WO2013009183A1 - Procédé de diagnostic pour le diagnostic de dépression et le suivi d'efficacité de traitement - Google Patents

Procédé de diagnostic pour le diagnostic de dépression et le suivi d'efficacité de traitement Download PDF

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Publication number
WO2013009183A1
WO2013009183A1 PCT/NL2012/050505 NL2012050505W WO2013009183A1 WO 2013009183 A1 WO2013009183 A1 WO 2013009183A1 NL 2012050505 W NL2012050505 W NL 2012050505W WO 2013009183 A1 WO2013009183 A1 WO 2013009183A1
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depression
lipocalin
subject
mood disorder
level
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PCT/NL2012/050505
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English (en)
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Eduard Antonius Joannes Arnoldussen
Ulrich Lothar Maria EISEL
Petrus Johan Wichardt NAUDÉ
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Brainlabs B.V.
Rijksuniversiteit Groningen
Academisch Ziekenhuis Groningen
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Publication of WO2013009183A1 publication Critical patent/WO2013009183A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G01N2800/304—Mood disorders, e.g. bipolar, depression
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/56—Staging of a disease; Further complications associated with the disease

Definitions

  • the invention relates to the field of diagnostics, more specifically diagnosis of affective disorders, more specifically diagnosis of depression, by assaying for a psychiatric disease-marker. Further, the invention relates to a method for monitoring the effect of antidepressant therapy, being medication, psychotherapy or a combination of both.
  • BACKGROUND Disorders of the mood are often called affective disorders, since affect is the external display of mood or emotion which is, however, felt internally.
  • Mood disorders are defined as mixtures of symptoms packaged into syndromes. These syndromes are consensus statements from committees writing the nosologies of psychiatric disorders for the Diagnostic and Statistical Manual of Mental Disorders (DSM) of the American
  • Diagnosis both in clinical practice and in clinical research studies is based on these sets of specific signs and symptoms. These criteria have helped distinguish various mood disorders that may have different causes and that certainly require different clinical management.
  • the most common and readily recognised mood disorder is major depression as a single episode or recurrent episodes.
  • Dysthymia is a less severe but often longer-lasting form of depression, i.e. over two years in duration and often unremitting.
  • Another type of mood disorder is bipolar disease, which is characterised by the occurrence of manic episodes besides depression.
  • Depressive disorders are associated with poor work productivity, as indicated by a 3-fold increase in the number of sick days in the month preceding the illness for workers with a depressive illness compared with coworkers who did not have such an illness (Parikh, S.V. et al., 1996, J. Affect. Disord. 38:57-65; Kessler, R.C. et al., 1999, Health Aff. 18:163- 171). Depressive illnesses also affect family members and caregivers (Denihan, A. et al., 1998, Int. J. Geriatr.Psychiatr.
  • depression is the leading cause of disability and premature death among people aged 18 to 44 years, and it is expected to be the second leading cause of disability for people of all ages by 2020 (Murray, C.J. and Lopez, A.D., 1997, The Lancet 349: 1498- 1504; Gredon, J.F., 2001, J. Clin. Psychiatr. 62:26-31).
  • Depressive illnesses have also been shown to be associated with increased rates of death and disability from cardiovascular disease (e.g. Pratt, L.A. et al., 1996, Circulation 94:3123-3129, Bush, D.E. et al., 2001, Am. J. Cardiol. 88:337-341).
  • cardiovascular disease e.g. Pratt, L.A. et al., 1996, Circulation 94:3123-3129, Bush, D.E. et al., 2001, Am. J. Cardiol. 88:337-341).
  • the odds ratio for acute myocardial infarction among the subjects who had a major depressive episode was 4.5 times higher than among those who did not have a depressive episode.
  • MDD major depressive disorder
  • Dysfunctions of monoaminergic systems may have a causal relation with MDD (Ruhe et al., 2007; Nutt et al., 2008).
  • MDD is caused by an impaired monoaminergic neurotransmission, resulting in decreased extracellular norepinephrine (NE) and/or serotonin (5-HT) levels (Schildkraut, 1965; Doris et al., 1999). Diminished concentrations of serotonin and its metabolites have been demonstrated in cerebrospinal fluid (Asberg et al., 1984) and in post mortem brain tissue of depressed patients (Cheethman et al., 1989).
