The effect of recombinant erythropoietin on plasma brain derived neurotrophic factor levels in patients with affective disorders: a randomised controlled study

Maj Vinberg, Kamilla Miskowiak, Pernille Hoejman, Maria Pedersen, Lars Vedel Kessing, Maj Vinberg, Kamilla Miskowiak, Pernille Hoejman, Maria Pedersen, Lars Vedel Kessing

Abstract

The study aims to investigate the effect of repeated infusions of recombinant erythropoietin (EPO) on plasma brain derived neurotrophic factor (BDNF) levels in patients with affective disorders. In total, 83 patients were recruited: 40 currently depressed patients with treatment-resistant depression (TRD) (Hamilton Depression Rating Scale-17 items (HDRS-17) score >17) (study 1) and 43 patients with bipolar disorder (BD) in partial remission (HDRS-17 and Young Mania Rating Scale (YMRS) ≤ 14) (study 2). In both studies, patients were randomised to receive eight weekly EPO (Eprex; 40,000 IU) or saline (0.9% NaCl) infusions in a double-blind, placebo-controlled, parallel--group design. Plasma BDNF levels were measured at baseline and at weeks 5, 9 and at follow up, week 14. In contrast with our hypothesis, EPO down regulated plasma BDNF levels in patients with TRD (mean reduction at week 9 (95% CI): EPO 10.94 ng/l (4.51-21.41 ng/l); mean increase at week 9: Saline 0.52 ng/l, p=0.04 (-5.88-4.48 ng/l) p=0.04, partial ŋ2=0.12). No significant effects were found on BDNF levels in partially remitted patients with BD (p=0.35). The present effects of EPO on BDNF levels in patients with TRD point to a role of neurotrophic factors in the potential effects of EPO seen in TRD and BD. The neurobiological mechanisms underlying these effects and the interaction between EPO and peripheral levels on BDNF need to be further elucidated in human studies including a broad range of biomarkers.

Trial registration: ClinicalTrials.gov: NCT00916552.

Conflict of interest statement

Competing Interests: MV has been a consultant for Eli Lilly, Lundbeck; Servier and Astra Zeneca. LVK has within the last 3 years been a consultant for Lundbeck, AstraZeneca and Servier. KWM has received consultancy fees from Lundbeck. All other authors report no financial interests or other potential conflicts of interest. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. CONSORT Flow Diagram.
Fig 1. CONSORT Flow Diagram.
Fig 2. Plasma Brain Derived Neurotrophic Factor…
Fig 2. Plasma Brain Derived Neurotrophic Factor (BDNF) levels according to treatment group in patients with treatment resistant depression.

