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Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin

Abstract

Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40 000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language–semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) – perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.

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Acknowledgements

We would like to express our gratitude to Professors Irving I Gottesman and Daniel R Hanson, Minneapolis, for their careful and critical reading of the paper. We would also like to thank the advisory board of this study, Professor Petra Netter, Marburg, Professor Heinz Häfner, Mannheim, and Professor Bruno Müller-Oerlinghausen, Berlin, for volunteering to serve as an external control organ. We are further indebted to Swetlana Sperling, Anja Ronnenberg and Lisa Barski, Göttingen, as well as Susanne Kell, Imke Petersen, Helga Dittmer, Verena Huth, Till Ole Bergmann and Oliver Völckers, Kiel, and Georg Vollmer, Fulda, for excellent technical and logistic help, and the practising psychiatrists and long-term inpatient institutions in Göttingen and Kiel for referring patients to the study. This study has been supported by the Max-Planck-Society, the DFG Center for Molecular Physiology of the Brain (CMPB), research grants from Lundbeck and Orthobiotech, as well as by private donations.

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Ehrenreich, H., Hinze-Selch, D., Stawicki, S. et al. Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin. Mol Psychiatry 12, 206–220 (2007). https://doi.org/10.1038/sj.mp.4001907

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