TW200920358A - Method of treating stress-mediated depression - Google Patents

Abstract

The present invention relates to a method for the treatment of depression comprising administering a therapeutically effective amount of gaboxadol to a patient, wherein the level of one or more inflammatory markers in said patient is increased or abnormal. The present invention also relates to a method for the treatment of stress-mediated depression comprising administering a therapeutically effective amount of gaboxadol to a patient, wherein the level of one or more inflammatory markers is increased or abnormal in said patient. The present invention also relates to a method for the treatment of depression or the amelioration of one or more depressive symptoms comprising administering a therapeutically effective amount of gaboxadol to a patient, wherein the clinical presentation of one or more symptoms of depression are the physiological effect of a general medical condition. Furthermore the present also relates to a method for testing the therapeutic effectiveness of a compound in the treatment of depression or reducing the symptoms of depression comprising measuring the amount of one or more inflammatory markers in a sample from a patient before said compound is administered to the patient and comparing with the amount of said one or more inflammatory markers in a sample from the same patient after administration of said compound to the patient.

Description

200920358 IX. Description of the Invention: [Technical Field] The present invention relates to a method for treating depression comprising administering to a patient a therapeutically effective amount of gaboxadol, wherein the patient has one or more inflammatory markers The content is increased or abnormal. The invention is also directed to a method of treating stress mediated depression comprising administering to a patient a therapeutically effective amount of gaboxadol wherein the amount of one or more inflammatory markers in the patient is increased or abnormal. The invention also relates to a method of treating depression or ameliorating one or more symptoms of depression comprising administering to a patient a therapeutically effective amount of gaboxadol, wherein one or more of the clinical manifestations of depression symptoms are physiological effects of a general medical condition. Furthermore, the present invention is also directed to a method of treating a compound for treating a depression or reducing the symptoms of depression, comprising measuring one or more inflammatory markers in a sample from the patient prior to administering the compound to the patient. The amount and the amount of one or more inflammatory markers in a sample from the same patient after administration of the compound to the patient. BACKGROUND OF THE INVENTION [Prior Art] Selective serotonin reuptake inhibitor (hereinafter referred to as SSRI) has become the preferred therapeutic agent for the treatment of depression, some forms of anxiety and social phobia, as it compares It is effective, well tolerated and has a favorable safety profile for traditional tricyclic antidepressants. However, clinical studies of depression and anxiety have shown that the proportion of non-response to sSRI is quite large, up to 30%. Another factor that is often overlooked in antidepressant treatment is 200920358. Another factor is compliance', which has a profound impact on patients' motivation to continue medication. Evidence of increased benefit indicates a link between inflammation and depression. For example, some depressed patients have been found to have high levels of inflammatory markers, such as proinflammatory cytokine, acute phase P(10)ein, chem〇kine, and cells. eeUular adhesion molecule ). In addition, therapeutically administered cytokine interferon-α has been found to cause depression in up to 50% of patients. Stress that can contribute to depression (such as past emotional experiences) can also promote inflammatory responses by affecting the sympathetic and parasympathetic nervous system pathways (Raison et al., 2006, Trends in Immunology, Vol. 27, No. 1, 24 -31). In addition, physiological stress caused by medical diseases or by overcoming diseases or drug treatments associated therewith, in many cases, causes anxiety or depression symptoms. Physiological stress is also associated with higher levels of inflammatory markers such as pro-inflammatory cytokines, acute phase proteins, chemokines, and cell adhesion molecules. The above indicates that an increased reversal of inflammatory markers may treat depression in patients with increased inflammatory markers, especially stress-mediated depression or stress-mediated depression. Addition of λ/wood (4,5,6,7-tetrahydroisoxazo[5,4_c]pyridine-3-ol) 1ΤΗΙΡ), as a selective excipient GABAa agonist, described in 2 continent patents No. 000338 and European Patent No. 84〇6〇1, and have previously shown great potential for treating sleep disorders. Gaposadu has the following pass 200920358

Gaboxadol can be used as is well known in the art, as disclosed in European Patent No. 0000,338. Method of preparation. For example, let gaboxadol be disclosed as a combination therapy for monotherapy or other drugs for the treatment of depression ‘,·-

„ 坪 s 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 The use of other drug combinations for the treatment of depression. However, there are various subindications in depression such as stress-mediated depression, in which the inflammatory markers are increased or abnormal. Compared with the reference value, there is an increased inflammatory mark or has Depressed patients with abnormal levels of inflammatory markers may be difficult to treat with some antidepressant compounds under certain conditions. One reason for this difficulty may be that treatment with antidepressant compounds does not result in increased or abnormal levels of inflammatory markers. Therefore, 'requires novel treatment for patients suffering from depression (such as stress-mediated depression), where the content of one or more inflammatory markers in the patient is increased or compared to the reference value Abnormal content of one or more inflammatory markers. It has been found that in the depression model, the inflammatory markers in animals are Exposure of the animal to a stressful environment increases, and this increase in inflammatory markers is reversed by administering gaboxadol to a stressed animal in 200920358. [Invention] One aspect of the present invention relates to a method of treating depression. A method comprising administering to a patient a therapeutically effective amount of gaboxadol, wherein the amount of one or more inflammatory markers in the patient is increased or abnormal. Another aspect of the invention is a method of treating stress-mediated depression comprising Therapeutic effective amount of gaboxadol is administered to the patient, wherein the content of the inflammatory marker is increased or abnormal. Another aspect of the invention relates to a method of treating depression or ameliorating - or a plurality of depression symptoms, comprising The patient is administered a therapeutically effective amount of gaboxadol's clinical manifestation of one or more of the symptoms of depression as a physiological effect of a general medical condition. Another aspect of the invention relates to a test compound for treating sorrow or reducing depression symptoms A method of therapeutic utility comprising measuring one or more of a sample from the patient prior to administering the compound to the patient The amount of inflammation is labeled and compared to the amount of one or more inflammatory markers in a sample from the same patient after administration of the compound to the patient. Another aspect of the invention relates to a method of treating depression comprising the following steps : a • Measure the amount of one or more inflammatory markers in the sample from the patient and compare the amount to the reference value of the one or more inflammatory markers; if the amount of the one or more inflammatory markers is compared to such The reference value is heterologous' then the patient is administered a therapeutically effective amount of gaboxadol. Another aspect of the invention relates to the use of gaboxadol for the treatment of patients suffering from depression in 200920358. A pharmaceutical composition wherein the content of one or more inflammatory markers in the string is increased or abnormal. Another sorrow of the present invention relates to the use of gaboxadol for the preparation of a medicament for the treatment of stress-mediated A pharmaceutical composition for a patient suffering from depression, wherein the amount of one or more inflammatory markers in the patient is increased or abnormal. Another aspect of the invention relates to the use of gaboxadol for the preparation of a pharmaceutical composition for treating a patient suffering from depression or for ameliorating one or more symptoms of depression in a patient, wherein one or more symptoms of depression Clinical manifestations are the physiological effects of general medical conditions. Another aspect of the invention relates to the use of gaboxadol for the treatment of a patient suffering from depression, wherein the amount of one or more inflammatory markers in the patient is increased or abnormal. Another aspect of the invention relates to the use of gaboxadol for the treatment of a patient suffering from stress-mediated depression, wherein the patient has an increased or abnormal level of one or more inflammatory markers. Another aspect of the present invention relates to gaboxadol, which is a method for treating a patient suffering from a worry or ameliorating one or more symptoms of depression in a general medical condition, wherein one or more clinical symptoms of depression It manifests as a physiological effect. [Embodiment] Description of the Invention In WO2004U2786, gaboxadol has previously been shown to have an antidepressant effect in animal models. In the novel experimental series, we studied the effect of gaboxadol on inflammatory melancholia in an animal model of depression. This model uses a chronically unpredictive stress (chr〇nic mild unpredictive stress) to induce an anhed〇nic state in an animal that can be reversed by a therapeutically active antidepressant. Surprisingly, independent administration of gaboxadol reversed most of the changes in cytokine induced by chronic mild stress, indicating a strong anti-inflammatory effect in stress-related conditions. This effect occurs only in animals with cytokine levels different from those of control animals, and is therefore a consequence of changes in the inflammatory system and is not a general effect. Gaboxadol is therefore capable of specifically normalizing inflammatory markers, such as cytokine levels in animals with abnormal cytokine levels. Since several stress-related diseases are part of a latent condition with a large change in cytokine content, the inventors propose that gaboxadol will have a therapeutic advantage over current treatments in such specific conditions, and current treatment generally does not affect Cytokine content. It is envisaged that the cytokine content is normalized to predict an increased response rate, an increased level of efficacy, and a reduced rate of remission. Defining the term "pressure-mediated melancholic lime Qdf. ^ ^ shock-hip foot" is sometimes referred to as stress-induced depression, which refers to past emotional experiences and/or physiological stress (such as medical illness or medical disease) The drug is caused by depression, in which one or more inflammatory markers are increased or abnormal. The term "sample from a patient" is a biological sample from a patient, and is intended to include tissue, cells, biological fluids (such as blood and its isolates) isolated from the patient. And tissues, cells and body fluids stored in the body of the patient. As used herein, the term "patient 仫 , , " is used to bind any mammal. Patients treated with gaboxadol (such as humans) can be used as human groups in 200920358

