WO2008013270A1 - Method for diagnosis of neuropsychiatric disease - Google Patents

Abstract

A method for measurement of a blood CRF level for use in the diagnosis of a neuropsychiatric disease, comprising the steps of: analyzing a blood collected from a mammal and calculating a CRF level in the blood; and comparing the calculated blood CRF level with the standard value for a blood CRF level.

Description

 Specification

 Diagnosis method for neuropsychiatric disorders

 Technical field

 [0001] The present invention relates to a method of measuring blood CRF (corticotropin-releasing factor) concentration, a method of diagnosing a neuropsychiatric disorder using the method, a method of adjusting blood CRF concentration, and a treatment of neuropsychiatric disease The present invention relates to a schedule determination method, a neuropsychiatric disorder treatment and / or symptom progression suppression method, a neuropsychiatric disorder recurrence prevention method, a neuropsychiatric disorder treatment or a symptom progression inhibitor screening method, and the like.

 Background art

 [0002] CRF is a 41 amino acid peptide isolated from the Hydge hypothalamus in 1981.

 This CRF was released from the hypothalamus and was suggested to be responsible for the regulation of adreno corticotropic hormone (ACTH) secretion from the pituitary gland (Science, 1982, Vol. 218). 377-379 (see Non-Patent Document 1)). The biological effect of CRF begins with the released CRF binding to CRF receptors present on the surface of membranes such as ACTH-producing cells in the anterior pituitary gland. It is clear that there are two subtypes of CRF receptors, each distributed in a different region of the brain. For example, receptor 1 is present in the pituitary gland, hypothalamus, cerebral cortex and the like, and receptor 2 is present mainly in the brain septum and hypothalamic paraventricular nucleus. CRF receptors are also present in peripheral organs such as heart, gastrointestinal tract, lung, adrenal medulla, spleen, liver, kidney and prostate. Specifically, there are many receptors 1 in the intestine and spleen, many receptors 2 in the stomach, and many 2βs among receptors 2 in the heart and skeletal muscle. ACTH, secreted by CRF stimulation, promotes the secretion of cortisol from the adrenal cortex and is associated with systemic effects on reproduction, growth, gastrointestinal function, inflammation, immune system and nervous system. Thus, CRF is considered to be one of the major factors in the hypothalamic-pituitary-adrenal system that promotes ACTH synthesis and secretion in the anterior pituitary gland.

[0003] Meanwhile, CRF is reported to be over-secreted in the brain in patients with depression and anxiety disorders (Science, 1984, 226, 1342-1343 (Non-Patent Document 2); New Science and Behavioral Reviews, 1998, No. 1) 22: 635-651 (Non-Patent Document 3); The 'Journal' of End-Clinology O. Endocrinol.), 1999, 160, 1-12 (Non-Patent Document 4)). CRF is also deeply involved in stress through the central nervous system and pituitary gland. For example, it has been reported that when CRF is administered into the brain, behavior, endocrine response, and the like are observed in animals exposed to a stress environment (Nature, 1982, 297, 331). See Non-Patent Document 5)). For these reasons, attention has been focused on the involvement of CRF in central nervous system and neuropsychiatric disorders, or peripheral organ diseases.

[0004] Currently, major depression is diagnosed by the American Psychiatric Association DSM-IV-TR (Mental Disease Diagnosis' Statistics Manual) and the World Health Organization (WHO) ICD-10 (International Disease Classification No. 10). A revised standard) is used. In addition, patients with neuropsychiatric disorders can be classified into mild, moderate, or severe patients according to the degree of their symptoms.For example, in depression, HAM-D (Hamilton Rating Scale For Depression), It can be evaluated according to criteria for depression diagnosis such as MADRS (Montgomery and Asberg Depression Rating Scale). However, since these are diagnoses centered on interviews, there are many cases of misdiagnosis.

 [0005] On the other hand, as one method of objectively diagnosing a neuropsychiatric disorder patient, a method is to measure CRF concentration in cerebrospinal fluid (hereinafter referred to as CSF) and make a diagnosis directly. It has been known. It has already been reported that CRF concentration in CSF of patients with neuropsychiatric disorders, especially major depression, is higher than that of healthy individuals (American Journal of Psychiatry), 1987, vol. 144, pages 873-877 (non-patent document 6), Biological Psychiatry, 1989, vol. 24, pages 355-359 (non-patent document 7) ). However, because CSF collection has a large physical burden and invasion, and it is highly dangerous, it has become a very difficult and practical means to use CSF for diagnosis and evaluation of drug efficacy in the medical field.

 Non-Patent Document 1: Science, 1982, Vol. 218, .377-379

Non-Patent Document 2: Science, 1984, Vol. 226, ρ · 1342-1343 Non-Patent Literature 3: Neuroscience 'Neuroscience and Behavioral Reviews', 1998, Vol. 22, ρ · 635-651

 Non-Patent Document 4: The 'Journal' Ob 'End Clinology (J. Endocrinol.), 1999, Volume 160, .1-12

 Non-Patent Document 5: Nature, 1982, Vol. 297, p.331

 Non-Patent Document 6: American Journal of Psyc hiatry, 1987, vol. 144, ρ · 873-877

 Non-Patent Literature 7: Biological Psychiatry, 1989, 24th, .355-359

 Disclosure of the invention

 Problems to be solved by the invention

[0006] The main object of the present invention is to provide a method for diagnosing a neuropsychiatric disorder and / or a method for treating a neuropsychiatric disorder and / or screening for a symptom progression inhibitor with little invasion to a subject. The title.

 Means for solving the problem

[0007] In order to solve the above problems, the present inventors have conducted research and found that there is a correlation between the blood CRF concentration and the symptoms of psychiatric neuropathy. Specifically, the CRF concentration in the CSF of healthy individuals and the CRF concentration in blood are compared, the CRF concentration in the CSF of patients with neuropsychiatric disorders is compared with the blood CRF concentration, and the CRF concentration in the CSF is compared. And found that there is a positive correlation between CRF concentrations in blood. Based on this knowledge, the present inventors have made further intensive studies and completed the present invention.

That is, the present invention provides:

 Item 1. The method includes the steps of analyzing blood collected from a mammal and calculating the CRF concentration in the blood, and comparing the obtained blood CRF concentration with a reference value of the blood CRF concentration. A method for measuring CRF concentration in blood for diagnosis of neuropsychiatric disorders.

