[go: up one dir, main page]

WO2007068983A1 - Nouveau traitement - Google Patents

Nouveau traitement Download PDF

Info

Publication number
WO2007068983A1
WO2007068983A1 PCT/GB2006/050457 GB2006050457W WO2007068983A1 WO 2007068983 A1 WO2007068983 A1 WO 2007068983A1 GB 2006050457 W GB2006050457 W GB 2006050457W WO 2007068983 A1 WO2007068983 A1 WO 2007068983A1
Authority
WO
WIPO (PCT)
Prior art keywords
epo
depression
task
placebo
effects
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2006/050457
Other languages
English (en)
Inventor
Kamilla Miskowiak
Catherine Harmer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Oxford University Innovation Ltd
Original Assignee
Oxford University Innovation Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oxford University Innovation Ltd filed Critical Oxford University Innovation Ltd
Publication of WO2007068983A1 publication Critical patent/WO2007068983A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • This invention relates to a new treatment of depression and/or anxiety, in particular major depression.
  • mood disorders are divided into depressive disorders ("unipolar depression”), bipolar disorders, and two disorders based on etiology - mood disorder due to general medical conditions and substance-induced mood disorder.
  • Depressive disorders i.e. major depressive disorder, dysthymic disorder, and depressive disorder not otherwise specified
  • bipolar disorders by the fact that there is no history of ever having had a manic, mixed, or hypomanic episode.
  • Mood disorder due to a general medical condition is characterized by a prominent and persistent disturbance in mood that is judged to be a direct physiological consequence of a general medical condition.
  • Major depressive disorder is characterized by one or more major depressive episodes (i.e. at least 2 weeks of depressed mood or loss of interest accompanied by at least four additional symptoms of depression).
  • Dysthymic disorder is characterized by at least 2 years of depressed mood for more days than not, accompanied by additional depressive symptoms that do not meet criteria for a Major Depressive Episode.
  • Depressive disorder not otherwise specified is included for coding disorders with depressive features that do not meet criteria for major depressive disorder, dysthymic disorder, adjustment disorder with depressed mood, or adjustment disorder with mixed anxiety and depressed mood"
  • references to depression in this description do not include bipolar disorder or mood disorder due to a general medical condition.
  • Major depression is characterized by feelings of intense sadness and despair, mental slowing and loss of concentration, pessimistic worry, agitation, and self- deprecation. Physical changes also occur, especially in severe or "melancholic" depression. These include insomnia or hypersomnia, anorexia and weight loss (or sometimes overeating), decreased energy and libido, and disruption of normal circadian rhythms of activity, body temperature, and many endocrine functions.
  • Anxiety is a group of disorders in which symptoms of anxiety are prominent. They include panic disorder, phobias (such as agoraphobia, specific phobia, social phobia), obsessive-compulsive disorder, posttraumatic stress disorder, generalised anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and anxiety disorder not otherwise specified.
  • phobias such as agoraphobia, specific phobia, social phobia
  • obsessive-compulsive disorder posttraumatic stress disorder
  • generalised anxiety disorder anxiety disorder due to a general medical condition
  • substance-induced anxiety disorder and anxiety disorder not otherwise specified According to the DSM-IV-TR Diagnostic and Statistical Manual of Mental Disorders (4 th Edition), American Psychiatric Association, Washington 2000, there is a close relation between depression and anxiety in that individuals with a Major Depressive Episode frequently present symptoms including obsessive rumination, anxiety, phobias and excessive worries over physical health.
  • a Major Depressive Episode some individuals have panic attacks that occur in a pattern that meets criteria for panic disorder
  • TCAs tricyclic antidepressants
  • MAOIs monoamine oxidase inhibitors
  • SSRIs selective serotonin re-uptake inhibitors
  • SNRIs selective norepinephrine re-uptake inhibitors
  • Novel treatment strategies with more rapid onset of antidepressant effects would therefore have immense impact on public health.
  • new agents for the treatment or prophylaxis of depression and anxiety are needed, particularly those which are recursive, or depressions that are difficult to treat, i.e. where the patient does not respond to traditional antidepressant drugs and need an adjunct treatment. If primary pathology in these disorders results from maladaptive neuronal structural change and regional neural atrophy, Epo is a potential candidate for future treatment strategies of depression and anxiety.