B Any individual (male or female) that can be divided into children, adults or the elderly. Any of these patient groups are specific examples of the invention. In the eight-body instance + self-aged for the elderly. In the __ specific example, the individual does not suffer from sleep disorders or sleep conditions. As used herein, the term "therapeutically effective amount" means a biological or medical response sufficient to produce an effective response when administered to a patient (ie, a tissue, system, animal or human being sought by a researcher, veterinarian, doctor or clinician). The amount/dosage of the compound or pharmaceutical composition. The "therapeutically effective amount" will vary depending on the disease and its severity, the age, weight, physical condition and reactivity of the patient to be treated. Furthermore, a "therapeutically effective amount" may vary if a compound of the invention is combined with one or more compounds, in which case the amount of a given compound may be reduced (such as a sub-effective amount) ° as used herein, the term "Treatment" means the clinical prevention or delay of a disease or condition in which a patient is suffering from a disease or condition that is afflicted with the disease or condition but has not experienced or manifested clinical or subclinical symptoms of the disease or condition. appear. "Treatment" also refers to the inhibition of a disease or condition, that is, delaying or slowing its progression or at least one of its clinical or subclinical symptoms. "Treatment" also refers to alleviating a disease or condition, i.e., causing a disease or condition or a decline in at least one of its clinical or subclinical symptoms. The benefit to the patient being treated is statistically significant or at least detectable by the patient and/or physician. Despite this, prophylactic and therapeutic treatments are still two separate examples of the invention. As used herein, the term "pharmaceutically acceptable" means a molecular entity and composition "generally recognized 12 200920358 is safe" - for example, when administered to humans

Gastric upset and the like). "In case of a specific example, this term refers to a molecule approved by the federal regulatory agency or state government or listed in the US Pharmacopoeia or another generally recognized pharmacopoeia for use in animals, and especially humans. Entities and compositions. The physician can determine whether the content of one or more inflammatory markers is increased or abnormal. This determination is based on the auscultation of the physician and can be based on comparisons with reference values, such as reference values from healthy individuals, in some cases, inflammation The mode of labeling content determines whether the inflammatory labeling content is abnormal. The following factors are generally considered in the judgment of the physician, such as the relevant environment, including the condition to be treated, the age, weight, sex, genetic background and ethnicity of the patient. In the example, if the inflammatory marker differs from, for example, a reference value from a healthy individual by more than 1%, or more than 5%, or more than 1%, or more than 15%, or more than 20%, or more than 25%, or more than 3% , or more than 35%, or more than 40%, or more than 45%, or more than 50 ° /., or more than 55 ° /., or more than 60% 'or more than 65% ' or more than 70% ' More than 75%, or more than 8%, or more than 85%, or more than 90%, or more than 95 ❶ /, or more than 1 〇〇❶ / ◦, or more than 1 50 ° / ❶, the inflammatory mark is increased or abnormal The conditions that can be treated according to the invention are known from established and accepted classifications. 'The classifications can be found in a variety of sources. For example, currently, Diagnostic and Statistical

Manual of Mental Disorders) (DSM-IVtm) (2000, Washington, USA £ American Psychiatric Association, 13 200920358

The fourth edition of Washington, D.C.)) provides diagnostic tools for identifying many of the conditions described herein. Similarly, the tenth edition of the International Classification of Diseases (Internati〇nal

