Could EPO studies improve mood disorder treatment strategies?

KEYWORDS:

• Erythropoietin
• mood disorder
• cognitive impairment
• treatment
• neuroplasticity

1. Cognitive impairment as a new treatment target in mood disorders

Major depressive disorder (MDD) and bipolar disorder (BD) cost an estimated $128 billion in the United States and €113 billion in Europe, with decreased workforce capacity accounting for 60%–80% of the expenditures [1,2]. A new key treatment priority is therefore to enhance patients’ functional recovery. A principal contributor to the functional disability and high unemployment rates in mood disorders is patients’ persistent cognitive impairment [3]. Specifically, studies have documented substantial cognitive deficits across memory, attention, and executive function in MDD and BD that persist after clinical remission from mood episodes and may be worsened by medication [4,5]. Treatment of cognitive impairment is therefore a key strategic focus for the next decade of research into new treatments for mood disorders. However, randomized, controlled, and/or open-label clinical studies of new candidate cognition treatments have produced disappointing or only preliminary findings (for systematic reviews, see [6,7]). Consequently, there is no available treatment to target patients’ persistent cognitive deficits.

2. Is neuroplasticity a target for cognitive enhancement strategies?

The neurobiological underpinnings of the cognitive impairments in mood disorders are unclear. However, converging evidence from preclinical studies, neuroimaging studies, and postmortem studies indicate that they arise from disrupted neuroplasticity and structural brain changes including reduction of hippocampal volume [8,9]. Putative neurobiological mechanisms are dendritic retraction, pyramidal cell death, and suppression neurogenesis due to glucocorticoid overexposure. In animal models, such neuroplasticity deficits lead to profound learning and memory impairments and reduced behavioral flexibility [10], which are reminiscent of the cognitive impairments observed in patients with mood disorders.

Conversely, restoration of neuroplasticity may be a common mechanism of long-term antidepressant or mood stabilizing drug treatment [11]. In particular, hippocampal volume increase occurs after long-term antidepressant drug treatment of MDD [12] and lithium treatment of BD [13]. Given this, development of novel treatments with direct enduring effects on neuroplasticity seems a promising avenue to target not only mood symptoms but also cognitive dysfunction.

3. Erythropoietin: a new role of an established player

The multifunctional trophic growth factor EPO may represent a unique therapeutic agent to target deficits in neuroplasticity and cognition in mood disorders. Erythropoietin is a body-own protein produced predominantly in the kidney that is widely used in the treatment of anemia as well as illicitly for blood doping in competitive sports. However, the functions of EPO are not confined to the hematopoietic system. Erythropoietin and a specific EPO receptor system are also present in the central nervous system and play a role in neurodevelopment and neuroprotection (for review see [14]). Multiple neurobiological mechanisms underlie the beneficial effects of EPO, including activation of antiapoptotic, anti-oxidant, and anti-inflammatory signaling in neurons, glial, and cerebrovascular endothelial cells, and promotion of dendritic sprouting, long-term potentiation, and neurogenesis. The discovery that systemically administered EPO enters the brain and has neuroprotective and neurotrophic effects was therefore a therapeutic breakthrough [14]. Indeed, pioneering translational studies revealed that weekly high-dose (40,000–48,000 IU) EPO treatment for 8–12 weeks improves cognition in multiple sclerosis and schizophrenia [14].

