Esketamine for the treatment of depression

Abstract

To provide an effective, long-term and safe pharmaceutical composition for use in a method of treating treatment-refractory or treatment-resistant depression in a patient diagnosed as having the depression.SOLUTION: A pharmaceutical composition for use in a method of treating treatment-resistant depression in a patient, wherein the pharmaceutical composition comprises esketamine and wherein the patient has not responded to at least two oral antidepressants in a current depressive episode, the pharmaceutical composition comprising: The method provides a pharmaceutical composition comprising: administering esketamine to the patient at least twice a week during a first induction phase of at least 4 weeks; evaluating the patient during the first induction phase; wherein the patient does not achieve a substantially complete response to esketamine; and re-starting the patient with the highest tolerated dose of esketamine in a second induction phase of at least 4 weeks.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is a continuation of U.S. Provisional Patent Application No. 62 / 755,905 (filed November 5, 2018), U.S. Provisional Patent Application No. 62 / 675,846 (filed May 24, 2018), U.S. Provisional Patent Application No. Application No. 62 / 667,406 (filed May 4, 2018), U.S. Provisional Patent Application No. 62 / 66 No. 3,206 (filed April 26, 2018), U.S. Provisional Patent Application No. 62 / 663,219 (filed April 26, 2018), and U.S. Provisional Patent Application No. 62 / 609,504 (filed April 26, 2018) No. 60 / 199,992 filed Dec. 22, 2003, all of which are incorporated herein by reference in their entireties. It will be incorporated into the specification.

[0002] FIELD OF THE INVENTION The present invention relates to pharmaceutical products and pharmaceutical products for the treatment of depression (e.g., major depressive disorder). In some embodiments, the methods are directed to treatment-refractory or treatment-resistant carcinomas. In another embodiment, the method is useful for treating suicidal ideation. The invention is clinically effective as a monotherapy or in combination with at least one antidepressant. Administering a proven, safe, and therapeutically effective dose of esketamine to patients in need This includes: [Background technology]

[0003] Major depressive disorder (MDD) affects approximately 7-15% of the general population. MDD is associated with significant morbidity and mortality and is a leading cause of disability worldwide. Approximately one-third of patients achieve remission despite treatment with multiple antidepressants. unable to do so and have treatment-resistant depression (TRD) Such patients may benefit from oral antidepressants (AD). Even with continued treatment, there is a high recurrence rate.

[0004] The impact of TRD on patients' lives is difficult to adequately describe. have depressive episodes that last for years. Severely depressed people lose their will to go on with their lives. They lose motivation and suicide attempts increase sevenfold. Life expectancy is reduced by 10 years. In extreme cases, they , basic self-care activities such as bathing or eating, or even engaging in self-care. This is not only for the patient themselves, but also for their families and They also find it difficult to do things they once enjoyed. The loss of the ability to feel joy robs people of the essence and motivation of life. In effect, their life is taken away from them by TRD. These effects are It is theorized to be related to dysregulation of the glutamate pathway.

[0005] Glutamate is the major excitatory neurotransmitter in the mammalian brain and mediates synaptic plasticity, It plays a prominent role in learning and memory. At high levels, glutamate is a potent neuroexcitotoxin that can induce delayed neurotoxicity. This abnormal activity likely contributes to the impaired synaptic plasticity observed in depressed patients. Therefore, over the years, there has been growing interest in the role of glutamate in the pathophysiology of depression. Ketamine, a classical anesthetic, has been shown to be effective not only in animal models of depression but also in the treatment of depression. A small clinical trial in patients with major depressive disorder, including subjects with treatment-resistant depression At subanesthetic doses administered by intravenous infusion, ketamine demonstrated robust antidepressant effects in patients that lasted for several days after a single dose and continued through repeated injections. and can be maintained for several weeks.

[0006] Ketamine (a racemic mixture of the corresponding S- and R-enantiomers) is a glutamate Phensin of N-methyl-D-aspartate (NMDA) receptors It is a nonselective antagonist at the clidinium binding site, which is primarily responsible for its antidepressant effects. The enantiomer S-ketamine (esketamine) may not be mediated by R-ketamine. Approximately 3-4 times higher affinity for glutamate NMDA receptors in vitro than The primary concern associated with ketamine and esketamine is the potential for adverse reactions associated with long-term use. The potential for toxicity and the long-term repeated administration of ketamine / esketamine may not provide significant antidepressant effects. The question is whether it can be maintained (Molero, et al., "An tidepressant Efficacy and Tolerability o f Ketamine and Esketamine:A Critical Rev. iew,” CNS Drugs (2018) 32: 411-420). Specifically, In a recent study, esketamine, in contrast to R-ketamine, demonstrated a sustained effect in rodent models. showed that it was not possible to elicit a sustained antidepressant effect (C. Yang et al. l., “R-Ketamine: a rapid onset and sustain ed antidepressant without psychotomimeti c side effects,”Transl.Psychiatry(2015)5 :1-11). Furthermore, esketamine appears to be associated with a greater reduction in psychiatric and cognitive impairment compared with R-ketamine. and more undesirable psychotic events, including a significant reduction in PV-positive cells in the brain associated with The literature does not address the cumulative effects or tolerability of long-term administration of esketamine. It does not provide guidance on Summary of the Invention [Problem to be solved by the invention]

[0007] Treatment-resistant depression is a common symptom of depression, particularly in patients diagnosed with treatment-refractory or treatment-resistant depression. There remains a need to provide effective, long-term and safe treatments for [Means for solving the problem]

[0008] The present invention provides a method for the treatment of depression (e.g., major depressive disorder), comprising administering to a subject in need of treatment Administer a clinically proven, therapeutically effective dose of esketamine to patients in need. The present invention is directed to a method, including:

[0009] The present invention further provides a method for the treatment of depression (e.g., major depressive disorder), comprising administering to a subject a therapeutically effective amount of a compound selected from the group consisting of benzodiazepines, ... A clinically proven safe treatment, as defined herein, is administered to patients in need of such treatment. The method comprises administering a combination therapy of a therapeutically effective amount of esketamine and at least one antidepressant. , methods are targeted.

[0010] The present invention also provides a method for treating depression in a patient after administration of a therapeutically effective amount of esketamine during an initial administration period. 20. A method of maintaining stable remission or stable response achieved by administering Therapeutic doses of esketamine should be administered continuously for at least 5 months during the treatment period. In some embodiments, the depression is a major depressive disorder or It is resistant depression.

[0011] The present invention further provides a method for the long-term treatment of depression in a patient in need of treatment, comprising administering to said patient a dose of 100mg of acetaminophen or 100mg of acetaminophen. Clinically proven safe and / or clinically proven effective in patients administering a therapeutically effective amount of esketamine to a patient for at least six months. In some embodiments, the depression is major depressive disorder or treatment-resistant depression. I am depressed.

[0012] The method of treatment includes long-term treatment, including a duration of at least about six months. In embodiments, the treatment is for at least about 1 year, at least about 18 months, or at least about 2 years. For example, long-term treatment may range in duration from about 6 months to about 2 years. Treatment may be continued for a much longer period to the extent that the patient benefits from the treatment. It may be extended by

[0013] In some embodiments, the at least one antidepressant is independently a monoamine oxy idase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic Reuptake inhibitors, noradrenergic and specific serotonergic agents, noradrenergic Narcotic reuptake inhibitors, natural products, dietary supplements, neuropeptides, neuropeptide receptors and hormone targeting compounds.

[0014] In other embodiments, methods are provided for the treatment of depression (e.g., major depressive disorder). , providing clinically proven safe and therapeutically effective doses of esketamine to patients in need. Irreversible MAOIs (phenezine, tranylcypromine) and reversible MAOIs (MOAIs) Monoamine oxidase inhibitors (MAOIs), such as bemide ), imipramine, amitriptyline, desipramine, nortriptyline, doxepin, Tricyclics such as protriptyline, trimipramine, clomipramine, and amoxapine; Tetracyclics such as Lotiline, acyclics such as Nomifensine, triazolopyri such as Trazodone anticholinergics (e.g., scopolamine), fluoxetine, sertraline, Serotonin reuptake inhibitors such as fluvoxamine, citalopram, and fluvoxamine, Serotonin receptor antagonists such as zadone and tianeptine, venlafaxine, and desmocycline Serotonin-norepinephrine drugs such as venlafaxine, milnacipran, and levomilnacipran noradrenergic-specific serotonin receptor reuptake inhibitors, such as mirtazapine Toninergic agents, norepinephrine reuptake inhibitors such as reboxetine, and bupropion Atypical antipsychotics such as lithium, triple reuptake inhibitors, kava, and seborrheic acid. Natural products such as St. John's wort, dietary supplements such as s-adenosylmethionine, and Neurokinin receptor antagonists, such as neuropeptides like thyrotropin-releasing hormone compounds that target neuropeptide receptors, such as thiazolidinedione, and compounds that target neuropeptide receptors, such as triiodothyronine and administering in combination with one or more compounds selected from the group consisting of hormones. .

[0015] In other embodiments, methods are provided for the treatment of depression (e.g., major depressive disorder). , providing patients in need of treatment with a clinically proven safe and therapeutically effective dose of esketamine. monoamine oxidase inhibitors, tricyclics, tetracyclics, acyclics, triazolopyridines, cephalosporins, Serotonin reuptake inhibitors, serotonin receptor antagonists, serotonin noradrenaline phosphodiesterase inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic Adrenergic and specific serotonergic agents, noradrenaline reuptake inhibitors , atypical antipsychotics, natural products, dietary supplements, neuropeptides, neuropeptide receptor targeting and one or more compounds selected from the group consisting of compounds targeted to Preferably, esketamine is administered as a monoamine oxidase inhibitor, Tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors Antipsychotics, noradrenergic and specific serotonergic drugs, atypical antipsychotics, and / or or antipsychotics (e.g., risperidone, olanzapine, quetiapine, aripiprazole) and one or more compounds selected from the group consisting of adjunctive therapy with cyclosporin (cyclosporin, cyclosporin, and ziprapradone). More preferably, esketamine is administered in combination with a monoaminooxidase inhibitor. Antidepressants, tricyclics, serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors The compound is administered in combination with one or more compounds selected from the group consisting of: Preferably, esketamine is a serotonin reuptake inhibitor and a serotonin norepinephrine inhibitor. and administering the compound in combination with one or more compounds selected from the group consisting of phosphodiesterase (phosphodiesterase) reuptake inhibitors. do.

[0016] In still further embodiments, a method for treating depression (e.g., major depressive disorder) comprises: The company will provide patients in need of treatment with a clinically proven, safe, and therapeutically effective dose of esophageal cancer. Ketamine, phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline Liptiline, desipramine, nortriptyline, doxepin, protriptyline, tritriptyline pramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine , citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine , bupropion, thyrotropin-releasing hormone, and triiodothyronine The present invention relates to a method for treating atopic dermatitis, and the method includes administering the same in combination with one or more compounds selected from the group consisting of:

[0017] Preferably, esketamine is used in combination with lithium, riluzole, phenelzine, tranylcyprone, amine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline doxepin, protriptyline, trimipramine, clomipramine, amoxapine, Fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, Benla Faxine, milnacipran, levomilnacipran, mirtazapine, and bupropion More preferably, the compound is administered in combination with one or more compounds selected from the group consisting of: Esketamine is a side effect of phenelzine, tranylcypromine, moclobemide, imipramine, and amphetamine. Mitriptyline, desipramine, nortriptyline, doxepin, protriptyline, Rimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine one or more compounds selected from the group consisting of cetin, citalopram, and fluvoxamine More preferably, esketamine is administered in combination with fluoxetine, ceritin, or consisting of ralin, paroxetine, citalopram, escitalopram, and fluvoxamine The compound is administered in combination with one or more compounds selected from the group.

[0018] In yet a further embodiment, a method for the treatment of depression (e.g., major depressive disorder) is provided. The company will provide patients in need of treatment with a clinically proven, safe, and therapeutically effective dose of escalation. thyrotropin-releasing hormone (THR) and other neuropeptides, neurokinin receptors, and Compounds that target neuropeptide receptors, such as antagonists, and triiodothyronines and administering the compound in combination with one or more compounds selected from the group consisting of hormones such as steroids, steroid hormones, and steroid hormones. Includes:

[0019] In other embodiments, methods are provided for the treatment of depression (e.g., major depressive disorder). , to patients in need of treatment, as defined herein, and a therapeutically effective amount of esketamine, at least one antidepressant, and at least one non-steroidal antidepressant; This includes administering combination therapy with antipsychotic drugs.

[0020] In a further embodiment, a method is provided for the treatment of depression (e.g., major depressive disorder). and administering a clinically proven, safe, and therapeutically effective dose of esketamine to patients in need of treatment. at least one antidepressant, as well as quetiapine, aripiprazole, brexipeptide from the group consisting of razole, olanzapine, lurasidone, risperidone, and paliperidone This involves administering combination therapy with at least one selected atypical antipsychotic.

[0021] In other embodiments, the method for the treatment of depression includes antipsychotic therapy, electroconvulsive therapy ( electroconvulsive therapy (ECT), transcranial magnetic stimulation can be combined with adjunctive therapies such as ionation, TMS, or a combination thereof .

[0022] The present invention further relates to a method for treating depression (e.g., major depressive disorder) in a patient in need of treatment. The present invention is directed to the use of esketamine in the preparation of a medicament for the treatment of In some embodiments, the medicament is for treating treatment-refractory or treatment-resistant depression. In embodiments, the medicament is for treating suicidal ideation.

[0023] The present invention further relates to a method for treating depression (e.g., major depressive disorder), preferably treatment-refractory or treatment-refractory. 2. A method for treating resistant depression in a subject in need of such treatment. Targeting ketamine.

[0024] In another embodiment, esketamine for the treatment of depression (e.g., major depressive disorder) is administered. In some embodiments, the composition comprises a treatment-refractory or treatment-resistant In another embodiment, the agent is for the treatment of suicidal behavior and / or autism. It is intended to treat homicidal thoughts. [Brief explanation of the drawings]

[0025] [Figure 1] 1 shows a schematic diagram of the study plan for the ESKETINTRD3002 Phase 3 clinical trial. [Figure 2]Figures show the least squares mean change (±SE) in observed-case MMRM (Mixed-effect Models for Repeated Measures) MADRS (Montgomery-Asberg Depression Rating Scale) total score over time during the double-blind induction phase. LS means and SE were based on the MMRM with change from baseline as the response variable and fixed-effect model terms for treatment (intranasal esketamine + oral antidepressant, oral antidepressant + intranasal placebo), day, country, class or oral antidepressant (SNRI or SSRI), and treatment per day, and baseline value as a covariate. A negative change in score indicated improvement. *One-sided p<0.025. [Figure 3] 1 is a bar graph of response rates on Day 2. Response is a ≧50% improvement in MADRS from baseline in patients taking esketamine and an oral antidepressant. [Figure 4] 1 is a bar graph of response rates at day 28. Response is a ≧50% improvement in MADRS from baseline in patients taking esketamine and an oral antidepressant. [Figure 5] Bar graph of remission rate at day 28. Remission is a MADRS total score ≦12. [Figure 6] 1 is a bar graph showing the percentage of subjects reporting problems (levels 2-5) with mobility, self-care, activity, pain, and anxiety / depression. [Figure 7] Arithmetic mean (±SE) of systolic blood pressure over time during the double-blind induction period using the safety analysis population is shown. [Figure 8] Arithmetic mean (±SE) of diastolic blood pressure over time during the double-blind induction period using the safety analysis set is shown. [Figure 9] Clinician-assessed dissociative symptom scale (CADSS) total scores over time during the double-blind phase using the safety analysis population are shown. [Figure 10]Arithmetic mean (±SE) of modified observer's assessment of alertness / sedation (MOAA / S) scores over time during the double-blind induction period using the safety analysis population is shown. [Figure 11] Figure 1 shows the least squares mean change (observed cases) in MADRS total score over time in US patients with TRD. [Figure 12] Figure 1 shows patient-rated depression severity (observed cases) in US patients with TRD as assessed by the PHQ-9. [Figure 13] Figure 1 shows functional impairment (observed cases) in US patients with TRD as assessed by the Sheehan Disability Scale (SDS). [Figure 14] The percentage of US patients with TRD who achieved a response 4 weeks after the first dose (observed cases) is shown. [Figure 15] Percentage of US patients with TRD who achieved clinician-assessed remission 4 weeks after first dose is shown. [Figure 16] Frequency distribution of PHQ-9 severity categories in US patients with TRD (observed cases) is shown. [Figure 17] The percentage of US patients with TRD (observed cases) who had a ≥ 1-point reduction in the CGI-S 4 weeks after first dose is shown. [Figure 18] 1 shows a schematic diagram of the study design for the ESKETINTRD3005 Phase 3 clinical trial. [Figure 19] Figure 1 shows the least squares mean change (±SE) in MADRS total score over time for observed case MMRM (double-blind induction phase (Study ESKETINTRD3005: full analysis set)). [Figure 20] Figure 1 shows arithmetic mean (±SE) systolic blood pressure over time during the double-blind induction period using the ESKETINTRD3005 safety analysis population. [Figure 21] Figure 1 shows arithmetic mean (±SE) diastolic blood pressure over time during the double-blind induction period using the ESKETINTRD3005 safety analysis population. [Figure 22] 1 is a plot of CADSS total score over time during the double-blind phase using the safety analysis set. [Figure 23] Figures show least-squares mean changes (±SE) in MADRS total scores from last observation carried forward (LOCF) analysis of covariance (ANCOVA) over time during the double-blind induction phase using the full analysis set. LS means and SE were based on ANCOVA with change from baseline as the response variable and factors for treatment (intranasal esketamine + oral AD, oral AD + intranasal placebo), region, and oral antidepressant class (SNRI or SSRI), and baseline value as the covariate. Results are not adjusted for sample size reestimation. A negative change in score indicates improvement. [Figure 24] Figure 1 shows a forest plot of MADRS total score showing the least squares mean treatment difference in change in MMRM from baseline (95% confidence interval) to day 28 by subgroup during the double-blind induction period using the full analysis set. Subgroups with fewer than five subjects are not presented. Results are not adjusted for sample size reestimation. [Figure 25] Arithmetic mean change (±SE) in MADRS total score over time for cases observed for the 65-74 age group during the double-blind induction period using the full analysis set is shown. [Figure 26] Arithmetic mean change (±SE) in MADRS total score over time for cases observed for the ≧75 year old group during the double-blind induction period using the full analysis set is shown. [Figure 27]Least-squares mean change (±SE) in MADRS total score over time for Stage 1 (observed cases) MMRM during the double-blind induction phase using the full analysis set is shown. LS means and SE were based on a mixed-effects model for repeated measures (MMRM) with change from baseline as the response variable and fixed-effects model terms for treatment (intranasal esketamine + oral AD, oral AD + intranasal placebo), day, region, oral antidepressant class (SNRI or SSRI), and treatment per day, and baseline value as a covariate. Results are not adjusted for sample size reestimation. A negative change in score indicates improvement. [Figure 28] Least-squares mean change (±SE) in MADRS total score over time for stage 2 during the double-blind induction phase (observed cases) on the MMRM is shown using the full analysis set. S-means and SE were based on a mixed-effects model for repeated measures (MMRM) with change from baseline as the response variable and fixed-effects model terms for treatment (intranasal esketamine + oral AD, oral AD + intranasal placebo), day, region, oral antidepressant class (SNRI or SSRI), and treatment per day, and baseline value as a covariate. Results are not adjusted for sample size reestimation. A negative change in score indicates improvement. [Figure 29] Figure 1 shows the least squares mean change (observed cases) in MADRS total score over time in US patients ≥ 65 years of age with TRD. MADRS total score ranges from 0 to 60. Higher scores indicate more severe disease. [Figure 30] Frequency distribution of illness severity based on CGI-S scores at baseline and double-blind endpoint (LOCF) is shown. CGI-S scores ranged from 1 (normal, not at all ill) to 7 (most severely ill patients). CGI-S scores ranged from 1 (normal, not at all ill) to 7 (most severely ill patients). [Figure 31]The percentage of US patients ≥ 65 years old with TRD who achieved a response (observed cases) as assessed by the MADRS is shown. Clinician-rated response a was defined as a ≥ 50% reduction from baseline in the MADRS total score. [Figure 32] Figure 1 shows the percentage of US patients aged ≥ 65 years with TRD who achieved remission (observed cases) as assessed by the MADRS. Clinician-rated remission was defined as a MADRS total score ≤ 12. [Figure 33] Figure 1 shows the percentage of US patients aged >65 years with TRD who achieved patient-rated remission (observed cases) as assessed by the PHQ-9. [Figure 34] 1 shows the percentage of US patients aged ≥ 65 years with TRD who had a clinically meaningful response as assessed by the CGI-S. [Figure 35] Figure 1 shows the percentage of US patients aged ≥ 65 years with TRD who had a clinically meaningful response as assessed by the CGI-S. Clinically meaningful and clinically significant responses were defined as a ≥ 1-point or ≥ 2-point reduction in the CGI-S from baseline, respectively. [Figure 36] FIG. 1 shows the frequency distribution of illness severity based on clinical global impression-severity (CGI-S) scores at baseline and double-blind endpoint. [Figure 37]

[0023] Figure 1 shows a study design to evaluate the efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of major depressive disorder, including suicidal ideation, in subjects assessed as being at imminent risk of suicide. [Figure 38] Least-squares mean change (±SE) from baseline in MADRS total score over time during the double-blind phase using last observation carried forward data. LS means and SE were based on analysis of covariance (ANCOVA) with treatment (placebo, esketamine 84 mg), antidepressant therapy (AD monotherapy, AD + augmentation therapy), and analysis center as factors and baseline value as a covariate. [Figure 39]The mean change (SE) in CGJSR from baseline to 4 and 24 hours is shown. The mean change and SE were based on ranks of the change from baseline (LOCF) data and analyzed using an ANCOVA model with treatment, analysis center, and SoC as fixed effects and baseline value (unranked as a covariate). [Figure 40] Correlate the proportion of patients whose suicide risk was resolved at 4 and 24 hours. [Figure 41] Frequency distributions of SIBAT scores at double-blind baseline, Day 1: 4 hours post-dose, double-blind endpoint, and follow-up endpoint are shown. The clinical global judgment of suicide risk scores ranges from 0 to 6. 0: No suicidal tendencies. 1: Occasional suicidal ideation is present, but no specific intervention is required. 2: Some degree of obvious suicidal ideation is present. Patients are encouraged to schedule specialist consultations as needed. 3: Suicide risk requires scheduled outpatient follow-up but no other immediate intervention. 4: Suicide risk requires immediate intervention but not hospitalization (e.g., medication, emergency outpatient follow-up). 5: Suicide risk requires immediate hospitalization but no suicide prevention measures. 6: Suicide risk requires hospitalization with suicide prevention measures. [Figure 42] The least squares mean change (SE) in MADRS scores from baseline to 4 hours (primary endpoint) and approximately 24 hours is shown. [Figure 43] The proportion of patients with each MADRS response and remission at Day 1, Day 2, and endpoint will be correlated. [Figure 44] The proportion of patients with remission at DB endpoints and during follow-up will be correlated. [Figure 45] Least squares mean change (±SE) from baseline in BSS total score over time during the double-blind phase using last observation carried forward data is shown. [Figure 46] 1 shows the mean blood pressure over time by treatment group during the double-blind phase. [Figure 47]1 shows the mean blood pressure over time by treatment group during the double-blind phase. [Figure 48] 1 is a plot of CADSS total score over time during the double-blind phase (Study ESKETINSUI2001: Safety Analysis Set). [Figure 49] 1 is a test plan for Example 4. [Figure 50] 1 is a flow chart summarizing subject and treatment information for Example 4. [Figure 51] Figure 1 shows the cumulative proportion of subjects who remained relapse-free during the maintenance phase (Kaplan-Meier estimates) (full (stable remitters) analysis population) for Example 4. [Figure 52] 1 shows the cumulative proportion of subjects who remained relapse-free in the maintenance phase (Kaplan-Meier estimates) (maximum (stable responder) analysis population) for Example 4. [Figure 53] 1 shows arithmetic mean (±SE) systolic blood pressure over time. Maintenance phase (safety (MA) analysis population) of Example 4. [Figure 54] 1 shows arithmetic mean (±SE) systolic blood pressure over time. Maintenance phase (safety (MA) analysis population) of Example 4. [Figure 55] Arithmetic mean (±SE) CADSS total score over time. Maintenance phase (safety (MA) analysis population) of Example 4. [Figure 56] FIG. 1 is a forest plot of hazard ratios by subgroup for Example 4: Cox regression (complete (stable remission) analysis population). Hazard ratio estimates for subgroups with no events in either arm are not shown. Subgroups with fewer than five subjects are not presented. [Figure 57] Study design for Example 5. At study entry, enrolled non-responder subjects continued to receive the same oral antidepressant medication initiated in the ESKETINTRD3005 study. New oral antidepressants were only available to direct-entry subjects. [Figure 58] 1 shows the frequency distribution of CGI-S in Example 5. [Figure 59]1 shows the arithmetic mean (±SE) of detection-attention (simple reaction time) for the ≧65 year age group in Example 5 (all enrolled analysis population). [Figure 60] The EQ-5D-5L indicates the level of disability by measuring anxiety / depression, usual activities, and pain / discomfort, respectively. [Figure 61] The EQ-5D-5L indicates the level of disability by measuring anxiety / depression, usual activities, and pain / discomfort, respectively. [Figure 62] The EQ-5D-5L indicates the level of disability by measuring anxiety / depression, usual activities, and pain / discomfort, respectively. [Figure 63] Arithmetic mean (±SE) systolic blood pressure over time. Induction and optimization / maintenance phases of Example 5 (all enrolled analysis population). [Figure 64] Arithmetic mean (±SE) systolic blood pressure over time. Induction and optimization / maintenance phases of Example 5 (all enrolled analysis population). [Figure 65] 1 is a plot of CADSS total score over time during the induction and optimization / maintenance phases (all enrolled analysis populations) of Example 5. [Figure 66] 1 is a plot showing the mean (±) SE of the Brief Psychiatric Rating Scale positive symptoms subscale total score over time during the induction and optimization / maintenance phases (all enrolled analysis populations) of Example 5. [Figure 67] 1 shows the mean MADRS total score over time in the IND and OP / MA periods based on the observed case data of Example 5. [Figure 68] Responses of patients with a response of ≧50% reduction from baseline and a remission of MADRS≦12 are shown. [Figure 69] 1 shows the mean PHQ-9 total score over time in the IND and OP / MA periods based on the observed case data of Example 5. [Figure 70]Illustrative diagram of activity decrease and increase. Activity changes induced by MK-801 are described in section 3.3 of Example 6. Gross pathology did not reveal any tissue changes. [Figure 71] Figure 71 shows a repeat-dose neurotoxicity study. Hematoxylin-eosin (HE) staining of the retrosplenial cortex demonstrates the absence of neuronal necrosis in rats treated with esketamine HCl (54 mg / day) and its presence in rats treated with (+)MK-801 maleate, as described in Example 6. Figure 71A shows an image of the retrosplenial cortex of a rat treated with esketamine HCl (54 mg / day), demonstrating the absence of neuronal necrosis. Figure 71B shows an image of the retrosplenial cortex from an animal treated with (+)MK-801 maleate. The arrow indicates a necrotic neuron (shrunken eosinophilic cytoplasm with a condensed nucleus). Figure 71C shows a high-power image of a necrotic neuron (arrow) in the retrosplenial cortex from an animal treated with (+)MK-801 maleate. [Figure 72] Figure 72 shows a repeat-dose neurotoxicity study. Fluoro-Jade (FJ) staining of the retrosplenial cortex demonstrates the absence of neuronal necrosis in rats treated with esketamine HCl (54 mg / day) and its presence in rats treated with (+)MK-801, as described in Example 6. Figure 72A shows an image of the retrosplenial cortex of a rat treated with esketamine HCl (54 mg / day) showing the absence of neuronal necrosis. Figure 72B shows an image of the retrosplenial cortex from an animal treated with (+)MK-801 maleate. [Figure 73]

[0023] Figure 1 is a flow chart illustrating patient disposition for Example 7. Seven participants who received two weeks of study drug during the open-label phase of the study began the follow-up period no earlier than Day 74. [Figure 74]Figures 74A and 74B are line graphs showing the mean change (±SE) in MADRS total score over time during the double-blind phase of Example 7. Changes are shown for Period 1 (A) and Period 2 (B). Period 2 consisted only of participants who received placebo in Period 1 and had moderate to severe symptoms (n=28). Period 1 (Days 1-8) and Period 2 (Days 8-15) are discussed in the Methods section and are shown on the vertical axis of Figure 73. BL indicates baseline. 2H, 2 hours post-dose. Error bars indicate SE. Period 2 consisted only of participants who received placebo in Period 1 and had moderate to severe symptoms (n=28). [Figure 75] 73 is a line graph showing the change in mean MADRS total score from baseline to follow-up endpoint for participants who entered the open-label period of Example 7. Period 1 (days 1-8), Period 2 (days 8-15), open-label period (days 15-74), and follow-up period (days 74-130) are described in the Methods Design section and are shown on the vertical axis of FIG. 73. BL indicates baseline. Error bars, SE. [Figure 76] Figures 76A and 76B are line graphs showing the mean (±SE) MADRS total score over time during the double-blind phase of Example 7. Period 2 consisted only of participants who received placebo in Period 1 and had moderate to severe symptoms (n=28). At 2 hours, a modified MADRS was used, and baseline scores for sleep and appetite items were carried forward. [Figure 77] 1 is a plot of mean systolic blood pressure over time by period for participants who received the same treatment across both periods during the double-blind phase of Example 7. [Figure 78] 1 is a plot of mean diastolic blood pressure over time by period for participants who received the same treatment across both periods during the double-blind phase of Example 7. [Figure 79] 1 is a plot of the mean CADSS total score over time for participants who received the same treatment over both periods in Example 7. [Figure 80] 1 is a plot of the mean plasma concentration-time profile of esketamine. [Figure 81] 1 is a plot of the mean plasma concentration-time profile of noresketamine. [Figure 82A] Cmax vs. dose for data from Example 10. Regression line shown for Cmax (r=0.53). [Figure 82B] AUClast vs. dose for the data of Example 10. Regression line shown for AUClast (r=0.70). DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention provides a clinically safe treatment for patients in need of treatment for depression (e.g., major depressive disorder). The present invention relates to a method for treating a rheumatoid arthritis, the method comprising administering a therapeutically effective amount of esketamine to a patient having a rheumatoid arthritis. In some embodiments, the methods include administering a medicament for the treatment of treatment-refractory or treatment-resistant depression. In another embodiment, the medicament is for treating suicidal ideation.

