Esketamine for the treatment of patients with major depressive disorder, including suicidal tendencies.

Abstract

The present invention provides a pharmaceutical composition for reducing symptoms in patients with major depressive disorder, including suicidal tendencies. [Solution] A pharmaceutical composition is provided for use in a method for reducing symptoms of major depressive disorder, including suicidal tendencies, in a human patient assessed to be at imminent risk of suicide, wherein the pharmaceutical composition comprises esketamine, and the method comprises (a) determining whether the patient has previously attempted suicide, and (ii) if the patient has previously attempted suicide, treating the patient with standard treatment and esketamine.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 892,841, filed Aug. 28, 2019 and U.S. Provisional Patent Application No. 62 / 897,593, filed Sep. 9, 2019, the entire disclosures of which are incorporated herein by reference.

[0002] (Field of the Invention) The present invention relates to a treatment for reducing symptoms of major depressive disorder (MDD) including suicidal tendency in patients evaluated as having an imminent risk of suicide.

[0003] (Background) Suicide is one of the leading causes of death worldwide. MDD is the most frequent condition associated with suicide. MDD patients showing active suicidal ideation with intent constitute a mental emergency with an imminent risk of suicide and require immediate intervention. However, there is no approved treatment for rapidly reducing the symptoms of MDD with suicidal ideation, and these patients are typically hospitalized for intensive treatment. <00000​​​​​​​​​​​​​​

[0005] Furthermore, patients with significant suicidal ideation and related behaviors are typically considered for clinical trials of antidepressant treatment. Excluded from. The severity of this disease and the large unmet medical need for effective treatment. Considering the needs, reforms to treat patients assessed as being at imminent risk of suicide A better method is needed.

[0006] (overview) In some embodiments, the present disclosure describes administering esketamine in addition to standard treatment. This includes major depression, including suicidal tendencies, in human patients assessed as being at imminent risk of suicide. This relates to a method for reducing the symptoms of a pathological disorder. In a particular embodiment, the method is used when a patient is To determine whether or not you have ever attempted suicide before, and if so, This includes treating such patients with standard treatment and therapeutically effective doses of esketamine. Insofar as it is determined that the patient has not previously attempted suicide, the patient will be treated as follows: The patient will receive standard treatment without being treated with ketamine. [Brief explanation of the drawing]

[0007] [Figure 1] This is the clinical trial design for Example 1. [Figure 2] This is a line graph showing the mean LS (±SE) of the total Montgomery-Asberg Depression Rating Scale (MADRS) score over time - ANCOVA LOCF; double-blind treatment phase for the maximal efficacy analysis population. The mean LS and SE were based on an analysis of covariance (ANCOVA) model with treatment (placebo, esketamine 84 mg), analysis site, and randomized standard antidepressant treatment (antidepressant monotherapy, antidepressant + augmentation therapy) as factors, and baseline values ​​as covariates. A negative change in score indicates improvement. [Figure 3] Clinical Global Impression Severity of Suicidal Tendency - Revised (CGI-SS-R) score: A bar graph showing the frequency distribution at baseline, 4 hours after the first dose, 24 hours after the first dose, and day 25; LOCF; Double-blind treatment phase for the population targeted for maximum efficacy analysis. [Figure 4] Montgomery-Asberg Depression Rating Scale (MADRS) total score: This is a line graph showing the mean LS (±SE) of change over time - an observed example of MMRM; double-blind treatment phase for the maximal efficacy analysis population. Mean LS and SE were based on MMRM analysis with baseline values ​​as covariates, with treatment (placebo, esketamine 84 mg), time, analysis site, randomized standard antidepressant treatment (antidepressant monotherapy, antidepressant + augmentation therapy), and time-treatment interaction as factors. A negative change in score indicates improvement. [Figure 5] This is the clinical trial design for Example 2. [Figure 6] This is a line graph showing the mean LS (±SE) of the total Montgomery-Asberg Depression Rating Scale (MADRS) score over time - ANCOVA LOCF; double-blind treatment phase for the maximal efficacy analysis population. The mean LS and SE were based on an analysis of covariance (ANCOVA) model with treatment (placebo, esketamine 84 mg), analysis site, and randomized standard antidepressant treatment (antidepressant monotherapy, antidepressant + augmentation therapy) as factors, and baseline values ​​as covariates. A negative change in score indicates improvement. [Figure 7] Clinical Global Impression Severity of Suicidal Tendency - Revised (CGI-SS-R) score: A bar graph showing the frequency distribution at baseline, 4 hours after the first dose, 24 hours after the first dose, and day 25; LOCF; Double-blind treatment phase for the population targeted for maximum efficacy analysis. [Figure 8]Montgomery-Asberg Depression Rating Scale (MADRS) total score: A line graph showing the mean LS (±SE) of change over time; observed example of MMRM; double-blind treatment phase for the maximal efficacy analysis population. Mean LS and SE were based on MMRM analysis with baseline values ​​as covariates, with treatment (placebo, esketamine 84 mg), time, analysis site, randomized standard antidepressant treatment (antidepressant monotherapy, antidepressant + augmentation therapy), and time-treatment interaction as factors. A negative change in score indicates improvement. [Figure 9] MADRS forest plot - shows the mean LS difference between groups of change from baseline to 24 hours after the first dose in Example 4. [Figure 10] MADRS forest plot - shows the mean LS difference between groups of change from baseline to 24 hours after the first dose in Example 5. [Figure 11] This is a forest plot of MADRS 24 hours after the first dose: Subgroup analysis pooled the analyses from Examples 4 and 5. [Figure 12] CGI-SS-R forest plot - showing the group difference in change from baseline to 24 hours after the first dose in Example 4. [Figure 13] CGI-SS-R forest plot - showing the group difference in change from baseline to 24 hours after the first dose in Example 5. [Figure 14] Forest plots of CGI-SS-R 24 hours after the first dose: Subgroup analysis of Examples 4 and 5. [Figure 15] This bar graph shows MADRS remission by history of suicide attempts - pooled analysis of Examples 4 and 5 for patients with a history of suicide attempts (MADRS remission refers to a MADRS total score of ≤12). [Figure 16] This bar graph shows MADRS remission by history of suicide attempts - pooled analysis of Examples 4 and 5 for patients without a history of suicide attempts (MADRS remission refers to a MADRS total score of ≤12). [Figure 17] Forest plot of subgroup analysis of past suicide attempts using CGI-SS-R in Examples 4 and 5. [Figure 18] Bar graph showing the MADRS remission rate over time (MADRS total score ≤ 12) during the DB treatment phase (the largest population for efficacy analysis) in Example 4. [Figure 19] Bar graph showing the MADRS remission rate over time (MADRS total score ≤ 12) during the DB treatment phase (the largest population for efficacy analysis) in Example 5. [Figure 20] Forest plot showing the odds ratios of improved scores for CGI-SS-R and other suicide tendency indices at 4 hours, 24 hours, and 25 days after the first dosing (IRT; LOCF; DB treatment phase in Example 4 (the largest population for efficacy analysis)). Based on the IRT model, findings of all indices of suicide tendency (CGI-SS-R, MADRS suicide thought item, CGI-SR-I, clinician-assessed FoST, and patient-reported FoST) at 4 hours and 24 hours after the first dosing and on the 25th day are provided. [Figure 21] Forest plot showing the odds ratios of improved scores for CGI-SS-R and other suicide tendency indices at 4 hours, 24 hours, and 25 days after the first dosing (IRT; LOCF; DB treatment phase in Example 5 (the largest population for efficacy analysis)). Based on the IRT model, findings of all indices of suicide tendency (CGI-SS-R, MADRS suicide thought item, CGI-SR-I, clinician-assessed FoST, and patient-reported FoST) at 4 hours and 24 hours after the first dosing and on the 25th day are provided.

[0008] (Detailed description of specific embodiments) Some of the quantitative expressions given in this specification are not modified by the term "about". Whether or not the term "about" is explicitly used, all quantities described in this specification are meant to refer to their actual values and include approximations due to experimental and / or measurement conditions of such values, An approximation of such a value that can be reasonably estimated based on the usual skill in the relevant technical field. It is understood that it can both point to something and mean something.

[0009] As used herein, unless otherwise specified, the term "esketamine" refers to ketamine. (S)-enantiomer refers to a compound of formula (I),

[0010] [ka] This is (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexano It is also known as "esketamine." "Esketamine" is also the (S)-enantiomer of ketamine. This also refers to salts of, for example, chloride salts such as hydrochloride salts, i.e., compounds of formula (II). death,

[0011] [ka] This is (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexano It is also known as nitrate hydrochloride.

[0012] In some embodiments, esketamine is the (R)-enantiomer of ketamine, that is, In other words, it substantially does not contain the compound of formula (III).

[0013] [ka]

[0014] In other embodiments, esketamine is calculated based on the weight of the esketamine sample. It contains less than about 10% by weight of the (R)-enantiomer of .In further embodiments, Tamin is the (R)-enantiomer of ketamine, based on the weight of the esketamine sample. to approximately 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.005, or 0 It contains less than 0.001% by weight. In yet another embodiment, esketamine is esketamine Based on the sample weight, the amount of ketamine (R)-enantiomer is approximately 0.001 to 10 times the weight. It contains % by amount. In further embodiments, esketamine is the weight of the esketamine sample. Based on the amount, the (R)-enantiomer of esketamine is used in concentrations of approximately 0.001 to 10%, and approximately 0 0.001 to approximately 5%, approximately 0.001 to approximately 1, approximately 0.001 to approximately 0.5, approximately 0.001 to approximately 0 .1, about 0.1 to about 5, about 0.1 to about 1, about 0.1 to about 5, or about 0.5 to about 5% by weight. To possess.

[0015] The term "esketamine" also refers to other pharmaceutically acceptable substances that can be readily selected by those skilled in the art. It may also contain that salt. A "pharmacopoeially acceptable salt" is one that is non-toxic and biologically tolerable. This refers to salts of esketamine that are, in some respect, or otherwise, biologically suitable for administration to the subject. This is intended to be the case. In general, see GSPaulekuhn, "Trends in Active Pharmaceutical Ingredient Salt S election based on Analysis of the Orange Book Database”, J.Med.Chem.,2007,50:6665 -72,SMBerge,"Pharmaceutical Salts",JP harm Sci., 1977, 66:1-19 and Handbook of Phar Maceutical Salts,Properties,Selection,an d Use,Stahl and Wermuth,Eds.,Wiley-VCH a See nd VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are It is pharmacologically effective and can be administered to patients without excessive toxicity, irritation, or allergic reactions. This salt is suitable for administration.

[0016] Other examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, Bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates Bromides (such as hydrobromides), iodides (such as hydroiodides), acetates, propion Salts, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, Heptanate, propionate, oxalate, malonate, succinate, suberinate, Sebacinate, fumarate, maleate, butin-1,4-dioate, hexin-1 ,6-Dioete, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate Salts, hydroxybenzoates, methoxybenzoates, phthalates, sulfons, xylene Sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citric acid Salt, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, Propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate Examples include mandelate salts. In particular, the salts of esketamine are hydrochloride salts.

[0017] Unless otherwise specified, the amounts of esketamine used herein refer to the amounts of esketamine free base β It is stated in -. That is, the amount is, for example, (for example, in a pharmaceutically acceptable salt This indicates the amount of esketamine molecules administered, excluding the counterions.

[0018] In certain embodiments, esketamine is administered intranasally. In other embodiments, esketamine is administered intranasally. Tamine is administered intranasally as its corresponding hydrochloride. In further embodiments, Esketa Min is the corresponding hydrochloride in a 16.14% wt / vol solution (14% wt / vol esketami It is administered intranasally as a base. In another embodiment, esketamine is administered in water At a pH of 4.5, 161.4 mg / mL of esketamine hydrochloride (140 mg / mL of esketamine hydrochloride) (equivalent to ketamine base), 0.12 mg / mL of ethylenediaminetetraacetic acid (EDTA), and It is administered intranasally as a solution containing 1.5 mg / mL of citrate. Further implementations are also being considered. In this state, esketamine is administered intranasally and delivered via intranasal delivery to water at a pH of 4.5. 161.4 mg / mL of esketamine hydrochloride (compared to 140 mg / mL of esketamine base) (This includes) 0.12 mg / mL of ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / m² A 100 μL solution containing L of citrate is administered. In other embodiments, esketamine is administered. It is delivered into the nasal cavity using an intranasal spray pump, which dispenses water at a pH of 4.5, and 16 1.4 mg / mL of esketamine hydrochloride (equivalent to 140 mg / mL of esketamine base) , 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL Deliver 100 μL of a solution containing citric acid.

[0019] Generally, one pump from an intranasal spray device dispenses approximately 50 μL to 200 μL (approximately 60 μL). Approximately 70 μL, approximately 80 μL, approximately 90 μL, approximately 100 μL, approximately 110 μL, approximately 120 μL, Approximately 130μL, approximately 140μL, approximately 150μL, approximately 160μL, approximately 170μL, approximately 180μL A solution of esketamine (containing L and approximately 200 μL) is configured to be delivered into the target nostril. It may be done this way. Therefore, the two pumps deliver approximately 100 μL to approximately 400 μL to the target. ru.

[0020] As used herein, the term "depression" refers to major depressive disorder, persistent depressive disorder, Seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholy, middle age Depression in early childhood, depression in later life, depression due to identifiable stressors, treatment-resistant depression, and This includes combinations thereof. In certain embodiments, depression is major depressive disorder. Diagnostic and statistical manual of men The major Disorders, 5th Edition: DSM 5 (See criteria for depression). In other embodiments, major depressive disorder is characterized by melancholic features or It is accompanied by distress due to anxiety. In a further embodiment, the depression is treatment-resistant depression.

[0021] As used herein, “suicide,” also known as attempted suicide, means “taking one’s own life.” It is an act of "suicide." http: / / en.wikipedia.org / wiki / Sui See cide-cite_note-7. "Suicide attempt" or non-fatal suicide related The behavior is self-inflicted, accompanied by a desire to end one's own life, but not to the point of death. Ultimately, it was carried out by an individual who, at the outset, foresaw that the series of actions would lead to their own death. It is a series of spontaneous actions. Risk factors for suicide include a history of suicide attempts, anhedonia, and comorbid sperm. Disorders, substance abuse, serious or chronic health conditions, and low levels of social support (for example) (living alone), the manifestation of feelings of despair, or stressful life events that trigger them (for example) Examples include, but are not limited to, death, divorce, separation, unemployment, and significant financial failure. .

[0022] As used herein, “suicidal tendencies” refers to one or more of the following: death Repeated thoughts (not just a fear of death), suicidal ideation without a concrete plan. Repeated suicide attempts, or specific plans to commit suicide.

