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

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

J Psychiatry Neurosci 2020;45(3):198-205 | PDF | Appendix

Kamilla W. Miskowiak, DMSc, PhD; Julie L. Forman, PhD; Maj Vinberg DMSc, PhD; Hartwig R. Siebner, DMSc; Lars V. Kessing, DMSc; Julian Macoveanu, PhD

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.


Submitted Oct. 29, 2018; Revised May 29, 2019; Accepted July 26, 2019; Published online Dec. 5, 2019

Affiliations: From the Neurocognition and Emotion in Affective Disorder (NEAD) Group, Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Miskowiak, Macoveanu); the Department of Psychology, University of Copenhagen (Miskowiak); the Section of Biostatistics, Department of Public Health, University of Copenhagen (Forman); the Danish Research Centre for Magnetic Resonance (DRCMR), Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen (Siebner); the Department of Neurology, Copenhagen University Hospital Bispebjerg (Siebner); the Institute for Clinical Medicine, Faculty of Medical and Health Sciences, University of Copenhagen (Vinberg, Siebner); and the Copenhagen Affective Disorder Research Centre (CADIC), Psychiatric Centre Copenhagen, Copenhagen University Hospital (Kessing), Copenhagen, Denmark.

Funding: The Danish Council of Independent Research, Novo Nordisk Foundation, Beckett Fonden, and Savværksejer Juhl’s Mindefond are acknowledged for their financial support for the study. The sponsors had no role in the planning or conduct of the study or in the interpretation of the results. The Lundbeck Foundation and the Weimann Foundation are acknowledged for their contribution to K. Miskowiak’s salary from 2012 to 2020.

Competing interests: 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.

Contributors: K. Miskowiak, M. Vinberg, H. Siebner, L. Kessing, and J. Macoveanu designed the study. K. Miskowiak acquired the data, which K. Miskowiak, J. Forman and J. Macoveanu analyzed. K. Miskowiak and J. Macoveanu wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.180205

Correspondence to: Kamilla W. Miskowiak, Neurocognition and Emotion in Affective Disorder (NEAD) Group, CADIC, Psychiatric Centre Copenhagen,
Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: kamilla@miskowiak.dk