Psychopharmacology

, Volume 207, Issue 1, pp 133–142 | Cite as

Effects of erythropoietin on emotional processing biases in patients with major depression: an exploratory fMRI study

  • Kamilla W. Miskowiak
  • Elisa Favaron
  • Sepehr Hafizi
  • Becky Inkster
  • Guy M. Goodwin
  • Philip J. Cowen
  • Catherine J. Harmer
Original Investigation

Abstract

Introduction

Erythropoietin (Epo) has neurotrophic effects and may be a novel therapeutic agent in the treatment of depression. We have found antidepressant-like effects of Epo on emotional processing and mood in healthy volunteers.

Objective

The current study aimed to explore the effects of Epo on the neural processing of emotional information in depressed patients.

Materials and methods

Seventeen patients with acute major depressive disorder were randomised to receive Epo (40,000 IU) or saline iv in a double-blind, parallel-group design. On day 3, we assessed neural responses to positive, negative and neutral pictures during fMRI followed by picture recall after the scan. Mood and blood parameters were assessed at baseline and on day 3.

Results

Epo reduced neural response to negative vs. positive pictures 3 days post-administration in a network of areas including the hippocampus, ventromedial prefrontal and parietal cortex. After the scan, Epo-treated patients showed improved memory compared with those that were given placebo. The effects occurred in the absence of changes in mood or haematological parameters, suggesting that they originated from direct neurobiological actions of Epo.

Conclusions

These findings are similar to the effects of conventional antidepressants and opposite to the negative biases in depression. The central effects of Epo therefore deserve further investigation as a potential antidepressant mechanism.

Keywords

Antidepressant Human Emotion Depression Neuroimaging 

Notes

Acknowledgements

We thank Drs. Digby Quested, Susan Shaw, Mary-Jane Attenburrow and Peter Sargent for their help with patient recruitment and Drs. Mike Browning, Danilo Arnone, Sarah McTavish and Matthew Taylor for the medical assistance. The study was supported by the Lundbeck Foundation, Denmark (grant no. 94/04).