[0023] As used herein, "suicidal ideation" refers to thoughts about suicide or an abnormality related to suicide. This refers to an obsession, or the thought of wanting to end one's own life or no longer wanting to live. However, this does not necessarily mean that they are actively attempting to commit suicide. The range of suicidal ideation The scope ranges from transient to chronic and detailed planning, role-playing, and failed These range from attempts to progress to other approaches, and these are intentionally designed to fail or be discovered. It may be composed of, or may be fully intended to bring about death. "Homicidal thoughts" should be identified through questions to the patient, taking into consideration the scales / tools disclosed herein. The intention or recognition that it may result in death Thoughts (even momentarily) of one's own injury, pain, or harm accompanied by awareness; or thoughts of suicide Thoughts about killing oneself (that is, thoughts about killing oneself and thoughts about killing oneself) This includes having the intention to act accordingly.

[0024] For the assessment of suicidal tendencies and / or suicidal ideation, the Beck Suicidal Ideation Scale (BSS) and Columbia Suicide Severity Rating Scale (C-SSRS), Suicidal Ideation and Related Behavior Assessment Tool (SIBAT) Clinical General Impression Score - Severity of Suicidal Tendency - Revised Edition (CGI-SS-R), Simplified Structure of Mental Illness Using specific scales / tools, including the Minimally Investigative Interview (MINI) and the Frequency of Suicidal Thoughts (FoST). It can be used.

[0025] As used herein, "at imminent risk of suicide" means a high level of suicidal ideation. Having the intention to act in accordance with suicidal thoughts, and possessing the current ability to injure oneself, and being in imminent danger This refers to patients who are highly likely to severely harm or kill themselves in the near future. These are typically short-term arrangements of less than two weeks, less than one week, less than two days, less than one day, or less than a few hours. This was the period.

[0026] The methods described herein are appropriate for patients assessed as being at imminent risk of suicide. This assessment is typically performed by the attending physician or other qualified medical professional or clinician. This assessment is carried out by using the scales / tools described herein. This includes the entire experience of the medical professional regarding the person, as well as the patient's medical records and medical history. For example, the patient However, regarding impulsive actions toward suicide, whether or not they involve planning or recent attempts Periodic thoughts accompanied by intention or possibility; intention accompanied or not accompanied by a recent suicide attempt. Frequent suicidal thoughts and / or carefully planned suicides; or nearly constant suicidal thoughts and intention and / or carefully planned, and ongoing preparations or recent attempts In such cases, an assessment of imminent risk may be conducted. An assessment of imminent risk is conducted in relation to suicide. Questions such as whether you have thought about it and whether you intend to act on suicidal thoughts. This can be confirmed by asking the patient.

[0027] As used herein, the term “standard treatment” means that the risk of suicide is considered imminent. Patients suffering from major depressive disorder, including those with suicidal tendencies and / or suicidal ideation. This refers to treatment prescribed by a physician for a patient. For the purposes of this disclosure, unless otherwise specified. Standard treatment does not include esketamine.

[0028] In some embodiments, standard treatment includes the standard treatment disclosed in the examples herein, It consists of, or essentially consists of. In certain aspects, standard treatment is the psychiatric care of hospitalized patients. Inpatient treatment and initiation or optimization of standard antidepressant medication (based on clinical judgment and diagnosis) This includes (determined by the attending physician based on medical guidelines). Standard treatment also includes any Psychotherapy is not prohibited, and other concomitant drug therapies, such as those containing benzodiazepines, are permitted. It may be. In other embodiments, standard treatment is for outpatients from initial hospitalization to after discharge. This further includes treatment. The frequency and duration of treatment for outpatients will be determined by the attending physician or other healthcare professional. It may be prohibited (proscribed), for example, for a maximum of 1 week, a maximum of 2 weeks, a maximum of 3 weeks, For a maximum of 4 weeks, or a maximum of 5 weeks, or longer, once a week, twice a week, three times a week, or This includes more outpatient visits. As disclosed in the examples, such outpatient treatment is for outpatients. In the facility or program, this may be done twice a week for an additional two hours each time. Outpatient Psychiatry Treatment may include one or more of the following: in particular, psychiatric evaluation, medical management, Group therapy, family intervention, neuropsychological testing, psychotherapy.

[0029] It should be noted that the standard treatments disclosed in the examples constituted clinical trial level care. This is because patients may not receive the same level of care outside the clinical trial environment. Therefore, the results of the clinical trials reflected in the examples need to be viewed in that context. For example, The differences reported between treatment groups were, for example, in the diffusion of sudden suicide risk among participants in the treatment group. For example, outpatient treatment for psychiatric inpatients and / or outpatient treatment in combination with inpatient treatment. The clinical trial situation, including the substantial beneficial effects of the hospital, needs to be considered. In trials involving high-risk patient populations, clinical trial plans are implemented to ensure ethical treatment and patient safety. Rotor will be enhanced or become more comprehensive.

[0030] Typically, standard treatment is prohibited by the attending physician or other healthcare professional. ) Provided as prescribed and administered in parallel with esketamine treatment, for example, standard treatment is esketamine The same treatment duration as with esketamine treatment is offered. Standard treatment is also performed before treatment with esketamine. It is fine to continue it after treatment with esketamine has been discontinued. Regarding antidepressants used, esketamine and antidepressants are administered via the same or different routes. It can be administered via [method of administration]. Examples of preferred methods of administration include oral, intravenous (IV), and intranasal administration. (in), intramuscular (im), subcutaneous (sc), percutaneous, buccal, or rectal are examples, but These are not limited to the above. In preferred embodiments, esketamine is administered intranasally.

[0031] As used herein, unless otherwise specified, the term “antidepressant” refers to the treatment of depression. This refers to any pharmaceutical product that can be used. A preferred example is monoami. oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors, serotonin-norepinephrine inhibitors Phosphating reuptake inhibitors, or noradrenergic and specific serotonergic drugs Drugs are listed, but are not limited to, these. Other examples include phenelzine and tranilx. Monoamine oxidase inhibitors such as promin and moclobemide, imipramine, amitriptyline Phosphorus, desipramine, nortriptyline, doxepin, protriptyline, trimipramine Tricyclic antidepressants such as clomipramine and amoxapine; tetracyclic antidepressants such as maprotiline; nomife Acyclic compounds such as synthia; triazolopyridines such as trazodone; fluoxetine, sertra Phosphorus, Paroxetine, Citalopram, Citalopram, Escitalopram, Fluvoxamine Serotonin reuptake inhibitors such as nefazadone; serotonin receptor antagonists such as nefazadone. To; Venlafaxine, Milnacipran, Desvenlafaxine, Duloxetine, etc. Serotonin-norepinephrine reuptake inhibitors, such as mirtazapine, are norepinephrine-producing drugs. Motion-specific serotonergic drugs; norepinephrine such as reboxetine and edivoxetine Reuptake inhibitors; natural products such as kava kava and St. John's wort; s-adenosyl Nutritional supplements such as rumethionine, and neuropeptides such as thyroid-stimulating hormone-releasing hormone. Tide; compounds targeting neuropeptide receptors such as neurokinin receptor antagonists Examples include, but are not limited to, substances and hormones such as triiodothyronine. In some embodiments, the antidepressant is imipramine, amitriptyline, or desipramine. Nortriptyline, Doxepin, Protriptyline, Trimipramine, Maprotiline , amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duro Xetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxane Min, Nefazadone, Venlafaxine, Milnacipran, Reboxetine, Mirtazapine , phenelzine, tranylcypromine, moclobemide, kava kava, St. John's wort Sodium, s-adenosylmethionine, thyroid-stimulating hormone-releasing hormone, neurokinin receptor The antagonist is a fluoride antagonist or triiodothyronine. Preferably, the antidepressant is fluoride. It consists of xetine, imipramine, bupropion, venlafaxine, and sertraline. Selected from the group.

[0032] Antidepressants (e.g., monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors) serotonin-norepinephrine reuptake inhibitors, noradrenergic and specific serotonin Rotonergic drugs, norepinephrine reuptake inhibitors, natural products, nutritional supplements, neuropathic drugs Peptides, compounds targeting neuropeptide receptors, hormones, and pharmaceuticals described herein. The therapeutically effective dose levels and dosing regimens for this product can be easily determined by those skilled in the art. It may be the case that therapeutic dosages and regimens for drugs approved for sale are generally It is available for use in, for example, packaging labels, standard medication guidelines, and physicians. 's Desk Reference(Medical Economics Comp (any or online at http: / / www.pdrel.com) It is listed in standard medication references or other sources.

[0033] In certain cases, antidepressant therapy may be augmented with antipsychotics. The term "antipsychotic drug" includes, but is not limited to, the following: (a) Typical or conventional antipsychotics, e.g., phenothiazines (e.g., chlorpro Mazine, thioridazine, fluphenazine, perphenazine, trifloperazine, levomep Lomazin (levomepromazin), thioxanthene (e.g., thiothixen, flupentixen) Sole), butyrophenone (e.g., haloperidol), dibenzoxazepine (e.g., Roxapine), dihydroindone (e.g., morindone), substituted benzamide (e.g., , sulpiride (amisulpride), etc.; and (b) Atypical antipsychotics and mood stabilizers, e.g., paliperidone, clozapine, risperidone Lidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, peros Pyrone, blonanserin, certindol, ORG-5222 (Organon), etc. And others, for example, sonepiprazole, aripiprazole, nemonapride, SR-31 742 (Sanofi), CX-516 (Cortex), SC-111 (Scotia ), NE-100 (Taisho), divalproate (mood stabilizer) etc.

[0034] In one embodiment, “atypical antipsychotic” is aripiprazole, quetiapine, or Selected from the group consisting of nzapine, risperidone, and paliperidone. In another embodiment Atypical antipsychotics include aripiprazole, quetiapine, olanzapine, and risperidone. Selected from the group consisting of lidone, preferably the atypical antipsychotic is aripiprazole. The drug is selected from the group consisting of quetiapine and olanzapine.

[0035] When used herein, the terms “treatment-refractory or treatment-resistant depression” and the abbreviation “TRD” are used. "In the current depressive episode, at least two different antidepressants, preferably It is defined as major depressive disorder in patients who do not respond adequately to 2 to 5 types of antidepressants. In other embodiments, TRD is, In patients who have not responded to at least two oral antidepressants at appropriate doses and durations It is defined as major depressive disorder. Patients who do not respond to this treatment method are considered to have treatment resistance. Further monitoring and treatment of the patient with additional therapies, including therapies for sexual depression. There are options. For example, esketamine is approved for the treatment of treatment-resistant depression. Such approved methods are prohibited by the attending physician or other medical professional (pros (cribed) It can be used as is. Methods for treating treatment-resistant depression include, for example, the United States Special Publication No. 2016 / 0074340 and International Publication No. 2019 / 126108 These are shown and are incorporated herein by reference.

[0036] Unresponsiveness to a given set of appropriate antidepressants can be determined retrospectively or anticipatoryly. Those skilled in the art will recognize this. In one embodiment, inability to respond to a suitable set of antidepressants. At least one of the answers is determined anticipatory. In another embodiment, a suitable set of antidepressants At least two of the no responses to are determined anticipatoryly. In another embodiment, appropriate one At least one of the non-responses to the antidepressant is determined retrospectively. In another embodiment, At least two of the unresponsive patients to a suitable set of antidepressants are currently experiencing depressive episodes. It will be determined retroactively in D.

[0037] When used herein, unless otherwise specified, terms such as "to treat" and "treatment" are used. This includes the management and care of human patients for the purpose of combating disease, condition, or disorder. For example, prevention of the onset of one or more of the symptoms or complications, or the treatment of symptoms or complications For the alleviation of one or more of the above, or for the elimination of a disease, condition, or disorder, the chemicals described herein This includes administering a compound.

[0038] The term "therapeutic dose" as used herein refers to the effective dose for the symptoms of the disease or disorder being treated. A human life expectancy requested by a physician or other clinician, including relief of one or more of the following This refers to the amount of an active compound or pharmaceutical product that induces a physical or pharmacokinetic response. In one embodiment, the therapeutically effective dose of esketamine is approximately 20 to 100 mg. In the administration method, the therapeutically effective dose is approximately 28 to 84 mg. In a further embodiment, the therapeutically effective dose is approximately 28 to 84 mg. The dose is approximately 56 to 84 mg. In further embodiments, the therapeutically effective dose is approximately 20 to 21 mg. ,22,23,24,25,26,27,28,29,30,31,32,33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 4 8, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 ,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 8 8, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 In a further embodiment, the therapeutically effective dose is approximately 28 mg. In another embodiment, The effective therapeutic dose is approximately 56 mg. In a further embodiment, the effective therapeutic dose is approximately 84 mg. It is mg.

[0039] In some embodiments, the patient is an adult. The term “adult” is used herein. This refers to a person who is approximately 18 years of age or older.

[0040] method In certain embodiments, this disclosure includes administering esketamine in addition to standard treatment. Major depressive disorder, including suicidal tendencies, in human patients assessed as being at imminent risk of euthanasia. Regarding methods to reduce the symptoms of [the condition]. As reflected in the reported data, suppressing Regarding the symptoms, the difference between the groups was superior in the administration of esketamine + standard treatment compared to standard treatment alone. It showed a tendency to overreact. Furthermore, patients who had previously attempted suicide (attempted suicide) and patients who had not attempted suicide (non-attempted suicide) There were also group differences between those who attempted the crime and those who did not (see, for example, the data reflected in Figures 9-17). ). For example, Figure 11 shows the change in the total MADRS score 24 hours after the first dose. The estimated difference (95% CI) between the esketamine + SOC and placebo + SOC treatment groups was, For the subgroups where a history of suicide attempts has been reported, the ratio is -4.81 (-7.26, -2.36). ) and for the subgroup in which no history of suicide attempts has been reported, -2.32 (-5.54 Figure 17 shows that it was 0.91). +Improved CGI-SS-R score 24 hours after the first dose of SOC The odds ratio (95% crI) is 2.0 for the subgroup in which a history of suicide attempts has been reported. 9(1.06;4.23), and for subgroups where no history of suicide attempts has been reported: This indicates that the result was 1.14 (0.46; 2.83). Therefore, the result is esketami N+SOC is considered particularly beneficial for a subgroup of patients with a history of suicide attempts. This demonstrated that the improvement in this group was in individuals with a history of attempted suicide who also had MDD. Considering that it has been identified as the single most important predictor / risk factor for suicide Considering this, it is clinically relevant.

