阅读说明：本技术 精神疾病的判断方法 (Method for judging mental disease ) 是由 斋藤邦明 山本康子 于 2019-03-18 设计创作，主要内容包括：本发明提供一种准确度(正确度、精度)高的抑郁性障碍、双相型障碍、精神分裂症、痴呆症等精神疾病的判断方法,本发明还涉及精神疾病的判断方法、精神疾病判断用标记物等。(The present invention provides a method for determining a psychiatric disorder such as depressive disorder, bipolar disorder, schizophrenia or dementia with high accuracy (accuracy, precision), a method for determining a psychiatric disorder, a marker for determining a psychiatric disorder, or the like.)

1. A method for judging a mental disease, comprising the following steps 1 to 3,

step 1: measuring the amount of anthranilic acid in the sample (A) and the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid in the sample (B),

and a step 2: calculating i) the ratio ((A)/(B)) of the amount of anthranilic acid (A) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B), or ii) the ratio ((B)/(A)) of the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B) to the amount of anthranilic acid (A),

step 3: the mental disease is judged based on the calculation result of the step 2.

2. The method according to claim 1, wherein the step 2 is a step of calculating i) a ratio ((A)/(B)) of the amount of anthranilic acid (A) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B).

3. The judging method according to claim 1, wherein the step 2 is a step of calculating a ratio of the amount of anthranilic acid to the amount of kynurenine or 3-hydroxyanthranilic acid.

4. The method according to claim 1, wherein the psychiatric disorder is depressive disorder, bipolar disorder, schizophrenia or dementia.

5. The method of claim 1, wherein the psychiatric disorder is depressive disorder.

6. The method according to claim 1, wherein the sample is serum, plasma, whole blood, urine or cerebrospinal fluid.

7. A method for acquiring data for judging mental diseases, characterized by comprising the following steps 1 and 2,

step 1: measuring the amount of anthranilic acid in the sample (A) and the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid in the sample (B),

and a step 2: calculating i) the ratio ((A)/(B)) of the amount of anthranilic acid (A) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B), or ii) the ratio ((B)/(A)) of the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B) to the amount of anthranilic acid (A).

8. The method for acquiring data according to claim 7, wherein the step 2 is a step of calculating i) a ratio ((a)/(B)) of the amount of anthranilic acid (a) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B).

9. The method of acquiring data as claimed in claim 7, wherein the process 2 is a process of calculating a ratio of the amount of anthranilic acid with respect to the amount of kynurenine or 3-hydroxyanthranilic acid.

10. A method of acquiring data as claimed in claim 7 wherein the psychiatric disorder is depressive disorder, bipolar disorder, schizophrenia or dementia.

11. A method of acquiring data as claimed in claim 7 wherein the psychiatric disorder is depressive disorder.

12. The method of obtaining data according to claim 7 wherein the sample is serum, plasma, whole blood, urine or cerebrospinal fluid.

13. A marker for judging mental disease, which comprises anthranilic acid and tryptophan, kynurenine or 3-hydroxyanthranilic acid.

Technical Field

The present invention relates to a method for determining a psychiatric disorder such as depressive disorder, bipolar disorder, schizophrenia, dementia, and the like.

Background

In modern society, mental diseases such as depressive disorder, bipolar disorder, schizophrenia and dementia have become social problems. According to the survey of the university of japan's university of great birth in 2011 (23 years), the number of people suffering from mental diseases reaches 320 thousands. Furthermore, mental diseases frequently occur in the so-called production age group of 15 to 65 years, which leads to economic loss due to labor reduction and the like, and the influence on the society is immeasurable. In particular, depressive disorders characterized by symptoms such as depression, decreased mental activity, loss of appetite, insomnia, and the like account for a high proportion of the above-mentioned mental diseases. Also, depressive disorder has recently become a leading cause of suicide, etc., and has formed a great social problem.

At present, diagnosis of mental diseases is performed based on subjective information of patients obtained by an inquiry, and thus it is difficult to perform diagnosis with high accuracy (accuracy, precision). In view of this, development of a diagnostic method for mental diseases with high accuracy (accuracy, precision) using objective indices (markers and the like) is required. Hitherto, various diagnostic methods for mental diseases using the above objective indices (markers, etc.) have been reported. For example, there is a method of detecting a marker, which is tryptophan in blood or a metabolite thereof (patent document 1, non-patent documents 1 to 2). However, none of the above methods has been put to practical use.