  • Erythropoietin is a glycoprotein occurring naturally in the body with a molecular weight of about 34,000. It is now known to protect the brain and spinal cord from ischaemic and traumatic injury, the peripheral nerve from diabetic damage, the kidney from ischaemic or toxic insults and the heart from acute ischemia, either permanent or with reperfusion. Epo is used clinically in the treatment of anaemia associated with chronic renal failure in paediatric and adult patients on haemodialysis and adult patients on peritoneal dialysis, as well as in the treatment of severe anaemia of renal origin accompanied by clinical symptoms in adult patients with renal insufficiency not yet undergoing dialysis. Epo is also used to treat anaemia in cancer patients undergoing chemotherapy.
  • a clinically used formulation is sold under the registered trademark Eprex and is used at a concentration of from 2000 to 40,000 IU (16.8 - 336 ⁇ g/mL) in water for injection containing sodium dihydrogen phosphate dehydrate, disodium phosphate dehydrate, sodium chloride, polysorbate 80, glycine.
  • Epo and its derivatives and analogues may be used in the treatment of depression and anxiety, in particular major depression.
  • a method for the treatment or prophylaxis of depression or anxiety which comprises administration of a therapeutically effective amount of Epo or a derivative or an analogue thereof to a patient suffering from such a condition.
  • the Epo may be administered parenterally/systemically, e.g. by injection.
  • Systemic administration may be effected vascularly, intranasally and/or by inhalation.
  • the administration may be effected intravenously, subcutaneously or intramuscularly.
  • Epo is administered intravenously.
  • the patient will be a mammal, in particular a human being.
  • depression is acute, it may be treated with a single dose from 2000 to 40,000 IU. However, generally, Epo is indicated in the treatment of chronic depression.
  • Typical daily doses range from 2,000 to 200,000 IU, which may be given from 1 to 4 times over the course of the day. More typically a daily dose is from 20,000 to 80,000 IU, for example 40,000 IU.
  • Epo derivatives include asialoerythropoietin (asialoEPO) and carbamylated Epo (CEPO).
  • Epo which is made by recombinant techniques from cloned hamster ovaries which have received a gene for human erythropoietin.
  • Epo or a derivative or analogue thereof is generally formulated as an aqueous solution.
  • Epo or a derivative or an analogue thereof in the manufacture of a medicament for the treatment of depression or anxiety, particularly major depression.
  • Table 1 shows haematological parameters for subjects treated with Epo and placebo.
  • Table 2 shows brain regions that were significantly activated during picture encoding and recognition and effects of Epo.
  • Table 3 shows peak cluster activation in brain regions of significantly increased BOLD response during facial expression processing in placebo-treated volunteers.
  • Table 4 shows peak cluster activation in brain regions of significantly increased BOLD response during 2-back spatial working memory vs. control task performance in placebo- treated volunteers (main effect of task) and effects of Epo.
  • Figure 1 shows neuronal response during picture encoding and effects of Epo.
  • Figure 2 shows hippocampus response during picture recognition under Epo and placebo.
  • Figure 3 shows neural response to overt presentations of feariul vs. neutral faces in volunteers given placebo and plot of mean percent BOLD signal change in this region under Epo and placebo.
  • Figure 4 shows neural response to overtly presented fearful, happy and neutral faces, effects of Epo and plot of mean percent signal change in this cluster under Epo (dark bars) and placebo
  • Figure 5 shows recognition of fearful facial expressions across different emotion intensity levels.
  • Figure 6 shows neural response during N-back working memory and control task performance, effects of Epo (areas of increased activation) and plot of mean percent signal change in this cluster under Epo and placebo.
  • Figure 7 shows neural response during N-back WM and control task performance, effects of Epo (areas of reduced activation) and plot of mean percent signal change in these areas under Epo and placebo.
  • Figure 8 shows verbal fluency performance of subjects given Epo and placebo. The effects of Erythropoietin on neural and cognitive function in human models of antidepressant drug action
  • Epo affects emotional, cognitive and neural function in healthy volunteers using models relevant to anxiety and depression and the effects of conventional antidepressant medication.