  • MAO-A monoamine oxidase A
  • cytokines may also account for the HPA-axis
  • Cytokines also influence monoaminergic neurotransmission, i.e. serotonin, norepinephrine and dopamine (Linthorst et al, 1995, Merali et al, 1997, Pauli et al, 1998 and Song et al, 1999, 2000; Lacosta et al, 2000). They might also reduce tryptophan (TRP) availability through activation of the TRP- metabolising enzyme indoleamine-2,3-dioxygenase (IDO).
  • TRP tryptophan
  • Characteristics of immune activation in depressive illness include increased serum levels of indicators of activated immune cells (e.g. neopterin, PGE2 and soluble IL-2 receptors), higher serum concentrations of C-Reactive Protein (CRP) as well as increased release of pro-inflammatory cytokines, such as IL-1, IL-2 and IL-6 by activated macrophages and IFN- ⁇ by activated T cells (Maes et al, 1995a,b; Maes, 1999; Irwin, 1999; Nunes et al, 2002).
  • activated immune cells e.g. neopterin, PGE2 and soluble IL-2 receptors
  • CRP C-Reactive Protein
  • PGE-2 prostaglandin E2
  • An in vitro study reports increased PGE2 secretion from lymphocytes of depressed patients compared to healthy controls (Song et al., 1998). Increased PGE2 levels in saliva, serum and cerebrospinal fluid of depressed patients have previously been described (Linnoila et al., 1983; Calabrese et al., 1986; Ohishi et al., 1998; Nishino et al., 1989).
  • COX-2 cyclo-oxygenase
  • Fig. 1 outlines some of the mechanisms underlying thishypothesis (Duman, R.S. et al., 1997, Arch. Gen. Psychiatry 54:597-608; Manji, H.K. et al., 2000, Mol. Psychiatry 5:578-593).
  • cAMP cyclic adenosine 3-5-monophosphate
  • MRI scans of patients with depression have revealed a number of abnormalities in brain structures compared with healthy controls. Despite some inconsistencies, meta-analyses have shown clear evidence for smaller hippocampal volumes and an increased number of hyper-intensive lesions (Videbech et al, 1997, 2004). Furthermore, a series of brain-imaging studies consistently showed reduced neuronal activity in the dorsolateral prefrontal cortex that covaried with the severity of the depression (i.e., the more severe the depression, the larger the prefrontal deficits) (Drevets, W.C., 1998, Ann. Rev. Med. 49:341-361).
  • brain-derived neurotrophic factor (BDNF), the second member of the "neurotrophic" family of neurotrophic factors, was shown to promote survival of a subpopulation of dorsal root ganglion neurons, and subsequently purified from pig brain (Barde, Y.A. et aL, 1982, EMBO J. 1:549-533).
  • BDNF brain-derived neurotrophic factor
  • BDNF brain-derived neurotrophic factor
  • BDNF levels in serum are influenced by various determinants, such as age, sex, smoking status, urbanicity, etc. (Bus, B. et al, 2011,
  • BDNF levels in the serum are unrelated to the clinical features of depression (Molendijk, M. et al, 2010, Mol. Psychiatr. 15: 1-8).
  • BDNF levels in the urine do provide a good indication of depression (WO 2011/002292).
  • the present inventors now have discovered that the level of lipocalin-2, which is detectable in the body fluid of a patient, is indicative of the presence of mood disorders.
  • the invention relates to a method for the diagnosis of a mood disorder comprising:
  • c. diagnose the mood disorder if the concentration of lipocalin-2 is higher than in control healthy subjects.
  • the mood disorder is chosen from depression, schizophrenia, psychosis and anxiety, more preferably the mood disorder is depression, chosen from dysthymia, endogenous depression, reactive depression, minor depression, major depression, psychotic depression, neurotic depression, unipolar depression and bipolar depression, most preferably major depression.
  • the invention comprises a method to determine the influence of antidepressant therapy, being medication, psychotherapy, or a combination of both, in a subject comprising:
  • step c Repeat step a) with regular intervals during said treatment; and d. Register any difference in the concentration of the measured compound in the body fluid.