Classification of Diseases, Tenth Revision) (ICD-10) provides a breakdown of many of the conditions described herein. Those skilled in the art will recognize that there are alternative nomenclature, disease taxonomy, and classification systems for the disorders described herein, including those described in DMS-IV and ICD-10, and the terminology and classification system along with the medical sciences. Progress and development. In addition, the scientific literature also gives a description of the meaning of the disease. For example, Rydmark et al., Bi〇i〇gicai Psychiatry, 2006, 00, 867-8 73 describe burn-out. Throughout the specification, "gaboxadol" is intended to include any form of the compound, such as a free base (zwitterion), a pharmaceutically acceptable salt (eg, a pharmaceutically acceptable acid addition salt), a base or a salt. Hydrates or solvates and anhydrates, as well as amorphous or crystalline forms. In another embodiment, gaboxadol is selected from the group consisting of zwitterions, usually hydrates thereof, although anhydrate is also suitable. A suitable specific example is a zwitterionic early hydrate. In another embodiment, gaboxadol is selected from the group consisting of acid addition salts, typically pharmaceutically acceptable acid addition salts. Suitable specific examples are organic acid addition salts such as maleic acid addition salts, fumaric acid addition salts, benzoic acid addition salts, ascorbic acid addition salts, succinic acid addition salts, oxalic acid addition salts Salt, bis-indenyl salicylic acid addition salt, decane sulfonic acid addition salt, ethane disulfonic acid addition salt, acetic acid addition salt, propionic acid addition salt, tartaric acid addition salt, salicylic acid addition Salt formation, citric acid addition salt, gluconic acid addition salt, lactic acid addition salt, malic acid addition salt, mandelic acid addition salt, cinnamic acid addition salt, citraconic acid plus 200920358 m salt, aspartame Acid addition salt, stearic acid addition salt, palmitic acid addition salt, itaconic acid addition salt, glycolic acid addition salt, p-aminobenzoic acid addition salt, glutamic acid addition salt, benzenesulfonate An acid addition salt or a theophylline acetic acid addition salt and an 8-halo group test (for example, an 8-iso-tea test) acetic acid addition salt. Another suitable specific example is a mineral acid addition salt such as a hydrochloric acid addition salt, a hydrobromic acid addition salt, a sulfuric acid addition salt, an amine sulfonic acid addition salt, a phosphoric acid addition salt or a nitric acid addition salt. By. In another embodiment, gaboxadol is in the form of a hydrochloride, hydrobromide or zwitterionic monohydrate. In another embodiment, gaboxadol is crystalline, such as crystalline hydrochloride, crystalline hydrobromide or crystalline zwitterionic monohydrate. The gaboxadol can be treated with an acid in an inert solvent, followed by precipitation, separation and, where appropriate, recrystallization by known methods, and if desired, micronization of the crystalline product by wet or dry milling or another convenient method. The microparticles are prepared from a solvent emulsification process to obtain the acid addition salt of the present invention. A suitable method (for example) is described in European Patent No. 338. The precipitation of the salt is usually carried out in an inert solvent such as an inert polar solvent such as an alcohol (e.g., ethanol, 2. propanol and n-propanol), but water or a mixture of water and an inert solvent may also be used. In another embodiment of the invention, the inflammatory marker or cytokine is selected from the group consisting of lipoprotein A1 (APolipGpr〇tein Ap〇1) and /3 2 microglobulin (Beta_2 Micr〇gl〇bulin) , ClUSterin, C Reactive protein (CRp), , * protease inhibitor _C ( Cystatin_c ), eosinophil chemokine 15 200920358 — (Eotaxin), Factor VII (Factor VII), Fibroblast Growth Factor-9 (FGF-9), Granulocyte Chemotactic Protein-2 (GCP-2), Growth Hormone, Immunoglobulin A ( Immunoglobulin A, IgA), Interleukin-10 (lL-l〇), Interleukin Cold (IL-1 /3), Interleukin-2 (IL-2), Interleukin-4 (IL_4), interleukin-5 (IL-5), insulin (Insulin), inducible protein-1 (IP-10), leptin (Leptin), leukemia inhibitor (Leukemia Inhibitory) Factor, LIF), macrophage-Derived Chemokine (MDC), giant cell cell hair Macrophage Inflammatory Protein-1 alpha (MIP-1 a), macrophage inflammatory protein-1/5 (MIP-1 cold), macrophage inflammatory protein-1 Τ (MIP-1 r ), Macrophage Inflammatory Protein-2 (MIP-2), Macrophage Inflammatory Protein-3 /3 (MIP-3 /3), Myeloperoxidase (MPO), Myoglobin, Myopia Neutrophil gelatinase-associated lipocalin (NGAL) (Lipocalin-2), Oncostatin M (OSM), Osteopontin, Serum Amyloid P 5 SAP, Stem Cell Factor (SCF), jk, Serum Glutamic-Oxaloacetic Transaminase (SGOT), Tissue of Type 1 Metalloproteinase Tissue Inhibitor of Metalloproteinase Type-1 (TIMP-1), Tissue Factor, Thrombopoietin (TPO) 16 200920358 0 and Vascuiar End〇thelial Cell Growth Factor (Vascuiar End〇thelial Cell Growth Factor, VEGF) 〇 in this hair In another embodiment the therapeutically effective amount of gaboxadol per day at 1 mg to 20 mg of gaboxadol, gaboxadol such as the range of 5 mg to 15 mg per day. In another embodiment of the invention, gaboxadol is administered as an oral dosage form. In another embodiment of the invention, gaboxadol is a solid oral dosage form such as a lozenge or capsule, or a liquid oral dosage form. In another embodiment of the invention, gaboxadol is crystalline. In another embodiment of the invention, the patient is a human. In another embodiment of the invention, the patient is additionally administered a therapeutically effective amount of escitalopram or a pharmaceutically acceptable salt thereof. In another embodiment, the pharmaceutically acceptable salt of escitalopram is an edetate, HCl salt or HBr salt. In another embodiment of the invention, the amount of one or more inflammatory markers in the patient to be treated is increased or abnormal. In another embodiment of the present invention, the stress-mediated depression is caused by work-related depression, overwork, chronic fatigue syndrome, post traumatic stress disorder (PTSD), and exhaustive fatigue. (exhaustion fatigue), failure depression or acute stress disorder (ASD). In another embodiment of the invention, the stress is caused by a past emotional experience (such as divorce), natural disasters, poverty, interpersonal conflicts, bereavement, and illness or unemployment. In another embodiment of the invention, the pressure is a physiological stress, such as a medical condition or a medical treatment associated with a medical condition. In another embodiment of the invention, the medical condition is multiple sclerosis; stroke; hypothyroidism; diabetes, such as type 1 or type 2 diabetes; heart disease, such as acute myocardial infarction or angina; cancer; HIV infection or AIDS (AIDS); neurological disorders such as cerebrovascular disorders, Parkinson's Disease; traumatic brain injury; stroke, such as the left cerebral hemisphere involving the dorsal lateral frontal cortex Stroke; chronic fatigue syndrome; fibromyalgia; neurosecretion (neur〇crine abnormalities), such as cortisol (cortis〇i) and / or corticotropin-releasing hormone secretion increased; Cytokines such as patients with interferon-α and/or interleukin-2; post-traumatic stress disorder (PTSD); overwork; work-related depression; exhaustive fatigue; I"sexual pain conditions; dyslipidemia (dySiipidemia); dysthymia; inflammatory disease; depressive depression or acute stress disorder (ASD). In another embodiment of the invention, the general medical condition is multiple sclerosis; stroke; hypothyroidism; diabetes, such as sputum or type 2 diabetes; heart disease such as acute myocardial infarction or angina; cancer; Or aIDS; neurological disorders, such as cerebrovascular disease, Parkinson's disease, traumatic brain injury; stroke, such as left cerebral hemisphere stroke involving the dorsolateral frontal cortex, chronic fatigue syndrome; fibromyalgia; nerves 18 200920358 Abnormal secretions, such as increased secretion of corticulin and/or corticotropin-releasing hormone; patients receiving cytokines such as interferon-α and/or interleukin-2; post-traumatic stress disorder (PTSD); overwork; Related depression; exhaustive fatigue; chronic pain conditions; dyslipidemia; mild depression; inflammation <disease; failure depression or acute stress disorder (ASD). In another embodiment of the invention, the compound to be tested for therapeutic utility is selected from the group consisting of antidepressants, such as SSRI, SNRI, or other antidepressant compounds approved by government agencies such as the FDA for use in this application. In a specific embodiment, the compound is gaboxadol. In another embodiment of the invention, the pharmaceutical composition comprises from 1 mg to 2 mg, such as from 5 mg to 15 mg gaboxadol. Another specific embodiment of the invention In an embodiment, the pharmaceutical composition is an oral dosage form. In another embodiment of the invention, the pharmaceutical composition is a solid oral dosage form, such as a lozenge or capsule, or a liquid oral dosage form. In another embodiment of the invention, the pharmaceutical The composition additionally comprises escitalopram or a pharmaceutically acceptable salt thereof. In another embodiment of the invention, the pharmaceutically acceptable salt of escitalopram is edetranol oxalate, HCl salt or HBr salt. In one embodiment of the invention, gaboxadol is used in maintenance therapy. The bismuth formulation plus poloxadol can be used as an oral dosage form, such as a solid oral dosage form. It is usually administered as a lozenge or capsule, or as a liquid oral dosage form. Gaporafil can be administered as an immediate release dosage form or as a controlled release (c〇ntr〇Ued 代卜) or sustained release dosage form. According to a specific example of 200920358, the dosage form provides controlled release or sustained release of gaboxadol in an amount lower than the amount of sleep induction. Gaborsadol can be about 1 to about 150 mg per day, about 0.2 to about 100 mg per day. , from about 0.5 to about 50 mg per day, from about 0.1 to about 5 mg per day, from about 1 to about 15 mg per day or from about 2 to about 5 mg per day, in unit dosage form containing the active ingredient, such as a lozenge or capsule, Conveniently administered orally. Typically the 'pharmaceutical composition comprises from about 5 mg to about 20 mg, such as about 5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 about 9 mg, about 9.5 mg, about 1 〇 mg, about 10.5 mg, about u mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, About 14.5 mg, about 15 mg, about 15_5 mg, about i6 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5%, about 19 mg, about 19 5 mg or about 2 〇 Mg of gaboxa. The gaboxadol is calculated based on the free base (zwitter ion) form. In a specific embodiment, gaboxadol is administered once daily (e.g., morning or afternoon) using an agent of from about mg to about 2 Torr. In another embodiment, gaboxadol is administered with a non-sleep-inducing concentration of gaboxadol (e.g., 2 times a day at a low dose) or modified release using a conventional method known in the art. The formulation (so that it is administered to the individual every 24 hours. = about 5 mg of gamma) is administered in a more persistent and sustained release manner - in the specific example, the gazapine is lower than the sleep-inducing amount. Give. According to the present invention, gaboxadol or a pharmaceutically acceptable salt thereof can be administered in any suitable manner (e.g., parenteral), and can be provided in any form suitable for the administration. For example, it can be used as a cold liquid or dispersion for tablets, capsules, powders, syrups or tablets for injection. In another embodiment, and in accordance with (4) of the present invention, gaboxadol is a solid pharmaceutical entity in the form of a solution, solution or dispersion for injection. In addition, gaboxadol can be administered with a pharmaceutically acceptable carrier such as an adjuvant and/or a diluent. A method for preparing a solid or liquid pharmaceutical preparation is in the art Remington: The Science and Practice of

Pharmacy, 21st ed., Lippincott Williams & Wilkins (2005). Thus, a tablet can be prepared by mixing the active ingredient with a conventional carrier such as an adjuvant and/or a diluent, and then compacting the mixture in a tablet machine. Non-limiting examples of adjuvants and/or diluents include: corn starch, lactose, talc, magnesium stearate, gelatin, lactose, gums, and the like. Other adjuvants or additives may also be used, such as coloring agents, fragrances, and preservatives, which are limited in their compatibility with the active ingredient. The pharmaceutical compositions of the present invention thus typically comprise an effective amount of gaboxadol and a pharmaceutically acceptable carrier. A suitable blend of gaboxadol is described in wo 02/094225. The invention is not limited in any way, and it is intended that any of the aspects or specific examples of the present patent application apply to the pharmaceutical or pharmaceutical compositions described herein. For example, 5 ‘title is “Granular Preparations of Granular Preparations of

WO 02/094225 to Gaboxadol) is particularly suitable for formulating acid addition salts with respect to specific melt granulations, but the invention is not limited in any way to this formulation. 21 200920358 The limulus test uses the chronic mild stress model in rats to perform the following experiments to assess the potential effects of gaboxadol on stress-related biochemical changes (Jayatissa MN, Bisgaard C, Tingstrom A, Papp M, Wiborg O. Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression. Neuropsychopharmacology· November 2006; 31(1 1): 2395-404)° Biochemical changes induced in animals studied in the stress model Inflammatory mediator/marker increased. At the end of the study, the final serum samples were collected for marker analysis to assess the effect of pressure on the content of about 60 blood markers with or without the drug. Previously published data indicate that chronic mild stress mediates the performance of many plasma proteins. The differential adjustment of gaboxadol and edephrine to this response may indicate different mechanisms of action and may be an alternative predictor of clinical efficacy. Experimental procedure Animals During the day after the last drug injection 24 hours (09:00 - 17:00), serum samples were taken from the tail without stunning. Blood was collected into a BD vacuum tube (BD vacutainer) containing a coagulant and gel for serum preparation, inverted 5 times and kept on ice until centrifugation at 3000 rpm for 10 minutes at 4 °C. The serum was decanted, placed on ice, and stored at -80 °C at the end of the day. The animal treatment group was as follows (see Table 1): 22 200920358 Animal group treatment coded pressure condition drug treatment or behavior CMS-VEH chronic mild pressure medium CMS-ECT chronic mild pressure edephrine CMS-GBX-5 mg/kg chronic mild pressure Gaposadu CMS-GBX-10 mg/kg Chronic mild pressure plus Posada CMS-RES Chronic mild pressure resistance NS-VEH No pressure medium NS-ECT No pressure ED-Puls NS-GBX No pressure plus Posada Table 1 Animal group analysis Subsequent analysis of serum samples showed the following results (see Table 2) 23 200920358 崭 f ffi-^'ΑΙ (Apo A1) /5-2 Xue tungsten worms #5 according to the life worm Ilh (calbindin) '0Sc^ Li φφηκρ) 滓 !!^隳菩寺JfC Ξ 屮VII 难孙#la赛忤-s:s屮-9 (FGF-9) 铮 铮 and Ang 4 (τ 蜗卧-2 (GCP-2) ^ ^链^ 释浑4浑8-长雄8| α (Glutathione S-Transferase alpha > GST- α ) GST-M/z 沙狰tungsten ^ΦΑ (IgA) ->φ_-10 (IL-10) Cold φ_-11 (IL-11) -> φ__18 (IL-18)

