Abstract
Neurodevelopmental abnormalities together with neurodegenerative processes contribute to schizophrenia, an etiologically heterogeneous, complex disease phenotype that has been difficult to model in animals. The neurodegenerative component of schizophrenia is best documented by magnetic resonance imaging (MRI), demonstrating progressive cortical gray matter loss over time. No treatment exists to counteract this slowly proceeding atrophy. The hematopoietic growth factor erythropoietin (EPO) is neuroprotective in animals. Here, we show by voxel-based morphometry in 32 human subjects in a placebo-controlled study that weekly high-dose EPO for as little as 3 months halts the progressive atrophy in brain areas typically affected in schizophrenia, including hippocampus, amygdala, nucleus accumbens, and several neocortical areas. Specifically, gray matter protection is highly associated with improvement in attention and memory functions. These findings suggest that a neuroprotective strategy is effective against common pathophysiological features of schizophrenic patients, and strongly encourage follow-up studies to optimize EPO treatment dose and duration.
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References
Thompson PM, Vidal C, Giedd JN, Gochman P, Blumenthal J, Nicolson R et al. Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia. Proc Natl Acad Sci USA 2001; 98: 11650–11655.
Hulshoff Pol HE, Kahn RS . What happens after the first episode? A review of progressive brain changes in chronically ill patients with schizophrenia. Schizophr Bull 2008; 34: 354–366.
Crespo-Facorro B, Roiz-Santianez R, Perez-Iglesias R, Pelayo-Teran JM, Rodriguez-Sanchez JM, Tordesillas-Gutierrez D et al. Effect of antipsychotic drugs on brain morphometry. A randomized controlled one-year follow-up study of haloperidol, risperidone and olanzapine. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1936–1943.
Thompson PM, Bartzokis G, Hayashi KM, Klunder AD, Lu PH, Edwards N et al. Time-lapse mapping of cortical changes in schizophrenia with different treatments. Cereb Cortex 2009; 19: 1107–1123.
Goldberg TE, Goldman RS, Burdick KE, Malhotra AK, Lencz T, Patel RC et al. Cognitive improvement after treatment with second-generation antipsychotic medications in first-episode schizophrenia: is it a practice effect? Arch Gen Psychiatry 2007; 64: 1115–1122.
Keefe RS, Mohs RC, Bilder RM, Harvey PD, Green MF, Meltzer HY et al. Neurocognitive assessment in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project schizophrenia trial: development, methodology, and rationale. Schizophr Bull 2003; 29: 45–55.
Carpenter WT, Gold JM . Another view of therapy for cognition in schizophrenia. Biol Psychiatry 2002; 51: 969–971.
Ehrenreich H, Degner D, Meller J, Brines M, Béhé M, Hasselblatt M et al. Erythropoietin: a candidate compound for neuroprotection in schizophrenia. Mol Psychiatry 2004; 9: 42–54.
Brines M, Cerami A . Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci 2005; 6: 484–494.
Sirén AL, Fasshauer T, Bartels C, Ehrenreich H . Therapeutic potential of erythropoietin and its structural or functional variants in the nervous system. Neurotherapeutics 2009; 6: 108–127.
Sirén AL, Radyushkin K, Boretius S, Kämmer D, Riechers C-C, Natt O et al. Global brain atrophy after unilateral parietal lesion and its prevention by erythropoietin. Brain 2006; 129: 480–489.
Taguchi A, Wen Z, Myojin K, Yoshihara T, Nakagomi T, Nakayama D et al. Granulocyte colony-stimulating factor has a negative effect on stroke outcome in a murine model. Eur J Neurosci 2007; 26: 126–133.
El-Kordi A, Radyushkin K, Ehrenreich H . Erythropoietin improves operant conditioning and stability of cognitive performance in mice. BMC Biol 2009; 7: 37.
Adamcio B, Sargin D, Stradomska A, Medrihan L, Gertler C, Theis F et al. Erythropoietin enhances hippocampal long-term potentiation and memory. BMC Biol 2008; 6: 37.