Item 2. The method according to Item 1, wherein the reference value of CRF concentration in blood is 12 to 15 pg / mL. Item 3. Analyzing blood collected from mammals, calculating the CRF concentration in the blood, comparing the obtained CRF concentration in the blood with a reference value for the CRF concentration in the blood, A method for determining a neuropsychiatric disorder when the CRF concentration is higher than a reference value.

 Item 4. The method according to Item 3, wherein the reference value of CRF concentration in blood is 12 to 15 pg / mL. Item 5. Analyzing blood collected from mammals, calculating the blood CRF concentration, comparing the obtained blood CRF concentration with the reference value of blood CRF concentration, and blood CRF concentration Administering a drug to a mammal having a reference value higher than the reference value.

 Item 6. The method according to Item 5, wherein the reference value of CRF concentration in blood is 12 to 15 pg / mL. Item 7. The method according to Item 5, wherein the drug is a CRF antagonist.

 Item 8. It includes the steps of analyzing blood collected from mammals with a neuropsychiatric disorder or suspected neuropsychiatric disorders and calculating the blood CRF concentration, and determining the dosage and administration period of the drug. A method for determining a treatment schedule for a neuropsychiatric disorder.

 Item 9. Analyzing blood collected from a mammal with a neuropsychiatric disorder, calculating the CRF concentration in the blood, and comparing the obtained CRF concentration in the blood with the CRF concentration in the blood at the previous blood collection. Administering a drug that lowers the blood CRF concentration to a mammal whose blood CRF concentration is equal to or higher than the blood CRF concentration at the time of the previous blood collection. Treatment of neuropsychiatric disorders and / or suppression of symptom progression.

 Item 10. Analyzing blood collected from mammals with neuropsychiatric disorders in remission and calculating the CRF concentration in the blood, and the obtained blood CRF concentration is the CRF concentration in the blood at the previous blood collection. And a step of administering to the mammal whose blood CRF concentration is higher than the blood CRF concentration at the time of the previous blood collection, an amount of the drug that lowers it. How to prevent disease recurrence.

 Item 11. The method according to Item 10, wherein the neuropsychiatric disorder is depression.

 Item 12. The method according to Item 10, wherein the drug is a CRF antagonist.

Item 13. A step of administering a test substance to a mammal, a step of analyzing blood collected from the mammal to which the test substance has been administered, calculating a CRF concentration in the blood, A treatment for a neuropsychiatric disorder characterized by comprising a step of comparing a CRF concentration with a blood CRF concentration before administration of a test substance, and a step of selecting a substance that lowers the blood CRF concentration by administration of the test substance. And / or screening method for symptom progression inhibitor or recurrence preventive agent.

 Item 14. Treatment for Psychiatric and Neurological Diseases and / or Symptom Progress Inhibitor, or Recurrence Preventive Agent Force Treatment of Psychiatric and Neurological Diseases by CRF Antagonism and / or Symptom Progress Inhibitor, or Recurrence Preventive Agent by CRF Antagonism The method described.

 Item 15. The method according to Item 13, wherein the test substance is selected such that a decrease in blood CRF concentration by administration of the test substance is 5% or more of the blood CRF concentration before administration of the test substance.

About. The present invention also provides:

 Item 16. A method for measuring CRF in blood for the diagnosis of neuropsychiatric disorders, characterized in that blood collected from mammals is subjected to analytical means, its CRF concentration is calculated and compared with a reference value.

 Item 17. The method according to Item 16, wherein the reference value is 12 to 15 pg / mL.

 Item 18. A sample of a neuropsychiatric disorder characterized by applying blood collected from a mammal to an analytical means, calculating its CRF concentration, and using the obtained CRF concentration as an index for diagnosis of a neuropsychiatric disorder. Diagnosis method.

 Item 19. The diagnostic method according to Item 18, wherein the reference value of blood CRF concentration, which is an index for diagnosis of a neuropsychiatric disorder, is 12 to 15 pg / mL.

 Item 20. Blood collected from a mammal is subjected to analysis means, its CRF concentration is calculated, and the drug is administered to a mammal whose blood CRF concentration is higher than a reference value. How to adjust CRF concentration.

 Item 21. The method according to Item 20, wherein the reference value of CRF concentration in blood is 12 to 15 pg / mL. Item 22. The method according to Item 21, wherein the drug is a CRF antagonist.

 Item 23. A method of treating a patient having a neuropsychiatric disorder by administering a drug, wherein blood collected from the patient is applied to an analysis means, the CRF concentration is calculated, and the dose of the drug is determined. A method for treating neuropsychiatric disorders.

Item 24. Collected from patients when administering drugs to treat patients with neuropsychiatric disorders A method for determining a treatment schedule for a neuropsychiatric disorder, comprising: subjecting the collected blood to an analysis means, calculating a CRF concentration thereof, and determining a dose and administration period of the drug.

 Item 25. A candidate compound of a CRF antagonist is administered to a mammal, and blood collected from the treated animal is applied to an analysis means, and the CRF concentration is calculated and compared with the CRF concentration in blood before the candidate compound is administered. A screening method for a CRF antagonist, which is characterized by the above.

 Item 26. The method according to Item 25, wherein a candidate compound having a CRF concentration in blood after administration of the candidate compound that shows a decrease of 5% or more in blood before administration of the candidate compound is selected as a CRF antagonist.

 Item 27. Blood collected from patients with neuropsychiatric disorders is applied to the analytical means, and the CRF concentration is calculated. The blood CRF concentration is equal to or higher than the blood CRF concentration at the previous blood collection. A method of treating a neuropsychiatric disorder and / or suppressing symptom progression, comprising administering to a patient with a neuropsychiatric disorder an amount of a drug that lowers the drug.

 Item 28. Blood collected from patients with neuropsychiatric disorders in remission is subjected to analysis, the CRF concentration is calculated, and the blood CRF concentration is higher than the blood CRF concentration at the previous blood collection. A method for preventing the recurrence of a neuropsychiatric disorder, comprising administering to a patient with a neurological disorder an amount that reduces the drug.

 Item 29. The method according to Item 28, wherein the neuropsychiatric disorder is depression.

 Item 30. The method according to Item 28, wherein the drug is a CRF antagonist.

 Item 31. The present invention relates to a method for determining a dose of a drug, comprising treating a patient with a neuropsychiatric disorder by administering a drug, applying blood collected from the patient to an analysis means, and calculating the CRF concentration.

