Fran Lowry

June 25, 2014

HOLLYWOOD, Florida — Erythropoietin (EPO), often thought of as a performance-enhancing substance in athletes, may be a promising treatment for cognitive and neural dysfunction in patients with severe affective disorders.

In research presented here at the American Society of Clinical Psychopharmacology (ASCP) 2014 Annual Meeting, patients with treatment-resistant depression or bipolar disorder in partial or complete remission who received EPO infusions showed increased growth in the left hippocampus as well as enhanced verbal memory.

"Our findings encourage further characterization of the neurobiological mechanisms of the beneficial cognitive effects of erythropoietin," presenter and lead investigator Kamilla Miskowiak, PhD, Psychiatric Center, Copenhagen University Hospital, Denmark, told Medscape Medical News.

"Normally with mood disorders, treatments reduce depressive symptoms, and this indirectly leads to an improvement in cognitive function. But in our study, the enhanced cognition with EPO was not mediated through indirect effects on mood. It appears that EPO was directly able to enhance cognitive function, even in our patient population who were in remission and were asymptomatic," Dr. Miskowiak said.

Dr. Kamilla Miskowiak

The study included 84 patients with treatment-resistant depression who were moderately depressed, as determined on the basis of a Hamilton Depression Rating Scale (HDRS) score of >17, or who had bipolar disorder in partial or full remission, established by HDRS and Young Mania Rating Scale scores of <14.

The patients were randomly assigned to receive 8 weekly infusions of EPO (Eprex, Janssen-Cilag, Ortho Biologics LLC) 40,000 IU (n = 42 patients) or saline (n = 42 patients) in a double- blind, parallel-group design.

They also underwent MRI and verbal memory assessments at study entry and again at week 14, which was 6 weeks after treatment completion. Structural changes in the hippocampus were also examined.

The results showed that EPO increased growth in the middle and posterior subregions of the left hippocampus in comparison with saline (P < .05).

EPO also enhanced verbal memory compared with saline (P = .05). Moreover, memory improvement was solely predicted by hippocampal growth.

This may be a key neurobiological mechanism underlying memory improvement in EPO-treated patients with affective disorder, Dr. Miskowiak said.

Speculating on how EPO could be used in the clinic, Dr. Miskowiak noted that an important limitation to its use currently is the agent's effect on red blood cells.

"Patients with mood disorders are not anemic, so EPO would increase the risk of high blood pressure and blood clotting, and blood levels need to be closely monitored. It also has to be given in a hospital setting, so it is a complicated treatment. But even so, it's a relatively short treatment, and we did have sustained effects in cognition. It might be that you could give this treatment for a short period of time in more severe patients," she said.

"Some of the patients in our study said they felt the effects from EPO were long lasting and that they were able to go back and complete their studies or otherwise get back on track with their lives. So, in more severe cases, where patients are suffering from real cognitive problems that are not related to the mood symptoms, EPO might be of benefit."

There are also EPO derivatives currently being explored that do not have the same effects on red blood cells but that do have a positive effect on cognition, Dr. Miskowiak said.

"Clinical studies evaluating the cognitive effects of nonhematopoietic erythropoietin analogues are warranted since the hematopoietic activities of EPO might limit its clinical use. We hope that other researchers will get inspired to take our explorative findings further and perform replication trials to establish whether the cognitive effect is reliable and clinically significant, and also prompt more research in developing EPO derivatives with no effects on red blood cells," she said.

Commenting on this study for Medscape Medical News, Bradley Gaynes, MD, MPH, professor of psychiatry at the University of North Carolina School of Medicine, Chapel Hill, said that EPO could be a potential treatment for cognitive impairment in patients with depression.

Dr. Bradley Gaynes

"These results build on other recently published evidence in treatment-resistant depressed patients suggesting increased neuroplasticity and cognitive functioning improvements with EPO," Dr. Gaynes, who was not part of the study, said.

The findings "offer a new and promising avenue for addressing cognitive impairment in depressed patients," he said.

Dr. Miskowiak and Dr. Gaynes report no relevant financial relationships.

American Society of Clinical Psychopharmacology (ASCP) 2014 Annual Meeting. Presented June 16, 2014.

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