References

    1. Chao MV, Lee FS. Neurotrophin survival signaling mechanisms. J Alzheimers Dis 2004. December;6(6 Suppl):S7–11.
    1. Goldstein BI, Young LT. Toward clinically applicable biomarkers in bipolar disorder: focus on BDNF, inflammatory markers, and endothelial function. Curr Psychiatry Rep 2013. December;15(12):425 10.1007/s11920-013-0425-9
    1. Molendijk ML, Spinhoven P, Polak M, Bus BA, Penninx BW, Elzinga BM. Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N = 9484). Mol Psychiatry 2013. August 20.
    1. Hayley S, Litteljohn D. Neuroplasticity and the next wave of antidepressant strategies. Front Cell Neurosci 2013;7:218 10.3389/fncel.2013.00218
    1. Nagahara AH, Tuszynski MH. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 2011. March;10(3):209–19. 10.1038/nrd3366
    1. Rasmussen P, Brassard P, Adser H, Pedersen MV, Leick L, Hart E, et al. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp Physiol 2009. October;94(10):1062–9. 10.1113/expphysiol.2009.048512
    1. Fernandes BS, Gama CS, Cereser KM, Yatham LN, Fries GR, Colpo G, et al. Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. J Psychiatr Res 2011. August;45(8):995–1004. 10.1016/j.jpsychires.2011.03.002
    1. de Oliveira GS, Cereser KM, Fernandes BS, Kauer-Sant'anna M, Fries GR, Stertz L, et al. Decreased brain-derived neurotrophic factor in medicated and drug-free bipolar patients. J Psychiatr Res 2009. September;43(14):1171–4. 10.1016/j.jpsychires.2009.04.002
    1. Barbosa IG, Rocha NP, Miranda AS, Huguet RB, Bauer ME, Reis HJ, et al. Increased BDNF levels in long-term bipolar disorder patients. Rev Bras Psiquiatr 2013. March;35(1):67–9.
    1. Sodersten K, Palsson E, Ishima T, Funa K, Landen M, Hashimoto K, et al. Abnormality in serum levels of mature brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in mood-stabilized patients with bipolar disorder: a study of two independent cohorts. J Affect Disord 2014. May;160:1–9. 10.1016/j.jad.2014.01.009
    1. Green MJ, Matheson SL, Shepherd A, Weickert CS, Carr VJ. Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis. Mol Psychiatry 2011. September;16(9):960–72. 10.1038/mp.2010.88
    1. Teixeira AL, Barbosa IG, Diniz BS, Kummer A. Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function. Biomark Med 2010. December;4(6):871–87. 10.2217/bmm.10.111
    1. Forsgren S, Grimsholm O, Dalen T, Rantapaa-Dahlqvist S. Measurements in the Blood of BDNF for RA Patients and in Response to Anti-TNF Treatment Help Us to Clarify the Magnitude of Centrally Related Pain and to Explain the Relief of This Pain upon Treatment. Int J Inflam 2011;2011:650685 10.4061/2011/650685
    1. Muller GC, Pitrez PM, Teixeira AL, Pires PS, Jones MH, Stein RT, et al. Plasma brain-derived neurotrophic factor levels are associated with clinical severity in school age children with asthma. Clin Exp Allergy 2010. December;40(12):1755–9. 10.1111/j.1365-2222.2010.03618.x
    1. Golden E, Emiliano A, Maudsley S, Windham BG, Carlson OD, Egan JM, et al. Circulating brain-derived neurotrophic factor and indices of metabolic and cardiovascular health: data from the Baltimore Longitudinal Study of Aging. PLoS One 2010;5(4):e10099 10.1371/journal.pone.0010099
    1. Sargin D, Friedrichs H, El-Kordi A, Ehrenreich H. Erythropoietin as neuroprotective and neuroregenerative treatment strategy: comprehensive overview of 12 years of preclinical and clinical research. Best Pract Res Clin Anaesthesiol 2010. December;24(4):573–94. 10.1016/j.bpa.2010.10.005
    1. Maiese K, Chong ZZ, Shang YC, Wang S. Erythropoietin: new directions for the nervous system. Int J Mol Sci 2012;13(9):11102–29. 10.3390/ijms130911102
    1. Chong ZZ, Shang YC, Mu Y, Cui S, Yao Q, Maiese K. Targeting erythropoietin for chronic neurodegenerative diseases. Expert Opin Ther Targets 2013. June;17(6):707–20. 10.1517/14728222.2013.780599
    1. Brines M, Cerami A. Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci 2005. June;6(6):484–94.
    1. Mengozzi M, Cervellini I, Villa P, Erbayraktar Z, Gokmen N, Yilmaz O, et al. Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke. Proc Natl Acad Sci U S A 2012. June 12;109(24):9617–22. 10.1073/pnas.1200554109
    1. Miskowiak KW, Vinberg M, Christensen EM, Bukh JD, Harmer CJ, Ehrenreich H, et al. Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled phase 2 trial. Neuropsychopharmacology 2014. May;39(6):1399–408. 10.1038/npp.2013.335