Disclosure of Invention

Problems to be solved by the invention

The purpose of the present invention is to provide a method for judging a psychiatric disease such as depressive disorder, bipolar disorder, schizophrenia, dementia, etc., which has high accuracy (accuracy, precision).

Means for solving the problems

In order to solve the above problems, the present invention is configured as follows.

1. A method for judging a mental disease, comprising the following steps 1 to 3,

step 1: measuring the amount of anthranilic acid in the sample (A) and the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid in the sample (B),

and a step 2: calculating i) the ratio ((A)/(B)) of the amount of anthranilic acid (A) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B), or ii) the ratio ((B)/(A)) of the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B) to the amount of anthranilic acid (A),

step 3: the mental disease is judged based on the calculation result of the step 2.

2. The determination method as described in the above 1, wherein the step 2 is a step of calculating i) a ratio ((A)/(B)) of the amount of anthranilic acid (A) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B).

3. The method of judging as described in the above 1 or 2, wherein the step 2 is a step of calculating a ratio of the amount of anthranilic acid to the amount of kynurenine or 3-hydroxyanthranilic acid.

4. The method according to any one of 1 to 3, wherein the psychiatric disorder is depressive disorder, bipolar disorder, schizophrenia or dementia.

5. The method according to any one of 1 to 4, wherein the mental disease is depressive disorder.

6. The method according to any one of the above 1 to 5, wherein the sample is serum, plasma, whole blood, urine or cerebrospinal fluid.

7. A method for acquiring data for judging mental diseases, the method for acquiring data comprising the following steps 1 and 2,

step 1: measuring the amount of anthranilic acid in the sample (A) and the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid in the sample (B),

and a step 2: calculating i) the ratio ((A)/(B)) of the amount of anthranilic acid (A) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B), or ii) the ratio ((B)/(A)) of the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B) to the amount of anthranilic acid (A).

8. The method of obtaining data as described in the above 7, wherein the step 2 is a step of calculating i) a ratio ((a)/(B)) of the amount of anthranilic acid (a) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B).

9. The method for acquiring data as described in the above 7 or 8, wherein the step 2 is a step of calculating a ratio of the amount of anthranilic acid to the amount of kynurenine or 3-hydroxyanthranilic acid.

10. The method for acquiring data according to any one of the above 7 to 9, wherein the mental disease is depressive disorder, bipolar disorder, schizophrenia or dementia.

11. The method for acquiring data as set forth in any one of the above 7-10, wherein the mental disease is depressive disorder.

12. The method for obtaining data according to any one of the above 7 to 11, wherein the sample is serum, plasma, whole blood, urine or cerebrospinal fluid.

13. A marker for judging mental disease, which comprises anthranilic acid and tryptophan, kynurenine or 3-hydroxyanthranilic acid.

ADVANTAGEOUS EFFECTS OF INVENTION

The method for determining a psychiatric disease and the marker for determining a psychiatric disease according to the present invention can be used for determining (diagnosing and examining) a psychiatric disease such as depressive disorder, bipolar disorder, schizophrenia, dementia, and the like, with high accuracy (accuracy and precision). Further, according to the method for acquiring data for determining mental diseases of the present invention, data for determining mental diseases such as depressive disorder, bipolar disorder, schizophrenia, dementia, and the like with high accuracy can be obtained.

Detailed Description

< method for determining mental diseases according to the present invention >

The method for determining mental disorders according to the present invention (hereinafter, also simply referred to as "the method for determining the present invention") is characterized by comprising the following steps 1 to 3,

step 1: measuring the amount of anthranilic acid in the sample (A) and the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid in the sample (B),

and a step 2: calculating i) the ratio ((A)/(B)) of the amount of anthranilic acid (A) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B), or ii) the ratio ((B)/(A)) of the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B) to the amount of anthranilic acid (A),

step 3: the mental disease is judged based on the calculation result of the step 2.

Mental disease

The present invention relates to a psychiatric disorder in which a depressive state is maintained, specifically, depressive disorder, bipolar disorder, schizophrenia, dementia, Alzheimer's disease, anxiety disorder, epilepsy, and the like. Among them, the judgment method of the present invention is suitable for depressive disorder, bipolar disorder, schizophrenia or dementia, particularly for depressive disorder. The depressive disorder is a kind of mood disorder, and is characterized by symptoms such as depression, decreased mental activity, loss of appetite, and insomnia. Also, the depressive disorders include major depressive disorder and mood disorder.

