Effects of recombinant human erythropoietin on cognition and neural activity in remitted patients with mood disorders and first-degree relatives of patients with psychiatric disorders: a study protocol for a randomized controlled trial

Jeff Zarp Petersen, Lejla Sjanic Schmidt, Maj Vinberg, Martin Balslev Jørgensen, Ida Hageman, Hannelore Ehrenreich, Gitte Moos Knudsen, Lars Vedel Kessing, Kamilla Woznica Miskowiak, Jeff Zarp Petersen, Lejla Sjanic Schmidt, Maj Vinberg, Martin Balslev Jørgensen, Ida Hageman, Hannelore Ehrenreich, Gitte Moos Knudsen, Lars Vedel Kessing, Kamilla Woznica Miskowiak

Abstract

Background: Bipolar disorder (BD) and unipolar disorder (UD) are associated with cognitive deficits and abnormal neural activity in a "cognitive control network." There is an increased prevalence of cognitive dysfunction in psychiatric patients' first-degree relatives, which constitutes a risk factor for psychiatric illness onset. However, there is no treatment with enduring pro-cognitive efficacy. We found preliminary evidence for beneficial effects of eight weekly doses of recombinant human erythropoietin (EPO) on cognition in BD in a recent randomized controlled trial (RCT). The present RCT consists of two sub-studies that extend our previous work by investigating important novel aspects: (1) the effects of 12 weekly doses of EPO on cognition in first-degree relatives of patients with BD, UD, or schizophrenia; and (2) the effects of extending the treatment schedule from 8 to 12 weeks in remitted patients with BD or UD; and (3) assessment of early treatment-associated neural activity changes that may predict cognitive improvement.

Methods: The trial comprises two parallel sub-studies with randomized, controlled, double-blinded, parallel group designs. First-degree relatives (sub-study 1; n = 52) and partially or fully remitted patients with BD or UD (sub-study 2; n = 52) with objectively verified cognitive dysfunction are randomized to receive weekly high-dose EPO (40,000 IU/mL) or placebo (saline) infusions for 12 weeks. Assessments of cognition and mood are conducted at baseline, after two weeks of treatment, after treatment completion, and at six-month follow-up. Functional magnetic resonance imaging (fMRI) is conducted at baseline and after two weeks of treatment. Psychosocial function is assessed at baseline, after treatment completion and six-month follow-up. The primary outcome is change in a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference by including 52 first-degree relatives and 52 patients with BD or UD, respectively. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data are analyzed with the FMRIB Software Library.

Discussion: If this trial reveals pro-cognitive effects of EPO, this may influence future treatment of mood disorders and/or preventive strategies in at-risk populations. The fMRI analyses may unravel key neurobiological targets for pro-cognitive treatment.

Trial registration: ClinicalTrials.gov , NCT03315897. Registered on 20 October 2017.

Keywords: Biomarker; Bipolar disorder; Cognition; Cognitive dysfunction; Depression; Erythropoietin; Functional magnetic resonance imaging; Prefrontal cortex; Pro-cognitive efficacy.

Conflict of interest statement

Ethics approval and consent to participate

The study has been approved by the Danish Medicines Agency (EudraCT number 2016–004023-24), the Ethics Committee in the Capital Region of Denmark (protocol number H-16043370), and The Danish Data Protection Agency Capital Region of Denmark (protocol number RHP-2017-020) and has been retrospectively registered at https://ichgcp.net/clinical-trials-registry/NCT03315897 on 20th October 2017. 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.

Consent for publication

Not applicable.

Competing interests

JZP, LSS, MBJ, and IH declare no competing interests. KWM has received consultancy fees from Lundbeck and Allergan. MV discloses consultancy fees from Lundbeck and Astra Zeneca within the last three years. GMK was supported by a Center grant from the Innovation Fond, Center for Experimental Medicine Neuropharmacology (Neuropharm). LVK reports having been a consultant for Lundbeck, AstraZeneca, and Sunovion within the last three years. HE holds user patents for EPO in stroke, schizophrenia, and MS.

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 enrolment, interventions, and assessments. EPO erythropoietin, RVP Rapid Visual Information Processing (CANTAB, Cambridge Cognition Ltd.), FAST Functional Assessment Short Test, RAVLT Rey Auditory Verbal Learning Test, RBANS Repeatable Battery for the Assessment of Neuropsychological Status, WAIS-III LNS Wechsler Adult Intelligence Scale Version III Letter-Number Sequencing, OTS One Touch Stockings of Cambridge, SWM Spatial Working Memory, TMT-A Trail Making Test Part A, TMT-B Trail Making Test Part B, AQoL Assessment of Quality of Life, COBRA Cognitive Complaints in Bipolar disorder Rating Assessment, SDS Sheehan Disability Scale, UPSA-B UCSD Performance-Based Skills Assessment-B, WHOQOL-BREF World Health Organization Quality of Life, WSAS Work and Social Adjustment Scale, DART Danish Adult Reading Test, CTQ Childhood Trauma Questionnaire, SCIP Screen for Cognitive Impairment in Psychiatry (Danish version)

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Source: PubMed

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