Impact of pretreatment interhemispheric hippocampal asymmetry on improvement in verbal learning following erythropoietin treatment in mood disorders: a randomized controlled trial

Abstract

Background: Treatment development that targets cognitive impairment is hampered by a lack of biomarkers that can predict treatment efficacy. Erythropoietin (EPO) improves verbal learning and memory in mood disorders, and this scales with an increase in left hippocampal volume. This study investigated whether pretreatment left hippocampal volume, interhemisphere hippocampal asymmetry or both influenced EPO treatment response with respect to verbal learning.

Methods: Data were available for 76 of 83 patients with mood disorders from our previous EPO trials (EPO = 37 patients; placebo = 39 patients). We performed cortical reconstruction and volumetric segmentation using FreeSurfer. We conducted multiple linear regression and logistic regression to assess the influence of left hippocampal volume and hippocampal asymmetry on EPO-related memory improvement, as reflected by change in Rey Auditory Verbal Learning Test total recall from baseline to post-treatment. We set up a corresponding exploratory general linear model in FreeSurfer to assess the influence of prefrontal cortex volume on verbal learning improvement, controlling for age, sex and total intracranial volume.

Results: At baseline, more rightward (left < right) hippocampal asymmetry — but not left hippocampal volume per se — was associated with greater effects of EPO versus placebo on verbal learning (p ≤ 0.05). Exploratory analysis indicated that a larger left precentral gyrus surface area was also associated with improvement of verbal learning in the EPO group compared to the placebo group (p = 0.002).

Limitations: This was a secondary analysis of our original EPO trials.

Conclusion: Rightward hippocampal asymmetry may convey a positive effect of EPO treatment efficacy on verbal learning.

Clinical trial registration: Clinicaltrials.gov NCT00916552

Conflict of interest statement

K. Miskowiak reports consultancy fees from Lundbeck, Allergan and Janssen within the past 3 years. M. Vinberg reports consultancy fees from Lundbeck within the last 3 years. H. Siebner has received honoraria as a speaker from Sanofi Genzyme and Novartis, as a consultant from Sanofi Genzyme and as senior editor of NeuroImage from Elsevier. He has received royalties as a book editor from Springer Publishers. He also holds a 5-year professorship in precision medicine at the Faculty of Health Sciences and Medicine, University of Copenhagen, that is sponsored by the Lundbeck Foundation (grant R186-2015-2138). L. Kessing reports having been a consultant for Lundbeck, AstraZeneca and Sunovion within the last 3 years. No other authors report competing interests.

© 2020 Joule Inc. or its licensors

Figures

Fig. 1

Association between (A) rightward hippocampal asymmetry and improvement in verbal learning from baseline to post-treatment across the 2 treatment groups, and (B) hippocampal asymmetry and greater effect of erythropoietin (EPO) on verbal memory.