References

  1. Adamcio B, Sargin D, Stradomska A, Medrihan L, Gertler C, Theis F, Zhang M, Müller M, Hassouna I, Hannke K, Sperling S, Radyushkin K, El-Kordi A, Schulze L, Ronnenberg A, Wolf F, Brose N, Rhee JS, Zhang W, Ehrenreich H (2008) Erythropoietin enhances hippocampal long-term potentiation and memory. BMC Biol 6:37CrossRefPubMedGoogle Scholar
  2. Beauregard M, Leroux JM, Bergman S, Arzoumanian Y, Beaudoin G, Bourgouin P, Stip E (1998) The functional neuroanatomy of major depression: an fMRI study using an emotional activation paradigm. Neuroreport 9:3253–3258PubMedCrossRefGoogle Scholar
  3. Beck AT, Ward CH, Mendelssohn MJ, Erbaugh J (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561–571PubMedGoogle Scholar
  4. Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7:137–151CrossRefPubMedGoogle Scholar
  5. Boynton GM, Engel SA, Glover GH, Heeger DJ (1996) Linear systems analysis of functional magnetic resonance imaging in human V1. J Neurosci 16:4207–4221PubMedGoogle Scholar
  6. Bradley PB, Mogg K, Williams R (1995) Implicit and explicit memory for emotion-congruent information in clinical depression and anxiety. Behav Res Ther 33:755–770CrossRefPubMedGoogle Scholar
  7. Brines M, Cerami A (2005) Emerging biological roles for erythropoietin in the nervous system. Nat Neurosci 6:484–494CrossRefGoogle Scholar
  8. Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97:10526–10531CrossRefPubMedGoogle Scholar
  9. Britton JC, Taylor SF, Sudheimer KD, Liberzon I (2006) Facial expressions and complex IAPS pictures: common and differential networks. Neuroimage 31:906–919CrossRefPubMedGoogle Scholar
  10. Brody AL, Saxena S, Silverman DH, Alborzian S, Fairbanks LA, Phelps ME, Huang SC, Wu HM, Maidment K, Baxter LR Jr (1999) Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine. Psychiatry Res 91:127–139CrossRefPubMedGoogle Scholar
  11. Chen ZY, Asavaritikrai P, Prchal JT, Noguchi CT (2007) Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation. J Biol Chem 282:25875–25883CrossRefPubMedGoogle Scholar
  12. Davidson RJ (2003) Affective neuroscience and psychophysiology: toward a synthesis. Psychophysiology 40:655–665CrossRefPubMedGoogle Scholar
  13. Dawson GR, Goodwin G (2005) Experimental medicine in psychiatry. J Psychopharmacol 19:565–566CrossRefPubMedGoogle Scholar
  14. Drevets WC (2000) Neuroimaging studies of mood disorders. Biol Psychiatry 48:813–829CrossRefPubMedGoogle Scholar
  15. Ehrenreich H, Hinze-Selch D, Stawicki S, Aust C, Knolle-Veentjer S, Wilms S, Heinz G, Erdag S, Jahn H, Degner D, Ritzen M, Mohr A, Wagner M, Schneider U, Bohn M, Huber M, Czernik A, Pollmächer T, Maier W, Sirén AL, Klosterkötter J, Falkai P, Rüther E, Aldenhoff JB, Krampe H (2007a) Improvement of cognitive function in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 12:206–220CrossRefPubMedGoogle Scholar
  16. Ehrenreich H, Fischer B, Norra C, Schellenberger F, Stender N, Stiefel M, Sirén AL, Paulus W, Nave KA, Gold R, Bartels C (2007b) Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 130:2577–2588CrossRefPubMedGoogle Scholar
  17. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–61CrossRefPubMedGoogle Scholar
  18. Hamilton JP, Gotlib IH (2008) Neural substrates of increased memory sensitivity for negative stimuli in major depression. Biol Psychiatry 63:1155–1162CrossRefPubMedGoogle Scholar
  19. Harmer CJ (2008) Serotonin and emotional processing: does it help explain antidepressant drug action? Neuropharmacology 55:1023–1028CrossRefPubMedGoogle Scholar
  20. Harmer CJ, Bhagwagar Z, Perrett DI, Völlm BA, Cowen PJ, Goodwin GM (2003) Acute SSRI administration affects the processing of social cues in healthy volunteers. Neuropsychopharmacology 28:148–152CrossRefPubMedGoogle Scholar
  21. Harmer CJ, Mackay CE, Reid CB, Cowen PJ, Goodwin GM (2006) Antidepressant drug treatment modifies the neural processing of nonconscious threat cues. Biol Psychiatry 59:816–820CrossRefPubMedGoogle Scholar
  22. Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, Rainey L, Kochunov PV, Nickerson D, Mikiten SA, Fox PT (2000) Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 10:120–131CrossRefPubMedGoogle Scholar
  23. Lang PJ, Bradley MM, Cuthbert BN, International Affective Picture System (IAPS) (1997) Technical Manual and Affective Ratings. NIMH Center for the Study of Emotion and Attention 1997. University of Florida, Gainesville FLGoogle Scholar
  24. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 19:1233–1239CrossRefPubMedGoogle Scholar
