Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled phase 2 trial

Abstract

Pharmacological treatments for depression have insufficient efficacy in 30-40% of patients and fail to reverse cognitive deficits. Erythropoietin (EPO) has neurotrophic actions and aids neurocognitive function. The aim of this exploratory study was to determine whether recombinant human EPO improves mood and memory in treatment-resistant depression. Forty treatment-resistant depressed unipolar patients with Hamilton Depression Rating Scale-17 (HDRS-17) score ≥ 17 were randomized to eight weekly EPO (Eprex; 40,000 IU) or saline infusions in a double-blind, placebo-controlled, parallel-group design. Patients were assessed at baseline and at weeks 5, 9, and 14. Primary outcome was reduction in HDRS-17 score. Global assessment of function (GAF) was reported in addition. Secondary outcome was remission rate, and tertiary outcomes were changes in Rey Auditory Verbal Learning Test (RAVLT), Beck Depression Inventory-21 (BDI-21), and World Health Organization Quality of life-BREF (WHOQOL-BREF). Exploratory outcomes were depression and cognition composite scores. HDRS-17, GAF, and remission rates showed no effects of EPO over saline at week 9 (P-value ≥ 0.09). However, EPO improved BDI (P=0.02) and WHOQOL-BREF (P=0.01), and this was maintained at follow-up week 14 (P-values ≤ 0.04). EPO enhanced verbal recall (P=0.02) and recognition (P=0.03), which was sustained at follow-up (P-values ≤ 0.04). Exploratory analysis in patients fulfilling depression severity criteria at trial start revealed ameliorated HDRS-17 in EPO (N=14) vs saline groups (N=17), which was sustained at week 14 (P-values ≤ 0.05). Exploratory analysis in the complete cohort showed that EPO reduced depression composite at weeks 9 and 14 (P-values=0.02). The findings of this exploratory study highlight EPO as an interesting compound for treatment-resistant depression, which deserves further investigation.

Figure 1

Patient flow through the phases of the trial.

Figure 2

Percent improvement of explorative depression and cognition composite scores from individual baseline. (a) Explorative depression composite. The dotted line denotes the estimated depression composite of healthy individuals within the lower normal range calculated by z-transformation and averaging the cutoffs 17-item Hamilton Depression Rating Scale (HDRS-17)=7, Beck Depression Inventory-21 (BDI-21)=7, global assessment of function (GAF)=70, and the mean World Health Organization Quality of Life BREF (WHOQOL-BREF) score in the Danish population (Noerholm et al, 2004). (b) Explorative Rey Auditory Verbal Learning Test (RAVLT) composite. This was obtained by summation of the four z-transformed RAVLT measures, addition of 10 to these summed score to obtain overall positive values, and calculation of percent change from individual baseline. P-values indicate the results of the analysis of covariance (ANCOVA) of the mean change from the individual baseline between the drug groups. The dotted line denotes the estimated RAVLT memory composite of healthy, age-matched individuals of average intelligence (Strauss et al, 2006). Mean and SEM are presented.