[0041] Furthermore, in subgroup analysis, those who attempted suicide showed a greater therapeutic effect in relation to standard treatment than those who did not attempt suicide. It was also shown that the number was small. As a result, physicians considered the enhanced effect profile, We can consider treatment options for those who have attempted suicide. For example, intentional suicidal ideation Patients exhibiting MDD constitute a mental emergency requiring immediate intervention. Given that the therapeutic effect shown by standard treatment alone is less, for such patients The benefits of including esketamine treatment may outweigh the risks associated with esketamine. Yes. In contrast, those who did not attempt the crime may not exhibit the same effect profile.

[0042] The inventors believe that in real-world clinical care settings, attempted drug users are augmented by esketamine administration. We believe that it retains the effect profile. Therefore, the group of attempted suicides is DSM-5 It is predicted that this population will show a greater reduction in depressive symptoms of MDD as defined by [the relevant definition]. Furthermore, this population For example, reduced levels of suicidal ideation and / or suicide attempts. They may have a suicidal tendency of that level.

[0043] Therefore, in certain embodiments, the method determines whether the patient has previously attempted suicide. To determine whether or not, and if so, to classify such patients under standard treatment and treatment. This includes treating with an effective dose of esketamine. In other embodiments, the patient has previously attempted suicide. Insofar as it is determined that the patient has never had such a reaction, the patient will not be treated with esketamine. The patient will receive standard treatment. The determination of whether the patient has previously attempted suicide will be made by the patient. Alternatively, by questioning or interviewing individuals familiar with the patient's medical history and / or by referring to medical records. This can be done by the attending physician or another medical professional.

[0044] In embodiments including esketamine and standard treatment, the method is such that the patient responds to the treatment. For the indicated treatment period, administer a therapeutically effective dose of esketami at a given frequency at least twice a week. This includes administering a drug. At some point during this time, the patient's illness is diagnosed by the attending physician or other healthcare professional. The condition may be evaluated. In some embodiments, the treatment period is approximately 1 to 4 weeks. In other embodiments, the introductory period may be up to approximately 1 week, up to approximately 2 weeks, up to approximately 3 weeks, or up to The period is approximately four weeks.

[0045] In a preferred embodiment, the method involves administering approximately 56 mg to approximately 84 mg of es per treatment session. The treatment session, which includes intranasal administration of ketamine, has a duration of approximately 4 weeks. It is performed twice a week throughout the treatment period. In certain embodiments, per treatment session Approximately 84 mg of esketamine is administered. Depending on the tolerance of the approximately 84 mg dose, subsequent treatments may be administered. The dose during treatment sessions may remain at approximately 84 mg, or it may be reduced to approximately 56 mg. This is also good. In certain embodiments, esketamine is more preferably administered by spraying it two or more times from an intranasal device. The medication is delivered in 4 to 6 sprays.

[0046] Typical intranasal spray devices are all incorporated herein by reference as U.S. Patent No. 6,322 Nos. 1,942, 7,299,949, and 9,555,950, and the United States This is disclosed in Patent Application No. 16 / 440,570. For example, continuous partial discharge is sprayed. The method disclosed herein is carried out using a disposable sprayer for discharging as a mist. It is possible. Typically, such a device can be used to treat both sides of the patient in two consecutive strokes. It allows the drug to be sprayed into one nostril. The device from which the drug is discharged from the medium container is It can be used immediately. The device typically involves a first discharge stroke followed by a second discharge stroke. This separates it from the troch and prevents the medium container from being completely emptied in a single movement. The device is discarded after a single use and allows for individual partial discharge with high administration accuracy and reliability. It can be made to function as a double-stroke disposable pump.

[0047] In one embodiment, the intranasal spray device sprays a total of 28 mg of esketamine twice (into the nostrils). It is a single-use device that delivers the drug with a single spray. The device is administered to the patient under the supervision of a healthcare professional. It is also acceptable to operate it in this way. Regarding the dosage, one device is used for a 28 mg dose, or two Whether one device is used for a 56 mg dose or three devices are used for an 84 mg dose Good. It is also preferable to have a 5-minute interval between the use of each device. (Example section) As shown in Tables 2 and 3, time 0 is the first time from the first intranasal device to one nostril. This is defined as the time for administering the intranasal spray. In a treatment session, the specified dose of escalator is administered. Esketamine is administered. For example, a "treatment session" for 56 mg of esketamine is This may include two sprays from the first device and two sprays from the second device. Another example is... Therefore, the "treatment session" for 84 mg of esketamine consists of two doses from the first device. Spray (one spray into each nostril), two sprays from the second device (one spray into each nostril) This may include, and two sprays from the third device (one spray into each nostril). However, for example... For example, if the device does not function properly, additional medication may be needed to administer the required dose or amount of esketamine. If equipment is needed, more equipment may be used as needed. The treatment session is a standard Typically, the treatment begins when the first spray is administered from the first device into one nostril. The suction ends when the last spray is administered into the nostril from the last device.

[0048] As used herein, the term "twice a week" refers to a frequency of twice a week (7 days). For example, "twice a week" in this specification may refer to the administration of esketamine. Furthermore, as disclosed herein, the frequency of patient monitoring, including outpatient visits. It may also refer to the frequency of the first and second days of the week. In some embodiments, twice a week refers to the frequency of the first and second days of the week. This refers to the frequency. In other embodiments, twice a week refers to the frequency of the first and third days of the week. In this embodiment, twice a week refers to a frequency of the first and fourth days of the week. So, twice a week refers to the frequency of doing it on the 1st and 5th days of the week. "The 1st day" is Sunday and Monday. It may be any day of the week, including Sunday, Tuesday, Wednesday, Thursday, Friday, or Saturday. Typically, with regard to the administration of esketamine, twice a week means on the 1st and 4th days of the week. This indicates the degree. As long as there is an error in dosage, take the dose as soon as possible thereafter, and then follow the instructions. You may continue with that regimen.

[0049] Composition and preparation method As used herein, the term “composition” means a product containing a specific component in a specific amount, and Furthermore, any product resulting directly or indirectly from a specific combination of amounts of a particular component It shall be included.

[0050] In some preferred pharmaceutical compositions, S-ketamine hydrochloride is used as the active ingredient, unlike conventional compositions. According to pharmaceutical formulation techniques, a pharmaceutical carrier is thoroughly mixed with water, and this carrier is then administered. It can take a wide variety of forms depending on the desired form of dispensing. Medically acceptable Suitable carriers are well known in the art. Some explanations are found in The Hand, published by the American Pharmaceutical Association and the British Pharmaceutical Association. It can be found in the book of Pharmaceutical Excipients. can.

[0051] The method for formulating pharmaceutical compositions was published by Marcel Dekker, Inc. Pharmaceutical Dosage Forms: Tablets, No. 2nd edition, revised and supplemented, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical al Dosage Forms:Parental Medications,Chapter 1 Volumes 1-2, edited by Avis et al., and Pharmaceutical Dosage Form s: Disperse Systems, Volumes 1-2, edited by Lieberman et al.; etc. It is mentioned in many publications.

[0052] One preferred aqueous formulation of S-ketamine comprises water and S-ketamine, wherein S-ketamine is Based on the total volume of the pharmaceutical composition, the concentration is approximately 25 mg / mL to approximately 250 mg / mL, preferably. Approximately 55 mg / mL to approximately 250 mg / mL, or approximately 100 mg / mL to approximately 250 mg / It exists in an amount in the range of mL, or any amount or range within that range. Preferably, S-digit Min is in an amount ranging from approximately 150 mg / mL to approximately 200 mg / mL, or any amount within that range. It exists in a range of approximately 150 mg / mL to approximately 17 It is present in an amount within the range of 5 mg / mL, or any amount or range within that range. More preferably S-ketamine is present in amounts ranging from approximately 160 mg / mL to approximately 163 mg / mL, for example, approximately 1 It is present in an amount of 61.4 mg / mL.

[0053] Another preferred aqueous formulation of S-ketamine comprises water and S-ketamine, where S-ketamine is Based on the total volume of the pharmaceutical composition, the range is approximately 100 mg / mL equivalent to approximately 250 mg / mL equivalent. It is present in the amount of the range, or any amount or range within that range. Preferably, S-ketamine. This refers to an amount in the range of approximately 125 mg / mL equivalent to approximately 180 mg / mL equivalent, or any amount within that range. It is present in any amount or range. More preferably, S-ketamine is present in about 140 mg / mL An amount in the range of equivalent to approximately 160 mg / mL equivalent, or any amount or range within that range, e.g. For example, it exists in an amount equivalent to approximately 140 mg / mL.

[0054] The pharmaceutical compositions preferred for use in this specification are preferably aqueous formulations. When used, unless otherwise specified, the term "aqueous" refers to a formulation in which the main liquid component is water. This shall mean the following. Preferably, water shall be more than about 80% by weight of the liquid component of the pharmaceutical composition. More preferably over approximately 90% by weight, more preferably over approximately 95% by weight, more preferably approximately 98% It constitutes a percentage by weight.

[0055] In a pharmaceutical composition suitable for use in this specification, the water content of the composition is the total weight of the composition. Based on the quantity, 85±14% by weight, more preferably 85±12% by weight, and even more preferably The weight is within the range of 85±10% by weight, most preferably 85±7.5% by weight, and especially 85±5% by weight. That is the case.

[0056] In a pharmaceutical composition suitable for use in this specification, preferably, the water content of the composition is Based on the total weight of the composition, 90±14% by weight, more preferably 90±12% by weight, and further More preferably 90±10% by weight, most preferably 80±7.5% by weight, and especially 90±5% by weight. It is within the range of %.

[0057] In another pharmaceutical composition for use herein, the water content of the composition is the total weight of the composition. Based on the quantity, 95±4.75% by weight, more preferably 95±4.5% by weight, and even more preferably More preferably 95±4% by weight, even more preferably 95±3.5% by weight, and most preferably 9 The weight is within the range of 5±3% of the weight, and especially within the range of 95±2.5% of the weight.

[0058] In further pharmaceutical compositions for use herein, the water content of the composition is the total water content of the composition. Based on weight, 75-99.99% by weight, more preferably 80-99.98% by weight, further More preferably 85-99.95% by weight, even more preferably 90-99.9% by weight, Most preferably, the amount is in the range of 95 to 99.7% by weight, and more preferably, 96.5 to 99.5% by weight.

[0059] In further pharmaceutical compositions for use herein, the composition comprises one or more buffering agents. and / or further comprising a buffer system (i.e., a conjugate acid-base pair).

[0060] As used herein, the term "buffering agent" means that when added to an aqueous formulation, it refers to the buffering agent of that formulation. This refers to any solid or liquid composition (preferably an aqueous liquid composition) that adjusts pH. As such, a person skilled in the art would know that a buffer can adjust the pH of an aqueous formulation in any direction (more acidic, more salty). It will be recognized that the pH can be adjusted (towards a neutral or more neutral pH). Preferably The buffering agent is pharmaceutically acceptable.

[0061] Suitable examples of buffering agents that can be used in aqueous formulations include citric acid and sodium dihydrogen phosphate. M, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, ri Examples include, but are not limited to, goic acid, lactic acid, and fumaric acid. Preferably, buffering The buffering agent or buffer system consists of NaOH, citric acid, sodium dihydrogen phosphate, and disodium hydrogen phosphate. Selected from the group consisting of lium.

[0062] In one embodiment, the buffering agent is an S-ketamine hydrochloride pharmaceutical composition (for example, as described herein). The pH of the aqueous formulation (as described) should be within the range of approximately pH 3.5 to approximately pH 6.5, or within that range. Selected to be adjusted to any amount or range. Preferably, the buffer is S-Ketami The pH of the hydrochloride composition is set to a range of approximately pH 4.0 to approximately pH 5.5, or any amount within that range. Or a range, more preferably a range of approximately pH 4.5 to approximately pH 5.0, or any amount within that range. Alternatively, it can be selected to adjust to a range.

[0063] Preferably, the concentrations of the buffering agent and buffering system, preferably NaOH, are sufficient for buffering. It is adjusted to provide the necessary functions.

[0064] In one embodiment, S-ketamine hydrochloride, water, and a buffer or buffering system, preferably Na A pharmaceutical composition containing OH is provided, and the buffer or buffer system has a pH of approximately pH 4.0 to approximately pH 6. A sufficient amount to obtain a formulation having a pH in the range of 0, or any amount or range within that range. It exists.

[0065] The pharmaceutical composition may optionally contain a preservative.

[0066] When used herein, unless otherwise specified, the terms “antimicrobial preservative” and “preservative” are used in the same sense. Preferably, in order to protect the pharmaceutical composition from microbial degradation or microbial growth, This refers to any substance added to a conventional pharmaceutical composition. In this regard, the growth of microorganisms is typical. It plays an essential role. In other words, preservatives serve the primary purpose of preventing microbial contamination. It is useful. In one respect, it is useful for determining the effects of microorganisms on the active ingredients and excipients, respectively. In some cases, it is desirable to avoid this as well, that is, to avoid microbial degradation.

[0067] Typical examples of preservatives include benzalkonium chloride, benzethonium chloride, and benzoic acid. Sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridin Nium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxyl Lenol, cresol, ethyl alcohol, glycerin, hexetidine, imidourea, f Phenol, phenoxyethanol, phenylethyl alcohol, phenylmercury nitrate, pro Pyrene glycol, sodium propionate, thimerosal, methylparaben, ethyl phosphate Lavender, propylparaben, butylparaben, isobutylparaben, benzylparaben, Examples include, but are not limited to, sorbic acid and potassium sorbate.

[0068] Due to its preservative properties, the desired shelf life or stability during use is affected by the presence of the drug itself. If the content of S-ketamine hydrochloride is sufficiently high to be achievable, it is used herein. Preferably, preservatives are completely absent from the pharmaceutical composition. Preferably, these conditions Below, the concentration of S-ketamine hydrochloride is at least 120 mg / mL equivalent, preferably about A range of 120 mg / mL equivalent to approximately 175 mg / mL equivalent, or any amount within that range. A range, more preferably a range of about 125 mg / mL equivalent to about 150 mg / mL equivalent, Any amount or range within that range, for example, approximately 126 mg / mL equivalent or approximately 140 mg / mL equivalent. This is an L equivalent.

[0069] As used herein, the terms "penetration agent" and "penetration enhancer" are used. And "penetrant" refers to the active ingredient of a pharmaceutical composition (for example, S-ketamine hydrochloride). This refers to any substance that increases or promotes the absorption and / or bioavailability of ). Preferably, The nasal stimulant facilitates the absorption of the active ingredient of the pharmaceutical composition (e.g., S-ketamine hydrochloride) after intranasal administration. and / or increase or promote bioavailability (i.e., absorption of active ingredients through mucous membranes) (and / or to increase or promote bioavailability).

