Hormone EPO shown to improve brain sharpness in patients with depression and bipolar disorder

Media Release: European College of Neuropsychopharmacology (ECNP)
“For the science and treatment of disorders of the brain”

Hormone EPO shown to improve brain sharpness in patients with depression and bipolar disorder
For immediate release: Sunday 18th September, 2016

Vienna, 18 September 2016: A study has found that EPO (erythropoietin) – best known as a performance-enhancing drug in sport – may improve cognitive functioning in patients suffering from bipolar disorder or depression. This raises hope for the first long-term treatment for this problem, which affects hundreds of millions of patients throughout the world. The work is presented today at the ECNP conference in Vienna*.
The hormone EPO, mostly produced by the kidney, is essential for the production of red blood cells. EPO gives the blood a greater capacity to carry oxygen, and it is this characteristic which makes it attractive as a performance-enhancing drug (the cyclist Lance Armstrong admitted to using EPO to improve physical performance). Medically, recombinant EPO is used for the treatment of anaemia.
Most people think of disorders such as bipolar disorder and depression as conditions which affect mood, but in reality they also affect cognitive function - how quickly and how well a brain functions. This slow-down in thinking can have serious effects on sufferers, making it more difficult to retain a job, pass an exam, or maintain a relationship. Now a group of Danish Scientists have discovered that EPO can help restore cognitive function in patients suffering from these mental disorders.
In two randomized controlled trials, the researchers assessed cognitive function in 79 patients suffering from depression or bipolar disorder. They assigned 40 of the patients to be given EPO for 9 weeks, with the remaining 39 being given a placebo. They found that EPO had beneficial effects on patients’ completion of a range of cognitive tests, including tests on verbal memory, attention span, and planning ability. Tests showed that this improvement was maintained for at least 6 weeks after treatment finished (the longest follow-up time in the trials).
Lead researcher, Dr Kamilla Miskowiak said:
“EPO treated patients showed a five times greater cognitive improvement from their individual baseline levels compared with placebo treated patients. EPO-treated patients showed 11% improvement while placebo treated patients improved only by 2%. This effect of EPO on cognition was maintained six weeks after patients had completed their treatment”.
In an interesting twist, it was found that patients who performed poorly in neuropsychological tests showed remarkably greater cognitive benefits when given EPO. Dr Miskowiak, commented:
“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”.
She continued
“We need bigger studies to confirm that the effects we have seen can be replicated, to confirm dosage, frequency of use and so on. EPO is already used medically, so we know quite a lot about safety. Although EPO is generally safe if patients’ red blood cell levels are controlled regularly, there are certain groups for whom the risk of blot clots is too high – for example people who smoke or who have previously had blood clots. So although these results hold out great promise, EPO treatment is not ready to be rolled out as a treatment just yet and may not be for everyone”.
The WHO estimates that around 350 million people suffer from depression, with a further 60 million suffering from bipolar disorder**, but the drugs normally used to treat depression and bipolar disorders don’t have any major effect on cognition. Up to 70% of patients in remission from bipolar disorder, and up to 40% in remission from depression continue to have cognitive problems. Currently there is no available effective treatment to target cognitive problems in these patients.
Commenting, Professor Eduard Vieta (Chair of the Department of Psychiatry and Psychology at the University of Barcelona Hospital Clinic and treasurer of the ECNP) said:

“The results of this study, albeit preliminary, 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”.
*This presentation is based on work just published in the August 2016 edition of the peer-reviewed journal, European Neuropsychopharmacology, see http://www.europeanneuropsychopharmacology.com/article/S0924-977X(16)30088-8/abstract
**For statistics see http://www.who.int/mediacentre/factsheets/fs396/en/
Contacts, abstract, funding information, and other details are listed in ‘Notes’.

Notes for editors
Please mention the European College of Neuropsychopharmacology Congress in any stories which result from this press release.