[0027] These methods advantageously allow for tailoring effective regimens for patients with depression. Such patients may be those already diagnosed with MDD, TRD, or those with suicidal tendencies. These include patients who have had or are otherwise untreated for depression.

[0028] In patients with depression after receiving a therapeutically effective dose of esketamine during the initial treatment period Methods for maintaining the stable remission or stable response achieved thereby are also described. The method comprises administering a therapeutically effective amount of esketamine continuously for at least five months between subsequent administration periods. This includes administering the drug to a patient.

[0029] Thus, methods for the long-term treatment of depression in a patient are also provided. The method is clinically proven safe and clinically effective in patients in need of treatment. A proven therapeutically effective dose of esketamine administered for at least 6 months Preferably, the patient's cognitive performance is assessed after six months of treatment, compared to the baseline measurement. In some embodiments, the treatment continues for at least about 1 year. It may be for a duration of at least about 18 months, or at least about 2 years. Treatment may range in duration from about 6 months to about 2 years. Treatment may also be administered by a doctor. As determined, these include, but are not limited to, 4, 5, 6, 7, 8, 9, 10 years or more In some embodiments, the escape route may be continued for a longer period of time. It is initially administered twice weekly for up to 4 weeks during the induction period, and then less frequently than twice weekly. It is administered frequently.

[0030] In certain embodiments of the present invention, esketamine is administered as described herein. In combination with one or more antidepressants, preferably in combination with one to three antidepressants, Preferably, it may be administered in combination with one or two antidepressants.

[0031] In certain embodiments of the present invention, esketamine is selected from one or more of the compounds described herein. in combination with one or more antidepressants and one or more atypical antipsychotics Good too.

[0032] In embodiments, the present invention is directed to combination therapies comprising esketamine and one or more antidepressants. and esketamine is administered as an acute treatment. For combination therapy including ketamine and one or more antidepressants, esketamine is used for acute treatment one or more antidepressants are administered as a chronic treatment.

[0033] In other embodiments, such as during the induction phase, esketamine may be used as monotherapy. It may not be used in combination with any other active compound.

[0034] Some of the quantitative expressions given herein are not modified by the term "about." Regardless of whether "about" is expressly used, amounts given herein are All figures are intended to refer to the actual values ​​shown and are not to be construed as a guarantee of experimental or and / or approximate values ​​based on the ordinary skill in the art, including values ​​obtained by measurement conditions. It is also meant to refer to approximations of such stated values ​​that may reasonably be estimated. It is understood.

[0035] As used herein, unless otherwise specified, the term "esketamine" refers to ketamine. means the (S)-enantiomer, i.e. the compound of formula (I),

[0036] [ka] as (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone "Esketamine" also refers to salts, such as the (S)-enantiomer of ketamine. and the chloride salts, such as the hydrochloride salts of mer, i.e. the compounds of formula (II),

[0037] [ka] (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride Also known as

[0038] In some embodiments, esketamine is the (R)-enantiomer of ketamine, i.e., That is, it is substantially free of the compound of formula (III).

[0039] [ka]

[0040] In other embodiments, the esketamine is present in an amount of about 10 based on the weight of the esketamine sample. In a further embodiment, the (R)-enantiomer of ketamine is less than 5% by weight. Ketamine was approximately 10, 9, 8, 7, 6, 5, and 4 mg per 1000 mg sample, based on the weight of the esketamine sample. , 3, 2, 1, 0.5, 0.1, 0.005, or less than 0.001% by weight of ketamine ( In yet another embodiment, esketamine contains the R)-enantiomer. About 0.001 to about 10% by weight of the (R)-enanthate of ketamine, based on the weight of the sample. In yet a further embodiment, the esketamine is an esketamine samphimer. About 0.001 to about 10%, about 0.001 to about 5%, about 0.001 to about 10% by weight of the Approximately 1, approximately 0.001 to approximately 0.5, approximately 0.001 to approximately 0.1, approximately 0.1 to approximately 5, approximately 0.1 to about 1, about 0.1 to about 5, or about 0.5 to about 5% by weight of the (R)-enantiomer of esketamine It contains mers.

[0041] The term "esketamine" also refers to other pharmaceutically acceptable salts that can be readily selected by one of skill in the art. The term "pharmaceutically acceptable salts" refers to salts that are non-toxic and biologically tolerable. and esketamine salts that are either soluble in water or are otherwise biologically suitable for administration to a subject. Generally, see GS Paulekuhn, "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Oran ge Book Database”, J.Med.Chem.,2007,50:66 65-72, SMBerge, “Pharmaceutical Salts”, J Pharm Sci., 1977, 66:1-19, and Handbook of P pharmaceutical salts,Properties,Selection ,and Use,Stahl and Wermuth,Eds.,Wiley-VC. H and VHCA, Zurich, 2002. Pharmaceutically acceptable salts Examples of compounds that are pharmacologically effective and can be administered without undue toxicity, irritation, or allergic reaction. The salt is suitable for administration to a patient.

[0042] Examples of other pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, Bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate , bromides (e.g., hydrobromide), iodides (e.g., hydroiodide), acetate, propionate acid salts, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, Heptanoate, propiolate, oxalate, malonate, succinate, suberate , Sebacic acid salt, Fumaric acid salt, Maleic acid salt, Butyne-1,4-dioate, Hexyne-1, 6-diazolate salts, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, Hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulfonates Phosphate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate Salt, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propane naphthalene-1-sulfonate, naphthalene-2-sulfonate, and In particular, the salt of esketamine is the hydrochloride salt.

[0043] In certain embodiments of the present invention, esketamine is administered intranasally. In certain embodiments, esketamine is administered intranasally as its corresponding hydrochloride salt. In one particular embodiment of the invention, esketamine is prepared as a 16.14% weight / volume solution (14% It is administered intranasally as the corresponding hydrochloride salt (weight / volume equivalent to esketamine base).

[0044] In certain embodiments of the present invention, esketamine has a pH of 161.4 at a pH of 4.5 in water. mg / mL esketamine hydrochloride (equivalent to 140 mg / mL esketamine base), 0. 12 mg / mL ethylenediaminetetraacetic acid (EDT) A) and 1.5 mg / mL citric acid are administered intranasally. In certain embodiments, esketamine is administered intranasally, and intranasal delivery is at 4.5°C in water. pH 7.0, 161.4 mg / mL esketamine hydrochloride (140 mg / mL esketamine base), 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and 1.5 In one particular embodiment, 100 μL of a solution containing 10 mg / mL citric acid is administered. Esketamine was delivered intranasally using a nasal spray pump, which dispensed 4.5 ml of esketamine in water. pH 7.0, 161.4 mg / mL esketamine hydrochloride (140 mg / mL esketamine base), 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and 1.5 100 μL of solution containing mg / mL citric acid is delivered.

[0045] Generally, one pump from a nasal spray device delivers about 50 μL to about 200 μL (about 60 μL, Approximately 70 μL, approximately 80 μL, approximately 90 μL, approximately 100 μL, approximately 110 μL, approximately 120 μL, approximately 130μL, approx. 140μL, approx. 150μL, approx. 160μL, approx. 170μL, approx. 180μL and about 200 μL of an esketamine solution into the nostril of the subject. Therefore, two pumps may deliver between about 100 μL and about 400 μL to a subject. .

[0046] In certain embodiments of the present invention, a therapeutically effective amount of esophageal squamous cell carcinoma (ESC) is administered. Patients requiring ketamine treatment are those with an episode of depression (e.g., major depressive disorder). In certain embodiments of the present invention, the patient in need of treatment is a patient suffering from suffers from an episode of depression (e.g., major depressive disorder) and Episodes of major depressive disorder (MDD) have not responded to treatment with at least two oral antidepressants. (i.e., patient has not responded to treatment with at least two oral antidepressants) In other embodiments, the elderly patient in need of treatment is suffering from depression (e.g., major depressive disorder). ) episodes, and episodes of depression (e.g., major depressive disorder) last for 2 The elderly patient had not responded to treatment with two oral antidepressants (i.e., the elderly patient had not responded to treatment with two oral antidepressants). (not responding to drug treatment).

[0047] In certain embodiments of the invention, the patient in need of treatment is suffering from depression (e.g., major depression). For example, if they have a score of 18 or higher on the MADRS , or patients with a score of 4 or higher on the CGI scale.

[0048] As used herein, the term "depression" includes major depressive disorder, persistent depressive disorder, Seasonal affective disorder, postpartum depression, menstrual dysphoria, situational depression, anhedonia, melancholia, Mid-stage depression, late-stage depression, depression caused by identifiable stressors, treatment-resistant depression or a combination thereof. In certain embodiments, the depression is major depressive disorder. In another embodiment, the major depressive disorder is accompanied by depressive features or anxiety distress. In a further embodiment, the depression is treatment-resistant depression.

[0049] As used herein, the term "non-responder" refers to a patient who does not fully recover from an antidepressant (e.g., This refers to patients with a change of 25% or less from baseline in the MADRS total score. do.

[0050] As used herein, the term "episode of major depressive disorder" refers to a period in which a patient experiences a major depressive disorder associated with the psychiatric disorder. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition l Manual of Mental Disorders,5th Edition Symptoms of major depressive disorder sufficient to meet the criteria for major depression as specified in the DSM-5 "Inflammatory" refers to a continuous period of time (e.g., about 2 weeks or more) that has a nasty or unpleasant tingling sensation.

[0051] As used herein, "suicide" means "the act of taking one's own life." http: / / en.wikipedia.org / wiki / Suicide-cite_note -7. Suicide includes suicide attempts or non-fatal suicidal behavior, which involves taking one's own life. It is self-inflicted injury accompanied by a desire to end, but does not result in death. At the start of a suicide attempt, A sequence of self-initiated actions by an individual who anticipates that the actions will lead to his or her own death. It is.

[0052] As used herein, "suicidal ideation" refers to thoughts about or abnormal desire to commit suicide. Obsession or thoughts of taking one's own life or not wanting to live any longer, but not necessarily suicidal Suicidal ideation refers to thoughts that do not involve any active attempt to kill oneself. From transient to chronic and detailed planning, role-playing, and failed attempts These range from deliberately designed to fail or be discovered. In some embodiments, the patient may be is considered "suicidal" when patients have a mean baseline MADRS total score of approximately 38 or greater. In another embodiment, the patient is classified as having a mean baseline risk of 22 or more. A subject is classified as suicidal when they have a line BBSS score. In this study, patients were assessed for suicide risk if they scored 6 or higher on the SIBAT Clinical Global Assessment of Suicide Risk. In yet another embodiment, a patient is classified as suicidal when they have these The score has one or more combinations of:

[0053] As used herein, the terms "concomitant therapy," "combination therapy," "adjunctive therapy," and "adjunctive therapy" are used interchangeably. "Combination therapy," "combined therapy," and "co-administration" refer to the combination of esketamine with one or more antidepressants. means the treatment of patients in need thereof by administering them in combination with other drugs, The amine and antidepressant(s) are administered by any suitable means. In its current form, esketamine is administered in a regimen with one to five antidepressants. In embodiments, esketamine is administered in a regimen with 1, 2, 3, 4, or 5 antidepressants. In another embodiment, esketamine is administered in combination with one or two antidepressants. In a further embodiment, esketamine is administered in combination with an anti-inflammatory drug currently being administered to the patient. In another embodiment, esketamine is administered in a regimen with a different antidepressant. In yet a further embodiment, esketamine is administered in a regimen using a previously In yet another embodiment, the patient is administered a regimen with an antidepressant not previously administered to the patient. In this study, esketamine was administered in a regimen with the antidepressant previously administered to the patient. When esketamine and antidepressant(s) are administered in separate dosage forms, for each compound: The number of doses administered per day may be the same or different, more typically different. Depressant medications are administered as prescribed by a doctor and / or according to their label. and esketamine is administered as described herein. Typically, the patient , under concurrent treatment with both antidepressants and esketamine, both of which It is administered according to a predetermined dosing regimen.

[0054] Esketamine and the antidepressant(s) may be administered via the same or different routes of administration. Suitable methods of administration include oral, intravenous (iv), intranasal (in), and intramuscular. These include, but are not limited to, intravenous (im), subcutaneous (sc), transdermal, buccal, and rectal. In some embodiments, esketamine is administered intranasally. Unless otherwise specified, the term "antidepressant" can be used to treat depression. Suitable examples include monoamine oxidase inhibitors Drugs, tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors blockers, noradrenergic and specific serotonergic drugs, or atypical antipsychotics Other examples include, but are not limited to, phenelzine, tranylcysteine, Monoamine oxidase inhibitors such as bromine and moclobemide, imipramine, and amitriptyline Triptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine tricyclics such as phenytoin, clomipramine, and amoxapine; tetracyclics such as maprotiline; acyclic drugs such as phenytoin, triazolopyridines such as trazodone, fluoxetine, and certo Larynx, paroxetine, citalopram, escitalopram, fluvoxamine serotonin reuptake inhibitors such as benzodiazepine, and serotonin receptor antagonists such as nefazadone. st, venlafaxine, milnacipran, desvenlafaxine, duloxetine levo Serotonin norepinephrine reuptake inhibitors such as milnacipran, mirtazapine, etc. noradrenergic and specific serotonergic drugs, reboxetine, edivoxetine norepinephrine reuptake inhibitors such as fluticasone, atypical antipsychotics such as bupropion, Natural products such as vacava and St. John's wort, and nutrients such as s-adenosylmethionine Supplements, and neuropeptides such as thyrotropin-releasing hormone, neurokinin receptors Compounds that target neuropeptide receptors, such as receptor antagonists, and triiodothyronine In some embodiments, hormones such as thrombin, thrombin, thrombin time ... Antidepressants include imipramine, amitriptyline, desipramine, nortriptyline, and Xepin, protriptyline, trimipramine, maprotiline, amoxapine, torazolam dromone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram ram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, flufenaxine, milnacipran, reboxetine, mirtazapine, phenelzine, trani Lucypromine, moclobemide, kavakava, St. John's wort, s-adenosylmethionine Thionine, thyroid hormone-releasing hormone, neurokinin receptor antagonist, or Preferably, the antidepressant is fluoxetine, imipramine, bromide, or thiazol-1,2-dioxetine. The active ingredient is selected from the group consisting of propionate, venlafaxine, and sertraline.

[0055] Antidepressants (e.g., monoamine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors) , serotonin and noradrenaline reuptake inhibitors, noradrenergic and specific serotonergic Rotonergic drugs, noradrenaline reuptake inhibitors, natural products, dietary supplements, neuropathic drugs Peptides, neuropeptide receptor-targeted compounds, hormones, and medicaments described herein Therapeutically effective amounts / dosage levels and dosing regimens for the compounds of the present invention are readily determined by those skilled in the art. For example, the therapeutic doses and regimens for pharmaceuticals approved for marketing are generally available, e.g., package labels, standard dosing guidelines, physician's s Desk Reference(Medical Economics Compa ny or online at http: / / / www.pdrel.com Listed in standard medication references or other sources.

[0056] As used herein, the term "antipsychotic" includes, but is not limited to: Not determined. (a) Typical or older antipsychotics, such as phenothiazines (e.g., chlorpromazine, Romazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levome promazine (levomepromazin), thioxanthenes (e.g., thiothixene, fluphen Thixol), butyrophenones (e.g., haloperidol), dibenzoxazepines ( loxapine), dihydroindolones (e.g., molindone), substituted benzamido amides (e.g., sulpride, amisulpride); and (b) Atypical antipsychotics and mood stabilizers, e.g., paliperidone, clozapine, lysperidone, Lidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, peros Pyrone, blonanserin, sertindole, ORG-5222 (Organon), etc.; and others, such as sonepiprazole, aripiprazole, nemonapride, SR-31 742 (Sanofi), CX-516 (Cortex), SC-111 (Scotia ), NE-100 (Taisho), etc.

[0057] In embodiments, the "atypical antipsychotic" is aripiprazole, quetiapine, olanzapine, In another embodiment, the compound is selected from the group consisting of ribenzyl benzoate, risperidone, and paliperidone. Atypical antipsychotics include aripiprazole, quetiapine, olanzapine, and risperidone. Preferably, the atypical antipsychotic is selected from the group consisting of aripiprazole, quercetin, The compound is selected from the group consisting of tiapine, and olanzapine.

[0058] As used herein, the term "treatment-refractory or treatment-resistant depression" and the abbreviation "TRD" " is defined as the use of at least two different antidepressants, preferably is defined as major depressive disorder in patients who have not responded adequately to two to five antidepressants. In another embodiment, TRD is a condition characterized by the initiation of appropriate treatment in a current depressive episode. Major depression in patients unresponsive to at least two oral antidepressants of varying doses and durations It is defined as a pathological disorder.

[0059] Non-response to an appropriate course of a given antidepressant can be determined retrospectively or prospectively. Those skilled in the art will recognize that, in embodiments, non-response to an appropriate course of antidepressants is At least one of the antidepressants is determined prospectively. At least two of the non-responses are determined prospectively. At least one of the non-response to antidepressants is determined retrospectively. Non-response to at least two of an appropriate series of antidepressants was associated with the current depressive episode The decision is made retroactively in the

[0060] "At least two oral antidepressants" or "at least two different oral antidepressants" are the main The patient is administered an appropriate dose, which can be determined by the treating physician. The administration is for a suitable duration as determined by the treating physician.

[0061] As used herein, unless otherwise specified, terms such as "treat" and "treatment" are used interchangeably. The term refers to a subject or patient (preferably a mammal, and the prevention of the onset of symptoms or complications, the management and care of the disease, and the prevention of the onset of symptoms or complications. or administration of a compound of the present invention to alleviate complications of, or eliminate, a disease, condition, or disorder. This includes the provision of

[0062] As used herein, unless otherwise specified, the term "clinically proven" (independently or used to modify the terms "safe" and / or "effective") is a U.S. Food and Drug Administration (FDA) Phase III clinical trials sufficient to meet the approval criteria of the FDA or the EMEA This means that the evidence has been verified by similar studies for approval. In addition, the esketamine trial requires appropriate clinical evidence to demonstrate the efficacy of esketamine. A large randomized, double-blind controlled trial is used. Most preferably, the study is for major depressive disorder. Harms, e.g., clinically demonstrating the effectiveness of esketamine for treating treatment-resistant depression Therefore, this is a randomized controlled trial for newly started or currently started oral antidepressants (active comparator). + Newly started or currently started oral antidepressants compared with intranasal placebo Concomitantly administered flexibly administered intranasal esketamine (28 mg, 56 mg, or This was a randomized, double-blind, active-controlled study in which patients received 84 mg of steroids daily. M, including evaluations on days 1-28 as well as evaluations during subsequent dosing periods as described herein. ADRS, Hamilton, CGI, Beck Depression Rating Scale, QIDS, or PHQ-9, etc. The results are evaluated by the techniques described herein.

[0063] As used herein, unless otherwise specified, the term "clinically proven effective" is used interchangeably with "clinically proven effective" or "clinically proven effective." "The effectiveness of the treatment has been proven to be statistically significant by a Phase III clinical trial." i.e., the results of clinical trials may be due to the probability that the alpha level is less than 0.05. or clinical efficacy results do not meet the approval criteria of the U.S. Food and Drug Administration or EMEA This means that the product is sufficient to meet the same tests for market authorization by the EU. Sketamine is available in flexible therapeutically effective doses of 28 mg, 56 mg, or 84 mg (±25%). It is administered intranasally and is used as part of a dosing regimen that includes an induction phase and a maintenance phase as described herein. Baseline MADRS scores were measured as described above and as specifically described in the Examples. For patients who have had a previous treatment, a new treatment plan is recommended if the patient's MADRS score is reduced by at least approximately 50%. major depressive disorder, when coadministered with a previously or currently initiated oral antidepressant; For example, it has proven clinically effective for treating patients with treatment-resistant depression.

[0064] As used herein, unless otherwise specified, the term "safety" refers to the safety of a pharmaceutical treatment. or when referring to combination therapy, excessive adverse side effects (such as toxicity, irritation, or allergic reaction) and when used in the manner of this invention, means that there is no reasonable benefit / risk Corresponding to the ratio.

[0065] As used herein, unless otherwise specified, the term "clinically proven safe" is used interchangeably with "clinically proven safe" or "clinically proven safe." "The safety of the treatment was demonstrated through a Phase III clinical trial based on analysis of the trial data and results." The treatment is clear and has no excessive side effects and is approved by the US Food and Drug Administration or EMEA. A statistically significant clinical benefit (efficacy) sufficient to satisfy similar trials for market approval by For example, esketamine can be administered at 28 mg, 56 mg, or 84 mg. mg (±25%) of the therapeutically effective dose administered intranasally and administered intranasally during the induction period described herein. and as part of a dosing regimen including a maintenance phase, and as specifically described in the Examples. When coadministered with newly started or currently started oral antidepressants, Clinically safe for the treatment of patients with depression, including treatment-resistant depression Proven.

[0066] As used herein, the term "therapeutically effective amount" refers to the amount of a substance administered to a subject by a researcher, veterinarian, physician, or other clinician. the alleviation of symptoms of the disease or disorder being treated, as claimed by or the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response in humans. Desirably, a therapeutically effective amount is a dose that has been proven clinically safe and has been shown to be clinically In some embodiments, the antidepressant is administered in an amount that has been proven to be effective. In another embodiment, esketamine is utilized in a therapeutically effective amount determined by the method of claim 1. It is used in.

[0067] The therapeutically effective amount of esketamine and / or an antidepressant, as described herein, may be used to treat an initial In some embodiments, the administration may be during the early (or late) phase(s) and / or the late (or late) phase(s). In another embodiment, the therapeutically effective amount of esketamine is about 20 to about 100 mg. An effective amount of esketamine is about 30 to about 90 mg. In a further embodiment, a therapeutically effective amount of esketamine is about 30 to about 90 mg. In yet another embodiment, the therapeutically effective amount of esketamine is about 40 to about 80 mg. Sketamine is approximately , 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 5 1, 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, 88, 89, 90, 9 1, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg. In embodiments, the therapeutically effective amount is about 28 mg, about 56 mg, or about 84 mg. In embodiments, the therapeutically effective amount is about 56 mg or about 84 mg. In another embodiment, the therapeutically effective amount of esketamine is about 28 mg. In a further embodiment, the therapeutically effective amount is about 84 mg of esketamine. It's esketamine.

[0068] As used herein, unless otherwise specified, the terms "subject" and "patient" an animal, preferably a mammal, most preferably a human, being subjected to treatment, observation or experiment Preferably, a subject or patient is a person suffering from a disease or disorder to be treated and / or prevented. Experiencing and / or exhibiting at least one symptom.

[0069] In some embodiments, the subject or patient is an adult. The term "adult," as used herein, refers to a human being between about 18 and about 65 years of age.

[0070] In other embodiments, the subject or patient is elderly or geriatric. The terms "senile" and "elderly" are used interchangeably to refer to human subjects aged about 65 years or older. Elderly patients aged ≥65 to ≤75 years respond better to treatment than patients ≥75 years. It seems that

[0071] In a further embodiment, the subject or patient is a pediatric subject. The term "child" refers to a human subject younger than about 18 years of age.

[0072] As used herein, the term "composition" refers to a product containing specified ingredients in specified amounts, as well as and any product resulting directly or indirectly from the combination of specific ingredients in specific amounts. It is intended to be inclusive.

[0073] As used herein, "stable remission" refers to a patient who is in stable remission after the induction period. for at least 3 of the past 4 weeks after achieving a substantially complete response to This refers to patients with a MADRS total score of 12 or less. In the illustrated embodiment, patients in "stable remission" are those with a MADRS total score of greater than 12. One deviation or one missed MADRS assessment at week 13 or 14 following the induction period In another embodiment, patients in "stable remission" are those with 15 or more steroid hormones following an induction phase. Patients with a MADRS total score of 12 or less at weeks 1 and 16 were included.

[0074] As used herein, a "stable response" refers to a patient who has tolerated esketamine during the induction period. After achieving a substantially complete response to MADRS total score from Day 1 of the induction phase (before randomization / before the first intranasal dose) is 50% This refers to patients whose blood pressure has decreased by more than 100 mg / kg, but who do not meet the criteria for stable remission.

[0075] As noted above, methods of treating depression in a patient are described, the methods comprising: Esketamine is administered in one, two, or optionally three phases: initial and subsequent administration phases. In some embodiments, the phases include an initial induction phase, an extension phase, and an administration of esketamine. The administration of an effective amount of esqueta may include an induction period, a maintenance period, or any combination thereof. The physician will assess the patient's condition and decide on the dosage regimen specified herein. The range and frequency of administration available will determine the initial / induction and maintenance doses that will be most beneficial for the patient. The effective amount of esketamine may be the same or different in each period. good.

[0076] The methods described herein can be used to treat patients with or without depression during the "optimal period." This allows for the optimization of the esketamine dosage for administration to susceptible patients. Optimization can be considered part of a maintenance phase following an induction phase. The methods described herein do not require adjustment of esketamine dosage. During the periods described herein (e.g., induction and maintenance periods), esquetamin The dose can be administered at the lowest dose frequency at which a minimal response is observed and maintained in the patient. An effective amount of esketamine has been found to be about 28 to about 84 mg.

[0077] As used herein, the "induction phase" or "acute administration phase" refers to the period during which esketamine is first administered to a patient. In some embodiments, the induction period is a period during which the drug is administered to a subject. The induction period is long enough to achieve a consistent reduction in the level of vasopressin. The induction period may vary depending on the particular patient and / or patient characteristics. including, but not limited to, type, age, weight, administration time, administration frequency, and any associated diseases. The induction period may depend on various factors. The induction period may include an initial induction period and an extended induction period. The total duration (including the initial and extended periods) was approximately 4 to 12 weeks, approximately 4 to 11 weeks, and approximately 4 to 1 0 weeks, about 4 to about 9 weeks, about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, about 5 to about 12 weeks, about 5 to about 11 weeks, about 5 to about 10 weeks, about 5 to about 9 weeks, about 5 to about 8 weeks, about 5 to 7 weeks, 5 to 6 weeks, 6 to 12 weeks, 6 to 11 weeks, 6 to 10 weeks 6 to 9 weeks, 6 to 8 weeks, 7 to 12 weeks, 7 to 11 weeks, 7 to 12 weeks 10 weeks, about 7 to about 9 weeks, about 8 to about 12 weeks, about 8 to about 11 weeks, or about 8 to about 10 weeks In some embodiments, the total induction period is from about 4 to about 8 weeks.

[0078] During the initial induction period, patients receive a therapeutically effective dose of escalate at a given frequency of at least twice weekly. In some embodiments, the patient receives a therapeutically effective dose of thiamine at a given frequency of three times per week. As long as the dose is three times a week, the doses are given on the first, third, and sixth days of the week. , and on day 5 ± 1. The initial induction period is typically performed after the patient is responsive to treatment. This is the period during which patients are shown to be in good condition but are not yet ready to progress to the maintenance phase. The patient's response is assessed by one skilled in the art. In some embodiments, the patient's response is assessed every In another embodiment, the patient's response is assessed twice weekly. In yet another embodiment, the patient's response is assessed every other day. Patient response is typically assessed using techniques and assays known to those skilled in the art. In some embodiments, the patient's MADRS score is determined and the initial The initial induction period is preferably used to determine whether the induction period has ended. In some embodiments, the initial induction period is of such length that it achieves a reduction in depressive symptoms. In other embodiments, the induction period is for a period of about 1 to about 4 weeks. In a further embodiment, the initial induction period is for a period of up to about 3 weeks, or up to about 4 weeks. The period is about 1 to about 3 weeks, about 1 to about 2 weeks, about 2 to about 4 weeks, about 2 to about 3 weeks, about 3 to about 4 week, 1 week, 2 weeks, 3 weeks, 4 weeks, up to 1 week, up to 2 weeks, up to 3 weeks, or up to The effective dose of esketamine administered during the initial induction period is determined by the attending physician. In some embodiments, the efficacy of esketamine administered during the initial induction period can be determined. The effective dose is about 28 mg. In some embodiments, the esophageal carcinoma administered during the initial induction period An effective amount of ketamine is about 56 mg. In another embodiment, the effective amount of ketamine administered during the initial induction period is about 56 mg. The effective dose of esketamine is approximately 84 mg.

[0079] As used herein, the term "twice weekly" refers to a frequency of two times in a one week (7 day) period. For example, "twice a week" may refer to the administration of esketamine herein. " may also refer to the frequency with which a patient is monitored during one or more of the phases discussed herein. In some embodiments, twice a week refers to a frequency that is the first and second day of the week. In some embodiments, twice a week refers to a frequency of one day and one day of the week. Twice per week refers to a frequency of 1 and 4 days per week. In yet another embodiment, twice per week refers to a frequency of 1 and 4 days per week. "Day 1" refers to the frequency of the first and fifth days of the month. "Day 1" refers to Sunday, Monday, Tuesday, Wednesday It may be any day of the week, including Thursday, Friday, or Saturday. With regard to ketamine administration, twice a week refers to the frequency of administration on the first and fourth days of the week. If there is any, take the dose as soon as possible thereafter and continue the prescribed regimen thereafter. good.