Test specimen

The sample of the present invention may be derived from an animal to be tested, and examples thereof include a sample derived from a living organism such as serum, plasma, whole blood, urine, saliva, cerebrospinal fluid, interstitial fluid, sweat, tear fluid, amniotic fluid, medullary fluid, pleural effusion, ascites, indirect fluid, aqueous humor, and vitreous humor, preferably a sample derived from blood such as serum, plasma, and whole blood, more preferably a sample derived from blood such as serum, plasma, and whole blood, and most preferably serum.

The animal to be tested may be a mammal such as a human, monkey, mouse, rat, dog, cat, pig, rabbit, etc., preferably a human, monkey, mouse or rat, more preferably a human.

The method for obtaining (collecting) the sample of the present invention from the animal to be tested is not particularly limited, and for example, the sample may be obtained (collected) from the animal to be tested by a method known per se, and if necessary, the sample may be separated, concentrated, purified, or the like by a method known per se.

The sample may be a sample just collected from the test animal or may be a stored sample. The method for storing the sample may be a method generally used in this field.

Step 1

Step 1 of the present invention is a step of measuring the amount of anthranilic acid in a sample and the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid in a sample.

Tryptophan in the process 1 of the present invention is one of the amino acids and is known to be substituted for 90% by the kynurenine pathway. In the step 1 of the present invention, anthranilic acid, kynurenine, and 3-hydroxyanthranilic acid are each one of amino acids, and are metabolites of tryptophan produced in the pathway of tryptophan, i.e., the kynurenine pathway.

The following structural formulae of anthranilic acid (structural formula 1), tryptophan (structural formula 2), kynurenine (structural formula 3) and 3-hydroxyanthranilic acid (structural formula 4) are shown, respectively.

In step 1 of the present invention, the method for measuring the amount of anthranilic acid, the amount of tryptophan, the amount of kynurenine or the amount of 3-hydroxyanthranilic acid may be a method generally used in the art, and specifically, a method using a mass spectrometer, an immunological measurement method, a method using NMR analysis, a method using an amino acid analyzer, FACS analysis or the like may be mentioned, and a method using a mass spectrometer or an immunological measurement method is preferable.

When the amount of anthranilic acid, the amount of tryptophan, the amount of kynurenine or the amount of 3-hydroxyanthranilic acid is measured by the method using the mass spectrometer described above, the measurement can be carried out by injecting a mobile phase (an organic solvent-based mobile phase such as acetonitrile, methanol, tetrahydrofuran, isopropanol or ethanol, and an aqueous mobile phase such as water, phosphoric acid, formic acid or acetic acid) and a sample into a device equipped with a chromatography column (an ODS (octadecylsilyl) column or the like) or a detector (a fluorescence detector, an electrochemical detector, an ultraviolet-visible light photodetector or the like), and then separating and detecting anthranilic acid and tryptophan, kynurenine or 3-hydroxyanthranilic acid. Further, a specific method of using the mass spectrometer can be performed based on a method known per se.

Specific examples of the method using the mass spectrometer include a method using High Performance Liquid Chromatography (HPLC), a method using Gas Chromatography (GC), a method using liquid chromatography-mass spectrometer (LC/MS), and a method using capillary electrophoresis-mass spectrometer (CE/MS), a method using a gas chromatography-mass spectrometer (GC/MS), a method using an inductively coupled plasma spectroscopy-mass spectrometer (ICP/MS), a method using a liquid chromatography-tandem mass spectrometer (LC/MS), a method using a gas chromatography-tandem mass spectrometer (GC/MS), and the like, preferably a method using High Performance Liquid Chromatography (HPLC) or a method using a liquid chromatography-tandem mass spectrometer (LC/MS), more preferably a method using High Performance Liquid Chromatography (HPLC).

When the amount of anthranilic acid and the amount of tryptophan, the amount of kynurenine or the amount of 3-hydroxyanthranilic acid are determined by the above-mentioned immunological determination method, by using a substance having affinity for anthranilic acid and a substance having affinity for tryptophan, a substance having affinity for kynurenine or a substance having affinity for 3-hydroxyanthranilic acid, a complex of anthranilic acid and a substance having affinity for anthranilic acid, and a complex of tryptophan and a substance having affinity for tryptophan, a complex of kynurenine and a substance having affinity for kynurenine or a complex of 3-hydroxyanthranilic acid and a substance having affinity for 3-hydroxyanthranilic acid are formed, respectively, to determine the complexes.