Ug/mL ug/mL ng/mL ug/mL ug/mL ng/mL pg/mL ng/mL ng/mL ng/mL ng/mL ng/mL ng/mL ug/mL pg/mL Og/mL ng/ mL 7.10 27800 129.00 0.07 S500 §500 005100 P300 PM L66 700 -S· hemp 6.83 22800 S5.00 0.14^ 1 1440.00 121P00 P95 0.23 5.67 7.30 5.91 24S0 128.00 007 P59 P19 7OS7 1140.00 116500 8.20 GWX ^51 6.5 Private 31700 166.00 1060.00 1300.00 0.90 P21 1.300 8.40 MSC5 Bg/kg 480 4500 0.40 11 1130.00 717.00 52.00 0,400 L70 P200 1200 P89 2080.00 5.70 360.00 16S0 0.53 5.80 5900 P12 14600 11 95600 165S0 007 2.40 0.31 2300 P40soo 7_60 Private One 1.00 98.00 P85 1190.00 έο 362.00 0.43

6.20 3800 58.00 150.00 69600 1072.00 0,30 1.70 0.29 3.S 潍 ΙΙΛ GBXS Bg/kg sleeve l·^拽 200920358 25

->π>ίψ-1 α (IL-lft) pg/mL ->φ^-1·εο(Ιί-1·&)) ng/mL ->φ_-2 (IL-2) pg /mL ->D>^-4 (IL-4) pg/mL ->nh:l:-5 (IL-5 ) ng/mL ->B>_-7 (IL-7) ng/ mL s_UIU/mL 4 beach, worm Φ-10 (IP-10) pg/mL βφng/mL 13>.01. 激^堂13+( LIF ) pg/mL ^eit^^^s+pymphotactin) - Pg/ mL +3 Weng ^^^π^^φ-ι pg/mL (Monocyte Chemoattractant Protein-MCP-1) Xiang Weng t·赛昂n= 蜗Φ-3 (MCP-3) pg/mL Hao Weng萚o= worm Φ-5 (MCP-5) pg/mL E.^?^^^.$_j^la^ng/mL (Macrophage-Colony Stimulating Factor > M-CSF) E. Poor game _^箩o^s 屮(MDC) pg/mL 螓 螓 皞泠 φ φ-ια (MIP-ια ) ng/mL 冲豳f赛皞辞10--1/3 (ΜΙΡ-lys) pg/mL豳 豳? Sai Xiong in the worm ^-7 (MIP-1 7) ng / mL ^ repair, ^ ^ ^ ^ ^ 11 > -2 ( MIP-2 ) pg / mL E. ^ 'r & ^ jl ^ m '-s'cbCMIP-s'tb) ng/mL Clean 1^10=1^81 (Mpo)_ng/mL 116.00 209.00 17300 244.00 6.42 13.10 7.95ΠΙΛΟ 005 0.11 008os 89.40 53000κίροοοso 813.00 875.00 865.00 566.00 0.76 65700 0.73 65500 P77 885.00 P87 94100 1095.00 S95.00 1185.00 1500.00 0.11 S.90 86.70 3_2 Private 36.60 41.80 P22 12.20 186.00 117 70.50 73.70 0.16 000000 138.00 2.59 53.90 53.80 22.30 38.80 31.30 24.65 46.70 29.60 8.12 13.80 11.30 15.40 38.80 51.70 P22 11.30 One macro.00 2.S 67.20 68.00 0·13 12000 Pol 1600 0.21 21.75 6S.00 0.26 S7.00 0.02 1500 P3 Private 13.70 39.85 Ρ12 12700 Pol ISO 0.22 29.70 533.00 196000 1610.00 1400.00 65300 Ρ75 703.00 0.75 65S0 P72 1065.00 1025.00 1020.00 0.53 3300 0·26 Shock 9.40 3100 0.9 Private 49.00 2.00 P65 46.00 0.51 00 Private 3.S 36.00 0.27 93.00 7200 P56 22.00 0.24^ 0.06 14.50 41.00 1.35 6700 63.00 >2. and 缈 wear 0> 瘠 A A^mJ^s 屮 SS-麻.弇^ 蜗 2>ng/mL NGAL (龉 age I!>-2) ng/mL ♦Jly^M (OSM) ng/mL Stele worm I!>ng/mL 5sii^iE f Tt Race&gt Zinc current»'θ屮(Regulation Upon Activation, I>Jormal T-Cell pg/mL Expressed and Secreted > RANTES )-ώ.^持寒萍^D>p (SAP) ug/mL ^1-^0 ^( SCF ) pg/mL Tbit 杂港踝-姑0»漭#翁严(SGOT) ug/mL Q—.c ng/mL net s^ng/mL 铕Cell cancer^®屮-a (Tumor Necrosis Factor-alpha > TNF- a ) ng/mL J&., J'^^^it(Tpo) ng/mL .1&-峨1-^ Weng^^^-1 ( VCAM-1 ) ng/mL b 蝶2^1-赛阼洳回屮 (VEGF) pg/mL ι^Α1^1^νΞι^( von Willebrand Factor ;WF )_ng/3T. 134.00 299.00 5500 142.00 381.00 8S0 147.00 361.00 81.00 sbo 409.00 56.00 sbo 12.55 P16 009 008 m.oo 15.30 P27 0.28 0.13 133.00 14.85 P21 0.16 0.10 17800 16.95 0.31 0.22 P15 188.00 39L00 396.00 310.00 P21 P12 0_17 0.22 24L00 39.20 6.16 0.37 006 2.55 130.00 330.00soo 198.00 50.80 6.M 0.77 003 16700 31100 24300 12.85 11.25 408.00ps 21.95 35600 sbo pll 岑90 509.00 520.00 P15 19.10soo 1P60 45.00 11_30 00.53 0.2 private 006 445 11900soo 7800 200920358 Data Collect the values of the concentration of each factor in each animal. RESULTS AND CONCLUSIONS The above-mentioned music theory showed that compared with chronic mild pressure, many blood slags were significantly changed to ... s protein 払. Rats that did not show behavior and response after CMS treatment (CMS-RFS, _ι * group) did not show up-regulation of this serum protein marker compared to the no-pressure control. The inventors have found that the treatment of gaboxadol significantly reverses the pressure-induced blood method q, β cup 屺 change to the content found in the no-pressure control. Therefore, the inventors have found from the above tests and the results that chronic mild stress significantly changes the performance of a group of serum markers, °H protein, and the partial or complete reversal of this effect by gaboxadol (but without the use of escitalopride) indicates that the wave is added. Sando affects the biochemical changes associated with stress by reducing the inflamed mediator. Because of the serotonin alone, gaboxadol can reverse or partially reverse most of the inflammatory parameters of chronic mild stressors. In contrast, escitalopram is inactive in most of these changes. Therefore, 'plus; Pisado can be used to effectively treat stress-mediated depression," one or more of these inflammatory parameters are involved in the progression of depression. All non-patents cited and discussed in this specification The references in the reference patents and the patents in the patents are all quoted in the text and the degree of citation is as if they were individually incorporated by reference. A single ambiguous statement is simple. Figure 27 200920358 [Main component symbol description] No 28

Claims (1)