[0009] (I) Diagnostic method for neuropsychiatric disorders

 Hereinafter, a method for measuring the CRF concentration in blood for diagnosis of a neuropsychiatric disorder of the present invention and a method for diagnosing a neuropsychiatric disorder will be described.

[0010] Target

Examples of mammals to be subjected to the method of the present invention include, but are not limited to, humans, rats, mice, rabbits, hedges, pigs, rabbits, cats, dogs, monkeys, and the like. In particular, human is a suitable target. Usually a mammal suffering from a neuropsychiatric disorder or mental Mammals suspected of having a neurological disease are targeted.

 [ooii] M

 In the present invention, the blood is preferably whole blood, serum or plasma which can be used. Whole blood can be collected from mammals with a syringe or the like. Plasma or serum can be separated from the collected whole blood by known means. The blood may be derived from arterial blood or venous blood.

 [0012] Blood analysis and CRF concentration extraction

 <Analysis> Extraction of concentration>

 The means for analyzing blood used in the method of the present invention is not particularly limited as long as it can analyze the amount of CRF in blood. Specific analysis means include, for example, a method of detecting CRF in blood using antigen-antibody reaction. By using such an analytical tool, it is possible to measure the amount of CRF in the blood and calculate the blood CRF concentration from a separately prepared calibration curve. In this case, the antibody is preferably an antibody that specifically recognizes CRF present in whole blood, serum, plasma or the like. The anti-CRF antibody may be a monoclonal antibody or a polyclonal antibody. Specifically, CRF derived from a mammal to be analyzed (for example, human, rat or mouse) is immunized to mammals of different species (for example, rabbit, goat, rat) by a known method. Examples thereof include obtained antibodies. Specific examples of means for detecting CRF in blood and measuring CRF concentration in blood include the radioimmunoassay (RIA) method, enzyme immunoassay (ELISA) method, and Western blot method. It is done.

 [0013] When measuring the CRF concentration in blood using the RIA method, a known RIA method can be used. Specifically, the anti-CRF antibody labeled with a radiolabeled substance is reacted with blood to form a complex, and the formed label (bound; B) and unreacted (free; F) are separated (B ' F separation), measuring the radioactivity to determine the B / F ratio, and calculating the CRF concentration from a separately prepared standard curve, the blood CRF concentration can be obtained.

[0014] As the RIA method, a two-antibody method is also preferable. When measuring the CRF concentration in blood by the two-antibody method, for example, after reacting blood with diluted CRF antiserum (final dilution factor of about 500 to 5000 times), CRF labeled with a radiolabeled substance is used. Add reaction Let Next, after the second antibody is added and reacted, for example, polyethylene glycol or the like is added to precipitate γ-globulin in the blood, and then the supernatant is removed by centrifugation, and the radioactivity of the precipitate is measured. The calculated calibration curve force CRF concentration can be calculated to obtain the blood CRF concentration. Examples of the second antibody include normal rabbit serum. Examples of the radiolabeling substance include ¹²⁵ I, ³² P, ³⁵ S, ³ H, ¹⁴ C and the like, and ¹²⁵ 1 is particularly preferable. The radiation dose can be measured by, for example, autoradiography, a γ counter or a liquid scintillation counter.

 [0015] When measuring the CRF concentration in blood using the ELISA method, it is possible to use a known ELISA method. Specifically, for example, an anti-CRF antibody is bound to a solid phase such as polystyrene, blood is added thereto, and CRF in the blood bound to the anti-CRF antibody is reacted with an enzyme-labeled antibody and visualized. CRF concentration in blood can be measured.

 [0016] Also, when measuring the CRF concentration in blood using Western blotting, a known Western blotting method can be used. Specifically, a denaturing agent such as sodium dodecyl sulfate (SDS) is added to the blood, and then subjected to polyacrylamide gel electrophoresis. After the electrophoresis is completed, the protein is transferred to a nitrocellulose membrane or the like. The CRF concentration in blood can be measured by visualizing the CRF using an anti-CRF antibody, or by subsequently quantifying it with densitometry or the like.

[0017] For measurement of blood CRF concentration, a blood CRF analysis kit can also be used. The embodiment of the analysis kit is not particularly limited as long as it is an analysis kit for simply performing CRF analysis in blood. Specifically, an analysis kit containing an anti-CRF antibody that specifically recognizes CRF contained in blood and capable of measuring the CRF concentration in blood using an antigen-antibody reaction is preferable. The above analysis kit only needs to contain at least one kind of antibody, equipment, or the like that enables measurement of blood CRF concentration. In particular, when using the RIA method, radiolabeled anti-CRF antibodies are preferably included in the assay kit, or when using the two-antibody method, radiolabeled CRF and anti-CRF antibodies, etc. Is preferably included in the assay kit. When using the ELISA method, it is preferable that a carrier on which an anti-CRF antibody is immobilized be included in the assay kit. When using Western plotting, anti-CRF antibodies, SDS and other denaturing agents, polyacrylamide gels, etc. Equipment necessary for electrophoresis and a transfer film such as a nitrocellulose membrane are preferably included in the assay kit.

<Pretreatment of blood>

Prior to measurement of the CRF concentration in blood, it is preferable to reduce impurities in the blood by pretreatment using, for example, solid-phase extraction (SPE). By this pretreatment, analysis and measurement can be speeded up and simplified, and as a result, the method disclosed in the present invention can be easily carried out. For example, solid phase extraction can be performed by a known method in which CRF is held (adsorbed) on a solid phase that matches CRF, and then CRF held (adsorbed) in the solid phase is eluted with the elution solvent in the following! / . Examples of the solid phase in the solid phase extraction method include octadecyl silylated silica gel (ODS), weakly basic anion exchanger, silica gel, styrene dibutylbenzene copolymer (SDB), propyl sulfoel silylated silica gel , Benzenesulfonylpropyl silylated silica gel, acrylamide copolymer-bound glyceryl silylated silica gel, ethylenediamine N-propyl silylated silica gel, carboxymethyl silylated silica gel, strongly basic anion exchanger or glycerylpropylsilanolated silica gel. It is not limited to. These solid phases can be used alone or in combination of two or more. Preferred solid phase combinations include, for example, a combination of ODS, weakly basic anion exchanger, silica gel, SDB and the like. In the solid phase extraction method, a commercially available cartridge or minicolumn filled with the above solid phase or a solid phase extraction disk plate can be used. Examples of such cartridges or mini-columns include Bond Elut C18 (Varian; ODS solid phase), Bond Elut LRC_C18 (Varian; ODS solid phase), S-Pak C 18 (Waters) ODS column), Sep-Pak Vac C18 (Waters; ODS solid phase), Sep-Pak Plus C 18 (Waters; O DS solid phase), Bond Elut DEA (Varian; weak base) Anion exchanger solid phase), abselut NE XUS (Varian; SDB solid phase) or S-Pak Plus PS-2 (Waters; SDB solid phase), etc., but are not limited thereto. . The cartridge or mu-column can be used alone or in combination of two or more. Examples of solid phase extraction disk plates include C-18-SD (manufactured by 3M), C-8-SD (manufactured by 3M), MPC-SD (manufactured by 3M), etc. Power S is mentioned. The solid phase extraction method includes a solid-phase micro extra ction (SPME). SPME includes a thin needle isotropic force S to which the solid phase is bound. Examples of the solvent for eluting CRF held (adsorbed) in the solid phase extraction method include ethyl acetate, chloroform, methanol, or acetonitrile in the ODS solid phase and SDB solid phase. For example, in a weakly basic anion exchanger solid phase, a water-acetonitrile mixed solution [for example, acetic acid aqueous solution (about 0 · ;! to 90% (v / v)) / acetonitol (about 2: 8 to 5: 5 (v / v))] and the like.

