précis

• Patients with treatment-resistant depression were randomized to receive weekly infusions of either erythropoietin (40,000 IU) or saline over 8 weeks, along with continuing on their antidepressant medication.

• There was no effect of erythropoietin over saline at week 9 or 14 on the primary outcome measure of change in the Hamilton Depression Rating Scale (HDRS-17), but erythropoietin patients did see improvement on other mood and memory measures.

• Researchers believe these results warrant larger-scale studies to examine further the potential of this hormone in addressing treatment-resistant depression.

Although a recent study did not find that use of recombinant human erythropoietin, a glycoprotein hormone, improved the primary outcome for persons with treatment-resistant depression, authors said enough promising results from the treatment were observed to warrant further investigation.

In the search for treatments to help the 30% to 40% of patients who do not respond fully to current antidepressant treatment strategies, researchers have explored evidence that restoration of synaptic plasticity might serve as an important factor in facilitating improvement. Erythropoietin’s main function is to control red blood cell production but it also is produced in the brain and has a significant role in neuroprotection. In previous research, a single dose of erythropoietin was shown to improve neurocognitive function in persons with depression.

Authors of this latest research conducted an exploratory study to determine whether the beneficial effects seen in a single dose administration could be observed for mood and memory with multiple doses.

Study details

Patients eligible for the study were adults ages 18 to 65 with major depression of moderate severity and treatment resistance based on not achieving remission after at least two adequate antidepressant treatments from different classes in previous and/or current episodes.

Exclusion criteria included but were not limited to significant medical illness, bipolar disorder, schizophrenia, and alcohol or drug misuse.

Patients were randomized to receive weekly infusions of either erythropoietin (40,000 IU) or saline over 8 weeks, and continued on their previous antidepressant medication regimen. Researchers measured patients’ depressive symptoms, psychosocial functioning, and quality of life in weeks 1, 5, 9, and 14.

The primary outcome in the study was change in the Hamilton Depression Rating Scale (HDRS-17) from baseline to week 9. Remission rate, based on an HDRS score < 8, was the secondary outcome measure evaluated.

Results

Data were analyzed for 39 patients (18 receiving erythropoietin and 21 receiving saline), and 4 erythropoietin patients and 1 saline patient did not complete treatment. Three of the erythropoietin patients discontinued treatment because of increased thrombocytes, while one was hospitalized because of acute suicide risk.

There was no effect of erythropoietin over saline at week 9 or 14 on the primary outcome measure of change in the HDRS-17. However, erythropoietin patients did show improvement over saline patients on several other measures, such as the Beck Depression Inventory-21 (BDI-21), enhanced total recall across five learning trials measuring verbal memory, and recognition memory scores.

Moreover, when a group of 8 patients who experienced unforeseen mood improvement just prior to the start of the trial were excluded and an analysis of the remaining subgroup was performed, the latter group saw a beneficial effect from erythropoietin on the primary outcome (p = 0.02), an effect that was sustained at week 14.

The authors did not find any serious adverse events over the course of the study.

Implications

While the authors acknowledged that “the study must be declared formally negative” because of the lack of efficacy on the primary outcome measure, further analysis did offer an indication of some antidepressant efficacy for erythropoietin. They added that this should encourage additional trials on a larger scale to explore the hormone’s potential in depression treatment.

Improvements in memory substantially exceeded the researchers’ prior estimation of a clinically relevant change based on an earlier study. Because of memory’s role in cognitive function, “It is also tempting to speculate that [erythropoietin] could be implemented to aid speed of recovery and effectiveness of cognitive behavioral therapy for treatment-resistant depression,” the authors stated.

Several limitations to the study were cited, such as extensive exclusion criteria that could limit the findings’ generalizability. In addition, erythropoietin’s clinical uses could be limited by its potential to increase risk of hypertension and blood clots, although the authors said careful monitoring may mitigate the risk and that use of the hormone may be justified in this highly impaired population.

Based on the results, the authors characterized erythropoietin as an “interesting compound” that may have potential for enhancing the treatment of mood and memory problems in patients with treatment-resistant depression.

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Several study authors reported consulting arrangements with pharmaceutical companies.

Miskowiak KW, Vinberg M, Christensen EM, et al. Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled Phase 2 trial. Neuropsychopharmacol 2014; published online Jan 22; Doi: 10.1038/npp.2013.335. E-mail: Kamilla@miskowiak.dk.