title: Neural correlates of improved executive function following erythropoietin treatment in mood disorders.
abstract: Cognitive dysfunction in depression and bipolar disorder (BD) is insufficiently targeted by available treatments. Erythropoietin (EPO) increases neuroplasticity and may improve cognition in mood disorders, but the neuronal mechanisms of these effects are unknown. This functional magnetic resonance imaging (fMRI) study investigated the effects of EPO on neural circuitry activity during working memory (WM) performance.
  
  
  
  Patients with treatment-resistant major depression, who were moderately depressed, or with BD in partial remission, were randomized to eight weekly infusions of EPO (40 000 IU) (N = 30) or saline (N = 26) in a double-blind, parallel-group design. Patients underwent fMRI, mood ratings and blood tests at baseline and week 14. During fMRI patients performed an n-back WM task.
  
  
  
  EPO improved WM accuracy compared with saline (p = 0.045). Whole-brain analyses revealed that EPO increased WM load-related activity in the right superior frontal gyrus (SFG) compared with saline (p = 0.01). There was also enhanced WM load-related deactivation of the left hippocampus in EPO-treated compared to saline-treated patients (p = 0.03). Across the entire sample, baseline to follow-up changes in WM performance correlated positively with changes in WM-related SFG activity and negatively with hippocampal response (r = 0.28-0.30, p < 0.05). The effects of EPO were not associated with changes in mood or red blood cells (p ⩾0.08).
  
  
  
  The present findings associate changes in WM-load related activity in the right SFG and left hippocampus with improved executive function in EPO-treated patients.
  
  
  
  clinicaltrials.gov: NCT00916552.
authors.affiliation: Psychiatric Centre Copenhagen,Copenhagen University Hospital,Rigshospitalet,Copenhagen,Denmark.
authors.forename: K W
authors.initials: KW
authors.lastname: Miskowiak
authors.affiliation: Psychiatric Centre Copenhagen,Copenhagen University Hospital,Rigshospitalet,Copenhagen,Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Vinberg
authors.affiliation: Psychiatric Centre Copenhagen,Copenhagen University Hospital,Rigshospitalet,Copenhagen,Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Glerup
authors.affiliation: Danish Research Centre for Magnetic Resonance (DRCMR),Centre for Functional and Diagnostic Imaging and Research,Hvidovre Hospital, University of Copenhagen,Copenhagen,Denmark.
authors.forename: O B
authors.initials: OB
authors.lastname: Paulson
authors.affiliation: Center for Integrated Molecular Brain Imaging,Rigshospitalet,Copenhagen,Denmark.
authors.forename: G M
authors.initials: GM
authors.lastname: Knudsen
authors.affiliation: Division of Clinical Neuroscience,Max Planck Institute of Experimental Medicine,Göttingen,Germany.
authors.forename: H
authors.initials: H
authors.lastname: Ehrenreich
authors.affiliation: Department of Psychiatry,University of Oxford,Oxford,UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Harmer
authors.affiliation: Psychiatric Centre Copenhagen,Copenhagen University Hospital,Rigshospitalet,Copenhagen,Denmark.
authors.forename: L V
authors.initials: LV
authors.lastname: Kessing
authors.affiliation: Danish Research Centre for Magnetic Resonance (DRCMR),Centre for Functional and Diagnostic Imaging and Research,Hvidovre Hospital, University of Copenhagen,Copenhagen,Denmark.
authors.forename: H R
authors.initials: HR
authors.lastname: Siebner
authors.affiliation: Psychiatric Centre Copenhagen,Copenhagen University Hospital,Rigshospitalet,Copenhagen,Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Macoveanu
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology*; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D061218:Depressive Disorder, Treatment-Resistant / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D004311:Double-Blind Method; D004921:Erythropoietin / Q000627:therapeutic use*; D056344:Executive Function; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term; D008875:Middle Aged; D065852:Spatial Memory; D016896:Treatment Outcome
chemical_list: D004921:Erythropoietin
keywords: Bipolar disorder; EPO; cognition; dorsolateral prefrontal cortex; erythropoietin; executive function; fMRI; treatment-resistant depression