 [0019] The solid phase is preferably conditioned so that CRF can be retained (adsorbed) before blood injection. The conditioning procedure varies depending on the solid phase.For example, in the ODS and SDB solid phases, the elution solvent (e.g., ethyl acetate, black mouth form, acetonitrile, and acetonitrile / acetic acid aqueous solution [acetonitrile / acetic acid aqueous solution ( About 0.;! ~ 90% (v / v)) (about 5: 5-8: 2 (v / v))]), etc.!, And highly polar! /, Solvent (eg, methanol, Ethanol, acetone, acetonitrile, acetonitrile / acetic acid aqueous solution [acetononitrile / acetic acid aqueous solution (approx. 0;! To 90% (v / v)) (approx. 5: 5 to 8: 2 (v / v))]], next A certain amount of aqueous solvent [for example, water, water / acetic acid mixed solution (about 100:;! ~ 80: 1 (v / v)), hydrochloric acid (0.1-0.5Ν), etc.] This can be done by force through a cartridge or minicolumn filled with phases, by injecting into a solid phase extraction disk plate and aspirating.

 [0020] The blood injected into the solid phase is preferably diluted with a buffer or the like. Examples of the buffer solution include a phosphate buffer solution, an acetate buffer solution, and a Tris-HCl buffer solution. The buffer may contain, for example, a protein denaturant such as urea or guanidine hydrochloride, or a surfactant such as Tween-20 or Triton X-100 (registered trademark). Further, it may be diluted with a solution such as guanidine hydrochloride.

 [0021] Prior to CRF elution, the solid phase holding CRF is, for example, water, water / acetic acid mixture (about 100 :;

 80: 1 (v / v)), hydrochloric acid (0 .;! To 0.2N), etc. By this washing, the force S can be removed to remove impurities other than CRF contained in the sample loaded on the solid phase.

 [0022] Diagnosis of neuropsychiatric disorders

If the CRF concentration in the blood thus obtained is higher than the reference value, the subject It can be determined that the patient is suffering from a neuropsychiatric disorder. In the present invention, the reference value means the CRF concentration in the blood of a mammal not suffering from a disease. For example, if a human is used as a mammal, the CRF concentration in blood of a human who does not suffer from a disease, that is, a so-called healthy person is referred to as a reference value. In this case, the reference value is obtained as an average value by collecting the CRF concentrations in the blood of multiple healthy individuals into a population and statistically analyzing them. The reference value varies depending on, for example, the type of mammal, measurement method, time factor, living environment of the animal, etc., for example, the human reference value is included in the range of about 12 to 15 pg / mL. .

 [0023] In the diagnostic method of the present invention, blood collected from a mammal is analyzed, the CRF concentration in the blood is calculated, and then compared with a reference value. It can be determined whether or not there is a high possibility of suffering from a neurological disease. At this time, it can be determined that the higher the CRF concentration in the blood of the mammal that provided the blood is higher than the reference value, the higher the possibility of suffering from a neuropsychiatric disorder. In mammals such as humans, for example, blood CRF concentrations are about 12 to 15 pg / mL, for example about 12 pg / mL, preferably about 13 pg / mL, more preferably about 14 pg / mL, even more preferably It can be judged that humans exceeding about 15 pg / mL are likely to have a neuropsychiatric disorder. It should be noted that the CRF concentration in mammals (preferably humans) suffering from neuropsychiatric disorders is usually at most about 50 pg / mL, preferably at most about 40 pg / mL, more preferably about 30 pg / mL. A value of not more than mL, even more preferably not more than about 25 pg / mL, particularly preferably not more than about 25 pg / mL.

[0024] Furthermore, by using the above-described method disclosed in the present invention, it is possible to determine the degree of disease of a mammal suffering from a neuropsychiatric disorder, so-called mild, moderate, or severe. . As the blood CRF concentration of the mammal that provided the blood becomes higher than the reference value, the degree of the disease can be judged to be more likely to be severe, such as mild, moderate, or severe. . For example, if the psychiatric neurological disorder is major depression, the blood CRF concentration is, for example, about 12 pg / mL, preferably about 13 pg / mL, more preferably about If it exceeds 14 pg / mL, it can be judged that there is a high possibility of mild major depression. In addition, the concentration of CRF in the blood is, for example, about 13 pg / mL, preferably about 14 pg / mL, more preferably about 15 pg / mL. It can be judged that there is a high possibility of major depression with isotosis. Serious if the CRF concentration in blood f is about 14 pg / mL, preferably about 15 pg / mL, more preferably about 16 pg / mL, more preferably about 17 pg / mL, and most preferably about 18 pg / mL. It can be determined that there is a high possibility of major depression.

 [0025] The reference value can also be applied to mammals other than humans.

