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.
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References
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 6:37
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 9:3253–3258
Beck AT, Ward CH, Mendelssohn MJ, Erbaugh J (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561–571
Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7:137–151
Boynton GM, Engel SA, Glover GH, Heeger DJ (1996) Linear systems analysis of functional magnetic resonance imaging in human V1. J Neurosci 16:4207–4221
Bradley PB, Mogg K, Williams R (1995) Implicit and explicit memory for emotion-congruent information in clinical depression and anxiety. Behav Res Ther 33:755–770
Brines M, Cerami A (2005) Emerging biological roles for erythropoietin in the nervous system. Nat Neurosci 6:484–494
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 97:10526–10531
Britton JC, Taylor SF, Sudheimer KD, Liberzon I (2006) Facial expressions and complex IAPS pictures: common and differential networks. Neuroimage 31:906–919
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 91:127–139
Chen ZY, Asavaritikrai P, Prchal JT, Noguchi CT (2007) Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation. J Biol Chem 282:25875–25883
Davidson RJ (2003) Affective neuroscience and psychophysiology: toward a synthesis. Psychophysiology 40:655–665
Dawson GR, Goodwin G (2005) Experimental medicine in psychiatry. J Psychopharmacol 19:565–566
Drevets WC (2000) Neuroimaging studies of mood disorders. Biol Psychiatry 48:813–829
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 12:206–220
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 130:2577–2588
Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–61
Hamilton JP, Gotlib IH (2008) Neural substrates of increased memory sensitivity for negative stimuli in major depression. Biol Psychiatry 63:1155–1162
Harmer CJ (2008) Serotonin and emotional processing: does it help explain antidepressant drug action? Neuropharmacology 55:1023–1028
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 28:148–152
Harmer CJ, Mackay CE, Reid CB, Cowen PJ, Goodwin GM (2006) Antidepressant drug treatment modifies the neural processing of nonconscious threat cues. Biol Psychiatry 59:816–820
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 10:120–131
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 FL
Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 19:1233–1239
Marvel CL, Paradiso S (2004) Cognitive and neurological impairment in mood disorders. Psychiatr Clin North Am 27:19–36
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 62:1244–1250
Miskowiak K, O'Sullivan U, Harmer CJ (2007b) Erythropoietin enhances hippocampal response during memory retrieval in humans. J Neurosci 27:2788–2792
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 37:904–911
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 33:611–618
Murphy SE, Downham C, Cowen PJ, Harmer CJ (2008) Direct effects of diazepam on emotional processing in healthy volunteers. Psychopharmacology Berl 199:503–513
Murray CLJ, Lopez AD (1997) Global disability, and the contribution of risk factors. Global Burden of Disease Study. Lancet 49:1439–1442
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 13:1011–1020
Pourtois G, Vuilleumier P (2006) Dynamics of emotional effects on spatial attention in the human visual cortex. Prog Brain Res 156:67–91
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 60:974–986
Snaith RP, Zigmond AS (1986) The hospital anxiety and depression scale. Br Med J 292:344 (clin res ed)
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 141:518–523
Spielberger CD (1983) Manual for the State-Trait Anxiety Inventory STAI. Consulting Psychologists Press, Palo Alto, CA
Talairach J, Tournoux P (1988) Co-planar stereotaxic atlas of the human brain. Thieme, New York
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 93:412–421
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 189–202
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–S72
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 54:1063–1070
Williams JMG, Watts FN, MacLeod C, Mathews A (1997) Cognitive psychology and emotional disorders. Wiley, Chichester
Woolrich MW, Ripley BD, Brady M, Smith SM (2001) Temporal autocorrelation in univariate linear modeling of fMRI data. Neuroimage 14:1370–1386
Woolrich MW, Behrens TE, Beckmann CF, Jenkinson M, Smith SM (2004) Multilevel linear modelling for fMRI group analysis using Bayesian inference. NeuroImage 21:1732–1747
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).
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Miskowiak, K.W., Favaron, E., Hafizi, S. et al. Effects of erythropoietin on emotional processing biases in patients with major depression: an exploratory fMRI study. Psychopharmacology 207, 133–142 (2009). https://doi.org/10.1007/s00213-009-1641-1
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DOI: https://doi.org/10.1007/s00213-009-1641-1