Ehrenreich H, Hinze-Selch D, Stawicki S, Aust C, Knolle-Veentjer S, Wilms S et al. Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 2007; 12: 206–220.
Randolph C . RBANS Manual—Repeatable Battery for the Assessment of Neuropsychological Status. Psychological Corporation: Harcourt, TX, 1998.
Kay SR, Fiszbein A, Opler LA . The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–276.
Wetzel SG, Johnson G, Tan AG, Cha S, Knopp EA, Lee VS et al. Three-dimensional, T1-weighted gradient-echo imaging of the brain with a volumetric interpolated examination. AJNR Am J Neuroradiol 2002; 23: 995–1002.
Shuter B, Yeh IB, Graham S, Au C, Wang SC . Reproducibility of brain tissue volumes in longitudinal studies: effects of changes in signal-to-noise ratio and scanner software. Neuroimage 2008; 41: 371–379.
Good CD, Johnsrude IS, Ashburner J, Henson RN, Friston KJ, Frackowiak RS . A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 2001; 14: 21–36.
Ashburner J, Friston KJ . Voxel-based morphometry-the methods. Neuroimage 2000; 11: 805–821.
Eickhoff SB, Stephan KE, Mohlberg H, Grefkes C, Fink GR, Amunts K et al. A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage 2005; 25: 1325–1335.
Krzanowski WJ . Principles of Multivariate Analysis. Oxford University Press: Oxford, 1988.
Glahn DC, Laird AR, Ellison-Wright I, Thelen SM, Robinson JL, Lancaster JL et al. Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis. Biol Psychiatry 2008; 64: 774–781.
Ellison-Wright I, Glahn DC, Laird AR, Thelen SM, Bullmore E . The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. Am J Psychiatry 2008; 165: 1015–1023.
Baiano M, Perlini C, Rambaldelli G, Cerini R, Dusi N, Bellani M et al. Decreased entorhinal cortex volumes in schizophrenia. Schizophr Res 2008; 102: 171–180.
Sim K, DeWitt I, Ditman T, Zalesak M, Greenhouse I, Goff D et al. Hippocampal and parahippocampal volumes in schizophrenia: a structural MRI study. Schizophr Bull 2006; 32: 332–340.
Killgore WD, Rosso IM, Gruber SA, Yurgelun-Todd DA . Amygdala volume and verbal memory performance in schizophrenia and bipolar disorder. Cogn Behav Neurol 2009; 22: 28–37.
Carter CS, Mintun M, Nichols T, Cohen JD . Anterior cingulate gyrus dysfunction and selective attention deficits in schizophrenia: [15O]H2O PET study during single-trial Stroop task performance. Am J Psychiatry 1997; 154: 1670–1675.
Sanfilipo M, Lafargue T, Rusinek H, Arena L, Loneragan C, Lautin A et al. Cognitive performance in schizophrenia: relationship to regional brain volumes and psychiatric symptoms. Psychiatry Res 2002; 116: 1–23.
Garver DL, Holcomb JA, Christensen JD . Cerebral cortical gray expansion associated with two second-generation antipsychotics. Biol Psychiatry 2005; 58: 62–66.
Rametti G, Segarra N, Junque C, Bargallo N, Caldu X, Ibarretxe N et al. Left posterior hippocampal density reduction using VBM and stereological MRI procedures in schizophrenia. Schizophr Res 2007; 96: 62–71.
Otsuka Y, Osaka N, Osaka M . Functional asymmetry of superior parietal lobule for working memory in the elderly. Neuroreport 2008; 19: 1355–1359.
Wolf RC, Höse A, Frasch K, Walter H, Vasic N . Volumetric abnormalities associated with cognitive deficits in patients with schizophrenia. Eur Psychiatry 2008; 23: 541–548.
Schirmer TN, Dorflinger JM, Marlow-O′Connor M, Pendergrass JC, Hartzell A, All SD et al. FMRI indices of auditory attention in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 25–32.
