Is Erythropoetin (EPO) a Candidate Drug for Depression?

Erythropoetin (EPO) is a naturally produced hormone that controls erythropoiesis (red blood cell production).  It’s been commercially available in the U.S. since 1989 and is used commonly used to combat anemia associated with chemotherapy treatment in cancer.  In addition to its effect on red blood cells, EPO appears to play a key role in the brain response to neuronal injury and some role in the healing of wounds.

EPO is infamous because of its use by cyclists and other athletes for performance enhancement.  By increasing the number of red blood cells, EPO can increase oxygen carrying capacity and produce improved aerobic performance.  Since it is a natural product, EPO was initially very difficult to assay for doping recognition.

EPO is felt to have effects on neuroplasticity, the ability of the brain to repair and maintain neurons.  Some classes of antidepressants (lithium, MAO-B inhibitors) show increased neuroplasticity in animal models.  Working back from this, it is possible to propose that drugs with neuroplasticity may be good candidates for novel antidepressant drug development.

This is the line of thinking being followed by a group of Danish researchers.  They note that EPO may also be able to directly affect some of the cognitive impairment associated with major mood disorders.  Here is a summary of some of this research and current research:

Effects of EPO in emotional processing biases associated with major depression:  Functional magnetic resonance imaging has been very helpful in showing in showing how people with depression process emotions.  Depressed patients tend to over-react to pictures of sad faces and under-react to pictures of happy faces.  In effect, they over-respond to negative stimuli and under-respond to positive stimuli.  Antidepressants appear to influence emotional processing moving those with depression in a direction of non-depressed individuals.  The effect appears to occur in brain regions known to be involved in emotional control.

Miskowiak and colleagues at the University Hospital of Copenhagen, used fMRI to study the change in emotional processing in major depression.  Seventeen subjects with acute major depression received either 40,000 IU of EPO or placebo via IV drip.  Three days later, fMRI studies showed EPO produced a reduced response to negative faces.  These effects were demonstrated in the amygdala, hippocampus, ventromedial prefrontal cortex and parietal cortex.  Subjects also demonstrated improved memory on a memory task provided after administration of EPO.  These effects with EPO mimic effects seen by antidepressants in those with depression. 

Current clinical trial of EPO for depression and neurocognitive symptoms in depression:  The Danish team is now conducting a clinical trial of EPO with the design outlined in the last manuscript below.  The key elements of the design for this study include: 

• Cases Definition: Treatment-resistant depression or patients with bipolar disorder in full or partial remission with residual cognitive problems
• Drug: EPO 40,000 IU IV or placebo once weekly for 8 weeks
• fMRI: Screening and week 14
• Neuropsych Testing: Baseline, week 9 and week 14
• Psychopathological Ratings:  Weekly for 5 weeks, week 9  and 14
• Safety monitoring:  Hematology, blood chemistries, BDNF, inflammatory and metabolic markers  regularly throughout the study.

EPO can have adverse effects.  Increased red cell blood mass can produce an increased clotting risk potentially increasing risk for thromboembolism, stroke or myocardial infarction.  Despite the potential risk, I think EPO deserves study and with these initial promising results may provide hope for a novel treatment for depression.

Image of molecular model for the hormone EPO courtesy of Creative Commons at Wikipedia—author unknown. 

Miskowiak KW, Favaron E, Hafizi S, Inkster B, Goodwin GM, Cowen PJ, & Harmer CJ (2009). Effects of erythropoietin on emotional processing biases in patients with major depression: an exploratory fMRI study. Psychopharmacology, 207 (1), 133-42 PMID: 19705104


Miskowiak KW, Favaron E, Hafizi S, Inkster B, Goodwin GM, Cowen PJ, & Harmer CJ (2010). Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients. Psychopharmacology, 210 (3), 419-28 PMID: 20401747


Miskowiak KW, Vinberg M, Harmer CJ, Ehrenreich H, Knudsen GM, Macoveanu J, Hansen AR, Paulson OB, Siebner HR, & Kessing LV (2010). Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder. Trials, 11 PMID: 20942940