Elsevier

Brain, Behavior, and Immunity

Volume 57, October 2016, Pages 53-57
Brain, Behavior, and Immunity

Short Communication
Effect of recombinant erythropoietin on inflammatory markers in patients with affective disorders: A randomised controlled study

https://doi.org/10.1016/j.bbi.2016.05.006Get rights and content

Highlights

  • Repeated EPO infusions had no effect on IL-6 and IL-8 in uni- and bipolar patients.

  • EPO produced a modest increase in hsCRP levels in unipolar patients.

  • In patients with higher baseline inflammation, EPO produced a reduction in hsCRP.

  • Changes in inflammatory markers were not correlated with changes in cognition.

Abstract

Aim

This study investigated the effect of repeated infusions of recombinant human erythropoietin (EPO) on markers of inflammation in patients with affective disorders and whether any changes in inflammatory markers were associated with improvements on verbal memory.

Methods

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) (sub-study 1) and 43 patients with bipolar disorder (BD) in partial remission (HDRS-17 and Young Mania Rating Scale (YMRS)  14) (sub-study 2). In both sub-studies, patients were randomised in a double-blind, parallel-group design to receive eight weekly intravenous infusions of EPO (Eprex; 40,000 IU/ml) or saline (0.9% NaCl). Plasma concentrations of interleukin 6 (IL-6), interleukin 18 (IL-18) and high sensitive c-reactive protein (hsCRP) were measured at week 1 (baseline) and weeks 5, 9 and 14. HDRS-17 and neuropsychological function was assessed at weeks 1, 9 and 14 using a test battery including the RAVLT Auditory Verbal Learning Test (primary depression and primary cognition outcomes in the original trial).

Results

EPO had no cumulative effect on plasma levels of IL-6 or IL-18 but increased hsCRP levels in patients with TRD (mean ± SD change in ng/L: EPO: 0.43 ± 1.64; Saline: −0.90 ± 2.43; F(1,39) = 4.78, p = 0.04). EPO had no effects on inflammatory markers in BD. There was no correlation between change in inflammatory markers and change in verbal memory.

Conclusions

Repeated EPO infusions had no effect on IL-6 and IL-18 levels but produced a modest increase in hsCRP levels in patients with TRD. Changes over time in inflammatory markers were not correlated with changes in cognition suggesting that modulation of the inflammatory pathway is not a putative mechanism of the EPO-associated improvement of cognition in affective disorders.

Introduction

Erythropoietin (EPO) activates distinct cellular pathways in different cells, has pleiotropic cellular protective effects and may decrease inflammation, oxidative stress and apoptosis (Toba et al., 2012). EPO is a potent growth factor that may protect central nervous system (CNS) cells against apoptosis and promote proliferation of neuronal cells (Chong et al., 2013). Evidence from preclinical studies, human neuroimaging studies, and recent clinical trials provide some indication for beneficial effects of EPO on cognition that might be mediated by action on EPO receptors located in the CNS (Ehrenreich et al., 2008, Mengozzi et al., 2012). EPO may further prevent cellular inflammation by inhibiting several proinflammatory cytokines including interleukin 6 (IL-6), interleukin 18 (IL-18) (Wiedenmann et al., 2015) and C-reactive protein (CRP) involved in chronic inflammatory disorders including atherosclerosis and cardiovascular disease perhaps indicating an underlying cellular stress phenomenon (Rietzschel and De, 2012).

However, the effect of EPO on the inflammatory response in humans is still unresolved. Some studies have demonstrated pro-inflammatory effects of EPO (Hojman et al., 2009, Poulsen et al., 2009) while findings from other studies point to no effect (Joyeux-Faure et al., 2012) or an anti-inflammatory effect (Avasarala and Konduru, 2005). There is accumulating evidence that affective disorders are associated with immune activation and neuro-inflammation which may be a key mediator of patients’ deficits in memory and other cognitive functions (Ryan and Nolan, 2015). We have previously shown that treatment with EPO improves cognition (Miskowiak et al., 2014a, Miskowiak et al., 2014b). Nevertheless, the association between peripheral inflammatory markers and EPO administration has not been studied in patients with affective disorders and it is an intriguing question whether the observed pro-cognitive effects of EPO across unipolar disorder (UD) and BD could be mediated by reduction in inflammation states. In the present study, a cohort of patients with treatment resistant depression (TRD) and patients with BD were randomized to weekly EPO versus saline infusions over 8 weeks. Plasma IL-6, Il-18 and high sensitive CRP (hsCRP) were measured at baseline (week one), at weeks 5 (half-way through treatment), 9 (one week after treatment cessation) and 14 (six weeks follow-up). Our primary hypothesis was that EPO would influence levels of inflammatory biomarkers in TRD and BD. Secondary, to explore whether there was an association between changes in inflammatory markers and verbal memory.

Section snippets

Study design and participants

The two original EPO trials from which the present data is derived had a double-blind, placebo-controlled, parallel-group design and their primary outcomes have been published elsewhere (Miskowiak et al., 2014a, Miskowiak et al., 2014b). Patients were recruited through the Copenhagen Clinic for Affective Disorders, Psychiatric Centre Copenhagen. Eligible patients had an ICD-10 diagnosis of TRD, defined as failure to respond to adequate treatment with at least two different types of

Study characteristics

Patients were included and randomised for the two trials between September 2009 and October 2012. Of the 84 randomised patients, one patient withdrew on the inclusion day, leaving 83 patients for analyses (EPO: N = 41; saline: N = 42), of whom 74 completed per protocol (PP) (EPO: N = 34, saline: N = 40). Of the nine patients who did not complete PP, six patients (EPO) discontinued medication after 5-6 infusions because of increased platelet count (>4 × 109/l) but completed all assessments and three

Discussion

The present study explored the effect of EPO on peripheral levels of IL-6, IL-18 and hsCRP in patients with affective disorders. First, no effects of EPO on IL-6 and IL-18 were observed in TRD or BD. Age, gender, baseline depression severity or changes from baseline to week 9 in depression severity and in verbal memory did not influence the results. EPO was associated with an increase in hsCRP levels in patients with TRD but produced no change in hsCPR levels in patients with BD. Second, no

Financial disclosures

The study was funded by the Danish Ministry of Science, Innovation and Higher Education, Novo Nordisk Foundation, Beckett Foundation, Savværksejer Jeppe Juhls and Hustru Ovita Juhls Foundation, and the Augustinus Foundation.

The funding source had no role in the study design, in the collection, analyses, and interpretation of data, in writing the manuscript, or in the decision to submit the paper for publication.

References (24)

  • J.R. Avasarala et al.

    Recombinant erythropoietin down-regulates IL-6 and CXCR4 genes in TNF-alpha-treated primary cultures of human microvascular endothelial cells: implications for multiple sclerosis

    J. Mol. Neurosci.

    (2005)
  • Z.Z. Chong et al.

    Targeting erythropoietin for chronic neurodegenerative diseases

    Exp. Opin. Ther. Targets

    (2013)
  • Cited by (0)

    View full text