[0080] In some patient populations (e.g., elderly patients), reduction of depressive symptoms during the initial induction period is insufficient An extended induction period is necessary. During the extended initial induction period, Continuous administration of a therapeutically effective amount of esketamine is performed at a frequency of 100 mg / kg / day. The response is again assessed by one skilled in the art. In some embodiments, the patient's response is assessed daily. In other embodiments, the patient's response is assessed twice weekly. Patient response is assessed every other day. Typically, patient response is assessed using techniques and methods known to those skilled in the art. In some embodiments, the patient's MADRS score is determined. The extended induction period is determined as follows: Desirably, a substantial reduction in depressive symptoms is achieved, thus achieving a substantial reduction in depressive symptoms relative to esketamine. The length of time is such that a complete response is achieved.

[0081] As used herein, the term "substantially complete response to esketamine" refers to a baseline response to esketamine. A reduction in MADRS score from baseline to at least a 50% improvement from baseline In some embodiments, a patient with a substantially complete response to esketamine. The answer is at least a 50% improvement from baseline, or approximately 10% improvement over the patient's baseline score. In another embodiment, the term refers to a patient with a MADRS score of -20 or lower. Complete responses were defined as MADRS scores of approximately -20 or less, -19 or less, -18 or less, and -17 or less. below, -16 or less, -15 or less, -14 or less, -13 or less, -12 or less, -11 or less, or In a further embodiment, a substantially complete response is a reduction of -10 or less. The patient has a reduction in their Sline score of about -15 to about -20. If the S score is reduced by approximately 50% from the MADRS score at the start of treatment, esketamine A substantially complete response to the escape may also be obtained. Patients may be observed at any time during treatment with methionine. In some embodiments, patients are observed at 4 days after treatment. A substantially complete reduction in the MADRS total score from baseline at time In another embodiment, the patient has a MADR from baseline 2 days after treatment. A substantially complete response is observed when there is a reduction in the S total score.

[0082] The prolonged induction period is the period that results in a substantially complete response to esketamine. In some embodiments, the extended induction period is from about 1 to about 8 weeks. The induction period is approximately 1 week at the longest, approximately 2 weeks at the longest, approximately 3 weeks at the longest, approximately 4 weeks at the longest, approximately 5 weeks at the longest, In further embodiments, the extended period is about 6 weeks, up to about 7 weeks, or up to about 8 weeks. The induction period is approximately 1 to 8 weeks, approximately 1 to 7 weeks, approximately 1 to 6 weeks, approximately 1 to 5 weeks, approximately 1 ~ about 4 weeks, about 1 to about 3 weeks, about 2 to about 8 weeks, about 2 to about 7 weeks, about 2 to about 7 weeks, about 2 ~6 weeks, ~5 weeks, ~4 weeks, ~8 weeks, ~7 weeks, ~3 weeks ~6 weeks, ~3 to ~5 weeks, ~4 to ~8 weeks, ~4 to ~7 weeks, ~4 to ~6 weeks, ~5 ~approx. 8 weeks, approx. 5 to approx. 7 weeks, approx. 1 week, approx. 2 weeks, approx. 3 weeks, approx. 4 weeks, approx. 5 weeks, approx. The duration of the extended induction period is approximately 6 weeks, approximately 7 weeks, or approximately 8 weeks. The effective amount can be determined by the attending physician. In some embodiments, administration during the extended induction period In another embodiment, the effective amount of esketamine administered during the extended induction phase is about 56 mg. The effective dose of esketamine administered is approximately 84 mg.

[0083] Administration may further include an optimization / maintenance phase following the induction phase, where the patient escapes during the induction phase. After achieving a substantially complete response to esketamine, esketamine was administered during the optimization / maintenance phase. In some embodiments, administration during the optimization / maintenance phase is The frequency can be once weekly, once every two weeks, once a month, or a combination thereof.

[0084] At any stage during one or more of the induction, optimization, or maintenance phases, The patient's response to the treatment may be assessed using the techniques described herein. The treatment is continued until the subject is deemed by one of ordinary skill in the art to have achieved a suitable response to the treatment regimen. In some embodiments, the induction period may be initiated after the patient's MADRS score has reached baseline. It can be said to be complete when the concentration is reduced by ≥ 50%, or from about 20 to about 13. In other embodiments, the patient's MADRS score is about 19, about 18, about 17, about 16, The MADRS score may be about 15, about 14, or about 13. Patients with a MADRS score ≦12 may be If the patient is considered in remission and has been stable for 4 weeks, they should be moved to or maintained in the maintenance phase. do.

[0085] At the end of the induction or extended induction phase, the treating physician evaluates the patient and determines whether they will enter the "maintenance" or "long-term" phase. The dose and frequency of any subsequent treatment phases, such as the "treatment phase" and "maintenance phase," should be optimized. The frequency of intranasal treatment during subsequent administrations of The frequency of administration is expected to be reduced from once a day to once weekly for at least 4 weeks. In some embodiments, subsequent administrations, such as a maintenance phase, are administered for at least about 4 weeks, about 5 weeks, About 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 1 3 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, 1 year, or about 2 years. In this condition, the continuation of esketamine administration during subsequent administration periods is for at least 6 months. In some embodiments, the continued administration of esketamine during the subsequent administration period is at least one year. In further embodiments, the dosing frequency during the subsequent dosing phase is once weekly or every two weeks. In yet another embodiment, the estradiol is administered once or twice during subsequent administration periods. The frequency and effective dose of ketamine should be determined based on the minimum dose required to maintain stable remission or stable response. Frequency and quantity.

[0086] Subsequent administrations, such as maintenance periods, may involve longer periods depending on the patient's condition. In some embodiments, these longer periods may be at least about 3 years, about 4 years, or more, including indefinitely. It may be about 1 year, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, or more than about 10 years. For example, for patients diagnosed with TRD, treatment may be indefinite. In some embodiments, the treatment frequency is reduced to every other week. In further embodiments, the treatment frequency is reduced to every three weeks. In yet another embodiment, the treatment frequency is reduced to once a month. Maintained on schedule until remission is achieved, response is maintained, or treatment failure occurs Patients achieve or maintain a remission with weekly treatment for at least 4 weeks. If symptoms persist, the frequency of intranasal treatment sessions should be biweekly maintenance based on the severity of depressive symptoms. In some patient populations, treatment frequency can be reduced to approximately It may be reduced to once every three or four weeks.

[0087] The maintenance phase described herein can be, for example, a long-term remission of depression (e.g., a 1-month period associated with depression). (including remission of one or more symptoms), social and / or occupational improvement to normal or pre-illness levels No further treatment is required, as indicated by improvement in functioning on or other known measures of depression Those skilled in the art will appreciate that this may continue until

[0088] An effective amount of esketamine is administered to the patient during the maintenance phase. The amount of esketamine administered during the induction phase determines the biological responses or responses in the tissue systems described above for the induction phase. is an amount that produces a medical response. In certain embodiments, an effective amount of esketamine is The dose is the amount that maintains the pharmacodynamic steady state of esketamine achieved during the induction phase. In this condition, if depressive symptoms begin to worsen with treatment every other week, every three weeks, or every four weeks The administration of esketamine is increased to stabilize the patient. For example, if the patient is given esketamine every other week, If symptoms begin to worsen, esketamine may be administered to patients with refractory steroids during the maintenance phase. Once weekly, the patient's response may be assessed at any time during the maintenance phase. It can be reassessed.

[0089] In elderly patients, the recommended dose of esketamine is approximately 28 to 84 mg. Approximately 28 mg of esketamine is recommended for one treatment session. Based on the efficacy and tolerability of the 28 mg dose, the dose in the next treatment session will be approximately 28 mg. The dose may remain at about 56 mg or may be increased to about 56 mg. Depending on tolerance, the dose in subsequent treatment sessions may remain at approximately 56 mg. or may be increased to about 84 mg or reduced to about 28 mg. Depending on dose tolerance, the dose in subsequent treatment sessions may remain at approximately 84 mg. or can be reduced to about 56 mg.

[0090] In patients with liver impairment, the recommended dose of esketamine is approximately 28 to 56 mg. In the first treatment session, approximately 28 mg of esketamine is recommended. Based on the efficacy and tolerability of the 8 mg dose, the dose in the next treatment session will be approximately 28 mg. The dose may remain at about 50 mg or may be increased to about 56 mg. Esketamine is released into the liver by Because it is extensively metabolized, physicians should regularly monitor patients with hepatic impairment for drug tolerance. be.

[0091] In the treatment of patients with major depressive disorder who have suicidal ideation and are at imminent risk of suicide Depending on the severity of the condition, the administration may be more aggressive. This method may be divided into one or two phases: administration of esketamine during the initial induction period and, optionally, in certain circumstances, the maintenance period. Due to the imminent risk to the patient's life, the initial dose of esketamine should be Patients are given the highest effective dose of esketamine they can tolerate twice weekly during the induction period. In some embodiments, patients are administered esketamine during the induction period, simultaneously with the initiation of treatment with esketamine. In another embodiment, the patient continues treatment with the antidepressant (i.e., currently initiated). Patients were treated with a new antidepressant simultaneously with the initiation of treatment with esketamine during the induction period. In a further embodiment, the patient is initiated concurrently with the initiation of treatment with esketamine during the induction period. Sometimes treatment with a previously administered antidepressant is continued. Antidepressants may be used depending on the patient's condition / health. The drug should be administered in a manner appropriate for the patient and as labeled for the treatment of MDD. is about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, and most preferably about 4 weeks. If, at the end of the induction period, the patient is responding adequately to treatment or is in remission, If the patient remains stable or Patients should be monitored to ensure that they are in remission from antidepressant medication alone. If the patient is not stable on the first combination of ketamine and an antidepressant, or if the administration of esketamine is discontinued, If treatment with an antidepressant started with esketamine after discontinuation fails, a second induction A period may be initiated.

[0092] In the second induction period, patients were treated with the highest tolerated dose of esketamine and simultaneously with a second new Alternatively, patients may be re-initiated with the highest tolerated dose of esketamine and At the same time, the same antidepressant used during the previous induction period is restarted. Antidepressants are administered twice weekly. Antidepressants are used to treat MDD in a manner appropriate to the patient's condition / health. The second induction period is about 4 to about 8 weeks, about 4 to about 7 weeks, At the end of the second induction period, the incubation time should be about 4 to about 6 weeks, most preferably about 4 weeks. If the patient responds adequately to treatment or is in remission, esketamine administration should be discontinued. and the patient remains stable and / or is in stable remission on antidepressant medication alone. If the patient is unstable or has difficulty in administering esketamine, If treatment with an antidepressant started with esketamine after discontinuation of A third induction period may be initiated.

[0093] In the third induction period, patients were treated with the highest tolerated dose of esketamine and simultaneously with a third new Alternatively, patients may be re-initiated with the highest tolerated dose of esketamine and At the same time, the same antidepressant used during the second induction period is restarted. Antidepressants are administered twice weekly. Antidepressants are used to treat MDD in a manner appropriate to the patient's condition / health. The third induction period is about 4 to about 8 weeks, about 4 to about 7 weeks, At the end of the third induction period, the incubation period should be about 4 to about 6 weeks, most preferably about 4 weeks. The patient is now qualified as a TRD patient, and therefore the patient will progress to the TRD-designated maintenance phase. The methods described herein can be used to treat patients with or susceptible to depression. This allows for the optimization of the dose of esketamine administered to patients. In embodiments, the methods described herein do not require adjustment of esketamine dosage.

[0094] Generally, patients are treated with the highest tolerated dose of esketamine and concurrently with any prior induction period. The same antidepressant used in the previous study (if the patient was not stabilized or otherwise failed treatment) For example, if the patient is taking other medications to treat a current depressive episode, Treatment-resistant caries in patients who have not responded to at least two oral antidepressants In a method for treating depression, a patient receives esketamine alone or in combination with esketamine during a first induction period. a first oral antidepressant that may be the same or different from a previously ineffective oral antidepressant; Both may be administered with esketamine at least twice weekly. To the extent that a virtually complete response cannot be achieved, patients should receive the highest tolerated dose of esketamine alone. or simultaneously with a second oral antidepressant that is the same or different from the first oral antidepressant during a second induction period. If the patient is significantly more sensitive to esketamine during the second induction period, the patient may be reinstated with oral depressants. To the extent that a complete response is achieved, patients are then treated less than twice weekly during the subsequent maintenance phase. A dose of esketamine may be administered.

[0095] One or more (e.g., two) doses in any of the phases described herein If the first dose of esketamine is missed, the next dose should be administered when possible based on the dosing frequency regimen. If more than two doses are not administered according to clinical judgment, An adjustment in the dose or frequency of esketamine may be necessary.

[0096] The preferred pharmaceutical composition of the present invention is S-ketamine hydrochloride as an active ingredient, which has been conventionally The compound is thoroughly mixed with a pharmaceutical carrier, preferably water, according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of the carriers used is given in The See Handbook of Pharmaceutical Excipients It can be put out.

[0097] Methods for formulating pharmaceutical compositions are disclosed in the US Pat. No. 6,629,493, developed by Marcel Dekker, Inc. Pharmaceutical Dosage Forms: Tablets, Second Edition,Revised and Expanded,Volu mes 1-3, edited by Lieberman et al, Pharma ceutical Dosage Forms:Parental Medicat ions, Volumes 1-2, edited by Avis et al, and Pharmaceutical Dosage Forms:Disperse Sys tems, Volumes 1-2, edited by Lieberman et al., among many other publications.

[0098] One suitable aqueous formulation of S-ketamine comprises water and S-ketamine, wherein S-ketamine is , about 25 mg / mL to about 250 mg / mL, preferably about 25 mg / mL based on the total volume of the pharmaceutical composition. about 55 mg / mL to about 250 mg / mL, or about 100 mg / mL to about 250 mg / mL, or any amount or range therein. Calcium is present in an amount ranging from about 150 mg / mL to about 200 mg / mL, or any amount therein. More preferably, S-ketamine is present in a concentration of about 150 mg / mL to about 1 More preferably, the amount of hydroxybenzoates is in the range of 75 mg / mL, or any amount or range therein. For example, S-ketamine is administered in an amount ranging from about 160 mg / mL to about 163 mg / mL, for example, about Present in an amount of 161.4 mg / mL.

[0099] Another suitable aqueous formulation of S-ketamine comprises water and S-ketamine, wherein S-ketamine is Based on the total volume of the pharmaceutical composition, the range is from about 100 mg / mL equivalent to about 250 mg / mL equivalent. Preferably, S-ketamine is present in an amount ranging from An amount in the range of about 125 mg / mL equivalent to about 180 mg / mL equivalent, or any amount therein More preferably, S-ketamine is present in an amount equivalent to about 140 mg / mL to about 160 mg / mL equivalent range, or any amount or range therein, e.g., about 140 mg / mL Present in amounts equivalent to g / mL.

[0100] Pharmaceutical compositions suitable for use in the present invention are preferably aqueous formulations. When used, unless otherwise specified, the term "aqueous" means that the primary liquid component of the formulation is water. Preferably, water comprises more than about 80% by weight of the liquid components of the pharmaceutical composition. , more preferably greater than about 90% by weight, more preferably greater than about 95% by weight, more preferably greater than about 9 It constitutes 8% by weight.

[0101] In pharmaceutical compositions suitable for use in the present invention, the water content of the composition is determined by the total weight of the composition. Based on the amount, 85±14% by weight, more preferably 85±12% by weight, even more preferably is in the range of 85±10% by weight, most preferably 85±7.5% by weight, especially 85±5% by weight is.

[0102] In pharmaceutical compositions suitable for use in the present invention, the water content of the composition is determined by the total weight of the composition. Based on the amount, 90±14% by weight, more preferably 90±12% by weight, even more preferably is in the range of 90±10% by weight, most preferably 80±7.5% by weight, especially 90±5% by weight is.

[0103] In another pharmaceutical composition for use in the present invention, the water content of the composition is less than or equal to the total weight of the composition. Based on the amount, 95±4.75% by weight, more preferably 95±4.5% by weight, even more preferably Preferably 95±4% by weight, even more preferably 95±3.5% by weight, most preferably 95±4% by weight. It is in the range of 5±3% by weight, in particular 95±2.5% by weight.

[0104] In another pharmaceutical composition for use in the present invention, the water content of the composition is less than or equal to the total weight of the composition. Based on the amount, 75 to 99.99% by weight, more preferably 80 to 99.98% by weight, and even more preferably More preferably, it is 85 to 99.95% by weight, even more preferably, it is 90 to 99.9% by weight, and most preferably, it is 85 to 99.95% by weight. The range is more preferably 95 to 99.7% by weight, and particularly preferably 96.5 to 99.5% by weight.

[0105] In another pharmaceutical composition for use in the present invention, the composition comprises one or more buffering agents and and / or further comprising a buffer system (i.e., conjugate acid-base pair).

[0106] As used herein, the term "buffering agent" refers to an agent that, when added to an aqueous formulation, Any solid or liquid composition (preferably an aqueous liquid composition) that adjusts pH Those skilled in the art will appreciate that a buffering agent can change the pH of an aqueous formulation in any direction (more acidic, more basic, etc.). It will be appreciated that the pH of the solution may be adjusted (towards a neutral or more neutral pH). The buffering agent is pharmaceutically acceptable.

[0107] Suitable examples of buffers that can be used in the aqueous preparation of the present invention include citric acid, dihydrogen phosphate, Sodium, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, alcohol Examples of suitable acidic acids include, but are not limited to, tartaric acid, malic acid, lactic acid, and fumaric acid. The buffer or buffer system is composed of NaOH, citric acid, sodium dihydrogen phosphate, and aqueous phosphate. Disodium phosphate is selected from the group consisting of:

[0108] In embodiments, the buffering agent is an S-ketamine hydrochloride pharmaceutical composition of the present invention (e.g., The pH of the aqueous formulation (as described in the document) is adjusted to about pH 3.5 to about pH 6.5, or any value therebetween. Preferably, the buffer is selected to adjust the pH to a range of the amount or range of the S The pH of the ketamine hydrochloride composition is in the range of about pH 4.0 to about pH 5.5, or any value therein. more preferably in the range of about pH 4.5 to about pH 5.0, or any amount or range therein. The amount or range may be selected to adjust the amount or range.

[0109] Preferably, the concentrations of the buffer and buffer system, preferably NaOH, respectively, are sufficient to provide a sufficient buffer. The system is adjusted to provide the following functionality:

[0110] In an embodiment, the present invention provides a pharmaceutical composition comprising S-ketamine hydrochloride, water, and a buffer or buffer system, preferably The present invention relates to pharmaceutical compositions containing NaOH, and the buffer or buffer system has a pH of about pH 4.0 to about pH 4.0. To obtain a formulation having a pH in the range of about pH 6.0, or any amount or range therein, present in sufficient quantities.

[0111] Optionally, the pharmaceutical compositions of the present invention may contain a preservative.

[0112] As used herein, unless otherwise specified, the terms "antimicrobial preservative" and "preservative" refer to Preferably, the pharmaceutical composition is prepared in a manner that preserves it against microbial degradation or microbial growth. In this regard, microbial growth is typically essential. That is, preservatives serve the primary purpose of avoiding microbial contamination. The main aspects are to avoid any microbial influence on the active ingredient and excipients, respectively. In some cases, it may be desirable to avoid microbial degradation.

[0113] Typical examples of preservatives include benzalkonium chloride, benzethonium chloride, and benzoic acid. , sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridin nium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxy Lenol, cresol, ethyl alcohol, glycerin, hexetidine, imidourea, Phenol, phenoxyethanol, phenylethyl alcohol, phenyl nitrate, Pyrene glycol, sodium propionate, thimerosal, methylparaben, ethylparaben Laven, propylparaben, butylparaben, isobutylparaben, benzylparaben, These include, but are not limited to, sorbic acid and potassium sorbate.

[0114] The complete absence of preservatives in the pharmaceutical compositions used in the present invention is due to their antiseptic properties. The S-catecholamine may be added to the PEG-100 so that the desired shelf life or stability in use can be achieved by the presence of the drug itself. It is preferred when the content of sucralose hydrochloride is sufficiently high. - The concentration of ketamine hydrochloride is at least the equivalent of 120 mg / mL, preferably about 120 mg 175 mg / mL to about 175 mg / mL, or any amount or range therein, Preferably, the amount is about 125 mg / mL to about 150 mg / mL, or any amount therebetween. or range, for example, the equivalent of about 126 mg / mL or the equivalent of about 140 mg / mL.

[0115] As used herein, the terms "penetration agent," "penetration enhancer," and "penetrant" refers to the active ingredient of a pharmaceutical composition (e.g., S-ketamine hydrochloride). It refers to any substance that increases or enhances the absorption and / or bioavailability of a steroid or anti-inflammatory drug (salt). The osmotic agent acts to dissolve the active ingredient (e.g., S-ketamine hydrochloride) of the pharmaceutical composition after nasal administration. Increase or enhance absorption and / or bioavailability (i.e., absorption of active ingredients through mucous membranes) Increase or enhance absorption and / or bioavailability).

[0116] Suitable examples include tetradecyl maltoside, sodium glycolcholate, and taurine. Tauroursodeoxycholic acid (TUDCA), lecithin, etc. Tosan (and salts), as well as benzalkonium chloride, sodium dodecyl sulfate, and dodecyl acid Sodium, Polysorbate, Laureth-9, Oxytocinol, Sodium Deoxycholate Surface active ingredients include, but are not limited to, thorium, polyarginine, and the like. Preferably, the penetrant is tauroursodeoxycholic acid (TUDCA).

[0117] Osmotic agents can, for example, increase membrane fluidity and form transient hydrophilic pores within epithelial cells. any function, including forming a thickening agent, reducing the viscosity of the mucus layer, or opening tight junctions. Some osmotic agents (e.g., bile salts and fusidic acid derivatives) may also act via It also inhibits enzyme activity in membranes, thereby improving the bioavailability of active ingredients. It is possible.

[0118] Preferably, the penetrant meets one or more, more preferably all, of the following general requirements: is selected to satisfy (a) Improving the absorption (preferably nasal absorption) of the active ingredient, preferably temporarily and / or reversibly It is effective in increasing the size of the (b) It is pharmacologically inactive. (c) non-allergenic, non-toxic, and / or non-irritating. (d) It is very potent (effective in small amounts). (e) be compatible with other ingredients of the pharmaceutical composition; (f) It is odorless, colorless, and / or tasteless. (g) Acceptable by a regulatory authority. (h) It is inexpensive and available in high purity.

[0119] In one embodiment of the present invention, the penetrant is a penetrant that provides penetrating (S-ketamine hydrochloride) without nasal irritation. The present invention provides a method for the preparation of a medicament for the treatment of ulcerative colitis, ... and ulcerative colitis. In this study, osmotic agents were used to improve the absorption and / or bioavailability of S-ketamine hydrochloride. It is selected to enhance uniform administration effectiveness.

[0120] In embodiments, the present invention is directed to a pharmaceutical composition comprising S-ketamine and water, In the document, the pharmaceutical composition does not contain an antimicrobial preservative, and the pharmaceutical composition does not contain a penetration enhancer, preferably Preferably, it further contains TUDCA.

[0121] In another embodiment, the present invention is directed to a pharmaceutical composition comprising S-ketamine and water, In the specification, the pharmaceutical composition does not contain an antimicrobial preservative, and the pharmaceutical composition does not contain taurol. It further contains sodeoxycholic acid (TUDCA), and the TUDCA concentration is about 1.0 mg / mL. in the range of about 25.0 mg / mL, or any amount or range therein, preferably about 2.5 10 mg / mL to about 15 mg / mL, or any amount or range therein, preferably At a concentration ranging from about 5 mg / mL to about 10 mg / mL, or any amount or range therein. In another embodiment, the present invention provides a pharmaceutical composition comprising a composition comprising TUDCA, wherein TUDCA is present at a concentration of about 5 mg / mL. In another embodiment, the present invention is directed to a pharmaceutical composition comprising TUDCA at a concentration of about 10 mg / mL. The present invention is directed to pharmaceutical compositions present in concentrations of 1000 mg / mL.

[0122] Pharmaceutical compositions for use in the present invention may contain one or more additional excipients, such as wetting agents, It may further contain surfactant components, solubilizers, thickeners, colorants, antioxidant components, etc. .

[0123] Examples of suitable antioxidant ingredients, if used, include the following: sulfites, ascorbic acid, acid, sodium ascorbate, calcium ascorbate, or potassium ascorbate Ascorbic acid salts such as ascorbate, ascorbyl palmitate, fumaric acid, ethylenediaminetetraacetic acid, EDTA or its sodium or calcium salt, tocopherol, gallic acid gallates such as propyl, octyl, or dodecyl gallate, vitamin E, and Antioxidants include, but are not limited to, one or more of the following: The component provides long-term stability to the liquid composition. The addition of the antioxidant component improves the stability of the composition. This can help to strengthen and ensure the composition remains stable even after 6 months at 40°C. A suitable amount of antioxidant component, when present, is about 0.01% by weight of the total weight of the composition. about 0.05% to about 2% by weight, preferably about 0.05% to about 3% by weight.

[0124] Solubilizers and emulsifiers are used to solubilize active ingredients or other excipients that are not generally soluble in the liquid carrier. Examples of suitable emulsifiers, if used, may be included to promote uniform dispersion. For example, gelatin, cholesterol, acacia, tragacanth, pectin, methylcellulose Suitable cellulose derivatives include, but are not limited to, cellulose, carbomer, and mixtures thereof. Examples of solubilizers include polyethylene glycol, glycerin, D-mannitol, and thiamin. Haloth, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethylenediamine Dextrose, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate thorium, and mixtures thereof.

[0125] Preferably, the solubilizer comprises glycerin. Solubilizers or emulsifiers generally comprise a carrier. The active ingredient, i.e., S-ketamine, is present in an amount sufficient to dissolve or disperse the active ingredient. Typical amounts of solubilizing or emulsifying agents, if present, range from about 1% 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 %.

[0126] Suitable tonicity agents, if used, are sodium chloride, glycerin, D-mannitol , D-sorbitol, glucose, and mixtures thereof. Suitable amounts of tonicity agent are typically from about 0.01% to about 15% by weight of the total weight of the composition. More preferably, about 0.3% by weight to about 4% by weight, and more preferably, about 0.5% by weight to about 3% by weight %.

[0127] Suspending or thickening agents may be added to the pharmaceutical compositions of the present invention, for example to increase residence time in the nose. Suitable examples include hydroxypropyl methylcellulose, caramel Sodium cellulose, microcrystalline cellulose, carbomer, pectin, sodium alginate, Chitosan salt, gellan gum, poloxamer, polyvinylpyrrolidone, xanthan gum, etc. These include, but are not limited to:

[0128] Advantageously, esketamine may be administered in a single daily dose, or the total daily dose may be 1 It may be administered in divided doses two, three, or four times daily, preferably twice daily. Ideally, the divided doses should be administered more closely together in time. Separate doses should be taken within about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, or about 4 minutes of each other. Within approximately 3 minutes, approximately 2 minutes, or approximately 1 minute. In some cases, patients may receive daily, twice weekly, weekly, biweekly, or monthly doses. One dose of esketamine is given on day 1, and another dose of esketamine is given on day 2. or one dose of esketamine is administered on day 1 and another dose of esketamine on day 3. or one dose of esketamine is administered on day 1 and another dose of esketamine is administered on day 2. is administered on day 4, or one dose of esketamine is administered on day 1 and Another dose of esketamine is administered on day 5. Additionally, esketamine is preferably administered via a nasal spray pump or the like. Administration in intranasal form can be via topical use of any suitable intranasal vehicle.

[0129] As described, the method of administering esketamine to a patient comprises administering esketamine at a dose of about 45 to about 165 ng / m The maximum plasma concentration of esketamine (C max ) resulting in a pharmacokinetic profile that achieves Those skilled in the art will be able to distinguish between ranges and individual C max Any of the values ​​may vary by ±30%. It will be understood that in some embodiments, C max is about 45, about 50, about 55, about 60, approx. 65, approx. 70, approx. 75, approx. 80, approx. 85, approx. 90, approx. 95, approx. 100, approx. 105 , about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145 , about 150, about 155, about 160, or about 165 ng / mL. C max Approximately 50 to 150, approximately 50 to 125, approximately 50 to 100, approximately 50 to 75 , about 75 to about 150, about 75 to about 125, or about 75 to about 100 ng / mL. In some embodiments, C max When approximately 28 mg of esketamine is administered, the 75, about 50 to about 70, about 55 to about 65, about 45 to about 70, about 45 to about 65, about 45 to about 60, about 45 to about 55, about 55 to about 75, or about 60 to about 70 ng / mL. In an embodiment of the present invention, max When approximately 56 mg of esketamine is administered, the 120, approx. 70 to approx. 120, approx. 70 to approx. 110, approx. 70 to approx. 100, approx. 70 to approx. 90, approx. 70 to approx. 80, approx. 80 to approx. 120, approx. 80 to approx. 110, approx. 80 to approx. 90, approx. 90 to approx. 12 0, or about 90 to about 110 ng / mL. max is approximately When 84 mg of esketamine is administered, the dose is about 90 to about 165, about 95 to about 165, about 9 5 to about 155, about 95 to about 145, about 95 to about 135, about 95 to about 125, about 95 to about 1 15, about 105 to about 165, about 105 to about 155, about 105 to about 145, about 105 to about 1 35, about 105 to about 125, about 105 to about 115, about 115 to about 165, about 115 to about 1 55, about 115 to about 145, about 115 to about 135, about 115 to about 125, about 125 to about 1 65, about 125 to about 155, about 125 to about 145, about 125 to about 135, about 135 to about 1 65, about 135 to about 155, about 135 to about 145, or about 145 to about 165 ng / mL be.