200920358 X. Patent application: 1 · A pharmaceutical composition for treating depression in patients, comprising a therapeutically effective amount of gaboxad(1), wherein the content of one or more inflammatory markers in the patient is increased Or abnormal. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered as a maintenance therapy. 3. The pharmaceutical composition according to claim 1 or 2, wherein the one or more inflammatory markers are selected from the group consisting of: lipoprotein A1 f (ApoFllte A1, Apo A1 ), cold 2 microspheres Protein (Beta-2 Microglobulin), Clusterin, c Reactive Protein (CRP), Cystatin-C, Cytosine Chemokine (Eotaxin), Factor VII (Factor VII), Fibroblast Growth Factor-9 (FGF-9), Granulocyte Chemotactic Protein-2' GCP-2, Growth Hormone, Immunoglobulin A (IgA), interleukin-10 (IL-10), interleukin _i cold (il_1 cold), interleukin-2 (IL-2), intermedia White pigment-4 (IL-4), interleukin-5 (IL-5), insulin (Insulin), inducible protein-10 (IP-10), leptin (Leptin), Leukemia Inhibitory Factor ' LIF , a chemokine produced by giant scorpion cells (Macrophage-Derived Chemokin e, MDC), Macrophage Inflammatory Protein-lalpha 'MIP-1 a, Macrophage Inflammatory Protein-1 /5 (MIP-1), Macrophage Inflammation 29 200920358 Protein - It* (MIP-lr), macrophage inflammatory protein-2 (MIP-2), macrophage inflammatory protein-3 (Mlp-3), myeloperoxidase (MPO), myoglobin Protein (Myoglobin), neutrophil gelatinase-associated lipocalin (GTAL) (Lipocalin-2), Oncostatin® (OSM), Osteopontin, Serum Amyloid P (SAP), Stem Cell Factor 'SCF, Serum Glutamic-Oxaloacetic Transaminase' SGOT, Tissue Inhibitor of Metalloproteinase Type-1 (ΤΙΜΡ-1), Tissue Factor, Thrombopoietin (Thr〇mb〇p〇ietin, τρ〇) and Vascular Endothelial Growth Factor (Vascular Endothelia l Cell Growth Factor, VEGF). 4. The pharmaceutical composition according to claim 1 or 2, wherein the gaboxadol is in the form of an acid addition salt or a zwitter ion hydrate or a zwitter ion anhydrate. 5. The pharmaceutical composition of claim 2 or 2, wherein gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from the group consisting of hydrochloride or hydrobromide or zwitterionic monohydrate form. 6. The pharmaceutical composition according to claim 1 or 2, wherein the therapeutically effective amount is in the range of i „^ to 2〇mgM Posado, such as 5 to 15 mg gaboxadol per day. The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition of the medical treatment 200920358 is administered as an oral dosage form. "The pharmaceutical composition of the patent range 帛1 or 2, wherein the medical group" For solid π dosage forms 'such as (four) u capsules, or liquid dosage forms. 2. A pharmaceutical composition as claimed in claim i or 2, wherein the gaza is crystalline. 10. The pharmaceutical composition of claim 1 or 2, wherein the patient is a human. A pharmaceutical composition according to claim 1 or 2, wherein the patient is additionally administered a therapeutically effective amount of escitalopram or a pharmaceutically acceptable salt thereof. .12. The pharmaceutical composition of claim 11, wherein the pharmaceutically acceptable sleep of the escitalopine is an oxalate, an HC1 salt or an HBr. salt. 13. A pharmaceutical composition for treating stress-mediated depression comprising treatment with a quantity of gaboxadol wherein one or more inflammatory markers in the patient have an increase or an abnormality. 14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is administered as a maintenance therapy. 15. The pharmaceutical composition of claim 13 or 14, wherein the property is mediated by Depression is caused by work-related depression, bunwna, chronic fatigue syndrome, post-traumatic stress disorder (PTSD), exhaustive fatigue (heart), depressive depression, or acute Lili disease price... 31 200920358 disorder ' ASD ). 16. The pharmaceutical composition of claim 13 or 14, wherein the pressure is caused by such things as divorce, natural disasters, poverty, interpersonal conflicts, bereavement, A past emotional experience in coping with medical illness or unemployment. 17. A pharmaceutical composition according to claim 13 or 14, wherein the stress is physiological stress, and the law is L-such as a dry disease or a drug related to medical disease. 18. The pharmaceutical composition of claim 17, wherein the medical condition is multiple sclerosis; stroke; hypothyroidism; diabetes Diseases such as type 1 or type 2 diabetes; heart disease such as acute myocardial infarction or angina; cancer; HIV infection or AIDS: neurological disorders such as cerebrovascular disorders, Parkinson's Disease; traumatic Brain injury; stroke, such as left cerebral hemisphere stroke involving the dorsal lateral frontal cortex, chronic fatigue syndrome; fibromyalgia; neurosecretion abnormalities such as cortisol (cortis〇l) and / Or increased secretion of corticotropin-releasing hormone; patients receiving cytokines such as interferon-α and/or interleukin-2; post-traumatic stress disorder (PTSD); overwork; work-related Depression; exhaustive fatigue; chronic pain conditions; dyslipidemia; dysthymia; inflammatory disease; depressive depression or acute stress disorder (ASD) 19. as claimed in claim 13 or 14 A pharmaceutical composition wherein gaboxadol is in the form of an acid addition salt or a zwitterionic hydrate or a zwitterionic anhydrate 32 200920358. 20 such as &amp Applying for the patent group No. 13 or 14 of the pharmaceutical group, Jiabosha Huaqi, the cockroach, the cockroach, and the cockroach is a medicinal compound selected from the hydrochloride or hydrobromide salt, and is acceptable. Acid #式' or is a zwitterionic monohydrate form. 2 1 Gentry, A, please patent No. 13 or I4 of the medicine fine eight private ^ The treatment has a 医哥医乐 composition, the amount is in daily 1 « ^ to 20 Posado, such as within the range of 5 mg to 15 mg gaboxadol per day. = The pharmaceutical composition of claim 13 or ", wherein the u w composition is administered as an oral dosage form. For example, please refer to the pharmaceutical composition of claim 13 or 14, wherein: ", and "the substance is a solid oral dosage form, such as a tablet oral dosage form. &, Agricultural 4 遐 24. If the patent application range 13 or 14 the gaboxadol is crystalline. The medical composition of the invention is the pharmaceutical composition of claim 13 or 14, wherein the patient is a human. A pharmaceutical composition according to claim 13 or 14, wherein the heart is additionally administered a therapeutically effective amount of escital 〇pram or a pharmaceutically acceptable salt thereof. 27. The pharmaceutical composition of claim 1 wherein the pharmaceutically acceptable salt of edetran is an oxalate, HCl salt or HBr salt of escitalopram. The pharmaceutical composition of claim 13 or 14, wherein the X-label d is selected from the group consisting of lipoprotein Ai (Ap. Chuan, 33 200920358 W microglobulin, clusterin, 〇 reaction) Protein (CRP), cystatin inhibitor-c, eosinophil chemokine, factor νπ, fibroblast growth factor-9 (FGF-9), granule chemokine protein (10) (1), growth hormone, immunoglobulin A (IgA), interleukin ig (il_ig), interleukin-1/5 (IL-1々), interleukin-2 (IL_2), interleukin-5 (IL-5), insulin , inducible protein _ι〇 (ιρ_ι〇), leptin, white A disease inhibitor (LIF), giant cell production of chemokine (MDC), macrophage inflammatory protein-1 〇; (test heart) , macrophage inflammatory protein · 1Θ (ΜΙΙΜΘ), megalin cell inflammatory protein_1τ (μπμ r), macrophage inflammatory protein 2 (μιρ_2), macrophage inflammatory protein-3 stone (ΜΙΡ-3/3) , myeloperoxidase (Μρ〇), myoglobin, (lipid protein · 2), oncostatin M (〇SM), osteopontin, serum powder-like protein p (SAP), stem cell factor (SCF ),blood Glutamine-oxaacetate transaminase (SG〇T), tissue inhibitor of type I metalloproteinase (TIMP-1), tissue factor, thrombopoietin (τρο), and vascular endothelial growth factor (VEGF). "29. A pharmaceutical composition for treating depression or improving one or more symptoms of a camping disorder in a patient" comprising a therapeutically effective amount of gaboxadol, wherein the clinical manifestation of one or more symptoms of depression is a physiological effect of a general medical condition. 3 如. The pharmaceutical composition of claim 29, wherein the general medical condition is multiple sclerosis; stroke; f-gonadal hypofunction; diabetes, 'such as type 2 diabetes mellitus' such as acute myocardial infarction Or & 'pain, cancer, HIV infection or AIDS; neurological disorders such as cerebrovascular disorders, Parkinson's disease; traumatic brain injury; stroke, such as left cerebral hemisphere stroke involving 34 200920358 dorsolateral frontal cortex; Chronic fatigue syndrome; fibromyalgia; abnormal neurosecretion such as increased cortisol and/or corticosteroid-releasing hormone, receiving cytokines such as interferon Patients with alpha and/or interleukin-2; post-traumatic stress disorder (PTSD); overwork; work-related and depression, exhaustive fatigue; chronic pain conditions; dyslipidemia; mild depression; inflammatory disease; Symptoms or acute stress disorder (ASD). 