[0070] Suitable examples include tetradecyl maltoside, sodium glycolate, and tauro. Taursodeoxycholic acid (TUDCA), lecithin, etc. Chitosan (and its salts), as well as benzalkonium chloride, sodium dodecyl sulfate, sodium Umdocusate, polysorbate, laureth-9, oxytoxyl, deoxycor Examples of surface-active ingredients include sodium arginine and polyarginine, but are not limited to these. No. Preferably, the penetrating agent is tauroursodeoxycholic acid (TUDCA).

[0071] Penetrating agents, for example, increase membrane fluidity and create transient hydrophilic pores within epithelial cells. To achieve this, by reducing the viscosity of the mucus layer, or by opening the tightly bonded joint, It can act through any mechanism. Several osmotic agents (e.g., bile salts and fusidic acid inducers) The body also inhibits enzyme activity in the membrane, thereby improving the bioavailability of the active ingredient. It is possible to do good.

[0072] Preferably, the penetrating agent meets one or more, more preferably all, of the following general requirements. Selected to satisfy the requirements. (a) Absorption of the active ingredient (preferably intranasal absorption), preferably temporary and / or reversible It is effective in increasing in a certain manner. (b) It is pharmacologically inactive. (c) Non-allergenic, non-toxic, and / or non-irritating. (d) It is very potent (effective in small amounts). (e) Compatible with other components of the pharmaceutical composition. (f) It is odorless, colorless, and / or tasteless. (g) Permitted by the regulatory authority (h) It is inexpensive and available in high purity.

[0073] In one embodiment, the penetrating agent penetrates without nasal irritation (absorption of S-ketamine hydrochloride and Selected to increase / or bioavailability. In another embodiment, the penetrating agent is selected to increase the following: Selected to improve the absorption and / or bioavailability of S-ketamine hydrochloride, and further, It is selected to enhance uniform drug efficacy.

[0074] In one embodiment, a pharmaceutical composition comprising S-ketamine and water contains an antimicrobial preservative. A pharmaceutical composition is provided which further contains a penetration enhancer, preferably TUDCA.

[0075] In another embodiment, a pharmaceutical composition comprising S-ketamine and water, wherein an antimicrobial preservative is used. It does not contain, and further contains tauroursodeoxycholic acid (TUDCA), and TUDCA is A range of approximately 1.0 mg / mL to approximately 25.0 mg / mL, or any amount or range within that range. Preferably in the range of about 2.5 mg / mL to about 15 mg / mL, or any amount within that range. The range is preferably about 5 mg / mL to about 10 mg / mL, or any amount within that range. Alternatively, a pharmaceutical composition is provided in which the TUDC is present at a concentration within a range. In another embodiment, TUDC A pharmaceutical composition is provided in which A is present at a concentration of approximately 5 mg / mL. In another embodiment, T A pharmaceutical composition is provided in which UDCA is present at a concentration of approximately 10 mg / mL.

[0076] The pharmaceutical compositions used herein may include one or more additional excipients, for example, wetting agents. Even if it contains surfactant components, solubilizers, thickeners, colorants, antioxidants, etc. good.

[0077] Examples of suitable antioxidant components, when used, include: sulfites; ascorbyl Acid, sodium ascorbate, calcium ascorbate, or potassium ascorbate Ascorbates such as sulfamethoxazole; ascorbyl palmitate; fumaric acid, ethylenediamine tetraphosphate Acetic acid (EDTA) or its sodium or calcium salts; tocopherol; gallic acid Gallates such as propyl gallate, octyl gallate, or dodecyl gallate; vitamin E; and Antioxidants include, but are not limited to, one or more of the mixtures thereof. The components provide long-term stability to the liquid composition. The addition of antioxidant components improves the stability of the composition. This can help strengthen and guarantee the composition, even after 6 months at 40°C. It may be useful. A suitable amount of antioxidant component, if present, is about 0.01% of the total weight of the composition. The amount is approximately 3% by weight, preferably approximately 0.05% by weight to approximately 2% by weight.

[0078] Solubilizers and emulsifiers are less soluble in the active ingredient or liquid carrier than other excipients. It may be included to promote uniform dispersion. Examples of suitable emulsifiers, when used, For example, gelatin, cholesterol, acacia, tragacanth, pectin, methylcellulose Examples include, but are not limited to, carbomers, carbomers, and mixtures thereof. Examples of solubilizers include polyethylene glycol, glycerin, D-mannitol, and tre Halos, benzyl benzoate, ethanol, trisaminomethane, cholesterol, trie Thanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate Examples include thorium and mixtures thereof.

[0079] Preferably, the solubilizer contains glycerin. The solubilizer or emulsifier is generally contained within the carrier. It is present in an amount sufficient to dissolve or disperse the active ingredient, namely S-ketamine. If a chemical or emulsifier is included, the typical amount is about 1% by weight to about 80% by weight of the total weight of the composition. %, preferably about 20% to about 65% by weight, more preferably about 25% to about 55% by weight It is a percentage.

[0080] Suitable isotonic agents, when used, include sodium chloride, glycerin, and D-mannitol. Examples include D-sorbitol, glucose, and mixtures thereof. If included, etc. A suitable amount of the tensor is typically about 0.01% to about 15% by weight of the total weight of the composition. Comfortably approximately 0.3% to 4% by weight, and more comfortably approximately 0.5% to 3% by weight. It is a percentage.

[0081] For example, to increase the retention time in the nasal cavity, a suspension or thickener may be added to the pharmaceutical composition. This may also be used. Preferred examples include hydroxypropyl methylcellulose, carmellose sodium Lilium, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salt Examples include gellan gum, poloxamer, polyvinylpyrrolidone, and xanthan gum. However, it is not limited to these.

[0082] manner Apparatus 1. Large number of human patients assessed as being at imminent risk of suicide, including suicidal tendencies. A method for reducing the symptoms of depressive disorder, provided that the patient has previously attempted suicide. To determine whether or not there is a condition, and if the patient has previously attempted suicide, (a) standard treatment and (b) treatment of the patient with a therapeutically effective dose of esketamine, including Hmm, a method.

[0083] Applicable case 2. If it is determined that the patient has never attempted suicide, the patient will be sent to the escort service. The method according to embodiment 1, wherein the patient is treated with the standard treatment without being treated with tamin.

[0084] Apparatus 3. The standard treatment is determined by the attending physician, as psychiatric hospitalization of the inpatient. The following describes the treatment and the initiation or optimization of standard antidepressant therapy as described in aspect 1 or 2. Method of loading.

[0085] Apparatus 4. The standard treatment is administered on an outpatient basis after the patient has been discharged from psychiatric inpatient treatment. The method according to aspect 3, further comprising the patient attending a psychiatric facility on an outpatient basis.

[0086] Appearance 5. Any of claims 1 to 4, wherein the symptoms include suicidal ideation accompanied by the intention to commit suicide. The method described in item 1.

[0087] Apparatus 6. Treatment of the patient with a therapeutically effective dose of esketamine is approximately The treatment session includes administering 56 mg to approximately 84 mg of esketamine, and the treatment session is approximately The treatment is performed twice a week over a treatment period of 4 weeks, according to either embodiment 1 or embodiment 3. The method described in any one of the five methods.

[0088] Applicable case 7. The previous suicide attempt occurred within one month prior to the first treatment session, Applicable case 6 Methods used.

[0089] Appearance 8. Approximately 84 mg of esketamine is administered per treatment session, as described in Appearance 6. The method.

[0090] Embodiment 9. The esketamine is delivered intranasally, as described in any one of Embodiments 1 to 8. method.

[0091] Embodiment 10. The esketamine is delivered by two or more sprays from an intranasal administration device. The method described in Item 8.

[0092] abbreviation ANCOVA covariance analysis CGI-SR-I Clinical Global Impression - Imminent Suicide Risk CGI-SS Clinical General Impression Score - Severity of Suicidal Tendency CGI-SS-R Clinical General Impression Scale - Severity of Suicidal Tendency - Revised Edition CrI confidence interval DB double-blind DNA (Deoxyribonucleic Acid) DSM-5 Diagnostic and Statistical Manual of Mental Disorders (5th Edition) ECG (Electrocardiogram) ECT (Electroconvulsive Therapy) EDTA (Ethylenediaminetetraacetic acid) ER emergency room ESK / Esk Esketamine FoST Frequency of suicidal thoughts ICD-10 International Statistical Classification of Diseases and Related Health Problems - 10th Edition ICF Informed Consent Form IM (Intramuscular) IRT (Item Response Theory) IV Intravenous LOCF interpolation using the most recent observations LSD (Lithium Sodium Diethylamide) MADRS Montgomery Asberg Depression Rating Scale MADRS-SI Montgomery Asberg Depression Rating Scale - Suicidal Thoughts Items related to mAMP Methamphetamine Major Depressive Disorder (MDD) MDMA 3,4-methylenedioxy-methamphetamine MedDRA Glossary of Pharmaceutical Regulatory Terms MINI (Minimum Integrative Structured Interview) PCP (Phencyclidine) PD Pharmacodynamics PK (Pharmacokinetics) SIBAT (Suicidal Ideation and Related Behavior Assessment Tool) SE standard error SOC standard of care Adverse events that occurred during TEAE treatment TRD (Treatment-Resistant Depression) w / v weight / volume

[0093] The following examples are described to assist in understanding the present invention and are not intended to limit, nor should they be construed as limiting, the invention described in the "claims" attached hereto in any way.

Example

[0094] Example 1: Registered patients Eligible subjects must be screened within 48 hours prior to the first administration of the intranasal test drug (if possible, within 24 hours prior to the first administration of the intranasal test drug).

[0095] The inclusion criteria and exclusion criteria for registering subjects for this study are described below.

[0096] A. Inclusion criteria Potential subjects must meet all of the following criteria in order to be registered for this study: 1. Subjects must be male or female, 18 years of age or older and 64 years of age or younger. 2. Subjects must meet the DSM-5 diagnostic criteria for MDD without psychiatric features, confirmed by MINI based on clinical evaluation. 3. Subjects must currently have suicidal ideation with intent, which is obtained by MINI in question B3 [Do you think about hurting yourself or causing pain or damage to yourself (even for a moment) with at least some degree of awareness or recognition that you might die as a result?]; or think about suicide (i.e., killing yourself)? And the answer to question B10 [Do you have the intention to act based on the thought of killing yourself?] is "yes". ​​​​​​​​​​It is confirmed by being "Yes (present)". Note: The answer to B3 needs to refer to the present, while the answer to B10 may reflect the past 24 hours. If the screening period is longer than 24 hours, it is necessary to repeat the evaluation of B3 and B10 of MINI before randomization to confirm eligibility. Although it needs to be mentioned, the answer to B10 may reflect the past 24 hours. If the screening period is longer than 24 hours, it is necessary to repeat the evaluation of B3 and B10 of MINI before randomization to confirm eligibility. If the screening period is longer than 24 hours, it is necessary to repeat the evaluation of B3 and B10 of MINI before randomization to confirm eligibility. It is necessary to repeat the evaluation of B3 and B10 of MINI before randomization to confirm eligibility. 4. In the opinion of the physician, due to the imminent risk of suicide of the subject, urgent inpatient psychiatric treatment is clinically justified. 5. The subject has a total MADRS score > 28 before dosing on Day 1. 6. As part of the standard treatment, the subject agrees to be admitted voluntarily over a recommended period of 5 days after randomization (it may be shorter or longer if clinically justified in the opinion of the principal investigator of the clinical trial), and takes the antidepressant therapy with non-investigational drugs prescribed over at least the double-blind treatment phase (25 days). 7. The subject is not resistant to self-administration of intranasal drugs and can follow the provided instructions. 8. The subject must be medically stable based on a health check, medical history, vital signs, and 12-lead ECG performed at the time of screening. If there are abnormalities, the subject may be included only if the principal investigator of the clinical trial determines that the abnormalities are clinically insignificant. This decision must be recorded in the subject's information source document and signed in initials by the principal investigator of the clinical trial. 9. The subject must be medically stable based on clinical laboratory tests performed in the facility's laboratory at the time of screening. If the results of a serum chemistry panel, blood test, or urine test are outside the normal reference range, the subject may be included only if the principal investigator of the clinical trial determines that the deviation from normal or abnormal is clinically insignificant. This decision must be recorded in the subject's information source document and signed in initials by the principal investigator of the clinical trial. 10. The subject must be medically stable based on clinical laboratory tests performed in the facility's laboratory at the time of screening. If the results of a serum chemistry panel, blood test, or urine test are outside the normal reference range, the subject may be included only if the principal investigator of the clinical trial determines that the deviation from normal or abnormal is clinically insignificant. This decision must be recorded in the subject's information source document and signed in initials by the principal investigator of the clinical trial. 11. The subject is not resistant to self-administration of intranasal drugs and can follow the provided instructions. 12. The subject must be medically stable based on a health check, medical history, vital signs, and 12-lead ECG performed at the time of screening. If there are abnormalities, the subject may be included only if the principal investigator of the clinical trial determines that the abnormalities are clinically insignificant. This decision must be recorded in the subject's information source document and signed in initials by the principal investigator of the clinical trial. 13. The subject must be medically stable based on clinical laboratory tests performed in the facility's laboratory at the time of screening. If the results of a serum chemistry panel, blood test, or urine test are outside the normal reference range, the subject may be included only if the principal investigator of the clinical trial determines that the deviation from normal or abnormal is clinically insignificant. This decision must be recorded in the subject's information source document and signed in initials by the principal investigator of the clinical trial. 14. The subject must be medically stable based on clinical laboratory tests performed in the facility's laboratory at the time of screening. If the results of a serum chemistry panel, blood test, or urine test are outside the normal reference range, the subject may be included only if the principal investigator of the clinical trial determines that the deviation from normal or abnormal is clinically insignificant. This decision must be recorded in the subject's information source document and signed in initials by the principal investigator of the clinical trial. 15. The subject must be medically stable based on clinical laboratory tests performed in the facility's laboratory at the time of screening. If the results of a serum chemistry panel, blood test, or urine test are outside the normal reference range, the subject may be included only if the principal investigator of the clinical trial determines that the deviation from normal or abnormal is clinically insignificant. This decision must be recorded in the subject's information source document and signed in initials by the principal investigator of the clinical trial. 16. The subject must be medically stable based on clinical laboratory tests performed in the facility's laboratory at the time of screening. If the results of a serum chemistry panel, blood test, or urine test are outside the normal reference range, the subject may be included only if the principal investigator of the clinical trial determines that the deviation from normal or abnormal is clinically insignificant. This decision must be recorded in the subject's information source document and signed in initials by the principal investigator of the clinical trial. 17. The subject must be medically stable based on clinical laboratory tests performed in the facility's laboratory at the time of screening. If the results of a serum chemistry panel, blood test, or urine test are outside the normal reference range, the subject may be included only if the principal investigator of the clinical trial determines that the deviation from normal or abnormal is clinically insignificant. This decision must be recorded in the subject's information source document and signed in initials by the principal investigator of the clinical trial. 18. The subject must be medically stable based on clinical laboratory tests performed in the facility's laboratory at the time of screening. If the results of a serum chemistry panel, blood test, or urine test are outside the normal reference range, the subject may be included only if the principal investigator of the clinical trial determines that the deviation from normal or abnormal is clinically insignificant. This decision must be recorded in the subject's information source document and signed in initials by the principal investigator of the clinical trial. 19. The subject must be medically stable based on clinical laboratory tests performed in the facility's laboratory at the time of screening. If the results of a serum chemistry panel, blood test, or urine test are outside the normal reference range, the subject may be included only if the principal investigator of the clinical trial determines that the deviation from normal or abnormal is clinically insignificant. This decision must be recorded in the subject's information source document and signed in initials by the principal investigator of the clinical trial. It must be signed by the master with their initials. - Accidental exclusive clinical laboratory values ​​("accidental" means that the subjects are grouped based on the clinical laboratory values ​​of the facility) Separate blood samples analyzed in the central laboratory become available after the inclusion and exclusion criteria are met. (Referring to the results of duplication from liquid samples) whether the subject should withdraw from the clinical trial. Each case is handled individually to determine whether it is a case or not. 10. The use of contraceptives by men or women is not contraceptive for subjects participating in the clinical trial. It must comply with local regulations regarding the use of the law. Before randomization, women must meet one of the following criteria: a. Incapacitated to give birth, as defined below: - Postmenopausal (>45 years old, amenorrhea for at least 12 months), permanent infertility (e.g., bilateral ovarian failure) Pregnancy due to tubal occlusion / ligation, hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or other reasons. I can't b. Having the ability to give birth, - A highly effective method of contraception (<1% failure rate per year when used consistently and correctly). ) will be implemented Examples of highly effective contraceptive methods include: - User-independent method: Implantable progestogens related to ovulation inhibition Mino hormone contraceptives, intrauterine devices (IUDs), intrauterine hormones Intrauterine hormone-releasing system (IUS), partner sperm Tube resection, abstinence (abstinence means refraining from sexual intercourse with the opposite sex for the entire duration of the risk associated with the investigational drug). It is only considered a very effective method if justified. The reliability of abstinence depends on the duration of the clinical trial. (This needs to be evaluated in relation to the subject's preferred and normal lifestyle patterns.) - User-dependent methods: Concomitant use related to ovulation inhibition (estrogen and progestin) (Terone-containing) hormonal contraceptives: oral, vaginal, and transdermal; progesterone associated with ovulation inhibition. Ron-only hormonal contraceptive: available orally and by injection. 11. Regarding a woman's ability to give birth, a negative urine pregnancy test is required during screening. be. 12. During the clinical trial (i.e., from day 1 of the double-blind phase) and after receiving the last dose of the investigational drug. After at least one spermatogenesis cycle (defined as approximately 90 days), the sperm's ability to reproduce continues. A man who has sexual intercourse with a woman, - You need to implement a highly effective method of contraception with your female partner, based on the list above. (See examples of highly effective contraceptive methods offered to women.) - If your partner is pregnant, you must use a condom. - You must agree not to provide sperm. 13. The subject is willing to abide by the prohibitions and restrictions specified in this protocol. That needs to be possible. 14. Each participant understands the purpose of the clinical trial and the necessary procedures, and participates in the clinical trial. You will need to sign an Informed Consent Form (ICF) to indicate your willingness to comply. There is. 15. If you agree to provide voluntarily selected DNA samples for research purposes, each subject will be... You will need to sign a separate informed consent form (if local regulations allow it). Even if you refuse to provide a voluntarily selected DNA research sample, you will not be excluded from participation in this study. They will not be excluded.

