Effects of erythropoietin on memory-relevant neurocircuitry activity and recall in mood disorders.
Erythropoietin (EPO) improves verbal memory and reverses subfield hippocampal volume loss across depression and bipolar disorder (BD). This study aimed to investigate with functional magnetic resonance imaging (fMRI) whether these effects were accompanied by functional changes in memory-relevant neuro-circuits in this cohort.



Eighty-four patients with treatment-resistant unipolar depression who were moderately depressed or BD in remission were randomized to eight weekly EPO (40 000 IU) or saline infusions in a double-blind, parallel-group design. Participants underwent whole-brain fMRI at 3T, mood ratings, and blood tests at baseline and week 14. During fMRI, participants performed a picture encoding task followed by postscan recall.



Sixty-two patients had complete data (EPO: N = 32, saline: N = 30). EPO improved picture recall and increased encoding-related activity in dorsolateral prefrontal cortex (dlPFC) and temporo-parietal regions, but not in hippocampus. Recall correlated with activity in the identified dlPFC and temporo-parietal regions at baseline, and change in recall correlated with activity change in these regions from baseline to follow-up across the entire cohort. The effects of EPO were not correlated with change in mood, red blood cells, blood pressure, or medication.



The findings highlight enhanced encoding-related dlPFC and temporo-parietal activity as key neuronal underpinnings of EPO-associated memory improvement.
Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.|Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
K W
KW
Miskowiak
Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.|Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.|Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark.
J
J
Macoveanu
Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
M
M
Vinberg
Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
E
E
Assentoft
Psychiatric Centre Copenhagen, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark.
L
L
Randers
Department of Psychiatry, University of Oxford, Oxford, UK.
C J
CJ
Harmer
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
H
H
Ehrenreich
Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.|Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark.|Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
O B
OB
Paulson
Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark.|Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
G M
GM
Knudsen
Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.|Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen, Denmark.|Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark.
H R
HR
Siebner
Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
L V
LV
Kessing
D000328:Adult; D003866:Depressive Disorder / Q000000981:diagnostic imaging / Q000188:drug therapy*; D061218:Depressive Disorder, Treatment-Resistant / Q000000981:diagnostic imaging / Q000188:drug therapy*; D004311:Double-Blind Method; D004921:Erythropoietin / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D011939:Mental Recall / Q000187:drug effects*; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging; D011569:Psychiatric Status Rating Scales; D016896:Treatment Outcome
D004921:Erythropoietin
bipolar disorder; cognition disorders; functional neuroimaging; randomized controlled trial