Neural correlates of improved executive function following erythropoietin treatment in mood disorders

Psychol Med. 2016 Jun;46(8):1679-91. doi: 10.1017/S0033291716000209. Epub 2016 Mar 21.


Background: 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.

Method: 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.

Results: 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).

Conclusions: 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.

Clinical trial registration: NCT00916552.

Keywords: Bipolar disorder; EPO; cognition; dorsolateral prefrontal cortex; erythropoietin; executive function; fMRI; treatment-resistant depression.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bipolar Disorder / diagnostic imaging
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / physiopathology
  • Bipolar Disorder / psychology
  • Brain / diagnostic imaging
  • Brain / physiopathology*
  • Cognitive Dysfunction / diagnostic imaging
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / physiopathology
  • Cognitive Dysfunction / psychology
  • Depressive Disorder, Major / diagnostic imaging
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / physiopathology
  • Depressive Disorder, Major / psychology
  • Depressive Disorder, Treatment-Resistant / diagnostic imaging
  • Depressive Disorder, Treatment-Resistant / drug therapy*
  • Depressive Disorder, Treatment-Resistant / physiopathology
  • Depressive Disorder, Treatment-Resistant / psychology
  • Double-Blind Method
  • Erythropoietin / therapeutic use*
  • Executive Function*
  • Female
  • Functional Neuroimaging
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Memory, Short-Term
  • Middle Aged
  • Spatial Memory
  • Treatment Outcome


  • Erythropoietin

Associated data