[0097] B. Exclusion criteria Potential candidates who meet any of the following criteria will be excluded from participating in the study. , 1. The subject has a current DSM-5 diagnosis of bipolar (or related disorder), antisocial personality disorder, or obsessive-compulsive disorder . 2. The subject currently meets the DSM-5 criteria for borderline personality disorder . - Although the subject does not meet all of the DSM-5 criteria for borderline personality disorder, subjects who exhibit repeated suicidal gestures, threats of suicide, or self-harm should also be excluded . 3. The subject has a current clinical diagnosis of autism, dementia, or intellectual disability 4. The subject has a current or past DSM- 5 diagnosis of MDD with a psychotic disorder or psychotic features 5. The subject meets the DSM-5 severity criteria for moderate or severe substance or alcohol use disorder (excluding nicotine or caffeine) within 6 months prior to screening .<> - A history (lifetime) of use disorder related to ketamine, phencyclidine (PCP), LSD, or MDMA hallucinogens is excluded . 6. The subject has any of the following conditions: - A history or current signs and symptoms of liver or kidney insufficiency - Clinically significant heart (including unstable coronary artery disease and congestive heart failure, tachyarrhythmias and subacute myocardial infarction), vascular, pulmonary, gastrointestinal, endocrine (including uncontrolled hyperthyroidism), neural (excluding uncomplicated childhood febrile seizures without sequelae, including current or past history of seizures), blood, rheumatologic, or metabolic (including severe dehydration / volume depletion ) disorders 7. The subject has uncontrolled hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg) at the time of screening despite treatment with a diet, exercise, or stable dose of antihypertensive medication for at least 2 weeks . Hypotension > 90 mmHg; or any past history of hypertensive crisis. - Elevated blood pressure poses a serious risk (unstable heart failure, severe cardiovascular disease, subacute brain injury, head injury) Increased intracranial pressure / intracranial mass lesion, cranial hemorrhage or acute stroke, untreated glaucoma or perforating eye injury. An object that has a condition that could result in damage (including injuries). -If blood pressure readings during screening are abnormal, a 5-minute re-examination will be conducted to determine eligibility for the subject. It may be repeated once after LAXS. On day 1 of the double-blind phase before randomization, Patients with a systolic blood pressure >140 mmHg or a diastolic blood pressure >90 mmHg in the supine or semi-supine position are excluded. do. 8. The subject has tested positive for phencyclidine (PCP), cocaine, or ANFO at the time of screening. A urine test result for effemin (including amphetamine, mAMP, and MDMA) was positive. It is a sexual thing. -By the appropriate use of prescribed opiates, benzodiazepines, or barbiturates Individuals who test positive may still be eligible to participate in the clinical trial, at the discretion of the clinician. Furthermore, opiates, benzodiazepines, or barbiturates used without a prescription Regarding subjects whose test results are positive, they will be subject to the judgment of the clinician and the sponsor of the clinical trial. In some cases, after consulting with a medical monitor, you may be deemed eligible. (Regarding the use of heroin) Subjects for whom this is known must be excluded from the clinical trial. - Opiates, benzodiazepines, or other substances taken (e.g., overdosed) in a suicide attempt. Patients who test positive for barbiturates may, at the discretion of their clinician, participate in clinical trials. In some cases, after consulting with the client's medical monitor, it may be determined that you are eligible to participate in the clinical trial. 9. The subject has a history of malignant tumors within 5 years prior to screening (squamous cell carcinoma of the skin). and basal cell carcinoma, and carcinoma in situ of the cervix, or, in the opinion of the principal investigator, With the consent of the patient's medical monitor, malignant tumors deemed to have only the minimum risk of recurrence Tumors are excluded. 10. In accordance with the clinical judgment of the principal investigator based on the evaluation, the subject may receive the intranasal investigational drug. They have any anatomical or medical conditions that may interfere with absorption. 11. The subject has a known allergy to esketamine or ketamine or its excipients. It may cause hypersensitivity, intolerance, or contraindication. 12. The subject has received any unauthorized therapy listed in Table 1.

[0098] [Table 1-1]

[0099] [Table 1-2] 13. The subject took the investigational drug (esketamine, ketamine, or the vaccine under investigation). If you have had an invasive investigational medical treatment within 60 days prior to the planned first dose of the investigational drug, Have you used the device before, or are you currently enrolled in a clinical trial? 14. If, while enrolled in this clinical trial or within 3 months after the last dose of the investigational drug, A woman who is pregnant, breastfeeding, or planning to become pregnant. 15. In the opinion of the principal investigator, participation is not in the best interest of the participant. Restrictions that (for example, impair welfare) or interfere with assessments specified in the clinical trial protocol. To have any circumstances or state that could cause or confuse. 16. The subject is the principal investigator or an employee of the research institution, and the principal investigator or research institution Persons directly involved in the proposed test or other tests based on the instructions of the testing organization, as well as They are employees or family members of the principal investigator.

[0100] Example 2: Drug administration, administration, and evaluation A. Investigational drug therapy All intranasal administration of investigational drug therapy shall be performed by the principal investigator or a person designated by the principal investigator. It is self-administered under direct supervision. Instructions for using the device are provided in a separate document. ru.

[0101] On day 1, intranasal esketamine 84 mg or intranasal esketamine is administered twice a week for 4 weeks. Participants will be randomized to receive either placebo or intranasal treatment. Intranasal treatment sessions will be conducted daily. It doesn't need to be there.

[0102] Food intake is restricted to at least 2 hours before each dose of the investigational drug therapy. Drinking any fluids is permitted. Restrictions are in place for at least 30 minutes before the first intranasal spray on each medication day if the subject has nasal congestion on the medication day. If this is the case, nasal congestion can be reduced using intranasal anticongestive drugs, or medication on day 1 Except in the case of the following, medication administration may be delayed. When reducing nasal congestion with intranasal anticongestive drugs, the nose It cannot be used within one hour before administering the investigational drug intracavitaryly.

[0103] The initial dose of the investigational drug therapy requires appropriate staffing to manage subjects with a strong suicidal tendency. It is administered in an emergency room (ER) or other permitted environment. If the first dose is administered in the ER... In addition, after the evaluation 4 hours after medication administration is completed, the subject is moved from the ER to the psychiatric ward for inpatients. It is not recommended. Due to the imminent risk of suicide, in the psychiatric ward for inpatients Patients who have been directly admitted, or those transferred from the internal medicine ward (after medical stabilization following a recent suicide attempt) The selected subjects will receive their first dose of the investigational drug therapy in a psychiatric ward for inpatients.

[0104] The target group consists of patients who remain in a psychiatric ward for a recommended 5-day period and follow the facility's standard treatment procedures. Shorter or longer hospital stays may be permitted if clinically justified.

[0105] After discharge from the psychiatric ward for inpatients, follow-up outpatient visits for the double-blind treatment phase are 25 The treatment is conducted twice a week at an outpatient psychiatric facility until day [number].

[0106] On all outpatient intranasal administration days, all subjects will remain at the clinical facility until the clinical trial procedure is completed. The patient needs to remain, and is ready for discharge according to the clinician's assessment. Post-medication monitoring The minimum time required for the procedure is 1.5 hours. The subject is released from the clinical trial site. An escort is required. The subject should not drive a car for 24 hours after receiving the investigational drug. It should not be done in this area. The target area is within 24 hours before and after each intranasal treatment session. The use of licorice should be avoided. If the subject is suspected to be poisoned, do not administer the medication. It is necessary to delay the appointment according to the permitted time slot.

[0107] Each day of medication administration: The subjects are measured at the following three time points: t=0, 5 minutes, and 10 minutes. Self-administer one spray into each nostril (i.e., a total of two times using one intranasal device). Spraying; time=0 is defined as the time to spray the first 100 μL. The target is this A separate intranasal device is used at each of the three time points (i.e., a total of three devices). To each nostril The sprays need to be delivered in succession at the scheduled time. Table 2 shows Esketamine 8 This document describes how 4 mg or placebo is administered in a double-blind treatment phase. .

[0108] [Table 2]

[0109] After the first dose (i.e., the fourth dose or the start thereafter), due to tolerability issues... If necessary, subsequent medication will be a single dose of 56 mg of intranasal esketamine. A reduction in dose or intranasal placebo is permitted. Further dose adjustments are permitted during the double-blind treatment phase. Not permitted. The subject will receive the reduced dose for all remaining medication days.

[0110] Table 3 shows how esketamine 56 mg or placebo was administered in a double-blind treatment phase. This section describes whether or not it will be done.

[0111] [Table 3]

[0112] B. Standard antidepressant treatment All eligibility criteria are determined by the attending physician based on clinical judgment and treatment guidelines. In the context of comprehensive standard clinical treatment, including hospitalization and initiation or optimization of antidepressant therapy. It will be treated. Standard antidepressant treatment (antidepressant monotherapy or antidepressant + augmentation therapy) is, All subjects are initiated or optimized at the time of randomization on day 1. Antidepressant monotherapy is administered from day 1. Those receiving drug therapy will continue on antidepressant monotherapy until the end of the double-blind phase (day 25). It is necessary to do so, while those receiving antidepressants + augmentation therapy from day 1 must complete the double-blind phase. (Day 25) Patients continue with antidepressants + augmentation therapy. Eligibility is determined at the time of clinical trial entry. You may or may not be taking antidepressants. Newly initiated or optimized The dose escalation / adjustment of standard antidepressant treatment should be done during the first two weeks of a double-blind treatment. In other words, it needs to be done by the 15th day, and the dosage will be used after the end of the double-blind phase (25th day). The condition remained stable until the eye. Screening was recently initiated (<2 weeks prior). Participants currently receiving antidepressant treatment are deemed clinically appropriate by the principal investigator. If this occurs, the current dose or optimized dose of antibiotics will be administered until the end of the double-blind phase (day 25). You may continue taking antidepressants (dosage adjustments are permitted during the first two weeks of double-blind treatment). If an additional change to antidepressant treatment is clinically indicated during a fully blinded phase of treatment, the clinical trial The principal investigator must consult with the clinical trial sponsor's medical monitor in advance.

[0113] During the observation phase, antidepressant treatment is managed based on the clinician's judgment.

[0114] C. Evaluation of effectiveness (i) Montgomery-Asberg Depression Rating Scale The primary efficacy endpoint is the MADRS total score. MADRS is a Montgomery drug. The interview is conducted using the Structured Interview Guide for the Asberg Depression Rating Scale. The DRS measures the severity of depression and detects changes due to antidepressant treatment, and is used in MDD. This is a clinician assessment scale designed for use in subjects with [specific condition]. The test consists of 10 items. Each item is rated from 0 (not present or normal) to 6 (severe or persistent symptoms). Points are scored, and the possible total score is 60. A higher score indicates a more severe condition. ADRS includes apparent sadness, reported sadness, internal tension, sleep, appetite, concentration, and fatigue. The test assesses interest levels, pessimistic thinking, and suicidal thoughts. The test is designed to ensure high interrater reliability. show.