  • the invention comprises a method to monitor the progress of a mood disorder in a subject comprising performing a method according to the invention. Further, the invention also relates to the use of lipocalin-2 in the diagnosis and monitoring of progression of a mood disorder.
  • Fig. 1 A molecular and cellular model for the action of antidepressant treatments and the pathophysiology of stress-related disorders.
  • This model of the hippocampus shows the major cell types in the hippocampus and how stress and antidepressant treatments may influence CA3 pyramidal cells.
  • the 3 major subfields of the hippocampus (CA3 and CAl pyramidal cells and dentate gyrus granule cells) are connected by the mossy fibre and Schaffer collateral pathways.
  • BDNF brain-derived neurotrophic factor
  • glucocorticoid levels are also known to decrease the survival of these neurons.
  • Other types of neuronal insult such as hypoxia-ischemia, hypoglycaemia, neurotoxins and viral infections, may also cause atrophy or damage of neurons and thereby make a person vulnerable to subsequent insults. These types of interaction may underlie the observations of decreased function and volume of hippocampus in patients with affective disorders and may explain the selective vulnerability of certain people to become depressed.
  • Long-term antidepressant treatments increase the expression of BDNF as well as tyrosine kinase receptor B (trkB) and prevent the down-regulation of BDNF elicited by stress. This may increase the growth or survival of neurons, or help repair or protect neurons from further damage.
  • trkB tyrosine kinase receptor B
  • BDNF and trkB seems to be mediated by the sustained elevation of the serotonin and norepinephrine (NE) systems and the cyclic adenosine monophosphate cascade. Normalization of glucocorticoid levels by long-term antidepressant treatments may also contribute to the recovery of CA3 neurons. (Adapted from Duman et al., supra).
  • Biomarker' is used for a distinctive biological or biologically derived indicator of a process, event or condition.
  • Biomarkers can be used in methods of diagnosis, e.g. clinical screening, and prognosis assessment and in monitoring the results of therapy. They also can be used for identifying patients that are most likely to respond to a certain treatment, for drug screening and for development in medicine. Biomarkers and their uses are therefore valuable for identification of new drug treatments and for discovery of new targets for drug treatment. Further they are valuable for exploring dosage regimes and drug combinations.
  • Lipocalin-2 (LCN-2) is known under many names: siderocalin, a2- microglobulin-related protein, neu-related lipocalin, human neutrophil lipocalin (HNL), 24p3, SIP24 and neutrophil gelatinase-associated lipocalin (NGAL).
  • the Lipocalin family comprises a diverse group of mostly secreted soluble proteins that bind hydrophobic ligands and act as transporters, carrying small molecules to specific cells. Lipocalins are related by possessing an 8-stranded beta-barrel structure.
  • Lipocalin- 1 also named tear lipocalin (TL), von Ebners gland protein (VEG) and tear pre-albumin, binds a large number of hydrophobic molecules and exhibits cysteine proteinase inhibitor and endonuclear activities.
  • Lipocalin-2 is a component of granules in neutrophils from tissues that are normally exposed to microorganisms and is upregulated during inflammation. Lipocalin-2 can form homodimers and can heterodimerize with the neutrophil gelatinase MMP-9.
  • the mature protein consists of a single protein chain of 178 amino acid residues and its molecular mass is 24-25 kDa in its glycosylated state (monomeric form).
  • the protein contains an intrachain disulfide bridge and the human forms contains an additional cysteinyl residue that is thought to participate in the formation of complexes with itself or with neutrophil gelatinase.
  • Lipocalin-2 An important role of Lipocalin-2 in innate immunity is suggested by the demonstration that the protein tightly binds bacterial enterobactin
  • Lipocalin-2 expression further is induced upon activation of Toll-like receptors on immune cells and thus constitutes an acute phase response to infection.
  • Lipocalin-2 has often been suggested and/or used as marker for inflammation- related conditions or diseases. It has been suggested as marker for neutrophil activation, indicating bacterial infection (WO 95/29404). Further it has been proposed as a urinary or blood biomarker for detecting renal tubular cell injury and acute renal failure (US 2004/219603; US 2005/272101; WO 2006/066587). Lipocalin-2 has also been mentioned as biomarker for diagnosing the presence and/or development of cancer. Yang, J. et al. (2009, PNAS 106:3913-3918) mentioned the involvement of lipocalin-2 in breast cancer and evidence for the presence of the compound in lung metastases was shown by Shi, H. et al. (2008, J. Exp. Clin.
