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 doubleblind, 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 (X1 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.

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

“…High-dose EPO (40,000 IU intravenously), applied over 12 weeks on a weekly basis, led to significant improvement of schizophrenia-relevant cognitive performance as compared to placebo-treated patients. 124 In addition to the stepwise improvement in cognitive performance, we found that EPO was able to delay progression of cortical gray matter loss in chronic schizophrenic patients, as determined by most comprehensive, voxel-based morphometrical MRI analysis (manuscript in preparation). In this respect, EPO-induced prevention of brain atrophy, as observed in rodent studies, 86 could be nicely reproduced in man.…”

“…To our knowledge, no EPO variants other than rhEPO itself have thus far been published in relation to the treatment of human nervous system diseases. The only studies published so far reporting on efficacy of rhEPO in human brain diseases are our own studies on ischemic stroke, schizophrenia and MS. 69,119,124 …”

“…27 From 2003 to 2005, we performed a double-blind, placebo-controlled multicenter trial (phase IIb) on EPO add-on treatment in chronic schizophrenic men displaying a defined cognitive deficit. 124 Participating centers included Göttingen, Kiel, Homburg, Cologne and Marburg. High-dose EPO (40,000 IU intravenously), applied over 12 weeks on a weekly basis, led to significant improvement of schizophrenia-relevant cognitive performance as compared to placebo-treated patients.…”

Erythropoietin Prevents Haloperidol Treatment-Induced Neuronal Apoptosis through Regulation of BDNF

“…Therefore, sustained or increased brain BDNF by exogenous rhEPO co-treatment has the potential to prevent and/or reverse neuropathological events in schizophrenia (Glantz et al, 2006). In support of this possibility, a recent clinical add-on therapy, rhEPO with antipsychotic medication, showed significant improvement in cognitive function in chronic schizophrenia patients (Ehrenreich et al, 2007). In addition, rhEPO has therapeutic advantages over other neurotrophic factors in terms of delivery to their target cells in the brain and clinical tolerability (Abicht and Lochmuller, 1999;Horina et al, 1991).…”

“…Furthermore, a recent study by Ehrenreich et al, 2007 has shown that rhEPO improves cognitive functions in chronic schizophrenic patients. We recently reported that HAL and olanzapine have distinct temporal effects on the expression of EPO and its receptor in adult rat brain .…”