  • the actions of Epo on neural responses during these processes were assessed using functional magnetic resonance imaging (fMRI), allowing the key sites of action to be identified.
  • fMRI functional magnetic resonance imaging
  • fMRI scanning also required the following exclusion criteria: spectacles, heart pacemaker, mechanical heart valve or any mechanical implants, potential pregnancy, and claustrophobia.
  • IQ was assessed with the National Adult Reading Test (NART). A blood test was taken to check that haemoglobin, renal function, liver function and ferritin were normal. A pregnancy test was performed on female volunteers as pregnancy was an exclusion criterion. After complete description of the study to the subjects, written informed consent was obtained. Letters were sent to volunteers' general practitioners two weeks before the study began to ensure that the GP was not aware of any contraindications to the person participating.
  • Epoetin-alfa (Eprex) (40,000 IU/ml formulation) or saline administered by a medical doctor in a double-blind randomised design.
  • a randomisation code was drawn up by a researcher who was not directly involved in the study and the information was kept in a sealed envelope.
  • Subjects' blood pressure, well-being and mood were monitored for three hours following the injection.
  • Subjects were given sets of mood questionnaires to take home. Daily ratings on these allowed for an assessment of any changes in mood and well-being in the week following the drug administration.
  • Picture encoding and retrieval These picture tasks were modified from Hariri et al. 2003 and were presented during scanning. Stimuli pictures were presented in a blocked paradigm in order to maximize power and sensitivity for BOLD signal change (Birn et al. 2002). In both tasks, eight blocks of pictures of complex visual scenes (24 sees) were presented interleaved with passive rest conditions (20 sees) all preceded by brief (2 sees) instructions, resulting in a task durance of 6 mins. All pictures were matched in terms of emotional valence, arousal and visual complexity. During encoding and retrieval blocks, subjects viewed six serially presented pictures.
  • Faces processing During fMRI, the facial expression processing task was projected from a computer using e-prime software (version 1.0; Psychology Software Tools Inc., Pittsburgh, PA) onto an opaque screen at the foot of the scanner bore. Subjects viewed the screen through angled mirrors and responded by pressing the keys of a response pad with their thumbs. Facial stimuli taken from the Pictures of Affect Series (Ekman and Friesen 1976) were presented in a blocked paradigm with covert and overt conditions. In the covert condition, 4 blocks each of fearful, happy and neutral faces were presented for 17ms followed by a neutral mask face for 183ms. Mask images were faces different from target faces but of the same gender.
  • e-prime software version 1.0; Psychology Software Tools Inc., Pittsburgh, PA
  • Facial expression recognition Following the fMRI scan, subjects were given a facial expression recognition task using a different set of facial stimuli. Pictures of faces from Ekman and Friesen (1976) were presented sequentially on a computer screen (randomized order) for 500msec. Faces expressed one of six basic emotions, happiness, surprise, sadness, fear, anger and disgust, and subjects were instructed to determine the particular emotions by pressing the corresponding keys on the keyboard as quickly and accurately as possible. Emotional expressions had been morphed between two standard images, each prototype (full emotion) and neutral, by taking a variable percentage of the shape and texture differences between the two in 10% steps (for details, see Harmer et al 2004).
  • N-back working memory The N-back task was presented in a blocked paradigm to maximise sensitivity for hippocampal BOLD signal change (Birn et al 2002).
  • the control task was similar in every aspect to the active 2-back condition.
  • the N-back task consisted of three 2-back WM blocks presented interleaved with three control blocks. Each block comprised 20 stimuli presentations and lasted 1 minute incl. 500 ms stimulus display and 2500 ms inter-stimulus delay. In addition, a blank screen was presented for 15 seconds in between each block to allow for normalisation of blood flow, leading to task duration of 7.5min. During this time, subjects responded by pressing the left button if the target was identical to the cue.
  • Verbal fluency Following the IMRI scan, executive function was measured with a verbal fluency task using letters previously been described as difficult (Fu et al 2002) to avoid ceiling effects. Subjects were given the letters A, G, O, N, E sequentially and instructed to generate as many words beginning with these letters as possible. Any words were allowed except for proper names or grammatical variations of a previously said word.