The specific method for the immunological measurement can be performed by a method known per se.

Examples of the Immunoassay method include enzyme-linked immunosorbent Assay (ELISA method), enzyme Immunoassay (EIA method), radioimmunoassay (RIA method), fluorescence Immunoassay (FIA method), chemiluminescence enzyme Immunoassay (CLEIA method), electrochemiluminescence Immunoassay (eclei method), turbidimetric Immunoassay, immunonephelometry, latex agglutination, immunochromatography, western blotting, chemiluminescence oxygen channel Immunoassay (LOCI Immunoassay), Liquid phase binding-electrically driven Transport Assay (Liquid-phase binding Assay-ElectroKinetic Assay, LBA-EATA), and the like, and preferably enzyme-linked immunosorbent Assay (ELISA method), enzyme Immunoassay (EIA method), radioimmunoassay (RIA method), fluorescence Immunoassay (FIA method), chemiluminescence enzyme Immunoassay (CLEIA method), and the like, Electrochemiluminescence immunoassay (ECLEIA method), immunoturbidimetry, latex agglutination or immunochromatography.

The substance having affinity for anthranilic acid, tryptophan, kynurenine and 3-hydroxyanthranilic acid include, specifically, antibodies, lectins, polysaccharides, DNA, enzyme substrates, proteins, various receptors and various ligands, and preferably antibodies such as an anti-anthranilic acid antibody, an anti-tryptophan antibody, an anti-kynurenine antibody and an anti-3-hydroxyanthranilic acid antibody.

The anti-anthranilic acid antibody, anti-tryptophan antibody, anti-kynurenine antibody and anti-3-hydroxyanthranilic acid antibody may be antibodies that specifically recognize anthranilic acid, tryptophan, kynurenine and 3-hydroxyanthranilic acid, respectively. The antibody may be either a polyclonal antibody or a monoclonal antibody, and may be used alone or in combination. The antibody may be an antibody fragment such as Fab, F (ab' 2), Fv or sFv, or a synthetic antibody such as a diabody, a triabody or a tetrabody. The antibody may be a commercially available antibody or an antibody prepared by a method known per se.

In addition, the preparation of the anti-anthranilic acid antibody, anti-tryptophan antibody, anti-kynurenine antibody and anti-3-hydroxyanthranilic acid antibody can be carried out by a method known per se, for example, by the method described in "immunoassay" (written by society for biochemical assays, lecture, 2014) or Japanese patent application laid-open No. 2018-501202.

Furthermore, the above-mentioned anti-anthranilic acid antibody, anti-tryptophan antibody, anti-kynurenine antibody and anti-3-hydroxyanthranilic acid antibody may be labeled with a label.

Specific examples of the labeling substance include enzymes such as horseradish peroxidase (HRP), bovine small intestine alkaline phosphatase, and beta-galactosidase,^99mTc、¹³¹I、¹²⁵I、¹⁴C、³H、³²P、³⁵radioisotopes such as S, fluorescent substances such as fluorescein, Fluorescein Isothiocyanate (FITC), 4-methylumbelliferone, rhodamine, and derivatives thereof, luminescent substances such as fluorescein, luminol, and ruthenium complexes, substances having an absorbing property in the ultraviolet region such as phenol, naphthol, anthracene, and derivatives thereof, substances having a property as a spin label represented by a compound having an oxygen group such as 4-amino-2, 2,6, 6-tetramethylpiperidine-1-oxy group, pigments such as a HiLyte-based pigment, an Alexa-based pigment, and a CyDye-based pigment, nanoparticles such as a gold colloid and a quantum dot, and the like.

Further, as a method for binding the above-mentioned marker to the above-mentioned anti-anthranilic acid antibody, anti-tryptophan antibody, anti-kynurenine antibody and anti-3-hydroxyanthranilic acid antibody, a method known per se may be used. The "amount" in the amount of anthranilic acid, tryptophan, kynurenine or 3-hydroxyanthranilic acid may be any of the absolute values of volume, mass, etc., or the relative values of concentration, ionic strength, absorbance, fluorescence strength, turbidity, etc., preferably the relative values of concentration, ionic strength, absorbance, fluorescence strength, turbidity, etc., more preferably the concentration.

In step 1 of the present invention, the reagent for measuring the amount of anthranilic acid, the amount of tryptophan, the amount of kynurenine or the amount of 3-hydroxyanthranilic acid is a reagent generally used in this field, and the concentration and pH thereof are also within the range generally used in the art. The conditions and operation method of the apparatus may be those generally used in the art.

