VIENNA – Recombinant human erythropoietin appears to be a cognitive enhancer in patients with unipolar or bipolar depression accompanied by cognitive impairment, Kamilla W. Miskowiak, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.

She presented a pooled analysis of her two pilot randomized, placebo-controlled clinical trials totaling 79 patients with treatment-resistant unipolar or partly remitted bipolar depression associated with baseline cognitive impairment. She found that 8 weeks of once-weekly intravenous infusions of high-dose human recombinant erythropoetin (Epogen), also known as epoetin alfa (EPO), resulted in clinically meaningful improvement in cognition 1 week post treatment, as measured on neuropsychological tests assessing the speed of complex cognitive processing, verbal memory, attention span, concentration, working memory, and strategic planning ability. Saline infusions had no effect.

Dr. Kamilla W. Miskowiak

Dr. Kamilla W. Miskowiak

Moreover, follow-up testing conducted 6 weeks after the final treatment session showed continued full maintenance of the initial cognitive gains, which averaged an 11% improvement over baseline. The full duration of effect will be determined in the next round of studies, which will feature 12 weeks of EPO and 6 months of off-treatment follow-up, added Dr. Miskowiak, a senior research psychologist at the University of Copenhagen.

In an interview, she emphasized that the mechanism of benefit doesn’t appear to be related to EPO’s signature ability to boost red blood cell (RBC) production and raise hemoglobin levels. After all, she noted, RBCs were back to normal within 2 weeks after treatment ended, yet the objective cognitive improvements continued. Instead, the mechanism involves EPO’s capacity to enhance brain neuroplasticity, an effect that was demonstrated first in animal studies and subsequently in Dr. Miskowiak’s clinical trials.

“We did MRI functional and structural brain scans at baseline and after completion of treatment, and we saw that EPO increased left hippocampal volume. In fact, it was the structural change in hippocampal volume in response to EPO that was the single strongest predictor of cognitive improvement in multivariate analyses adjusted for age, illness chronicity, depressive symptom severity, gender, and other factors,” according to Dr. Miskowiak.

Physicians who use EPO to treat anemia might blanch at the doses of EPO administered to improve cognitive impairments in patients with affective disorders. Instead of giving 50-100 U/kg of body weight several times per week, as is common in treating anemia, the patients in her studies typically received 40,000 U/wk.

“We used much, much higher doses than are given to affect the bone marrow in patients with anemia, because only about 1% of the IV dose passes across the blood/brain barrier,” she explained.

Because EPO, even in conventional doses, is associated with an increased risk of blood clots, patients were ineligible for the cognition-improvement trials if they had a history of venous thromboembolism, coronary disease, or cancer. Moreover, their RBC and platelet activity levels were monitored on a weekly basis. No untoward effects were seen, Dr. Miskowiak continued.

“Patients really liked coming in for this therapy. Many of them were quite chronic, with years of illness, yet adherence was excellent,” she said.

Early in the developmental pipeline are an intranasal variant of EPO and a carbamylated EPO designed to cross the blood/brain barrier efficiently in order to achieve direct brain neuroplasticity-stimulating effects with minimal impact on RBC production.

Dr. Miskowiak stressed that EPO as a treatment for cognitive dysfunction associated with affective disorders is not ready for prime time use in clinical practice. The next round of randomized, placebo-controlled clinical trials, due to start early in 2017, will attempt to replicate her pilot study findings while pinning down the optimal dosing regimen. The new trials will feature longer off-treatment follow-up as well as quality-of-life measures and an economic analysis that includes assessment of the ability to return to work.

“This therapy may be attractive from an economic perspective,” according to the psychologist. “I don’t see this as first-line therapy in clinical practice, though,” she added. “It will be reserved for the more severely cognitively impaired patients.”

Eduard Vieta, MD, professor and chair of the department of psychiatry and psychology at the University of Barcelona, commented that cognitive impairment is now recognized as a core aspect of affective disorders. There is a huge unmet need for treatments that address this disease aspect. The drugs now available for treatment of bipolar disorder and unipolar depression don’t improve the associated cognitive impairments. Indeed, up to 40% of patients in remission from major depressive disorder and 70% in remission from bipolar disorder continue to experience neurocognitive symptoms.

Dr. Miskowiak’s work was funded by the Danish Ministry of Science, Innovation, and Higher Education. She reported having no relevant financial conflicts of interest.

bjancin@frontlinemedcom.com