outcome measure is change in MADRS scores after randomized treatment as assessed by raters blind to treatment modality. DISCUSSION: This multi-centre study will help identify molecular, imaging, and clinical characteristics of patients with treatment-resistant and/or severe MDEs who would benefit most from either type of therapeutic strategy. In addition to informing clinical practice and influencing health care delivery, this trial will add to the robust platform and database of CAN-BIND studies for future research and biomarker discovery. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03674671. Registered September 17, 2018.

Assessment of health systems guidance using the Appraisal of Guidelines for Research and Evaluation - Health Systems (AGREE-HS) instrument.

Health systems guidance (HSG) documents contain systematically developed statements or recommendations intended to address a health system challenge. The concept of HSG is fairly new and considerable effort has been undertaken to build tools to support the contextualization of recommendations. One example is the Appraisal of Guidelines for REsearch and Evaluation - Health Systems (AGREE-HS), created by international stakeholders and researchers, to assist in the development, reporting and evaluation of HSG. Here, we present the quality appraisal of 85 HSG documents published from 2012 to 2017 using the AGREE-HS. The AGREE-HS consists of five items (Topic, Participants, Methods, Recommendations, and Implementability), which are scored on a 7-point response scale (1=lowest quality; 7=highest quality). Overall, AGREE-HS item scores were highest for the 'Topic' and 'Recommendations' items (means above the mid-point of 4), while the 'Participants', 'Methods', and 'Implementability' items received lower scores. Documents without a specific health focus and those authored by the National Institute for Health and Care Excellence group, achieved higher AGREE-HS overall scores than their comparators. No statistically significant changes in overall scores were observed over time. This is the first time that the AGREE-HS has been applied, providing a current quality status report of HSG and identifying where improvements in HSG development and reporting can be made.