[0130] Similarly, the method of administering esketamine to a patient may include administering from about 125 to about 490 mg of esketamine at time 0. * The last quantifiable concentration (AUC last ) area under the plasma concentration-time curve As used herein, the term "AUC las t " refers to the area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration. "Time 0" in a general context refers to the intended starting point of the dose. In the given Example 1, time 0 is the first intranasal device delivered to one nostril. Defined as the time of administration of the intraluminal spray. The intended dose requires administration of two oral tablets. As long as time 0 is the time of administration of the first tablet, those skilled in the art will be able to determine ranges or individual AUClast It will be understood that any of the values ​​may vary ±30%. In embodiments, the AUC last is about 125, about 130, about 135, about 140, about 145 , about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220 , about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300 , about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380 , about 390, about 400, about 410, about 420, about 430, about 440, about 450, about 460 , about 470, about 480, about 490ng * h / mL. In another embodiment, the AUC la st is about 150 to about 450, about 200 to about 400, about 250 to about 350, about 150 to about 350, or about 200 to about 300 ng * h / mL. In a further embodiment, the AUC l ast When about 28 mg of esketamine is administered, the to about 180, about 135 to about 175, about 140 to about 170, about 145 to about 165, or about 1 50~160ng * h / mL. In yet another embodiment, the AUC last is about 5 When 6 mg of esketamine is administered, the 230 to about 300, about 240 to about 290, about 250 to about 280, or about 260 to about 270 ng * h / mL. In yet a further embodiment, the AUC last Approximately 84 mg of When sketamine is administered, the blood glucose level is about 305 to about 490, about 310 to about 480, about 320 to about 470, approx. 330 to approx. 460, approx. 340 to approx. 450, approx. 350 to approx. 450, approx. 360 to approx. 440, about 370 to about 430, about 380, about 420, or about 390 to about 410 ng * h / mL.

[0131] The method of administering esketamine also includes the above C max and AUC last Individual values ​​of This may result in a pharmacokinetic profile that achieves a combination of doses and ranges.

[0132] Representative nasal spray devices are described in U.S. Pat. No. 6,321,929, which is incorporated herein by reference. For example, the use of a continuous partial discharge as a spray is disclosed in US Pat. Disposable sprayers can be utilized to carry out the methods disclosed herein. Such a device sprays medication into both nostrils of a patient in two successive strokes. The device, in which the drug is expelled from the medium reservoir, is ready to use. The device typically separates the first ejection stroke from the second ejection stroke to form a single This movement prevents the medium container from being completely emptied. Dual-stroke design allows for individual partial discharges with high dosing accuracy and reliability It may take the form of a disposable pump.

[0133] In one embodiment, the nasal spray device delivers two sprays (per nostril) totaling 28 mg of esketamine. It is a single-use device that delivers a single spray of steroids per dose. The device is administered by the patient under the supervision of a healthcare professional. Regarding dosage, one device may be used for a 28 mg dose, or two One device may be used for a 56 mg dose, or three devices may be used for an 84 mg dose. It is also preferable to have a 5-minute interval between each use of the device. Thus, time 0 corresponds to the administration of the first intranasal spray into one nostril from the first intranasal device. is defined as time.

[0134] Aspects of the disclosure The present disclosure relates to and includes at least the following aspects: 1. A method for treating major depressive disorder, comprising administering to a patient in need of treatment a clinically A therapeutically effective dose of esophageal squamous cell carcinoma (ESC) that has been proven safe and clinically proven effective. including intranasal administration of ketamine, The patient in need thereof is a human patient having a major depressive episode, have not responded to at least two oral antidepressants in the current depressive episode, . 2. A method for treating major depressive disorder, comprising administering esketamine to a patient in need of treatment. administering The patient in need thereof has had a major depressive episode, and the patient is currently have not responded to at least two oral antidepressants during the sexual episode; Esketamine is administered intranasally, The therapeutically effective doses of esketamine administered to patients have been clinically proven safe and effective. The way it is done. 3. A method for treating major depressive disorder in a human patient, comprising: (a) determining a baseline MADRS score for the human patient; diagnosing a human patient; (b) administering a therapeutically effective amount of esketamine that has been clinically proven safe and effective to the patient; administering intranasally to a human patient, A therapeutically effective dose is a measure of at least 50% improvement in baseline MADRS score. Improve the MADRS score, esketamine is administered at predetermined intervals; (c) following step (b), re-evaluating the human patient at regular intervals to determine the relative efficacy determining the sex of the subject, wherein the reassessment comprises measuring the MADRS score of the human patient. . 4. Aspects 1 and 2, wherein the major depressive disorder is treatment-refractory or treatment-resistant depression. Or the method according to item 3. 5. An embodiment in which a therapeutically effective amount of at least one antidepressant is co-administered with esketamine. 1. The method according to claim 1, 2, 3, or 4. 6. The method of embodiment 5, wherein the combination therapy comprises esketamine and one to two antidepressants. 7. Each antidepressant is independently imipramine, amitriptyline, desipramine, norprednisolone, Triptyline, doxepin, protriptyline, trimipramine, maprotiline, amo acetaminophen, trazodone, bupropion, clomipramine, fluoxetine, duloxetine escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, Nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenytoin Nelzin, tranylcypromine, moclobemide, kavakava, St. John's wort, s-Adenosylmethionine, Thyroid Hormone-Releasing Hormone, Neurokinin Receptor Antagonist 6. The method of embodiment 5, wherein the agonist is selected from the group consisting of an agonist, and triiodothyronine. 8. Each antidepressant independently acts as a monoamine oxidase inhibitor, tricyclic, or serotonin reuptake inhibitor. uptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic serotonergic and specific serotonergic agents, and atypical antidepressants, The method according to embodiment 5. 9. Each antidepressant is independently administered as phenelzine, tranylcypromine, moclobemide, or ibuprofen. Mipramine, amitriptyline, desipramine, nortriptyline, doxepin, prothrombin Liptiline, trimipramine, clomipramine, amoxapine, fluoxetine, Certo Larynx, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran The method of embodiment 5, wherein the compound is selected from the group consisting of oran, mirtazapine, and bupropion. . 10. Concomitant therapy includes esketamine and, independently, fluoxetine, imipramine, or bupivacaine. One or two antibiotics selected from the group consisting of thiazolidine dihydrochloride, venlafaxine, and sertraline and a depressant. 11. The combination therapy containing esketamine and at least one antidepressant is an atypical antidepressant. 6. The method of embodiment 5, further comprising: 12. Atypical antidepressants include aripiprazole, quetiapine, olanzapine, and risperidone. 12. The method of embodiment 11, wherein the medicament is selected from the group consisting of paliperidone, and paliperidone. 13. Atypical antidepressants consist of aripiprazole, quetiapine, and olanzapine. 13. The method of embodiment 12, wherein the 14. Esketamine, optionally at least one antidepressant, and at least one pharmaceutical Pharmaceutical composition for the treatment of treatment-refractory or treatment-resistant depression comprising a carrier acceptable for . 15. For the treatment of treatment-refractory or treatment-resistant depression in patients in need of treatment. Use of esketamine in the preparation of a drug for 16. For the treatment of treatment-refractory or treatment-resistant depression in patients in need of treatment. Esketamine for use in this manner. 17. A composition comprising esketamine for the treatment of treatment-refractory or treatment-resistant depression. 18. A pharmaceutical containing esketamine for administration to patients suffering from treatment-resistant depression A product that delivers esketamine to the patient in amounts that have been clinically proven to be safe and effective. A medicinal product administered intranasally. 19. By depressed patients after administration of a therapeutically effective dose of esketamine during the initial treatment period. A method of maintaining the stable remission or stable response achieved during subsequent dosing periods A method comprising administering a therapeutically effective amount of esketamine continuously for at least five months. Law. 20. The method of aspect 19, wherein the depression is treatment-resistant depression. 21. Therapeutically effective amounts of esketamine are administered intranasally, intramuscularly, or intravenously during the initial and subsequent administration phases. 21. The method of embodiment 19 or 20, wherein the administration is subcutaneous, transdermal, buccal, or rectal. 22. The method of aspect 21, wherein the administration is intranasal. 23. A therapeutically effective amount of at least one antidepressant is administered to the esophagus during the initial and subsequent administration periods. 23. The method of any one of aspects 19-22, wherein the method is co-administered with ketamine. 24. The method of claim 23, wherein esketamine is co-administered with one to two antidepressants. . 25. Each antidepressant is independently imipramine, amitriptyline, desipramine, Iltriptyline, doxepin, protriptyline, trimipramine, maprotiline, Moxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine fluvoxamine, escitalopram, citalopram, sertraline, paroxetine , nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, Enelzine, tranylcypromine, moclobemide, kavakava, St. John's wort , s-adenosylmethionine, thyroid hormone-releasing hormone, neurokinin receptor antagonist 25. The method of claim 24, wherein the agonist is a thyroid hormone receptor agonist, or triiodothyronine. 26. Each antidepressant is independently a monoamine oxidase inhibitor, tricyclic, or serotonin inhibitor. Reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrena 26. The method of claim 23, wherein the agonist is a serotonergic-specific serotonergic agent or an atypical antidepressant. The method according to any one of the preceding claims. 27. Each antidepressant is independently phenelzine, tranylcypromine, moclobemide, Imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline Triptyline, trimipramine, clomipramine, amoxapine, fluoxetine, cefotaxime Traline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnaci 27. The method of claim 23, wherein the compound is benzodiazepine, mirtazapine, or bupropion. How to do it. 28. Each antidepressant is independently administered to: fluoxetine, imipramine, bupropion, and benzamidine. 28. The method of any one of aspects 23-27, wherein the medicament is lafaxine or sertraline. 29. The method of aspect 23, wherein at least one antidepressant is an atypical antidepressant. 30. Atypical antidepressants include aripiprazole, quetiapine, olanzapine, and risperidone. 30. The method of embodiment 29, wherein the medicament is paliperidone or paliperidone. 31. The atypical antidepressant is aripiprazole, quetiapine, or olanzapine. 31. The method according to claim 30. 32. The initial treatment phase will consist of an induction period in which esketamine is administered at least twice weekly. 32. The method of any one of aspects 19 to 31, comprising: 33. The method of embodiment 32, wherein the frequency is twice a week. 34. The method of claim 32 or 33, further comprising assessing patient response during the induction period. Law. 35. The initial treatment phase further comprises an optimization phase following an induction phase, and the patient receives esquetabolism during the induction phase. After achieving a substantially complete response to esketamine, esketamine was administered twice weekly during the optimization phase. 35. The method of any one of aspects 32-34, wherein the dose is administered less frequently than 36. Evaluate patient response during the optimization phase to achieve stable remission or stable response. and adjusting the frequency of administration during the optimization phase based on the response. 36. The method of claim 35. 37. During the optimization phase, the dosing frequency is once weekly, once every two weeks, or a combination of these. 37. The method of claim 36, wherein 38. The effective dose of esketamine is 28 mg, 56 mg, or The method of any one of aspects 19 to 37, wherein the amount of the sachet is 84 mg. 39. The duration of esketamine administration between subsequent administration periods is at least 6 months. 39. The method according to any one of claims 32 to 38. 40. Aspect 3, wherein the continued administration of esketamine during the subsequent administration period is at least 1 year. 20. The method according to any one of claims 2 to 39. 41. The frequency of administration during subsequent dosing periods is once weekly or once every two weeks, or 41. The method according to any one of aspects 32 to 40, wherein the combination of 42. The effective dose of esketamine during the subsequent administration period is 56 mg or 84 mg. 42. The method according to any one of claims 32 to 41. 43. The frequency and effective dose of esketamine during subsequent treatment periods is sufficient to achieve stable remission or stable 43. The method of claim 32, wherein the minimum frequency and amount of the administration is sufficient to maintain a predetermined response. How to post. 44. Therapeutically effective doses of esketamine have been proven clinically safe and are clinically 44. The method of any one of aspects 19 to 43, wherein the amount is proven to be clinically effective. 45. A method for the long-term treatment of depression in a patient, comprising administering to the patient in need thereof , clinically proven safe and clinically proven effective treatments The method comprises administering a dose of esketamine to a patient in need thereof for at least six months. 46. ​​The method of embodiment 45, wherein the esketamine is administered for at least one year. 47. The method of aspect 45 or 46, wherein esketamine is administered for up to 2 years. 48. The method according to any one of aspects 45 to 47, wherein the depression is treatment-resistant depression. Law. 49. The method of any one of aspects 45 to 47, wherein esketamine is administered intranasally. Law. 50. A condition in which a therapeutically effective amount of at least one antidepressant is co-administered with esketamine. 49. The method according to any one of claims 45 to 48. 51. The method of embodiment 50, wherein esketamine is co-administered with one to two antidepressants. . 52. Each antidepressant is independently imipramine, amitriptyline, desipramine, Iltriptyline, doxepin, protriptyline, trimipramine, maprotiline, Moxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine fluvoxamine, escitalopram, citalopram, sertraline, paroxetine , nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, Enelzine, tranylcypromine, moclobemide, kavakava, St. John's wort , s-adenosylmethionine, thyroid hormone-releasing hormone, neurokinin receptor antagonist 52. The method of claim 51, wherein the agonist is a thyroid hormone receptor agonist, or triiodothyronine. 53. Each antidepressant is independently a monoamine oxidase inhibitor, tricyclic, or serotonin inhibitor. Reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrena 53. The method of claim 50, wherein the agonist is a serotonergic-specific serotonergic agent or an atypical antidepressant. The method according to any one of the preceding claims. 54. Each antidepressant is independently phenelzine, tranylcypromine, moclobemide, Imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline Triptyline, trimipramine, clomipramine, amoxapine, fluoxetine, cefotaxime Traline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnaci 54. The method of any one of aspects 50 to 53, wherein the compound is benzodiazepine, mirtazapine, or bupropion. How to do it. 55. Each antidepressant is independently administered to: fluoxetine, imipramine, bupropion, and benzamidine. 55. The method of any one of aspects 50-54, wherein the medicament is lafaxine or sertraline. 56. The method of embodiment 55, wherein at least one antidepressant is an atypical antidepressant. 57. Atypical antidepressants include aripiprazole, quetiapine, olanzapine, and risperidone. 57. The method of claim 56, wherein the agonist is paliperidone or paliperidone. 58. The atypical antidepressant is aripiprazole, quetiapine, or olanzapine. 58. The method according to claim 57. 59. Esketamine is initially administered twice weekly for up to 4 weeks during the induction period, followed by weekly 59. The method of any one of aspects 45 to 58, wherein the administration is less frequent than twice a day. 60. Aspect 5, wherein esketamine is administered once a week or once every two weeks following an induction period. 9. The method according to claim 9. 61. The therapeutically effective amount of esketamine is 28 mg, 56 mg, or 84 mg. 45 to 60. A method according to any one of claims 45 to 60. 62. Patient's cognitive performance remains stable based on baseline measurements after 6 months of treatment. 62. The method according to any one of aspects 45 to 61, 63. A method for treating major depressive disorder in an elderly patient, comprising: Patients requiring treatment for major depressive disorder receive a therapeutically effective dose of esketamine, as defined administered at least twice weekly during the initial induction phase of the duration; assessing patient response following an initial induction period; Based on an assessment of whether the patient achieved a substantially complete response to esketamine and continuing to administer the compound at a frequency of at least twice a week during the extended induction period. 64. Elderly patients are taking at least two oral antidepressants in the current depressive episode. 64. The method of embodiment 63, wherein the patient has not responded to 65. A therapeutically effective amount of esketamine is administered intranasally, intramuscularly, subcutaneously, transdermally, orally, or rectally. 65. The method of embodiment 64, wherein the 66. The method of any one of aspects 63-65, wherein administration is intranasal. 67. The method of any one of aspects 63 to 66, wherein the initial induction period is up to 2 weeks. . 68. The method of any one of aspects 63 to 66, wherein the initial induction period is up to 3 weeks. . 69. The method of any one of aspects 63 to 66, wherein the initial induction period is up to 4 weeks. . 70. The method of any one of aspects 63 to 66, wherein the extended induction period is up to 8 weeks. . 71. An effective amount of 28 mg, 56 mg, or 84 mg, as described in any one of aspects 63 to 70. How to post. 72. Elderly patients achieve a virtually complete response to esketamine and then:

[0033] Any of aspects 63-71, wherein esketamine is administered no more frequently than once a week during the optimization phase. The method described in one. 73. The method of claim 72, further comprising periodically evaluating the patient's response during the optimization phase. How to do it. 74. The frequency of the initial induction phase, the extended induction phase, or a combination thereof is twice weekly. The method according to any one of embodiments 63 to 73, 75. Aspects 63 to 65, wherein the major depressive disorder is treatment-refractory depression or treatment-resistant depression. 74. The method according to any one of claims 1 to 74. 76. A therapeutically effective amount of at least one antidepressant is co-administered with esketamine. 63 to 75. A method according to any one of claims 63 to 75. 77. Any of aspects 63-76, wherein the combination therapy includes esketamine and one or two antidepressants. The method according to any one of the preceding claims. 78. Each antidepressant is independently imipramine, amitriptyline, desipramine, Iltriptyline, doxepin, protriptyline, trimipramine, maprotiline, Moxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine fluvoxamine, escitalopram, citalopram, sertraline, paroxetine , nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, Enelzine, tranylcypromine, moclobemide, kavakava, St. John's wort , s-adenosylmethionine, thyroid hormone-releasing hormone, neurokinin receptor antagonist 78. The method of embodiment 77, wherein the agonist is a thyroid hormone receptor agonist, or triiodothyronine. 79. Each antidepressant is independently a monoamine oxidase inhibitor, tricyclic, or serotonin inhibitor. Reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrena 77 or 78, which is a serotonergic-specific serotonergic drug or an atypical antidepressant. The method described below. 80. Each antidepressant is independently phenelzine, tranylcypromine, moclobemide, Imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline Triptyline, trimipramine, clomipramine, amoxapine, fluoxetine, cefotaxime Traline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnaci 80. The method of any one of aspects 77 to 79, wherein the compound is benzodiazepine, mirtazapine, or bupropion. How to do it. 81. Independently, fluoxetine, imipramine, bupropion, venlafaxine, or sertraline. The method described below. 82. The method of embodiment 79, wherein at least one antidepressant is an atypical antidepressant. 83. Atypical antidepressants include aripiprazole, quetiapine, olanzapine, and risperidone. 83. The method of embodiment 82, wherein the medicament is paliperidone or paliperidone. 84. The atypical antidepressant is aripiprazole, quetiapine, or olanzapine. 84. The method of claim 82 or 83. 85. The method of any one of aspects 63 to 84, wherein the patient is at least 65 years old. . 86. A method for treating a patient with major depressive disorder, comprising administering to a patient a dose of 100mg of benzodiazepine or ... Provide clinically proven safe and clinically effective drugs to patients in need of treatment. The method comprises administering a therapeutically effective amount of esketamine proven to be effective in treating a range of conditions. 87. The patient is taking at least one of the following medications at an appropriate dose and duration in the current depressive episode: 87. The method of embodiment 86, wherein the patient has not responded to at least two oral antidepressants. 88. The method of claim 86, wherein the patient has been diagnosed with treatment-refractory or treatment-resistant depression. is the method described in 87. 89. The method of claim 86, wherein the patient has suicidal ideation as a symptom of major depressive disorder. . 90. The method of embodiment 89, wherein the patient is at imminent risk of suicide. 91. The method of any one of aspects 86-90, wherein the patient is an adult. 92. The method of any one of aspects 86-91, wherein the patient is an elderly patient. 93. Esketamine is administered intranasally, intramuscularly, subcutaneously, transdermally, orally, or rectally. A method according to any one of embodiments 86 to 92. 94. The method of any one of aspects 86 to 93, wherein esketamine is administered intranasally. Law. 95. A therapeutically effective amount of at least one antidepressant is co-administered with esketamine. 86 to 94. A method according to any one of claims 86 to 94. 96. The method of embodiment 95, wherein esketamine is co-administered with one or two antidepressants. . 97. Each antidepressant is independently imipramine, amitriptyline, desipramine, Iltriptyline, doxepin, protriptyline, trimipramine, maprotiline, Moxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine fluvoxamine, escitalopram, citalopram, sertraline, paroxetine , nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, Enelzine, tranylcypromine, moclobemide, kavakava, St. John's wort , s-adenosylmethionine, thyroid hormone-releasing hormone, neurokinin receptor antagonist 97. The method of claim 95 or 96, wherein the agonist is a thyroid hormone receptor agonist, or triiodothyronine. 98. Each antidepressant is independently a monoamine oxidase inhibitor, tricyclic, or serotonin inhibitor. Reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrena 95 or 96, which is a serotonergic-specific serotonergic drug or an atypical antidepressant. The method described below. 99. Each antidepressant is independently phenelzine, tranylcypromine, moclobemide, Imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline Triptyline, trimipramine, clomipramine, amoxapine, fluoxetine, cefotaxime Traline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnaci 99. The method of any one of aspects 95 to 98, wherein the compound is benzodiazepine, mirtazapine, or bupropion. How to do it. 100. Each antidepressant, independently, is a fluoxetine, imipramine, bupropion, or venom. 99. The method of any one of aspects 96 to 99, wherein the compound is flufenaconazole or sertraline. . 101. The method of embodiment 95, wherein at least one antidepressant is an atypical antidepressant. . 102. Atypical antidepressants include aripiprazole, quetiapine, olanzapine, and lisperidone. 102. The method of claim 101, wherein the medicament is paliperidone or paliperidone. 103. The atypical antidepressant is aripiprazole, quetiapine, or olanzapine. 103. The method according to claim 101 or 102, 104. Esketamine, optionally at least one antidepressant, and at least one pharmaceutical 10. A pharmaceutical composition for the treatment of major depressive disorder comprising a therapeutically acceptable carrier. 105. Esketamine, optionally at least one antidepressant, and at least one pharmaceutical Pharmaceutical composition for treating treatment-refractory or treatment-resistant depression, comprising a therapeutically acceptable carrier composition. 106. Esketamine, optionally at least one antidepressant, and at least one pharmaceutical A pharmaceutical composition for the treatment of suicidal ideation comprising a therapeutically acceptable carrier. 107. In preparing a drug for the treatment of a patient in need of treatment for major depressive disorder Use of esketamine. 108. Aspect 107, wherein the patient suffers from treatment-refractory or treatment-resistant depression. Use as described in. 109. The use according to aspect 107, wherein the patient is suffering from suicidal thoughts. 110. For use in a method for the treatment of major depressive disorder in a patient in need thereof Esketamine for. 111. The embodiment 110, wherein the patient suffers from treatment-refractory or treatment-resistant depression. Esketamine as described in 112. Esketamine according to aspect 110, wherein the patient is suffering from suicidal thoughts. 113. A composition comprising esketamine for the treatment of major depressive disorder. 114. esketamine, including esketamine, for the treatment of treatment-refractory or treatment-resistant depression. composition. 115. A composition comprising esketamine for the treatment of suicidal ideation. 116. A pharmaceutical composition containing esketamine for administration to a patient suffering from major depressive disorder. A product that delivers esketamine to the patient in amounts that have been clinically proven to be safe and effective. A medicinal product administered intranasally. 117. The embodiment 116, wherein the patient suffers from treatment-refractory or treatment-resistant depression. The pharmaceutical product described in 118. The pharmaceutical product of aspect 116, wherein the patient is suffering from suicidal thoughts. 119. A method of administering esketamine to a patient, comprising: The first phase lasts from about 1 week to about 4 weeks, and the dose is about 28 mg to about 84 mg of esketamine. The drug is administered to patients twice a week and has been clinically proven to be safe. Law. 120. The method of embodiment 119, wherein about 28 mg of esketamine is administered. 121. Administration of esketamine results in a maximum plasma concentration of esketamine of approximately 45 to approximately 75 ng / mL. Concentration (Cmax), about 125~185ng * Time 0 to last quantifiable concentration in h / mL Achieving the area under the plasma concentration-time curve (AUClast), or a combination thereof; 121. The method according to embodiment 119 or 120. 122. The method of any one of aspects 119 to 121, wherein esketamine is administered intranasally. How to post. 123. About 28 mg of esketamine is administered in at least two sprays. The method described in 2. 124. Approximately 28 mg of esketamine is administered via one spray in each nostril. 124. The method according to claim 123. 125. The method of embodiment 119, wherein about 56 mg of esketamine is administered. 126. Esketamine administration results in a maximum blood glucose level of approximately 65 to approximately 120 ng / mL. Plasma concentration (Cmax), approximately 210~320ng * Time 0 to last quantifiable concentration in h / mL Achieve a plasma concentration-time curve of a certain level (AUClast), or a combination thereof. 126. The method of claim 119 or 125. 127. The method of aspect 125 or 126, wherein esketamine is administered intranasally. 128. About 56 mg of esketamine is administered in at least four sprays. 7. The method described in Item 7. 129. Esketamine is administered via one spray in each nostril for a total of approximately 28 mg. and repeated about 5 minutes later for a total of about 56 mg. The method described. 130. The method of embodiment 119, wherein about 84 mg of esketamine is administered. 131. Esketamine administration results in a maximum blood glucose level of approximately 90 to approximately 165 ng / mL. Plasma concentration (Cmax), approximately 305~490ng * Time 0 to last quantifiable concentration in h / mL Achieve a plasma concentration-time curve of a certain level (AUClast), or a combination thereof. 131. The method according to embodiment 119 or 130. 132. The method of aspect 130 or 131, wherein esketamine is administered intranasally. 133. About 84 mg of esketamine is administered in at least 6 sprays. The method described in 2. 134. Esketamine is administered via one spray in each nostril for a total of approximately 28 mg. is administered at time 0 and repeated approximately 5 minutes later for a total of approximately 56 mg, for a total of approximately 84 134. The method of embodiment 133, wherein the administration of 1 mg of 1 mg of 10 ... 135. Any one of aspects 119-134, wherein the first phase is about 4 weeks in duration. The method described. 136. Following the first period, a second period lasting about 1 to about 4 weeks is further included, and the dose is about 56 mg. About 84 mg of esketamine is administered to the patient once per week. 9 to 135. 137. Approximately 56 mg of esketamine was administered to the patient once per week during the second phase. 137. The method of embodiment 136, wherein the 138. Approximately 84 mg of esketamine is administered to patients once per week during the second phase. 137. The method of embodiment 136, wherein the 139. Any of embodiments 136-138, wherein esketamine is administered intranasally in the second period. The method described in one. 140. Any one of aspects 136-139, wherein the second phase is about 4 weeks in duration. The method described. 141. The second phase is followed by a third phase of at least about one week duration, mg to approximately 84 mg of esketamine is administered to patients every two weeks or once a week. The method according to any one of embodiments 119 to 140, 142. Approximately 56 mg of esketamine every 2 weeks or once a week during the third phase 142. The method of embodiment 141, wherein the dose is administered to the patient at a frequency of 143. Approximately 84 mg of esketamine every 2 weeks or once a week during the third phase 142. The method of embodiment 141, wherein the dose is administered to the patient at a frequency of 144. Any of aspects 141-143, wherein esketamine is administered intranasally during the third period. The method described in one. 145. Any of aspects 141-144, wherein the third stage is at least about 1 month in duration. The method according to any one of the following: 146. Any of aspects 141-144, wherein the third stage is at least about 2 months in duration. The method according to any one of the following: 147. Any of aspects 141-144, wherein the third stage is at least about 3 months in duration. The method according to any one of the following: 148. Any of aspects 141-144, wherein the third stage is at least about 4 months in duration. The method according to any one of the following: 149. Any of aspects 141-144, wherein the third stage is at least about 5 months in duration. The method according to any one of the following: 150. Any of aspects 141-144, wherein the third stage is at least about 6 months in duration. The method according to any one of the following: 151. Any of aspects 141-144, wherein the third stage is at least about 1 year in duration. or one of the methods described above. 152. Any of aspects 141-144, wherein the third stage is at least about 2 years in duration. or one of the methods described above. 153. The method further comprises co-administering an antidepressant, and the method is for treating major depressive disorder. Any one of aspects 119-152, which has been proven clinically effective to treat The method described below. 154. The method of embodiment 153, wherein the antidepressant is administered orally. 155. The method according to any one of claims 153 to 154, wherein the major depressive disorder is treatment-resistant depression. method. 156. Pharmaceutical products containing one or more nasal spray devices, one or more of which is an esophageal spray. The device comprises a ketamine composition, and one or more devices administer from about 28 to about 84 mg of esketamine. and the pharmaceutical product is clinically safe for treating major depressive disorder. A medicinal product that has been proven to be effective and / or has been clinically proven to be effective. 157. The pharmaceutical product of aspect 156, wherein the major depressive disorder is treatment-resistant depression. 158. The pharmaceutical product of aspect 156 or 157, wherein the product comprises one device. 159. The device is configured to administer esketamine in two or more sprays. 156. A pharmaceutical product according to claim 156. 160. The method of claim 158 or 159, wherein the device contains about 28 mg of esketamine. Medicinal products. 161. The product contains two or more devices, each device containing approximately 28 mg of esketamine. 157. The pharmaceutical product according to embodiment 156. 162. The pharmaceutical product of aspect 161, wherein each device is a single-use device. 163. The pharmaceutical product of embodiment 162, comprising three devices. 164. Instructions for carrying out any one of the methods described in embodiments 119-155. 164. The pharmaceutical product of any one of aspects 156 to 163, further comprising: 165. A method for treating major depressive disorder accompanied by suicidal ideation, comprising: During a first induction period of defined duration, esketamine will be administered twice weekly at the highest tolerated dose. To do, administering a first oral antidepressant concurrently with esketamine; and Patients were evaluated to determine whether a substantially complete response to esketamine was achieved. and evaluating the person. 166. If a patient achieves a substantially complete response to esketamine, discontinue treatment. The method of embodiment 165, 167. Patient remains stable or in remission on first oral antidepressant alone. The method of embodiment 166, wherein the patient is monitored to ensure that 168. If a substantially complete response is not achieved during the first induction period, a second induction period may be initiated. The method of embodiment 165, wherein the method is initiated. 169. A patient is treated with the highest tolerated dose of esketamine during the second induction period and with oral The method of embodiment 168, wherein the administration is resumed concurrently with the antidepressant. 170. The method of claim 169, wherein the second oral antidepressant is the same as the first oral antidepressant. How to do it. 171. The method of claim 169, wherein the second oral antidepressant is different from the first oral antidepressant. method. 172. Patient remains stable or in remission on a second oral antidepressant alone. 172. The method of any one of embodiments 169 to 171, wherein the patient is monitored to ensure Law. 173. If a substantially complete response is not achieved during the second induction period, a third induction period may be initiated. 173. The method of any one of aspects 169 to 172, wherein 174. A patient is treated with the highest tolerated dose of esketamine during the third induction period and with oral 174. The method of embodiment 173, wherein the administration is resumed concurrently with the antidepressant. 175. The method of claim 174, wherein the third oral antidepressant is the same as the second oral antidepressant. How to do it. 176. The method of claim 174, wherein the third oral antidepressant is different from the second oral antidepressant. method. 177. A therapeutically effective dose of esketamine is administered to a patient less than twice weekly during the subsequent maintenance phase. 177. The method of any one of embodiments 165 to 176, further comprising: 178. An embodiment in which the first, second, and third induction periods are independently at least 4 weeks. 165 to 177. 179. A method for treating treatment-resistant depression in a patient, comprising: have not responded to at least two oral antidepressants in a depressive episode, administering to the patient a first oral antidepressant; Patients were administered esketamine at least twice weekly during a first induction period of defined duration. Giving and assessing the patient during a first induction period; If the patient fails to achieve a substantially complete response to esketamine In a second induction period of defined duration, patients were treated with the highest tolerated dose of esketamine. and resuming the administration of the second oral depressant simultaneously. 180. The first oral antidepressant is at least one of at least two oral antidepressants. The method of embodiment 179, wherein the method is the same as the method of embodiment 179. 181. The first oral antidepressant is at least one of at least two oral antidepressants. 180. The method of claim 179, wherein the first and second electrodes are different from each other. 182. Aspect 17, wherein the first oral antidepressant is different from at least two oral antidepressants. 9. The method according to claim 9. 183. A patient achieves a substantially complete response to esketamine during the second induction period. If not, patients were treated with esketamine in a third induction period of defined duration. and a third oral depressant. Law. 184. The method of claim 183, wherein the third oral antidepressant is the same as the second oral antidepressant. How to do it. 185. The method of claim 183, wherein the third oral antidepressant is different from the second oral antidepressant. method. 186. A therapeutically effective dose is when a patient achieves a substantially complete response to esketamine. to the patient up to once weekly during a subsequent maintenance phase. A method according to any one of embodiments 179 to 185. 187. An embodiment in which the first, second, and third induction periods are independently at least 4 weeks. 179 to 186. 188. A method of treating treatment-resistant depression in a patient, the method comprising: administering to said patient a therapeutically effective amount of an oral antidepressant; A therapeutically effective dose of esketamine was administered at least twice weekly during an induction period of at least 4 weeks. administering intranasally to said patient; A therapeutically effective amount of esketamine is administered intranasally to patients up to once weekly during the subsequent maintenance phase. and The method has been clinically proven safe and / or clinically proven effective The way it is done. 189. Embodiment 188, in which esketamine is administered once every two weeks during the subsequent maintenance phase. The method described below. 190. The method according to embodiment 188, wherein the administration frequency can be adjusted during the induction and / or maintenance phases. How to do it. 191. The therapeutically effective amount of esketamine administered during the induction period is approximately 28 mg to approximately 84 mg. The method of embodiment 188, wherein 192. The method of embodiment 191, wherein the therapeutically effective amount of esketamine is about 28 mg. 193. The method of embodiment 191, wherein the therapeutically effective amount of esketamine is about 56 mg. 194. The method of embodiment 191, wherein the therapeutically effective amount of esketamine is about 84 mg. 195. The therapeutically effective dose of esketamine is approximately 56 mg at the start of the induction period. The method of embodiment 191, wherein the dosage is adjusted to about 84 mg between doses. 196. The method of embodiment 192, wherein the patient is 65 years of age or older. 197. The therapeutically effective amount of esketamine administered during the maintenance phase is about 56 mg or about 84 mg. The method of embodiment 188, wherein the total amount of the hydroxybenzoates is 10 mg. 198. A therapeutically effective dose of esketamine during the induction and maintenance periods is delivered from an intranasal device in 2 198. The method of any one of embodiments 188-197, wherein the dose is delivered in one or more sprays. 199. Any one of aspects 188-198, wherein treatment continues for at least 6 months. The method described. 200. The method of any one of aspects 188 to 198, wherein the treatment continues for up to two years. Law.

