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.

Single dose antidepressant administration modulates the neural processing of self-referent personality trait words.

Miskowiak K, Papadatou-Pastou M, Cowen PJ, Goodwin GM, Norbury R, Harmer CJ. 


Neuroimage. 2007 Sep 1;37(3):904-11.


Drugs which inhibit the re-uptake of monoamines in the brain are effective in the treatment of depression; howevere, the neuropsychological mechanisms which lead to the resolution of depressive symptomatology are unclear. Behavioral studies in healthy volunteers suggest that acute administration of the selective norepinephrine reuptake inhibitor reboxetine modulates emotional processing. The current study therefore explored the neural basis of this effect. A single dose of reboxetine (4 mg) or placebo was administered to 24 healthy volunteers in a double-blind between-group design. Neural responses during categorisation and recognition of self-referent personality trait words were assessed using event-related functional Magnetic Resonance Imaging (fMRI). Reboxetine had no effect on neuronal response during self-referent categorisation of positive or negative personality trait words. However, in a subsequent memory test, reboxetine reduced neuronal activation in a fronto-parietal network during correct recognition of positive target words vs. matched distractors. This was combined with increased speed to recognize positive vs. negative words compared to control subjects and suggests facilitated memory for positive self-referent material. These results support the hypothesis that antidepressants have early effects on the neural processing of emotional material which may be important in their therapeutic actions.

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.