Onitsuka T, Shenton ME, Kasai K, Nestor PG, Toner SK, Kikinis R et al. Fusiform gyrus volume reduction and facial recognition in chronic schizophrenia. Arch Gen Psychiatry 2003; 60: 349–355.
Bleich-Cohen M, Strous RD, Even R, Rotshtein P, Yovel G, Iancu I et al. Diminished neural sensitivity to irregular facial expression in first-episode schizophrenia. Hum Brain Mapp 2009; 30: 2606–2616.
O′Daly OG, Frangou S, Chitnis X, Shergill SS . Brain structural changes in schizophrenia patients with persistent hallucinations. Psychiatry Res 2007; 156: 15–21.
Jeong B, Wible CG, Hashimoto RI, Kubicki M . Functional and anatomical connectivity abnormalities in left inferior frontal gyrus in schizophrenia. Hum Brain Mapp 2009; 30: 4138–4151.
Zhu Z, Zhang JX, Wang S, Xiao Z, Huang J, Chen HC . Involvement of left inferior frontal gyrus in sentence-level semantic integration. Neuroimage 2009; 47: 756–763.
Ellison-Wright I, Glahn DC, Laird AR, Thelen SM, Bullmore E . The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis. Am J Psychiatry 2008; 165: 1015–1023.
Hickok G, Poeppel D . The cortical organization of speech processing. Nat Rev Neurosci 2007; 8: 393–402.
Beeli G, Esslen M, Jancke L . Time course of neural activity correlated with colored-hearing synesthesia. Cereb Cortex 2008; 18: 379–385.
Onitsuka T, Shenton ME, Salisbury DF, Dickey CC, Kasai K, Toner SK et al. Middle and inferior temporal gyrus gray matter volume abnormalities in chronic schizophrenia: an MRI study. Am J Psychiatry 2004; 161: 1603–1611.
Allen P, Larøi F, McGuire PK, Aleman A . The hallucinating brain: a review of structural and functional neuroimaging studies of hallucinations. Neurosci Biobehav Rev 2008; 32: 175–191.
Torrey EF . Schizophrenia and the inferior parietal lobule. Schizophr Res 2007; 97: 215–225.
Wolf RC, Hose A, Frasch K, Walter H, Vasic N . Volumetric abnormalities associated with cognitive deficits in patients with schizophrenia. Eur Psychiatry 2008; 23: 541–548.
Juckel G, Schlagenhauf F, Koslowski M, Wustenberg T, Villringer A, Knutson B et al. Dysfunction of ventral striatal reward prediction in schizophrenia. Neuroimage 2006; 29: 409–416.
Lieberman JA, Tollefson GD, Charles C, Zipursky R, Sharma T, Kahn RS et al. Antipsychotic drug effects on brain morphology in first-episode psychosis. Arch Gen Psychiatry 2005; 62: 361–370.
Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M et al. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA 1998; 95: 4635–4640.
Trapp BD, Wujek JR, Criste GA, Jalabi W, Yin X, Kidd GJ et al. Evidence for synaptic stripping by cortical microglia. Glia 2007; 55: 360–368.
Sargin D, Hassouna I, Sperling S, Siren AL, Ehrenreich H . Uncoupling of neurodegeneration and gliosis in a murine model of juvenile cortical lesion. Glia 2009; 57: 693–702.
Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M et al. Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 2004; 305: 239–242.
Acknowledgements
We express our gratitude to Ruth Schubert, Charité-University Medicine, Berlin, Germany, for her ideas regarding the statistical data analysis. This study has been supported by the Max Planck Society, the DFG Research Center for Molecular Physiology of the Brain (CMPB) as well as by private donations.
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HE holds a user patent for the treatment of schizophrenia with EPO.
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Wüstenberg, T., Begemann, M., Bartels, C. et al. Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia. Mol Psychiatry 16, 26–36 (2011). https://doi.org/10.1038/mp.2010.51
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DOI: https://doi.org/10.1038/mp.2010.51
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