  • a control visual stimulation paradigm was used to assess whether drug-related effects observed during facial expression processing may reflect global effects of Epo on baseline cerebral blood flow.
  • BDI Beck Depression Inventory
  • EPQ Eysenck Personality Questionnaire
  • BFS Befindiges Scale
  • STAI State-Trait Anxiety Inventory
  • VAS Visual Analogue Scales
  • PANAS positive and negative affective mood scales
  • fMRI data were pre- processed and analysed using FEAT (FMRIB Expert Analysis Tool) version 5.43, part of FSL (FMRIB Software Library) (www.fmrib.ox.ac.uk/fsl). This included within- subject image realignment, spatial normalisation to a standard template using an affine procedure and spatial smoothing using a Gaussian kernel (5mm full- width-half-maximum). The time series in each session was high pass-filtered to remove large-scale non-stationary components and low frequency noise.
  • FEAT FMRIB Expert Analysis Tool
  • FSL FMRIB Software Library
  • FSL was used to compute individual subject analyses in which the time series were pre-whitened to remove temporal autocorrelation (Jezzard et al. 2001).
  • Brain areas with significant activation were localised using Talairach co- ordinates (Stereotaxic Atlas of the Human Brain) (Talairach & Tournoux, 1988).
  • ROIs for the left and right hippocampus in standard space were obtained using mri3dX (http://www.aston.ac.uk/lhs/staff/singhkd/mri3dX/mri3dX.isp), which utilises a stored representation of the Talairach Daemon Database (Lancaster et al. 2000).
  • Mean percent hippocampal BOLD signal change during encoding and recognition was computed and compared between Epo and placebo groups.
  • the two groups were well matched in terms of general mood, personality and subjective state, indicated by the absence of significant baseline differences in BDI, EPQ, STAI, and VAS scores (all P > 0.05).
  • picture encoding and recognition additionally produced activation in a distributed neural network involved in visuospatial processing, including bilateral parahippocampal gyri, middle and inferior frontal gyri, cingulate gyri and middle temporal, parietal and occipital cortices (Hariri et al 2003) (Fig. La and l.b; areas marked with mid-grey).
  • N 1 l
  • Fig. l.a for cluster maxima see Table 2.
  • Non-conscious processing of fearful and happy expressions elicited neural response within a similar network including the right amygdala and medial temporal gyrus, left inferior and medial frontal gyrus and bilateral inferior parietal (BA 40) and occipital regions (data not shown).
  • Amygdala ROI We found no effects of Epo on amygdala BOLD signal change during conscious and non-conscious processing of happy and fearful expressions (all P > 0.07).
  • Whole brain During overt presentations of fearful vs. neutral expressions, there was a significant interaction between drug group and emotion within a region encompassing the right precuneus and inferior parietal and middle occipital cortex with peak cluster activation in the right precuneus (Table 3; Fig. 4.a).
  • Figure 4.a shows neural response to overtly presented fearful, happy and neutral faces and effects of Epo. Shaded areas are the regions significantly activated by overt fearful, happy and neutral faces across control subjects. Epo reduced activation during conscious processing of fearful vs.
  • volunteers given Epo demonstrated reduced recognition of fearful facial expressions at high emotion intensity levels (80% and 90% intensity of emotion) compared to placebo (solid line).
  • 1 star (*) represents p ⁇ 0.05 and 2 stars (**) represents p ⁇ 0.01.
  • There were no effects on the recognition of other emotions all P > 0.06).
  • spatial working memory activated a broad neural network including bilateral middle and inferior frontal cortex, anterior cingulate, insula, thalamus, middle temporal cortex and precuneus in placebo- treated volunteers (Fig. 6; see cluster maxima in Table 4).
  • Region of interest analysis of the hippocampus demonstrated no consistent engagement of this region in spatial working memory (all P > 0.39), which is consistent with hippocampal disengagement in healthy human volunteers during working memory in contrast with schizophrenic patients (Meyer-Lindenberg et al 2001).
  • ROI demonstrated no effect on hippocampal activation during N-back WM (P > 0.16).
  • Exploratory whole brain mixed-effects group cluster analysis revealed a complex up- and down regulation of neural response by Epo during working memory vs. control task; Epo increased activation in the right-hemisphere middle and superior frontal gyri, precuneus and cuneus with peak cluster activation in the right precuneus and inferior frontal gyrus (Fig 6.a; for cluster maxima see Table 4).