    1. Miskowiak K, Kessing LV, Christensen EM, Ehrenreich H, Vinberg M. Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder: A double-blind, randomized, placebo-controlled phase 2 trial. J Clin Psychiatry 2014.
    1. Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 2004. July;35(7):1732–7.
    1. Viviani B, Bartesaghi S, Corsini E, Villa P, Ghezzi P, Garau A, et al. Erythropoietin protects primary hippocampal neurons increasing the expression of brain-derived neurotrophic factor. J Neurochem 2005. April;93(2):412–21.
    1. Girgenti MJ, Hunsberger J, Duman CH, Sathyanesan M, Terwilliger R, Newton SS. Erythropoietin induction by electroconvulsive seizure, gene regulation, and antidepressant-like behavioral effects. Biol Psychiatry 2009. August 1;66(3):267–74. 10.1016/j.biopsych.2008.12.005
    1. Miskowiak KW, Vinberg M, Harmer CJ, Ehrenreich H, Knudsen GM, Macoveanu J, et al. Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder. Trials 2010;11:97 10.1186/1745-6215-11-97
    1. Wing JK, Babor T, Brugha T, Burke J, Cooper JE, Giel R, et al. SCAN. Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry 1990. June;47(6):589–93.
    1. Hamilton M. A Rating Scale for Depression. Journal of Neurology, Neurosurgery and Psychiatry 23, 56–62. 1960.
    1. Beck AT. An inventory for measuring depression. Arch Gen Psychiatry 4, 561–571. 1961.
    1. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133, 429–435. 1978.
    1. Posternak MA, Young D, Sheeran T, Chelminski I, Franklin CL, Zimmerman M. Assessing past treatment history: test-retest reliability of the Treatment Response to Antidepressant Questionnaire. J Nerv Ment Dis 2004. February;192(2):95–102.
    1. Fava M, Iosifescu DV, Pedrelli P, Baer L. Reliability and validity of the Massachusetts general hospital cognitive and physical functioning questionnaire. Psychother Psychosom 2009;78(2):91–7. 10.1159/000201934
    1. Ehrenreich H, Fischer B, Norra C, Schellenberger F, Stender N, Stiefel M, et al. Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain 2007. October;130(Pt 10):2577–88.
    1. Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K, et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke 2009. December;40(12):e647–e656. 10.1161/STROKEAHA.109.564872
    1. Miskowiak K O 'Sullivan U, Harmer CJ. Erythropoietin enhances hippocampal response during memory retrieval in humans. J Neurosci 2007. March 14;27(11):2788–92.
    1. Miskowiak K, Vinberg M, Macoveanu J, Ehrenreich H, Koester N, Inkster B, et al. Effects of erythropoietin on hippocampal volume and memory in mood disorders. Biological Psychiatry. In press 2015.
    1. Sen S, Duman R, Sanacora G. Serum brain-derived neurotrophic factor, depression, and antidepressant medications: meta-analyses and implications. Biol Psychiatry 2008. September 15;64(6):527–32. 10.1016/j.biopsych.2008.05.005
    1. van der Meij A, Comijs HC, Dols A, Janzing JG, Oude Voshaar RC. BDNF in late-life depression: effect of SSRI usage and interaction with childhood abuse. Psychoneuroendocrinology 2014. May;43:81–9. 10.1016/j.psyneuen.2014.02.001
    1. Ricken R, Adli M, Lange C, Krusche E, Stamm TJ, Gaus S, et al. Brain-derived neurotrophic factor serum concentrations in acute depressive patients increase during lithium augmentation of antidepressants. J Clin Psychopharmacol 2013. December;33(6):806–9. 10.1097/JCP.0b013e3182a412b8
    1. Grande I, Kapczinski F, Stertz L, Colpo GD, Kunz M, Cereser KM, et al. Peripheral brain-derived neurotrophic factor changes along treatment with extended release quetiapine during acute mood episodes: an open-label trial in drug-free patients with bipolar disorder. J Psychiatr Res 2012. November;46(11):1511–4. 10.1016/j.jpsychires.2012.08.017
    1. Yoshimura R, Nakano Y, Hori H, Ikenouchi A, Ueda N, Nakamura J. Effect of risperidone on plasma catecholamine metabolites and brain-derived neurotrophic factor in patients with bipolar disorders. Hum Psychopharmacol 2006. October;21(7):433–8.
    1. Brunoni AR, Baeken C, Machado-Vieira R, Gattaz WF, Vanderhasselt MA. BDNF blood levels after electroconvulsive therapy in patients with mood disorders: A systematic review and meta-analysis. World J Biol Psychiatry 2014. March 16.
    1. Geslain R, Uddin S, Liu H, Jiang H, van BK, Pan T, et al. Distinct functions of erythropoietin and stem cell factor are linked to activation of mTOR kinase signaling pathway in human erythroid progenitors. Cytokine 2013. January;61(1):329–35. 10.1016/j.cyto.2012.10.017