[0135] As used herein, AD = antidepressant, AE = adverse event, ESK = esketamine nasal spray Mist, PBO = placebo nasal spray, PHQ-9 = Patient Adherence Questionnaire, SDS = Seeha CGI-S = Clinical Global Impression-Severity Scale, MADRS = Montgomery Disability Scale y-Åsberg Depression Rating Scale, SD = standard deviation, SNRI = serotonin and norepinephrine Nephrin reuptake inhibitors, SSRI = selective serotonin reuptake inhibitors, LS = minimal squared, SE=standard error, BMI=body mass index, BPIC-SS=bladder pain / interstitial cystitis symptoms score, BPRS+ = 4-item positive symptom subscale of the Brief Psychiatric Rating Scale, C = visit, C ADSS = Clinician-Administered Dissociative Status Scale, CGADR = Clinical Global Assessment of Readiness for Discharge, C- SSRS = Columbia Suicide Severity Rating Scale, DNA = deoxyribonucleic acid, ECG = electrocardiogram , EQ-5D-5L=EuroQol-5 Item-5 Level, EW=Early Withdrawal, GAD-7= Generalized anxiety disorder, 7-item scale, HE = hematoxylin and eosin staining, HbA1c test Experiment, glycosylated hemoglobin test, HRUQ = Healthcare Resource Utilization Questionnaire, HVLT-R = Hopkins IDS-C, Interdisciplinary Language Learning Test-Revised 30 = Depressive Symptoms Scale, a 30-item clinician-rated scale; LOE=lack of validity, MDD-major depressive disorder, LTF=lost to follow-up, MGH-ATRQ =Massachusetts General Hospital - Antidepressant Treatment History Questionnaire, MGH-Female RLHQ=Massachusetts General Hospital-Female Reproductive Cycle / Hormones Questionnaire, MINI = Mini International Neuropsychiatric Interview, MOAA / S = modified observer assessment of alertness / sedation, NS = statistically significant Not, OL = open label, OTH = other reasons for withdrawal, PAQ, Patient Adherence Questionnaire, P HQ-9 = Patient Health Questionnaire-9, PWC-20 = Physician Withdrawal Checklist, 20-item scale Degree, QIDS = 16-item Brief Depressive Symptom Scale - self-report, RNA = ribonucleic acid, SDS, -Han Disability Scale, SAFER = state-trait, evaluative, face validity, biological validity, 3 The Three Ps Law, STOP-Bang = Snoring, Tiredness, Observed Observed apnea, high blood pressure, body mass index ex), Age, Neck circumference, Gender (questionnaire), TRD = treatment-resistant depression, TSH = thyroid-stimulating hormone, RA = remote assessment only, LOCF = last observation carried forward, WBP = patient withdrawal, WD = withdrawal.

[0136] The following examples are included to aid in the understanding of the present invention and are incorporated by reference in their entirety. It is not intended to limit in any way the invention described in the claims. is not, and should not be construed as,

[0137] Example 1: Efficacy of intranasal esketamine for treating treatment-resistant depression (TRD), a phase 3 clinical trial Floor Test The ability of esketamine to treat treatment-refractory or treatment-resistant depression (TRD) is discussed below. The clinical trials described herein were conducted to evaluate the efficacy and safety of steroids in adult subjects with TRD. Efficacy and safety of flexibly administered intranasal esketamine plus newly initiated oral antidepressants This study evaluated the efficacy, efficacy, and tolerability of intranasal esketamine for the treatment of TRD. Pivotal Phase 3 short-term efficacy and safety studies supporting regulatory requirements for registration was provided.

[0138] The hypothesis of this study is to provide nasal steroid therapy for adult subjects with TRD from failed antidepressant treatment. Intracavitary esketamine plus a switch to a newly initiated oral antidepressant improved depressive symptoms. In this study, a newly initiated oral antidepressant treatment (active comparator) plus intranasal placebo It was better than switching.

[0139] The primary objective of this study is to assess the efficacy and safety of steroids from Day 1 (pre-randomization) to the end of the 4-week double-blind induction period. Depression, as assessed by change from baseline in the MADRS total score In improving depressive symptoms, a newly started oral antidepressant (active comparator) plus nasal Adult subjects with TRD were randomized to receive steroid therapy after a previous antidepressant treatment compared with switching to placebo Intranasal esketamine (28 mg, 5 mg) was administered flexibly from the treatment (those who were not responding). To evaluate the efficacy of switching to a newly initiated oral antidepressant (6 mg, or 84 mg) That was the case.

[0140] Key secondary objectives are to evaluate the following new parameters in adult subjects with TRD: Intranasal esketamine was compared with an oral antidepressant (active comparator) plus intranasal placebo. The objective of this study was to evaluate the effects of newly initiated oral antidepressants on: (a) depressive symptoms ( (b) onset of clinical response by day 2; and (c) functional and related impairments. Additional secondary objectives include: (a) depression response rate, (b) depression remission rate, and (c) depression severity. (d) overall severity of anxiety symptoms; and (e) health-related quality of life and well-being. was.

[0141] Newly initiated oral antidepressants (active comparator) plus nasal antidepressants in adult subjects with TRD Safety of Intranasal Esketamine Plus Newly Initiated Oral Antidepressants Compared with Intranasal Placebo To investigate the efficacy and tolerability, the following parameters were also measured: (a) A of special interest; (b) TEAEs including E; (b) local nasal tolerability; (c) heart rate, blood pressure, respiratory rate, and blood oxygen saturation. (d) effects on alertness and sedation; (e) potential psychotic-like effects; (f) dissociative symptoms, (g) potential effects on cognitive function, and (h) potential effects on suicidal ideation / behavior. (i) potential treatment-emergent symptoms of cystitis and / or lower urinary tract symptoms; (j) intranasal potential withdrawal and / or rebound symptoms following cessation of sketamine treatment, and (k) loss of sense of smell Potential effect.

[0142] A study of adult subjects with TRD receiving intranasal esketamine plus a newly initiated oral antidepressant The PK of intranasal esketamine in the body was also evaluated as part of the secondary objectives.

[0143] Investigational Drug Information Esketamine is delivered in a nasal spray pump as a clear, colorless intranasal solution of esketamine hydrochloride. Supplied as (16.14 weight / volume [w / v], 14% w / v esketamine salt The solution was prepared by dissolving 0.12 mg / mL of ethylenediaminetetraacetic acid (EDT) in water for injection. A) and 161.4 mg / mL formulated in 1.5 mg / mL citric acid (pH 4.5) of esketamine hydrochloride (equivalent to 140 mg of esketamine base). Delivered in a pump, it delivers 16.14 mg esketamine hydrochloride (14 mg) per 100-µL spray. Each individual nasal spray pump (device) delivered a total of 28 mg (esketamine base). (i.e., two sprays).

[0144] The placebo solution was supplied as a clear, colorless intranasal solution of water for injection, containing no bittering agent (final concentration Add 0.001 mg / mL denatonium benzoate (Bitrex®) The taste of the intranasal solution was simulated with the active drug. A placebo solution was administered in a matching nasal spray. Benzalkonium chloride was used as a preservative at a concentration of 0.3 mg / mL. Each individual nasal spray pump (device) contained two doses of spray.

[0145] Oral antidepressants Duloxetine 30 mg was obtained from commercial stock and provided under the sponsor's responsibility. Please see package insert / SmPC for physical description and list of excipients.

[0146] Escitalopram 10 mg was obtained from commercial stocks and provided under the sponsor's responsibility. Please refer to package insert / SmPC for physical description and list of excipients.

[0147] Sertraline 50 mg and 25 mg (if applicable) were obtained from commercial stocks. , provided under the responsibility of the sponsor. Package insert / SmPC for physical description and excipients See the list below.

[0148] Venlafaxine 75 mg and 37.5 mg (if applicable) from commercial stock The package insert / SmPC for physical description and See list of ingredients and excipients.

[0149] Test Plan Overview This was compared with a newly started oral antidepressant (active comparator) plus intranasal placebo. Flexible intranasal esketamine (28 mg, 56 mg, or 84 mg) plus a newly developed To evaluate the efficacy, safety, and tolerability of newly introduced oral antidepressants in patients with TRD This was a randomized, double-blind, active-controlled, multicenter study in adult male and female subjects. The study had three phases, briefly described below. Figure 1 outlines the study design.

[0150] Screening / prospective observation period (4 weeks duration) This phase will prospectively assess the treatment response to the subject's current oral antidepressant treatment regimen. After 4 weeks of continuing the same treatment regimen (at the same dose), Subjects who were non-responders to current oral antidepressant treatment (as assessed by the investigator) were included in the double Patients were eligible to proceed to the blinded induction phase. The site investigators were The study was blinded.

[0151] Eligible subjects who entered the double-blind induction period discontinued their current oral antidepressant(s). If clinically indicated, the subject's current antidepressant(s) should be listed in the local prescribing information or clinical The dose may be tapered and discontinued for any additional period of up to 3 weeks, according to clinical judgment.

[0152] Because new oral antidepressants were started on day 1 of the double-blind induction period, Eligible subjects who did not require tapering discontinuation(s) proceeded immediately to the double-blind induction period. That's right.

[0153] Double-blind induction period (4 weeks duration) The study involved double-blind treatment with either intranasal esketamine or intranasal placebo. Subjects were randomly assigned in a 1:1 ratio (n=98 subjects per treatment arm) to Twenty-seven randomized subjects were included (four of whom received intranasal and / or oral AD). did not receive the study drug and were therefore not included in the analysis population). The treatment (esketamine or placebo) was administered twice weekly. In addition, all subjects received a new A new open-label oral antidepressant was started, which was taken daily for the duration of this period. The assigned oral antidepressant was administered to the subject to determine whether the subject was non-responsive in the current depressive episode. Not previously had, not previously intolerant (lifetime), and available in participating countries Four oral antidepressants (duloxetine, escitalopram, sertraline, or benlazolinone) were used. It was one of the drugs (Faxin® extended-release [XR]).

[0154] At the end of the induction period, subjects who were responders (from baseline [pre-randomization on Day 1] to Defined as a ≥ 50% reduction in the MADRS total score by the end of the 4-week double-blind induction period (e.g., a person who meets all other exam entry criteria) may be admitted to the subsequent exam ESKETINTRD3. were eligible to participate in ESKETINTRD3003 (ESKETINTRD3003 is a randomized controlled trial of intranasal Esketamine and a longer-term efficacy maintenance trial involving repeated treatment sessions of Min.

[0155] If a subject withdraws from the study before the end of the double-blind induction period for reasons other than withdrawal of consent. The early withdrawal visit was conducted within 1 week of the discontinuation date and followed by the follow-up period. .

[0156] Follow-up period (24-week duration) This period included patients who were not eligible or who were in the maintenance efficacy trial ESKETINTRD3003. chose not to participate and received at least one dose of intranasal study drug during the double-blind induction period. All subjects receiving the treatment were included. The intranasal treatment sessions administered during this period were It didn't exist.

[0157] At the start of the follow-up period, further clinical / standard care for the treatment of depression was initiated by the investigator. The subjects were given oral antidepressants during this period, and the results were arranged by the attending physician and / or the subjects' treating physician. The decision to continue was at the discretion of the investigator, but potential withdrawal symptoms from the intranasal study drug were excluded. To better assess the risk of urinary tract infection, oral antidepressants were not used unless clinically appropriate. It was recommended that patients continue for at least the first two weeks of the follow-up period.

[0158] The follow-up period also monitored the progress of subjects' major depressive episodes over a 6-month period. This allowed for the collection of additional information data to be evaluated.

[0159] Allowing for an optional tapering period of up to 3 weeks, the duration of study participation for subjects was 11 weeks. (for subjects continuing into ESKETINTRD3003) or 35 weeks (follow-up) (Subjects who completed the follow-up period).

[0160] Study population The inclusion criteria for enrolling subjects in this study were as follows: Each subject met all of the following criteria to be enrolled in this study: 1. Sign the informed consent form (ICF) At the time of the study, subjects must be 18 years of age (or the minimum legal age for consent in the country where the study is being conducted). Participants were men and women aged between 19 and 64 if over 18 years old. 2. At the start of the screening / prospective observation period, subjects will be assessed for M Single-episode MDD (single-episode MDD, persistent) confirmed by INI (duration ≥ 2 years) or met DSM-5 diagnostic criteria for recurrent MDD without psychotic features. It was. 3. At the start of the screening / prospective observation period, subjects must complete the MGH-ATRQ Current depression, as assessed by the pharmacy and confirmed by documented medical history and pharmacy / prescription records A history of non-response to 2 to 5 oral antidepressant medications during a depression episode Subjects were non-responders and on oral antidepressant treatment at the start of the screening / prospective observation period. As documented in the PAQ, subjects were Patients were adherent to their oral antidepressant medication(s) (without dosage adjustments) throughout the study. If an antidepressant is not taken for 4 or more days in a 2-week period, it is considered inadequate adherence. Screening / Subjects who were non-responders to their current oral antidepressant(s) from the prospective observation phase were Patients were eligible for randomization if all other entry criteria were met. 4. At the start of the screening / prospective observation period, subjects must meet the IDS-C 30 Total score had ≥34. 5. The subject's current major depressive episode and antidepressant therapy for the current depressive episode. Depressant medication response was confirmed using an independent institutional eligibility assessment. 6. Subjects undergo a physical examination, medical history, vital signs (including blood pressure), pulse oximetry - and medically based on a 12-lead ECG performed during the screening / prospective observation period If any abnormalities not specified in the inclusion and exclusion criteria were present, If so, the determination of clinical significance will be determined by the investigator and recorded in the subject's source documentation. and initialed by the investigator. 7. Subject is medically healthy based on clinical tests performed during the screening / prospective observation period. The serum chemistry panel, hematology, or urinalysis results were outside the normal reference range. If so, the investigator may determine that the abnormality or deviation from normal is not clinically significant or or were considered appropriate and relevant for the population under study. This decision was made This was recorded on the subject source document and initialed by the investigator. Subjects with a pre-existing history of thyroid disease / disorder treated with monocytes should be screened at screening / pre-treatment. Patients receiving a stable dose for 3 months prior to the start of the screening / prospective period will be Thyroid-stimulating hormone (TSH) levels were within the normal range during the follow-up period. 8. Subject is comfortable self-administering intranasal medications and is able to follow the intranasal administration instructions provided. This was possible. 9. Prior to the start of the screening / prospective phase, female subjects had any of the following: (a) Non-childbearing potential: Postmenopausal (amenorrhea for at least 12 months) Age over 45 years or amenorrhea for at least 6 months and serum follicle-stimulating hormone (FSH) levels Any age with a FSH (follicle stimulating hormone) level >40 IU / L, permanent Infertility (e.g., blocked fallopian tubes, hysterectomy, bilateral salpingectomy) or inability to conceive for other reasons or (b) the use of contraception for subjects of childbearing potential participating in a clinical trial Highly effective methods of contraception, such as oral, injectable, or or those who practice the established use of implanted hormonal contraception, intrauterine devices ( intrauterine device (IUD) or intrauterine system placement; barrier methods (e.g., spermicidal Foam / gel / film / cream / condom with suppository or spermicidal foam / Gel / film / cream / suppository with occlusive cap [diaphragm or cervical / vaginal cuff] vasectomized partners are the only ones eligible for the procedure. or true abstinence (if this is the subject's preferred and usual lifestyle). If fertility changes after the start of the study (e.g., if heterosexual Women who were not active became active), and female subjects, as mentioned above, were given very effective evacuation. Women were to continue their pregnancy throughout the study and at least once after the last dose of intranasal study drug. Both women agreed to continue using these methods for six weeks. 10. Women of childbearing potential must have serum (β- Negative human chorionic gonadotropin (β-hCG) and undergo a double-blind induction period before randomization A urine pregnancy test was negative on day 1 of the study. 11. Men who are sexually active with women of childbearing potential and who have not had a vasectomy: From day 1 of the double-blind induction period (pre-randomization) until 3 months after the last dose of intranasal study drug, Barrier methods of pregnancy, e.g. spermicidal foam / gel / film / cream / suppository Use condoms or have your partner use spermicidal foam / gel / film / cream / Use an occlusive cap (pessary or cervical / vaginal vault cap) with a suppository Alternatively, the female partner of childbearing potential must use a highly effective form of contraception. established use of oral, injected, or implanted hormonal methods, intrauterine devices (IUDs), UD) or placement of an intrauterine system; or sterilization of the male partner. If fertility changes after the start of the study, the female partner of a male subject should So, I started a highly effective form of birth control. 12. Subject is willing to abide by the prohibitions and restrictions specified in the clinical trial protocol. Yes, it was possible. 13. Each subject will understand the purpose of the study and the procedures required to participate in the study. I signed the ICF, which shows my willingness.

[0161] The exclusion criteria for enrolling subjects in this study were as follows: Any potential subject who meets any of these criteria will be excluded from participating in this study. Ta. 1. The subject's depressive symptoms are (a) in a current major depressive episode according to clinical judgment or (b) a current major depressive episode (MGH- The double-blind run-in period of each country's available oral antidepressant treatments (based on the ATRQ) Treatment options (i.e., duloxetine, escitalopram, sertraline, and benflurane) (c) unilateral electroconvulsive therapy (e.g., unilateral electroconvulsive therapy) Current major depressive episode, defined as at least seven treatments with ECT (e.g., ECT) The patient had previously shown non-response to an adequate course of treatment with ECT in the rhesus monkey. 2. The subject will receive an implant for vagal nerve stimulation (VNS). or have had a history of depression or have had a current episode of depression and are considering deep brain stimulation. tion, DBS). 3. Subject has a psychotic, bipolar or related disorder (confirmed by MINI), co-occurring Obsessive-compulsive disorder, intellectual disability (DSM-5 diagnostic code 319 only), borderline personality disorder, antisocial personality disorder Presence of psychotic disorder or MDD with personality disorder, histrionic personality disorder, or narcissistic personality disorder had a current or previous DSM-5 diagnosis. 4. The subject had homicidal ideation / intent according to the investigator's clinical judgment, or according to the investigator's clinical judgment or based on the C-SSRS had suicidal ideation with some intention to act on it within 6 months prior to the start of the prospective observation period (Item 4 of the C-SSRS on suicidal ideation (with some intention to act without a specific plan) for item 5 (active suicidal ideation with specific plan and intent) or item 6 (active suicidal ideation with specific plan and intent) a "yes" response to the question or a history of suicidal behavior in the year prior to the start of the screening / prospective observation period (corresponding to history). Prior to the start of the double-blind induction period, patients were asked to report any suicidal ideation or suicidal behavior with intent to act. Subjects who reported were excluded. 5. Subjects have not used nicotine or caffeine within 6 months prior to the start of the screening / prospective observation period. Moderate or severe substance or alcohol use disorder according to DSM-5 criteria, excluding Fain He had a history of drug abuse involving ketamine, phencyclidine (PCP), and diethyl lysergic acid. LSD, or 3,4-methylenedioxy-methamphetamine (MDMA) hallucinogenic Lifetime history of continual use disorder was excluded. 6. Subject had a current or past history of seizures (uncomplicated children without sequelae) Febrile seizures are not excluded). 7. Subject has a UPSIT total score indicating anemia during the screening / prospective observation period. had a ≤18. 8. Subject had one of the following cardiovascular-related conditions: (a) stroke or (b) cerebrovascular disease with a history of transient ischemic attacks; (c) aneurysmal vascular disease (intracranial, thoracic, or juvenile) or abdominal aorta, or peripheral arterial vessels), (c) during the screening / prospective observation period Myocardial infarction, unstable angina, or revascularization procedures (e.g., coronary angioplasty) within 12 months prior to initiation (d) coronary artery disease with associated mitral regurgitation, aortic stenosis, or coarctation; (e) Hemodynamically significant valvular heart disease, such as aortic regurgitation, or (f) New York City heart disease of any cause New York Heart Association (NYHA) Class III-IV heart failure . 9. Subject has a history of steroid use during screening / History of uncontrolled hypertension or previous hypertensive emergency at the start of the prospective observation period History or supine systolic blood pressure of >140 mmHg during the screening / prospective observation period supine systolic blood pressure (SBP) or diastolic blood pressure (diasBP) > 90 mmHg Tolic blood pressure (DBP) is defined as the and had ongoing evidence of uncontrolled hypertension. On day 1 of the double-blind induction period, supine SBP > 140mmHg or DBP > 90mmHg was also excluded. Potential subjects will be asked to provide their current antihypertensive medications adjusted during the screening / prospective observation period. The patient may have a regimen and then be re-evaluated to assess blood pressure control. Subjects must have received a stable regimen for at least 2 weeks prior to Day 1 of the double-blind induction period. I did it. 10. Subjects must be taking any of the following drugs at the start of the screening / prospective observation period or on Day 1 prior to randomization: Current or past history of significant pulmonary insufficiency / condition or arterial oxygen saturation (SpO2) < 93% 2). 11. Subjects must be enrolled in the double-blind study at the start of the screening / prospective observation period or prior to randomization. On day 1 of the induction period, (a) the corrected QT interval (QTc F): ≥ 450 msec, (b) second- and third-degree AV block with PR interval > 200 msec Locking, first-degree AV block, left bundle branch block (LBBB) ), or evidence of right bundle branch block (RBBB), (c) new characteristics of ischemia, (d) arrhythmias (premature atrial contractions) traction, PAC] and premature ventricular contraction [premature ventricular contraction] clinically significant, defined as a unilateral contraction or PVC The patient had an abnormal ECG. 12. Subject is at additional risk of Torsades de Pointes History of underlying factors (e.g., heart failure, hypokalemia, family history of long QT syndrome), or QT interval / They were taking concomitant medications that prolong the corrected QT (QTc) interval. 13. Subject has a history of liver cirrhosis (e.g., esophageal varices, ascites, and prothrombin time Increased alanine alanine levels at ≥2 times the upper limit of normal during the screening / prospective observation period Alanine aminotransferase (ALT) or aspartate Aminotransferase (aspartate aminotransferase, AST) levels or >ULN The patient had 1.5 times the total bilirubin. The investigator's opinion on the elevated bilirubin In this study, and with the consent of the sponsor's medical staff, the increase in bilirubin was If a match was found, the subject was allowed to participate in the study. 14. Subjects must be enrolled in a double-blind induction study at the start of the screening / prospective observation period or prior to randomization. On day 1 of the induction period, addictive drugs (barbiturates, methadone, opiates, cocaine, phenytoin) were administered. Positive test(s) for benzodiazepines (including benzodiazepines, benzodiazepines, and amphetamines / methamphetamines) ) prescription / over-the-counter opiates, barbiturates, or amphetamines Subjects who have a positive test result on screening by the Subject to the restrictions reproduced in Table 6 below, dosing may be initiated prior to Day 1 of the double-blind induction period (prior to randomization). If discontinued for at least 1 week or 5 half-lives, whichever is longer, Patients were allowed to continue into the observation period. Day 1 (pre-randomization) test for drugs of abuse Test results had to be negative for subjects to be randomized. Except for the reasons stated above Retesting of positive test result(s) was not permitted. Screening / Prospective Previous intermittent use of cannabinoids before the start of the observation period may have prevented the subject from meeting criteria for a substance use disorder. However, if the patient had not undergone any of the above treatments before the first day of the double-blind induction period, Positive test results for nabinoids were excluded. 15. Subject has severe diabetic ketoacidosis, hyperglycemic coma, or loss of consciousness. Screening for hypoglycemia in the 3 months prior to the start of the prospective observation period / Screening for hypoglycemia in the 3 months prior to the start of the prospective observation period / Prospective observation period Uncontrolled urinary tract infection, as evidenced by HbA1c >9% during the prognosis or history Had diabetes or secondary diabetes. 16. Subject has untreated glaucoma, current penetrating or perforating eye injury, brain injury, hypertension, Pressure encephalopathy, intrathecal therapy with ventricular shunt, or increased intracranial or intraocular pressure or planned had any other condition related to the eye surgery. 17. Subject has any anatomical or medical condition that may interfere with the delivery or absorption of intranasal investigational drug. had a condition (e.g., significant structural or functional abnormality of the nose or upper respiratory tract, nostrils or nasal passages) obstruction or mucosal lesions, sinus surgery in the past 2 years). 18. Subject has an abnormal or unrepaired nasal cavity with any one or more of the following symptoms: (a) had a septal deviation in one or both of the following cases within the past few months that may affect study participation: (b) nasal congestion (especially on one side); (c) frequent nosebleeds; (d) frequent sinus congestion infection, or (e) wheezing during sleep. 19. Subject has a history of malignancy within 5 years prior to the start of the screening / prospective observation period. had squamous cell carcinoma and basal cell carcinoma of the skin, and intraepithelial carcinoma of the cervix, or In the opinion of the investigator, and in agreement with the sponsor's medical monitor, there is a minimal risk of recurrence. (The exception was malignant tumors that were considered cured by the procedure.) 20. Subject will receive esketamine / ketamine and / or its vehicle, or double-blind induction known allergies to any of the available oral antidepressant treatment options for the induction phase, had hypersensitivity, intolerance, or contraindications. 21. Subjects will be randomly assigned to receive the study drugs outlined in the sections entitled Preliminary Study and Concomitant Therapy and in Table 6. Patients receiving any prohibited therapy that would not be permitted to be administered on Day 1, as was. 22. Subjects must be on 6 mg / day of lorazepam at the start of the screening / prospective observation period. were taking a total daily dose of benzodiazepines greater than the equivalent dose. 23. Subject has a score of ≥ 5 on the STOP-Bang questionnaire, in which case obstructive Sleep apnea had to be excluded (e.g., apnea-hypopnea index [apnea-hypopnea Subjects with obstructive sleep apnea were individually fitted with a positive pressure breathing device. or other treatments / therapies that effectively treated sleep apnea were included. obtain. 24. Subjects must have received an investigational drug (investigational water) within 60 days prior to the start of the screening / prospective observation period. had undergone any investigational medical procedure (including surgery), or used an invasive investigational medical device, or Two or more clinical episodes of MDD or other psychiatric conditions in the year prior to the start of the study / prospective observation period Participated in or currently enrolled in a clinical trial. 25. Subjects must be at least 18 years of age or older while enrolled in this study or 6 weeks after their last dose of intranasal investigational drug. Women who were pregnant, breastfeeding, or planning to become pregnant in the near future. 26. The subject has acquired immunodeficiency syndrome (AIDS). He had a diagnosis of human immunodeficiency virus (HIV). , HIV) testing was not required for this study. 27. The subject has a medical condition for which, in the opinion of the investigator, participation is not in the subject's best interest. (impairs well-being) or interferes with, limits, or confuses the evaluation specified in the protocol. had any condition or situation / circumstance that could have caused 28. Subject must have received a 24-hour course of steroids (e.g., steroids) within 12 weeks prior to the start of the screening / prospective observation period. have had major surgery (requiring general anesthesia) or have not fully recovered from surgery, or Subjects were undergoing planned surgery during the period during which they were expected to participate in the study. Subjects scheduled for an underlying surgical procedure were allowed to participate. 29. The subject is an employee of the investigator or trial facility and is not any person directly involved in the study or other study submitted under the direction of the institution, and were employees or family members of the investigator.