  • figure 6.a which shows neural response during N-back WM and control task performance and effects of Epo, areas marked with light grey are the regions significantly activated by N-back WM vs. control task performance across control subjects.
  • Figure 6.b shows a plot of mean percent signal change in these sites under Epo (dark bars) and placebo (light bars). Bars show the mean; error bars show the standard error ( ⁇ M).
  • Epo additionally down-regulated activation in network encompassing left medial frontal gyrus and bilateral precentral, cingulate, superior temporal and parietal cortices and insula (Fig 7. a; for cluster maxima, see Table 4).
  • Figure 7.a shows neural response during N-back WM and control task performance and effects of Epo. Areas marked with light grey are the regions significantly activated by N-back WM vs. control task performance across control subjects. Epo reduced activation during N-back WM vs. control task performance in the left medial frontal gyrus and bilateral precentral, superior temporal and parietal cortices, cingulate and insula (areas marked with mid-grey) compared to placebo.
  • Epo influences cognitive and neurobio logical function in man and, if so, whether these effects could indicate a potential clinical value of Epo in the treatment of depression and anxiety.
  • Epo 40,000 IU
  • the data demonstrate that one dose of Epo (40,000 IU) applied peripherally to healthy volunteers (1) modified neurobio logical function in a manner that suggested increased neurogenesis in the hippocampus and improved memory processes (2) influenced cognitive function and emotional processing in ways similar to serotonergic and noradrenergic antidepressant drugs and opposite to the negative biases reported in depression, (3) improved mood in the days after drug administration and after one week
  • Epo modulates neural response during picture encoding and retrieval
  • Epo modified the neural underpinnings of picture encoding and recognition in healthy volunteers.
  • Epo enhanced bilateral hippocampal response during picture recognition. This is comparable to effects of increased BDNF expression found a similar paradigm (Hariri et al. 2003) and consistent with in vitro and in vivo evidence that Epo directly upregulates biologically active BDNF in the hippocampus (Viviani et al. 2005). Increased hippocampal activation has been reported during correct vs. incorrect picture recognition (Cansino et al 2002) which is consistent with a beneficial effect of Epo on recognition memory.
  • the DG of the hippocampus plays a role in spatial memory acquisition which suggests that neurogenesis in this region is important for spatial learning and memory.
  • Newborn cells take weeks to mature but may influence learning processes in early stages because of unique properties such as increased capacity for long term potentiation (LTP) - a main neurobiological mechanism underlying early memory formation (Aimone et al. 2006).
  • LTP long term potentiation
  • Computational simulation shows that neurogenesis improves network capacity for new information storage and forgetting of old irrelevant information (Chambers et al. 2004).
  • Increased hippocampal neurogenesis may hence improve learning and adaptive cognitive and emotional responses to novel challenging contexts, whereas reduced neurogenesis might impair ability to cope with stress and be a basis for psychiatric disorders like depression (Chambers et al. 2004).
  • upregulation of BDNF and neurogenesis in the hippocampus and increased response in hippocampus-dependent tasks are important factors in the treatment of depression as hypothesized, Epo seems a promising candidate
  • Epo reduces neuronal response to fear
  • Epo reduces recognition of fear
  • the effects of Epo on neuronal responses during facial expressions processing were accompanied by modest reduction in recognition of fear in a facial expression recognition task after the scan. This is similar to the effects of repeated doses of SSRIs and SNRIs in healthy volunteers (Harmer et al 2004). Behavioral effects may be more difficult to demonstrate in a scanning environment and after repeated exposure to a similar set of images during scanning, so this finding lends important support to the primary neuroimaging outcome measures. Taken together, these results suggest that Epo reduces threat-relevant processing and is a promising agent for the treatment of anxiety and depression. Clinical application of Epo in depressed and anxious patients in combination with conventional antidepressants may represent a multi-mechanism pharmacological treatment approach.
