The effect of erythropoietin on cognition in affective disorders – Associations with baseline deficits and change in subjective cognitive complaints

Abstract

This is a secondary data analysis from our erythropoietin (EPO) trials. We examine (I) whether EPO improves speed of complex cognitive processing across bipolar and unipolar disorder, (II) if objective and subjective baseline cognitive impairment increases patients׳ chances of treatment-efficacy and (III) if cognitive improvement correlates with better subjective cognitive function, quality of life and socio-occupational capacity. Patients with unipolar or bipolar disorder were randomized to eight weekly EPO (N=40) or saline (N=39) infusions. Cognition, mood, quality of life and socio-occupational capacity were assessed at baseline (week 1), after treatment completion (week 9) and at follow-up (week 14). We used repeated measures analysis of covariance to investigate the effect of EPO on speed of complex cognitive processing. With logistic regression, we examined whether baseline cognitive impairment predicted treatment-efficacy. Pearson correlations were used to assess associations between objective and subjective cognition, quality of life and socio-occupational capacity. EPO improved speed of complex cognitive processing across affective disorders at weeks 9 and 14 (p≤0.05). In EPO-treated patients, baseline cognitive impairment increased the odds of treatment-efficacy on cognition at weeks 9 and 14 by a factor 9.7 (95% CI:1.2-81.1) and 9.9 (95% CI:1.1-88.4), respectively (p≤0.04). Subjective cognitive complaints did not affect chances of treatment-efficacy (p≥0.45). EPO-associated cognitive improvement correlated with reduced cognitive complaints but not with quality of life or socio-occupational function. As the analyses were performed post-hoc, findings are only hypothesis-generating. In conclusion, pro-cognitive effects of EPO occurred across affective disorders. Neuropsychological screening for cognitive dysfunction may be warranted in future cognition trials.

Introduction

Cognitive deficits are common across unipolar and bipolar disorder and often persist after clinical remission from acute mood episodes (Arts et al., 2008, Bortolato et al., 2016). There are currently no available treatments to directly target cognitive dysfunction in affective disorders although some candidate compounds seem promising (for reviews see Bortolato et al. (2016) and Miskowiak et al. under review). A particularly interesting candidate treatment is recombinant human erythropoietin (EPO), which has neuroprotective effects, stimulates neuroplasticity and improves cognition in preclinical models and across several neuropsychiatric patient groups (for reviews see Miskowiak et al. (2012), Sargin et al. (2010), and Sirén et al. (2009)). We previously demonstrated in a randomized placebo-controlled trial that (EPO) improves speed of complex cognitive processing across attention, memory and executive function in partially remitted patients with bipolar disorder (BD) (Miskowiak et al., 2014a). In a parallel trial we investigated the effects of EPO on mood symptoms in moderately depressed patients with treatment-resistant unipolar disorder (UD), and observed a mood-independent improvement of verbal memory in EPO versus saline treated patients (tertiary outcome) (Miskowiak et al., 2014b). Pooling verbal memory data from these two studies showed that the effect of EPO on verbal memory was comparable across UD and BD (Miskowiak et al., in press). However, it remains to be investigated whether the observed effects of EPO on “speed of complex cognitive processing” across several cognitive domains in BD (Miskowiak et al., 2014a), also occur across unipolar and bipolar disorder. Indeed, it cannot be assumed that a pro-cognitive effect of an intervention in one patient group necessarily applies to other groups, as illustrated by the discrepancy between meta-analytic evidence for beneficial effects of cognitive remediation (CR) on cognition in schizophrenia, but lack of cognitive benefits of CR in BD patients (Demant et al., 2015b). Interestingly, we recently demonstrated that baseline cognitive dysfunction substantially increased patients׳ chances of achieving EPO treatment efficacy on verbal memory in a pooled sample of UD and BD patients (Miskowiak et al., in press). Subjective cognitive complaints at baseline and longer illness duration were also associated with a small but significant increase in the odds for EPO treatment efficacy on cognition. These preliminary findings suggest that treatments targeting memory dysfunction may be particularly efficacious in patients with baseline cognitive deficits and greater illness progression, in line with the staging and allostatic load models of affective disorders (Berk et al., 2011, Grande et al., 2015, Kapczinski et al., 2008, Vieta et al., 2013).

The present study builds on these findings by investigating (I) whether the observed effects of EPO on speed of complex cognitive processing are specific to BD, or if they occur across diagnostic groups of affective disorders, (II) whether objective cognitive dysfunction and/or subjective cognitive complaints at baseline will increase EPO-treated patients׳ chances of achieving a clinically relevant improvement in cognition, and (III) whether treatment-related improvement in objective cognition is accompanied by increase in subjective cognitive function, quality of life and socio-occupational capacity. Insight into these questions has implications for future clinical trials of EPO by elucidating who is likely to show cognitive benefits of EPO treatment, and may also inform the design of other trials targeting cognition.