[0115] The typical recall period for MADRS is 7 days. In this trial, MADRS also showed the most Subsequent evaluation recall, 4-hour recall on day 1 and day 25 after medication administration, and 24-hour recall on day 2 were used. It is performed using the following method. In the case of MADRS performed 4 hours after drug administration on day 1 and day 25, This complements the MADRS score for sleep items recorded before medication administration on the same day.

[0116] To the greatest extent possible, the same MADRS assessment was used at each site to evaluate the same subjects throughout the clinical trial. Every effort must be made to use the valuer. If this is not possible, then Accordingly, it is necessary to review appropriate prior assessments and communication with previous evaluators.

[0117] (ii) Suicidal Ideation and Related Behavior Assessment Tool (SIBAT) SIBAT is a patient-reported and clinician-reviewed study of suicidal ideation and related behaviors. This suicide assessment tool captures the severity of suicidal tendencies and the imminent, long-term nature of the suicidal activity. This enables the efficient collection and documentation of clinical impressions of euthanasia risk, as well as the development of treatment plans.

[0118] SIBAT has the potential to have a wide variety of demographic, cultural, and demographic backgrounds. This enables efficient, comprehensive, and flexible data collection from a wide range of patients with specific sexual characteristics. It is processed by a computer using branching logic and organized into eight modules. SIB The AT consists of eight modules: patient reports (Modules 1-5) and clinician evaluation (Modules 1-6). ~8) Divide into sections. This modular structure allows for customization. This allows for adjustments to the management of specific modules to meet clinical needs. (Examples of changes) For example, responses less affected by demographics and medical history may fluctuate over shorter time intervals. Higher responses (e.g., current suicidal ideation) are separated into different modules. Generally speaking, The patient reporting module includes the severity of suicidal ideation and risk, as well as the risk of suicide and specific suicides. Document information on protective factors associated with killing behaviors. In addition to the patient reporting module. Information from the simplified semi-structured clinician interview in Module 6 is used to assess the clinical severity of suicidal tendencies. Overall Impression Score - Revised Edition (CGI-SS-R), Clinical Overall Impression of Imminent Suicide Risk (CGI-SR-I), the overall clinical impression of long-term suicide risk, and the frequency of suicidal thoughts. A comprehensive profile for evaluating overall clinical impression in Module 7, including the degree of assessment. This represents the overall clinical judgment for optimal suicide management, which is included in Module 8.

[0119] SIBAT is a scale available to assess suicidal tendencies: for example, schizophrenia and schizophrenia. A 12-point scale designed to assess current suicidal ideation in patients with phasoaffective disorder. The InterSePT scale (ISST) for suicidal thoughts, which is a means of observation, and suicidal tendencies. The previous studies used to develop the Clinical General Impression Scale (CGI-SS) for the severity of the disease were reviewed. It is being used as the basis. Module 7 of SIBAT (General Clinical Impression) is the main focus in this clinical trial. A revised version of CGI-SS (CGI-SS-R) used to evaluate secondary purposes, Furthermore, the imminent risk of suicide is used to assess secondary and exploratory objectives. Includes Clinical General Impression (CGI-SR-I). Furthermore, Module 5 from SIBAT (self Using Question 3 (Frequency of suicidal thoughts reported by patients) in the risk of two The secondary objective was to assess suicidal tendencies reported by patients until the end of the fully blinded treatment phase. ru.

[0120] Formal testing of intra- and inter-evaluator reliability, as well as construct validity and internal consistency. The evaluation will be performed on SIBAT.

[0121] (iii) Overall clinical impression - severity of suicidal tendencies. The CGI-SS-R score ranges from 0 (normal, no suicidal tendencies at all) to 6 (highest suicidal tendencies). The patient is scored on a 7-point scale, and the information available to clinicians includes information from SIBAT. Based on the whole. The CGI-SS-R requires a clinician's overall impression of the severity of suicidal tendencies. This score is used to evaluate the primary secondary endpoints in this clinical trial. It functions similarly to many other CGI severity scales used in other psychiatric clinical trials. These methods demonstrate clinical validity and sensitivity to change.

[0122] [Table 4]

[0123] The CGI-SS-R summarizes clinicians' overall impressions of the severity of suicidal tendencies, and this treatment This score is used to evaluate the primary secondary outcome measures in the trial. These measures function similarly to many other CGI severity scales used in academic clinical trials. It demonstrates clinical validity and sensitivity to change. CGI-SR-I is used when patients are This summarizes the best clinician assessment of the likelihood of a suicide attempt within a 7-day period.

[0124] (iii) Overall clinical impression of imminent suicide risk (CGI-SR-I) CGI-SR-I is a clinician's best assessment of the likelihood of a subject attempting suicide in the next 7 days. This is a scale for summarizing evaluations.

[0125] CGI-SR-I is -4 hours after administration on day 1, 24 hours after administration on day 2, and until the end of the double-blind treatment phase. A secondary objective is to assess changes in the risk of imminent suicide, - With the exploratory purpose of evaluating changes in imminent suicide risk until the end of the observation phase, Used for evaluation.

[0126] (iv) Minimally Intensive Structured Interview (MINI) MINI was developed for the DSM-5 5th Edition and the ICD-10 Mental Disorders 10th Revised Edition. It was a short, structured diagnostic interview, lasting approximately 15-30 minutes. It has the ability to provide accurate, structured psychiatric interviews for multicenter clinical trials. MIN I will confirm the current diagnosis of MDD with suicidal ideation and determine whether other psychotic conditions are present. It is used to make a determination.

[0127] (v) Frequency of suicidal thoughts FoST describes the estimation of the frequency of suicidal thoughts among participants. The FoST score is 6 points. Scored on the Likert scale: 0 (never), 1 (rarely), 2 (sometimes), 3 (often) 4 (most of the time), and 5 (all the time). CGI-FoST (Clinical Evaluation FoS) T) is a response chosen by the principal investigator based on the overall evidence forming the SIBAT. It is one of the evaluation items in Module 7 of SIBAT. Patient-reported FoST is It is located at Joule 5 and is reported directly by the patient.

[0128] Example 3: Investigational drug The esketamine supplied for this clinical trial is esketamine salt in an intranasal spray pump. A colorless, transparent intranasal solution of salt (16.14% w / v, 14% w / v) It is available as a ketamine base. The solution contains 0.12 mg / mL of EDTA and 1.5 mg / mL of citric acid (pH 4.5) is combined with 161.4 mg / mL of es It consists of ketamine hydrochloride (equivalent to 140 mg of esketamine base). It is used as an intranasal spray. It is supplied in a spray bottle, with 16.14 mg of esketamine hydrochloride (14) per 100 μL of spray solution. Delivers mg of esketamine base. Each individual intranasal spray pump (device) delivers a total of 28 mg. It contains g (i.e., enough spray solution for two applications).

[0129] The placebo solution contains a bittering agent (final concentration 0.5%) to simulate the taste of the active drug in the intranasal solution. Denatonium benzoate [Bitrex®] at 0.01 mg / mL is added. It is provided as a colorless, transparent intranasal solution of water for injection. The placebo solution is provided as a suitable intranasal spray. It is supplied in a pumping device. Benzalkonium chloride is used as a preservative at a concentration of 0.3 mg / mL. Add the following. Each individual intranasal spray pump (device) contains enough spray solution for two doses.

[0130] Example 4: Clinical Trial 1 The sample size used in this example was MADRS between esketamine and placebo. The effect size in the total score was 0.45 points, the two-sided significance level was 0.05, and 24 The calculation assumed a dropout rate of 5% over time. Approximately 112 participants, with a 90% dropout rate... To achieve the required power level, patients were randomized to each treatment group.

[0131] A. Main purpose The primary objective is to measure the baseline MADRS total score 24 hours after the first dose. In subjects assessed as being at imminent risk of suicide, as measured by changes in [specific factor]. In addition to comprehensive standard treatment for reducing MDD symptoms, including suicidal ideation, nasal cavity The objective is to evaluate the efficacy of intranasal esketamine 84 mg compared to an internal placebo.

[0132] B. Subject and Treatment Information This refers to suicide in adult male and female patients who were assessed as being at imminent risk of suicide. In addition to comprehensive standard treatment for reducing MDD symptoms, including delirium, intranasal pharyngeal A randomized, double-blind study to evaluate the efficacy of intranasal esketamine 84 mg compared to racebo. This is a placebo-controlled, multicenter clinical trial.

[0133] This clinical trial involves a screening evaluation conducted within 48 hours prior to intranasal administration on day 1, and A 25-day double-blind treatment phase (days 1-25) and a 65-day observation phase (days 2) immediately following the treatment. It consisted of days 6 through 90. The total duration of the trial for each subject was approximately 13 weeks. Ta.

[0134] Throughout the clinical trial period, a total of 270 participants were screened across 51 sites in 10 countries. The study was conducted. Of these, 226 subjects were placed in one of two treatment groups in a 1:1 ratio. Randomized (114 patients to esketamine 84mg + SOC and 112 patients to placebo + SOC) (Persons). Randomization is determined by the clinical trial site and the standard treatment of participants before randomization on day 1. Regarding the necessity of antidepressant treatment (i.e., antidepressant monotherapy or antidepressant + augmentation therapy) They were stratified based on their teacher's evaluation.

[0135] This clinical trial involves a screening evaluation conducted within 24-48 hours before medication administration on day 1, and A 25-day double-blind treatment phase (days 1-25) with twice-weekly medication sessions immediately following the initial treatment. This consisted of a 9-week observation phase (days 26-90). All participants were hospitalized. Inpatient psychiatric treatment for the patient, and initiation or optimization of standard antidepressant medication. Comprehensive (including decisions made by the attending physician based on clinical judgment and treatment guidelines) I took the SOC (Systems of Conduct) test.

[0136] The first dose of the investigational drug therapy may be administered in an emergency room or other authorized psychiatric ward for inpatients. It is administered in the environment. All patients will be treated by their attending physician, including hospitalization and antidepressant therapy. Treatment is provided within the context of comprehensive standard clinical treatment, including the initiation or optimization of treatment. Depressive medication treatment is initiated or optimized for all patients on day 1.

[0137] After the first dose (i.e., at the start of the fourth day of medication or thereafter), subjects were randomized. The patient can tolerate the administration of esketamine 84 mg or placebo into the nasal cavity. If not available, the single dose may be reduced to 56 mg of intranasal esketamine or intranasal placebo. Permitted. Further dose adjustments during the double-blind treatment phase are not permitted.

[0138] Newly initiated or optimized standard antidepressant therapy dose escalation / adjustment is a double-blind study. It must be done during the first two weeks of treatment (i.e., by the 15th day), and the dosage is The patient remained stable until the end of the post-double-blind phase (day 25). During the observation phase, antidepressant treatment was administered. This is managed based on the clinician's judgment.

[0139] The target group consists of patients who remain in a psychiatric ward for a recommended 5-day period and follow the facility's standard treatment procedures. Shorter or longer hospitalization may be permitted if clinically justified. 5 days Any earlier discharge will need to be discussed and approved by the clinical trial sponsor's medical monitor. After discharge from the psychiatric ward for inpatients, subsequent outpatient visits for the double-blind treatment phase are 2 The observation period is conducted twice a week at an outpatient psychiatric facility until day 5. During the observation phase, the subjects are those taking the investigational drug. For the first two weeks after treatment, monitoring will be conducted twice a week (on days 28, 32, 35, and 39). ru.

[0140] C. Baseline Clinical Characteristics The majority of participants in the DB phase were women, and the average age of all participants was approximately 3 The child was 9 years old. The average baseline MADRS total score was over 41 (severe ulceration). (Equivalent to depression). It should be noted that this average MADRS score is for treatment-resistant depression. This is even higher than what was observed in short-term trials of esketamine in (TRD). Participants had active suicidal thoughts and intentions within 24 hours of randomization. When measured using the CGI-SS-R scale obtained from SIBAT, the majority of participants 89% were scored as having moderate to severe suicidal tendencies at baseline. Approximately two-thirds of the participants had a history of suicide attempts, and about one-third of the participants had attempted suicide within the past month. He had attempted suicide in the past. He had a very high average MADRS score at the time of entry. Recent suicide attempts all highlight the high clinical risk to the population and the need for immediate treatment. As newly initiated or optimized SOC antidepressants, compared to antidepressant + augmentation therapy. A slightly larger proportion (55.4%) of participants were treated with antidepressant monotherapy.

[0141] [Table 5]

[0142] [Table 6]

[0143] [Table 7]

[0144] [Table 8]

[0145] [Table 9]

[0146] Of the 226 randomized subjects, one person in the esketamine 84 mg + SOC group The subjects did not receive any investigational drug therapy, making them the target population for safety and maximum efficacy analysis. It is not included. Furthermore, one subject in the esketamine 84mg + SOC study was the investigational drug After the first dose of therapy, the patient experienced an adverse event during treatment, "visual hallucinations," which led to the discontinuation of treatment. and did not have any MADRS or CGI-SS-R scores after any baseline. Therefore, it is included in the safety analysis population but not in the maximum efficacy analysis population. The average age was 39.3 years, and the age range was 18 to 64 years.

[0147] Of the 226 randomized subjects, 195 (86.3%) underwent a 25-day trial. The double-blind treatment phase was completed. The most frequent reason for withdrawal was adverse events, affecting 10 patients (4. This was reported by 4% of the subjects. Of the three subjects who completed the double-blind phase, the observation phase was... They did not enter. Subsequently, 192 subjects entered the observation phase. Five people in each treatment group Although participants discontinued treatment due to adverse events, the PBO+SOC group showed a greater lack of efficacy. Many participants interrupted the session (6 participants in the PBO+SOC group vs. 6 participants in the ESK+SOC group). (One participant) Similarly, in the PBO+SOC group, more people dropped out due to the subject. Participants were interrupted (6 participants in the PBO+SOC group vs. 6 participants in the ESK+SOC group) (2 participants).

[0148] Approximately 87% of participants in the ESK+SOC group received all eight doses of the investigational drug therapy. On the other hand, in the PBO+SOC group, 81% of participants received all of the investigational drug therapies.

[0149] D. Results (i) Primary outcome measures The change in the total MADRS score was greater in the ESK+SOC group than in the PBO+SOC group. The impact was significant. The mean change (SD) from baseline to 2 hours after the first dose was ESK+ SOC was -16.4 (11.95), and PBO+SOC was -12.8 (10.7) 3) The difference between treatment groups in this LOCF ANCOVA analysis is clinically significant. The difference was statistically significant (LS mean [SD] difference -3.8 [1.39]; two-sided p = (0.006). The effect size was 0.34 at the 24-hour initial time.