Dr Kamilla Miskowiak kamilla@miskowiak.dk
Professor Eduard Vieta EVIETA@clinic.cat
ECNP Press Officer, Tom Parkhill press@ecnp.eu tel +39 349 238 8191 (Italy)
The European College of Neuropsychopharmacology (ECNP)
The ECNP is an independent scientific association dedicated to the science and treatment of disorders of the brain. It is the largest non-institutional supporter of applied and translational neuroscience research and education in Europe. Website: www.ecnp.eu
The 29th annual ECNP Congress takes place from 17th to 20th September in Vienna. It is Europe’s premier scientific meeting for disease-oriented brain research, annually attracting between 4,000 and 6,000 neuroscientists, psychiatrists, neurologists and psychologists from around the world. Congress website: http://www.ecnp-congress.eu/
This presentation is based on work published in the peer-reviewed journal, European Neuropsychopharmacology (Aug 2016): The effect of erythropoietin on cognition in affective disorders – Associations with baseline deficits and change in subjective cognitive complaints
Caroline Vintergaard Ott et al, DOI: http://dx.doi.org/10.1016/j.euroneuro.2016.05.009
Congress Abstract P.2.b.004 The effect of erythropoietin on cognition in affective disorders – associations with baseline deficits and change in subjective cognitive complaints
C.V. Ott, M. Vinberg, L.V. Kessing, K.W. Miskowiak: Psychiatric Centre Copenhagen- Copenhagen University Hospital- Rigshospitalet, Dep. 6233, Copenhagen, Denmark
Background: We previously demonstrated in a randomized placebo-controlled trial that recombinant human erythropoietin (EPO) improves ‘speed of complex cognitive processing’ across attention, memory and executive function in partially remitted patients with bipolar disorder (BD) [1]. In a parallel trial, including patients with treatment-resistant unipolar disorder (UD), mood-independent improvement of verbal memory in EPO versus saline treated patients was observed [2]. Pooling verbal memory data from these parallel trials with identical design showed a comparable effect of EPO on verbal memory across UD and BD [3]. Post-hoc analysis showed that objective memory dysfunction at baseline substantially increased patients' chances of EPO treatment efficacy on memory, while subjective cognitive complaints at baseline had a smaller, albeit significant, effect [3].
Objective: This secondary data analysis from our EPO trials examines (1) whether EPO improves speed of complex cognitive processing across UD and BD (2) whether objective and subjective cognitive impairment at baseline increase patients' chances of treatment efficacy on cognition, and (3) if objective cognitive improvement correlates with improvement in subjective cognitive function, quality of life and socio-occupational function.
Methods: Patients with UD and BD were randomized to eight weekly EPO (N = 40) or saline (N = 39) infusions. Patients were assessed with selected neuropsychological tests, comprising speed of complex cognitive processing, and rated for mood symptoms. Questionnaires concerning subjective cognitive function, quality of life and socio-occupational function were administered. Patients were assessed at baseline (week 1), after treatment completion (week 9) and at follow-up (week 14). We used repeated measures analysis of covariance, adjusted for diagnosis and depressive symptom severity, to investigate the effect of EPO on speed of complex cognitive processing. Logistic regression analyses were performed to determine whether baseline objective cognitive impairment, defined as a score ≥1 SD from the norm on ≥2 neuropsychological tests, predicted treatment efficacy. Logistic regression analyses were used to assess whether subjective cognitive complaints at baseline predicted treatment efficacy. Pearson correlations were employed to explore associations between changes in objective and subjective cognition, quality of life and socio-occupational capacity from baseline to weeks 9 and 14, respectively.
Results: EPO improved speed of complex cognitive processing across affective disorders at weeks 9 and 14 (p≤0.05). In EPO-treated patients, objective (but not subjective) cognitive baseline deficits increased the odds of achieving a clinically relevant improvement of cognition by a factor 9.7 (95% CI:1.2–81.1) and 9.9 (95% CI:1.1–88.4) at weeks 9 and 14 (p≤0.04). EPO-associated cognitive improvement correlated with reduction in subjective cognitive complaints at week 9 (r(38)=-0.41, p = 0.01), which was mediated by reduced depressive symptom severity. However, at week 14, the significant correlation persisted independently of change in depressive symptoms (β=-0.48, p < 0.01). Improved objective cognition did not correlate with change in quality of life or socio-occupational function.
Conclusions: The pro-cognitive effects of EPO seem to apply across several patient groups. Neuropsychological screening for cognitive dysfunction may be warranted in future cognition trials to ensure enriched patient samples, and in clinical settings to identify the patients most likely to benefit from cognition treatment.

[1] Miskowiak, K.W., Ehrenreich, H., Christensen, E.M., Kessing, L.V., Vinberg, M., 2014a. Recombinant human erythropoietin to target cognitive dysfunction in bipolar disorder: a double-blind, randomized, placebo-controlled phase 2 trial. The Journal of Clinical Psychiatry, 75(12), 1347–1355. http://doi.org/10.4088/JCP.13m08839.
[2] Miskowiak, K.W., Vinberg, M., Christensen, E.M., Bukh, J.D., Harmer, C.J., Ehrenreich, H., Kessing, L.V., 2014b. Recombinant human erythropoietin for treating treatment-resistant depression: a double-blind, randomized, placebo-controlled phase 2 trial. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 39(6), 1399–1408. http://doi.org/10.1038/npp.2013.335.
[3] Miskowiak, K.W., Rush, A.J., Gerds, T.A., Vinberg, M., Kessing, L.V., in press. Predictors of treatment success in cognition trials: analyses of randomized, controlled trials of erythropoietin in mood disorders. Journal of Clinical Psychiatry.
Funding: The original trials were funded by the Danish Ministry of Science, Innovation and Higher Education; Novo Nordisk Foundation; Beckett Foundation and Savværksejer Juhl’s Mindefond. The Lundbeck Foundation provided support for KWM's postdoctoral salary from 2012–2015 for her to do full-time research in this period.