In the step 1 of the present invention, the amount of anthranilic acid and the amount of kynurenine or the amount of 3-hydroxyanthranilic acid are preferably measured, and the amount of anthranilic acid and the amount of 3-hydroxyanthranilic acid are more preferably measured.

Step 2

The step 2 of the present invention is a step of calculating i) a ratio of the amount of anthranilic acid to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid, or ii) a ratio of the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid to the amount of anthranilic acid.

Specifically, the step 2 of the present invention is a calculation process of i) dividing the amount of anthranilic acid obtained in the step 1 of the present invention by the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid obtained in the step 1 of the present invention, or ii) dividing the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid obtained in the step 1 of the present invention by the amount of anthranilic acid obtained in the step 1 of the present invention.

In the step 2 of the present invention, the ratio of the amount of anthranilic acid to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid is preferably calculated, more preferably the ratio of the amount of anthranilic acid to the amount of kynurenine or 3-hydroxyanthranilic acid is calculated, and particularly preferably the ratio of the amount of anthranilic acid to the amount of 3-hydroxyanthranilic acid is calculated.

Step 3

Step 3 of the present invention is a step of determining a mental disease based on the calculation result of step 2 of the present invention. Specifically, step 3 of the present invention is performed using a value obtained by the steps 1 and 2 of the present invention using a sample derived from a test animal (hereinafter, also simply referred to as "value derived from a test animal"), and a preset reference value (such as a cutoff value). That is, i) when the value derived from the animal to be tested is equal to or greater than a predetermined reference value (such as a cutoff value), it can be determined that "the animal to be tested has a possibility of suffering from a mental disease or the animal to be tested has a high possibility of suffering from a mental disease" or the like, and ii) when the value derived from the animal to be tested is smaller than a predetermined reference value (such as a cutoff value), it can be determined that "the animal to be tested does not have a possibility of suffering from a mental disease or the animal to be tested has a low possibility of suffering from a mental disease" or the like.

In another embodiment, i) when the value derived from the animal to be tested is equal to or less than a predetermined reference value (e.g., a cutoff value), it may be determined that "the animal to be tested has a possibility of suffering from a mental disease or the animal to be tested has a high possibility of suffering from a mental disease", or the like, and ii) when the value derived from the animal to be tested exceeds the predetermined reference value (e.g., a cutoff value), it may be determined that "the animal to be tested does not have a possibility of suffering from a mental disease or the animal to be tested has a low possibility of suffering from a mental disease" or the like.

The reference value (e.g., cutoff value) may be determined based on statistical analysis such as roc (receiver Operating characterization) curve analysis, using a sample derived from an animal suffering from a mental disease and obtained through the steps 1 and 2 of the present invention, or using a sample derived from a healthy animal and obtained through the steps 1 and 2 of the present invention. The sensitivity and/or specificity of the reference value (e.g., cut-off value) is, for example, 60% or more, preferably 70% or more, more preferably 80% or more, still more preferably 90% or more, and particularly preferably 95% or more.

< specific example of the judging method of the present invention >

Hereinafter, a specific example of the determination method of the present invention will be described.

1) Process 1 of the present invention

A sample (for example, serum) derived from an animal (for example, human) to be tested is extracted in an amount of 10 to 200. mu.L, and after adding 25 to 800. mu.L of a protein denaturing agent (for example, 5 to 10% perchloric acid), the mixture is centrifuged at 10000 to 15000rpm at 4 ℃ for 5 to 15 minutes. Subsequently, 40 to 60. mu.L of the supernatant is injected into a mass spectrometer (e.g., a high performance liquid chromatography) equipped with a reverse phase column such as ODS column, and the components in the sample are separated by feeding a basic solution (e.g., 5 to 15mM sodium acetate) and an organic solvent (e.g., acetonitrile) as mobile phases at a flow rate of 0.1 to 1 mL/min. Next, the amount of anthranilic acid as well as the amount of tryptophan, the amount of kynurenine or the amount of 3-hydroxyanthranilic acid in the supernatant is measured by a detector (e.g., an ultraviolet-visible light photodetector, a fluorescence detector, an electrochemical detector, etc.).

2) Step 2 of the present invention

The ratio is calculated by dividing the amount of anthranilic acid derived from the animal to be tested measured in 1) by the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid.