  • Epo modulates neural response during spatial N-back working memory
  • Epo modulated executive function as reflected by a complex up- and down- regulation of neural responses during 2-back spatial working memory.
  • Epo increased response in a right-lateralised fronto-parietal network and reduced activation in the left medial frontal gyrus and bilateral precentral, superior temporal and parietal cortices, cingulate and insula.
  • Compiling neuroimaging evidence suggests a degree of hemisphere domain dominance of spatial and non-spatial working memory. While verbal working memory activates a predominantly left-lateralised fronto-parietal network, spatial working memory recruits more right-hemisphere homologous regions (Prabhakaran et al 2000). Support for such domain dominance in the PFC comes from comparison of two fMRI studies in which verbal and spatial working memory were assessed using physically identical stimuli (Walter et al 2003a). The currently employed n-back task contained manipulation of both letters and spatial locations, of which only the latter were task- relevant. The up-regulation of right-lateralised and down-regulation of left-lateralised fronto-parietal activation by Epo is therefore consistent with enhanced task-relevant strategies. This is noteworthy because schizophrenic patients fail to show such prefrontal domain dominance during verbal versus spatial n-back working memory tasks in contrast with healthy controls (Walter et al 2003b).
  • Epo-treated subjects generated more words to the most difficult letters compared to subjects given placebo, suggesting a facilitating effect of Epo on some aspects of executive function in healthy volunteers.
  • Such effects may again be relevant to drug treatment of psychiatric disorders like schizophrenia and depression since executive dysfunction is believed to be a core deficit in these disorders (Henry and Crawford 2005).
  • Epo alters emotional processing in ways compatible with an antidepressant action in healthy volunteers and indicate that Epo may have clinical effects in patients suffering from anxiety and depression. If a reduction in the processing of negative threat-related information is important in the therapeutic actions of antidepressant drugs as hypothesized (Harmer et al 2004), then Epo may have some potential benefit in these patients.
  • the present study provides novel insights to the effects of Epo on the memory, processing of emotional information, executive function and mood in healthy humans.
  • Epo 40,000 IU
  • Epo enhanced hippocampal response during hippocampus-dependent memory retrieval, reduced the psychological and neural processing of fearful facial expressions in ways consistent with effects of antidepressant drugs, and had beneficial effects on executive function in healthy volunteers.
  • Epo also improved self-reported mood for three days post administration.
  • the present results provide evidence of the suitability of Epo as a neuroprotective and neurotrophic adjunct treatment of depression and anxiety.
  • BA Brodmann area.
  • BA Brodmann area.
  • Table 4 Peak cluster activation in brain regions of significantly increased BOLD response during 2-back spatial working memory vs. control task performance in placebo-treated volunteers (main effect of task) and effects of Epo.
  • BA Brodmann area.
  • Ehrenreich H et al. (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. MoI Med 8:495-505. Ehrenreich et al. (2004) A novel role for an established player: anemia drug erythropoietin for the treatment of cerebral hypoxia/ischemia. Transfus Apher Sci 31:39-44.
  • Harmer et al. (2003 a) Acute SSRI administration affects the processing of social cues in healthy volunteers.
  • Neuropsychopharmacology 28:148-52 Harmer et al. (2003b) Toward a neuropsychological theory of antidepressant drug action: increase in positive emotional bias after potentiation of norepinephrine activity. Am J Psychiatry 160:990-2.
  • Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23:6690-4.
  • Walter et al. (2003 a) Evidence for quantitative domain dominance for verbal and spatial working memory in frontal and parietal cortex. Cortex 39(4-5): 897-911. Walter et al. (2003b) No hypofrontality, but absence of prefrontal lateralization comparing verbal and spatial working memory in schizophrenia. Schizophr Res 61(2- 3):175-84.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Procédé de traitement ou de prévention de la dépression et/ou de l'anxiété, en particulier de la dépression majeure, impliquant l'administration d'érythropoïétine ou d'un de ses dérivés ou analogues.
PCT/GB2006/050457 2005-12-15 2006-12-15 Nouveau traitement Ceased WO2007068983A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0525540.1A GB0525540D0 (en) 2005-12-15 2005-12-15 New treatment
GB0525540.1 2005-12-15