  25. Marvel CL, Paradiso S (2004) Cognitive and neurological impairment in mood disorders. Psychiatr Clin North Am 27:19–36CrossRefPubMedGoogle Scholar
  26. Miskowiak K, O'Sullivan U, Harmer CJ (2007a) Erythropoietin reduces neural and cognitive processing of fear in human models of antidepressant drug action. Biol Psychiatry 62:1244–1250CrossRefPubMedGoogle Scholar
  27. Miskowiak K, O'Sullivan U, Harmer CJ (2007b) Erythropoietin enhances hippocampal response during memory retrieval in humans. J Neurosci 27:2788–2792CrossRefPubMedGoogle Scholar
  28. Miskowiak K, Papadatou-Pastou M, Cowen PJ, Goodwin GM, Norbury R, Harmer CJ (2007c) Single dose antidepressant administration modulates the neural processing of self-referent personality trait words. Neuroimage 37:904–911CrossRefPubMedGoogle Scholar
  29. Miskowiak K, Inkster B, Selvaraj S, Wise R, Goodwin GM, Harmer CJ (2008) Erythropoietin improves mood and modulates the cognitive and neural processing of emotion 3 days post administration. Neuropsychopharmacology 33:611–618CrossRefPubMedGoogle Scholar
  30. Murphy SE, Downham C, Cowen PJ, Harmer CJ (2008) Direct effects of diazepam on emotional processing in healthy volunteers. Psychopharmacology Berl 199:503–513CrossRefPubMedGoogle Scholar
  31. Murray CLJ, Lopez AD (1997) Global disability, and the contribution of risk factors. Global Burden of Disease Study. Lancet 49:1439–1442Google Scholar
  32. Norbury R, Mackay CE, Cowen PJ, Goodwin GM, Harmer CJ (2008) The effects of reboxetine on emotional processing in healthy volunteers: an fMRI study. Mol Psychiatry 13:1011–1020CrossRefPubMedGoogle Scholar
  33. Pourtois G, Vuilleumier P (2006) Dynamics of emotional effects on spatial attention in the human visual cortex. Prog Brain Res 156:67–91CrossRefPubMedGoogle Scholar
  34. Schaefer HS, Putnam KM, Benca RM, Davidson RJ (2006) Event-related functional magnetic resonance imaging measures of neural activity to positive social stimuli in pre- and post-treatment depression. Biol Psychiatry 60:974–986CrossRefPubMedGoogle Scholar
  35. Snaith RP, Zigmond AS (1986) The hospital anxiety and depression scale. Br Med J 292:344 (clin res ed)CrossRefGoogle Scholar
  36. Snaith RP, Baugh SJ, Clayden AD, Husain A, Sipple MA (1982) The Clinical Anxiety Scale: an instrument derived from the Hamilton Anxiety Scale. Br J Psychiatry 141:518–523CrossRefPubMedGoogle Scholar
  37. Spielberger CD (1983) Manual for the State-Trait Anxiety Inventory STAI. Consulting Psychologists Press, Palo Alto, CAGoogle Scholar
  38. Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the human brain. Thieme, New YorkGoogle Scholar
  39. Viviani B, Bartesaghi S, Corsini E, Villa P, Ghezzi P, Garau A, Galli CL, Marinovich M (2005) Erythropoietin protects primary hippocampal neurons increasing the expression of brain-derived neurotrophic factor. J Neurochem 93:412–421CrossRefPubMedGoogle Scholar
  40. Von Zerssen D, Strain F, Schwartz D (1974) Evaluation of depressive states, especially in longitudinal studies. In: Pichot P (ed) Psychological measurement in psychopharmacology. Modern problems in pharmacopsychiatry. Karger, Basel, pp 189–202Google Scholar
  41. Wagner V, Muller JL, Sommer M, Klein HE, Hajak G (2004) Changes in the emotional processing in depressive patients: a study with functional magnetoresonance tomography under the employment of pictures with affective contents. Psychiatr Prax 31:S70–S72CrossRefPubMedGoogle Scholar
  42. Watson D, Clark LA, Tellegen A (1988) Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 54:1063–1070CrossRefPubMedGoogle Scholar
  43. Williams JMG, Watts FN, MacLeod C, Mathews A (1997) Cognitive psychology and emotional disorders. Wiley, ChichesterGoogle Scholar
  44. Woolrich MW, Ripley BD, Brady M, Smith SM (2001) Temporal autocorrelation in univariate linear modeling of fMRI data. Neuroimage 14:1370–1386CrossRefPubMedGoogle Scholar
  45. Woolrich MW, Behrens TE, Beckmann CF, Jenkinson M, Smith SM (2004) Multilevel linear modelling for fMRI group analysis using Bayesian inference. NeuroImage 21:1732–1747CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Kamilla W. Miskowiak
    • 1
  • Elisa Favaron
    • 2
  • Sepehr Hafizi
    • 2
  • Becky Inkster
    • 3
  • Guy M. Goodwin
    • 2
  • Philip J. Cowen
    • 2
  • Catherine J. Harmer
    • 2
  1. 1.Department of PsychiatryUniversity Hospital of Copenhagen, RigshospitaletCopenhagenDenmark
  2. 2.Department of PsychiatryUniversity of OxfordOxfordUK
  3. 3.Faculty of MedicineImperial College LondonLondonUK

Personalised recommendations