Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder.

Miskowiak KW, Vinberg M, Harmer CJ, Ehrenreich H, Knudsen GM, Macoveanu J, Hansen AR, Paulson OB, Siebner HR, Kessing LV.

 

Trials. 2010; vol. 11 pp. 97

 

ABSTRACT: BACKGROUND: Depression and bipolar disorder are associated with reduced neural plasticity and deficits in memory, attention and executive function. Drug treatments for these affective disorders have insufficient clinical effects in a large group and fail to reverse cognitive deficits. There is thus a need for more effective treatments which aid cognitive function. Erythropoietin (Epo) is involved in neuroplasticity and is a candidate for future treatment of affective disorders. The investigators have demonstrated that a single dose of Epo improves cognitive function and reduces neurocognitive processing of negative emotional information in healthy and depressed individuals similar to effects seen with conventional antidepressants. The current study adds to the previous findings by investigating whether repeated Epo administration has antidepressant effects in patients with treatment resistant depression and reverses cognitive impairments in these patients and in patients with bipolar disorder in remission. METHODS/DESIGN: The trial has a double-blind, placebo-controlled, parallel-group design. 40 patients with treatment-resistant major depression and 40 patients with bipolar disorder in remission are recruited and randomised to receive weekly infusions of Epo (Eprex; 40,000 IU) or saline (NaCl 0.9%) for 8 weeks. Randomisation is stratified for age and gender. The primary outcome parameters for the two studies are: depression severity measured with the Hamilton Depression Rating Scale 17 items (HDRS-17) 1 in study 1 and, in study 2, verbal memory measured with the Rey Auditory Verbal Learning Test (RAVLT) 23. With inclusion of 40 patients in each study we obtain 86% power to detect clinically relevant differences between intervention and placebo groups on these primary outcomes. TRIAL REGISTRATION: The trial is approved by the Local Ethics Committee: H-C-2008-092, Danish Medicines Agency: 2612-4020, EudraCT: 2008-04857-14, Danish Data Agency: 2008-41-2711 and ClinicalTrials.gov: NCT 00916552.

Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients.

Miskowiak KW, Favaron E, Hafizi S, Inkster B, Goodwin GM, Cowen PJ, Harmer CJ.

 

Psychopharmacology (Berl). 2010 Jun: vol. 210(3) pp. 419-28

 

OBJECTIVE: Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers. The current study investigates the effects of Epo on the neural and cognitive response to emotional facial expressions in depressed patients. METHOD: Nineteen acutely depressed patients were randomized to receive Epo (40,000 IU) or saline intravenously in a double-blind, parallel-group design. On day 3, we assessed neuronal responses to fearful and happy faces using functional magnetic resonance imaging and measured facial expression recognition after the scan. RESULTS: Epo reduced neural response to fearful vs. happy faces in the amygdala and hippocampus, and to fearful faces vs. baseline in superior temporal and occipitoparietal regions 3 days after administration in acutely depressed patients. This was accompanied by a specific reduction in the recognition of fear in Epo-treated patients after the scan similar to the effects on face recognition seen with antidepressant drug treatment. CONCLUSIONS: The present findings are similar to the effects of conventional antidepressants in acutely depressed patients and opposite to hypervigilance to negative facial expressions in depression. This highlights a potential antidepressant mechanism and warrants further investigation of Epo as a new candidate compound for treatment of depression.

Effects of erythropoietin on emotional processing biases in patients with major depression: an exploratory fMRI study.

Miskowiak KW, Favaron E, Hafizi S, Inkster B, Goodwin GM, Cowen PJ, Harmer CJ.

 

Psychopharmacology (Berl). 2009 Aug 25.