Publications (1)

Publication Number Publication Date
WO2007068983A1 true WO2007068983A1 (fr) 2007-06-21

Family

ID=35736185

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2006/050457 Ceased WO2007068983A1 (fr) 2005-12-15 2006-12-15 Nouveau traitement

Country Status (2)

Country Link
GB (1) GB0525540D0 (fr)
WO (1) WO2007068983A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090267758A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Systems and apparatus for measuring a bioactive agent effect
US9358361B2 (en) 2008-04-24 2016-06-07 The Invention Science Fund I, Llc Methods and systems for presenting a combination treatment
US9449150B2 (en) 2008-04-24 2016-09-20 The Invention Science Fund I, Llc Combination treatment selection methods and systems
US9504788B2 (en) 2008-04-24 2016-11-29 Searete Llc Methods and systems for modifying bioactive agent use
US9662391B2 (en) 2008-04-24 2017-05-30 The Invention Science Fund I Llc Side effect ameliorating combination therapeutic products and systems
CN109816630A (zh) * 2018-12-21 2019-05-28 中国人民解放军战略支援部队信息工程大学 基于迁移学习的fMRI视觉编码模型构建方法
US20230282028A1 (en) * 2022-03-04 2023-09-07 Opsis Pte., Ltd. Method of augmenting a dataset used in facial expression analysis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061164A1 (fr) * 1999-04-13 2000-10-19 Kenneth S. Warren Laboratories Modulation de la fonction d'un tissu excitable par administration peripherique d'une erythropoietine
WO2005084364A2 (fr) * 2004-03-03 2005-09-15 The Kenneth S. Warren Institue, Inc. Cytokines de protection tissulaire a action prolongee pour la protection, la restauration, et l'amelioration de cellules, tissus et organes sensibles

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061164A1 (fr) * 1999-04-13 2000-10-19 Kenneth S. Warren Laboratories Modulation de la fonction d'un tissu excitable par administration peripherique d'une erythropoietine
WO2005084364A2 (fr) * 2004-03-03 2005-09-15 The Kenneth S. Warren Institue, Inc. Cytokines de protection tissulaire a action prolongee pour la protection, la restauration, et l'amelioration de cellules, tissus et organes sensibles