  • lipocalin-2 has been named as an adjuvant biomarker for the diagnosis of cervix cancer tissues (Wang, P.H. et al., 2011, Reprod. Sci. 18:447-455).
  • cerebrospinal lipocalin-2 concentration can also serve as a biomarker for Alzheimer's disease and/or other forms of neurodegenerative diseases.
  • the levels of lipocalin-2 in body fluids are also indicative for mood disorders like depression, more specifically major depression disorder.
  • a diagnosis on basis of the level of lipocalin-2 in a body fluid can be performed, e.g. to confirm the suspicion.
  • the body fluid in which lipocalin-2 is measured can be blood (which can be whole blood, serum or plasma), saliva or urine.
  • Body fluid samples can be prepared in the usual way, diluted or concentrated where necessary, and stored as appropriate.
  • the body fluid that is obtained from the patient preferably is peripheral blood serum or urine.
  • urine is preferred, since this can be obtained with the least physical burden for the patient.
  • a special advantage of an assay wherein the detection is performed on a urine sample is that no invasive techniques are necessary to obtain a sample from the patient. In principle, it would even be possible to perform the assay outside a clinical setting, i.e. at the subject's own premises.
  • the lipocalin-2 level in urine there is a difference in the lipocalin-2 level in urine between men and women.
  • the correct control values should be used or the level measured should be compared with a control sample of a healthy person of the same sex and preferably also a similar age.
  • the concentration of the compounds can greatly differ on basis of the amount of water contained in the urine, preferably the ratio of lipocalin-2 with respect to a more or less constant reference compound is used.
  • measurements in urine advantageously the ratio between the compound to be analyzed (in this case lipocalin-2) and creatinine is used. This means that for men the diagnosis that the patient is suffering from a mood disorder
  • lipocalin-2 in the urine corrected for creatinine i.e. lipoclain-2/creatinine ratio
  • lipoclain-2/creatinine ratio a level of lipocalin-2 in the urine corrected for creatinine
  • a diagnosis can be established when the lipocalin-2/creeatinine ratio exceeds 0.4, preferably when it exceeds 0.5, more preferably when it exceeds 0.75, most preferably when it exceeds 1.0.
  • Detection of lipocalin-2 can take place in any manner that would be known to a person of skill in the art.
  • Assay kits for detection of lipocalin-2 in serum
  • these assays can easily be adapted for detection of lipocalin-2 in any body fluid.
  • most of these assays rely on an immunochemical reaction between the lipocalin-2 in the sample and a lipocalin-2- antibody (e.g. detectable through an ELISA assay).
  • the invention is not limited to immunoassays.
  • Analysis of lipocalin-2 in the sample of the patient may be carried out with chemical analytical methods (like mass spectrometry, MALDI-TOF, micro-Raman spectrometry), with magnetic radio imaging, flow cytometric analyses and all other quantitative analysis systems that are suitable for detecting proteins in fluids. Also receptor-based assays, using the lipocalin-2 receptor (24pR3, LRP2, see Devireddy, L.R. et al., 2005, Cell 123:1293-1305; and Hvidberg, V. et al., 2005, FEBS Lett. 579:773-777) as analytical tool may be used.
  • the assays that are useful in the present invention are preferably quantitative assays, in which the concentration of lipocalin-2 in the sample can be determined. This can - in principle - be achieved with all of the above mentioned detection methods. For interpretation of the results of such an assay, various determinants such as sex, age, smoking status, urbanicity, food and alcohol intake should be taken into account, since these factors may affect the lipocalin-2 levels in the blood. Also it should be considered if the patient suffers from one or more of the conditions, which have been indicated to be related with changed lipocalin-2 levels, such as renal failure, cancer and Alzheimer' s disease or any other neurodegenerative disease.
  • the assay when performed on a urine sample, also includes a simultaneous assay for creatinine.