31. The pharmaceutical composition of claim 29 or 3, Lizhong == is an acid addition salt, or zwitterionic hydrate or zwitterionic anhydrous:: patent application The pharmaceutical composition of claim 29 or 3, wherein the sputum is in the form of a pharmaceutically acceptable salt form selected from the group consisting of hydrochloride or hydrobromide or in the form of a zwitterionic monohydrate. I Acid 33_ As in the scope of application No. 29 or 3, the therapeutically effective amount is in preparation, ... "Les composition, wherein the sputum is in the range of 1 mg to 20 mg per day to 15 gaboxadol. - as for example, 5 mg per day. The pharmaceutical composition is administered as an oral dosage form as claimed in claim 29 or 3. The medical composition is in which 35. The pharmaceutical composition is as claimed in claim 29 or 3 Pharmaceutical composition, wherein the oral dosage form. The cooling agent capsules or liquids. The gaboxadol is crystallized according to the medical application of claim 29 or 30. The medical music composition, wherein 37. Or a medical treatment of 30. The patient is a human. The medical composition of claim 29, wherein the patient is additionally administered a therapeutically effective amount of eptidamide or A pharmaceutically acceptable salt. The pharmaceutical composition according to claim 38, wherein the pharmaceutically acceptable salt of eptopram is an oxalate, HCl salt or HBr salt of escitalopram. 4〇_-test compound in treatment A method of treating depression in a depression or reducing the symptoms of depression' comprising measuring the amount of one or more inflammatory markers in a sample from the patient prior to administering the compound to the patient, and after administering the compound to the patient 41. A method of comparing the amount of one or more inflammatory markers in a sample from the same patient. 41. The method of claim 4, wherein the compound is selected from an antidepressant compound, such as SSRI, SNRI, or approved by a government such as the ship Other antidepressant compounds for this purpose. The method of the invention, wherein the compound is a force 1 42_ as claimed in the patent range diophanyl. Interleukin-5 (IL-5), , inducible protein · 1 〇 (Ip -10), -2 microspheres. 4 3 · If you apply for the specialty τ 松 m 令 令 该 该 该 该 该 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 /5 , eosinophils; maternal growth factor-9 (FGF-9), growth hormone, immunoglobulin A (igA) interleukin (IL-1々), interleukin-2 (36 200920358 leptin, White disease inhibitory factor (LIF), macrophage-derived chemokine (MDC), macrophage inflammatory protein_1α (ΜΙρ_1α), macrophage inflammatory protein-1 /5 (ΜΙΡ-1 call), macrophage Cellular inflammatory protein a γ (ΜΙΙΜ Τ ), macrophage inflammatory protein 2 ( ΜΙΡ 2 ), macrophage inflammatory protein-3 / 3 ( MIP-3 /5 ), myeloperoxidase (Mp 〇), muscle red Protein, NgAL (lipoprotein-2), Oncostatin M (〇SM), Osteopontin, Serum Amyloid P (SAP), Stem Cell Factor (SCF), Serum Face Acid, Oxalic Acid Transaminase ( SGOT), tissue inhibitor of type 1 metalloproteinase (TIMP-1), tissue factor, thrombopoietin (τρ〇), and vascular endothelial growth factor (VEGF) p 44. A pharmaceutical composition comprising a therapeutically effective amount of gaboxadol in an amount of a plurality of inflammatory markers compared to the one or more inflammatory markers having a reference value for treating depression in the patient, wherein one of the samples from the patient is determined The abnormality is observed when the amount of the inflammatory marker is compared with the reference value of the one or more inflammatory markers. 45. The pharmaceutical composition of claim 44, wherein the inflammatory marker is selected from the group consisting of Group: Lipoprotein Ai (A-)... Microglobulin, clusterin, C-reactive protein ((10)), cystatin inhibitor-C, eosinophil chemotactic factor, due to VH, fibroblast growth Factor 9 (FGF-9), granule chemokine-2 (Gcp immunoglobulin), interleukinTM, interleukin-2 (IL_1/3), interleukin-2 (IL_2), interleukin- 4 (IL-4), interleukin-5 (IL-5), insulin, inducible protein _ι〇 (ιρ_(4), leptin, disease inhibitory factor (LIF), chemokine produced by giant sputum cells ((4)c ), 37 200920358 Macrophage Inflammatory Protein _丨α ( MIP-1 α ), H also, ) Inflammatory protein-1 point, megalin cell inflammatory protein]r (Mip_h), macrophage inflammatory protein-2 (elbow „>_2), macrophage inflammatory protein-no), Zhao peroxidase (MPO), Myoglobin, NGAL (lipocin-2), oncostatin M (OSM), osteopontin, serum amyloid p (SAP), stem cell factor (SCF), serum glutamate, oxaloacetate transaminase (SG〇T), tissue inhibitor of type 1 metalloproteinase (TIMP-1), tissue factor gray plateletin (TPO), and vascular endothelial growth factor (VEGF). 46. The pharmaceutical composition of claim 44, wherein the gaboxadol is an acid addition salt, or a zwitterionic hydrate or a zwitterionic anhydrate form. 47. The pharmaceutical composition of claim 44 or 45, wherein the addition of 'small powder is a pharmaceutically acceptable acid addition salt form selected from the group consisting of hydrochloride or hydrobromide' or is a zwitterionic single Hydrate form. 4 g L. • A pharmaceutical composition according to claim 44 or 45, wherein the treatment has a θ + Huan:!: 1 mg to 20 mg gaboxadol on the mother's day, such as 5 mg to 15 & Within the range of LL mg gaboxadol. 49 a. The pharmaceutical composition of claim 44 or 45, wherein the drug pharmaceutical composition is administered as an oral dosage form. 5. A pharmaceutical composition according to claim 44 or 45, wherein the medical product Z is in the form of a solid oral dosage form such as a tablet or capsule, or a liquid oral dosage form. 5. The pharmaceutical composition of claim 44 or 45, wherein 38 200920358 the gaboxadol is crystalline β 52. The pharmaceutical composition of claim 44 or 45 wherein the patient is a human. 53. The pharmaceutical composition of claim 44 or 45, wherein the patient is additionally administered a therapeutically effective amount of epticillin or a pharmaceutically acceptable salt thereof. 54. The pharmaceutical composition according to claim 53 of the patent scope, wherein the The pharmaceutically acceptable salt of pulan is edetate oxalate, HCl salt or HBr salt. 5 5. Use of gaboxadol for the preparation of a pharmaceutical composition for treating a patient suffering from sorrow, wherein the amount of one or more inflammatory markers in the patient is increased or abnormal. 56. The use of claim 55, wherein the pharmaceutical composition is for maintenance therapy. 5 7. The use of claim 55 or 56, wherein the one or more inflammatory markers are selected from the group consisting of: lipoprotein A1 (ApA1), /3-2 microglobulin, clusterin , c-reactive protein (CRp), cystatin inhibitor-c, eosinophil chemotactic factor, factor VII, fibroblast growth factor _9 (FGF_9), granule chemokine e_2 (Gcp_2) \ growth hormone, Immunoglobulin A (IgA), interleukin-1 (IL_l〇), interleukin-1/S (IL-1 phantom, interleukin-2 (1)^2), interleukin _4 (il_4) ) Interleukin-5 (IL_5), Tenjinsu, Inducible Protein-1 () (ιρ_(4), Leptin, Leukemia Inhibitory Factor (LIF), Chemotactic Factor (MDC), Giant Clam Cellular inflammatory protein ~ (ΜΠΜα), 巨嗤小廉39 200920358 Inflammatory protein-1 (MIP-l cold), giant cell inflammatory protein-ΐγ (Mip-i 7*) -2), Python cell inflammatory protein-3 (MIP-3 call), myeloperoxidase (MPO), myoglobin, NGAL (lipoprotein-2), oncostatin M (〇SM), Osteopontin, Qiqingdian powdery protein P (SAP), dry fine Factor (SCF), serum sulphate-sodium ethion Sx transaminase (SGOT), tissue inhibitor of type 1 metalloproteinase (TIMP-1), tissue factor, thrombopoietin (τρ〇), and vascular endothelial growth factor (VEGF) f ' 58. The use of the invention in claim 55 or 56, wherein gaboxadol is an acid addition salt, or a zwitter ion hydrate or a zwitter ion anhydrate form. Or the use of 56, wherein gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from the group consisting of hydrochloride or hydrobromide, or in the form of a zwitterionic monohydrate. Use of 55 or 56, wherein the medicine, 'and & 〇 3 1 mg to 20 mg gaboxadol, such as 5 mg to 15 mg gaboxadol. 61. Use as claimed in claim 55 or 56 Wherein the pharmaceutical composition is administered as an oral dosage form. 62. The use of claim 55 or 56, wherein the pharmaceutical composition is a solid oral dosage form such as a lozenge or capsule, or a liquid oral dosage form. 63. If the scope of patent application is 5 Use of 5 or 56, wherein the gaboxadol is crystalline. 64. The use of claim 55 or 56 wherein the patient 40 200920358 is a human. 65. Use as claimed in claim 55 or 56 Wherein the pharmaceutical composition additionally comprises escitalopram or a pharmaceutically acceptable salt thereof. 66. For the use of claim 65, wherein the pharmaceutically acceptable salt of eptidipride is the use of edetranol oxalate, HCl salt or HBr salt 〇 67 _ gaboxadol, It is used to prepare a pharmaceutical composition for treating a patient suffering from stress-mediated depression, wherein the amount of one or more inflammatory markers in the patient is increased or abnormal. 68. The use of claim 67, wherein the pharmaceutical composition is for maintenance therapy. 