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This systematic review summarizes and critically appraises the literature on the effect of erythropoietin (EPO) in schizophrenia patients and the pathophysiological mechanisms that may explain the potential of its use in this disease. EPO is mainly known for its regulatory activity in the synthesis of erythrocytes and is frequently used in treatment of chronic anemia. This cytokine, however, has many other properties, some of which may improve the symptoms of psychiatric illness. The review follows the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement guidelines. Three databases (Medline, Web of Science, and Cochrane) were searched combining the search terms ‘erythropoietin AND (psychotic disorders OR schizophrenia)’. Seventy-eight studies were included in qualitative synthesis, a meta-analytic approach being prohibited. The findings suggest that several EPO cerebral potential properties may be relevant for schizophrenia treatment, such as neurotransmission regulation, neuroprotection, modulation of inflammation, effects on blood–brain barrier permeability, effects on oxidative stress and neurogenesis. Several potentially detrimental side-effects of EPO therapy, such as increased risk of thrombosis, cancer, increased metabolic rate and mean arterial blood pressure leading to cerebral ischemia could severely limit or halt the use of EPO. Overall, because the available data are inconclusive, further efforts in this field are warranted.
ERYTHROPOIETIN (EPO) IS approved by the Food and Drug Administration for the treatment of anemia, but a recent body of work has found that EPO is not only required for erythropoiesis, but also functions in other organs and tissues, such as the brain, heart, and vascular system.1–10 EPO and its derivatives could be a treatment of choice in the negative symptoms of schizophrenia, a clinically heterogeneous psychotic illness, the etiology of which remains poorly understood. We propose here a systematic review on the effect of EPO in schizophrenia patients and the pathophysiological mechanisms underlying its potential therapeutic role in this disease. The purpose of this paper was not to make an extensive review of the work and fundamental data published since 1977 on EPO, but after a few reminders on the general and cerebral physiology of EPO (part 1), to extract the data that seem relevant for understanding its potential therapeutic role in schizophrenia (part 2), and to present a short overview of preliminary studies on the effects of EPO in patients with chronic schizophrenia (part 3).
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Many concerns should be addressed in the practical use of EPO. First, the cognitive deficit in schizophrenia is not an acute response, therefore EPO should be given by injection at regular intervals for the whole life long. In the Ehrenreich et al. study an infusion (40 000 IU rhEPO) was given weekly for 3 months.49 That was the only double-blind study to adopt EPO in human schizophrenia (n = 39 for schizophrenia patients, n = 19 for normal controls), so that no one can deny that the improved effect on cognitive batteries is only temporary. This is partly because no following study was performed after the initial study. Second, unlike renal anemia, it is not expected that hemoglobin could be an indicator protein for cognitive performance. Therefore we will not know exactly when this injection should be stopped, or whether the quantity is appropriate or not.
Moreover, one limitation of the use of EPO is that this cytokine, as an autocrine–paracrine hormone, triggers both the neurological and the general pathways (such as the stimulation of bone marrow).30
The potential progression of cancer has been a significant concern raised with EPO use.17,55 EPO may promote the growth of malignant tumors sensitive to EPO both in vitro and in vivo.30 Not only have both EPO and its receptor expression been found in tumor specimens, but under some conditions EPO has been suggested to block tumor cell apoptosis through Akt,56 enhance tumor progression and increase metastatic disease.57 In studies of patients with head and neck cancer, EPO decreased disease progression-free survival and overall survival.58 Similar results were reported in trials with metastatic breast cancer.59 It should be noted, however, that the potential risk of EPO in either initiating tumor growth or inducing tumor progression is not entirely understood.
In addition to the concerns outlined in patients with cancer, other important considerations for EPO exist such as problems associated with EPO abuse and gene doping.60–62 EPO has also been correlated with the alteration of red cell membrane properties leading to a cognitive decrease in rodent animal models.17,20 Finally, several potentially detrimental vascular side-effects of EPO therapy, such as increased risk of thrombosis, increased metabolic rate and mean arterial blood pressure leading to cerebral ischemia could severely limit or halt the use of EPO, especially in neurovascular diseases.30,63
Strategies for future research
New studies are investigating the role of targeted bioavailability for EPO such as in bone marrow stromal cells genetically engineered to secrete EPO64 and controlled release of EPO from encapsulated cells.65 The passage of EPO into the CNS continues to attract significant interest, as does the use of novel intranasal routes for EPO.66 Other pathways of interest are the development of derivations of EPO with lesser erythropoietic activity and therefore less potential vascular complications.67 This research has led to the discovery of asialoEPO, generated by total enzymatic desialylation of rhEPO.68
Yet, these lines of investigation are not without limitations, because chemical derivatives of EPO can become devoid of clinical effectiveness,17,20 as well as possibly lose the ability to promote sustainable cytoprotective effects, such as neurogenesis.69
Erythropoietin appears as a cytokine of interest in the treatment of cognitive symptoms of schizophrenia, but the molecule still has some side-effects that do not currently allow its use in clinical practice, and the long-term effects are not known as yet. Research in the development of new molecules and the study of its physiological mechanisms may open new therapeutic leads for many psychiatric illnesses and especially schizophrenia with chronic cognitive impairment. In addition, based on the aforementioned data, preventive treatment ought to be considered as early as the first episode of the disease, in order to halt the neurodegenerative process.