3) Step 3 of the present invention

Comparing the value derived from the animal to be tested calculated in the above 2) with a predetermined reference value (cut-off value or the like), and when the value derived from the animal to be tested is equal to or more than the predetermined reference value (cut-off value or the like), determining that "the animal to be tested has a high possibility of suffering from a mental disease or the animal to be tested has a high possibility of suffering from a mental disease". On the other hand, the value derived from the animal to be tested calculated in the above 2) is compared with a preset reference value (cut-off value or the like), and when the value derived from the animal to be tested is smaller than the preset reference value (cut-off value or the like), it is determined that "the animal to be tested does not have the possibility of suffering from a mental disease or the possibility of suffering from a mental disease is low".

In another embodiment, the value derived from the animal to be tested calculated in the above 2) is compared with a preset reference value (cut-off value or the like), and when the value derived from the animal to be tested is equal to or less than the preset reference value (cut-off value or the like), it is determined that "the animal to be tested has a high possibility of suffering from a mental disease, or the animal to be tested has a high possibility of suffering from a mental disease". On the other hand, the value derived from the animal to be tested calculated in the above 2) is compared with a preset reference value (cut-off value or the like), and when the value derived from the animal to be tested exceeds the preset reference value (cut-off value or the like), it is determined that "the animal to be tested does not have the possibility of suffering from a mental disease or the possibility of suffering from a mental disease is low".

< method of acquiring data for judging mental disease of the present invention >

The method of acquiring data for determining mental disease of the present invention (hereinafter, also simply referred to as "the method of acquiring data of the present invention") is characterized by comprising

Step 1: measuring the amount of anthranilic acid in the sample (A) and the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid in the sample (B),

and a step 2: calculating i) the ratio ((A)/(B)) of the amount of anthranilic acid (A) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B), or ii) the ratio ((B)/(A)) of the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B) to the amount of anthranilic acid (A).

Examples of the data in the method of acquiring data of the present invention include i) a value calculated in step 2 of the method of acquiring data of the present invention, ii) a value obtained by subjecting the value to multivariate analysis such as multivariate logistic regression analysis, discriminant analysis, poisson regression analysis, multivariate regression analysis, cox's proportional hazards model, and pathway analysis, iii) data (comparison result) indicating the magnitude relationship between the value calculated in step 2 of the method of acquiring data of the present invention and the above-mentioned reference value (cutoff value, etc.), iv) data indicating the possibility that the test animal has a mental disease, and the like, and preferably i) or iii), and more preferably i).

The "sample", "mental disease", "step 1" and "step 2" in the method of acquiring data according to the present invention are the same as those described in < method of determining according to the present invention >, and the preferred examples and specific examples are also the same.

< marker for determining mental disease of the present invention >

The marker for determining mental disorders of the present invention (hereinafter, also simply referred to as "the marker of the present invention") is characterized by containing anthranilic acid and tryptophan, kynurenine or 3-hydroxyanthranilic acid. The "mental disease" in the marker of the present invention is the same as that described in < method of determining the present invention >, and the preferred examples and specific examples are also the same.

As the marker of the present invention, anthranilic acid and kynurenine or 3-hydroxyanthranilic acid are preferably contained, and anthranilic acid and 3-hydroxyanthranilic acid are more preferably contained.

< apparatus for judging mental diseases of the present invention >

The device for determining mental disease according to the present invention (hereinafter, also simply referred to as "determination device of the present invention") includes at least a measurement unit and a processing unit. Further, the apparatus may further include a determination unit, an output unit, and an input unit.

The measuring portion in the determination device of the present invention can measure the amount of anthranilic acid in the sample (A), and the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid in the sample (B). Specifically, there may be mentioned measurement devices such as a mass spectrometer used in the above-mentioned measurement method, a device used in an immunological measurement method, an NMR analyzer, an amino acid analyzer, and a device used in FACS analysis.

The processing section in the determination device of the present invention may calculate the ratio ((a)/(B)) of i) the amount of anthranilic acid (a) to the amount of tryptophan, the amount of kynurenine, or the amount of 3-hydroxyanthranilic acid (B), or the ratio ((B)/(a)) of the amount of tryptophan, the amount of kynurenine, or the amount of 3-hydroxyanthranilic acid (B) to the amount of anthranilic acid (a), measured by the measurement section. If necessary, the amount of anthranilic acid, the amount of tryptophan, the amount of kynurenine, or the amount of 3-hydroxyanthranilic acid may be calculated based on the measurement value measured by the measurement portion, and then the above-mentioned ratio ((A)/(B) or (B)/(A)) may be calculated based on the calculation result.