[0150] These positive results were consistent with susceptibility analysis using the MMRM approach. This analysis also shows that ESK surpasses PBO+SOC in terms of changes in the total MADRS score. The benefits of +SOC were evident 4 hours after administration and at the end of the DB period. Ta.

[0151] (ii) Effectiveness Statistical analysis was performed at a two-sided significance level of 0.05. Multiple endpoints (primary and important secondary) were analyzed. With regard to testing the next (subsequent), redundancy is controlled by a fixed sequence of test procedures. In other words, only after the null hypothesis for the primary endpoint is not met can the important secondary hypotheses be considered. We tested it.

[0152] (iii) Primary efficacy endpoint: The primary efficacy analysis included all randomized subjects who received at least one dose of the double-blind investigational drug therapy. It is based on the maximum effectiveness analysis population defined as the optimized target population, Montgom Ery Asberg Depression Rating Scale (MADRS) total score or clinically global impression - self Baseline and baseline for the Severity of Homicidal Tendency - Revised Edition (CGI-SSR) It has both post-evaluation and post-evaluation aspects.

[0153] The MADRS consists of 10 items that cover all of the core depressive symptoms, and each item is: Scoring is on a scale of 0 (no symptoms or normal) to 6 (severe or persistent symptoms). The total score (0-60) was calculated by adding up the scores of all 10 items. A higher score indicates a more severe condition.

[0154] The primary efficacy variable (MADRS from baseline to 24 hours [day 2] after the first dose) Based on the most recent observed (LOCF) analysis of ANCOVA for the change in total score, The improvement in the esketamine 84mg + SOC group was statistically significant compared to the placebo + SOC group. (Two-sided p=0.006) was reached. 2 days from baseline in the MADRS total score. The mean (SD) change (LOCF) to the eye was -16 with esketamine 84mg + SOC. The score was 4 (11.95), and with placebo + SOC it was -12.8 (10.73), and this In this case, a decrease from baseline indicates improvement. Based on ANCOVA analysis, esketamine The least squares mean difference (SE) between 84mg + SOC and placebo + SOC was -3.8 (1. 39) The primary evaluation criterion, effect size, was 0.34. The size of the brain is considered clinically significant for major depressive disorder.

[0155] [Table 10]

[0156] [Table 11]

[0157] (iv) Key secondary efficacy endpoints Changes in CGI-SS-R from baseline to 24 hours after the first dose (day 2). The CGI-SS-R obtained from the Situational Impulse and Related Behavior Assessment Tool (SIBAT) assessment was 0 The patient was scored on a 7-point scale from (normal, no suicidal tendencies) to 6 (patient with the highest suicidal tendencies). ru.

[0158] [Table 12]

[0159] ANC of changes in CGI-SS-R scores from baseline to 24 hours after the first dose Based on OVA LOCF analysis, the improvement in the esketamine 84mg + SOC group was compared to the placebo group. Compared to the +SOC group, statistical significance was not reached (two-sided p=0.107). The median (range) change (LOCF) from day 1 to day 2 is esketamine 84mg + SO In group C, the score was -1.0 (-6;2), while in group placebo + SOC, it was -1.0 (-5;1). The difference between esketamine 84mg + SOC and placebo + SOC was measured by the Hodges-Le. The Hmann estimate (95% CI) was 0.0 (-1.00; 0.00).

[0160] (v) Safety Intranasal ESK + SOC was safe and tolerable. Overall, esketamine 84mg The study included 100 participants (88.5%) in the g+SOC group and 83 participants (74%) in the placebo+SOC group. 1% of participants experienced at least one TEAE during the double-blind phase. The most common (≧20%) TEAE was dizziness (35) in the esketamine 84mg + SOC group. The reported symptoms were (0.4%), dissociation (29.2%), and nausea (20.4%), while the placebo + SOC group remained unchanged. It wasn't there.

[0161] One death occurred in this clinical trial. One participant in the esketamine 84mg + SOC group developed a serious condition. The patient, who was an AE (Accidental Exposure) in the observation phase, committed suicide during the third day of the last dose of the investigational drug therapy. This occurred later. This event is not considered to be related to the investigational drug therapy.

[0162] Ten subjects (4 people [3.5%] receiving esketamine 84mg + SOC, and placebo + SOC) Six of the patients [5.4%] experienced a serious TEAE during the double-blind phase of treatment. ESK+SO SAE in group C included one participant with each of the following events: attempted suicide, depression. Suicidal tendencies due to illness, worsening of depression, and diabetic ketoacidosis. PBO+SOC group SAEs include the following events: attempted suicide, suicidal tendencies due to depression, and high transaminase levels. One participant with each of the following conditions (hypertransaminasemia), and two participants whose suicidal ideation worsened. The participants included one participant whose depression and aggression worsened.

[0163] In the ESK+SOC group and the PBO+SOC group, 10 people (8.8%) and 6 people, respectively. 5.4% of participants had severe TEAEs. The principal investigator determined that there was a causal relationship. Most of the events (7) in ESK+SOC participants were related to investigational drug therapy. In contrast to the group that was thought to have multiple subjects, the PBO+SOC group had only one subject.

[0164] 23 participants (13 [12.9%] receiving esketamine 84mg + SOC, placebo + S Ten patients [11.0%] of those with OC experienced a serious adverse event during the observation phase, and ESK+SOC In the group, there were 13 people (12.9%), and in the PBO+SOC group, there were 10 people (11.0%). The SAEs of the 13 participants previously randomized to the ESK+SOC group included the following events: Cases included: 1 completed suicide, 3 attempted suicides, 7 events related to suicidal ideation, and 7 events related to depression. Three events occurred. The SAEs of the 10 participants previously randomized to the PBO+SOC group were as follows: The cases included: 2 suicide attempts, 6 cases related to suicidal ideation, and 6 cases related to depression. One incident occurred.

[0165] Across the entire treatment group, the following proportions resulted in permanent discontinuation of investigational drug therapy due to adverse events. : 5 subjects (4.4%) in the esketamine 84mg + SOC group and placebo + SO The subjects were 5 people (4.5%) in Group C.

[0166] [Table 13]

[0167] [Table 14]

[0168] [Table 15]

[0169] [Table 16]

[0170] [Table 17]

[0171] [Table 18]

[0172] [Table 19]

[0173] E. Overview In meeting the primary outcome criteria, individuals assessed as being at imminent risk of suicide This first of two Phase 3 trials of esketamine in patients with MDD is In the rapid and robust reduction of symptoms of necrosis, ESK+SOC is superior to PBO+SOC. It demonstrated superiority. ESK+SOC compared to PBO+SOC for initial medication. Clinically meaningful and statistically significant MADRS total scores of participants in the following 24 hours. It resulted in a significant improvement. Furthermore, the advantages of ESK+SOC over PBO+SOC are: This was evident at both 4 hours after the first dose and at the end of the DB study (4 hours after the 25th day dose). there were.

[0174] Participants in both treatment groups showed clinically significant results from baseline in the CGI-SS-R. While some improvement was observed, the difference in these changes was observed 24 hours after the first dose of the investigational drug therapy. The results did not reach statistical significance.

[0175] The adverse events observed in this clinical trial were consistent with the established safety profile of esketamine. In a study of women previously randomized to esketamine, one case of suicide occurred. The death occurred three days after the last dose of the investigational drug therapy. She had only minimal depressive symptoms. It has not been reported, and there were no suicidal tendencies at the time of the last clinical trial visit, but there are five suicide attempts in the patient's lifetime. The patient had a history of the condition, most recently within one month of randomization. It occurred during the double-blind phase. All adverse events related to depression and suicide are considered to be unrelated to the investigational drug therapy. The frequency was similar between the two treatment groups. During the double-blind phase, both subjects (each treatment group) attempted suicide. One person from the treatment group had a history of attempted suicide within the past month. They were observed during a 9-week follow-up period. Adverse events related to depression and suicide were observed in subjects previously randomized to esketamine. Although it occurred slightly more frequently, the PBO+SOC group showed a lack of efficacy during the DB phase, resulting in more frequent occurrences. It is important to note that many participants discontinued the treatment. Therefore, during the observation phase, A slightly higher incidence of events in participants previously treated with esketamine suggests that PBO+SOC This may be due to the fact that insufficient responders were discontinued earlier in the group. The onset of events was spread throughout the entire follow-up period, with similar timings across the two treatment groups. It should be noted that the five participants who attempted suicide during the follow-up period were All of them had a history of suicide attempts within the month prior to the incident.

[0176] Psychiatric SA associated with suicidal ideation, suicide attempts, or worsening of depression during the DB phase. E occurs rarely (<5%), and in the ESK+SOC and PBO+SOC groups respectively This occurred in 3 and 5 participants. During the 9-week observation period, suicidal ideation, suicide attempts, and suicide occurred. Psychiatric SAEs associated with completion or exacerbation of depression are ESK+SOC and PBO+S In the OC group, this occurred in 13 and 9 participants, respectively.

[0177] Positive results for the primary endpoint indicate that the patient has a life-threatening condition for which there is no approved treatment. The rapid and robust reduction of depressive symptoms in a patient population with severe illness. To clearly demonstrate effectiveness. This clinical trial also addresses the very high-risk conditions of the participants included. However, the proportion of suicide-related adverse events was different from the proportion expected based on published literature. It was extremely low in comparison.

[0178] These results indicate that intranasal esketamine suppresses this very severely ill and vulnerable patient population. It demonstrates that it is an effective treatment for rapidly reducing depressive symptoms. The clinical effects of esketamine, demonstrated by the improvement of depressive symptoms that occurs within a few hours, are significant. It offers welcome relief to patients suffering from severe mental anguish. Oral antidepressants typically require several weeks to produce any effect, but Eske Tamin provides robust and clinically meaningful improvement within hours. In fact, in this clinical trial... The size of the therapeutic effect observed within 24 hours of the first dose of esketamine was: This is seen only after 4-8 weeks of oral antidepressants or augmentants, and in TRD. This is equivalent to what was observed at the end of the induction phase in the Phase 3 esketamine trial. Furthermore, all The participants received newly initiated or optimized 4-week psychiatric inpatient treatment for hospitalized patients. Although he received comprehensive standard treatment consisting of oral antidepressants and intensive psychosocial support, S The clinical effects of ketamine were clear. The significant benefits of comprehensive standard treatment. In light of nonspecific effects, the clear benefits of esketamine throughout the entire course of treatment are particularly noteworthy. It deserves it. Participants in this clinical trial also had a high suicide rate, as measured by CGI-SS-R. We experienced a clinically significant and rapid reduction in the severity of the trend.

[0179] Example 5: Clinical Trial 2 This example involves a patient assessed as being at imminent risk of suicide, including suicidal ideation. In addition to comprehensive standard care (SOC), a comparison of placebo with MDD symptoms was found. The effectiveness of intranasal esketamine will be evaluated.

[0180] This includes suicidal ideation in adult patients assessed as being at imminent risk of suicide. In rapid reduction of MDD symptoms, intranasal ESK+S ​​is superior to intranasal PBO+SOC. This is a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy of OC. Primary objective: The target is the change from baseline in the total MADRS score 24 hours after the first dose. The effectiveness of ESK+SOC in reducing MDD symptoms, including suicidal ideation, when measured. The goal is to compare it with PBO+SOC.

[0181] The sample size planned for this clinical trial was the MAD between esketamine and placebo. RS total score effect size 0.45 points, two-sided significance level 0.05, and 24 hours The calculation assumed a dropout rate of 5%. Approximately 112 participants had a 90% success rate. The plan was to randomize participants into each treatment group in order to achieve the desired outcome.

[0182] A. Main purpose The primary objective is to measure the baseline MADRS total score 24 hours after the first dose. In subjects assessed as being at imminent risk of suicide, as measured by changes in [specific factor]. In addition to comprehensive standard treatment for reducing MDD symptoms, including suicidal ideation, nasal cavity The objective is to evaluate the efficacy of intranasal esketamine 84 mg compared to an internal placebo.

[0183] B. Subject and Treatment Information A total of 273 participants were screened at 50 sites in 12 countries throughout the entire clinical trial period. The study was conducted. Of these, 230 subjects received a 1:1 ratio (esketamine 84mg + SO). (115 patients in group C and 115 patients in group placebo + SOC) were randomized to one of two treatment groups. Randomization was performed by the clinical trial site and by the standard treatment of antidepressants for the subjects (i.e.) Stratification based on the physician's assessment of the need for antidepressant monotherapy or antidepressant augmentation therapy. The standard of care was determined before randomization on day 1. All participants received the same standard of care as hospitalized patients. Inpatient psychiatric treatment and initiation or optimization of standard antidepressant medication (clinical judgment) A comprehensive SOC (State of Computation) including (determined by the attending physician based on diagnosis and treatment guidelines) I received it. Of the 230 randomized subjects, 2 subjects in the placebo + SOC group and One subject in the esketamine 84mg + SOC study was not receiving any other investigational drug therapy. Therefore, this group was not included in the safety and maximum efficacy analysis population. The average age was 40.8 years. The age range was 18 to 64 years old.

[0184] The majority of participants in the DB phase were women. Average baseline Montgomery The total score on the Ry-Asberg Depression Rating Scale (MADRS) was approximately 40 (heavy (Equivalent to a degree of depression). All participants experienced active suicidal ideation within 24 hours of randomization. and had the will. In randomization, the CGI-SS-R scale obtained from SIBAT Therefore, when measured, the majority of participants (91%) had moderate to severe symptoms at baseline. They were scored as having suicidal tendencies. Furthermore, more than two-thirds of the participants had a history of attempted suicide. More than a quarter of the participants had attempted suicide within the past month. Furthermore, 3% of the participants More than two out of ten participants had a history of suicide attempts, and more than a quarter of the participants had attempted suicide within the past month. There was a case where ESK+SOC (3%) had a higher percentage than PBO+SOC (21%). 2% of randomly selected participants had recently attempted suicide. As a SOC antidepressant, it was used by a larger proportion of participants (61%) compared to antidepressant monotherapy. They were randomized to receive treatment with antidepressants plus augmentation therapy.

[0185] This clinical trial involves a screening evaluation conducted within 48 hours prior to intranasal administration on day 1, and A 25-day double-blind treatment phase (days 1-25) with twice-weekly medication sessions immediately following the initial treatment. This consisted of a 65-day observation phase (days 26-90). All trials for each subject continued. The period was approximately 13 weeks.

[0186] Of the 230 randomized participants, 184 (80.0%) underwent a 25-day trial. The double-blind induction phase was completed. Approximately 75% of participants in the ESK+SOC group received the investigational drug therapy. In contrast to the PBO+SOC group, 83% of participants received all eight doses of the investigational drug therapy. I received all of the prescribed medications.

