VIENNA — Erythropoietin (EPO), which improves oxygen capacity in the blood by boosting red blood cell production, may improve cognitive performance in patients with bipolar disorder or major depression, new research shows.

The analysis, which was presented here at the 29th European College of Neuropsychopharmacology (ECNP) Congress and was also published in the journal European Neuropsychopharmacology, showed that EPO improved objective cognitive performance across a range of measures. These effects persisted for at least 6 weeks.

Crucially, the benefits associated with EPO, which is used in recombinant form as a treatment for anemia and is associated with performance enhancement in sport, were substantially greater in patients who performed poorly on baseline neuropsychological tests.

"This is interesting, as it means that we may be able to target patients for EPO treatment, and perhaps other future cognition treatments, based on how they do on neuropsychological tests," said lead researcher Kamilla Miskowiak, PhD, Psychiatric Center Copenhagen, Copenhagen University Hospital, Denmark.

Currently there are no clinical treatments that have a long-lasting impact on cognitive impairments for patients with bipolar disorder or major depressive disorder. However, in two parallel trials, the researchers previously showed that EPO has a beneficial effect across cognitive domains in patients in partial remission of bipolar disorder and treatment-resistant unipolar disorder.

For these trials, 79 patients completed questionnaires on objective and subjective cognition, mood, quality of life, and socio-occupational function during week 1. They were then randomly allocated to receive eight weekly infusions of EPO or saline. The assessments were repeated immediately following treatment at week 9 and again at week 14. The results were adjusted for diagnosis and the severity of depression symptoms.

For the current study, the team conducted a secondary analysis of their prior EPO trials to determine whether the treatment improves the speed of complex cognitive processing, whether baseline impairments increase the likelihood of improvements, and whether objective improvements correlate with improvements in subjective and daily functioning.

Speeds Cognitive Processing

Both for patients with bipolar disorder and those with unipolar disorder, EPO significantly improved the speed of complex cognitive processing between baseline and week 9 (P < .01) and between baseline and week 14 (P = .01). Benefits were seen on a range of tests, including those that measured verbal memory, attention span, and planning ability.

Furthermore, the researchers found that objective, as opposed to subjective, cognitive deficits at baseline were associated with a significant increase in the likelihood of achieving clinically relevant improvement, at an odds ratio of 9.7 (P = .04) at week 9 and an odds ratio of 9.9 (P = .04) at week 14.

Improvements in cognitive performance associated with EPO were linked to reductions in subjective cognitive complaints at week 9, at an r (38) value of -0.41 (P = .01), an effect that was mediated by a reduction in the severity of symptoms of depression. The correlation persisted at week 14 (beta = -0.48; P < .01), albeit independently of change in depression symptoms.

The improvements in cognitive performance associated with EPO did not correlate with changes in either quality of life or socio-occupational function. However, Dr Miskowiak told Medscape Medical News that this lack of effect is likely the result of the short follow-up period of the trials. She pointed to studies of the use of EPO in patients with schizophrenia and multiple sclerosis in which benefits persisted for up to at least 6 months.

The finding from the current analysis of an association between objective and subjective measures of cognition supports the notion, she said, as it suggests that "the patients not only improved on cognitive tests, which was the primary measure, but also in daily life.

"But it does seem to take a bit longer for them to actually feel it. It's a bit like the analogy of when you have a sprained ankle – you have a physical healing of the ankle, but it will still take you some time until you can go running or training in the same way as before, and that you realize that you can do that," she added.

To examine the longer-term impact of EPO, the team will start new trials in January 2017, in which patients with bipolar disorder who have cognitive deficits will be treated for 12 weeks. The patients will be followed for 6 months.

Direct Effects

More work is needed to determine the exact mechanism of action of EPO in the brain, said Dr Miskowiak. She pointed out that single doses of EPO have been associated with improvements brain responses on functional MRI during cognitive testing, independent of changes in the levels of red blood cells.

"That was really the proof of concept for a direct effect of EPO in the brain, as directly as we can measure it in humans, of course. There are also a lot of animal studies showing direct effects of EPO on neuroplasticity," she said.

Moreover, results in animal models suggest that there is an "EPO receptor system" in the brain that is unregulated during hypoxia and that protects neurons from apoptosis. "It really seems to be separate from the effect on the bone marrow, although the exact mechanisms are not fully understood yet," Dr Miskowiak said.

As part of the original parallel trials, the researchers also conducted structural and functional MRI scans at baseline and after treatment completion, which showed that EPO was associated with an increase in the volume of an area of the left hippocampus; for patients who did not receive the treatment, there was a decrease in volume.

This structural increase in volume in the left hippocampus was the only independent predictor of improvement on a memory test, after adjusting for age, sex, illness chronicity, and symptom change, among other potentially confounding factors.

In light of the fact that animal studies have indicated that EPO is associated with increased neuroplasticity in the hippocampus, Dr Miskowiak said that "the pieces of the puzzle are kind of coming together and indicating that this might be the mechanism.

"I think drugs or even psychological interventions that increase neuroplasticity might have the same effects," she added.

Commenting on the findings, Eduard Vieta, MD, PhD, chair of the Department of Psychiatry and Psychology at the University of Barcelona Hospital Clinic, Spain, and treasurer of the ECNP, said that although the results are preliminary, they "give hope to people suffering from mood disorders and associated neurocognitive symptoms.

"Those symptoms are now recognized as a core part of affective disorders and are not appropriately tackled by the currently available pharmacological armamentarium, despite their close association with relevant clinical outcomes, such as the ability to return to work," he added.

The original trials were funded by the Danish Ministry of Science, Innovation and Higher Education; the Novo Nordisk Foundation; the Beckett Foundation; and Savværksejer Juhl's Mindefond. The Lundbeck Foundation provided support for Dr Miskowiak's postdoctoral salary from 2012 to 2015 for her full-time research during this period. The other authors have disclosed no relevant financial relationships.

29th European College of Neuropsychopharmacology (ECNP) Congress. Abstract P.2.b.004. Presented September 18, 2016.

Eur Neuropsychopharmacol. 2016;26:1264-1273. Abstract