 [0026] Psychiatric and neurological disorders

 In the present invention, the neuropsychiatric disorder means a neuropsychiatric disorder involving CRF. Psychiatric and neurological disorders in which CRF is involved include, for example, mood disorders (eg depression (major depression (MDD), minor depression, single episode depression, postpartum depression, child abuse-induced depression, the elderly) Sexual depression, masked depression, seasonal depression, etc.), bipolar emotional disorder, indefinite complaints, premenstrual dysphoric disorder, postpartum mood disorder, perimenopausal or menopausal mood disorder), anxiety disorder (eg general Sexual anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, phobic anxiety disorder (elevation phobia, claustrophobia, agoraphobia, social phobia, etc.), adaptation disorder (eg emotional disorder) Behavioral disorders, disorders with both, physical complaints, social withdrawal, occupational or academic stagnation), stress-related disorders (eg post-traumatic stress disorder (PTSD), stress-induced immunity) Suppression, stress-induced headache, stress Induced fever, stress-induced pain, surgical attack stress, gastrointestinal dysfunction associated with stress (gastritis, gastric ulcer, duodenal ulcer, etc.), irritable bowel syndrome, decreased libido, erectile dysfunction), eating disorders ( For example, anorexia nervosa, bulimia, neurogenic vomiting), symptoms caused by psychoactive substance use or its dependence (eg alcohol withdrawal symptoms, alcoholism, drug addiction, drug addiction), organic Psychiatric disorders (eg Alzheimer's senile dementia, multi-infarct dementia), schizophrenia, attention deficit / hyperactivity disorder, neurodegenerative diseases (eg Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral cord) Sclerosis), pain, convulsive disorders (eg, convulsions, muscle spasms), seizure disorders (eg, epilepsy, seizures, migraine pain) or sleep disorders (eg, non-organic sleep disorders, fibrosis) Muscular pain disorder).

[0027] In addition, the neuropsychiatric disorder in the present invention also includes a disease involving CRF, that is, a disease in which the CRF concentration in blood fluctuates, which accompanies the above neuropsychiatric disorder. like this Diseases include, for example, gastrointestinal diseases (eg, peptic ulcer (gastric ulcer, duodenal ulcer, etc.), inflammatory bowel disease (eg, ulcerative colitis, Crohn's disease), irritable bowel syndrome, gastrointestinal tract associated with stress. Dysfunction (gastritis, gastric ulcer, duodenal ulcer, etc.), diarrhea or constipation, etc., respiratory diseases (eg, asthma, bronchitis, chronic obstructive pulmonary disease or allergic rhinitis), endocrine diseases (eg, thyroid function) Disorder syndrome, Cushing's disease or antidiuretic hormone incompatible secretion syndrome, etc.), metabolic disease (eg obesity or hypoglycemia), cardiovascular disease (eg hypertension, ischemic heart disease, tachycardia, congestive heart failure) Or cerebrovascular disease), skin disease (eg, atopic dermatitis, allergic contact dermatitis or psoriasis), urinary tract system disease (eg, dysuria, frequent urination) Or urinary incontinence), eye diseases (for example uveitis, etc.), musculoskeletal diseases (for example, rheumatoid arthritis, degenerative osteoarthropathy or osteoporosis, etc.).

 [0028] In the present invention, it is preferable to target as a neuropsychiatric disorder, in particular, major depression (MDD), in particular, mild or moderate major depression.

 [0029] (II) Spirit Ne Kyung's' 7

 The following explains how to adjust the blood CRF concentration, how to determine the treatment schedule for neuropsychiatric disorders, how to treat neuropsychiatric disorders and / or how to suppress the progression of symptoms, and how to prevent relapse of neuropsychiatric disorders. The target mammal species, blood, blood analysis, CRF concentration calculation, and neuropsychiatric disorder types are as described above.

[0030] In the above-described method, the CRF concentration in blood can be adjusted by further combining administration of drugs. Specifically, for example, by analyzing blood collected from a mammal, calculating its CRF concentration, and administering a drug to the mammal when the CRF concentration in the blood is higher than the reference value. It is possible to make adjustments such as lowering the blood CRF concentration. In particular, in the case of suffering from a mammal with psychological neurological disease whose blood CRF concentration is higher than the reference value, such a regulation method is a treatment for neuropsychiatric disease or a symptom progression suppression method. In other words, by adjusting the blood CRF concentration in mammals (especially humans) affected by neuropsychiatric disorders, the above neuropsychiatric disorders can be treated, alleviated, or the progression of symptoms can be suppressed. In this case, blood collected from a mammal, usually a patient with a neuropsychiatric disorder or a person suspected of suffering from a neuropsychiatric disorder, is analyzed. It is possible to calculate the CRF concentration in the medium and determine the type of drug and the dose of the drug accordingly. Further, when treating a mammal (especially a human) suffering from a neuropsychiatric disorder, blood collected from the mammal is analyzed, and its CRF concentration is calculated. For example, a drug, administration of the drug It is also possible to determine a treatment schedule for a neuropsychiatric disorder including the amount and the administration period of the drug. In the present invention, the drug may be any drug as long as it is generally used for the prevention and treatment of neuropsychiatric disorders and / or the suppression of symptom progression! /.

[0031] In the present invention, "prevention" means to prevent or delay the establishment of the disease itself, and "treatment" means to guide the disease state toward healing or to completely recover. In addition, “suppression of symptom progression” means that the progression of the disease state is suppressed and the progression is stopped. As the drug in the present invention, for example, a drug used for the treatment of depression or anxiety disorder is preferably used.

 [0032] Further, in the above-described method disclosed in the present invention, blood CRF concentration is measured over time, so that blood CRF concentration can be more effectively adjusted to treat or develop symptoms of neuropsychiatric disorders. Suppression and treatment schedules for neuropsychiatric disorders can be determined. Specifically, blood CRF concentration is measured over time, so-called monitoring is performed, and when the blood CRF concentration is higher than the blood CRF concentration at the previous measurement, or equivalent When the value is shown, administration of an amount of a drug that lowers the blood CRF concentration can more effectively treat neuropsychiatric disorders or suppress the progression of symptoms. For example, it is preferable to measure the CRF concentration in blood once every half year to once a year, once every half month to several months, or about once a week to several weeks. Here, the dosage of the “drug that reduces the CRF concentration in the blood” is the dosage that the drug is usually used for the prevention, treatment and / or suppression of symptom progression. However, if the dose is unknown, the dose should be increased sequentially until a decrease in the blood CRF concentration is confirmed while monitoring the blood CRF concentration. Ikebyo.