 

INTRODUCTION: Erythropoietin (Epo) has neurotrophic effects and may be a novel therapeutic agent in the treatment of depression. We have found antidepressant-like effects of Epo on emotional processing and mood in healthy volunteers. OBJECTIVE: The current study aimed to explore the effects of Epo on the neural processing of emotional information in depressed patients. MATERIALS AND METHODS: Seventeen patients with acute major depressive disorder were randomised to receive Epo (40,000 IU) or saline iv in a double-blind, parallel-group design. On day 3, we assessed neural responses to positive, negative and neutral pictures during fMRI followed by picture recall after the scan. Mood and blood parameters were assessed at baseline and on day 3. RESULTS: Epo reduced neural response to negative vs. positive pictures 3 days post-administration in a network of areas including the hippocampus, ventromedial prefrontal and parietal cortex. After the scan, Epo-treated patients showed improved memory compared with those that were given placebo. The effects occurred in the absence of changes in mood or haematological parameters, suggesting that they originated from direct neurobiological actions of Epo. CONCLUSIONS: These findings are similar to the effects of conventional antidepressants and opposite to the negative biases in depression. The central effects of Epo therefore deserve further investigation as a potential antidepressant mechanism.

Erythropoietin improves mood and modulates the cognitive and neural processing of emotion 3 days post administration.

Erythropoietin improves mood and modulates the cognitive and neural processing of emotion 3 days post administration.


Miskowiak K, Inkster B, Selvaraj S, Wise R, Goodwin GM, Harmer CJ.

 

Neuropsychopharmacology. 2008 Feb;33(3):611-8.

 

Erythropoietin (Epo) has neuroprotective and neurotrophic effects and is a promising candidate for treatment of neurodegenerative and psychiatric disorder. Recently, we demonstrated that Epo modulates memory-relevant hippocampal response and fear processing in human models of antidepressant drug action 1 week post-administration, and improves self-reported mood for 3 days immediately following administration. The present study explored the effects of Epo (40 000 IU) vs saline on self-reported mood and on neural and cognitive function in healthy volunteers 3 days post-administration to test the reliability of the rapid mood improvement and its neuropsychological basis. Neuronal responses during the processing of happy and fearful faces were investigated using functional magnetic resonance imaging (fMRI); facial expression recognition performance was assessed after the fMRI scan. Daily ratings of mood were obtained for 3 days after Epo/saline administration. During faces processing Epo enhanced activation in the left amygdala and right precuneus to happy and fearful expressions. This was paired with improved recognition of all facial expressions, in particular of low intensity happiness and fear. This is similar to behavioral effects observed with acute administration of serotonergic antidepressants. Consistent with our previous finding, Epo improved self-reported mood for all 3 days post-administration. Together, these results suggest that characterization of the effects of Epo in a clinically depressed group is warranted.

Differential effects of erythropoietin on neural and cognitive measures of executive function 3 and 7 days post-administration.

Miskowiak K, Inkster B, O’Sullivan U, Selvaraj S, Goodwin GM, Harmer CJ.

 

Experimental Brain Research. 2008 Jan;184(3):313-21.

 

Erythropoietin (Epo) has neuroprotective and neurotrophic effects and improves cognitive function in animal models of neurodegenerative and neuropsychiatric illness. In humans, weekly Epo administration over 3 months improves cognitive function in schizophrenia. The neural underpinnings and time-course of this effect of Epo are currently unknown. It is also unclear whether the cognitive improvement reflects direct neurobiological actions or is secondary to hematological effects. We therefore assessed the actions of single administration of Epo (40,000 IU) vs. saline to healthy volunteers on cognitive and neural measures of executive function using a verbal fluency task and N-back working memory (WM) paradigm during functional magnetic resonance imaging (fMRI) on day 3 and 7 after administration in two separate cohorts of subjects. Epo modulated neuronal response in a fronto-parietal network during WM performance at both time points; on day 3 after administration, activation was increased in left-hemisphere frontal and cingulate cortex and reduced in the right parietal cortex; in contrast, neural response was enhanced in a right-lateralized fronto-parietal network and reduced in left-side regions 1 week post-administration. In addition, Epo-treated volunteers displayed improved verbal fluency performance 1 week post-administration. These effects occurred in the absence of changes in hematological measures suggesting that they reflect direct neurobiological actions of Epo. The findings are consistent with enduring effects of Epo on neurotrophic signaling and induction of neurochemical changes over time in neural networks typically affected in neuropsychiatric illness. The present study supports the notion that Epo may have clinical applications in the treatment of psychiatric disorder characterized by cognitive dysfunction.