Encouraged by this evidence, Miskowiak and colleagues at University of Oxford, United Kingdom, conducted the first human proof-of-concept functional magnetic resonance study, which demonstrated that a single dose of EPO vs. placebo enhanced memory-related hippocampus response in the absence of changes in red blood cells [15]. The authors therefore set up two parallel randomized, placebo-controlled, double-blind clinical trials at the Copenhagen University Hospital, Rigshospitalet, Denmark, to investigate the potential of EPO to treat mood symptoms and cognitive dysfunction in treatment-resistant depression (TRD) (N = 40) and BD in remission (N = 44), respectively [16,17]. Erythropoietin had no effect on the primary measure of depression severity in the TRD trial (the Hamilton Depression Rating Scale 17-items score) although additional depression-relevant measures including self-rated depression and quality of life showed improvement in EPO vs. placebo groups [16]. The most remarkable finding was that EPO-treated patients displayed pronounced, long-lasting improvement of verbal learning and memory that was twice the size of our a priori estimation of a clinically relevant change [16]. The BD trial revealed only a trend toward EPO-associated verbal memory improvement (primary outcome). However, EPO produced substantial improvement in sustained attention, social cognition, processing speed, and executive function (secondary and tertiary outcomes) and in an exploratory global ‘speed of complex cognitive processing’ composite score, ranging from attention to learning and executive function. Secondary analysis of the pooled data sets from the two trials showed that the EPO-associated improvement of speed of complex cognitive processing occurred across both BD and TRD groups and persisted until at least six weeks after treatment completion [18]. This observation corroborates with EPO-associated improvement in similar complex cognitive processing speed in multiple sclerosis and in schizophrenia [14] and suggests that broad pro-cognitive effects of EPO occur across several neuropsychiatric patient populations with cognitive deficits. Intriguingly, structural neuroimaging of the EPO trial participants revealed that the effects of cognition were accompanied by EPO-associated prevention of brain matter loss in a subfield of the left hippocampus encompassing the CA1-3 and subiculum [19]. Notably, the EPO-associated improvement in objective cognition was accompanied by reduced subjectively perceived cognitive difficulties, which highlights a clinical relevance of this effect [18]. Taken together, these findings provide promising—albeit still preliminary—evidence for beneficial effects of EPO to target deficits in neuroplasticity and cognition in mood disorders.

4. Clinical limitations of EPO in non-anemic populations

Despite the promising evidence for EPO as a new add-on cognition treatment, three limitations of EPO may impede its clinical use. First, the hematopoietic actions of EPO with repeated administration require careful monitoring by a physician, blood tests, and, potentially, blood lettings in these non-anemic patient populations (in about 15% of cases), which is labor-intensive and costly. An important next step for further clinical development of EPO is therefore to investigate whether the undesirable hematopoietic effects can be avoided with more infrequent EPO administration or with use of carbamylated EPO or other non-hematopoietic EPO analogues. The second limitation is the concern that EPO could potentially promote malignant tumor growth, although the evidence for this adverse effect remains controversial [20]. Indeed, low-dose EPO is widely used in the treatment of chemotherapy-induced anemia to avoid red blood cell transfusions, and EPO is only counter-indicated in non-anemic cancer patients [20]. The third limitation is the high costs of EPO; 1 ml vial of EPO (40,000 IU) costs about 420$ in the United States and 200–500 euros in Europe depending on the country. Since enduring effects on cognition most likely require several doses of EPO, this would impose large costs on patients and society. Ongoing research efforts therefore aim to delineate the neurocognitive effects of modified EPO molecules that can be manufactured and purchased at lower costs. Another alternative is to develop and test neurochemically distinct compounds with similar downstream effects on neuroplasticity and cognition.

5. Conclusion and perspectives

Cognitive impairment is an important new treatment target to aid functional recovery in mood disorders. Identification of novel candidate treatments with rapid enduring effects on neuroplasticity may improve both cognition and mood disturbances. The multifunctional growth factor EPO is among the most promising candidate treatments to target deficits in neuroplasticity and cognition. There are several clinical limitations of EPO including its high cost. However, it is conceivable that the caveats are outweighed by the potential cognitive and associated socio-occupational benefits of EPO in the patient groups who suffer a substantial loss of work force capacity. An essential step for future trials is therefore to determine whether the EPO-related improvement of cognitive function translate into better socio-occupational functioning including work force capacity longer term. If so, this could have important implications for the future mood disorder treatment strategies.

Declaration of interest

K.W Miskowiak has received consultancy fees from Lundbeck and Allergan in the last 3 years. The Lundbeckfonden and the Weimann Foundation are acknowledged for providing support for half of Dr Miskowiak’s salary as senior research psychologist at Copenhagen Affective Disorders Research Centre and University of Copenhagen, Denmark, which enables her to do fulltime research until 2020. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.