[0033] Furthermore, the method disclosed in the present invention can also be used for preventing recurrence of a mammal (preferably a patient) in remission of a neuropsychiatric disorder. Psychiatric and neurological disorders, especially depression, A force known as a disease that repeats remission and recurrence For example, in the remission phase, blood CRF concentration is monitored as described above, and the blood CRF concentration is higher than the blood CRF concentration at the previous measurement. In this case, it is possible to prevent, ie prevent, the recurrence of the neuropsychiatric disorder by administering an amount of a drug that lowers the CRF concentration in the blood. Here, the dosage of “a drug that reduces the blood CRF concentration” may be understood according to the above.

As described above, in the present invention, the drug may be any drug as long as it is generally used for the prevention, treatment and / or suppression of symptom progression of neuropsychiatric disorders, for example, depression. Drugs used for the treatment of anxiety disorders are preferably used. Such drugs include, for example, AVP_923, JDS_103, JZP_3, ODS_II, ORG-34517, PRX-00023, SLV_308, ST_200, TJ_96, VEC_162, agomelatine, ademetionine, adraphitane (adrafmil), (aprepitant), ammisnopride amisulpride, amibegron), amoxapine, aripiprazole, anoleprazolam alprazolam, armodafmil (istradefylline), ethyl eicosapentaenoate, etizolam, etif oxine, etoperidone, ef. Linonserine (eplivanserin), entacapone (ent acapone), oxasenom (.oxazepam ;, oxazolam), oxaf lozane, oxitriptan, osemozotan, olanzapine, casanthito Force mathenomu (camazepam), canoleno mazepine (carba mazepine), quinupramine (quinupramine), quazepam (clozeazolam), cloxazolam (cloxazolam), kutiacenom ^ clotiazepam), kunosum (clobazam), ke ), Gepirone ER (gepirone-ER), desvenlafaxine succi nate, sub, stans fever drug substance P antagonists, salettantant (saredutantj, diazepam), gazeno muemenoresion (diazepam) emulsion), dihydroenore cocliffe (dihydroergocryptine, ziprasidone) Oxalate Esushitaro Plum (escitalopram oxalate), setiptiline, setiptiline), Senoretorarin, sertraline), cell Regirin (selegiline), zotepine (zotepine), zonisamide (zonisamide), dapoxetine (dap oxetine), tara gourmet tado (talaglumetad), tandospirone (tandospirone), ti agabine (ti agabine), tianeptine (tianeptine), ashenofu akino (desvenlaiaxine), atof nome (tetrabamate, temexipinoline), terex Dosulpine (dosul sign ine), topiramate (topiramate), tofisopam (tofisopam), trazodone, toloxatone (toloxatone), nitroxazepine (nitroxaz sign ine), nemifitide ditriflutate, palone (clone) ), Halazepam, paliperidone, valproic acid, sodium valproate sodium, paroxetine, pinazepam, bifeprunox , Vilazodone, pillind pirlindole), viloxazine, buspirone, bupropion, bupropion EA salt, bupropion SR (bupropion SR), quetiapine fumarate fumarate, fuchs: Ron, prasterone) , Pufzem prazepam), puf ^ hexoré (pramipexole), funoreisase / mu (fludiazepam), funoretanfum (flutazolam), funoretoprazepam (flutoprazepam), funolefoxamine (fluvoxamine), precanoline flu (pregetine flu) Floxetine 'olanzapine combination (fluoxetine + olanzap ine), flotizolam, bromazepam, benaze pam, benrafaxine XR (venkfaxine XR), asenabin maleate ( asenapine malea te), trimifif maleate. Lamin (trimipramine maleate), mianserin (mianserin), mitazolam (midazolam), minaprine (Miraxion), minoletazapine (mirt azapine), minorenacipun, milnacipran, mexazolam (.mexazolam), rosinole acid paroxetine mesylate), rasagiline mesylate, rasagiline mesylate, methaclaseham ^ metaclazepam, metifoxamine, metraiindole, metraindole, moclobemide, modafmil, ramelteonra, ramelteonra (lamotrigine), ricanoreno zehi ⁰ (licarbazepine), risperidone (risperidone), linole mazafone (rilmazafone li, norefuinamide (rufmamide), levetiracetam (levetiracetam), repoxetine (reboxetine), levosulpipramine (levosulpipride) , Loflazepate Chinole (ethyl loflazepate), oral noremetazenome (lormetazepam), atomoxetine hydrochloride, alosetron hydrochloride) Imipramine hydrochloride, hydrochloride.

、塩酸フリバンセリン（flibanse

、塩酸マプロチ ジジンン ((mmaapprroottiilliinnee hhyyddrroocchhlloorriiddee))、、

chloride),

Flibanserin hydrochloride (flibanse

, Maproti dizin hydrochloride ((mmaapprroottiilliinnee hhyyddrroocchhlloorriiddee)),

 , And lithium carbonate carbonate ((lliitthhiiuumm ccaarrbboonnaattee)) and the like. .

 [0035] These one common drug drugs have been used to prevent, prevent, treat and / or treat patients with spiritual neuropathy As a result, it has a function to lower the CCRRFF concentration in blood and blood fluids. To bring back. . Immediately after the administration of a drug, the concentration of CCRRFF in blood and blood is measured and determined. The prophylactic, preventive, therapeutic, and / or mama or symptomatic progress and suppression control system has been confirmed. I can do it. .

 [0036] In addition, as the drug agent used in the present invention, it may be in blood or blood fluid, in CCSSFF, or in living organisms. The other pathological states of CCRRFF in the other parts of the body block the action of CCRRFF and the pathophysiology of patients with spiritual neuropathy disease. Chemical compounds that have the action of improving and improving the quality can also be favored. . Examples of such chemical compounds include CCRRFF antagonist antagonists and the like, for example. . As a CCRRFF antagonist antagonist, for example, for example, 88-((33 pepentynyl luminamino)) —— 22 Memethicyl roo 33—— ((22 chlorochloro 44— Metotoxifushi fujininorele))-66 ,, 77——Dijihydridoro 55HH——Chiclochloropepentata [[dd]] Pipirarazozo mouth [[11,, 55——aa]] Pyrimimidinine Memetatanance Sulfophonic Acid Salt, BBMMSS__556622008866, GGSSKK--887766000088, DDPPCC__336688, SSSSRR --112255554433, TTSS__004411, AAAAGG__556611, NNBB Toto 3344004411, 88 , Urourocorcortintin IIII ((uurroo ccoorrttiinn--IIII)), pipivavaaggaabbiinne ((ppiivvaaggaabbiinnee)), etc. are limited to these. Don't be fooled. . CCRRFF antagonism antagonist drugs, psychiatric psychiatric neuropathic disease patients, pre-prevention prevention, treatment and / or treatment or suppression of progression of symptoms As a result, it is effective to bring the work of lowering the concentration of CCRRFF in blood and blood. .