[0162] The investigator ensured that all study entry criteria were met. If the subject's condition changes (including receipt of test results or additional medical records) before the dose is administered ), if a subject can no longer meet all eligibility criteria, the subject may be withdrawn from the study. will be excluded from participation.

[0163] Additionally, potential subjects must meet the following criteria during the course of the study to be eligible to participate: They had to be willing and able to abide by the prohibitions and restrictions. 1. Inclusion and Exclusion Criteria, 2. Preliminary testing and concomitant therapy restrictions, including a list of prohibited concomitant medications for intranasal investigational drugs . 3. Phencyclidine (P) from Day 1 of the induction phase to the final visit in the double-blind induction phase CP), 3,4-methylenedioxy-methamphetamine (MDMA), or cocaine use A positive urine drug screen for use will lead to discontinuation. 4. Subjects will abstain from alcohol use for 24 hours before and after each intranasal treatment session. If the subject appears intoxicated, do not administer the drug. 5. On all intranasal study drug administration days, all subjects must complete study procedures and must remain at the clinical trial site until they are ready to be released and must be removed from the clinical trial site. Subjects were required to be accompanied by a responsible adult upon release. During this time, people should not drive or work with machinery. 6. Subject must have taken grapefruit juice for 24 hours prior to receiving an intranasal dose of study drug. No root juice, Seville orange juice, or quinine was to be consumed. 7. ECT, DBS, transcranial magnetic stimulation (TMS) ), and VNS were prohibited from study entry until the end of the double-blind induction period. 8. Subjects receiving psychiatric therapy must be in a state where this therapy is discontinued prior to the screening / prospective observation period. were stable in frequency over the past 6 months and remained unchanged until the end of the double-blind induction period. Unless otherwise specified, patients could continue receiving psychiatric treatment.

[0164] Treatment assignment, randomization, and blinding This study was centrally randomized. Subjects were randomized by the sponsor or by the sponsor's Based on a computer-generated randomization schedule prepared before the study under supervision, participants were assigned to: Patients were randomly assigned to treatment group 1 or 2 in a ratio of 1:1. Randomization was performed by random permutation. The study was balanced by using a block of 1000 sera, and the double-blind induction period was initiated. Stratified by oral antidepressant class (SNRI or SSRI). Interactive web response The system (interactive web response system, IWRS) includes a treatment assignment for subjects. A unique treatment code was assigned to determine the matched investigational drug kit. After selecting oral antidepressant treatment for the double-blind induction period, the facility entered this information into the IWRS. The claimant must use his / her user identification and personal identification number when contacting IWRS. , and obtained relevant subject details to uniquely identify that subject.

[0165] The investigators were not provided with a randomization code; this code was maintained within the IWRS. maintains the functionality to allow investigators to unblind individual subjects. was doing.

[0166] To ensure that the integrity of the blinding is maintained and the potential for bias is minimized Additionally, data that could potentially unblind treatment assignment (e.g., intranasal investigational drug bleeds) Plasma concentration, treatment allocation) were treated with particular attention. The investigator, clinical team, or others, as appropriate, may be contacted until the time is locked and unblinded. This may include providing special exceptions, such as preventing the data from being viewed by others.

[0167] Under normal circumstances, the study will continue until all subjects have completed the study and the database has been finalized. The blind must not be broken, otherwise knowledge of the subject's treatment status may be lost. The blind may be broken only if a specific emergency treatment / course of action can be indicated. In such cases, the investigator will determine the identity of the treatment by contacting the IWRS in an emergency. The investigator should, if possible, consult with the sponsor or It is recommended that you contact your designee to discuss your specific situation. The designee was available by phone 24 hours a day, 7 days a week. If so, the sponsor was notified as soon as possible. The date and time of the unblinding was determined by the IWRS. The reason for unblinding will be documented in the electronic case report form. , eCRF) and in the source documents received from the IWRS. Documentation showing decryption is kept with the subject's source documents in a secure manner. can be.

[0168] Subjects whose treatment assignments were unblinded were randomly selected for scheduled early withdrawal and follow-up visits. I decided to continue visiting again for this reason.

[0169] Generally, randomization codes are used once the trial is completed and the clinical database is closed. For interim analyses, the randomization code and, if necessary, the randomized control group were fully disclosed. Translation of the standardized codes into treatment and control groups will be included in the interim analysis for those who qualify. Only subjects were disclosed.

[0170] At the end of the double-blind induction period, the database was locked for analysis and reporting of this period. Subject treatment assignment was known only to the sponsor's study staff. Investigators and site personnel until the subject completes study participation through the follow-up period. were blinded to treatment assignment.

[0171] To maintain the blinding of the intranasal study drug, the esketamine and placebo intranasal devices were indistinguishable. It was Noh.

[0172] A total of 227 subjects were randomized in the study. Of these, 3 subjects did not receive any study drug (intranasal or oral AD), and one subject received both intranasal and oral did not receive both AD study drugs.

[0173] The demographic and baseline characteristics of the subjects in the study are listed in Table 1 below. In general, the treatment groups were similar with respect to baseline characteristics. Most were female, and the mean age of all subjects was 45.7 years, ranging from 19 to 64 years.

[0174] [Table 1-1]

[0175] [Table 1-2]

[0176] Of the 227 randomized subjects, 197 completed the 28-day double-blind induction period. The most common reason for withdrawal was adverse events. 86 subjects subsequently returned to follow-up. The study entered the pilot phase, with 118 subjects continuing on to the ESKETINTRD3003 clinical trial. Table 2 below presents the number and reasons for withdrawal from the study.

[0177] [Table 2]

[0178] Baseline psychiatric history was as presented in Table 3 below. Mean (SD) baseline The Sline MADRS total score was 37.1, with a range of 21 to 52.

[0179] [Table 3-1]

[0180] [Table 3-2]

[0181] Dosage and Administration Screening / prospective observation period At the start of the screening / prospective observation period, subjects Patients who were on oral antidepressant therapy at the start of the study and were non-responders, and who continued this same therapy during the continuation phase Non-response was confirmed over a period of time. The study criteria for non-response were met by the site and investigator. During this period, adherence to antidepressant treatment was assessed using the PAQ. It was worth it.

[0182] After completion of 4 weeks of prospective antidepressant treatment and assessment of antidepressant treatment response, antidepressants were administered locally. in accordance with the prescribing information or clinical judgment (e.g., paroxetine and venlafaxine XR) antidepressant treatment with a short half-life, or tolerability concerns), for a period of up to 3 weeks It was tapered and discontinued.

[0183] Double-blind induction period During this period, subjects received either esketamine (56 mg or 84 mg) or placebo. Double-blind intranasal treatment with 2 mg / kg of benzodiazepine (B1) was administered twice weekly for 4 weeks in a flexible dosing regimen at the study site. Additionally, subjects were administered a new open-label oral antidepressant (i.e., , duloxetine, escitalopram, sertraline, or venlafaxine XR) at the same time It began at 12:00 and continued for the duration of this period.

[0184] Intranasal investigational drug During all intranasal treatment sessions, a doctor, nurse, or cardiopulmonary resuscitation (CPR) Recent (i.e., within the past year) training in cardiopulmonary resuscitation (CPR) Other appropriate members of the facility staff will be present during the intranasal treatment session and post-administration observation period. In addition, there was supportive ventilation and resuscitation equipment. Table 4 below shows the Describe how intranasal treatment sessions will be administered during the double-blind induction period.

[0185] [Table 4]

[0186] Prior to the first intranasal administration on Day 1, subjects received a demonstration nasal sachet filled with placebo solution. We practiced spraying the intranasal device (into the air, not into the nasal cavity).

[0187] All subjects received two treatment sessions per week for four weeks at the study site. Patients self-administered the intranasal study drug (esketamine or placebo). The first treatment session was It was performed on day 1. Intranasal treatment sessions were not performed on consecutive days.

[0188] On Day 1, subjects randomized to intranasal esketamine started at a dose of 56 mg On Day 4, the dose will be adjusted to 100 mg / kg / day as determined by the investigator based on efficacy and tolerability. On day 8, the dose was increased to 84 mg or remained at 56 mg. The dose was increased to 84 mg (4 mg / day) as determined by the investigator based on efficacy and tolerability. If the dose on day 1 was 56 mg, it remained the same or was reduced to 56 mg. (If the dose on Day 4 was 84 mg.) On Day 11, the dose was adjusted based on efficacy and tolerability. The dose was increased to 84 mg on day 8 as determined by the investigator based on the 56 mg), remained the same, or was reduced to 56 mg (day 8 use) On day 15, if necessary for tolerability, the dose may be increased from 84 mg. Dose reduction to 56 mg was possible. Dose escalation on day 15 was not permitted. After that, the dose remained stable (unchanged).

[0189] Food was restricted for at least 2 hours before each administration of study drug. Drinking any fluids was prohibited until the first Nasal sprays were restricted for at least 30 minutes before use.

[0190] If the subject had nasal congestion on the day of dosing, they were asked to It was recommended to delay the administration of intranasal decongestant. If used to reduce nasal congestion, it cannot be used within 1 hour before intranasal administration of the study drug. There wasn't.

[0191] In all intranasal treatment sessions, subjects were required to complete the study procedure and release the remain at the clinical site until ready to be released and be released to a responsible Subjects were not permitted to drive for 24 hours after the last dose of intranasal study drug on each dosing day. It was decided that they would not work with machinery or with other equipment.

[0192] Oral antidepressants Beginning on Day 1, all subjects were initiated on new open-label oral antidepressant treatment. The oral antidepressants were administered for the duration of this period. one of the following: cetethone, escitalopram, sertraline, or venlafaxine XR Antidepressants were selected based on the MGH-ATRQ and related information regarding previous antidepressant treatment. Based on the review, the investigator will assign the study to determine whether the subject has a current depressive episode. In Sword, in countries that are not previously non-responsive, not previously non-tolerant (lifetime), and participating It was what was available.

[0193] Oral antidepressants should be administered starting on day 1 and according to local prescribing information for each product. The protocol-specified dose titration schedule is shown in the table below. As presented in 5.

[0194] [Table 5]

[0195] If higher doses were not tolerated, dose reduction was permitted based on clinical judgment. While the subject's maximum tolerated dose must be equal to or greater than the following minimum therapeutic doses: Larin (50 mg / day), venlafaxine XR (150 mg / day), escitalopram (10 mg / day), and duloxetine (60 mg / day). Subjects requiring lower doses Although such subjects were able to continue in the study and complete the double-blind induction period, Participate in the maintenance of study ESKETINTRD3003 and follow up after completion of the double-blind induction phase He was not eligible to move on to the up phase.

[0196] All subjects will have no interruption of antidepressant therapy during transition to further clinical / standard care To ensure this, an additional 4-week supply of oral antidepressants was provided.

[0197] Study site personnel will administer oral anti-inflammatory drugs supplied during the double-blind induction period for home use. Subjects were instructed on how to administer and store the medication.

[0198] In the intranasal treatment session, oral antidepressant treatment was administered at night and at the same time during the double-blind induction period. Furthermore, on the day of intranasal administration, the frequency of oral antidepressants was recommended to be once daily. If more than twice daily (e.g., twice daily), the dose should be administered at least 3 hours after the intranasal treatment session. It was recommended that it should not be taken until

[0199] Guidelines for blood pressure monitoring on the day of intranasal administration: Considering the possibility of transient increases in systolic and diastolic blood pressure occurring during treatment, On the day of oral administration, the following guidelines were followed.

[0200] After meeting the inclusion and exclusion criteria on Day 1, subjects' pre-dose systolic blood pressure (SBP) ≥ 160mmHg and / or diastolic blood pressure (DBP) ≥ 100mmHg If this occurs, it is recommended that the blood pressure measurement be repeated after the subject has rested in a sitting or lying position for 10 minutes. Pre-dose SBP ≥ 160mmHg and / or DBP ≥ 100mmHg In some cases, administration is postponed and subjects are scheduled to return the next day or within a given visit period. If elevated blood pressure persisted at the next visit, the subject was asked to consult a cardiologist before further administration. A consultation with a doctor or attending physician was scheduled.

[0201] SBP ≥ 180mmHg, < 200mmHg at any time after administration on the day of administration and / or if DBP was ≥ 110mmHg, < 120mmHg, further intranasal Dosing will be discontinued and the subject will be referred to a cardiologist or primary care physician for follow-up evaluation. It was.

[0202] As long as the subject is approved to continue in the study after evaluation by a cardiologist or attending physician If the pre-dose blood pressure at the next scheduled visit is within acceptable limits, the subject will continue with intranasal administration. I was able to continue.

[0203] SBP ≥ 200 mmHg and / or DBP ≥ 200 mmHg at any time point after administration on the day of administration If ≥ 120 mmHg, the subject was to discontinue further administration and return to a follow-up assessment. Patients were to be referred to a cardiologist or their primary care physician for further information.

[0204] During the double-blind induction period, SBP was ≥ 160 mmHg at 1.5 hours post-dose; and / or DBP was ≥ 100mmHg, SBP < 160mmHg and Subjects should seek appropriate medical care until DBP < 100 mmHg or if clinically indicated. Evaluations must continue every 30 minutes until the patient is referred to the competent authority.

[0205] Follow-up period received at least one dose of intranasal study drug during the double-blind induction period but did not receive any subsequent maintenance clinical Subjects who did not enter the ESKETINTRD3003 study were included in the 24-week follow-up. The patients then proceeded to the nasal administration phase. No intranasal study drug was administered during this phase.

[0206] At the start of the follow-up period, further clinical / standard care for the treatment of depression was initiated by the investigator. The subjects were given oral antidepressants during this period, and the results were arranged by the attending physician and / or the subjects' treating physician. The decision to continue was at the discretion of the investigator, but potential withdrawal symptoms from the intranasal study drug were excluded. To better assess the risk of urinary tract infection, oral antidepressants were not used unless clinically appropriate. It was recommended that patients continue for at least the first two weeks of the follow-up period.

[0207] Treatment compliance The investigator or designated study site personnel must ensure that all intranasal treatments are distributed and returned. A log of study medication and oral antidepressant medication was required to be maintained. Each subject's medication supply was recorded at the end of the study. The entire system was managed in a list format.

[0208] Subjects were instructed to comply with oral antidepressant treatment. Designated study site personnel will monitor any subject's compliance with oral antidepressants to ensure compliance. Serves as a source of additional instruction for retraining subjects.

[0209] Antidepressant treatment adherence during the screening / prospective observation period was assessed using the PAQ. If antidepressants were not taken for 4 or more days in the previous 2-week period, , was considered inadequate adherence.

[0210] Antidepressant treatment compliance during the double-blind induction period was assessed by pill counts (i.e., co-administration). This was assessed by conducting a compliance check and investigational drug management.

[0211] All doses of intranasal investigational drug are administered at the investigational site under the direct supervision of the investigator or designee. The test is self-administered by the subject and recorded.

[0212] Pilot studies and combination therapy Pre-study non-antidepressants administered for up to 30 days before the start of the screening / prospective observation period Therapy was recorded at the beginning of this period.

[0213] taken during the current depressive episode (i.e., screening / prospective observation) All treatments, including adjunctive treatments for MDD (including those taken more than 30 days before the start of treatment) All antidepressant treatment(s) were recorded at the start of the screening / prospective observation period. Four antidepressant options (i.e., duloxetine, escitalopram, and cetrialidomide) were compared. Also, information on any history of intolerance to either venlafaxine or venlafaxine XR Got it.

[0214] Concomitant medications were recorded throughout the study, starting with the signing of the informed consent form. Information on concomitant therapy was also included solely for the mitigation of events. Any new or worsening adverse events beyond this time were reported.

[0215] Subjects were taking permitted concomitant medications (e.g., antihypertensives) on their regular schedule. However, there were limitations and Table 6 below was taken into consideration. If oral antihypertensive drugs are taken in the morning, Note that the dose is taken on the day of intranasal administration.

[0216] Subjects receiving psychotropic therapy must have completed this therapy prior to the screening / prospective observation period. It has remained stable in frequency over the past 6 months and has not changed since completion of the double-blind induction period. They were able to continue receiving psychiatric treatment on the condition that they were not

[0217] All treatments other than the investigational drug (prescription or over-the-counter drugs, vaccines, vitamins, herbal nutrients) Non-pharmacological treatments such as nutritional supplements, psychotherapy, electrical stimulation, acupuncture, special diets, and exercise regimens Modification of existing effective treatments was not permitted unless permitted by the protocol. (e.g., blood pressure medication adjustments) for the express purpose of enrolling the subject in the study It shouldn't be.

[0218] Rescue medication Rescue medication was not provided by the sponsor. Treatment-emergent adverse events that were not resolved by discontinuing further administration of Sebo In such cases, the following rescue medications could be considered: For agitation or anxiety: Midazolam (maximum dose 2.5 mg orally or i.v.) as needed. M), or short-acting benzodiazepines For nausea: Ondansetron 8 mg sublingually, metoclopramide (10 mg sublingually) as needed g oral or IV or IM), or dimenhydrinate (25-50 mg IV or (or IM)

[0219] Transient increases in blood pressure are not treated because blood pressure typically returns to pre-dose levels within 2 hours It is recommended that any treatment be given with caution as it may result in hypotension.

[0220] Prohibited drugs A list of prohibited medications (not comprehensive) is provided as a general guide for investigators, The sponsor must notify in advance (or in writing) any instances in which prohibited therapies are administered. (as soon as possible thereafter)

[0221] [Table 6-1]

[0222] [Table 6-2]

[0223] The number of doses of intranasal study drug is summarized in Table 7 below.

[0224] [Table 7]

[0225] A summary of the mean, mode, and final doses of intranasal study drug is summarized in Table 8 below.

[0226] [Table 8]

[0227] On day 25 of the double-blind induction period, 66 of 99 (66 / 7%) subjects received the 84 mg The cysts of 115 subjects treated with intranasal esketamine were Of these, 11 (9.6%) subjects had their dose reduced during the double-blind phase. The duration of exposure to the antidepressant study medication was as summarized in Table 9 below.

[0228] [Table 9]

[0229] Test evaluation The time and event schedule is shown in Tables 10 and 11 below. K, biomarkers, pharmacogenomics, healthcare resource utilization, health economics, and other relevant Summarize the frequency and timing of available safety measurements.

[0230] [Table 10-1]

[0231] [Table 10-2]

[0232] [Table 10-3]

[0233] [Table 10-4]

[0234] [Table 11-1]

[0235] [Table 11-2]

[0236] With the exception of post-dose assessments, visit-specific subject-reported outcome assessments did not affect subject perception. performed or completed before any test, procedure, or other examination to prevent adverse effects A recommended test procedure sequence is provided. Actual evaluation dates and times will be determined by the source document. and recorded on the eCRF.

[0237] The approximate total blood volume drawn from each subject was 123.5 mL (see Table 12 below). For safety reasons or technical problems with the samples, repeat samples or Unscheduled samples could be collected. If required by local regulations, an additional serum or urine pregnancy test may be performed. Establish that the subject was not pregnant at any time during their participation in the study. I was able to do this.

[0238] [Table 12]

[0239] Screening / prospective observation period Before performing any study procedures, the investigator (or designated study personnel) must The ICF was reviewed and explained to each subject. After signing the ICF, subjects were asked to complete the ICF at the age of 18 (or when the study ended). 19 years or older (if the minimum legal age of consent in the country where the practice is held is >18 years) to 64 years old The following subjects were screened to determine eligibility for study participation:

[0240] Subjects were randomly assigned to a clinically assessed, MINI-confirmed, single-episode MD group. D (for single-episode MDD, duration was ≥ 2 years) or without psychotic features Patients were required to meet the DSM-5 diagnostic criteria for recurrent MDD. At the start of the prospective observation period, subjects were 30 Must have a total score ≥ 34 It must be.

[0241] At the start of this period, subjects were assessed and documented using the MGH-ATRQ. ≥ 2 episodes of current depressive episode confirmed by medical history and pharmacy / prescription records Subjects must have a history of non-response to ≤5 oral antidepressant treatments. were non-responsive and receiving oral antidepressant treatment at entry and had continued this treatment for the duration of this period. Patients were continued at the same dose for 24 hours and prospectively confirmed non-response. Treatment adherence was assessed. Patients were assessed by whether they had taken antidepressants for ≥4 days in the previous 2-week period. Failure to do so was considered inadequate adherence.

[0242] Used during the subject's current major depressive episode and current depressive episode Antidepressant treatment response to antidepressant therapy was confirmed using an independent institutional eligibility assessment. It was.

[0243] An independent blinded assessor performed remote MADRS assessments to assess depression during this period. The investigators and study sites were responsible for determining the response criteria for entry into the double-blind induction period. Eligible non-responders (by a remote blinded assessor) were blinded to the specific details of the study. (to be determined) current antidepressant(s) and any other prohibited psychotropic medications (adjuvant The patient was discontinued from any benzodiazepine or non-benzodiazepine sleep-wake medication (including antipsychotics). Sleep medication was allowed to continue, but with specific restrictions on administration time for intranasal treatment sessions. had.

[0244] All other subjects who did not proceed to the double-blind induction period terminated study participation at this time. No further study visits or follow-up were required.

[0245] Optional antidepressant tapering period All non-responder subjects were initiated on a new oral antidepressant during the double-blind induction period. Therefore, a drug-free or drug-free period is not necessary after discontinuing current antidepressant treatment. However, any additional period of up to 3 weeks may be permitted as per local prescribing information or clinical judgment. Following the diagnosis, patients were allowed to taper and discontinue their current oral antidepressants.

[0246] The tapering period will not begin until after completion of 4 weeks of prospective antidepressant treatment and assessment of antidepressant treatment response. It didn't start.

[0247] Double-blind induction period During this period, subjects received either esketamine (56 mg or 84 mg) or placebo. Double-blind intranasal treatment with 20 mg CI 6.25 or 6.4 ... In addition, subjects were concurrently started on a new open-label oral antidepressant.

[0248] Study subjects (with TRD) were randomly assigned to receive one of the following two treatments in a 1:1 ratio (approximately 98 per group): were randomly assigned to one of two double-blind treatment groups: 1. intranasal placebo or 2. Intranasal esketamine (56 mg or 84 mg). On the same day (i.e., day 1), Subjects were switched to a new open-label oral antidepressant treatment. Oral antidepressants (duloxetine, escitalopram, sertraline, or venlafaxine) XR). Antidepressants were (MGH-ATRQ and related previous anti-urinary assigned by the investigator (based on review of the patient's current medication information) In the last depressive episode, no prior non-response, no prior intolerance (lifetime), no participation Oral antidepressants were administered starting on day 1. The dose was titrated up to the maximum tolerated dose according to the local prescribing information for each product. The titration schedules for the selected oral antidepressants were as presented in Table 5 above. .

[0249] If the information was obtained by telephone, the call should be transcribed for review against the source document. During telephone contact with the subject by site personnel, adverse events were reported. Additionally, specific clinician dosing assessments were performed by appropriately qualified staff. This was carried out by the

[0250] At the end of the double-blind induction period, subjects who were responders (baseline [randomization on Day 1]) A ≥ 50% reduction in the MADRS total score from [pre-treatment] to the end of the 4-week double-blind induction period was defined as (defined as a phenotype of HIV-1 deficiency syndrome) will enter a subsequent maintenance clinical trial (Study ESKETINTRD3003). To maintain the blindness of the study, an active comparator (i.e., oral antidepressants + All responder subjects, including those responding to intranasal placebo, will be included in Study ESKETINT Participation in ESKETINTRD3003 is a dual The blinded induction period began immediately after completion of the blinded induction period. Subjects received oral antidepressants and were administered the following treatment at the next study visit (i.e., (i.e., the first study visit of the stabilization period in Study ESKETINTRD3003) He was instructed to continue taking his oral antidepressant.

[0251] Subjects who did not enter Study ESKETINTRD3003 continued into the follow-up period. is.

[0252] Early withdrawal If a subject withdraws before the end of the double-blind induction period for reasons other than withdrawal of consent, the subject will be considered for early withdrawal. The withdrawal visit occurred within one week of the discontinuation date, followed by the follow-up period. If an early withdrawal visit occurred on the same day as a follow-up visit, the early withdrawal visit was conducted on the same day and no overlapping assessments were made. No price was required.

[0253] Further clinical / standard care for the treatment of depression may be recommended by the investigator and / or the subject's treatment. The investigator and / or treating physician must ensure that the patient is continuing their current oral antidepressant medication. decided whether to continue or not.

[0254] If applicable, withdrawn subjects should receive additional oral antidepressants early and as clinically appropriate. Oral antibiotics were administered for at least the first 2 weeks of the follow-up period unless deemed necessary. It was recommended that he continue taking his antidepressant medication.

[0255] Follow-up period Receive at least one dose of intranasal study drug during the double-blind induction period and subsequently enter the next ESKETI All subjects not enrolled in the NTRD3003 study were included in the 24-week follow-up period. Clinic visits and remote assessment visits were scheduled as specified in the time and event schedule. During this period, the patient was monitored for potential withdrawal symptoms, including those after discontinuation of intranasal esketamine. Safety and tolerability were assessed first. Additionally, subjects' current major depression was assessed over a 6-month period. Data were collected to assess the course of sexual episodes.

[0256] Further clinical / standard care for the treatment of depression may be recommended by the investigator and / or the subject's treatment. Intranasal study medication was not administered during this period. To better assess these potential withdrawal symptoms, It is recommended that oral antidepressants be continued for at least the first 2 weeks of the follow-up period, provided The decision to continue antidepressants was at the discretion of the investigator.

[0257] If information is obtained by telephone, transcribe the call for review against the source document. The records were made available.

[0258] Any clinically significant abnormalities that persist at the end of the study should be treated until resolution or clinical stability is achieved. Patients were followed by the investigator until the predetermined endpoint was reached. Regardless of the severity of the adverse event, all adverse events and special reporting circumstances should be reported to the subject's last study-related procedure. The completion of the procedure was reported.

[0259] Efficacy assessment It was recommended that various subject-reported outcome assessments be completed before any other procedures.

[0260] Primary efficacy evaluation The primary efficacy outcome was the MADRS total score. The MADRS was administered independently during the study. It is a 10-item clinician-administered, clinician-rated scale administered by a remote rater. The MADRS measures the overall severity of depressive symptoms, including depression severity, and the effect of antidepressant treatment. It is designed to be used in subjects with MDD to detect changes due to The MADRS scale was validated as a primary measure to determine its effectiveness in major depression. The primary efficacy measure of this study was established, reliable, and acceptable to regulatory health authorities. It was used as.

[0261] The MADRS scale consists of 10 items, each rated from 0 (item absent or normal) to 6 (severe). The score is based on the severity of the condition (the presence of symptoms or the persistence of symptoms), with a total possible score of 60. A indicates more severe symptoms. The MADRS measures apparent sadness, reported sadness, and internal sadness. tension, sleep, appetite, concentration, fatigue, interest level, pessimistic thoughts, and thoughts of suicide Evaluate: The test exhibits high inter-rater reliability.

[0262] The primary efficacy endpoint was a double-blind randomized control group (P2000) from baseline (day 1 before randomization) to 4 weeks. The change in the MADRS total score by the end of the induction period was the outcome.

