Erythropoietin as an add-on treatment for cognitive side effects of electroconvulsive therapy: a study protocol for a randomized controlled trial

Lejla Sjanic Schmidt, Jeff Zarp Petersen, Maj Vinberg, Ida Hageman, Niels Vidiendal Olsen, Lars Vedel Kessing, Martin Balslev Jørgensen, Kamilla Woznica Miskowiak, Lejla Sjanic Schmidt, Jeff Zarp Petersen, Maj Vinberg, Ida Hageman, Niels Vidiendal Olsen, Lars Vedel Kessing, Martin Balslev Jørgensen, Kamilla Woznica Miskowiak

Abstract

Background: Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, but its use is impeded by its cognitive side effects. Novel treatments that can counteract these side effects may therefore improve current treatment strategies for depression. The present randomized trial investigates (1) whether short-term add-on treatment with erythropoietin (EPO) can reduce the cognitive side -effects of ECT and (2) whether such effects are long-lasting. Further, structural and functional magnetic resonance imaging (MRI) will be used to explore the neural underpinnings of such beneficial effects of EPO. Finally, the trial examines whether potential protective effects of EPO on cognition are accompanied by changes in markers of oxidative stress, inflammation, and neuroplasticity.

Methods/design: The trial has a double-blind, randomized, placebo-controlled, parallel group design. Patients with unipolar or bipolar disorder with current moderate to severe depression referred to ECT (N = 52) are randomized to receive four high-dose infusions of EPO (40,000 IU/ml) or placebo (saline). The first EPO/saline infusion is administered within 24 h before the first ECT. The following three infusions are administered at weekly intervals immediately after ECT sessions 1, 4, and 7. Cognition assessments are conducted at baseline, after the final EPO/saline infusion (3 days after eight ECT sessions), and at a 3 months follow-up after ECT treatment completion. The neuronal substrates for potential cognitive benefits of EPO are investigated with structural and functional MRI after the final EPO/saline infusion. The primary outcome is change from baseline to after EPO treatment (3 days after eight ECT sessions) in a cognitive composite score spanning attention, psychomotor speed, and executive functions. With a sample size of N = 52 (n = 26 per group), we have ≥ 80% power to detect a clinically relevant between-group difference in the primary outcome measure at an alpha level of 5% (two-sided test). Behavioral, mood, and blood-biomarker data will be analyzed using repeated measures analysis of covariance. Functional MRI data will be preprocessed and analyzed using the FMRIB Software Library.

Discussion: If EPO is found to reduce the cognitive side effects of ECT, this could have important implications for future treatment strategies for depression and for the scientific understanding of the neurobiological etiology of cognitive dysfunction in patients treated with ECT.

Trial registration: ClinicalTrials.gov, NCT03339596 . Registered on 10 November 2017.

Keywords: Bipolar disorder; Cognition; Cognitive side effects; Depression; Electroconvulsive therapy; Erythropoietin; Functional magnetic resonance imaging; Unipolar disorder.

Conflict of interest statement

Ethics approval and consent to participate

The study has been approved by the Danish Medicines Agency (EudraCT number 2016-002326- 36), the Ethics Committee in the Capital Region of Denmark (protocol number H-16038506), and the Danish Data Protection Agency Capital Region of Denmark (protocol number RHP-2017-023), and it has been registered at ClinicalTrials.gov (NCT03339596) https://ichgcp.net/clinical-trials-registry/NCT03339596 on the 10th of November 2017 (retrospectively registered). Any important protocol modifications will be reported to the Danish Medicines Agency, the Ethics Committee in the Capital Region of Denmark, and the Danish Data Protection Agency. Written informed consent has been and will be obtained from all participants.

Competing interests

KWM has received consultancy fees from Lundbeck and Allergan. Within the past 3 years, MBJ has received speaker fees for Lundbeck and consultant fees for Shire. MV discloses consultancy fees from Lundbeck and AstraZeneca within the last 3 years. LVK reports having been a consultant for Lundbeck, AstraZeneca, and Sunovion within the last 3 years. LSS, JZP, IH, and NVO declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Schedule of enrollment, interventions, and assessments. Abbreviations: AMI-SF Columbia University Autobiographical Memory Interview-Short Form, RAVLT Rey Auditory Verbal Learning Test, TMT-B Trail Making Test Part B, WAIS-III LNS Wechsler Adult Intelligence Scale Version III Letter-Number Sequencing, RBANS Coding Repeatable Battery for the Assessment of Neuropsychological Status Coding, RVP Rapid Visual Processing (CANTAB Cambridge Cognition Ltd.), HDRS-17 Hamilton Depression Rating Scale, 17-item version, BDI-21 Beck Depression Inventory, 21 items, COBRA Cognitive Complaints in Bipolar Disorder Rating Assessment, CTQ Childhood Trauma Questionnaire

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