The determination unit in the determination device of the present invention may determine the mental disease based on the calculation result obtained by the processing unit. The output unit of the determination device of the present invention may output the calculation result obtained by the processing unit and/or the determination result obtained by the determination unit. The input unit in the determination device of the present invention receives an operation by an operator, and then sends a signal for operating the measurement unit and/or the processing unit to the measurement unit and/or the processing unit.

In addition, the measurement, calculation, and determination by the measurement unit, the processing unit, and the determination unit of the determination device of the present invention may be performed according to < determination method of the present invention >, and preferable examples, specific examples, and the like may be performed according to < determination method of the present invention >.

According to the above-described determination device of the present invention, the determination method of the present invention and/or the method of acquiring data of the present invention can be performed simply, in a short time, and with high accuracy.

< method for measuring and calculating mental disease according to the present invention >

For judging mental diseases, the method for measuring and calculating the mental diseases comprises

A measurement step: measuring the amount of anthranilic acid in the sample (A) and the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid in the sample (B),

a calculation procedure: calculating i) the ratio ((A)/(B)) of the amount of anthranilic acid (A) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B), or ii) the ratio ((B)/(A)) of the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B) to the amount of anthranilic acid (A).

In the above-mentioned calculation step, the amount of anthranilic acid and the amount of tryptophan, the amount of kynurenine or the amount of 3-hydroxyanthranilic acid in the sample may be calculated based on the measurement values obtained as a result of the measurement step, and then the above-mentioned ratio ((a)/(B) or (B)/(a)) may be calculated based on the calculation result, if necessary.

The measurement steps and the calculation steps in the above-described measurement and calculation method of the present invention are the same as those described in < determination method of the present invention >, and the preferred examples and specific examples are also the same.

< method for assisting judgment of mental disease of the present invention >

The method for assisting judgment of mental disease of the present invention (hereinafter, also simply referred to as "the method for assisting of the present invention") includes

Step 1: measuring the amount of anthranilic acid in the sample (A) and the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid in the sample (B),

and a step 2: calculating i) a ratio ((A)/(B)) of the amount of anthranilic acid (A) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B), or ii) a ratio ((B)/(A)) of the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B) to the amount of anthranilic acid (A), and

step 3: the judgment of the mental disease is assisted based on the calculation result of the step 2.

The support method of the present invention can be used as a method for assisting a doctor or the like in diagnosing a mental disease. The "sample", "mental disease", "step 1", "step 2" and "step 3" in the method for acquiring data according to the present invention are the same as those described in < method for determining the present invention >, and preferred examples and specific examples thereof are also the same.

In the step 2, the amount of anthranilic acid, the amount of tryptophan, the amount of kynurenine or the amount of 3-hydroxyanthranilic acid in the sample may be calculated based on the measurement values obtained from the measurement results of the step 1, and then the ratio ((a)/(B) or (B)/(a)) may be calculated based on the calculation results.

< methods for judging and treating mental diseases of the present invention >

The method for judging and treating mental diseases of the present invention (hereinafter, also simply referred to as "the treatment method of the present invention") includes

Step 1: measuring the amount of anthranilic acid in the sample (A) and the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid in the sample (B),

and a step 2: calculating i) the ratio ((A)/(B)) of the amount of anthranilic acid (A) to the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B), or ii) the ratio ((B)/(A)) of the amount of tryptophan, kynurenine or 3-hydroxyanthranilic acid (B) to the amount of anthranilic acid (A),

a step 3 of judging mental disorder based on the calculation result of the step 2, an

And a step 4 of performing appropriate treatment on the patient who is determined to have a high possibility of suffering from a psychiatric disease or a psychiatric disease, based on the determination result in the step 3.

The "sample", "mental disease", "step 1", "step 2" and "step 3" in the treatment method of the present invention are the same as those described in < method of determining the present invention >, and the preferred examples and specific examples are also the same. In the step 2, the amount of anthranilic acid, the amount of tryptophan, the amount of kynurenine or the amount of 3-hydroxyanthranilic acid in the sample may be calculated based on the measurement values obtained from the measurement results of the step 1, and the above ratio ((a)/(B) or (B)/(a)) may be calculated based on the calculation results. Suitable treatments in step 4 of the treatment method of the present invention include, for example, psychotherapy typified by interview with medical staff such as a physician, pharmacotherapy using antidepressants such as amoxapine (trade name), maprotiline (trade name), fluvoxamine (trade name), paroxetine (trade name), milnacipran (trade name), and mirtazapine (trade name), improved electroconvulsive therapy, home therapy, psychological guidance, and the like.