    1. Yu Y, Shiou SR, Guo Y, Lu L, Westerhoff M, Sun J, et al. Erythropoietin protects epithelial cells from excessive autophagy and apoptosis in experimental neonatal necrotizing enterocolitis. PLoS One 2013;8(7):e69620 10.1371/journal.pone.0069620
    1. Munkholm K, Pedersen BK, Kessing LV, Vinberg M. Elevated levels of plasma brain derived neurotrophic factor in rapid cycling bipolar disorder patients. Psychoneuroendocrinology 2014. September;47:199–211. 10.1016/j.psyneuen.2014.05.011
    1. Vinberg M, Bukh JD, Bennike B, Kessing LV. Are variations in whole blood BDNF level associated with the BDNF Val66Met polymorphism in patients with first episode depression? Psychiatry Res 2013. May 16.
    1. Birkenhager TK, Geldermans S, Van den Broek WW, van BN, Fekkes D. Serum brain-derived neurotrophic factor level in relation to illness severity and episode duration in patients with major depression. J Psychiatr Res 2012. March;46(3):285–9. 10.1016/j.jpsychires.2011.12.006
    1. Dell'Osso L, Del DA, Veltri A, Bianchi C, Roncaglia I, Carlini M, et al. Associations between Brain-Derived Neurotrophic Factor Plasma Levels and Severity of the Illness, Recurrence and Symptoms in Depressed Patients. Neuropsychobiology 2010. August 14;62(4):207–12. 10.1159/000319946
    1. Oral E, Canpolat S, Yildirim S, Gulec M, Aliyev E, Aydin N. Cognitive functions and serum levels of brain-derived neurotrophic factor in patients with major depressive disorder. Brain Res Bull 2012. August 1;88(5):454–9. 10.1016/j.brainresbull.2012.03.005
    1. Nettiksimmons J, Simonsick EM, Harris T, Satterfield S, Rosano C, Yaffe K. The associations between serum brain-derived neurotrophic factor, potential confounders, and cognitive decline: a longitudinal study. PLoS One 2014;9(3):e91339 10.1371/journal.pone.0091339
    1. Diniz BS, Reynolds CF III, Begley A, Dew MA, Anderson SJ, Lotrich F, et al. Brain-derived neurotrophic factor levels in late-life depression and comorbid mild cognitive impairment: a longitudinal study. J Psychiatr Res 2014. February;49:96–101. 10.1016/j.jpsychires.2013.11.004
    1. Fernandes BS, Berk M, Turck CW, Steiner J, Goncalves CA. Decreased peripheral brain-derived neurotrophic factor levels are a biomarker of disease activity in major psychiatric disorders: a comparative meta-analysis. Mol Psychiatry 2014. July;19(7):750–1. 10.1038/mp.2013.172
    1. Fujimura H, Altar CA, Chen R, Nakamura T, Nakahashi T, Kambayashi J, et al. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost 2002. April;87(4):728–34.
    1. Watanabe K, Hashimoto E, Ukai W, Ishii T, Yoshinaga T, Ono T, et al. Effect of antidepressants on brain-derived neurotrophic factor (BDNF) release from platelets in the rats. Prog Neuropsychopharmacol Biol Psychiatry 2010. December 1;34(8):1450–4. 10.1016/j.pnpbp.2010.07.036
    1. Karege F, Bondolfi G, Gervasoni N, Schwald M, Aubry JM, Bertschy G. Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol Psychiatry 2005. May 1;57(9):1068–72.
    1. Pedersen BK, Pedersen M, Krabbe KS, Bruunsgaard H, Matthews VB, Febbraio MA. Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals. Exp Physiol 2009. December;94(12):1153–60. 10.1113/expphysiol.2009.048561
    1. Schuch FB, Vasconcelos-Moreno MP, Borowsky C, Zimmermann AB, Wollenhaupt-Aguiar B, Ferrari P, et al. The effects of exercise on oxidative stress (TBARS) and BDNF in severely depressed inpatients. Eur Arch Psychiatry Clin Neurosci 2014. February 1.
    1. Nofuji Y, Suwa M, Moriyama Y, Nakano H, Ichimiya A, Nishichi R, et al. Decreased serum brain-derived neurotrophic factor in trained men. Neurosci Lett 2008. May 23;437(1):29–32. 10.1016/j.neulet.2008.03.057
    1. Lee BH, Kim H, Park SH, Kim YK. Decreased plasma BDNF level in depressive patients. J Affect Disord 2007. August;101(1–3):239–44.
    1. Monteleone P, Serritella C, Martiadis V, Maj M. Decreased levels of serum brain-derived neurotrophic factor in both depressed and euthymic patients with unipolar depression and in euthymic patients with bipolar I and II disorders. Bipolar Disord 2008. February;10(1):95–100. 10.1111/j.1399-5618.2008.00459.x
    1. Hasselbalch BJ, Knorr U, Bennike B, Hasselbalch SG, Sondergaard MH, Vedel KL. Decreased levels of brain-derived neurotrophic factor in the remitted state of unipolar depressive disorder. Acta Psychiatr Scand 2012. September;126(3):157–64. 10.1111/j.1600-0447.2012.01831.x

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