 [0037] The route of administration and administration of the medicinal drug shown in the above example varies depending on the kind of medicinal drug. .

[0038] Spirit of God Nene Dean Yasuyasu, of, Metallurgy Bibi // or ii))) Deity of Nene Dean Yasuyasu, of Chichikata IIII The method of scoring

The method of measuring and measuring the concentration of CCRRFF in blood and blood fluid disclosed in the present invention is the treatment and treatment of patients with spiritual neuropathy disease. / A method of screening for the prevention or suppression of progression of symptomatic progression, or the prevention / prevention of re-relapse, or the like. It can be used for the CCRRFF antagonist antagonist drug method as well. . The method of the screening method is as follows: mammalian animals, or undesirably, the concentration of CCRRFF in blood and blood fluid is based on the standard reference value. A mammalian drug that has a high or high value is administered with a drug such as a CCRRFF antagonist antagonist candidate drug compound. The blood and blood fluid collected from the mammals and animals before the administration of the medicinal agent was analyzed and analyzed. CCRRFF concentration in the blood and blood fluid of mammals and animals prior to administration of the drug This can be done by comparing with the concentration. The dosage varies depending on the type of drug.For example, several tens of micrograms to several hundred milligrams per kg body weight, preferably about 30 ^ to about 600 mg per kg body weight, more preferably about 0.3 mg to about 60 mg per kg body weight. Even more preferably, it may be in the range of about 1 mg to about 20 mg per kg of body weight. If blood CRF concentration decreases after drug administration, it may be used as a CRF antagonist. In this case, the CRF concentration of the blood of the mammal to which the drug is administered is about 5% or more, preferably about 5% to 30%, more preferably about 10%, compared to the CRF concentration in the blood before the drug is administered. Such agents can be identified or selected as CRF antagonists that favor agents that reduce -30%, particularly preferably about 20% to 30%, particularly preferably about 25% to 30%. The above methods are not limited to CRF antagonists, and are generally used as screening methods for drugs used for treatment of neuropsychiatric disorders and / or suppression of symptom progression, or for screening for drugs used for prevention of recurrence of neuropsychiatric disorders. It can be applied to.

[0039] In addition, if a compound that increases the blood CRF concentration after drug administration is found in the screening, the compound may be used as a CRF agonist. The invention's effect

 [0040] According to the present invention, blood collected from a patient with a neuropsychiatric disorder, or some! /, Who is suffering from a neuropsychiatric disorder! By this, it is possible to diagnose whether or not a neuropsychiatric disorder is simple and safely without taking a physical burden or invasion as in CSF collection, or the severity of a neuropsychiatric disorder. For this reason, it is possible to suppress the patient's pain at the time of CSF collection and the occurrence of, for example, low spinal cord syndrome and headache, which are observed after CSF collection. It also avoids the risk of spinal cord injury when collecting CSF.

 [0041] In the reference value of blood CRF concentration, there is a correlation between the blood CRF concentration and the CRF concentration contained in the CSF. By measuring the blood CRF concentration, for example, the following (1) Through the effects of (7).

 (1) Diagnosis of neuropsychiatric disorders involving CRF becomes possible.

 (2) When treating a patient with a neuropsychiatric disorder involving CRF by administering the drug, the drug and its dose can be determined.

(3) When administering drugs to treat patients with neuropsychiatric disorders involving CRF The therapeutic schedule for the disease can be determined by determining the drug to be administered, its dose and the period of drug administration.

 (4) When treating a patient with a neuropsychiatric disorder involving CRF by administering the drug, the effectiveness of the administered drug can be judged.

 (5) By collecting blood from patients with neuropsychiatric disorders over time and administering the drug while monitoring the CRF concentration in the blood, treatment of neuropsychiatric disorders and / or suppression of symptom progression is effective. · Can be done efficiently.

 (6) In a neuropsychiatric disorder that repeats relapses and remissions, blood is collected over time from patients with neuropsychiatric disorders in remission, and the drug is administered while monitoring the CRF concentration in the blood. Can prevent the recurrence of neuropsychiatric disorders.

 (7) Efficacy of the administered drug is evaluated by administering a drug such as a CRF antagonist candidate compound to a mammal and comparing the blood CRF concentration before and after the drug is administered. Thus, it can be used for a method of screening for the treatment of a neuropsychiatric disorder and / or a symptom progression inhibitor, or a relapse prevention agent, particularly a CRF antagonist.

 Brief Description of Drawings

 [0042] [Fig. 1] Fig. 1 is a graph showing the correlation between CRF concentration in CSF and plasma CRF concentration in healthy individuals. The vertical axis indicates the CRF concentration in CSF, the horizontal axis indicates the CRF concentration in plasma, and R indicates the correlation coefficient.

 [Fig. 2] Fig. 2 is a graph showing the correlation between CRF concentration in CSF and plasma CRF concentration in patients with major depression. The vertical axis shows the CRF concentration in CSF, the horizontal axis shows the CRF concentration in plasma, and R shows the correlation coefficient.

 FIG. 3 is a graph showing the correlation between CSF CRF concentration and plasma CRF concentration in the healthy person and major depression patient shown in FIGS. 1 and 2 on the same graph. The vertical axis indicates CRF concentration in CSF, the horizontal axis indicates plasma CRF concentration, and R indicates the correlation coefficient. BEST MODE FOR CARRYING OUT THE INVENTION

[0043] The ability to explain the present invention using examples below The present invention is not limited to these. In the following examples, the ratio indicates a volume ratio.

Example 1 [0044] (1) Specimen

 As samples, blood (2.5 mL) or CSF (2.5 mL) collected from healthy subjects (9 people) or patients with mild to moderate major depression (12 people) were used.

 [0045] (2) Sample pretreatment

 First, Sep-Pak C18 (manufactured by Waters; ODS column) was sequentially washed with a mixed solution of acetonitrile / 0.5% acetic acid (6/4), methanol and water, and conditioned. A sample solution obtained by adding 6% guanidine hydrochloride solution to the sample was applied to Sep-Pak C18 after the conditioning. Next, the Sep-Pak C18 was washed with 0.1N hydrochloric acid, and developed and eluted with a solution of acetonitrile / 0.5% acetic acid (6/4), so that the deproteinized plasma and CSF eluate were obtained. Got. Each obtained eluate was freeze-dried.

