Effects of Erythropoietin on Hippocampal Volume and Memory in Mood Disorders

Biol Psychiatry. 2015 Aug 15;78(4):270-7. doi: 10.1016/j.biopsych.2014.12.013. Epub 2014 Dec 18.


Background: Persistent cognitive dysfunction in depression and bipolar disorder (BD) impedes patients' functional recovery. Erythropoietin (EPO) increases neuroplasticity and reduces cognitive difficulties in treatment-resistant depression (TRD) and remitted BD. This magnetic resonance imaging study assessed the neuroanatomical basis for these effects.

Methods: Patients with TRD who were moderately depressed or BD in partial remission were randomized to 8 weekly EPO (40,000 IU) or saline infusions in a double-blind, parallel-group design. Patients underwent magnetic resonance imaging, memory assessment with the Rey Auditory Verbal Learning Test, and mood ratings with the Beck Depression Inventory, Hamilton Depression Rating Scale, and Young Mania Rating Scale at baseline and week 14. Hippocampus segmentation and analysis of hippocampal volume, shape, and gray matter density were conducted with FMRIB Software Library tools. Memory change was analyzed with repeated-measures analysis of covariance adjusted for depression symptoms, diagnosis, age, and gender.

Results: Eighty-four patients were randomized; 1 patient withdrew and data collection was incomplete for 14 patients; data were thus analyzed for 69 patients (EPO: n = 35, saline: n = 34). Compared with saline, EPO was associated with mood-independent memory improvement and reversal of brain matter loss in the left hippocampal cornu ammonis 1 to cornu ammonis 3 and subiculum. Using the entire sample, memory improvement was associated with subfield hippocampal volume increase independent of mood change.

Conclusions: EPO-associated memory improvement in TRD and BD may be mediated by reversal of brain matter loss in a subfield of the left hippocampus. EPO may provide a therapeutic option for patients with mood disorders who have impaired neuroplasticity and cognition.

Trial registration: ClinicalTrials.gov NCT00916552.

Keywords: Bipolar disorder; Cognition; Erythropoietin; Hippocampus; MRI; Treatment-resistant depression.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Bipolar Disorder / drug therapy
  • Bipolar Disorder / pathology*
  • Depressive Disorder / drug therapy
  • Depressive Disorder, Treatment-Resistant
  • Erythropoietin / administration & dosage*
  • Erythropoietin / therapeutic use
  • Female
  • Hippocampus / drug effects*
  • Hippocampus / pathology*
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Memory / drug effects*
  • Middle Aged
  • Mood Disorders / drug therapy
  • Mood Disorders / pathology*
  • Psychiatric Status Rating Scales


  • Erythropoietin

Associated data

  • ClinicalTrials.gov/NCT00916552