[0187] In ESK+SOC, more participants dropped out due to the target audience (ESK+S (10 participants in the OC group vs. 5 participants in the PBO+SOC group). More participants in the ESK+SOC group than in group C (9 participants in each group compared to 3 participants in the ESK+SOC group) experienced adverse events. Although interrupted due to an elephant, the PBO+SOC group had more participants than the ESK+SOC group. The participants (6 to 2 in each case) discontinued the study due to lack of effectiveness. The two most frequent The reasons for withdrawal were withdrawals reported by 15 people (6.5%) and 12 people This was an adverse event reported by 5.2% of the subjects. One person who completed the double-blind phase... The individuals were not placed in the observation phase. Subsequently, 183 individuals were placed in the observation phase.

[0188] [Table 20]

[0189] [Table 21]

[0190] [Table 22]

[0191] [Table 23-1]

[0192] [Table 23-2]

[0193] [Table 24]

[0194] C. Results (i) Effectiveness Statistical analysis was performed at a two-sided significance level of 0.05. Multiple endpoints (primary and important secondary) were analyzed. With regard to testing the next (subsequent), redundancy is controlled by a fixed sequence of test procedures. In other words, only after the null hypothesis for the primary endpoint is not met can the important secondary hypotheses be considered. We tested it.

[0195] (ii) Primary efficacy endpoints: The primary efficacy analysis included all randomized subjects who received at least one dose of the double-blind investigational drug therapy. It is based on the maximum effectiveness analysis population defined as the optimized target population, Montgom Ery Asberg Depression Rating Scale (MADRS) total score or clinically global impression - self Baseline and baseline for the Severity of Homicidal Tendency - Revised Edition (CGI-SSR) It has both post-evaluation and post-evaluation aspects.

[0196] Primary efficacy variable / primary time point: From baseline to 24 hours after the first dose (day 2). Changes in the total MADRS score. MADRS covers all core depressive symptoms. It consists of 0 items, and each item ranges from 0 (no symptoms or normal) to 6 (severe or The score is based on the persistence of the symptoms. The total score is calculated by adding up the scores for all 10 items. The core score (0-60) was calculated. A higher score indicates a more severe condition.

[0197] The primary efficacy variable (MADRS from baseline to 24 hours [day 2] after the first dose) Based on the most recent observed (LOCF) analysis of ANCOVA for the change in total score, The improvement in the esketamine 84mg + SOC group was statistically significant compared to the placebo + SOC group. (Two-sided p=0.006) was reached. The change in the total MADRS score was greater than that of the PBO+SOC group. The baseline score in the MADRS total score was significantly larger in the ESK+SOC group. The mean (SD) change (LOCF) from the starting line to day 2 was for esketamine 84mg + SO In group C, the score was -15.7 (11.56), while in group placebo + SOC, it was -12.4 (10.43). ) and in this case, a decrease from the baseline represents improvement. This LOCF ANCOVA The differences between treatment groups in the analysis were clinically meaningful and statistically significant, according to ANCOV. Based on analysis A, least squares of the difference between esketamine 84 mg + SOC and placebo + SOC. The average difference (SE) was -3.9 (1.39). The primary evaluation criterion, effect size, was 0. It was 0.35. An effect size of 0.3 is clinically significant for major depressive disorder. It is considered to exist.

[0198] These positive results were consistent with susceptibility analysis using the MMRM approach. This analysis also shows that ESK surpasses PBO+SOC in terms of changes in the total MADRS score. The benefits of +SOC are clear 4 hours after administration, but not at the end of the DB period. It showed that it did not exist.

[0199] [Table 25]

[0200] [Table 26]

[0201] (iii) Key secondary efficacy endpoints Important secondary efficacy variable: CG from baseline to 24 hours after the first dose (day 2). Changes in the I-SS-R score, obtained from the Suicidal Ideation and Related Behavior Assessment Tool (SIBAT) assessment. The CGI-SS-R score ranges from 0 (normal, no suicidal tendencies) to 6 (patients with the highest suicidal tendencies). It will be scored on a 7-point scale.

[0202] ANC of changes in CGI-SS-R scores from baseline to 24 hours after the first dose Based on OVA LOCF analysis, the improvement in the esketamine 84mg + SOC group was compared to the placebo group. Compared to the +SOC group, statistical significance was not reached (two-sided p=0.379). The median (range) change (LOCF) from day 1 to day 2 is esketamine 84mg + SO In group C, the score was -1.0 (-6;2), while in group placebo + SOC, it was -1.0 (-5;2). The difference between esketamine 84mg + SOC and placebo + SOC was measured by the Hodges-Le. The Hmann estimate (95% CI) was 0.0 (0.00;0.00).

[0203] [Table 27]

[0204] (iv) Safety The adverse events observed in this clinical trial were similar to those seen in the safety profile of esketamine in previous clinical trials. It matches the file. It relates to suicidal ideation, suicide attempts, or worsening of depression that occur during the DB phase. Related psychiatric SAEs are rare (<5%); three participants in each treatment group committed suicide. An attempted suicide was made. During the 9-week follow-up period, suicidal ideation, suicide attempts, or worsening of depression occurred. The psychiatric SAE was observed in 9 people in the ESK+SOC and PBO+SOC groups, respectively. It occurred in 6 participants. ESK+ was more common in participants treated with PBO+SOC (1 person). A higher incidence of suicide attempts was observed among participants (4 people) who had previously received treatment at SOC.

[0205] Intranasal ESK + SOC was safe and tolerable. Overall, esketamine 84mg 104 people (91.2%) in the g+SOC group and 87 people (77.2%) in the placebo+SOC group. Of the 0% of participants, at least one TEAE was experienced during the double-blind phase. The most common (≧20%) TEAE was dizziness (41) in the esketamine 84mg + SOC group. 0.2%, dissociation (38.6%), nausea (33.3%), taste disturbance (25.4%), somnolence ( 22.8% reported headache (21.9%) and paresthesia (20.2%), compared to placebo + SOC. In this group, headache was the most common symptom (23.0%). There were no deaths during this trial.

[0206] 11 subjects (5 people [4.4%] receiving esketamine 84mg + SOC, and placebo + SOC) Six of the 21 subjects (5.3%) experienced a serious TEAE during the double-blind phase of treatment. (9 people [10.1%] received esketamine 84mg + SOC, 12 people [1] received placebo + SOC. 2.8% experienced a serious adverse event (AE) during the observation phase. The principal investigator determined that there was a causal relationship. Most of the events (17) in ESK+SOC participants were related to investigational drug therapy. In contrast to this, no subjects were found in the PBO+SOC group.

[0207] The SAEs in the ESK+SOC group included the following events: 3 suicide attempts, and One participant each reported suicidal ideation and depersonalization / derealization disorder. PBO+SOC The group's SAE included the following events: 3 suicide attempts and 2 suicidal ideation-related events. Furthermore, one participant each had depression, arrhythmia, pericardial effusion, and pneumothorax. .

[0208] Of the 21 participants, 9 experienced SAE during the 9-week follow-up phase, with 9 in the ESK+SOC group. (10.1%), and in the PBO+SOC group, there were 12 people (12.8%). Previously, ESK+S The SAEs of the nine participants randomized to the OC group were the following events: 4 suicide attempts, 3 The study included events related to suicidal ideation, and each participant had a history of depression. The patient presented with the following events: acute stress disorder and hemothorax. Previously, the patient was randomized to the PBO+SOC group. The SAEs of the 12 participants were related to the following events: 1 suicide attempt, 5 suicidal ideation. The incidents included three infection-related incidents, and in each case, one participant was involved in murder. The patient had thought disorder, overdose, thyroid cancer, and encephalopathy.

[0209] Across the entire treatment group, the following proportions resulted in permanent discontinuation of investigational drug therapy due to adverse events. : 9 subjects (7.9%) in the esketamine 84mg + SOC group and placebo + SO This group consisted of 3 individuals (2.7%) in Group C.

[0210] [Table 28]

[0211] [Table 29]

[0212] [Table 30]

[0213] [Table 31]

[0214] [Table 32]

[0215] [Table 33]

[0216] [Table 34]

[0217] D. Overview The results showed that intranasal esketamine caused depressive symptoms in this very severely ill and vulnerable patient population. It demonstrates that it is an effective treatment for rapidly reducing [the condition]. [The condition] occurs within just a few hours after the first dose. The clinical effect of esketamine, demonstrated by the improvement of depressive symptoms, is significant in treating major mental distress. It offers welcome relief to patients suffering from this condition. Standard oral antidepressants While it typically takes several weeks for any effect to be imparted, esketamine requires several weeks. To provide clinically meaningful improvement within a timeframe. In fact, the most effective result of esketamine in this trial. The treatment effect size observed within 24 hours of the first dose was the same as that observed with 4-8 weeks of oral antidepressants. This is equivalent to what is seen only after medication or enhancer. Furthermore, all participants were hospitalized patients. Inpatient psychiatric treatment, 4 weeks of newly initiated or optimized oral antidepressants, and concentrated Although comprehensive standard treatment consisting of psychosocial support was received, the clinical effect of esketamine was It was clear. In light of the significant nonspecific effects brought about by comprehensive standard treatment, The clear benefits of esketamine throughout the entire course of treatment are particularly noteworthy. In this clinical trial... The participants also clinically assessed the severity of suicidal tendencies as measured by the CGI-SS-R. We experienced a significant and rapid reduction.

[0218] The adverse events observed in this clinical trial were consistent with the established safety profile of esketamine. In the double-blind phase, the frequency of SAEs potentially associated with suicidal tendencies was lower than that of two treatments. The situation was similar across the groups, with three people in each group attempting suicide. During the 9-week observation period, The frequency of SAEs potentially associated with homicidal tendencies was similar across treatment groups, but PBO+SOC More participants who were previously randomized to ESK+SOC (4 people) than the participant who received the test (1 person) ) attempted suicide. A history of suicide attempts is the most important predictor of subsequent attempts. Therefore, the higher rate of suicide attempts in the esketamine group suggests that the group had not recently committed suicide before randomization. This may be related to a higher proportion of participants who committed suicide. The initiation of SAEs related to this condition was distributed throughout the entire observation phase in both treatment groups.

[0219] The results of this example are consistent with the results of Example 1. The risk of suicide is assessed as imminent. Both clinical trials of esketamine in MDD patients met their primary endpoints and were approved. In reducing depressive symptoms in a group of critically ill patients with life-threatening conditions for which there is no recognized treatment, This clearly demonstrates the rapid effectiveness of esketamine.

[0220] In both Examples 1 and 2, participants in the PBO+SOC group received ESK+ In participants previously treated with SOC, more suicide attempts occurred, and during follow-up, cases were observed. In case 1, one person successfully committed suicide. The initiation of SAEs potentially associated with suicidal tendencies occurred during the observation period. The overall dispersion does not suggest a rapid withdrawal effect from esketamine. Furthermore, a recurrence of suicidal tendencies can be an indicator of treatment-resistant depression (TRD), and in some patients... This suggests the need for long-term treatment with esketamine.

[0221] The above specification, along with the examples given for illustrative purposes, teaches the principles of the present invention. However, the implementation of this invention is included within the scope of the following claims and equivalents. It will be understood that this includes all common variations, adaptations, and / or modifications.

Claims

1. Major depressive disorder, including suicidal tendencies, in human patients assessed as being at imminent risk of suicide. Esketamine for use in a method for reducing the symptoms of a disorder, the said method The law (a) determines whether the patient has previously attempted suicide, and ( ii) If the patient has previously attempted suicide, standard treatment and esketamine The treatment of the patient, including esketamine.

2. If it is determined that the patient has never attempted suicide before, the patient will be sent to Esketami The escape method according to claim 1, which treats the patient with the standard treatment without treating with the escape method. Min.

3. The aforementioned standard treatment is determined by the attending physician, including psychiatric inpatient treatment for hospitalized patients. The claim according to claim 1 or 2, comprising initiating or optimizing pharmacotherapy with a standard antidepressant. Esketamine.

4. The aforementioned standard treatment is for outpatients after discharge from psychiatric inpatient treatment for the aforementioned inpatient. The esketamine according to claim 3, further comprising outpatient treatment at a psychiatric facility.

5. The symptoms described in any one of claims 1 to 4 include suicidal ideation accompanied by the intention to commit suicide. Esketamine is listed.

6. The treatment of the aforementioned patients with esketamine was approximately 56 mg to 84 mg per treatment session. The treatment session contains esketamine, and the treatment period has a duration of approximately four weeks. This is performed twice a week, as described in claim 1 or any one of claims 3 to 5. Tamin method.

7. Claim 6 states that the aforementioned prior suicide attempt occurred within one month prior to the first treatment session. Esketamine.

8. The treatment comprises approximately 84 mg of esketamine per treatment session, as described in claim 6. Esketamine.

9. Any one of claims 1 to 8, wherein the esketamine is formulated for intranasal delivery. Esketamine as described in item 1.

10. The esketamine is formulated to be delivered by two or more sprays from an intranasal administration device. The esketamine described in claim 8.

11. Major depressive disorder, including suicidal tendencies, in human patients assessed as being at imminent risk of suicide. A method for reducing the symptoms of a disorder, and whether the patient has previously attempted suicide. To determine whether the patient has previously attempted suicide, (a) standard treatment A method comprising (b) treating the patient with a therapeutically effective dose of esketamine.

12. If it is determined that the patient has never attempted suicide, the patient will be given esketamine. The method according to claim 11, wherein the patient is treated with the standard treatment without receiving any treatment.

13. The aforementioned standard treatment is determined by the attending physician, including psychiatric inpatient treatment for hospitalized patients. The following is a description of claim 11 or 12, which includes initiating or optimizing pharmacotherapy with standard antidepressants. Method of loading.

14. The aforementioned standard treatment is for outpatients after discharge from psychiatric inpatient treatment for the aforementioned inpatient. The method according to claim 13, further comprising outpatient treatment at a psychiatric facility.

15. Any one of claims 11 to 14, wherein the symptoms include suicidal ideation accompanied by the intention to commit suicide. Methods used.

16. The treatment of the patient with a therapeutically effective dose of esketamine was approximately 56 mg per treatment session. ~The treatment session includes administering approximately 84 mg of esketamine, and the treatment session lasts for approximately 4 weeks. The treatment according to claim 11 or 13-15, which is performed at a frequency of twice a week over a period of time. The method described in any one of the items.

17. Claim 16 states that the aforementioned previous suicide attempt occurred within one month prior to the first treatment session. Method of loading.

18. The method according to claim 16, wherein approximately 84 mg of esketamine is administered per treatment session. Law.

19. The method according to any one of claims 11 to 18, wherein the esketamine is delivered intranasally. Law.

20. Claim 18, wherein the esketamine is delivered by two or more sprays from an intranasal administration device. Method of description.

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