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; October 2003 (2003-10-01), ZHANG WEI-DONG ET AL: "[Studies on sexual dysfunction in male patients with chronic renal insufficiency]", XP002427392, Database accession no. NLM14628593 *
ZHONGHUA NAN KE XUE = NATIONAL JOURNAL OF ANDROLOGY OCT 2003, vol. 9, no. 7, October 2003 (2003-10-01), pages 489 - 493, ISSN: 1009-3591 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090267758A1 (en) * 2008-04-24 2009-10-29 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Systems and apparatus for measuring a bioactive agent effect
US9358361B2 (en) 2008-04-24 2016-06-07 The Invention Science Fund I, Llc Methods and systems for presenting a combination treatment
US9449150B2 (en) 2008-04-24 2016-09-20 The Invention Science Fund I, Llc Combination treatment selection methods and systems
US9504788B2 (en) 2008-04-24 2016-11-29 Searete Llc Methods and systems for modifying bioactive agent use
US9560967B2 (en) * 2008-04-24 2017-02-07 The Invention Science Fund I Llc Systems and apparatus for measuring a bioactive agent effect
US9649469B2 (en) 2008-04-24 2017-05-16 The Invention Science Fund I Llc Methods and systems for presenting a combination treatment
US9662391B2 (en) 2008-04-24 2017-05-30 The Invention Science Fund I Llc Side effect ameliorating combination therapeutic products and systems
US10572629B2 (en) 2008-04-24 2020-02-25 The Invention Science Fund I, Llc Combination treatment selection methods and systems
US10786626B2 (en) 2008-04-24 2020-09-29 The Invention Science Fund I, Llc Methods and systems for modifying bioactive agent use
CN109816630A (zh) * 2018-12-21 2019-05-28 中国人民解放军战略支援部队信息工程大学 基于迁移学习的fMRI视觉编码模型构建方法
US20230282028A1 (en) * 2022-03-04 2023-09-07 Opsis Pte., Ltd. Method of augmenting a dataset used in facial expression analysis
US12142077B2 (en) * 2022-03-04 2024-11-12 Opsis Pte., Ltd. Method of augmenting a dataset used in facial expression analysis

Also Published As

Publication number Publication date
GB0525540D0 (en) 2006-01-25

Similar Documents

Publication Publication Date Title
Schreiner et al. Multi-modal neuroimaging of adolescents with non-suicidal self-injury: Amygdala functional connectivity
Eisenberger et al. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward
Cornblatt et al. Can antidepressants be used to treat the schizophrenia prodrome? Results of a prospective, naturalistic treatment study of adolescents.
Chen et al. Antidepressant and antisuicidal effects of ketamine on the functional connectivity of prefrontal cortex-related circuits in treatment-resistant depression: a double-blind, placebo-controlled, randomized, longitudinal resting fMRI study
Krüger et al. State and trait influences on mood regulation in bipolar disorder: blood flow differences with an acute mood challenge
Goldin et al. Effects of mindfulness-based stress reduction (MBSR) on emotion regulation in social anxiety disorder.
Britton et al. Training-associated changes and stability of attention bias in youth: Implications for Attention Bias Modification Treatment for pediatric anxiety
Yeap et al. Early visual sensory deficits as endophenotypes for schizophrenia: high-density electrical mapping in clinically unaffected first-degree relatives
Müller et al. Contributions of subregions of the prefrontal cortex to working memory: evidence from brain lesions in humans
Park et al. The effects of a virtual reality treatment program for online gaming addiction
Dunn et al. Principal components of the Beck Depression Inventory and regional cerebral metabolism in unipolar and bipolar depression
Reitz et al. Incision and stress regulation in borderline personality disorder: neurobiological mechanisms of self-injurious behaviour
Quintana et al. Right lateral fusiform gyrus dysfunction during facial information processing in schizophrenia
Williamson et al. Brain activation by central command during actual and imagined handgrip under hypnosis
Bremner et al. Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder
Alexopoulos et al. Functional connectivity in apathy of late-life depression: a preliminary study
Pavuluri et al. An fMRI study of the neural correlates of incidental versus directed emotion processing in pediatric bipolar disorder
Reinders et al. Opposite brain emotion-regulation patterns in identity states of dissociative identity disorder: a PET study and neurobiological model
Delaveau et al. Dopaminergic modulation of the default mode network in Parkinson's disease
Giakoumatos et al. Effects of lithium on cortical thickness and hippocampal subfield volumes in psychotic bipolar disorder
Wunderlich et al. Visual hallucinations in recovery from cortical blindness: Imaging correlates
Kohn et al. Neural correlates of effective and ineffective mood induction
Phillipou et al. Resting state functional connectivity in anorexia nervosa
Suslow et al. Affective priming in schizophrenia with and without affective negative symptoms
Miskowiak et al. Effects of erythropoietin on emotional processing biases in patients with major depression: an exploratory fMRI study

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 06820682

Country of ref document: EP

Kind code of ref document: A1