  • Creatinine is one of the byproducts of protein metabolism. Under normal conditions it is present in the blood and is excreted as a final metabolite in the urine.
  • Urine creatinine levels are routinely used as part of kidney function diagnosis. In particular, altered creatinine levels in urine are indicative of kidney diseases such as acute or chronic nephritis, nephrosis, and the like. Because normative values for creatinine excretion have been established, urine creatinine levels are also useful for correction of assays for other compounds, as they document the adequacy of the urine collection for such assays.
  • the creatinine correction can be used to correct for urine dilution, thus giving a possibility to standardize measured concentrations irrespective of the water content of the urine and/or the time of the day when the urine was produced. Further, changes in renal function, which influence rates of excretion, can be corrected by measurement of creatinine in urine. Further, it is also preferred when the diagnosis on basis of lipocalin-2 will be affirmed with the diagnosis on basis of the presence of BDNF. As is shown in WO 2011/002292 the level of BDNF in the urine can be used to diagnose mood disorders, especially depression. Recently, it has been established that serum concentrations of BDNF can, under circumstances, also be used as a marker (Bus, B. et al., 2011, World J. Biol. Psychiatry, early online 1-9, posted online 19 January 2011).
  • the invention provides for a method for diagnosing the presence of a mood disorder in a patient by determining the levels of both lipocalin-2 and BDNF in a body fluid of the patient, preferably wherein said body fluid is urine.
  • a mood disorder generally have a BDNF urine concentration in the range of 100 g/ml to 1600 pg/ml, more specifically 100 pg/ml tot 600 pg/ml, whereas healthy persons have a BDNF urine concentration below 50 pg/ml.
  • the assay for BDNF when used in conjunction with the assay for lipocalin-2 increases the diagnostic performance of the lipocalin-2 assay.
  • the assay for BDNF can be performed as described in the Examples of WO 2011/002292 or in any other way as will be known to the skilled person.
  • detection and/or quantification of both biomarkers may be performed using an immunological method, involving an antibody, or fragment thereof, capable of specific binding to the biomarker.
  • immunological methods include sandwich immunoassays, such as sandwich ELISA, in which the detection of the biomarkers is performed using two antibodies which recognize different epitopes on the biomarker;
  • RIA radioimmunoassay
  • ELISA enzyme immunoassays
  • FIA fluorescence immunoassays
  • chemiluminescent immunoassays western blotting, immunoprecipitation and any particle based immunoassay (e.g. using gold, silver or latex particles, magnetic particles, or Q-dots).
  • Immunological methods may for example be performed on a microtitre plate or on test strips. It is also possible to perform the analysis with concurrent lab-on-a-chip techniques. For both markers commercial immunoassays are available. These markers can all be assayed in the same body fluid (e.g.
  • biomarkers one type of body fluid is preferred (e.g. BDNF is preferably measured in a urine sample).
  • BDNF body fluid
  • if two or more markers are tested it can be the case that one marker is tested in the blood and the other marker is tested in the urine. While interpreting the results of such an assay, various determinants such as sex, age, smoking status, urbanicity, food and alcohol intake should be taken into account.
  • a panel of both lipocalin-2 and BDNF as markers will be provided in an assay for the diagnosis of a mood disorder, preferably depression, in a patient.
  • both markers can be used to affirm a diagnosis based on any other diagnostic tool (such as personal communications, cognitive testes, etc.).
  • the biomarkers lipocalin-2 and BDNF may be replaced by a molecule, or a measurable fragment of the molecule, found upstream or downstream of the biomarker in a biological pathway.
  • the biomarkers of the present invention or their replacement molecule(s) are recognised by 'biosensors', which may comprise a ligand or ligands capable of specific binding to the biomarker.
  • Such biosensors are useful in detecting and/or quantifying the biomarker, preferably in quantifying.
  • Especially useful biosensors are antibodies.
  • the term 'antibody' as used herein may comprise polyclonal, monoclonal, bispecific, humanised or chimeric antibodies, single chain antibodies, Fab fragments and F(ab')2 fragments, fragments produced by a Fab expression library, anti-idiotypic antibodies and epitope-binding fragments.
