Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST): protocol for identification of novel biomarkers via neurophysiology

Zafiris J Daskalakis, Shawn M McClintock, Itay Hadas, Elisa Kallioniemi, Reza Zomorrodi, Alanah Throop, Lucy Palmer, Faranak Farzan, Kevin E Thorpe, Carol Tamminga, Daniel M Blumberger, Zafiris J Daskalakis, Shawn M McClintock, Itay Hadas, Elisa Kallioniemi, Reza Zomorrodi, Alanah Throop, Lucy Palmer, Faranak Farzan, Kevin E Thorpe, Carol Tamminga, Daniel M Blumberger

Abstract

Background: Electroconvulsive therapy (ECT) is the most effective treatment for treatment-resistant depression (TRD), especially for acute suicidal ideation, but the associated cognitive adverse effects and negative stigma limit its use. Another seizure therapy under development is magnetic seizure therapy (MST), which could potentially overcome the restrictions associated with ECT with similar efficacy. The neurophysiological targets and mechanisms of seizure therapy, however, remain poorly understood.

Methods/design: This neurophysiological study protocol is published as a companion to the overall Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST) protocol that describes our two-site, double-blind, randomized, non-inferiority clinical trial to develop MST as an effective and safe treatment for TRD. Our aim for the neurophysiological component of the study is to evaluate two biomarkers, one to predict remission of suicidal ideation (primary outcome) and the other to predict cognitive impairment (secondary outcome). Suicidal ideation will be assessed through cortical inhibition, which according to our preliminary studies, correlates with remission of suicidal ideation. Cortical inhibition will be measured with simultaneous transcranial magnetic stimulation (TMS) and electroencephalography (EEG), TMS-EEG, which measures TMS-evoked EEG activity. Cognitive adverse effects associated with seizure therapy, on the contrary, will be evaluated via multiscale entropy analysis reflecting the complexity of ongoing resting-state EEG activity.

Discussion: ECT and MST are known to influence cortical inhibition associated with depression, suicidal ideation severity, and clinical outcome. Therefore, evaluating cortical inhibition and brain temporal dynamics will help understand the pathophysiology of depression and suicidal ideation and define new biological targets that could aid clinicians in diagnosing and selecting treatments. Resting-state EEG complexity was previously associated with the degree of cognitive side effects after a seizure therapy. This neurophysiological metric may help clinicians assess the risk for adverse effects caused by these useful and effective treatments.

Trial registration: ClinicalTrials.gov NCT03191058 . Registered on June 19, 2017.

Keywords: Cortical inhibition; Electroconvulsive therapy; Electroencephalography; Magnetic seizure therapy; Neurophysiology; Transcranial magnetic stimulation; Treatment-resistant depression.

Conflict of interest statement

The study received in-kind equipment support from MagVenture A/S (Farum, Denmark) for this investigator-initiated research. In the last 5 years, ZJD has received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc and Magventure Inc. His work is supported by the Canadian Institutes of Health Research (CIHR), the National Institutes of Mental Health (NIMH), Brain Canada and the Temerty Family and Grant Family and through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Institute. SMH has received research support from NIH. He is a consultant to Pearson Assessment. He received a teaching honoraria from Duke University School of Medicine. EK is funded by Instrumentarium Science Foundation, Helsinki, Finland, and Orion Research Foundation sr, Espoo, Finland. FF has no competing interests related to this trial. FF received funding from NARSAD (Grand ID: 22317). She has also received funding from Michael Smith Foundation for Health Research (Scholar Award), NSERC, and CIHR. DMB has received research support from CIHR, NIH, Brain Canada and the Temerty Family through the CAMH Foundation and the Campbell Family Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. He is the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He also receives in-kind equipment support from Magventure for investigator-initiated research. He received medication supplies for an investigator-initiated trial from Indivior.

© 2021. The Author(s).

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