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

Jennifer L Phillips, Natalia Jaworska, Elizabeth Kamler, Venkat Bhat, Jean Blier, Jane A Foster, Stefanie Hassel, Keith Ho, Lisa McMurray, Roumen Milev, Zahra Moazamigoudarzi, Franca M Placenza, Stéphane Richard-Devantoy, Susan Rotzinger, Gustavo Turecki, Gustavo H Vazquez, Sidney H Kennedy, Pierre Blier, CAN-BIND Investigator Team, Jennifer L Phillips, Natalia Jaworska, Elizabeth Kamler, Venkat Bhat, Jean Blier, Jane A Foster, Stefanie Hassel, Keith Ho, Lisa McMurray, Roumen Milev, Zahra Moazamigoudarzi, Franca M Placenza, Stéphane Richard-Devantoy, Susan Rotzinger, Gustavo Turecki, Gustavo H Vazquez, Sidney H Kennedy, Pierre Blier, CAN-BIND Investigator Team

Abstract

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.

Keywords: Biomarkers; Bipolar disorder; Clinical trial; Depression; Electroconvulsive therapy; Genomics; Intravenous ketamine; Major depressive disorder; Neuroimaging.

Conflict of interest statement

RM has received consulting and speaking honoraria from Allergan, Janssen, KYE, Lundbeck, Otsuka, Pfizer and Sunovion, and research grants from Janssen, Lallemand, Lundbeck, Nubiyota, and Pfizer.

GT has received an Investigator-initiated grant from Pfizer Canada, and honoraria from Bristol-Meyers Squibb Canada and Janssen Canada.

GHV has received honoraria for participation in advisory boards, giving lectures, and/or expert consultation from Allergan, Gador, Janssen, Lundbeck/Otsuka, Raffo and Sunovion.

SHK has received research funding or honoraria from Abbott, Alkermes, Allergan, BMS, Janssen, Lundbeck, Lundbeck Institute, Otsuka, Pfizer, Servier, Sunovion and Xian-Janssen.

PB received honoraria for participation in advisory boards, giving lectures, and/or expert consultation from Allergan, Bristol Myers Squibb, Janssen, Lundbeck, Otsuka, Pierre Fabre Medicaments, Pfizer and Sunovion; he received grants from Allergan, Janssen, and Lundbeck/Otsuka.

JLP, NJ, EK, VB, JB, JAF, SH, KH, LM, ZM, FMP, SRD, SR list no competing interests.

Figures

Fig. 1
Fig. 1
Study design

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