[0263] In this study, subjects in either of the two treatment groups who responded to the investigational drug (i.e., Responders) from baseline (day 1 before randomization) to the end of the 4-week double-blind induction period Subjects who met criteria for response, defined as a ≥ 50% reduction in the MADRS total score, were considered to be was defined as

[0264] In addition to being the primary efficacy measure, the MADRS also assessed the duration of the double-blind induction period. A significant side effect was the onset of clinical response (i.e., antidepressant effect) by day 2, which was maintained over time. The onset of clinical response was measured during the double-blind phase. The study continued until day 2 (i.e., the day after the first dose of double-blind intranasal medication was taken) was defined as a ≥ 50% improvement in the MADRS total score at

[0265] MADRS also assessed the response and remission of subjects at the end of a 4-week double-blind induction period. The proportion of subjects with a MADRS total score of ≤12 was assessed. The study was used to evaluate the secondary objective of

[0266] Key secondary efficacy assessments (clinician-completed) MADRS was a clinical response by day 2 that was maintained for the duration of the double-blind induction phase. A modified 24-hour recall period was used for the key secondary efficacy assessments related to the initiation of treatment. It was administered using

[0267] The MADRS with a 24-hour recall period was used on Day 2. This shortened recall period The feasibility of this has been confirmed by patients and physicians, and the psychological impact of this shortened recall period is There are data supporting its measurement properties. The MADRS with 7-day recall was used as a key secondary The MADRS was used for all subsequent assessments used for clinical efficacy evaluation (achieved on Day 2). maintenance of clinical response for the duration of the double-blind induction period.

[0268] Key secondary efficacy measures (patient-reported outcomes) The Patient Health Questionnaire (PHQ-9) assesses depressive symptoms. This is a nine-item subject-reported outcome measure used to measure cognitive decline. -5 Each of the nine symptom domains of the MDD criteria was scored and assessed using the screening tool and depression Each item was rated on a 4-point scale. (0 = never, 1 = several days, 2 = more than half the days, 3 = almost every day). Responses were added to provide a total score (ranging from 0 to 27), with higher scores indicating more severe depression. The recall period was 2 weeks.

[0269] The Sheehan Disability Scale (SDS) was used to assess functional impact and The secondary objective of related disability was assessed. The SDS is a subject-reported outcome measure and It is a five-item questionnaire that is widely used and accepted for the assessment of disability and related disorders. The first three items were rated on a 0-10 scale for (1) work / school; (2) social life; and (3) disruption of family life / family responsibilities. The scores for the first three items were added together to obtain A total score of 0 to 30 was created, with higher scores indicating greater impairment. There was also one item about days missed from school or work, and one item about days of low productivity. The recall period for this study was 7 days.

[0270] The Clinical Global Impression-Severity Scale (CGI-S) measures the subject's medical history, psychosocial status, symptoms, Consider all available information, including the impact of symptoms on behavior and the subject's ability to function. The present invention provides an overall clinician-determined summary measure of the subject's illness severity, entered into the The CGI-S assesses the severity of psychopathology on a scale of 0 to 7. Subjects were rated for the severity of their psychiatric illness at the time of assessment according to the following: 0 = not assessed; 1 = normal (not ill at all), 2 = borderline psychotic, 3 = mildly ill 4 = moderately ill, 5 = markedly ill, 6 = severely ill, 7 = very ill = the most severely ill patient. The CGI-S is a measure of the overall condition of a subject at a given time. This allows for objective evaluation.

[0271] Anxiety was assessed using the 7-item subject-report Generalized Anxiety Disorder 7-item Scale (GAD-7). Symptoms were measured as a secondary objective. The GAD-7 is a brief and validated measure of global anxiety. Each item was rated on a 4-point scale (0 = not at all, 1 = several days, 2 = more than half the days). Item responses were summed to obtain a total score ranging from 0 to 21. Higher scores indicated higher anxiety. The recall period was 2 weeks.

[0272] The Euro-Qol-5 Item-5 Level (EQ-5D-5L) was primarily self-completed by respondents. It is a standardized instrument for use as a measure of health outcomes designed for It is based on the EQ-5D-5L descriptor system and the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptor system consists of the following five items: mobility, care for daily activities, These include: reasoning, usual activities, pain / discomfort, and anxiety / depression. Each of the five items has a five-level scale. of perceived problems (level 1 indicates no problems, level 2 indicates slight problems, level Level 3 indicates moderate problems, level 4 indicates severe problems, and level 5 indicates extreme problems). It will be divided.

[0273] Subjects were asked to rate each of the five items based on the response that best matched their health "today." The participants selected the answer. A descriptive system was used to describe their health status. The EQ-VAS self-ratings were Respondents' own assessment of their health status at completion was recorded on a scale of 0 to 100.

[0274] Primary endpoint The primary efficacy endpoint was a double-blind randomized control group (P2000) from baseline (day 1 before randomization) to 4 weeks. The change in MADRS total score was measured by the change by the end of the induction period.

[0275] Primary endpoint results: Apply a serial gatekeeping (fixed order) approach to adjust the multiplicity and identify the main The efficacy endpoint and three key secondary efficacy endpoints (initiation of clinical response, The type I error for the change in SDS total score and the change in PHQ-9 total score was strongly predicted. Three key secondary endpoints were analyzed sequentially, with the endpoint being unilateral. were individually significant at the 0.025 level and were significantly associated with the preceding endpoint (primary endpoint) in the hierarchy. at the one-sided level of 0.025 only if the If the primary endpoint was statistically significant, the inclusion criteria were met. The selected secondary endpoints were the onset of clinical response, change in SDS total score, and PHQ- The results were evaluated in order of change in the total score of 9.

[0276] The primary efficacy endpoint was the MADRS total score from baseline to day 28. The change in MADRS total score ranged from 0 to 60. The primary efficacy analysis was The full analysis set was performed, which included at least one dose of intranasal study drug and one dose of All randomized subjects who received oral antidepressant study medication were included. As shown, the results for change in MADRS total score were significantly higher with oral AD + intranasal placebo than with placebo. The results also supported intranasal esketamine plus oral AD (Figure 2). Least-squares mean change from baseline in MADRS total score over time during the blinded phase ( Mean changes from baseline (SD) at day 28 were The mean mean age for the oral AD group was -21.4 (12.32) and for the active comparator group was -17.0 (1 The mean age was 3.88. ... Based on the MMRM model with the baseline value as a covariate, The least squares mean difference (SE) between tamponadone plus oral AD and the active comparator was -4.0 (1.69 The difference between the treatment groups was statistically significant (one-sided p=0.010). The analysis was considered the primary analysis for all non-EU dossiers.

[0277] Treatment, country, and oral antidepressant class were used as factors, and baseline value was used as a covariate. The change in MADRS total score from baseline to endpoint (DB) was calculated using the The results based on the ANCOVA model for esketamine + oral The least squares mean difference (SE) between AD and the active comparator was -3.5 (1.63), one-sided p = The result was 0.017.

[0278] [Table 13]

[0279] Secondary endpoints The first key secondary endpoint was subject-reported outcome using the PHQ-9 total score. Depressive symptoms from baseline (Day 1 before randomization) to the end of the 4-week double-blind induction period This was a change that continued until the end.

[0280] The second key secondary endpoint was maintained through the end of the 4-week double-blind induction period The proportion of subjects showing an onset of clinical response by Day 2. Onset of clinical response was at 4 weeks. The day after taking the first dose of double-blind study medication, which continued until the end of the double-blind induction period [Day 2] defined as a ≥ 50% reduction in the MADRS total score before the end of the double-blind induction period Subjects who discontinued the study after 2 weeks were not considered to have maintained a clinical response.

[0281] The third key secondary endpoint was baseline (day 1 before randomization) to 4 weeks The change in SDS total score was measured by the change in the SDS score by the end of the double-blind induction period. Ta.

[0282] Other secondary efficacy endpoints included: (a) response at the end of the 4-week double-blind induction period; (b) proportion of patients with a ≥ 50% reduction from baseline in MADRS total score; The proportion of subjects in remission (MADRS ≤ 12) at the end of the 1-week double-blind induction period, and (c) CGI-S, anxiety symptoms as measured by GAD-7, and EQ-5D-5L Benchmarking of depression severity using assessed health-related quality of life and health status Changes from baseline (day 1 before randomization) to the end of the 4-week double-blind induction period were included. Ta.

[0283] Secondary endpoint results Initiation of clinical response At each visit, subjects completed a MADRS score with onset by Day 2 maintained through Day 28. A clinical response was defined as at least a 50% improvement from baseline in the total score. Subjects were defined as having one deviation (non-response) on Day 8, Day 15, or Day 22. were allowed, but the score had to show at least a 25% improvement. Subjects who did not meet these criteria or who discontinued the study for any reason before Day 28 were Subjects were considered non-responders and assigned a value of "No" and did not meet the criteria for the initiation of a clinical response. It means that it was not done.

[0284] As shown in Table 14 below, 7.9% of subjects in the esketamine + oral AD group received the active drug A clinical response was achieved compared with 4.6% of subjects in the comparator group. The difference between the treatment groups was determined by a one-sided level of The mean mean of 0.025 was not statistically significant. Therefore, the significant secondary endpoints Based on a specific test sequence, the SDS total score and the PHQ-9 total score were formally calculated. could not be evaluated.

[0285] [Table 14]

[0286] Response and remission rates based on MADRS total score Response rate (≥50% improvement from baseline in MADRS total score) and remission rate (MADRS total score ≦12) are presented in Table 15 and Figures 3-5. there were.

[0287] [Table 15]

[0288] Sheehan Disability Scale (SDS) The SDS is a subject-reported outcome measure widely used to assess functional impairment and related disorders. It is a well-used and accepted five-item questionnaire. The first three items are rated from 0 to 10. Using the scale, we assessed the following areas: (1) work / school, (2) social life, and (3) family life / home responsibilities. Assess the collapse by adding the scores of the first three items to create a total score from 0 to 30. Higher scores indicate greater impairment.

[0289] As shown in Table 16 below, the results of the change in SDS total score were The study favored intranasal esketamine plus oral AD over placebo. The mean change from baseline was -13.3 (8.22) for esketamine + oral AD, For the drug comparator, the ratio was -9.5 (8.38). Treatment, day, country, oral antidepressant class, and MMRM using treatment per day as a factor and baseline value as a covariate. Based on the model, the least squares mean difference (SE) between esketamine plus oral AD and the active comparator ) was -3.6 (1.18). Based on the data, there were no statistically significant differences between the treatment groups in the onset of clinical response. The SDS total score could not be formally assessed. Nominal one-sided p-value = 0.001 .

[0290] Treatment, country, and oral antidepressant class factors, as well as baseline values, were used as covariates. Regarding the change in SDS total score from baseline to endpoint (DB), The results based on the ANCOVA model were consistent with the MMRM analysis.

[0291] [Table 16]

[0292] Patient Health Questionnaire - 9 items (PHQ-9) The PHQ-9 is a nine-item self-report scale assessing depressive symptoms. Each item is on a four-point scale. The frequency was rated (0 = not at all, 1 = several days, 2 = more than half the days, 3 = almost every day), and the total Scores range from 0 to 27. Higher scores indicate more severe depression.

[0293] As shown in Table 17 below, the results of the change in PHQ-9 total score were The study favored intranasal esketamine plus oral AD over placebo. The mean change from baseline (SD) for esketamine + oral AD was -12.8 (6.43); For the active comparator, the ratio was -10.2 (7.84). MMRM with ras and day of treatment as factors and baseline value as a covariate Based on the model, the least squares mean difference (SE) between esketamine plus oral AD and the active comparator ) was -2.2 (0.89). Based on the data, there were no statistically significant differences between the treatment groups in the onset of clinical response. PHQ-9 total score cannot be formally assessed. Nominal one-sided p-value = 0.006 .

[0294] Factors for treatment, country, and oral antidepressant class, with baseline as a covariate The PHQ-9 total score from baseline to endpoint (DB) using the values The results based on the ANCOVA model of change were consistent with the MMRM analysis (Appendix 3 (See

[0295] [Table 17]

[0296] Safety evaluation Any clinically relevant changes that occur during the study should be reported in the adverse events section of the eCRF. Any clinically significant abnormalities persisting at the end of the study / early withdrawal were recorded. Patients will be followed by the investigator until resolution or clinically stable endpoint is reached. The study was conducted at safety according to the time points provided in the time and event schedule. The following assessments of efficacy and tolerability were included:

[0297] Adverse events Adverse events will be reported to the subject (or, where appropriate, caregiver, surrogate, or Adverse events were reported by the investigator (or the subject's legally acceptable representative). TEAEs of special interest were examined separately.

[0298] Laboratory tests Blood samples for serum chemistry and hematology and urine samples for urinalysis were collected. The investigator will review the laboratory reports, document this review, and report any issues that arise during the study. Any clinically relevant changes were recorded in the adverse events section of the eCRF. The initiation of treatment or safety follow-up is time-critical. The results from the central laboratory must be received before administration is required to begin. It was not expected that the equipment would be available or measures had to be taken for safety reasons. If available, local laboratories were allowed to be used.

[0299] The following tests were performed by a central laboratory unless otherwise noted.

[0300] [Table 18]

[0301] [Table 19]

[0302] [Table 20]

[0303] The following tests were performed at the times specified in the time and event schedule. 1. Lipid panel: total cholesterol, low density lipoprotein n, LDL)-cholesterol, low density lipoprotein (HD) L)-cholesterol and triglycerides 2. Serum and urine pregnancy tests (for women of childbearing potential only) 3. Urine Drug Screening: Barbiturates, Methadone, Opiates, Cocaine, Cannabidiol Nabinoids (cannabinoids were tested only pre-dose on Day 1), phencyclidine , and amphetamine / methamphetamine 4. Alcohol breath test 5. Thyroid-stimulating hormone (TSH) 6. Glycated hemoglobin (HbA1c) test 7. Only when required to demonstrate that the female subject is not of childbearing potential Serum follicle-stimulating hormone (FSH) level test (referring to inclusion criterion No. 0)

[0304] Single 12-lead ECG During ECG collection, subjects were asked to sit quietly and without distractions (e.g., television, cell phone). Subjects should be in a comfortable environment and rest in a supine position for at least 5 minutes before ECG collection. and should refrain from talking or moving their arms or legs.

[0305] All ECG tracings were sent to a central ECG laboratory. ECGs were taken at the time of the study and summarized by a central ECG laboratory. The attending physician will conduct study visits to assess evidence of any potential safety concerns or exclusions. All ECGs were required to be reviewed during the study.

[0306] Vital signs (temperature, pulse / heart rate, respiratory rate, blood pressure) Blood pressure and pulse / heart rate measurements were assessed in the supine position using fully automated equipment. Manual techniques were used only when automated equipment was not available. Before blood pressure and pulse / heart rate measurements , in a quiet environment free of distractions (e.g., television, cell phone) for at least 5 minutes. I rested.

[0307] Tympanic temperature was recommended. Respiratory rate was measured using an automated device.

[0308] Pulse oximetry Arterial oxygen saturation was measured using pulse oximetry. The device is attached to a finger, toe, or ear before spraying, and then monitored and documented after the first spray. <93% lasted longer than 2 minutes and were confirmed by further manual measurements on another part of the body. Any change in arterial oxygen saturation (SpO2) was reported as an adverse event.

[0309] On the day of the intranasal treatment session, pulse oral administration was administered every 15 minutes from pre-dose until t = 1.5 hours post-dose. Cholesterol serotonin was measured at ≤93% at any time during the 1.5-hour post-dose interval. If so, continue treatment until recovery returns to ≥ 93% or until the subject is referred to appropriate medical care if clinically indicated. Pulse oximetry was performed every 5 minutes until the patient was seen.

[0310] Physical examination, height, weight, and neck circumference Physical examination, weight, and height were performed or measured per time and event schedule. Calculate body mass index (BMI) and neck circumference, information required for the STOP-Bang questionnaire. was measured as part of

[0311] Nose examination Nasal examination (including upper airway / throat) was performed by a certified medical practitioner. The purpose of testing in this study is to identify any anatomical or medical conditions that may interfere with drug delivery or absorption. Any subject with a history of steroid use was excluded.

[0312] Subsequent examinations include nasal erythema, rhinitis, rhinitis, capillary / vascular breakdown, and nasal bleeding. Consists of a visual inspection of the nasal mucosa, and pharynx, and graded as absent, mild, moderate, or severe. Any treatment-emergent change or deterioration from baseline was considered an adverse event. Recorded.

[0313] nasal symptom questionnaire Subjects completed a nasal symptom questionnaire to assess nasal tolerance after intranasal administration of the study drug. To assess the nasal symptoms, a nasal symptom questionnaire was developed. Subjects were asked to rate their condition as none, mild, moderate, or severe based on how they felt at the time of the assessment. was more highly rated.

[0314] C-SSRS The C-SSRS was administered to assess potential suicidal thoughts and behaviors. , to assess severity and track suicidal events throughout any treatment. The spectrum of suicidal ideation and behavior developed in a study of treatment for adolescent suicide attempters by the Institute of This is a low-burden scale for the Suicidality Test. Clinical trials that provide an overview of both suicidal thoughts and behaviors may be administered during an assessment or risk assessment. The C-SSRS is a comprehensive interview that can also be used during treatment to monitor clinical deterioration. It can be used.

[0315] This study included two versions of the C-SSRS: baseline and screening versions. John and Since Last Visit versions were used. The baseline / screening version of S was used during the screening / prospective observation period. This version assesses suicidal ideation at two time points: lifetime and within the past six months. ) and suicidal behavior was assessed at two time points ("lifetime" and "within the past year"). All subsequent C-SSRS assessments in the study will use the latest version since the last visit. Subjects were assessed for suicidal thoughts and behaviors since their last visit.

[0316] CADSS The CADSS is a tool for measuring current dissociative symptoms and assesses dissociative symptoms that occur during treatment. The CADSS consists of 23 subjective items and has three components: Depersonalization (items 3-7, 20, and 23), derealization (items 1, 2, 8-13, and 16) Participation can be divided into two categories: memory loss (items 14, 15, and 22). Subject responses were coded on a 5-point scale (0 = not at all to 4 = extremely). It has good inter-rater reliability and internal consistency.

[0317] BPRS+ Four items of the BPRS were administered to assess potential treatment-emergent psychotic symptoms. The BPRS is a measure of psychotic symptoms and mood, assessed both by subject observation and by subject self-report. It is an 18-item rating scale used to assess a range of affective symptoms. It provides rapid and efficient evaluation of therapeutic response in clinical drug trials and clinical settings. In this study, the four-item positive symptom subscale of the BPRS+ (i.e., suspiciousness, hallucinations, abnormal thought content) was used. Only the variances (i.e., variances in the variances, and conceptual confusion) were used, which are highly sensitive to change and are consistent with training and standard Good interrater reliability can be achieved using a simple interview procedure.

[0318] MOAA / S Using MOAA / S, the American Society of Anesthesiologists Sedation levels occurring during treatment correlated with the level of sedation defined by the ASA (Association of Sedatives and Sedatives) continuum. The MOAA / S score was calculated as follows: 0 = no response to pain stimuli (AS of general anesthesia); A continuum) ~5 = Responds easily to name spoken in normal tone (alertness, minimal (corresponding to the ASA continuum of sedation).

[0319] On each intranasal administration day, MOAA / S was administered every 15 minutes from before administration until t = +1.5 hours after administration. If the score was ≤3 at any time during the 1.5-hour post-dose interval, the study was discontinued. MOAA / S was performed every 5 min until the core reached 4 (at which point t = post-administration + 1 min). (Subjects may resume every 15 minutes for up to 1.5 hours after administration). If a subject did not have at least a score of 5 by the time the test was administered, the subject was further monitored. For subjects with a score of ≤3, the assessment was repeated every 15 minutes. The assessment was repeated every 5 minutes until the score returned to 5, or if clinically indicated. , subjects were referred to appropriate medical care.

[0320] CGADR The CGADR is used to measure the subject's current clinical status and is used to assess the The clinician's assessment of the subject's overall clinical condition was based on their readiness to undergo the procedure. considered ready to be released based on (e.g., sedation, blood pressure, and other adverse events) They answered "yes" or "no" to the question "Can you get it?"

[0321] On each day of intranasal administration, CGADR was performed 1 hour and 1.5 hours after administration. If the response is not "yes" at 5 hours, continue treatment until a "yes" response is achieved or until clinical If clinically indicated, repeat the assessment every 15 minutes until the subject is referred to appropriate medical care. Subjects were not released prior to the 1.5 hour time point. All intranasal treatment sessions On the injection day, the subject will remain in the clinical facility until study procedures are completed and the subject is ready for release. It remained in place.

[0322] PWC-20 Administer PWC-20 to assess potential withdrawal symptoms following cessation of intranasal esketamine treatment Assessments were performed on day 25 to determine baseline before discontinuing intranasal esketamine treatment. Clinically relevant methods have been established to better assess potential withdrawal symptoms from intranasal medications. Oral antidepressants should be administered for at least the first 2 weeks of the follow-up period unless otherwise determined. It was recommended to continue.

[0323] The PWC-20 is a 20-item questionnaire designed to assess the potential occurrence of discontinuation symptoms after cessation of investigational drug. The PWC-20 is a simple and accurate method for assessing discontinuation symptoms. Discontinuation symptoms occur early and are dependent on the rate of tapering, daily dose, and drug elimination. Depending on the half-life, it disappears rather quickly.

[0324] BPIC-SS BPIC-SS is a suitable bladder screening program for clinical trials evaluating new treatments for bladder pain syndrome. A subject-reported outcome measure developed to identify the bladder pain syndrome / interstitial cystitis population be.

[0325] Using the BPIC-SS, potential symptoms of cystitis, bladder pain, and interstitial cystitis were assessed. The BPIC-SS contains eight questions with a recall period of the past 7 days and measures bladder function. Symptoms of bladder pain and / or pressure, including urinary frequency, as reported by subjects with BPS Addressing identified important symptoms. Subjects responded to items using a 5-point scale (frequency For questions based on this, 0 = never, 1 = rarely, 2 = occasionally, 3 = most of the time, 4 = For items regarding always and symptom-related hassle, 0 = not at all, 1 = a little, 2 = Question 8 asks participants to rate their past 7 experiences using a 0-10 numeric rating scale. The number of days with the most severe bladder pain is recorded and the response option selected by the subject is recorded. The total score was calculated by adding the scores from the scale. A total score of 19 or greater demonstrates good sensitivity / specificity and indicates significant bladder symptoms. or was considered as a relevant cut-off for distinguishing from cystitis.

[0326] If any item was missing, a total score could not be calculated.

[0327] In the current study, subjects had a score >18 on the BPIC-SS scale and underwent urinalysis and microscopy. If there was no evidence of urinary tract infection based on the microscopic examination, the subject was referred to a specialist for further evaluation. Therefore, in addition to the urine test, the BPIC-SS score was used as an applicable test. If day was >18, a urine culture was obtained.

[0328] Cognitive testing: Computerized cognitive battery and HVLT-R The computerized cognitive battery measures multiple cognitive functions, including attention, visual learning, and memory. The test provides an assessment of domains of cognitive function, as well as executive function. Allows for use in multilingual / multicultural environments. Computerized battery: Includes. Simple reaction and choice reaction time tests, response speed was scored (log10 transformation of correct responses) average reaction time) Visual episodic memory, visual memory scored using the arcsine transformation of the percentage of correct responses Startup test Score working memory (n-back), correct response rate (log10 transformed response rate of correct responses) average over time) Executive function, maze / sequencing tests (scored for total number of errors)

[0329] All measures have been validated against traditional neuropsychological tests and are associated with alcohol and Sensitive to the effects of various drugs on cognitive performance, including benzodiazepines. Cognitive Battery Completion of the test takes approximately 25 minutes.

[0330] The HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. The administration consisted of three learning trials, a recognition list of 24 words (12 target words and 12 phonics words), and The trial included a 20-minute delayed recall trial (including a 'letter word'), and a 20-minute delayed recall trial. The instructions and word list appear on the screen. The tester scores each correctly recalled word. Vocabulary is recorded and learning, short-term and delayed recall are scored via testing software. The HVLT-R is a well-validated and widely used measure of verbal episodic memory. This is the scale that is used.

[0331] The tests were administered in the following order: HVLT-R, computerized cognitive test; Battery, and HVLT-R (delayed).

[0332] UPSIT and Odor Threshold Test Pre-test and test to assess any potential treatment-induced effects on smell perception. At designated time points during the study, olfactory function was qualitatively assessed using a validated standard olfactory test. The two tests administered were as follows:

[0333] The UPSIT assesses a subject's ability to identify odors. It is the most widely used This standardized test, derived from basic psychological test measurement theory, targets odorants at suprathreshold levels. The UPSIT focuses on the subject's ability to identify and compare. Each consisted of 10 children, located on the brown strip at the bottom of the booklet page. embedded in ~50 μm polymer microcapsules, 10 “scratch-and- The internal consistency and test-retest reliability coefficients for this instrument are > 0.90. Numerous studies have shown that this and related tests are effective against viruses, head trauma, and Subtle changes in olfactory function associated with multiple etiologies, including those resulting from various neurodegenerative diseases This indicates that they are sensitive to

[0334] The olfactory threshold test assesses olfactory threshold using an alternative single-step threshold procedure. The test was conducted on the rose-scented odorant phenyl ethyl alcohol (phenyl ethyl alcohol). This odorant has the property of stimulating the trigeminal nerve in the nose. This test is sensitive to olfactory impairment from a wide range of disorders. do.

[0335] These tests were administered bilaterally (i.e., both nostrils simultaneously). This was done during the screening / prospective observation period to establish the baseline sensitivity of the The magnitude of change from this baseline was determined over time. The conversion rate served as the dependent measure for each subject for each test.

[0336] MINI Subjects will have a diagnosis of MDD confirmed and whether other psychiatric conditions are present. To do this, they underwent a MINI (Mini Structured Diagnostic Interview), which was conducted at approximately It has a 15 minute administration time.

[0337] MGH-ATRQ The MGH-ATRQ was used to determine treatment resistance in MDD. The duration and dose of all antidepressants used for the current major depressive episode were Furthermore, the MGH-ATRQ was evaluated on a scale ranging from 0% (no improvement) to 100%. The MGH-ATRQ is evaluated by a clinician on a scale of % (completely improved) to % (completely improved). It was completed in collaboration with the body.

[0338] STOP-Bang Questionnaire The STOP-Bang questionnaire is used to evaluate obstructive sleep apnea (OS). A) is a simple, easy-to-use, validated and sensitive screening tool for The questionnaire has eight items that address important risk factors for obstructive sleep apnea: Snoring, tiredness, observed breathlessness during sleep ing interruption during sleep, high blood pressure, body mass index ass index, age, neck size, and gender. STOP- The Bang questionnaire does not specify a recall period. Subjects were asked to report snoring, fatigue, and observed breathing patterns. Respond yes or no to questions about stopping and high blood pressure (these are (This is the "STOP" item in the NG acronym.) This takes approximately one minute.

[0339] Test facility staff were asked to 2 age (over 50?) ), neck circumference (greater than 17 inches [43 cm] for men or 16 inches [41 cm] for women) cm?), and gender (male?) were answered yes or no.

[0340] STOP-BANG is scored by adding up the number of positive responses and obtaining a score range of 0 to 8. A total score was calculated. A STOP-Bang score of ≥ 5 was associated with moderate obstructive sleep apnea. indicates moderate to severe risk (apnea-hypopnea index >30).

[0341] Independent qualification of the facility An independent psychiatrist / psychologist will be present at all times to confirm the diagnosis of depression and eligibility for testing. All subjects were independently interviewed by telephone during the screening / prospective observation period. A qualification assessment was performed.

[0342] IDS-C 30 30 items IDS-C 30 is designed to assess the severity of depressive symptoms. The DS assesses all criteria symptom domains specified by the DSM-5 to identify major depression. These assessments can be used to screen for depression. Although these are available, they are primarily used as a measure of symptom severity. is the usual time frame for assessing symptom severity. 30 Psychometric properties of has been established in a variety of test samples.

[0343] Massachusetts General Hospital Female Reproductive Cycle and Ho Lemon Questionnaire (MGH-Female RLHQ): Module I and Menstrual Cycle Tracking MGH-Female RLHQ Module I (fertility, menopausal status, and menstrual cycle) A concise approach aimed at standardizing the minimum collection of relevant information on reproductive hormones and conditions. This is a questionnaire completed by a clinician. This information is used to assess the progress of treatment for MDD. We will promote exploratory analyses of the effects of endogenous and exogenous reproductive hormones on MDD in the future. This could potentially inform the care of women who

[0344] Menstrual cycle tracking (start date of last menstrual period) specified in time and event schedule The study visits were documented at the scheduled visits.

[0345] PAQ Subjects to their oral antidepressant treatment regimen during the screening / prospective observation period Adherence to anticoagulant therapy was assessed using the PAQ, which measures how frequently subjects take anticoagulant therapy. Subjects were on a depressant treatment regimen or had not been on an antidepressant treatment regimen in the past 2 weeks. to assess whether any changes in intent were made. It is a brief, two-item, subject-reported outcome measure developed in the center. The total score is , calculated by adding the response choices for questions 1c–1f (0 = adherence adherence, ≥1 = non-adherence).

[0346] Sample collection and handling The exact date and time of sample collection was recorded on the eCRF or laboratory requisition form. If blood samples were taken via an indwelling cannula, the blood sample should be taken before each blood sample was taken. At this time, remove an appropriate amount of serous fluid (1 mL) from the cannula, slightly more than the free capacity of the lock. After blood samples were taken, the cannula was reconstituted with 0.9% sodium chloride, USP (United States Pharmacopeia, USP) (or equivalent) to flush and unlock Filled to volume.