  • the term 'antibody' also refers to immunoglobulin and T-cell receptor molecules, i.e. molecules that contain an antigen-binding site that specifically binds an antigen.
  • the immunoglobulin molecules can be of any class (e.g. IgA, IgD, IgE, IgG and IgM) or subclasses thereof.
  • biomarkers that are specific for a mood disorder, especially depression and more particularly major depressive disorder is key to integration of diagnostic procedures and therapeutic regimes.
  • Appropriate diagnostic tools such as biosensors can be developed in methods and uses of the invention; and detection and quantification of the biomarker can be performed using a biosensor in a microanalytical system, a microengineered system, a microsepration system, an immunochromatography system or other suitable analytical devices (such as Raman or mass spectrography and the like).
  • the biosensor may be incorporated in an immunological method for detection of the biomarker(s), or via electrical, thermal, magnetic, optical (e.g. hologram) or acoustic technologies. Using these techniques, it is possible to detect the target biomarker(s) at the anticipated concentrations found in biological samples.
  • an apparatus for diagnosing or monitoring a mood disorder, especially depression and more particularly major depressive disorder which comprises a biosensor in a microanalytical, microengineered, microseparation and/or
  • immunochromatography system configured to detect and/or quantify the biomarkers lipocalin-2 and/or BDNF.
  • the biomarker(s) of the invention can be detected using a biosensor
  • a holographic image is stored in a thin polymer film that is sensitized to react specifically with the biomarker.
  • the biomarker reacts with the polymer leading to an alteration in the image displayed by the hologram.
  • the test result read-out can be a change in the optical brightness, image, color and/or position of the image.
  • a sensor hologram can be read by eye, thus removing the need for detection equipment.
  • a simple color sensor can be used to read the signal when quantitative measurements are required. Opacity or color of the sample does not interfere with operation of the sensor.
  • the format of the sensor allows multiplexing for simultaneous detection of several substances. Reversible and irreversible sensors can be designed to meet different requirements, and continuous monitoring of a particular biomarker of interest is feasible.
  • methods for detection the biomarkers according to the invention combine biomolecular recognition with appropriate means to convert detection of the presence or quantity of the biomarker in the sample into a signal.
  • Biosensors to detect the biomarkers can also be detected by acoustic, plasmon resonance, holographic and microengineered sensors. Imprinted recognition elements, thin film transistor technology, magnetic acoustic resonator devices and other novel acousto-electrical systems may be employed for detection of the one or more biomarkers of the invention. Methods involving detection and/or quantification of the biomarkers of the invention can be performed on bench-top instruments, or can be incorporated onto disposable, diagnostic or monitoring platforms that can be used in a non- laboratory environment, e.g . in the physician's office or at the patient's bedside. Suitable platforms for performing methods of the invention include "credit" cards with optical or acoustic readers.
  • the sensor systems can be configured to allow the data collected to be electronically transmitted to the physician for interpretation and thus can form the basis for remote diagnosis.
  • Methods of the invention can be performed in array format, e.g. on a chip, or as a multiwell array. This enables testing for several biomarkers or for only one biomarker in multiple subjects or samples simultaneously. Methods can be adapted into platforms for single tests, or multiple identical or multiple non- identical tests, and can be performed in high throughput format. Methods of the invention may comprise performing one or more additional, different tests to confirm or exclude diagnosis, and/or to further characterize a condition.
  • kits for diagnosing or monitoring a mood disorder, especially depression and more particularly major depressive disorder, or predisposition thereto is provided.
  • a kit according to the invention may contain one or more components selected from the group: a biosensor specific for the biomarker or a molecule upstream or downstream in the biological pathway for that biomarker, where the biomarker is lipocalin-2 or BDNF; one or more controls; one or more reagents and one or more consumables; optionally together with instructions for use of the kit in accordance with any of the methods defined herein.
  • biomarkers for mood disorders especially depression and more particularly major depressive disorder permits integration of diagnostic procedures and therapeutic regimes.
  • effectiveness of drug treatment or psychotherapy is difficult to test, and it has thus far not been possible to perform rapid assessment of therapy response.
  • many anti- depressant therapies require treatment lasting weeks to months for a given therapeutic approach.
  • Detection of a biomarker of the invention can be used to screen subjects prior to their participation in clinical trials.