 [0046] (3) CRF measurement by RIA method

Plasma or CSF (specimen) lyophilized in (2) above and anti-CRF serum prepared using Usagi were prepared using buffer solution (0 · 05% Tween20, 0.1% BSA (usi serum albumin) and 0 · A sample solution was prepared by adding 0.1 M PBS (phosphate buffered saline; ρΗ7.4)) containing 1% sodium azide, and the sample solution was incubated at 4 ° C for 24 hours. Next, ¹²⁵ I-CRF was added to the sample solution after incubation, and the mixture was further incubated at 4 ° C for 24 hours. Further, 1% NRS (Normal Rabbit Serum) and 25% polyethylene glycol were added to the sample solution as the second antibody and incubated at 4 ° C. for 4 hours with stirring. Thereafter, the sample solution was centrifuged (3000 rpm), the supernatant was removed, and the radioactivity of the precipitate was measured with a γ-counter (ARC-1000; manufactured by Aroca). The CRF concentration of the specimen was calculated from a separately prepared calibration curve.

 The results are shown below.

[0047] [Table 1] CR F concentration (pg / mL)

 C S F Medium Blood

1 9.66 13.86

2 13.26 8.79

3 12.36 9.68

4 12.14 9.53

5 14.68 12.67

6 12.71 10.92

7 17.74 13.77

8 18.01 16.57

9 13.94 12.61

 [0049] In healthy individuals, CSF CRF concentrations ranged from 9.66 to 18.01 pg / mL, and blood CRF concentrations ranged from 9.53 to 16.57 pg / mL. There was a positive correlation between the blood CRF concentration in healthy people and the CRF concentration in CSF (Figure 1). In patients with major depression, CRF concentrations in CSF ranged from 14.63 to 30.55 pg / mL, and blood CRF concentrations ranged from 7.10 to 22.58 pg / mL. A positive correlation was found between CRF levels in blood and CSF in patients with major depression (Figure 2).

[0050] In addition, CRF concentrations in CSF of many patients with major depression exceeded 20 pg / mL, and although there were variations in blood CRF concentrations, there were many cases of high values exceeding 15 pg / mL. On the other hand, the CRF concentration in CSF of healthy individuals is less than 20 pg / mL, and the concentration of CRF in blood is less than 15 pg / mL with little variation, which is lower than in patients with major depression. ! /, There were many values. [0051] Next, FIG. 3 shows the relationship between the CRF concentration in blood and the CRF concentration in CSF of a healthy person and a major depression patient as one graph. Also in Fig. 3, a positive correlation was observed between the CRF concentration in blood and the CRF concentration in CSF. This result indicates that blood CRF concentration is an indicator of major depression.

 Industrial applicability

[0052] By using the method disclosed in the present invention, a neuropsychiatric disorder involving CRF can be diagnosed, and a treatment schedule thereof, for example, selection of a drug to be used, determination of a dose of the drug, and administration of the drug It can be used to select the period. The method disclosed in the present invention can also be used for screening for CRF antagonists and the like.

Claims

The scope of the claims  [1] The method includes the steps of analyzing blood collected from a mammal and calculating the CRF concentration in the blood, and comparing the obtained blood CRF concentration with a reference value of the blood CRF concentration. A method for measuring CRF concentration in blood for diagnosis of neuropsychiatric disorders.  [2] The method according to claim 1, wherein the reference value of CRF concentration in blood is 12 to 15 pg / mL.  [3] Analyzing blood collected from mammals, calculating the CRF concentration in blood, comparing the obtained blood CRF concentration with the reference value of blood CRF concentration, and blood CRF concentration A method for determining a neuropsychiatric disorder when the value is higher than a reference value.  [4] The method according to claim 3, wherein the reference value of CRF concentration in blood is 12 to 15 pg / mL.  [5] Analyzing blood collected from mammals, calculating the CRF concentration in the blood, comparing the obtained blood CRF concentration with the reference value of the blood CRF concentration, and the blood CRF concentration And a method of regulating the CRF concentration in blood, comprising a step of administering a drug to a mammal having a higher than reference value.  [6] The method according to claim 5, wherein the reference value of CRF concentration in blood is 12 to 15 pg / mL.  [7] The method according to claim 5, wherein the drug is a CRF antagonist.  [8] It includes the steps of analyzing blood collected from a mammal with a neuropsychiatric disorder or a mammal suspected of having a neuropsychiatric disorder, calculating the CRF concentration in the blood, and determining the dose and duration of the drug. A method for determining a treatment schedule for a neuropsychiatric disorder. [9] Analyzing blood collected from mammals with neuropsychiatric disorders, calculating the CRF concentration in the blood, and comparing the obtained CRF concentration in the blood with the CRF concentration in the blood at the previous blood collection. Administering a drug that lowers the blood CRF concentration to a mammal whose blood CRF concentration is equal to or higher than the blood CRF concentration at the previous blood collection. Treatment of neuropsychiatric disorders and / or suppression of symptom progression [10] Analyzing blood collected from mammals with neuropsychiatric disorders in remission and calculating the blood CRF concentration, and calculating the blood CRF concentration in the blood from the previous blood collection And a step of administering to a mammal whose blood CRF concentration is higher than the blood CRF concentration at the time of the previous blood collection, a dose of a drug that lowers the concentration. A method for preventing the recurrence of neurological diseases. [11] The method according to claim 10, wherein the neuropsychiatric disorder is depression. [12] The method of claim 10, wherein the drug is a CRF antagonist. [13] A step of administering a test substance to a mammal, a step of analyzing blood collected from the mammal administered the test substance and calculating a CRF concentration in the blood, and a CRF concentration in the blood obtained And a method of comparing a CRF concentration in a blood before administration of a test substance, and a step of selecting a substance that lowers the blood CRF concentration by administration of the test substance, and / or Or screening method for symptom progression inhibitor or relapse preventive agent [14] The treatment for neuropsychiatric disorders and / or the symptom progression inhibitor, or the preventive agent for recurrence is a treatment for neuropsychiatric disorders and / or a symptom progression inhibitor by CRF antagonism, or an agent for preventing recurrence by CRF antagonism. A method according to claim 13 in the scope.  [15] The method according to claim 13, wherein the test substance is selected such that the decrease in blood CRF concentration by administration of the test substance is 5% or more of the blood CRF concentration before administration of the test substance.