title: Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder: a double-blind, randomized, placebo-controlled phase 2 trial.
abstract: OBJECTIVE
  Available drug treatments for bipolar disorder fail to reverse patients' cognitive deficits. Erythropoietin has neurotrophic actions and aids neurocognitive function. The aim of the study was to investigate the potential of erythropoietin to treat cognitive dysfunction in bipolar disorder.
  
  
  METHODS
  Patients with an ICD-10 diagnosis of bipolar disorder in remission were randomized, with stratification by age and gender, to receive 8 weekly erythropoietin (40,000 IU) or saline (sodium chloride [NaCl], 0.9%) infusions in a double-blind, parallel-group design. The first patient was randomized in September 2009 and last assessment was completed in October 2012. Patients were assessed at baseline and at weeks 9 and 14. The primary outcome was change in verbal memory indexed by the total words recalled across Rey Auditory Verbal Learning Test learning trials (I-V) from baseline to week 9; secondary outcomes were sustained attention and facial expression recognition; and tertiary outcomes were attention, executive function, subjective cognitive function, and mood. Analysis was by intention to treat, using repeated-measures analysis of covariance adjusted for stratification variables and mood. The statistical threshold for which results were considered significant was P ≤ .05 (2-tailed).
  
  
  RESULTS
  44 patients were randomized; given 1 dropout after baseline, results were analyzed for 43 patients (erythropoietin: n = 23; saline: n = 20). There was no significant improvement of verbal memory in erythropoietin versus saline groups (P = .10). However, erythropoietin enhanced sustained attention (P = .001), recognition of happy faces (P = .03), and speed of complex information processing across learning, attention, and executive function (P = .01). These effects occurred in absence of changes in simple reaction times or mood (P values ≥ .16) and were maintained after red blood cell normalization.
  
  
  CONCLUSIONS
  This is the first trial investigating erythropoietin to treat cognitive dysfunction in bipolar disorder. The findings highlight erythropoietin as a candidate treatment for deficits in attention and executive function in bipolar disorder.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT00916552.
authors.affiliation: Department of Psychiatry, Copenhagen Psychiatric Centre, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark Kamilla@miskowiak.dk.
authors.forename: Kamilla W
authors.initials: KW
authors.lastname: Miskowiak
authors.forename: Hannelore
authors.initials: H
authors.lastname: Ehrenreich
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Christensen
authors.forename: Lars V
authors.initials: LV
authors.lastname: Kessing
authors.forename: Maj
authors.initials: M
authors.lastname: Vinberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001288:Attention / Q000187:drug effects; D001714:Bipolar Disorder / Q000150:complications / Q000188:drug therapy*; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy*; D004311:Double-Blind Method; D004921:Erythropoietin / Q000627:therapeutic use*; D056344:Executive Function / Q000187:drug effects; D005260:Female; D006801:Humans; D007858:Learning / Q000187:drug effects; D008297:Male; D011939:Mental Recall / Q000187:drug effects; D008875:Middle Aged; D011930:Reaction Time / Q000187:drug effects; D021641:Recognition, Psychology / Q000187:drug effects; D011994:Recombinant Proteins / Q000627:therapeutic use; D055815:Young Adult
chemical_list: C554270:EPO protein, human; D011994:Recombinant Proteins; D004921:Erythropoietin