69. The use of stress-mediated depression is caused by work-related depression, overwork, chronic fatigue syndrome, post-traumatic stress disorder (PTSD), exhaustive fatigue, as in the application of Section 67 or 68 of the patent application. Caused by depressive depression or acute stress disorder (ASD). 70. If the application of patent application No. 67 or 68 is applied, the pressure is caused by past emotional experiences such as divorce, natural disasters, poverty, interpersonal conflicts, bereavement, medical illness or unemployment. 71. The use of claim 67 or 68, wherein the stress is a physiological stress such as a medical condition or a medical treatment associated with a medical condition. 72. The use of claim 71, wherein the medical condition is sclerotherapy; stroke; hypothyroidism; diabetes, such as type 1 or type 2 diabetes; heart disease, such as acute myocardial infarction or angina; , HIV infection or AIDS; neurological disorders such as cerebral vascular disease, 200920358 Parkinson's disease, traumatic brain injury; stroke, such as left cerebral hemisphere stroke involving the dorsolateral frontal cortex; chronic fatigue syndrome; fibromyalgia Abnormal neurosecretion, such as increased secretion of cortisol and/or cortisol-releasing hormone, patients receiving cytokines such as interferon _^; and/or interleukin-2; post-traumatic stress disorder (PTSD); Work-related depression; debilitating fatigue; chronic pain conditions; dyslipidemia; mild depression; inflammatory disease; depressive depression or acute stress disorder (ASD). 73. The use of claim 67 or 68, wherein gaboxadol is an acid addition salt, or a zwitterionic hydrate or a zwitterionic anhydrate form. 74. The use of claim 67 or 68, wherein gaboxadol is in the form of a pharmaceutically acceptable acid addition salt selected from the group consisting of hydrochloride or hydrobromide or in the form of a zwitterionic monohydrate. . 75. The use of claim 67 or 68, wherein the pharmaceutical composition comprises from 1 mg to 20 mg of gaboxadol, such as from 5 mg to 15 mg of gaboxadol. 76. The use of claim 67 or 68, wherein the pharmaceutical composition is administered as an oral dosage form. 77. The use of claim 67 or 68, wherein the pharmaceutical composition is a solid oral dosage form such as a lozenge or capsule, or a liquid oral dosage form. 78. For the use of claim 67 or 68, wherein the gaboxa is crystalline. 79. For the purposes of claim 67 or 68, the patient is a human. 42. The use of the pharmaceutical composition comprising escitalopram or a pharmaceutically acceptable salt thereof, as claimed in claim 67. 81. The use of the pharmaceutically acceptable salt of edephrine as edetranol oxalate, HCl salt or HBr salt 〇82, as claimed in claim 8 of the patent application. Or use of 68, wherein the inflammatory marker is selected from the group consisting of lipoprotein A1 (ApA1), CAM-2 microglobulin, clusterin, C-reactive protein (CRp), and cystatin inhibitor- c, eosinophil chemokine, factor νπ, fibroblast growth factor-9 (FGF-9), granule chemokine g_2 (GCp_2), growth hormone, immunoglobulin A (IgA), interleukin _1〇 (IL_1〇), Jiebaisuxin (IL-1S), interleukin-2 (IL_2), interleukin-4 (iL_4), interleukin-5 (IL-5), insulin, inducible Protein_1〇(11>_1〇), leptin, leukemia inhibitory factor (LIF), chemokine (mdc) produced by macrophages, macrophage inflammatory protein-1α (ΜΙΡ_1α), macrophage inflammatory protein q /3 ( MIP-1 yj), giant mouth cell inflammatory protein γ), macrophage inflammatory protein-2 (ΜΙΡ·2), macrophage inflammatory protein _30,000 (ΜΙρ_3 /3), myelin Oxidase (ΜΡΟ) 'myoglobin, NGAL (lipid protein-2), oncostatin M (OSM), osteopontin, serum amyloid p (SAP), stem cell factor (SCF), serum glutamine Acid-oxaacetate transaminase (SGOT),;! Tissue inhibitors of metalloproteinases, tissue factor, thrombopoietin (ΤΡΟ) and vascular endothelial growth factor (VEGF). 83. The use of gaboxadol for the preparation of a pharmaceutical composition for treating a patient suffering from depression, or for improving one or more symptoms of depression, wherein one or more clinical symptoms of depression It manifests as a physiological effect of a general medical condition. 84. The use of claim 83, wherein the general medical condition is multiple sclerosis; stroke; hypothyroidism; diabetes, such as type 1 or type 2 diabetes; heart disease such as acute myocardial infarction or angina; cancer HIV infection or AIDS; neurological disorders such as cerebrovascular disorders, Parkinson's disease; traumatic brain injury; strokes such as left cerebral hemisphere stroke involving the dorsolateral frontal cortex; chronic fatigue syndrome; fibromyalgia; Abnormal secretions, such as increased secretion of cortisol and/or cortisol-releasing hormone; patients receiving cytokines such as interferon-α and/or interleukin-2; post-traumatic stress disorder (PTSD); overwork; Related depression; debilitating fatigue; chronic pain conditions; dyslipidemia; mild depression; inflammatory disease; failure depression or acute stress disorder (ASD). 85. For the use of claim 83 or 84, wherein gaboxadol is an acid addition salt, or a zwitterionic hydrate or a zwitterionic anhydrate form. 86. The use of gaboxadol in the form of a pharmaceutically acceptable acid addition salt selected from the group consisting of hydrochloride or hydrobromide, or in the form of a zwitterionic monohydrate, as claimed in claim 83. . 87. The use of claim 83 or 84, wherein the pharmaceutical group 5 comprises from 1 mg to 20 mg of gaboxadol such as 5 mg to 15 mg of gaboxadol. 88. The use of the pharmaceutical composition according to claim 83, wherein the pharmaceutical composition is administered as an oral dosage form. 44 200920358 89. The invention of claim 83, wherein the pharmaceutical composition is a solid oral dosage form such as a lozenge or capsule, or a liquid oral dosage form. 9〇·If the application of the patent application range 83 or 84, the gaboxa is crystalline. 91. The use of claim 83 or 84, wherein the patient is a human. 92. The use of claim 83, wherein the pharmaceutical composition comprises escitalopram or a pharmaceutically acceptable salt thereof. 93. The use of claim 92, wherein the pharmaceutically acceptable salt of eptopram is edetranol oxalate, HCl salt or HBr 〇ie, ο 94. gaboxadol In a method for treating a patient suffering from depression, wherein the amount of one or more inflammatory markers in the patient is increased or abnormal. 9 5. For example, the gaboxadol of claim 94, wherein the gaboxadol is used for maintenance therapy. 96. The gaboxadol of claim 94, wherein the one or more inflammatory markers are selected from the group consisting of: lipoprotein Α "Αρ〇Α1" θ · 2 microglobulin, clusterin, C-reactive protein (cRp), chymotrypsin inhibitor-C, eosinophil chemotactic factor, factor V, fibroblast growth factor·9 (Κ}Ρ·9), granule chemokine protein·2 (Gcp_2) ), growth hormone 'immunoglobulin A (human ^ main), interleukin] 〇 UL-10), interleukin-1 cold (IL-1 call), interleukin ττ interleukin-2 (IL· 2), interleukin-4 (IL-4), 45 200920358 interleukin-5 (IL-5), insulin, inducible protein_1〇(115_1〇), alizarin, leukemia inhibitory factor (LIF) , macrophage-derived chemokine (MDC), mega-cell inflammatory protein-la (MIP-1 〇;), python cell inflammatory protein-1々 (ΜΙΡ-1 /9), macrophage inflammatory protein jr ( Μιιμ 7), macrophage inflammatory protein-2 (ΜΙΡ-2), macrophage inflammatory protein -30,000 (ΜΙΡ-3 points), myeloperoxidase (ΜΡΟ), myoglobin, Ngal (fat cage) Protein-2), oncostatin M ( OSM), osteopontin, serum amyloid P (SAP), stem cell factor (SCF), serum glutamate _ oxaloacetate transaminase (SGOT), tissue inhibitor of type 1 metalloproteinase (TIMP-1), Tissue factor, thrombopoietin (τρ〇) and vascular endothelial growth factor (VEGF). 97. The gaboxadol of claim 94 or 95, wherein the gaboxadol is an acid addition salt, or a zwitterionic hydrate or a zwitterionic anhydrate. 98. The gaboxadol of claim 94 or 95, wherein the gamma J is in the form of a pharmaceutically acceptable acid addition salt selected from the group consisting of hydrochloride or hydrobromide, or zwitterionic monohydrate Form of matter. "Gassardot, as claimed in Section 94 or 95 of the patent application, wherein the amount of the addition is from i mg to 2 〇 mg, such as $ to 15%. 100. The gaboxadol of claim 94 or % of the patent application, wherein the gaboxadol is used as an oral dosage form. 101. gaboxadol, as claimed in claim 94 or 95, wherein the gaboxadol is a solid oral dosage form such as a lozenge or capsule, or a liquid orally 46 200920358 ¥ 〇 2. If Shen Qing patent scope is 94 or 95 Gaborsa, wherein the gaboxa is crystalline. 1 〇 3. For example, the gaboxadol of claim 94 or 95, wherein the patient is a human. 1 〇4· gazazadu, as claimed in claim 94 or 95, wherein the medicinal drug, the gaboxadol in the mouth, additionally contains escitalopram or a pharmaceutically acceptable salt thereof. 105. For the gaboxadol of claim 1, wherein the pharmaceutically acceptable salt of edetranol is edetranol oxalate, HCl salt or HBr salt. 106. A method of treating gaboxadol in a patient suffering from stress-mediated depression, wherein the amount of one or more inflammatory markers in the patient is increased or abnormal. 107. For example, the gaboxadol of claim 106, wherein the gaboxadol is used for maintenance therapy. 