  • the biomarkers provide the means to indicate therapeutic response, failure to respond, unfavorable side-effect profile, and degree of medication compliance.
  • the biomarkers may be used to stop treatment in non-responders at a very early stage. They can also be used to fine-tune dosage, minimize the number of prescribed medications, and to reduce the delay in attaining effective therapy.
  • patient care can be tailored precisely to match the needs determined by the disorder and the
  • the biomarker can thus be used to titrate the optimal dose and to identify a positive therapeutic response.
  • Biomarker-based tests provide a first line assessment of 'new' patients, and provide objective measures for accurate and rapid diagnosis, in a time frame and with precision, not achievable using the current subjective measures. Furthermore, diagnostic biomarker tests are useful to identify family members of patients at high risk of developing a mood disorder such as depression and more particularly major depressive disorder. This permits initiation of appropriate therapy, or preventive measures, e.g. managing risk factors. These approaches are recognized to improve outcome and may prevent overt onset of the disorder. Biomarker monitoring methods, biosensors and kits are also vital as patient monitoring tools. If pharmacological treatment is assessed to be inadequate, then therapy can be reinstated or increased; a change in therapy can be given if appropriate. As the biomarkers are sensitive to the state of the disorder, they provide an indication of the impact of drug therapy.
  • a method of diagnosis or monitoring the biomarkers may comprise quantifying the biomarker in a sample from the patient and comparing the level of the biomarker present in said sample with one or more controls.
  • the control may be a test sample of the same patient at an earlier point in time.
  • the diagnosis for the presence of a mood disorder in a patient according to the present invention is used to confirm a suspicion of a mood disorder, such as depression and more particularly major depression disorder.
  • a mood disorder such as depression and more particularly major depression disorder.
  • the patient is already suspected of having a mood disorder at the moment that de the assay for measuring the level of lipocalin-2 is performed.
  • lipocalin-2 is also useful as a biomarker in other disease, such as cancer end renal failure.
  • the invention can be considered as a method for enhancing the diagnosis of depression.
  • the lipocalin-2 values for a subject are determined at a certain moment (null-value) and after an amount of time this procedure is repeated. Over the time, several repeat measurements can be performed. In the mean time therapy can e.g. be started or changed.
  • the time elapsed between taking samples from a subject undergoing monitoring will be several days, a week, two weeks, a month, several months or longer.
  • Samples may be taken prior to and/or during and/or following antidepressant therapy.
  • Samples can be taken at intervals over the remaining life, or a part thereof, of a patient.
  • the lipocalin-2 assay can be complemented with an assay for BDNF.
  • an assay for BDNF As has been described in WO 2011/002292, especially the level of BDNF in urine can be used to monitor progress of disease and therapy.
  • Lipocalin-2 is indicative of depression.
  • Urine samples were collected from both MD patients and healthy individuals. All subjects provided informed consent prior to participation. The urine samples were stored at 4°C. For quantifying lipocalin-2 in the urine samples, an ELISA test was used, which was based on a protocol provided by R&D Systems (Minneapolis, MN):
  • wash Buffer Aspirate each well and wash with Wash Buffer, repeating the process two times for a total of three washes. Wash by filling each well with Wash Buffer (200 ⁇ ) using a manifold dispenser. Complete removal of liquid at each step is essential for good performance. After the last wash, remove any remaining Wash Buffer by aspirating or by inverting the plate and blotting it against clean paper towels.
  • dilute recombinant human Lcn2 to a concentration of 5000 pg/ml. Add 200 ⁇ to row A of colums 1 and 2. Add 100 microliter to row B-H of columns 1 and 2. Perform six 1 :2 serial dilutions. Do not add Lcn2 to row H! ! !
  • Dilution of the samples depends on expected Lcn2 levels in these samples.

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  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

La présente invention concerne un procédé de diagnostic ou de suivi de la progression d'un trouble de l'humeur, par le dosage biologique du niveau de la lipocaline-2 dans le liquide organique d'un sujet. De préférence ledit trouble de l'humeur est la dépression, parmi le groupe constitué de la dysthymie, la dépression endogène, la dépression mineure, la dépression majeure, la dépression psychotique, la dépression nerveuse, la dépression postnatale, le syndrome d'épuisement professionnel, la fatigue excessive, la dépression unipolaire et la dépression bipolaire. L'invention concerne également une détection combinée de la lipocaline-2 et le facteur neurotrophique dérivé du cerveau (BNDF) pour un procédé selon l'invention.