Erythropoietin reduces neural and cognitive processing of fear in human models of antidepressant drug action.

Miskowiak K, O’Sullivan U, Harmer CJ.

 

Biological Psychiatry. 2007 Dec 1;62(11):1244-50.

 

BACKGROUND: Erythropoietin (Epo) has neuroprotective and neurotrophic effects in animal models and affects cognitive and associated neural responses in humans. These effects have highlighted Epo as a candidate for treatment of psychiatric disease including schizophrenia and depression. The current study aimed to explore the effects of Epo on neural and behavioral measures of emotional processing relevant for depression and the effects of conventional antidepressant medication. METHODS: In the present study, we used functional magnetic resonance imaging to explore the effects of Epo (40,000 IU) versus saline on the neural processing of happy and fearful faces in 23 healthy volunteers. Facial expression recognition was assessed outside the scanner. RESULTS: One week after administration, Epo reduced neural response to fearful versus neutral faces in the occipito-parietal cortex consistent with reduced attention to fear. Erythropoietin additionally reduced recognition of fearful facial expressions without affecting recognition of other emotional expressions. These actions occurred in the absence of changes in hematological parameters. CONCLUSIONS: The present study demonstrates that Epo directly modulates brain responses to emotional information in humans in a manner consistent with the actions of conventional antidepressants. The characterization of the effects of Epo in a clinically depressed group is therefore warranted.

Erythropoietin enhances hippocampal response during memory retrieval in humans.

Erythropoietin enhances hippocampal response during memory retrieval in humans. 

Miskowiak K, O’Sullivan U, Harmer CJ.

 

Journal of Neuroscience 2007 Mar 14;27(11):2788-92.

 

Although erythropoietin (Epo) is best known for its effects on erythropoiesis, recent evidence suggests that it also has neurotrophic and neuroprotective properties in animal models of hippocampal function. Such an action in humans would make it an intriguing novel compound for the treatment of neurological and psychiatric disorders. The current study therefore aimed to explore the effects of Epo on neural and behavioral measures of hippocampal function in humans using a functional magnetic resonance imaging paradigm. Volunteers were randomized to receive intravenous injection of Epo (40,000 IU) or saline in a between-subjects, double-blind, randomized design. Neural response during picture encoding and retrieval was tested 1 week later. Epo increased hippocampus response during picture retrieval (n = 11) compared with placebo (n = 12; p = 0.04) independent of changes in hematocrit. This is consistent with upregulation of hippocampal BDNF and neurotrophic actions found in animals and highlights Epo as a promising candidate for treatment of psychiatric disorders.

Erythropoietin improves place learning in fimbria-fornix-transected rats and modifies the search pattern of normal rats.

Mogensen J, Miskowiak K, Sørensen TA, Lind CT, Olsen NV, Springborg JB, Malá H.

 

Pharmacology Biochemistry and Behavior. 2004 Feb;77(2):381-90.

 

The acquisition of a water-maze-based allocentric place learning task was studied in four groups of rats: two groups subjected to bilateral transections of the fimbria-fornix and two groups undergoing a sham control operation. At the moment of surgery all animals were given one systemic (intraperitoneal) injection of either human recombinant erythropoietin (EPO) (at a dosage of 5000 IU/kg body weight), given to one of the fimbria-fornix-transected groups and one of the sham-operated groups, or vehicle (saline), given to the two remaining groups. The 25-day task acquisition period (one session/day) began 6 or 7 days after the day of surgery. The fimbria-fornix-transected and saline-injected group exhibited a pronounced and long-lasting impairment of task acquisition. In contrast, the fimbria-fornix-transected and EPO-treated group demonstrated a less pronounced and more transient lesion-associated impairment. The two sham-operated groups did not differ with respect to the proficiency of task acquisition. But administration of EPO to intact animals caused a significant modification of swim patterns-apparently reflecting a somewhat modified strategy of task solution. It is concluded that systemic administration of EPO significantly improves the posttraumatic functional recovery of the presently studied place learning task after transections of the fimbria-fornix. Additionally, administration of EPO influences the strategy, although not quality, of task solution in normal (sham-operated) rats.