[0347] Subject Completion / Withdrawal completion Subjects were randomized to MADRS at the end of the 4-week double-blind induction period (i.e., Day 28 MADRS). The double-blind induction phase of the study was considered complete if the DRS assessment was completed. Subjects who prematurely discontinue study treatment for any reason before completion of the induction period will be considered for inclusion in the study. Subjects who entered the follow-up period were not considered to have completed the double-blind induction period. Completion of the MADRS assessment at week 24 of the follow-up period constituted completion of this phase of the study. It was considered.

[0348] Withdrawal from the study Subjects were withdrawn from the study for any of the following reasons: 1. Untraceable 2. Withdrawal of consent 3. Violation of protocol procedures (determined on a case-by-case basis) 4. The blind was broken (double-blind induction period) 5. Lack of effectiveness 6. The investigator or sponsor has provided a rationale for safety or tolerability (e.g., adverse events) It was considered to be in the subject's best interest to discontinue the study (for any reason). 7. The subject becomes pregnant 8. The trial was terminated by the sponsor due to futility 9.Death

[0349] If a subject is lost to follow-up, the subject will be contacted to determine the reason for discontinuation / withdrawal. , all reasonable efforts were made by test facility personnel.

[0350] If a subject withdrew before completing the study, the reason for withdrawal was documented. The investigational drug assigned to the subject was not assigned to another subject. If a patient withdraws from the study before the end of the double-blind induction period for any reason other than a medical condition, the early withdrawal visit will be considered a discontinuation. The study was conducted within one week of the date of the study and followed by a follow-up period.

[0351] Safety analysis Safety data were analyzed for the double-blind induction period using the safety analysis set.

[0352] Adverse events Verbatim terms used by investigators in eCRFs to identify adverse events All reported cases with onset during the double-blind induction period were coded using MedDRA. Adverse events reported (i.e., TEAEs and adverse events that worsened since baseline) were analyzed. For each adverse event, the proportion of subjects experiencing at least one occurrence of a given event was included. Rates were summarized by treatment group. Adverse events occurring during the follow-up period were summarized separately.

[0353] TEAEs of special interest were examined separately. AEs of special interest were listed in the SAP There were no deaths, discontinuation of treatment due to adverse events, or severe or serious adverse events. Subjects who experienced adverse events were summarized separately.

[0354] Clinical Laboratory Testing Laboratory data were summarized by type of laboratory test. Reference ranges and significantly abnormal results (specified in the statistical analysis plan) were used to summarize the laboratory data. Descriptive statistics were performed for each laboratory analyte at baseline and each scheduled time point. Calculated. Changes from baseline results were presented. A summary of the frequency of abnormalities was provided. A list of subjects with out-of-range laboratory results and significantly abnormal results was provided.

[0355] ECG Effects on cardiovascular variables were assessed by descriptive statistics and frequency summaries. These tables are , including observed values ​​and changes from baseline values.

[0356] Electrocardiogram data were summarized by ECG parameters. Descriptive statistics were calculated at baseline. Observed values ​​and changes from baseline were calculated at each scheduled time point. was carried out.

[0357] Use the following correction methods: QT corrected according to the Bazett formula (QTcB) and QTcF The ECG variables analyzed were heart rate, PR interval, QRS interval, QT interval, and QTc interval. It was a long distance.

[0358] Descriptive statistics of QTc interval and change from double-blind baseline were obtained at each scheduled time point. The baseline was <30 msec, 30-60 msec, or >60 msec. The proportion of subjects with QTc interval >450 msec, >480 msec, as well as the proportion of subjects with QTc interval increase The percentage of subjects with a mean mean ≥500 msec or >500 msec was summarized.

[0359] Report any significant abnormalities in the ECG waveform that changed from the baseline reading. (e.g., changes in T wave morphology or the occurrence of U waves).

[0360] Vital signs Body temperature, pulse / heart rate, respiratory rate, pulse oximetry, and blood pressure (systolic and diastolic) Descriptive statistics of (supine) values, as well as changes from baseline, were summarized at each scheduled time point. The proportion of subjects with values ​​above clinically important limits was summarized.

[0361] Nose examination Changes in findings from baseline nasal examination (including upper airway / pharynx) were listed by treatment group. Examination will be performed on the nostrils, nasal mucosa for nasal erythema, rhinitis, rhinitis, capillary / vascular breakdown, and nosebleeds. and provided a rating (absent, mild, moderate, or severe) based on visual inspection of the pharynx. Shift tables for changes from double-blind baseline in study assessments are presented by treatment group. did.

[0362] nasal symptom questionnaire Scores from the nasal symptom questionnaire were summarized descriptively by treatment group for each scheduled time point. .

[0363] C-SSRS Suicidal thoughts and behaviors based on the C-SSRS were summarized in incidence and shift tables by treatment group. Separate endpoints for suicidal ideation and behavior were defined and described by treatment group. Missing scores were not imputed.

[0364] CADSS, BPRS+, and MOAA / S Descriptive statistics and change from pre-dose for each score were summarized at each scheduled time point.

[0365] Clinical Global Assessment of Readiness for Release, PWC-20, BPIC-SS, UPSIT, and Odor Threshold Value Test Descriptive statistics for each score, as well as the change and / or percent change from baseline, were analyzed in a planned Each time point was summarized.

[0366] Cognitive testing Descriptive statistics and changes from baseline in cognitive domain scores were collected at each scheduled time point. We agreed.

[0367] Definitions and classification of adverse events Adverse events are those that occur in clinical trial subjects who receive a drug (investigational or non-investigational). Adverse events are any untoward medical occurrence that does not necessarily have a causal relationship with treatment. Therefore, adverse events are not defined as events that occur due to the effects of a drug (investigational or non-investigational drug). Any undesirable or unintended symptoms (including abnormal findings) temporally related to use It can be a medical condition, symptom, or disease, and can be a drug (investigational or non-investigational) (Pharmaceutical Regulatory Agency). International Conference on Harmon This includes new developments, regardless of whether they are related to the definition in accordance with the ICH standard. any episode that is a worsening in severity or frequency from the baseline condition, or abnormal results of diagnostic procedures, including abnormal laboratory tests.

[0368] ICH and EU Guidelines for Pharmaceutical Safety and Health Monitoring for Human Use Based on the Guidelines on Pharmacovigilance for Medicinal Products for Human Use A serious adverse event is any untoward medical occurrence regardless of dose: Deadly Life-threatening (e.g., the subject was at risk of death at the time of the event. "Life-threatening" does not refer to events that, if more severe, could have resulted in death. do not have.) -Requires hospitalization or extension of current hospitalization period Anything that results in permanent or serious damage / disability ·Congenital anomalies / birth defects - Suspected transmission of any infectious agent via a medicine - Medically important * * Immediately life-threatening or potentially endangering the subject without resulting in death or hospitalization or intervention to prevent one of the other consequences listed in the definition above. Determine whether it is appropriate in other circumstances, such as serious medical events, where intervention may be necessary. Medical and scientific judgment should be exercised in determining whether or not a person is seriously ill. It should be considered.

[0369] Evidence suggesting a causal relationship between the investigational drug and the event (e.g., death due to anaphylaxis) If a serious and unexpected adverse event occurs, which constitutes a study endpoint, The event is serious, unexpected, and suspected to be serious, even if it is a component (e.g., all-cause mortality). reported as an adverse reaction.

[0370] If the nature or severity is inconsistent with the applicable product standard safety information, the adverse event will be listed. For esketamine, the expected value of adverse events is The standard is determined by whether it is listed in the Standard Safety Information section of the nurse's pamphlet. Ta.

[0371] For duloxetine, escitalopram, sertraline, and venlafaxine XR For drugs, the expected value of adverse events can be determined based on whether they are listed in the SmPC or US prescribing information. It has been decided.

[0372] Attribution is considered probable, probable, or likely according to the definitions of attribution listed below. If very high, the adverse event is considered to be related to the use of the drug. Unrelated: Adverse events not related to drug use. Doubtful: An adverse event for which an alternative explanation is more likely, e.g., concomitant medication(s) , comorbidity(ies), or time relationship suggests that a causal relationship is unlikely. Possible: Adverse events that can be attributed to the use of the drug. Alternative explanations, e.g., concomitant medications (multiple The comorbidity(ies) is / are not determinative. The time relationship is reasonable, therefore, A causal relationship could not be ruled out. High probability: Adverse event that can be attributed to drug use. The time relationship was suggestive (e.g. (Confirmed by discontinuation of medication, if applicable). Alternative explanations, e.g., concomitant medication(s) , comorbidity(ies) were less likely. Likely: Listed as a possible adverse reaction and alternative explanations, e.g., concomitant medications (multiple Adverse events that could not be reasonably explained by a comorbidity or complications. The relationship between the two was highly suggestive (e.g., confirmed by interrupting and restarting the drug). ).

[0373] Severity grade assessment was performed using the following general categorical descriptors: Mild: Symptoms that are easily tolerated, cause minimal discomfort, and do not interfere with daily activities. Knowledge. Moderate: Sufficient discomfort was present to cause interference with usual activities. Severe: Extreme distress causing significant impairment or disability of function. Normal daily activities are hindered. To be harmed.

[0374] The investigator may assess the severity of events not directly experienced by the subject (e.g., laboratory abnormalities). Clinical judgment was used in assessing.

[0375] Special Reporting Situations Safety of interest to sponsor investigational products that may require expedited reporting and / or safety evaluation Serious events include, but are not limited to: Overdose of investigational drug by the sponsor Suspected abuse / misuse of sponsor's investigational drug Inadvertent or accidental exposure to the sponsor's investigational drug Medication errors involving sponsor drug products (involving subject / patient exposure to sponsor investigational drug products) (with or without, e.g., name confusion)

[0376] Special reporting circumstances were recorded on the eCRF. Any special reporting circumstances that met the criteria for a serious adverse event were recorded on the eCRF. Reporting status was recorded on the serious adverse event page of the eCRF.

[0377] Procedure: All adverse events All adverse events, whether serious or non-serious, and special reporting circumstances The subject's last study-related procedure from the time the signed and dated ICF was obtained. The study drug was reported until completion of the procedure (which may include contact for safety follow-up). Serious adverse events, including those spontaneously reported to the investigator, within 30 days after the last dose Serious adverse events were reported using the serious adverse event form. Any safety information spontaneously reported by investigators beyond the timeframes specified will be evaluated. It was worth it.

[0378] All events that meet the definition of a serious adverse event are considered to be protocol-specific. These events were reported as serious adverse events, regardless of whether they occurred or not. He declared.

[0379] All adverse events, regardless of seriousness, severity, or presumed relationship to the investigational drug, Whenever possible, medical terms were recorded on the source document and eCRF using medical terminology. A diagnosis was given when the signs and symptoms were attributable to a common etiology (e.g., Cough, runny nose, sneezing, sore throat, and headache are reported as "upper respiratory tract infection." The investigator recorded their opinion regarding the relationship of the adverse event to the study treatment in the eCRF. All measurements required for adverse event management were recorded and reported in source documents.

[0380] The sponsor was responsible for appropriate reporting of adverse events to regulatory authorities.

[0381] In all studies with an outpatient phase, including open-label studies, subjects were required to You will be provided with a "Card" to carry for the duration of the exam that indicates: was instructed. Exam number A statement in the local language(s) that the subject is participating in a clinical trial Investigator's name and 24-hour contact number Name of local sponsor and 24-hour contact number (for medical staff only) Facility number Target number Any other information necessary to perform emergency unblinding

[0382] Serious adverse events All serious adverse events occurring during the study should be reported to the study physician within 24 hours of recognition of the event. The appropriate sponsor contact person was notified by the site personnel.

[0383] Not resolved by the end of the study or resolved at the time of discontinuation of the subject's participation in the study All serious adverse events not associated with the treatment were followed until one of the following occurred: The event was alleviated The event stabilized If baseline values / conditions are available, the event has returned to baseline The event could be attributed to a drug other than the investigational drug or to factors unrelated to the study. - The likelihood of obtaining any additional information was reduced (subject or healthcare professional was unable to obtain additional information) Refuses to provide information and is unable to follow up after due diligence in follow-up efforts It became a Noh play).

[0384] Suspected transmission of infectious agents by medicinal products was reported as a serious adverse event. Any event requiring hospitalization (or prolonged hospitalization) occurring during the course of a subject's participation in the study The following were reported as serious adverse events, with the exception of hospitalization: Hospitalizations not intended to treat acute illnesses or adverse events (e.g., in long-term care facilities) (social reasons such as waiting for placement) Surgery or procedures planned prior to study entry (must be documented on the eCRF) ) The hospitalization was planned before the signing of the ICF and the underlying condition for which the hospitalization was planned had worsened. If no adverse events were observed, they were not considered serious adverse events. Any adverse events that occurred were to be reported as new serious adverse events.

[0385] For convenience, investigators may choose to hospitalize subjects for the duration of the treatment period. I was able to choose.

[0386] The cause of death of a subject in the study was either expected or related to the investigational drug. were considered serious adverse events regardless of whether they occurred or not.

[0387] pregnancy The first report of any pregnancy must be made using the appropriate pregnancy notification form to notify the doctor of their knowledge of the event. Abnormal pregnancy outcomes were to be reported to the sponsor by study site personnel within 24 hours. Pregnancy outcomes (e.g., spontaneous abortion, stillbirth, and congenital anomalies) are considered serious adverse events and Adverse events were to be reported using the appropriate adverse event form. Any subject who became pregnant during the study The patient was promptly withdrawn from the study and discontinued further study treatment.

[0388] The effects of the investigational drug on sperm are unknown, so the partners of male subjects included in the study Pregnancy in must be reported within 24 hours of becoming aware of the event using the appropriate pregnancy notification form. This will be reported by the test facility personnel.

[0389] Follow-up information on the outcome of the pregnancy and any postnatal complications for the infant is also needed. there were.

[0390] Summary of all adverse events A complete summary of all treatment-emergent adverse events (TEAEs) during the double-blind phase is shown in Table 18. Overall, 84.3% of subjects in the esketamine + oral AD group and the active comparator 60.6% of subjects in the group experienced at least one TEAE during the double-blind phase.

[0391] [Table 21]

[0392] Figure 6 shows the baseline and end-point scores determined by the individual items of the EQ-5D-%L. The percentage of subjects reporting a problem at each point is shown.

[0393] Treatment-emergent events occurring during the double-blind period (≥ 5% of subjects in either treatment group) Adverse events observed are summarized by treatment group for the safety analyses shown in Table 19 below. The most common (≥20%) TEAEs in the esketamine + oral AD group during the study period were adverse events. cardiac (26.1%), vertigo (26.1%), taste disturbance (24.3%), and dizziness (20.9%). The most common TEAE in the active comparator group was headache (17. 4%).

[0394] [Table 22]

[0395] Adverse events leading to withdrawal from the study drug Nine subjects discontinued the double-blind induction phase intranasal study drug due to treatment-emergent adverse events. There were 8 subjects in the esketamine + oral AD group and 1 active comparator (Table 20). A double-blind induction-phase oral antidepressant study was discontinued due to an adverse event that occurred during the study. There were 4 subjects in the esketamine + oral AD group (Table 21). Three subjects discontinued the double-blind phase due to both intranasal and oral AD medications (Table 20 and 21).

[0396] [Table 23]

[0397] [Table 24]

[0398] Serious adverse events Two subjects experienced serious treatment-emergent adverse events during the double-blind phase. One subject in the comparator group experienced postural vertigo, which was not associated with intranasal placebo and intravenous administration. There was a suspected relationship to both oral AD and esketamine. One subject suffered multiple injuries resulting from a motorcycle accident (subsequent formal data (The patient died after base lock.) This event was not related to esketamine and was not associated with oral AD. were considered to have a suspicious relationship.

[0399] One subject in the esketamine + oral AD group experienced a 83-minute period after the last intranasal dose of esketamine. During the follow-up period, the patient experienced a cerebral hemorrhage, which was suspected to be due to esketamine. were considered relevant and not related to oral AD.

[0400] blood pressure In the esketamine group, the transient increase in blood pressure peaked approximately 40 minutes after administration and decreased to 90 minutes after administration. The maximum mean increase in systolic BP (across all treatment days) was The mean score was 11.6 in the sketamine + oral AD group and 5.0 in the active comparator group. The maximum mean increase in diastolic BP (across all dosing days) was 8.5 in the esketamine group. 0.1 in the active comparator group and 4.5 in the active comparator group. Figures 7 and 8 show the treatment-related changes during the double-blind phase. The mean blood pressures measured over time by group are shown.

[0401] Clinician-Rated Dissociative Symptoms Scale (CADSS) The Clinician-Administered Assessment of Dissociative State Scale (CADSS) was administered before the start of each dose, 40 minutes after administration, and 1 minute after administration. The CADSS was measured at 0.5 hours. It assessed dissociative symptoms and perceptual changes that occurred during treatment. The total score ranges from 0 to 92, with higher scores indicating more severe symptoms. Dissociative symptoms and perceptual changes measured by the CADSS are indicative of these symptoms. The symptoms began soon after the start of administration and subsided by 1.5 hours after administration (as shown in Figure 9). This suggests that...

[0402] Modified Observer Assessment of Arousal / Sedation (MOAA / S) The modified observer's assessment of alertness / sedation (MOAA / S) was used, and the American Society of Anesthesiologists ( Measure sedation occurring during treatment in correlation with sedation levels defined by the ASA (American Sedation Association) continuum The MOAA / S score was 0 (no response to pain stimulation, ASA association for general anesthesia). (corresponding to the conjunctive form) ~ 5 (immediate response to name spoken in a normal tone [arousal], minimal calming) The range was measured by MOAA / S (corresponding to the ASA continuum for static loads). Sedation was observed by 1.5 hours post-dose (as shown in Figure 10). is doing.

[0403] Pharmacokinetics At the time points specified in the time and event schedule, esketamine, norethinib, Approximately 2 mL of ketamine was used for measurement of plasma concentrations of ketamine and other metabolites (if warranted). Venous blood samples were taken and the exact date and time of PK blood sampling was recorded.

[0404] Plasma samples were analyzed to identify specific Achiral and highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS / MS) ) was used to determine the concentrations of esketamine (and, where warranted, noresketamine). If necessary, some plasma samples will be analyzed to compare others using certified laboratory methods. The presence of analytes (e.g., circulating metabolites or denatonium) was documented. Additionally, plasma PK samples were Samples could be stored for future analysis of metabolite profiles.

[0405] Pharmacokinetic parameters Plasma concentration-time data for esketamine (and, where appropriate, noresketamine) were collected from the population. The basic PK parameters (e.g., esketamine) were analyzed using group PK modeling. Typical population values ​​for clearance (volume of distribution) were estimated along with inter-individual variability. Investigate the effect of subject demographics, laboratory parameter values, and other covariates on the PK of the drug did.

[0406] Pharmacokinetic / pharmacodynamic evaluation MADRS total score (and in some cases, selected additional PD parameters) The relationship between adverse events (AEs) and PK metrics of esketamine was evaluated. If there were any visual trends in the analysis, the model was selected as a suitable model to explain the exposure-effect relationship. Dell was applied.

[0407] Biomarker, pharmacogenomic (DNA), and expression (RNA) assessment Biomarker assessments will be performed over the course of the study at time points indicated in the time and event schedule. Blood was drawn for biomarker blood samples collected prior to dosing. A low-fat diet was preferred on the day of sample collection.

[0408] In the blood, immune system activity, hypothalamic pituitary adrenal (HPA) axis activation, neurotrophic factors, and Biomarkers related to, but not limited to, metabolic factors (proteins, metabolic The total blood volume collected was not increased. Biomarkers were added or removed based on scientific information or technological innovations.

[0409] Blood samples for DNA analysis were analyzed to identify pathways related to depression (e.g., HPA axis, inflammation) genes in genes involved in circadian rhythms (e.g., growth factors, monoamine transporters, ion channels, and circadian rhythms) For the evaluation of genetic and epigenetic variations, a time and event schedule is provided. Genotyping was performed on screening samples only. Biomics and epigenetic assessments were performed on any / all collected samples. It was possible to carry out the project.

[0410] DNA samples were used for research related to esketamine, oral antidepressants, TRD, or MDD. They were also used in the treatment of esketamine, oral antidepressants, TRD, or MDD-related disorders. Pharmacogenomics research could also be used to develop tests / assays for One or more of the following clinical endpoints: ketamine, oral antidepressants, TRD, or MDD analysis of candidate genes or (if necessary) genome-wide genetic markers was composed.

[0411] Medical resource utilization Consultation-related health resource utilization data were collected during the follow-up phase of the study. Protocol-defined procedures, tests, and visits were excluded. Exploratory economic analyses can be conducted to assess (a) the number and duration of medical visits, including surgeries, and and other selected procedures (inpatient and outpatient), (b) length of stay (ward (e.g., intensive care unit) (c) the number and characteristics of diagnostic and therapeutic tests and procedures; and / or (d) outpatient medical visits and treatments (doctor or emergency room visits, tests, and (including medical devices and treatments, as well as drugs).

[0412] Pharmacokinetic analysis Plasma esketamine (and, where appropriate, noresketamine) concentrations were measured for all subjects. Plasma concentration-time data for esketamine (and, where appropriate, noresketamine) were The data were analyzed using population PK modeling. The data supported the relevant structural model. Data from other selected studies may be combined to support the basic Typical population values ​​of PK parameters were estimated along with inter-individual variability. PK of esketamine The effects of subject demographics, laboratory parameter values, and other covariates on CI were investigated.

[0413] Pharmacokinetic / pharmacodynamic analysis MADRS total score (and in some cases, selected additional PD parameters) The relationship between adverse events (AEs) and PK metrics of esketamine was evaluated. If there were any visual trends in the analysis, the model was selected as a suitable model to explain the exposure-effect relationship. Dell was applied.

[0414] Biomarker and Pharmacogenomic Analysis Baseline biomarker values, and time to event from baseline biomarker values Changes were summarized up to the time points specified in the schedule. Exploratory analyses were performed to examine the differences between treatment groups. Comparison of biomarker measurements, correlation with baseline, and efficacy and other measures Further exploratory analyses may also include changes from baseline biomarker values. , baseline, and the relationship between change from baseline to clinical response in biomarker measurements These may include: relationship, maintained / stabilized response, relapse, and non-response.

[0415] Pharmacogenomic analysis also provides insight into treatment response, maintained / stabilized response, relapse, non-response, and MD. This may include candidate gene analysis or genome-wide association analysis for D / TRD. The current analysis included known messenger RNAs associated with antidepressant treatment response and MDD / TRD. A / microRNA (mRNA / miRNA) transcript examination or transcriptome It may also include a wide analysis.

[0416] Statistical methods used in the analysis A general description of the statistical methods used to analyze efficacy and safety data is provided below. At the end of the double-blind induction period, the database will be compiled for analysis and reporting of this period. Subject treatment assignment was only known to sponsor study staff. The investigator and the patient must remain in the study until all subjects have completed their participation in the follow-up period. Site personnel were blinded to treatment allocation.

[0417] The primary efficacy and safety analysis populations were as follows: Full analysis population: Patients who received at least one dose of intranasal study drug and All randomized subjects received one dose of oral antidepressant. Safety analysis population: Patients who received at least one dose of intranasal study drug or All randomized subjects received one dose of oral antidepressant.

[0418] The maximum sample size planned for this study was 1.0 mg / kg / day. The double-blind induction treatment difference in MADRS total score was 6.5 points, with a standard deviation of 12. The calculation was performed assuming a 2-sided significance level of 0.0125 and a dropout rate of 25%. subjects were randomized to each treatment group to achieve a 90% success rate using a fixed design with no interim analyses. The treatment difference and standard deviation used in this calculation are This was based on the results of Panel A of the INTRD2003 trial and clinical judgment.

[0419] Interim analysis for sample size re-estimation or stopping for futility One open-label interim analysis was conducted 4 weeks after randomization of 66 subjects in the study. At that time, the full analysis set was Approximately 50 subjects in the study were expected to complete the double-blind induction phase (treatment). (Approximately 25 subjects per treatment group). Dropout rates will be monitored to ensure a sufficient number of subjects are included. The purpose of the interim analysis was to re-estimate the sample size. The trial was either stopped due to futility or discontinued due to futility. is adjusted to achieve the desired power while maintaining control of the overall Type I error The maximum planned sample size for this study was 98 per treatment group. there were.

[0420] Based on the preliminary data and how the analysis was performed, the approach for sample size re-estimation A rigorous preliminary statistical analysis plan (SA) detailing the algorithms used The IDMC conducted an interim analysis and defined the interim SAP. Recommendations for any sample size adjustments were made based on the established rules. Any changes to the data should be reported to the IDMC (or a statistician from the statistical support group) Communicated with WRS vendor to ensure adequate number of subjects were enrolled in the study. Any esketamine team member or staff member at the investigational site where the study was conducted , the results of the interim analysis, and any adjustments made to the sample size. I couldn't.

[0421] Ensure that the results of the interim analysis will not affect the conduct of the study, investigators, or subjects Procedures were established to do so.

[0422] Efficacy analysis The efficacy analysis was performed in the full analysis set, which included a small number of patients in the double-blind induction period. All randomized participants received at least one dose of intranasal study drug and one dose of oral antidepressant study drug. The study included subjects who had been

[0423] The primary efficacy variable was the MADRS total score at week 4 of the double-blind induction period. Changes from baseline in CI were analyzed using MMRM. Models included CI as a covariate. Baseline MADRS total score, as well as treatment, country, and antidepressant class as fixed effects. The interaction between treatment (SNRI or SSRI), day, and treatment per day, as well as randomization The study included a subject effect: esketamine + oral antidepressant vs. oral antidepressant + intranasal placebo. Comparisons with were performed using appropriate contrasts.

[0424] For the EU dossier, the primary efficacy analysis used last observation carried forward (LOCF) data. The model was based on an analysis of covariance (ANCOVA) model. , and a factor for oral antidepressant class (SNRI or SSRI) as covariates. The baseline MADRS total score and esketamine + oral antidepressant arthritis were included. Comparisons of the drug with intranasal placebo plus oral antidepressants were performed using appropriate contrasts.

[0425] Subject to regulatory acceptance of the PHQ-9 as a key secondary endpoint The first of three key secondary efficacy endpoints was the fourth week of the double-blind induction period. The change from baseline in the PHQ-9 total score was compared with the MADRS total score. were analyzed using the same model as above.

[0426] For the analysis of the second key secondary efficacy endpoint, esketamine plus oral antidepressant Clinical outcomes up to Day 2 were maintained for the duration of the double-blind induction period in the drug arm. The proportion of subjects showing an onset of floor response was compared by country and antidepressant class (SNRI or SSRI). Oral antidepressants using the Cochran-Mantel-Haenszel chi-squared test adjusting for Clinical responses were compared with the drug plus intranasal placebo arm. Clinical responses were assessed by a 2-day follow-up period that continued until the end of the double-blind phase. MADRS total score by the first day (i.e., the day after taking the first dose of double-blind intranasal medication) Defined as ≥ 50% impro...

Claims

1. 1. A method of treating treatment-resistant depression in a patient, said method comprising: administering to said patient a therapeutically effective amount of an oral antidepressant; A therapeutically effective amount of esketamine is administered at least twice weekly during an induction period of at least 4 weeks. administering the compound intranasally to said patient; A therapeutically effective amount of esketamine is administered intranasally to the patient up to once weekly during a subsequent maintenance phase. providing the The method has been clinically proven safe and has been clinically proven effective. The way it is done.

2. 10. The method of claim 1, wherein the esketamine is administered once every two weeks during the subsequent maintenance phase. The method described.

3. 3. The method of claim 1 or 2, wherein the administration frequency can be adjusted during the induction and / or maintenance phases. The method described.

4. The therapeutically effective amount of esketamine administered during the induction period is from about 28 mg to about 84 mg. The method according to any one of claims 1 to 3, wherein

5. 5. The method of claim 4, wherein the therapeutically effective amount of esketamine is about 28 mg.

6. 5. The method of claim 4, wherein the therapeutically effective amount of esketamine is about 56 mg.

7. 5. The method of claim 4, wherein the therapeutically effective amount of esketamine is about 84 mg.

8. the therapeutically effective amount of esketamine is about 56 mg at the start of the induction period; 5. The method of claim 4, wherein the dose is adjusted to about 84 mg during the period.

9. 6. The method of claim 5, wherein the patient is 65 years of age or older.

10. The therapeutically effective amount of esketamine administered during the maintenance phase is about 56 mg or about 84 mg.

2. The method of claim 1, wherein the amount of the hydroxybenzoate is 1 mg.

11. The therapeutically effective amount of esketamine during the induction and maintenance periods is delivered from an intranasal administration device in a 2- to 3-well tube. The method of any one of claims 1 to 10, wherein the method is delivered in one or more sprays.

12. The method according to any one of claims 1 to 11, wherein the treatment lasts for at least 6 months. Law.

13. 13. The method of any one of claims 1 to 12, wherein the treatment continues for up to one year.

14. 13. The method of any one of claims 1 to 12, wherein the treatment continues for up to two years.

15. 1. A pharmaceutical product comprising one or more intranasal spray devices, said one or more devices comprising: and wherein the one or more devices administer from about 28 to about 84 mg of esketamine. and wherein the pharmaceutical product is clinically safe for treating major depressive disorder. and / or have been clinically proven to be effective. Product.

16. 16. The pharmaceutical product of claim 15, wherein the major depressive disorder is treatment-resistant depression.

17. 17. The pharmaceutical product of claim 15 or 16, wherein the product comprises a device.

18. wherein the device is configured to administer the esketamine in two or more sprays.

18. The pharmaceutical product of claim 17.

19. 19. The pharmaceutical product of claim 17 or 18, wherein the device contains about 28 mg of esketamine. 。

20. The article of manufacture includes two or more devices, each device containing about 28 mg of esketamine.

16. The pharmaceutical product of claim 15.

21. 21. The pharmaceutical product of claim 20, wherein each device is a single-use device.

22. 22. The pharmaceutical product of claim 21, comprising three devices.

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