PCT/NL2012/050505 2011-07-14 2012-07-13 Procédé de diagnostic pour le diagnostic de dépression et le suivi d'efficacité de traitement WO2013009183A1 (fr)

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US201161507869P 2011-07-14 2011-07-14
NL2007112A NL2007112C2 (en) 2011-07-14 2011-07-14 Novel diagnostic method for diagnosing depression and monitoring therapy effectiveness.
NL2007112 2011-07-14
US61/507,869 2011-07-14

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WO2014120010A1 (fr) * 2013-01-31 2014-08-07 Brainlabs B.V. Nouveau procédé diagnostique pour diagnostiquer la dépression et surveiller l'efficacité d'une thérapie
WO2016112467A1 (fr) * 2015-01-15 2016-07-21 Centre For Addiction And Mental Health Mesure périphérique d'une inflammation cérébrale centrale, ses marqueurs et ses utilisations
NL1041151A (nl) * 2015-01-21 2016-09-27 Maria Johanna Kousemaker Dr Diagnostiek van burnout en/of overtraining bij zoogdieren (inclusief de mens) middels een miRNA-profiel in lichaamsvloeistofen.
WO2019008987A1 (fr) * 2017-07-07 2019-01-10 パナソニックＩｐマネジメント株式会社 Dispositif de fourniture d'informations, système de traitement d'informations, terminal d'informations et procédé de traitement d'informations
WO2023052261A1 (fr) * 2021-09-28 2023-04-06 Société des Produits Nestlé S.A. Procédé pour détecter et/ou quantifier un trouble de l'humeur et/ou des améliorations de l'état d'un trouble de l'humeur à l'aide de trigonelline en tant que biomarqueur et procédés améliorés et compositions associées

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014120010A1 (fr) * 2013-01-31 2014-08-07 Brainlabs B.V. Nouveau procédé diagnostique pour diagnostiquer la dépression et surveiller l'efficacité d'une thérapie
CN105228521A (zh) * 2013-01-31 2016-01-06 布雷恩勒布斯有限公司 诊断抑郁症和监控治疗效果的新的诊断方法
US10151761B2 (en) 2013-01-31 2018-12-11 Brainlabs B.V. Diagnostic method for diagnosing depression and monitoring therapy effectiveness
WO2016112467A1 (fr) * 2015-01-15 2016-07-21 Centre For Addiction And Mental Health Mesure périphérique d'une inflammation cérébrale centrale, ses marqueurs et ses utilisations
US10302625B2 (en) 2015-01-15 2019-05-28 Centre For Addiction And Mental Health Peripheral measure of central brain inflammation, markers therefor and uses thereof
NL1041151A (nl) * 2015-01-21 2016-09-27 Maria Johanna Kousemaker Dr Diagnostiek van burnout en/of overtraining bij zoogdieren (inclusief de mens) middels een miRNA-profiel in lichaamsvloeistofen.
WO2019008987A1 (fr) * 2017-07-07 2019-01-10 パナソニックＩｐマネジメント株式会社 Dispositif de fourniture d'informations, système de traitement d'informations, terminal d'informations et procédé de traitement d'informations
JPWO2019008987A1 (ja) * 2017-07-07 2020-05-07 パナソニックＩｐマネジメント株式会社 情報提供方法、情報処理システム、情報端末、及び情報処理方法
JP7170250B2 (ja) 2017-07-07 2022-11-14 パナソニックＩｐマネジメント株式会社 情報提供方法、情報処理システム、及び情報処理方法
WO2023052261A1 (fr) * 2021-09-28 2023-04-06 Société des Produits Nestlé S.A. Procédé pour détecter et/ou quantifier un trouble de l'humeur et/ou des améliorations de l'état d'un trouble de l'humeur à l'aide de trigonelline en tant que biomarqueur et procédés améliorés et compositions associées

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