108. For gaussaudu, in the scope of patent application No. 〇6 or ι〇7, the stress-mediated depression is caused by work-related depression, overwork, chronic fatigue syndrome, post-traumatic stress disorder (PTSD). ), debilitating fatigue, depressive depression, or acute stress disorder (ASD). 109. For the gaboxadol of claim 1, paragraph 6, or 107, where the stress is caused by past emotional experiences such as divorce, natural disasters, poverty, interpersonal conflicts, bereavement, medical illness or unemployment. 110. If gaboxadol is applied for in the scope of Patent No. 1〇6 or 107, the stress is physiological stress, such as medical disease or medicine related to medical disease 47 200920358. 111. The gaboxadol of claim 11 wherein the medical condition is multiple sclerosis; stroke; hypothyroidism; diabetes, such as type 1 or type 2 diabetes; heart disease, such as acute myocardial infarction or heart Red pain; cancer; HIV infection or AIDS; neurological disorders such as cerebrovascular disease, Parkinson's disease; traumatic brain injury; stroke, such as left cerebral hemisphere stroke involving the dorsolateral frontal cortex; chronic fatigue syndrome; Pain, abnormal neurosecretion, such as corticulin and / or troponin-releasing hormone secretion; patients receiving cytokines such as interferon alpha and / or interleukin; post-traumatic stress disorder (PTSD); overwork; and work Related depression; exhaustive fatigue; chronic pain conditions; dyslipidemia; mild depression; inflammatory disease; failure depression or acute stress disorder (ASD). 11 2. For gaboxadol in the scope of patent application No. 1〇6 or 1〇7, wherein gaboxadol is an acid addition salt, or a zwitter ion hydrate or a zwitterionic anhydrate form... 113. Item 106 or item 1.7 gaboxadol wherein the addition is a pharmaceutically acceptable acid addition salt form selected from the group consisting of hydrochloride or hydrobromide or in the form of a zwitterionic monohydrate. 114. For gaboxadol according to Section 106 or 107 of the patent application, wherein the amount of gaboxadol is from i mg to 2 〇mg, such as 5 mg to i5 ^ 115 · as added in the application of claim 106 or 107 Sandy, in which §Heijiabosha is used as an oral dosage form. ^ 116. gazazadu, as claimed in claim 106 or 107, wherein '• haijiaposha is a solid oral dosage form such as a lozenge or capsule, or a liquid mouth 48 200920358 dosage form. 117 If the patent application scope is m (7), the gaboxadol is crystalline. Knife and "木,,〒 This patient is a person: 加 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The gaboxadol comprises edephrine or its medicinal medicinal lan lan lan ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga ga Chlorooxalate, HCl salt or HBr salt. / 2, as in Patent Application No. 106 or 107, gaboxadol, (4) selected from the group consisting of: lipoprotein A1 (Ap〇A1), Θ-2 microglobulin, condensate preparation , C-reactive protein (CRP), cystatin inhibitor-c, eosinophilic granules 2 progenitor chemokines, factor VII, fibroblast growth factor-9 (FGF-9), granule chemokine Protein_2 (Gcp_2), growth hormone, immunoglobulin A (IgA), interleukin-i〇 (il-(8), interleukin-1"IL_1/S), interleukin-2 (IL_2), White pigment _4 (IL-4), interleukin _5 (IU5), insulin, inducible protein · 10 (ΙΡ · 10), alizarin, leukemia inhibitory factor (LIF), chemotaxis Factor (MDC), mega-cell inflammatory protein heart (ΜΠΜα), giant sputum cell inflammatory protein W (ΜΠΜ3), giant heart inflammatory protein seven (Μπμ r), giant t cell inflammatory protein-2 (ΜΙρ·2), giant嗟 cell inflammatory protein _3 0 (ΜΙΡ), myeloperoxidase (_), myoglobin, 4949 200920358 4 (lipid-2), oncostatin OS (OSM), osteopontin, serum Amyloid P (SAP), Stem cell factor (SCF), serum glutamate-oxaacetate transaminase (SGOT), tissue inhibitor of type 1 metalloproteinase (TIMP-1), tissue factor, thrombopoietin (τρ〇), and vascular endothelial growth factor (VEGF). 122. A gaboxadol for use in a method of treating a patient suffering from depression or ameliorating one or more symptoms of depression in a patient, wherein the clinical manifestation of one or more of the symptoms of depression is a physiological effect of a general medical condition. 123. The gaboxadol of claim 122, wherein the general medical condition is multiple sclerosis; stroke; hypothyroidism; diabetes such as type 1 or type 2 diabetes; heart disease, such as acute myocardial infarction or angina pectoris Cancer; HIV infection or AIDS; neurological disorders such as cerebrovascular disease, Parkinson's disease; traumatic brain injury; stroke, such as left cerebral hemisphere stroke involving the dorsolateral frontal cortex; chronic fatigue syndrome; fibromyalgia Abnormal neurosecretion, such as increased secretion of cortisol and/or cortisol-releasing hormone; patients receiving cytokines such as interferon-α and/or interleukin-2; post-traumatic stress disorder (pTSD); overwork; Work-related depression; exhaustive fatigue; chronic pain conditions; dyslipidemia; mild depression; inflammatory disease; sorrow depression or acute stress disorder (ASD). 124. For example, the gaboxadol of claim 122 or ι 23, wherein gaboxadol is an acid addition salt, or a zwitterionic hydrate or a zwitterionic anhydrate form. 125. The gaboxadol of claim 122 or 123, wherein gaboxadol is a pharmaceutically acceptable acid selected from the group consisting of hydrochloride or hydrobromide 50 200920358 addition salt form, + & π p or a zwitterionic monohydrate form. The: == the gaboxadol of the 122nd or 123th range, wherein the sputum is set to 1mg to 20mg, such as 5 to 15 calls. • If the scope of application for patents is 122戋123, the gaboshadu r... Posado '/ where the wood is used as an oral dosage form. SI SI SI SI 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 129. For example, the gaboxadol of the patent application range m (2), wherein the gaboxadol is crystalline. 〇·If you apply for gaboxadol in Article 122 or 123, the patient is a human. 131 ± 0 gaboxadol of the 122nd or 123th patent application, wherein the pharmaceutical composition φ $ # 4, Τ之之海加波沙朵 contains edetran or its pharmaceutically acceptable salt. 132. The gaboxadol of claim 131, wherein the pharmaceutically acceptable salt of edetranol is edetranol oxalate, HCl salt or HBr salt. 133. Use of a gaboxadol for the manufacture of a medicament for treating a patient suffering from depression, wherein the amount of one or more inflammatory markers in the patient is abnormal compared to the one or more inflammatory markers, wherein the assay is from The abnormality is observed when the amount of one or more inflammatory markers in the patient's sample is compared to the reference value of the one or more inflammatory markers. 134. The use of claim 133, wherein the inflammatory marker 51 200920358 2 comprises a population of: lipoprotein A1 (Ap〇Ai) microspheres, clusterin, c-reactive protein (CRP), cystatin inhibition eC eosinophil chemotactic factor, factor v, fibroblast growth factor (FGF-9), granule chemokine protein 2 (GCp_2), growth hormone, immunoglobulin A (IgA), interleukin -IO(IL-IO), interleukin-1), interleukin-2 (IL-2), interleukin-4 (IL_4), interleukin-5 (il_5), temsin, inducible protein, (Ip_1Q), leptin, leukemia inhibitory factor (LIF), chemokine (mdc) produced by giant scorpion cells, inflammatory protein-Ια (ΜΙΡ-ΐα) of giant scorpion cells, inflammatory protein of giant scorpion cells (μ~ 幻,巨嗟 cell inflammatory protein VII (Yong Qi), python cell inflammatory protein-2 (MIP-2), python cell inflammatory protein _30,000 (Μιρ_3, myeloperoxidase (MP〇), myoglobin, NGAL (lipid protein-2), oncostatin M (OSM), osteopontin, serum powder-like protein p ( s Ap ), stem cell factor (SCF), serum glutamate _ grass B Transaminase (SG〇), tissue inhibitor of type 1 metalloproteinase (BMpq), tissue factor, thrombopoietin (τρο) & vascular endothelial growth factor (VEGF). 135. Claim No. 133 or 134 The use of the item, wherein gaboxadol is an acid addition salt, or a zwitter ion hydrate or a zwitter ion anhydrate form. 136. The use of gapensate as a hydrazine salt, as claimed in claim 133 or 134. Or a pharmaceutically acceptable acid addition salt form of the hydrobromide salt, or a zwitterionic monohydrate form. 137. The use of the gaboxadol daily effective as claimed in claim 133 or 134 The amount is from i mg to 2 〇, such as 5 52 200920358 0 to 15 mg per day. 13 8. If the patent application is the oral dosage form, the use of 133 or 134, wherein the medical application ～ 139. (1) The use of 134 items, wherein the medicine is an oral dosage form such as a lozenge or capsule, or a liquid oral dosage form. For example, the application of the patent application scope 133 or 134, wherein the gaboxa is a knot 141. The use of claim 133 or 134, wherein the patient is a human _ ^ 142. as claimed in claim 133 or 134, wherein the patient is additionally administered a therapeutically effective amount of eptidiprine Or a pharmaceutically acceptable salt thereof. 143. The use of the pharmaceutically acceptable salt of escitalopram according to claim 142, wherein the pharmaceutically acceptable salt of escitalopram is an oxalate, HCl salt or HBr salt of escitalopram. XI. Ming style: None 53