< reagent for determining mental diseases of the present invention >

The reagent for determining mental disease of the present invention (hereinafter, also simply referred to as "the reagent of the present invention") includes a reagent for detecting the marker of the present invention as a component.

The reagent for detecting the above-mentioned marker of the present invention includes a reagent containing a substance having affinity for the marker of the present invention, and specifically includes, for example, an antibody, lectin, polysaccharide, nucleic acid, enzyme, protein and the like, and preferably an antibody such as an anti-anthranilic acid antibody, an anti-tryptophan antibody, an anti-kynurenine antibody, an anti-3-hydroxyanthranilic acid antibody and the like. The antibody is the same as described in < method of determining of the present invention >, and preferred examples and specific examples thereof are also the same.

The reagent of the present invention may include a reagent which is generally used in the art and does not interfere with the stability of the coexisting reagents and the like, and examples thereof include a buffer, a detergent, a reaction accelerator, a stabilizer such as a saccharide, a protein, a salt, a surfactant and the like, a preservative, a solution for diluting a sample, an immobilized stationary phase such as an antibody-immobilized stationary phase and an antigen-immobilized stationary phase, a secondary antibody or an antibody fragment thereof labeled with a labeling substance, a reagent for detecting a labeling substance, and the like. The concentration and pH are also within the ranges generally used in the art.

The immobilized stationary phase such as the antibody immobilized stationary phase and the antigen immobilized stationary phase is not particularly limited as long as an antibody or an antibody fragment thereof such as anthranilic acid, tryptophan, kynurenine, 3-hydroxyanthranilic acid or an anti-anthranilic acid antibody, an anti-tryptophan antibody, an anti-kynurenine antibody, or an anti-3-hydroxyanthranilic acid antibody can be immobilized on a magnetic particle such as magnetic silica, polystyrene, polycarbonate, polyvinyltoluene, polypropylene, polyethylene, polyvinyl chloride, nylon, polymethacrylate, gelatin, agarose, cellulose, polyethylene terephthalate, glass, ceramic, or the like. The material for the above-mentioned immobilized phase such as an antibody-immobilized stationary phase and an antigen-immobilized stationary phase can be produced by a method known per se, or a commercially available product can be used. For example, when the magnetic particles such as the magnetic silica particles are produced by a method known per se, the magnetic particles can be produced by the method described in WO 2012/173002.

The secondary antibody or an antibody fragment thereof labeled with a labeling substance is an antibody or an antibody fragment thereof that binds to an anti-anthranilic acid antibody, an anti-tryptophan antibody, an anti-kynurenine antibody, and an anti-3-hydroxyanthranilic acid antibody, respectively. The method for binding the label and the labeling substance in the secondary antibody labeled with the labeling substance or the antibody fragment thereof is the same as described in < judgment method of the present invention >, and preferred examples and specific examples thereof are also the same.

The reagent for detecting a labeling substance is a reagent for detecting a labeling substance labeled with an antibody such as an anti-anthranilic acid antibody, an anti-tryptophan antibody, an anti-kynurenine antibody or an anti-3-hydroxyanthranilic acid antibody or a labeling substance in an antibody fragment thereof and/or a labeling substance in a labeled secondary antibody or an antibody fragment thereof, and examples of the reagent for detecting a labeling substance include an absorbance measurement substrate such as tetramethylbenzidine or phenylenediamine, a fluorescent substrate such as hydroxyphenylpropionic acid or hydroxyphenylacetic acid, a luminescent substance such as luminol, an absorbance measurement reagent such as 4-nitrophenylphosphate, and a fluorescent substance such as 4-methylumbelliferone phosphate.

The reagent of the present invention may further contain a description or the like used in the determination method and/or the data acquisition method of the present invention. The "specification" refers to an instruction manual, a pamphlet (leaflet), and the like of the reagent of the present invention, and these specifications and diagrams are used to describe the features, the principle, the operation procedure, the judgment procedure, and the like of the judgment method and/or the data acquisition method of the present invention with reference to the text description and/or the drawings.

Thus, the reagent of the present invention can easily perform the determination method of the present invention and/or the data acquisition method of the present invention in a short time with high accuracy. The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples.