Esketamine for treatment of depression

Abstract

To provide an effective, long-term and safe treatment in patients diagnosed as having treatment-refractory or treatment-resistant depression.SOLUTION: The present invention provides methods for treating depression in a patient, comprising administering to the patient in need of the treatment a therapeutically effective amount of esketamine. In some embodiments, combination therapy with at least one antidepressant is applied. Examples of the depression include major depressive disorder or treatment resistant depression. Also provided are methods to mitigate the risk or misuse or abuse of esketamine, instructions for use of the esketamine products, and methods for selling a drug product containing esketamine.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 / 813,767, filed March 5, 2019, and U.S. Provisional Patent Application No. 2019 / 02 / 016644. This application claims the benefit of application Ser. No. 62 / 814,274, filed March 5, 2019. , the disclosures of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention is directed to pharmaceutical products and methods for the treatment of depression (e.g., major depressive disorder). In some embodiments, the method is useful for treating treatment-refractory or treatment-resistant depression. In another embodiment, the method is useful for treating suicidal ideation. It has been clinically proven safe as a treatment option or as a combination therapy with at least one antidepressant. The method comprises administering a therapeutically effective amount of esketamine to a patient in need of treatment.

[0003] BACKGROUND OF THE INVENTION 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 are unable to perform basic self-care tasks such as bathing or eating, or to take care of themselves. This is not only a problem for the patient themselves, but also for the family. It also affects the family and those who depend on them. They are also unable to do things they previously enjoyed. This is because people lose the ability to feel joy in anything and everything, which takes away from them the essence and motivation of life. In effect, their life is taken away from them by TRD. These effects are , which 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. This 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

[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

[0008] (Summary of the Invention) 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. , the present invention is further directed to a method.

[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 patients in need of treatment with a clinically proven safe and therapeutically effective dose of esketamine. monoamine oxidase inhibitors (MAOIs), e.g. Irreversible MAOIs (phenezine, tranylcypromine), reversible MAOIs (MOAIs) moclobe Imipramine, amitriptyline, desipramine, nortriptyline, doxorubicin, etc. Tricyclics such as rifapril, protriptyline, trimipramine, clomipramine, and amoxapine tetracyclics such as maprotiline; acyclics such as nomifensine; triazoline such as trazodone anticholinergics, such as scopolamine; fluoxetine, sertraline serotonin reuptake inhibitors such as paroxetine, citalopram, and fluvoxamine; Serotonin receptor antagonists such as fazadone and tianeptine; venlafaxine, Serotonin-receptor drugs such as desvenlafaxine, milnacipran, and levomilnacipran noradrenergic reuptake inhibitors; specific noradrenergic drugs such as mirtazapine Serotonergic agents; norepinephrine reuptake inhibitors such as reboxetine; bupropion atypical antipsychotics such as steroids; lithium, triple reuptake inhibitors, cyclosporine, cyclosporine, cyclosporine, cyclosporine Natural products such as St. John's wort; dietary supplements such as s-adenosylmethionine; and and neuropeptides such as thyrotropin-releasing hormone; neurokinin receptor antagonists compounds that target neuropeptide receptors, such as agonists; and compounds such as triiodothyronine and administering the compound in combination with one or more compounds selected from the group consisting of any of the hormones include.

[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; Serotonin reuptake inhibitor; serotonin receptor antagonist; serotonin norepinephrine Serotonin noradrenergic reuptake inhibitors; Serotonin noradrenergic reuptake inhibitors; Adrenergic and specific serotonergic agents; noradrenaline reuptake inhibitors ;Atypical antipsychotics;Natural products;Nutraceuticals;Neuropeptides;Neuropeptide receptor targeting and a compound targeted to the treatment of rheumatoid arthritis; ... 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 and other neuropeptides; neurokinin receptors Compounds that target neuropeptide receptors, such as antagonists; and triiodothyronine 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.

[0025] The present invention also provides a method for treating depression, comprising administering to a subject with depression esketamine and administering an approved drug product containing the compound in the amount prescribed in the drug product labeling of the approved drug product. Target methods.

[0026] The present invention provides a method for marketing an approved drug product containing esketamine, the method comprising: and marketing such formulations, including the reference list drug product label for treating depression. Further covered are methods including instructions.

[0027] The present invention also provides a method of offering for sale a formulation containing esketamine, the method comprising: the drug product label for a reference list drug for depression; The present invention is directed to a method for treating a rheumatoid arthritis, including instructions for treating the rheumatoid arthritis.

[0028] The present invention provides an approved drug product having at least one approved indication, comprising Esqueta The present application also covers approved formulations containing phenytoin.

[0029] The present invention also provides methods of using the approved products described herein, including the steps of: the article of manufacture includes one or more intranasal spray devices, the one or more devices containing esketamine; One or more devices are configured to administer about 28 to about 84 mg of esketamine. , methods are targeted.

[0030] The present invention provides a method for reducing the risk of esketamine misuse or abuse, comprising administering an approved esketamine-containing This includes restricting the distribution of sketamine preparations to selected dealers, who must comply with the drug trade regulations. is registered with the U.S. Food and Drug Administration and is authorized to distribute approved esketamine products only to pre-approved care facilities. The present invention is further directed to a method. [Brief explanation of the drawings]

[0031] [Figure 1] FIG. 1 is a schematic diagram of the study design for the ESKETINTRD3002 Phase 3 clinical trial. [Figure 2] Figure 1 shows 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 run-in phase. LS means and SE were based on MMRM with change from baseline as the response variable and fixed-effect model terms for treatment (intranasal esketamine + oral AD, oral AD + 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] Bar graphs showing the percentage of subjects reporting problems (levels 2-5) with mobility, self-care, activity, pain, and anxiety / depression. [Figure 7] FIG. 1 shows the arithmetic mean (±SE) of systolic blood pressure over time during the double-blind run-in period using the safety analysis set. [Figure 8] FIG. 1 shows the arithmetic mean (±SE) of diastolic blood pressure over time during the double-blind run-in period using the safety analysis set. [Figure 9] FIG. 1 shows the clinician-assessed dissociative symptom scale (CADSS) total score over time during the double-blind phase using the safety population. [Figure 10] FIG. 1 shows the arithmetic mean (±SE) of modified observer's assessment of alertness / sedation (MOAA / S) scores over time during the double-blind run-in phase using the safety analysis set. [Figure 11] FIG. 1 shows least squares mean change in MADRS total score over time (observed cases) in US patients with TRD. [Figure 12] FIG. 1 shows patient-rated depression severity (observed cases) in US patients with TRD as assessed by the PHQ-9. [Figure 13]FIG. 1 shows functional disability (observed cases) in US patients with TRD as assessed by the Sheehan Disability Scale (SDS). [Figure 14] FIG. 1 shows the percentage of US patients with TRD who achieved a response 4 weeks after the first dose (observed cases). [Figure 15] FIG. 1 shows the percentage of US patients with TRD who achieved clinician-rated remission 4 weeks after first dose. [Figure 16] FIG. 1 shows frequency distribution of PHQ-9 severity categories in US patients with TRD (observed cases). [Figure 17] FIG. 1 shows the proportion of US patients with TRD (observed cases) who had a ≧1-point decrease in the CGI-S 4 weeks after first dose. [Figure 18] 1 shows a schematic diagram of the study design for the ESKETINTRD3005 Phase 3 clinical trial. [Figure 19] FIG. 1 shows the least squares mean change (±SE) in MADRS total score over time for observed case MMRM (double-blind run-in phase (Study ESKETINTRD3005: full analysis set)). [Figure 20] FIG. 1 shows arithmetic mean (±SE) systolic blood pressure over time during the double-blind run-in period using the ESKETINTRD3005 safety analysis population. [Figure 21] FIG. 1 shows arithmetic mean (±SE) diastolic blood pressure over time during the double-blind run-in 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]Figure 1 shows least squares mean change (±SE) in MADRS total score from last observation carried forward (LOCF) analysis of covariance (ANCOVA) over time during the double-blind run-in phase using the full analysis set. LS means and SE were based on an 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] Forest plot of MADRS total score showing least squares mean treatment difference in change in MMRM from baseline (95% confidence interval) to day 28 by subgroup during the double-blind run-in phase using the full analysis set. Subgroups with fewer than five subjects are not presented. Results are not adjusted for sample size reestimation. [Figure 25] Figure 1 shows the arithmetic mean change (±SE) in MADRS total score over time for cases observed for the 65-74 age group during the double-blind run-in phase using the full analysis set. [Figure 26] Figure 1 shows the arithmetic mean change (±SE) in MADRS total score over time for cases observed for the ≥ 75 year old group during the double-blind run-in phase using the full analysis set. [Figure 27]Figure 1 shows the least squares mean change (±SE) in MADRS total score over time for Stage 1 (observed cases) MMRM during the double-blind run-in phase using the full analysis set. 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] Figure 1 shows the least squares mean change (±SE) in MADRS total score over time for Stage 2 (observed cases) MMRM during the double-blind run-in phase using the full analysis set. Smeans 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 old with TRD. MADRS total score ranges from 0 to 60. Higher scores indicate more severe disease. [Figure 30] Figure 1 shows the frequency distribution of illness severity based on CGI-S scores at baseline and double-blind endpoint (LOCF). 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]1 shows the proportion of US patients ≥ 65 years old with TRD who achieved a response (observed cases) as assessed by the MADRS. Clinician-rated response a was defined as a ≥ 50% reduction from baseline in the MADRS total score. [Figure 32] Figure 1 shows the proportion of US patients aged >65 years with TRD who achieved remission (observed cases) as assessed by MADRS. Clinician-rated remission was defined as a MADRS total score <12. [Figure 33] FIG. 1 shows the proportion of US patients aged >65 years with TRD who achieved patient-rated remission (observed cases) as assessed by the PHQ-9. [Figure 34] FIG. 1 shows the proportion of US patients aged >65 years with TRD who had a clinically meaningful response as assessed by the CGI-S. [Figure 35] 1 shows the proportion 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 phase endpoint. [Figure 37] FIG. 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 to be at imminent risk of suicide. [Figure 38] Figure 1 shows the 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] Figure 1 shows the mean change (SE) in CGJSR from baseline to 4 and 24 hours. Mean changes and SEs are based on ranks of the change from baseline (LOCF) data and were analyzed using an ANCOVA model with treatment, analysis center, and SoC as fixed effects and baseline value (unranked as a covariate). [Figure 40] FIG. 1 correlates the proportion of patients with remission of suicide risk at 4 and 24 hours. [Figure 41] Figure 1 shows the frequency distribution of SIBAT scores at double-blind baseline, Day 1: 4 hours post-dose, double-blind endpoint, and follow-up endpoint. The clinical global judgment of suicide risk scores ranges from 0 to 6. 0: No suicidal tendencies. 1: Occasional suicidal ideation present, but no specific intervention required. 2: Some degree of definite suicidal ideation 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] FIG. 1 shows least squares mean change (SE) in MADRS scores from baseline to 4 hours (primary endpoint) and to about 24 hours. [Figure 43] FIG. 10 correlates the proportion of patients with MADRS response and remission at Day 1, Day 2, and endpoint, respectively. [Figure 44] FIG. 10 correlates the proportion of patients with remission at DB endpoint and during follow-up. [Figure 45] FIG. 1 shows least squares mean change (±SE) from baseline in BSS total score over time during the double-blind phase using last observation carried forward data. [Figure 46]FIG. 1 shows mean blood pressure over time by treatment group during the double-blind phase. [Figure 47] FIG. 1 shows 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] FIG. 1 shows the cumulative proportion of subjects who remained relapse-free; maintenance phase (Kaplan-Meier estimate) (full (stable remitters) analysis population) of Example 4. [Figure 52] FIG. 1 shows the cumulative proportion of subjects who remained relapse-free; maintenance phase (Kaplan-Meier estimate) (maximum (stable responder) analysis population) of Example 4. [Figure 53] FIG. 1 shows arithmetic mean (±SE) systolic blood pressure over time; Maintenance Phase (Safety (MA) Analysis Population) of Example 4. [Figure 54] FIG. 1 shows arithmetic mean (±SE) diastolic blood pressure over time; maintenance phase (safety (MA) analysis population) of Example 4. [Figure 55] FIG. 1 shows the arithmetic mean (±SE) CADSS total score over time; Maintenance Phase (Safety (MA) Analysis Population) of Example 4. [Figure 56] Figure 4 is a forest plot of hazard ratios by subgroup for Example 4: Cox regression (full (stable remission) analysis population). Hazard ratio estimates for subgroups with no events in either arm are not shown. Subgroups with fewer than 5 subjects are not presented. [Figure 57] Study design for Example 5. At the time of study entry, enrolled non-responder subjects continued to receive the same oral antidepressant medication that was initiated in the ESKETINTRD3005 study. New oral antidepressants were only available to direct enrollment subjects. [Figure 58]FIG. 10 is a diagram showing the frequency distribution of CGI-S in Example 5. [Figure 59] FIG. 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] FIG. 1 shows the EQ-5D-5L disability level by measuring anxiety / depression, usual activities, and pain / discomfort, respectively. [Figure 61] FIG. 1 shows the EQ-5D-5L disability level by measuring anxiety / depression, usual activities, and pain / discomfort, respectively. [Figure 62] FIG. 1 shows the EQ-5D-5L disability level by measuring anxiety / depression, usual activities, and pain / discomfort, respectively. [Figure 63] Figure 1 shows arithmetic mean (±SE) systolic blood pressure over time. Lead-in and optimization / maintenance phases of Example 5 (all enrolled analysis population). [Figure 64] Figure 1 shows arithmetic mean (±SE) diastolic blood pressure over time. Lead-in 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 lead-in and optimization / maintenance phases of Example 5 (all enrolled analysis populations). [Figure 67] FIG. 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] FIG. 1 shows the response of patients with a response of ≧50% reduction from baseline and remission of MADRS≦12. [Figure 69] FIG. 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. The activity changes induced by MK-801 are described in section 3.3 of Example 6. Gross pathology did not reveal any tissue changes. [Figure 71A]

[0023] Figure 1 shows a repeat-dose neurotoxicity study. Retrosplenial cortex stained with hematoxylin-eosin (HE) shows 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.

[0024] Figure 1 shows an image of the retrosplenial cortex of a rat treated with esketamine HCl (54 mg / day) showing the absence of neuronal necrosis. [Figure 71B]

[0023] Figure 1 shows a repeat-dose neurotoxicity study. Retrosplenial cortex stained with hematoxylin-eosin (HE) shows 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.

[0024] Figure 1 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]

[0023] Figure 1 shows a repeat-dose neurotoxicity study. Retrosplenial cortex stained with hematoxylin-eosin (HE) shows 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. High-power view images of necrotic neurons (arrows) in the retrosplenial cortex from animals treated with (+)MK-801 maleate. [Figure 72A]

[0023] Figure 1 shows a repeat-dose neurotoxicity study. Retrosplenial cortex stained with Fluoro-Jade (FJ) shows 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.

[0024] Figure 1 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] Figure 1 shows a repeat-dose neurotoxicity study. Retrosplenial cortex stained with Fluoro-Jade (FJ) shows 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. Images of the retrosplenial cortex from animals treated with (+)MK-801 maleate are shown. [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 74A] 7 is a line graph 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 Design section and are shown on the vertical axis of Figure 73. BL indicates baseline, and 2 hours is 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 74B]7 is a line graph 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 Design section and are shown on the vertical axis of Figure 73. BL indicates baseline, and 2 hours is 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 Figure 73. BL indicates baseline and error bars are SE. [Figure 76A] 1 is a line graph showing the mean (±SE) MADRS total score over time during the double-blind period 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 76B] 1 is a line graph showing the mean (±SE) MADRS total score over time during the double-blind period 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 throughout 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] Figures 1A-1C show Cmax vs. dose and AUClast vs. dose, respectively, for the data of Example 10. Regression lines shown for Cmax (r=0.53) and AUClast (r=0.70). [Figure 82B] Figures 1A-1C show Cmax vs. dose and AUClast vs. dose, respectively, for the data of Example 10. Regression lines shown for Cmax (r=0.53) and AUClast (r=0.70). [Figure 83A] 1 is a set of instructions for use of an exemplary nasal spray device. [Figure 83B] 1 is a set of instructions for use of an exemplary nasal spray device. [Figure 83C] 1 is a set of instructions for use of an exemplary nasal spray device. [Figure 83D] 1 is a set of instructions for use of an exemplary nasal spray device. [Figure 83E] 1 is a set of instructions for use of an exemplary nasal spray device. [Figure 84] FIG. 1 is a flow diagram of approved esketamine formulations through a possible healthcare system.

[0032] DETAILED DESCRIPTION OF THE INVENTION 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.

[0033] 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.

[0034] 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.

[0035] 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 baseline measurements. In some embodiments, the treatment continues for at least about 1 year. For example, the duration may be at least about 18 months, or at least about 2 years. Phase treatment may range in duration from about 6 months to about 2 years. Treatment may also be administered by the attending physician. These include, but are not limited to, 4, 5, 6, 7, 8, 9, 10 years or more, as determined by the In some embodiments, the esophagus may be extended for an indefinite period of time. Ketamine is initially administered twice weekly for up to 4 weeks during the induction phase, and then less frequently than twice weekly. It is administered infrequently.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] In other embodiments, esketamine may be used as monotherapy, such as during the induction phase. It may not be used in combination with any other active compound.

[0040] 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.

[0041] As used herein, unless otherwise specified, the term "esketamine" refers to ketamine. means the (S)-enantiomer, i.e. the compound of formula (I),

[0042] [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),

[0043] [ka] (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride Also known as

[0044] In some embodiments, esketamine is the (R)-enantiomer of ketamine, i.e., That is, it is substantially free of the compound of formula (III).

[0045] [ka]

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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).

[0050] 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 100 mg / mL citric acid is administered. Esketamine is delivered intranasally using a nasal spray pump, which is submerged in water for 4 hours. At a pH of 0.5, 161.4 mg / mL of esketamine hydrochloride (140 mg / mL of esketamine (equivalent to ethanol base), 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and Deliver 100 μL of a solution containing 1.5 mg / mL citric acid.

[0051] Generally, one pump from a nasal spray device delivers about 50 μL to about 200 μL (about 60 μL, approx. 70 μL, approx. 80 μL, approx. 90 μL, approx. 100 μL, approx. 110 μL, approx. 120 μL L, approx. 130 μL, approx. 140 μL, approx. 150 μL, approx. 160 μL, approx. 170 μL, approx. 18 0 μL, and about 200 μL) of esketamine solution into the nostrils of a subject. Therefore, the two pumps may deliver about 100 μL to about 400 μL to the target. Reach.

[0052] 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 a pulmonary artery disease. 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).

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] As used herein, "suicidal ideation" refers to thoughts about or an inclination to commit suicide. obsession with ending one's own life or not wanting to live any longer but not necessarily wanting to commit suicide Suicidal ideation ranges from transient thoughts to thoughts that do not involve any active attempts to kill someone. Progression from simple to chronic and detailed planning, role-playing, and failed attempts These vary widely and can be intentionally constructed to fail or be discovered. In some embodiments, the patient may be fully intended to cause death or death. "Suicidality" is defined as when a person has a mean baseline MADRS total score of approximately 38 or higher. In other embodiments, the patient is classified as having an average baseline risk of 22 or more. In a further embodiment, a subject is classified as suicidal when the subject has a BBSS score of Patients have a score of 6 or higher on the SIBAT Clinical Global Assessment of Suicide Risk In yet other embodiments, a patient is classified as suicidal when these scores are met. It has one or more combinations of the above.

[0059] 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 are administered by any suitable means. Esketamine is administered in a regimen with 1 to 5 antidepressants. Esketamine may be administered in a regimen with one, two, three, four, or five antidepressants. In another embodiment, esketamine is administered in a regimen with one or two antidepressants. In a further embodiment, esketamine is administered in combination with an antidepressant currently administered to the patient. In another embodiment, esketamine is administered in a regimen that includes a different antidepressant. In yet a further embodiment, esketamine is administered in a regimen previously administered to the patient. In yet another embodiment, the esophageal ulcer is administered in a regimen with an antidepressant not prescribed. Esketami is administered in a regimen with the antidepressant previously administered to the patient. When the steroid and antidepressant are administered in separate dosage forms, the daily dosage for each compound is The number of doses may be the same or different, more typically different. It may be administered as prescribed by and / or according to its label, The drug is administered as described herein. Typically, the patient is taking an antidepressant and an esophageal squamous cell carcinoma (ESC). ketamine, both of which are administered at their prescribed dosing regimens. It is administered by

[0060] The esketamine and the antidepressant may be administered via the same or different routes of administration. Examples of suitable methods of administration include oral, intravenous (iv), intranasal (in), intramuscular (im) These include, but are not limited to, subcutaneous (sc), transdermal, buccal, and rectal. In some embodiments, esketamine is administered intranasally. Unless otherwise specified, the term "antidepressant" refers to any medical drug that can be used to treat depression. Suitable examples include monoamine oxidase inhibitors, tricyclic , serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, These include noradrenergic and specific serotonergic drugs, or atypical antipsychotics. Other examples include, but are not limited to, phenelzine, tranylcypromine, mogamulizumab, and thiazolinone. Monoamine oxidase inhibitors such as clobemide; imipramine, amitriptyline, Cipramine, nortriptyline, doxepin, protriptyline, trimipramine, cloprid Tricyclics such as mipramine and amoxapine; tetracyclics such as maprotiline; nomifensine any acyclic; triazolopyridines such as trazodone; fluoxetine, sertraline, Cialopram, escitalopram, fluvoxamine, etc. Serotonin reuptake inhibitors; serotonin receptor antagonists such as nefazadone; Lafaxine, Milnacipran, Desvenlafaxine, Duloxetine Levomilnacipran serotonin-norepinephrine reuptake inhibitors such as oran; noradrenaline such as mirtazapine Renarinergic and specific serotonergic drugs; reboxetine, edivoxetine, etc. adrenaline reuptake inhibitors; atypical antipsychotics such as bupropion; , natural products such as St. John's wort; nutritional supplements such as s-adenosylmethionine; and thyrotropin-releasing hormone; neuropeptides such as neurokinin receptor antagonists Compounds that target neuropeptide receptors, such as agonists; and triiodothyronine, etc. In some embodiments, antidepressants include, but are not limited to, the hormones are imipramine, amitriptyline, desipramine, nortriptyline, doxepin, Protriptyline, trimipramine, maprotiline, amoxapine, trazodone, buprenorphine clopidogrel, clomipramine, fluoxetine, duloxetine, escitalopram, sita Lopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine Synth, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromide , moclobemide, kava kava, St. John's wort, s-adenosylmethionine, Thyroid hormone-releasing hormone, neurokinin receptor antagonist, or triiodothyronine Preferably, the antidepressant is fluoxetine, imipramine, or bupropion. , venlafaxine, and sertraline.

[0061] Antidepressants (e.g., monoamine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors) , serotonin noradrenergic reuptake inhibitor, noradrenergic specific serotonergic agents, noradrenaline reuptake inhibitors, natural products, dietary supplements, Neuropeptides, compounds targeting neuropeptide receptors, hormones, and Therapeutically effective amounts / dosage levels and dosing regimens of pharmaceuticals can be readily determined by those skilled in the art. For example, the therapeutic doses and regimens for pharmaceuticals approved for marketing may be Publicly available information, such as packaging labels, standard dosing guidelines, Physicia n's Desk Reference(Medical Economics Com (website or online at http: / / / www.pdrel.com) These are listed in standard medication references or other sources.

[0062] 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), divalproate (mood stabilizer) etc.

[0063] 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.

[0064] 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.

[0065] 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

[0066] "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.

[0067] 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) for the purpose of treating a disease, condition, or disorder. and the management and care of animals, more preferably humans, including the prevention of the onset of symptoms or complications, ... administration of a compound of the present invention for the alleviation of symptoms or complications, or for the elimination of the disease, condition, or disorder. This includes administration.

[0068] 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.

[0069] 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 induction and maintenance phases 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.

[0070] 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) means that there is no reasonable benefit / risk when used in the manner of this invention. Corresponding to the ratio.

[0071] 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 has been proven to have no excessive side effects and meets the standards of approval of the U.S. Food and Drug Administration. or statistically significant clinical trials sufficient to satisfy similar studies for market authorization by the EMEA. For example, esketamine is available in 28 mg and 56 mg doses. mg, or 84 mg (±25%), administered flexibly intranasally and in a therapeutically effective dose as described herein. As part of a dosing regimen including induction and maintenance phases as described above and as specifically described in the Examples. As described above, coadministration with newly started or currently started oral antidepressants When administered intravenously, it has clinically proven beneficial effects on the treatment of patients with major depressive disorder, e.g., treatment-resistant depression. has been proven to be safe.

[0072] As used herein, the term "therapeutically effective amount" refers to the amount of a substance administered by a researcher, veterinarian, physician, or other clinical the tissue, organ, or system, including the relief of symptoms of the disease or disorder being treated, as sought by a physician. It means the amount of an active compound or pharmaceutical agent that elicits a biological or pharmaceutical response in a subject or human. Desirably, a therapeutically effective amount is a dose that has been proven clinically safe and is clinically effective. In some embodiments, the antidepressant is administered in an amount that has been proven effective by a doctor. In another embodiment, esketamine is utilized in a therapeutically effective amount determined by It is used in quantity.

[0073] The therapeutically effective amount of esketamine and / or an antidepressant, as described herein, may be used to treat an initial In some embodiments, a therapeutically effective amount of escalation may be administered during the post-operative period. In another embodiment, the therapeutically effective amount of esketamine is about 20 to about 100 mg. In a further embodiment, the therapeutically effective amount of esketamine is about 30 to about 90 mg. In yet another embodiment, the therapeutically effective amount of esketamine is about 14 to about 80 mg. , 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 4 1, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 , 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 8 1, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 In a further embodiment, the therapeutic dose is 95, 96, 97, 98, 99, or 100 mg. The effective amount is about 28 mg, about 56 mg, or about 84 mg. In yet a further embodiment, the therapeutically effective amount of esophageal cancer is about 56 mg or about 84 mg. In another embodiment, the therapeutically effective amount of esketamine is about 5 mg. In a further embodiment, the therapeutically effective amount is about 84 mg of esketamine.

[0074] As used herein, unless otherwise specified, the terms "subject" and "patient" refer to refers to an animal, preferably a mammal, most preferably a human, that has been subjected to treatment, observation or experiment Preferably, the subject or patient is at least one of: Also experiencing and / or exhibiting one symptom.

[0075] 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.

[0076] In other embodiments, the subject or patient is elderly or aged. 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 are more likely to respond to treatment than patients ≥75 years. It seems so.

[0077] 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.

[0078] 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. This includes:

[0079] As used herein, "stable remission" refers to a patient who is in stable remission after a period of initiation of esketamine therapy. for at least 3 of the last 4 weeks after achieving an essentially complete response to In certain specific examples herein, In the illustrated embodiment, patients in "stable remission" have a MADRS total score of greater than 12. One deviation from the standard deviation (GD) or one MADRS assessment at week 13 or 14 following the run-in phase In another embodiment, patients in "stable remission" include those with a deficiency of Patients with a MADRS total score of 12 or less at weeks 15 and 16 were included.

[0080] As used herein, "stable response" refers to a patient who has successfully completed the induction phase of esketamine therapy. MADRS total score in each of the last 2 weeks after achieving an essentially complete response to ≥50% improvement from baseline (Day 1 of the run-in period; before randomization / before the first intranasal dose) This refers to patients whose disease has declined but who do not meet the criteria for stable remission.

[0081] 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 a steroid hormone. The administration of an effective amount of esquetatin may include an induction phase, a maintenance phase, 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 most beneficial initial / induction and maintenance doses for the patient. The effective amount of esketamine may be the same or different in each period. good.

[0082] 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. The steroids may be administered during the periods described herein (e.g., induction and maintenance periods). 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.

[0083] 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 phase is a period during which the drug is administered to a patient. The induction phase is long enough to achieve a consistent reduction in the including, but not limited to, type, age, weight, administration time, administration frequency, and any associated diseases. The induction phase may include an initial induction phase and an extended induction phase. 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.

[0084] 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 phase is typically performed after the patient has responded 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 initially evaluated. The initial introduction period is preferably used to determine whether the introduction period is over. In some embodiments, the initial induction phase is of such length that it achieves a reduction in depressive symptoms. In other embodiments, the induction phase is for a period of about 1 to about 4 weeks. In a further embodiment, the initial induction phase is for a period of up to about 1 week, 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 phase can be determined. The effective dose is about 28 mg. In some embodiments, the esophageal carcinoma administered during the initial induction phase An effective amount of ketamine is about 56 mg. In another embodiment, the effective amount of ketamine administered during the initial induction phase is about 56 mg. The effective dose of esketamine is approximately 84 mg.

[0085] 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.

[0086] 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. An extended initial induction period requires at least two doses per week. 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 Lead-in Period is determined and used to determine whether the Extended Lead-in Period has ended. 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.

[0087] 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.

[0088] The extended induction phase 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 enrollment 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 implementation 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 phase is approximately 6 weeks, approximately 7 weeks, or approximately 8 weeks. The effective amount can be determined by the attending physician. In some embodiments, the administration during the extended induction phase 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.

[0089] Administration may further include an induction phase followed by an optimization / maintenance 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 a week, once every two weeks, once a month, or a combination thereof.

[0090] Treatment at any stage during one or more of the induction, optimization, or maintenance phases The patient's response to the test can be assessed using the techniques described herein. , until the patient is deemed by one skilled in the art to have achieved a suitable response to the treatment regimen. In some embodiments, the run-in period is based on the patient's MADRS score. It is considered complete when the line 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 1 6, about 15, about 14, or about 13. Patients with a MADRS score ≦12 is considered to be in remission and should be maintained or progressed to maintenance if stable for 4 weeks. is.

[0091] At the end of the induction or extension phase, the treating physician will evaluate the patient and decide whether to proceed to 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 every week or once every two weeks. In yet another embodiment, the esqueta The administration frequency and effective dose of amine should be determined based on the minimum frequency required to maintain stable remission or stable response. and quantity.

[0092] 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.

[0093] 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

[0094] An effective amount of esketamine is administered to the patient during the maintenance phase. The amount of esketamine administered during the induction phase will determine the biological responses or responses within 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 initial 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. Again, at any time during the maintenance phase, the patient may receive one dose per week to maintain normal activity. The patient's response can be reassessed.

[0095] 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.

[0096] 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 can remain at about 56 mg or can 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.

[0097] 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 phase and, optionally, in certain circumstances, the maintenance phase. Due to the imminent risk to the patient's life, the initial dose of esketamine should be Patients are administered the highest effective dose of esketamine they can tolerate twice weekly during the induction phase. In some embodiments, patients are administered esketamine during the induction phase 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 at the same time as treatment with esketamine was initiated during the run-in phase. In a further embodiment, the patient is initiated concurrently with the initiation of treatment with esketamine during the induction phase. 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 phase, 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 introduction A period may be initiated.

[0098] In the second induction phase, patients received the highest tolerated dose of esketamine and simultaneously received 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 in the treatment of MDD in a manner appropriate to the patient's condition / health. The second induction period is about 4 to about 8 weeks, and the second induction period is about 4 to about 7 weeks. At the end of the second induction period, the duration 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 phase may be initiated.

[0099] In the third induction phase, patients received the highest tolerated dose of esketamine and simultaneously received 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 phase is restarted. Antidepressants are administered twice weekly in the treatment of MDD in a manner appropriate to the patient's condition / health. The third induction period is about 4 to about 8 weeks, and the second induction period is about 4 to about 7 weeks. At the end of the third induction period, the duration 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.

[0100] Generally, patients are treated with the highest tolerated dose of esketamine and concurrently with any previous 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 a first induction phase. 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. A second oral antidepressant, which may be the same or different from the first oral antidepressant in the second induction phase, is administered concurrently with or at the same time as the first oral antidepressant in the second induction phase. If the patient is significantly more tolerant to esketamine during the second induction period, To the extent that a complete response is achieved, patients are then treated effectively less than twice weekly during the subsequent maintenance phase. A dose of esketamine may be administered.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] Another suitable aqueous formulation of S-ketamine comprises water and S-ketamine, wherein S-ketamine is In the range of about 100 mg / mL equivalent to about 250 mg / mL equivalent, based on the total volume of the pharmaceutical composition. Preferably, S-ketamine is present in the range of An amount ranging from about 125 mg / mL equivalent to about 180 mg / mL equivalent, or any amount within that range More preferably, S-ketamine is present in an amount or range equivalent to about 140 mg / mL. to about 160 mg / mL equivalent, or any amount or range therein, e.g. It is present in an amount equivalent to about 140 mg / mL.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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).

[0112] As used herein, the term "buffering agent" refers to an agent that, when added to an aqueous formulation, reduces the pH of the formulation. It is understood that the term "aqueous liquid composition" refers to any solid or liquid composition (preferably an aqueous liquid composition) that adjusts Those skilled in the art will appreciate that buffers can change the pH of aqueous formulations in any direction (more acidic, more basic, It will be appreciated that the pH may be adjusted (towards a neutral or more neutral pH). The agent is pharmaceutically acceptable.

[0113] 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:

[0114] 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.

[0115] 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:

[0116] 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.

[0117] Optionally, the pharmaceutical compositions of the present invention may contain a preservative.

[0118] 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. One aspect is to avoid any microbial influence on the active ingredient and excipients, respectively. In some cases, it may be desirable to avoid microbial degradation.

[0119] 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, phenylmercuric 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.

[0120] 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 equivalent to 120 mg / mL, preferably about 120 mg 175 mg / mL equivalent to about 175 mg / mL equivalent, or any amount or range therein; More preferably, the amount is in the range of about 125 mg / mL equivalent to about 150 mg / mL equivalent, or Any amount or range within the range, e.g., the equivalent of about 126 mg / mL or about 140 mg / mL equivalent.

[0121] 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).

[0122] Suitable examples include tetradecyl maltoside, sodium glycolcholate, and taurine. Tauroursodeoxycholic acid (TUDCA), lecithin, etc.; and and chitosan (and salts), as well as benzalkonium chloride, sodium dodecyl sulfate, dodecyl Sodium phosphate, Polysorbate, Laureth-9, Oxytoxinol, Deoxychol Surface active ingredients include, but are not limited to, sodium hydroxybenzoate, polyarginine, etc. Preferably, the penetrating agent is tauroursodeoxycholic acid (TUDCA).

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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. .

[0129] Examples of suitable antioxidant ingredients, if used, include: sulfites; ascorbic acid; Acids; sodium ascorbate, calcium ascorbate, or potassium ascorbate Ascorbic acid salts such as ascorbate; ascorbyl palmitate; fumaric acid; ethylenediaminetetraacetic acid Acetic 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.

[0130] 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.

[0131] 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 %.

[0132] 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 %.

[0133] 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:

[0134] 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. The drug is administered within about 3 minutes, about 2 minutes, about 1 minute, or less. Therefore, flexible dosing regimens allow patients to receive daily, twice-weekly, weekly, biweekly, or monthly dosing. For example, one dose of esketamine may be administered on day 1 and another dose of esketamine may be administered on day 2. One dose of esketamine is administered on day 2, or one dose of esketamine is administered on day 1 and Another dose of esketamine is administered on day 3, or one dose of esketamine is administered on day 1, Another dose of esketamine 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 or intranasally via topical use of a suitable intranasal vehicle such as a nasal spray pump. It is administered at .

[0135] 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.

[0136] 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 nasal injection from the first intranasal device 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 AUC last 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 AUCl ast When about 28 mg of esketamine is administered, the about 1 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.

[0137] 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.

[0138] Representative nasal spray devices are disclosed in U.S. Pat. No. 6,332,432, which is incorporated herein by reference. For example, in order to discharge a continuous partial discharge as a spray, A disposable sprayer such as the one described above can be utilized to carry out the methods disclosed herein. Typically, such a device sprays medication into both nostrils of a patient with two successive strokes. The device, in which the drug is dispensed from the media container, is ready for use. The device typically separates the first ejection stroke from the second ejection stroke. This prevents the complete emptying of the media container in a single movement. The double-stroke system is discarded after use and allows for individual partial discharge with high dosing accuracy and reliability. The device may take the form of a high-pressure disposable pump.

[0139] In one embodiment, the nasal spray device delivers two sprays (nasal) totaling 28 mg of esketamine. It is a single-use device that delivers one spray per orifice. The device is administered to patients under the supervision of a healthcare professional. Regarding dosage, one device may be used for a 28 mg dose. Two devices are used for the 56 mg dose, or three devices are used for the 84 mg dose. It is also preferable to have a 5-minute interval between each use of the device. As shown, time 0 corresponds to the time of administration of the first intranasal spray into one nostril from the first intranasal device. It is defined as the time given.

[0140] As shown in Figures 83A-83E, instructions for use are provided for the esketamine nasal spray of the present disclosure. In one embodiment, the instructions for use are provided on the formulation label of the approved formulation. In certain embodiments, the formulation comprises one or more intranasal spray devices, wherein one or more of the devices comprises an intranasal spray device. One or more devices may be administered by two or more sprays, preferably two sprays, containing sketamine. It is designed to administer esketamine in one spray per nostril of the patient.

[0141] An exemplary device is shown in FIG. 83A and includes a tip, nose rest, indicator, fin, The indicator shows if the device is full and how many times it is filled. The indication may be, for example, a color This can be done by using dots, where two colored dots indicate a full device. A single colored dot indicates one spray has been administered, and no colored dot indicates an empty dose. means the device.

[0142] In certain embodiments, the device is administered by a patient under the supervision of a healthcare professional (HCP). It is intended that healthcare professionals, for example, should Education and training to provide information to healthcare professionals on the appropriate use of esketamine. This may be a doctor, psychiatrist, or nurse who has completed a clinical training program. This may include educator-led educational programs, instructional materials, video and web-based education. do.

[0143] In an exemplary embodiment of use, the first step involves blowing one's nose before using the first device. The device includes instructing the patient to administer about 28 to about 84 mg of esketamine. In a preferred embodiment, each device contains approximately 28 mg of esqueta. When administering 56 mg or 84 mg of esketamine, an additional device is used. For example, three devices can be used to administer 84 mg of esketamine. The device should be primed before use as priming results in loss of medication. At the beginning of use, the patient's head should preferably be held back to keep the medication inside the nose. It can be tilted at about 45 degrees.

[0144] Typically, the tip of the device is inserted into the first nostril and the patient actuates the plunger to inject the medication. While releasing the medication, close the other nostril and breathe through your nose. Then, insert the tip of the device into the second Insert it into the nostril to administer the remaining dose of esketamine. At this point, the HCP should remove the device from the patient. If the device is not empty, the patient should spray again into the second nostril.

[0145] Before the next dose from the second device, the patient may administer additional esketamine from the second device. You should rest, preferably in a leaning back position, for approximately 5 minutes before each step. If a third device is required, the patient should undergo additional escalation. After the second spray into the second nostril, approximately 10 minutes after the second spray into the second nostril, before administering tamoxifen from the third device into the first nostril. After each device, the patient must wait approximately five minutes to allow the medication to Used equipment can be disposed of in accordance with local requirements.

[0146] In certain embodiments, methods for marketing formulations containing esketamine are also provided. As used herein, the term "sale" or "to sell" refers to the sale of a formulation, e.g., a pharmaceutical composition or dosage form. In some embodiments, the term "liquid" is used to refer to a drug product. The prescription labeling of the drug contains instructions for treating depression, including treatment-resistant depression. The method also includes offering for sale a formulation comprising esketamine. As used herein, the term "offering for sale" refers to the sale of a formulation, e.g., pharmaceutical composition and dosage form. These methods refer to the proposal by a distributor to sell a drug product to a purchaser. This includes conducting extraction.

[0147] The term "drug" is used by government agencies, such as the Food and Drug Administration or other agencies in the United States. Products containing active ingredients approved for manufacture and sale by the same agency.

[0148] Similarly, a "label" or "package insert" is a document that provides relevant information about a drug product to the patient. Such information includes drug description, clinical pharmacology, indications ( Use of the preparation), contraindications (people who should not take the preparation), warnings, precautions, adverse events (side effects) Use), drug abuse and dependence, dosage and administration, use during pregnancy, use in nursing mothers, children and elderly patient use, drug delivery methods, patient safety information, or any combination of these. In certain embodiments, the label may be one or more of the following: The drug or product labeling provides directions for use in patients with treatment-resistant depression. In other embodiments, the product label may include a comparison of the efficacy and safety of the drug to placebo and / or standard of care. In a further embodiment, the label or formulation label includes data regarding the alleviation of symptoms. In yet another embodiment, the label identifies esketamine as the approved chemical moiety. provides instructions for use in patients with depression, including treatment-resistant depression.

[0149] As used herein, the term "Reference Listed Drug" or "RL" refers to a D" is the formulation to which the new generic product is compared to demonstrate bioequivalence. It also refers to the application of the EU Member States or on the basis of a complete file, i.e. Article 8(3), 10a, 10b or 10c of Directive 2001 / 83 / EC The pharmaceutical company has been granted marketing authorization by the committee upon submission of quality, preclinical and clinical data by the The application for marketing authorization for generic / hybrid drugs is based on bioequivalence. By substantiation, usually through the submission of appropriate bioavailability studies, .

[0150] In the United States, companies seeking approval to market generic equivalents must submit their Abbreviated New Drug Application (ANA) The RLD must be referenced in the Abbreviated New Drug Application (ANDA). For example, an ANDA applicant may be required to demonstrate that a previously approved drug product, i.e., an RLD, is safe and effective. The FDA has relied on its findings to determine whether generic products are the same as RLDs. Something needs to be demonstrated in a specific way. Specifically, the exception must be limited. The drug product submitted in the ANDA must have, among other things, the same active ingredient, conditions of use, and administration as the RLD. It must have the route, dosage form, strength, and package insert (with specific tolerances). RLD is a listed drug, whereas the ANDA applicant must , among other characteristics, active ingredient, dosage form, route of administration, strength, package insert, and conditions of use. The electronic Orange Book states that RLDs are the same in terms of In the printed Orange Book, there is a column for RLDs and reference standards. Standards are identified by specific symbols.

[0151] The reference standard is a formulation selected by the FDA and applicants seeking approval of an ANDA must , should be used to conduct the in vivo bioequivalence studies required for approval. The DA generally covers the in vivo bioequivalence studies that an ANDA applicant should use. Typically, the FDA selects a single reference standard for a drug. However, in some cases (e.g., when a reference drug is withdrawn from the market and Cases where the FDA determined that a drug was not withdrawn for safety or effectiveness reasons, and In the case of the FDA selecting an ANDA as the reference standard, what are the reference list drugs and reference standards? , may differ.

[0152] FDA defines Prescription Drug Product, OTC Drug Product and Discontinued Drug Product List In ts, identify the reference list drug. The list drug identified as the reference list drug is A Represents a drug product on which an applicant seeking approval of an NDA may rely. FDA, as appropriate, escription Drug Product, OTC Drug Product and identified in the Discontinued Drug Product Lists The reference list of drugs is planned to be updated periodically.

[0153] FDA also regulates prescription drug products and OTC drugs. Reference standards are also identified in the Product Lists. The drugs listed have not undergone any in vivo bioequivalence studies required for approval. Represents FDA's best judgment at the time regarding an appropriate comparator for purposes of conducting the study. It is something.

[0154] In some cases, the FDA has not designated the listed drugs as reference listed drugs. If the applicant does not have a copy of the drug, such a listed drug may be protected from generic competition. If FDA has not designated a reference list drug for a drug product intended for , they can ask the FDA to designate a reference list drug for their formulation.

[0155] FDA may select new reference standards on its own initiative and, by doing so, For example, the listed drugs currently selected as reference standards have other characteristics besides safety and efficacy. When a drug is withdrawn from the market for a reason, a generic drug application is submitted and evaluated. This helps ensure that

[0156] In Europe, applicants must submit a written application for their generic / hybrid pharmaceutical product. This includes ANDA or supplemental NDA (sNDA) formulations, reference drug products (products), Same as name, strength, dosage form, Marketing Authorisation Holder (MAH, first authorisation, Member State / Community) and is synonymous with RLD as follows: 1. Basis for demonstrating that the data protection period provided for in European pharmaceutical legislation has expired medicinal products that are or have been authorised in the European Economic Area (EEA) for use as The reference medicinal product is identified for the purpose of calculating the expiry of the data protection period and is for strength, dosage form, route of administration, or labeling that differs from the generic / hybrid drug product. It is also possible. 2. Generic / hybrid application file (product name, strength, pharmaceutical form, MA H, marketing authorization number) is cross-referenced to the medicinal product. This reference medicinal product is A drug product licensed under a different name and under a separate procedure, specified for purposes of calculating expiration In principle, the product information of this reference drug product is It serves as the basis for product information claimed for hybrid pharmaceutical products. 3. Pharmaceutical products used in bioequivalence studies (product name, strength, dosage form, MAH, supplier) Member States of the EU) (where applicable).

[0157] Different abbreviated approval pathways for drug products under the Food, Drug, and Cosmetic (FD&C) Act are available at the FD&C Chapters 5050 and 505(b)(2) of the Act (21 U.S.C. 3550 and 21 This is an abbreviated approval pathway as set forth in U.S.C. 23 355(b)(2).

[0158] FDA(``Determining Whether to Submit an A NDA or a 505(b)(2)Application Guidance f or Industry,” U.S. Department of Health and Human Services, October 2017, pp. 1– 14, the contents of which are incorporated herein by reference), NDAs and ANDAs are They can be classified into the following four categories: (1) A "stand-alone NDA" is one filed under section 505(b)(1) of the FD&C Act. and approved under Chapter 505(c), which includes the or safety, which has been carried out for the applicant or which the applicant has a right to see or use. and a full report of the efficacy study. (2) A chapter 505(b)(2) petition is filed under chapter 505(b)(1) of the FD&C Act. The NDA was approved under Chapter 505(c) and includes a safety and efficacy study. A complete report is included and at least some of the information required for approval has been provided by the applicant. was not carried out by or for the applicant, or was not referred to or performed by the applicant Derived from a study for which the rights to use have not been obtained. (3) An ANDA is a previously approved drug product submitted and approved under chapter 5050 of the FD&C Act. An ANDA is an application for the duplication of a previously approved drug product, i.e., Rely on FDA's finding that the Reference List Drug (RLD) is safe and effective. AND A generally includes generic products (a) that have the same active ingredients, conditions of use, route of administration, dosage form, The strength and package insert (with specific tolerances) are the same as the RLD, and b) It must contain information to demonstrate that the RLD is bioequivalent. If studies are necessary to demonstrate the safety and effectiveness of the product, the ANDA must be submitted It is not possible. (4) The ANDA submitted is a drug that differs from the RLD in dosage form, route of administration, strength, or active ingredient. ANDA for a class of drugs (for products with two or more active ingredients) and FD A. filed a claim under chapter 505(j)(2) of the FD&C Act (compliance claim) In response, the company determined that the study was not necessary to demonstrate the safety and effectiveness of the drug product. It is something.

[0159] The scientific premise underlying the Hatch-Waxman Act is that under chapter 505(j) of the FD&C Act, The drug product approved in the ANDA is presumed to be therapeutically equivalent to its RLD. Products classified as therapeutically equivalent are interchangeable and are designated on the label. When administered to patients under defined conditions, the substituted product has the same clinical efficacy and safety as the prescribed product. In contrast to ANDAs, Chapter 505(b) Section 505(b)(2) of the Act provides greater flexibility regarding product characteristics. The application does not need to be rated as therapeutically equivalent to the listed drug referenced at the time of approval.

[0160] The term "therapeutically equivalent to a reference-listed drug" means that a formulation is therapeutically equivalent to the reference-listed drug. Generic equivalents, i.e., pharmaceutical equivalents, and therefore not covered by the FDA. are rated as AB therapeutic equivalents to the referenced products, thereby reducing actual or potential Bioequivalence issues support in vivo and / or in vivo bioequivalence equivalents. This means that the issue has been fully resolved with in vitro evidence.

[0161] "Pharmaceutical equivalent" means a product containing the same active pharmaceutical ingredient in the same amount as the reference listed drug. It refers to a formulation of the same dosage form and route of administration.

[0162] FDA classifies products as therapeutically equivalent if they meet the following general criteria: (1) their (2) they are approved as safe and effective; (a) they are in the same dosage form; (b) contain the same amount of the same active pharmaceutical ingredient in the same dosage form and route of administration; or other applicable standards of strength, quality, purity, and identity (3) they are (a) subject to known or potential bioequivalence questions; (b) that such a product meets acceptable in vitro standards without demonstrating any problems; If a product shows known or potential problems, it should be evaluated to ensure that it meets the appropriate bioequivalence criteria. (4) they are appropriately labeled; and (5) These are Current Good Manufacturing Practices Manufactured in compliance with regulations.

[0163] The terms "bioequivalent" or "bioequivalence" refer to pharmaceutical equivalents or pharmaceutical substitutes. The active ingredient or active moiety in When administered at a dose, the rate or extent to which the drug becomes available at the site of action is significant. Chapter 505(j)(8)(B) of the FD&C Act requires testing and reference lists. The FDA lists one set of conditions for drugs to be considered bioequivalent: [Test] The rate and extent of drug absorption was measured using either a single dose or multiple doses. Under similar experimental conditions, when the therapeutic component is administered in the same molar dose, [reference] the absorption of the drug The yield and extent of absorption are not significantly different; or [Test] The extent of drug absorption was measured under similar experimental conditions, either with a single dose or multiple doses. When administered at the same molar dose as the therapeutic component, the degree of drug absorption and significant The difference in the absorption rate of the drug is not intended to be a difference. This is reflected in the label and is essential for achieving effective body drug concentrations during chronic use. and is not considered pharmacologically significant with respect to the drug.

[0164] If these above methods are not applicable (e.g., if the product is not intended to be absorbed into the bloodstream), other scientifically valid, in vivo studies to demonstrate bioequivalence. In vivo or in vitro test methods may be appropriate.

[0165] For example, bioequivalence is particularly important when such in vitro studies are used to validate in vivo studies in humans. In vitro bioavailability data correlates with in vivo bioavailability data. In other situations, bioequivalence can be demonstrated using controlled clinical trials. Or it can be demonstrated by pharmacokinetic studies.

[0166] The method also includes placing esketamine in a stream of commerce. In certain embodiments, the composition may comprise or consist essentially of esketami. The drug uses esketamine to safely and effectively treat depression, including treatment-resistant depression. A package insert containing instructions for treatment is included.

[0167] In still further aspects, the esketamine formulations described herein are esketamine, comprising, consisting of, or consisting essentially of, In certain embodiments, the esketamine formulation is Indications for the safe and effective treatment of depression, including treatment-resistant depression, using tacrolimus Includes a package insert containing instructions.

[0168] 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 of treatment is a human patient having a major depressive episode, and the patient is currently 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 of treatment has had a major depressive episode and the patient has a current depression. 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) Identifying human patients by measuring their baseline MADRS scores. a diagnosing step; (b) administering a therapeutically effective amount of esketamine that has been clinically proven safe and effective to a human patient; administering intranasally to a subject, A therapeutically effective dose is a measure of at least 50% improvement in baseline MADRS score. Improved MADRS scores, esketamine is administered at predetermined intervals; (c) Following step (b), the human patient is re-evaluated at regular intervals to determine relative efficacy. determining whether The reassessment includes 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 in which esketamine is administered nasally to a patient in an amount clinically proven to be safe and effective. A pharmaceutical product that is administered intracavitarily. 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 period 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. A method according to embodiment 36. 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 the subsequent administration period is once every week or once every two weeks, or a combination thereof. The method according to any one of aspects 32 to 40, wherein the method is a 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 any one of aspects 32 to 42, wherein the minimum frequency and amount of 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 phase, followed by weekly 59. The method of any one of aspects 45 to 58, wherein the administration is less frequent than twice. 60. The method of claim 59, wherein esketamine is administered weekly or biweekly following an induction period. The method described. 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. The patient's cognitive performance stabilizes based on baseline measurements after 6 months of treatment. 62. The method of any one of aspects 45 to 61, wherein the 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 period; and assessing patient response following the initial induction phase; and 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 weekly during the extended induction phase. 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 phase 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, 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 according to 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 in which esketamine is administered nasally to a patient in an amount clinically proven to be safe and effective. A pharmaceutical product that is administered intracavitarily. 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. In one embodiment, the dose is administered at about 0 mg / kg 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 intranasal spray devices, wherein one or more of the devices: The device contains an esketamine composition, and one or more devices administer about 28 to about 84 mg of esketamine. and wherein 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 phase 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 phase, a second induction phase may be initiated. The method of embodiment 165, wherein the method is initiated. 169. Patients receive the highest tolerated dose of esketamine during the second induction phase and the second 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 phase, a third induction phase 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 long. 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 will receive esketamine at least twice weekly during a first induction phase 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 phase 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 phase. 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 long. 179 to 186. 188. A method of treating treatment-resistant depression in a patient, the method comprising: administering to the patient a therapeutically effective amount of an oral antidepressant; A therapeutically effective dose of esketamine was administered to patients at least twice weekly during a lead-in period of at least 4 weeks. and administering the same intranasally to a subject. 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. The method of claim 188, wherein esketamine is administered once every two weeks during a subsequent maintenance phase. How to post. 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 dose 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 was approximately 56 mg at the start of the induction phase, and 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 phases is delivered via 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.

[0169] 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 efficacy, MDD - major depressive disorder, LTF = lost to follow-up, MGH -ATRQ=Massachusetts General Hospital-Antidepressant Medication History Questionnaire, MGH-Female RLHQ = Massachusetts Ge Neural Hospital - Female Reproductive Cycle / Hormones Questionnaire, MINI = Mini International Neurological Interview, MOAA / S = Modified Observer Assessment of Arousal / Sedation, NS = Statistically Significant Not intentional, OL = open label, OTH = other reasons for withdrawal, PAQ, patient adherence questionnaire, PHQ-9 = Patient Health Questionnaire-9, PWC-20 = Physician Withdrawal Checklist, 20 items Scale, QIDS = 16-item Brief Depressive Symptom Scale-Self-Report, RNA = Ribonucleic Acid, SDS, Sheehan Disability Scale, SAFER = state-trait, evaluative, face validity, biological validity, The Three Ps: STOP-Bang = Snoring, Tiredness, Observed Observed apnea, high blood pressure, body mass index index), age, neck size, gender (questionnaire), TRD = treatment-resistant depression, TSH = thyroid-stimulating hormone, RA = remote assessment only, LOCF = last observation carried forward, WBP = patient withdrawal, WD = withdrawal.

[0170] 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, [Example]

[0171] 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 and conducted to evaluate the efficacy of steroids in adult subjects with TRD. Efficacy and safety of flexibly administered intranasal esketamine plus a newly initiated oral antidepressant 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.

[0172] The hypothesis of this study is to provide a nasal stool sample from failed antidepressant treatment in adult subjects with TRD. 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.

[0173] The primary objective of this study was to assess the progression-free survival (FFS) of patients from Day 1 (pre-randomization) to the end of the 4-week double-blind run-in period. as assessed by change from baseline in the MADRS total score In improving symptoms, a newly started oral antidepressant (active comparator) plus intranasal Adult subjects with TRD were randomized to receive steroid therapy after prior antidepressant therapy compared with switching to placebo. Intranasal esketamine (28 min) was administered flexibly from the treatment (the subject was not responding). g, 56 mg, or 84 mg) plus the efficacy of switching to a newly started oral antidepressant. It was worth it.

[0174] Key secondary objectives are to evaluate the following 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 associated impairments. Additional secondary objectives include (a) depression response rate, (b) depression remission rate, and (c) overall depression. These included (a) physical severity, (b) anxiety symptoms, and (c) health-related quality of life and health status. .

[0175] Newly initiated oral antidepressants (active comparator) plus nasal 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.

[0176] Paired Adults with TRD Receiving Intranasal Esketamine Plus a Newly Initiated Oral Antidepressant The PK of intranasal esketamine in elephants was also evaluated as part of the secondary objective.

[0177] Investigational Drug Information Esketamine is a clear, colorless nasal spray of esketamine hydrochloride in a nasal spray pump. Supplied as an internal solution (16.14 weight / volume [w / v], 14% w / v Esqueta The solution is prepared as 0.12 mg / mL ethylenediaminetetraacetic acid ( 161.4 mg / mL formulated in 1.5 mg / mL citric acid (pH 4.5) and EDTA It consisted of L of esketamine hydrochloride (equivalent to 140 mg of esketamine base). Supplied in a spray pump, containing 16.14 mg esketamine hydrochloride per 100-µL spray (14 mg esketamine base). Each individual nasal spray pump (device) delivered It contained a total of 28 mg (i.e., two spray doses).

[0178] 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. The placebo solution was administered with a matching nasal spray. It was delivered in a Ray pump device. Benzalkonium chloride was used as a preservative at 0.3 mg / mL. Each individual nasal spray pump (device) contained two sprays. there was.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] Study design 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 subjects of both sexes. The study had three phases, briefly described below. Figure 1 outlines the study design.

[0184] Screening / prospective observation period (4 weeks duration) This phase prospectively evaluates 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 their current oral antidepressant treatment (as assessed by double-blind Patients were eligible to proceed to the induction phase. Site investigators were blinded to the study criteria for non-response. It has been transformed.

[0185] Eligible subjects entering the double-blind run-in phase discontinued their current oral antidepressant medication. If approved, the subject's current antidepressant should be discontinued for up to 3 weeks according to local prescribing information or clinical judgment. The dose may be tapered and discontinued for any additional period in between.

[0186] The new oral antidepressants were started on day 1 of the double-blind period, so the gradual release of these antidepressants was not observed. Eligible subjects who did not require tapered discontinuation proceeded immediately to the double-blind run-in phase.

[0187] Double-blind run-in period (4-week 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 Seven randomized subjects were included (four of whom were in intranasal and / or oral AD trials). (They did not receive medication and were therefore not included in the analysis population). The treatment (ketamine or placebo) was administered twice weekly. In addition, all subjects were required to report a new non-steroidal anti-inflammatory drug (NSAID) on Day 1. Blinded oral antidepressants were initiated, which were taken daily for the duration of this period. The oral antidepressant administered was administered if the subject had previously experienced non-response in the current depressive episode. had no previous intolerance (lifetime) and had four steroids available in the participating countries. Oral antidepressants (duloxetine, escitalopram, sertraline, or venlafaxine) It was one of the four steroids (extended-release [XR]).

[0188] At the end of the run-in period, subjects who were responders (4 days after baseline [pre-randomization on Day 1]) defined as a ≥ 50% reduction in the MADRS total score by the end of the 1-week double-blind run-in period (e.g., a person who meets all other test entry criteria) may be admitted to the subsequent test ESKETINTRD30. 03 (ESKETINTRD3003 is a randomized controlled trial of intranasal esketamine (This is a longer-term maintenance efficacy study involving repeated treatment sessions of the same drug.)

[0189] If a subject withdraws from the study before the end of the double-blind run-in period for reasons other than withdrawal of consent, The early withdrawal visit occurred within 1 week of the discontinuation date, followed by the follow-up period.

[0190] 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 run-in period. All subjects who were enrolled in the study were included. No intranasal treatment sessions were administered during this period. There was no.

[0191] At the start of the follow-up period, further clinical / standard care for the treatment of depression was initiated by the investigator. The patient's oral antidepressant medication was administered during this period and arranged by the attending physician and / or the patient's treating physician. The decision to continue was at the discretion of the investigator, but was based on potential withdrawal symptoms from the intranasal study drug. For better evaluation, oral antidepressants should be administered without prescription unless clinically appropriate. It was recommended that the study be continued for at least the first 2 weeks of the follow-up period.

[0192] The follow-up phase also assessed the progress of subjects' major depressive episodes over a 6-month period. This allowed for the collection of additional information and data to evaluate the effectiveness of the study.

[0193] Considering an optional tapering period of up to 3 weeks, the duration of study participation for subjects was 11 weeks ( If subjects continue into ESKETINTRD3003) or 35 weeks (follow-up (Subjects who completed the study period).

[0194] Study population The inclusion criteria for enrolling subjects in this study were: Each subject met all of the following criteria to be enrolled in this study: 1. Sign the informed consent form (IGF) 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 based on clinical evaluation and will not have MI. Single-episode MDD (single-episode MDD, persistent) confirmed by NI (interval >2 years) or met DSM-5 diagnostic criteria for recurrent MDD without psychotic features was doing. 3. At the start of the screening / prospective observation period, subjects must be Current depression as assessed and confirmed by documented medical history and pharmacy / prescription records A history of non-response to 2 to 5 oral antidepressant medications in a single 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 received Patients were adherent to continuous oral antidepressant medication (without dosage adjustment) during the previous 2-week period. In this study, if an antidepressant was not taken for more than four days, it was considered inadequate adherence. Considered screening / prospective observation (assessed by independent remote raters) Subjects who were non-responders to their current oral antidepressant medication from the previous period were excluded if all other inclusion criteria were met. If met, they were eligible for randomization. 4. At the start of the screening / prospective observation period, subjects must have an IDS-C30 total score ≥ He had 34. 5. Subject's current major depressive episode and resistance to current depressive episodes Drug treatment response was confirmed using an independent institutional eligibility assessment. 6. Subjects will undergo a physical examination, medical history, vital signs (including blood pressure), and pulse oximetry. and medically stable based on a 12-lead ECG performed during the screening / prospective observation period. If any abnormality not specified in the inclusion and exclusion criteria was present, Determination of clinical significance will be determined by the investigator and recorded in the subject's source documentation. , initialed by the investigator. 7. Subjects are medically healthy based on clinical tests performed during the screening / prospective observation period. The patient was stable. No serum chemistry panel, hematology, or urinalysis results were outside the normal reference range. If so, the subject will be considered to have a normal range of normality, and the investigator will determine that the abnormality or deviation from normal is not clinically significant or were included only if they were judged to be appropriate and relevant for the population under study. This was recorded in the source document and initialed by the investigator. Subjects with a pre-existing history of thyroid disease / disorder treated with thyroid hormones should be screened. Patients were required to have received a stable dose for 3 months prior to the start of the screening / prospective observation period. All patients had thyroid-stimulating hormone (TSH) levels within the normal range during the follow-up / prospective observation period. 8. Subject is comfortable self-administering intranasal medications and will follow the provided intranasal administration instructions. was created. 9. Prior to the start of the screening / prospective phase, the female subject was one of the following: (a) Non-childbearing potential: Postmenopausal (amenorrhea for at least 12 months) Age >5 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 impotence pregnancy (e.g., blocked fallopian tubes, hysterectomy, bilateral salpingectomy); or inability to become pregnant for another reason or (b) the use of contraception for subjects of childbearing potential participating in a clinical trial. Consistent with local regulations regarding highly effective contraception, such as oral, injectable, or Practice established use of implantable hormonal contraception; intrauterine device (IU) D) Placement of an intrauterine system; barrier methods (e.g., spermicidal foam / gel / film) / cream / condoms with suppositories or spermicidal foam / gel / film / cream / Occlusive cap with suppository (pessary or cervical / vaginal vault cap); male part Sterilization of the vasectomized partner (the partner who has had a vasectomy should be the only partner of the subject) or true abstinence (if this is consistent with the subject's preferred normal lifestyle). If fertility changes after starting pregnancy (for example, if a woman who was not heterosexually active becomes heterosexually active), After the trial, female subjects were initiated on highly effective contraceptive methods, as described above. These findings were consistent throughout the study and for at least 6 weeks after the last dose of intranasal study drug. She agreed to continue using her birth control method. 10. Women of childbearing potential must have serum (β- Negative human chorionic gonadotropin (β-hCG) and in the double-blind run-in 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 run-in 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 study initiation, the female partner of a male subject should be started a highly effective method of birth control. 12. Subjects are willing to abide by the prohibitions and restrictions specified in the clinical trial protocol. And it was possible. 13. Each subject understands the purpose of the study and the procedures involved, and is willing to participate in the study. I have signed the ICF, which shows my commitment to

[0195] The exclusion criteria for enrolling subjects in this study were as follows: Any of the following criteria: Any potential subject who met any of the above criteria was excluded from participating in this study. 1. Subject's depressive symptoms are (a) in the current major depressive episode according to clinical judgment; (b) esketamine or ketamine, or (b) a current major depressive episode (MGH-A Oral antidepressant treatments available in each country during the double-blind run-in period (based on TRQ) Options (i.e., duloxetine, escitalopram, sertraline, and venrafael) (c) unilateral electroconvulsive therapy Current major depressive episode, defined as at least seven treatments with ECT (Elective Corticosteroids) had previously shown non-response to an adequate course of treatment with ECT in 2. Subjects undergo implantation for vagal nerve stimulation (VNS). or have a current episode of depression and are considering deep brain stimulation tion, DBS). 3. Subjects must have a history of psychotic, bipolar or related disorders (as confirmed by MINI), co-occurring hyperactivity disorder (Hyperactivity Disorder), or Compulsive disorder, intellectual disability (DSM-5 diagnostic code 319 only), borderline personality disorder, antisocial personality disorder Current status of psychotic disorder or MDD with personality disorder, histrionic personality disorder, or narcissistic personality disorder or had a previous DSM-5 diagnosis. 4. Subject had homicidal ideation / intent according to the investigator's clinical judgment, or Screening is based on the investigator's clinical judgment or the C-SSRS. / Had suicidal ideation with some intention to act within 6 months prior to the start of the prospective observation period ( Item 4 of the C-SSRS for suicidal ideation (with some intention to act without a specific plan) for item 5 (active suicidal ideation) or item 6 (active suicidal ideation with specific plan and intent) A "yes" response or a history of suicidal behavior in the year prior to the start of the screening / prospective observation period (corresponding to a history of suicidal ideation or behavior with intent to act) before the start of the double-blind run-in period. Subjects who reported this were excluded. 5. Subjects must not have used nicotine or cuff therapy 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 methadone He had a history of ketamine, phencyclidine (PCP), and diethylamino lysergic acid. LSD or 3,4-methylenedioxy-methamphetamine (MDMA) hallucinogenic Lifetime history of use disorders was excluded. 6. Subjects had a current or past history of seizures (uncomplicated childhood fever without sequelae) (sexual seizures are not excluded). 7. Subjects must have a UPSIT total score indicating anosmia during the screening / prospective observation period. had ≦18 cores. 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 (c) the screening / prospective observation period Myocardial infarction, unstable angina, or revascularization procedures (e.g., coronary angioplasty) within the past 12 months (d) coronary artery disease with mitral regurgitation, aortic stenosis, or aortic bypass graft surgery; (e) any cause of hemodynamically significant valvular heart disease, such as venous regurgitation; or (f) any cause of New York City New York Heart Association (NYHA) Class III-IV heart failure. 9. Subject has not had any adverse events related to diet, exercise, or antihypertensive therapy at screening / pre-screening. History of uncontrolled hypertension or previous hypertensive emergency at the start of the observation period history, or a supine systolic blood pressure (su) of >140 mmHg during the screening / prospective observation period pine systolic blood pressure (SBP) or diastolic blood pressure >90 mmHg (Repeated tests during this period should be performed to determine this category.) had ongoing evidence of uncontrolled hypertension (continuing to exceed the normal range). On day 1 of the double-blind run-in period, patients with supine SBP > 140mmHg or DBP > 90mmHg were also Excluded. Potential subjects were asked to provide their current antihypertensive medication regimen adjusted during the screening / prospective observation period. Subjects may have a dimen- sion and then be re-evaluated to assess blood pressure control. received a stable regimen for at least 2 weeks prior to Day 1 of the double-blind run-in period . 10. Subjects must have a significant risk of developing cerebrovascular disease 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% ) 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 run-in period, had a clinically significant ECG abnormality defined as: (a) F Corrected QT interval according to the ridericia formula (QTcF): ≥ 450 ms, ( b) Second- and third-degree AV block, or first-degree AV block with a PR interval >200 ms , evidence of left bundle branch block (LBBB) or right bundle branch block (RBBB), (c) new (d) characteristics of new ischemia, (e) arrhythmias (premature atrial contractions [PACs] and premature ventricular contractions [PVCs]), ]). 12. Subject has no additional risk factors for Torsades de Pointes. Child's history (e.g., heart failure, hypokalemia, family history of long QT syndrome) or QT interval / complementary They were taking concomitant medications that prolong the QT (QTc) interval. 13. Subject has a history of liver cirrhosis (e.g., esophageal varices, ascites, and prothrombin time Increased alanine alanine levels) or ≥2 times the upper limit of normal during the screening / prospective observation period Alanine aminotransferase (ALT) or aspartate Aminotransferase (aspartate aminotransferase, AST) levels, or 1 of the ULN The patient had a total bilirubin level greater than 0.5 times higher than normal. In the opinion of the sponsor and with the consent of the sponsor's medical staff, the increase in bilirubin was If the condition was consistent with rheumatoid arthritis, subjects were eligible to participate in the study. 14. At the start of the screening / prospective observation period or during the double-blind run-in period before randomization On day 1, addictive drugs (barbiturates, methadone, opiates, cocaine, phencyclidine) were administered. Subjects with positive test results for methamphetamine (including lysine and amphetamine / methamphetamine) Screening with prescription / over-the-counter opiates, barbiturates, or amphetamines Subjects who had a positive test result at screening were presented to the investigator and are reproduced in Table 6 below. Subject to the restrictions set forth in the supplementary material, at least 1 week of medication must have stopped before Day 1 of the double-blind run-in period (before randomization). If treatment is discontinued within 3 days or 5 half-lives, whichever is longer, the patient will be reinstated into the screening / prospective observation period. The results of day 1 (pre-randomization) testing for drugs of abuse were randomized. A positive test result, except for the reasons stated above, was required to be negative for the subject being studied. Retesting of cannabinoids before the start of the screening / prospective observation period was not permitted. Previous intermittent use of drugs was not excluded unless the subject met criteria for a substance use disorder. However, a positive test for cannabinoids before dosing on Day 1 of the double-blind run-in period The results were excluded. 15. The subject has severe diabetic ketoacidosis, hyperglycemic coma, or loss of consciousness. Hypoglycemia screening / screening 3 months before the start of the prospective observation period / prospective observation Uncontrolled diabetes as evidenced by HbA1c > 9% during or after had urinary tract disease or secondary diabetes. 16. Subject has untreated glaucoma, current penetrating or perforating eye injury, brain injury, or high blood pressure. encephalopathy, intrathecal therapy with ventricular shunt, or increased intracranial or intraocular pressure or planned Had any other condition related to ocular surgery. 17. Subject has any anatomical or medical condition that may interfere with the delivery or absorption of intranasal investigational drug had significant structural or functional abnormalities of the nose or upper airway (e.g., significant structural or functional abnormalities of the nostrils or nasal passages) obstruction or mucosal lesions, sinus surgery in the past 2 years). 18. Subject has an abnormal or unrepaired nasal septum with any one or more of the following symptoms: had one or both of the following conditions within the past few months that may affect study participation: (b) nasal congestion (especially on one side); (c) frequent nosebleeds; (d) frequent sinus pain infection, or (e) wheezing during sleep. 19. Subjects must have 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 minimal risk of recurrence. (The exception was malignant tumors that were considered cured by chemotherapy.) 20. Subjects are receiving esketamine / ketamine and / or its vehicle, or a double-blind run-in study. known allergies, hypersensitivity reactions, and allergies to any of the available oral antidepressant treatment options for had a sensitivity, intolerance, or contraindication. 21. Subjects must meet the criteria outlined in the section entitled Preliminary Study and Concomitant Therapy and in Table 6. Receiving any prohibited therapy that would not be permitted to be administered on Day 1, as there was. 22. Subjects must be on 6 mg / day of lorazepam at the start of the screening / prospective observation period. He was taking a total daily dose of benzodiazepines that was greater than equivalent. 23. Subject has a score of 5 or greater on the STOP-Bang questionnaire, in which case they have 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 Patients may be included if they are using other treatments / therapies that effectively treat sleep apnea. do. 24. Subjects must have received an investigational drug (investigational vaccine) within 60 days prior to the start of the screening / prospective observation period. had undergone any investigational medical procedure (including immunization), or used an invasive investigational medical device, or had undergone any screening test Two or more clinical episodes of MDD or other psychiatric conditions in the year prior to the start of the study / prospective observation period were participating in a clinical trial or were currently enrolled in a clinical trial. 25. Subjects must not receive intranasal study drug for at least 6 weeks while enrolled in this study or for at least 6 weeks after their last dose of intranasal study drug. Women who were pregnant, breastfeeding, or planning to become pregnant within the next few years. 26. The subject has acquired immunodeficiency syndrome (AIS) He had a diagnosis of human immunodeficiency virus (HIV). HIV testing was not required for this study. 27. The subject has a medical condition in which, in the opinion of the investigator, participation would not be in the subject's best interest (e.g., (e.g., impairing well-being) or preventing, limiting, or confusing the evaluation specified in the protocol. had any condition or situation / circumstance that could cause it to 28. Subject must have received any of the following treatments within 12 weeks prior to the start of the screening / prospective observation period: have had major surgery (requiring anesthesia) or have not fully recovered from surgery, or Subjects underwent planned surgery during which they were expected to participate in the study. Under local anesthesia Subjects scheduled for a surgical procedure were allowed to participate. 29. The subject is an employee of the investigator or the trial facility and is not a any person directly involved in a study or other study submitted under the direction of the were employees or family members of the investigator.

[0196] The investigator ensured that all study entry criteria were met. A change in the subject's condition (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 will be withdrawn from the study. will be excluded from

[0197] Additionally, potential subjects must comply with the following prohibitions during the course of the study to be eligible to participate: The person in charge had to be willing and able to abide by the restrictions and limitations. 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 Run-in Phase to the Final Visit in the Double-Blind Run-in Phase CP), 3,4-methylenedioxy-methamphetamine (MDMA), or cocaine use A positive urine drug screen for use will lead to discontinuation. 4. Subjects must abstain from alcohol for 24 hours before and after each intranasal treatment session. If the subject appears intoxicated, do not administer. 5. On all intranasal study drug administration days, all subjects must complete study procedures and withdraw the subject. Patients must remain at the clinical trial site until they are ready to be discharged from the clinical trial site. Subjects were required to be accompanied by a responsible adult when driving. Do not drive or work with machinery. 6. Subject must have consumed grapefruit for 24 hours prior to receiving an intranasal dose of study drug. Patients were to avoid consumption of fruit juice, Seville oranges, or quinine. 7. ECT, DBS, transcranial magnetic stimulation (TMS) ), and VNS were prohibited from study entry until the end of the double-blind run-in period. 8. Subjects receiving psychotropic therapy must have had this therapy discontinued prior to the screening / prospective observation period. Stable in frequency over the past 6 months and remained unchanged until the end of the double-blind run-in period Patients could continue receiving psychiatric treatment as long as they were able to do so.

[0198] Treatment assignment, randomization, and blinding This study was centrally randomized. Subjects were randomized by or overseen by the sponsor. The randomization schedule was prepared in advance of the study under the supervision of the patient, and the subjects were randomized 1:1 based on a computer-generated randomization schedule. Patients were randomly assigned to treatment group 1 or 2 in a ratio of . Randomization was randomly permuted. The study was balanced by the use of a blockade and oral anticoagulants initiated during the national and double-blind run-in phases. The data were stratified by depression medication class (SNRI or SSRI). The interactive web response system (IWRS) includes treatment assignment and matching of subjects. A unique treatment code was assigned to determine which investigational drug kit to use. After selecting the oral antidepressant treatment for the run-in phase, the facility entered this information into the IWRS. When contacting IWRS, users will use their user identification and personal identification number to Relevant object details were obtained to uniquely identify the elephant.

[0199] The investigators were not provided with a randomization code; this code was maintained within the IWRS. maintains the functionality to allow the investigator to unblind individual subjects was.

[0200] 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 making exceptions such as preventing others from seeing the data.

[0201] Under normal circumstances, blinding is required until all subjects have completed the study and the database has been finalized. Otherwise, knowledge of the subject's treatment status will not be sufficient to determine whether the The blind may be broken only if a specific emergency treatment / course of action can be indicated. In such cases, the investigator may determine the identity of the treatment by contacting the IWRS in an emergency. The investigator should, if possible, consult with the sponsor or a designated It is recommended that you contact the sponsor or its designee to discuss your specific situation. Telephone contact with participants was available 24 hours a day, 7 days a week. The sponsor was notified as soon as possible. The date and time of unblinding was documented by the IWRS. The reason for the unblinding was the electronic case report form (eCRF) ) and documented in the source documentation. The document representing the information is kept together with the source document in a secure manner.

[0202] Subjects unblinded to treatment assignment were excluded from planned early withdrawal and follow-up visits. Therefore, I decided to continue visiting again.

[0203] 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 the subject was disclosed.

[0204] At the end of the double-blind run-in period, the database was locked for analysis and reporting of this period. The treatment assignment of the subjects was known only to the sponsor's study staff. The investigator and site personnel will be kept in constant contact with the patient until the patient has completed study participation through the follow-up period. Patients were blinded to treatment allocation.

[0205] To maintain the blinding of the intranasal study drug, the esketamine and placebo intranasal devices were indistinguishable. It was Noh.

[0206] A total of 227 subjects were randomized in the study. Of these, 3 subjects Not receiving any investigational drug (intranasal or oral AD), one subject was in both the intranasal and oral AD trials I didn't receive either medication.

[0207] 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. The majority of subjects entering the study were female. The mean age of all subjects was 45.7 years, ranging from 19 to 64 years.

[0208] [Table 1-1]

[0209] [Table 1-2]

[0210] Of the 227 randomized subjects, 197 completed the 28-day double-blind run-in period. The most common reason for withdrawal was adverse events. 86 subjects subsequently withdrew from the study during the follow-up period. 118 subjects continued on to the ESKETINTRD3003 clinical trial. 2 presents the number and reasons for withdrawal from the study.

[0211] [Table 2]

[0212] Baseline psychiatric history was as presented in Table 3 below. Mean (SD) The line MADRS total score was 37.1, with a range of 21 to 52.

[0213] [Table 3-1]

[0214] [Table 3-2]

[0215] Dosage and Administration Screening / prospective observation period At the start of the screening / prospective observation period, subjects were Non-responders receiving oral antidepressant therapy at the start and continuing this same therapy for the duration of this period Non-response was confirmed over a period of 1 year. 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. did.

[0216] 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.

[0217] Double-blind run-in period During this period, subjects received either esketamine (56 mg or 84 mg) or placebo. Double-blind intranasal treatment was administered twice weekly for 4 weeks as a variable dose regimen at the study site. Additionally, subjects were asked to self-administer a new open-label oral antidepressant (i.e., duplex) on Day 1. coadministration of loroxetine, escitalopram, sertraline, or venlafaxine XR This began and continued for the duration of this period.

[0218] 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 intracavitary treatment sessions will be administered during the double-blind run-in phase.

[0219] [Table 4]

[0220] Prior to the first intranasal administration on Day 1, subjects received a demonstration nasal spray filled with placebo solution. They practiced spraying the intranasal device (into the air, not into the nasal cavity).

[0221] All subjects received nasal steroids at the study facility for two treatment sessions per week for four weeks. The intravenous study drug (esketamine or placebo) was self-administered. The first treatment session was The intranasal treatment sessions were not performed on consecutive days.

[0222] On day 1, subjects randomized to intranasal esketamine started at a dose of 56 mg. On Day 4, the dose was increased 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 days) as determined by the investigator based on tolerability. The eye dose was 56 mg, remained the same, or was reduced to 56 mg ( On Day 11, the dose was adjusted based on efficacy and tolerability. The dose was increased to 84 mg on day 8 (5 mg on day 8) as determined by the investigator. 6 mg), remained the same, or was reduced to 56 mg (dose on day 8) On day 15, if necessary based on tolerability, the dose may be increased from 84 mg to Dose reduction to 56 mg was permitted. Dose escalation was not permitted on day 15. Day 15 and beyond , the dose remained stable (unchanged).

[0223] 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.

[0224] If the subject had nasal congestion on the day of dosing, the dosing day was changed (according to the allowed visit period). It was recommended to delay the administration. The dose was not to be administered daily. If used to reduce nasal congestion, it should not be used within 1 hour before intranasal administration of the investigational drug. It was.

[0225] For all intranasal treatment sessions, subjects were asked to complete the study procedures and then discharged. remain at the clinical site until they are ready to leave and have a responsible adult present when they are discharged from the clinical site. Subjects were instructed not to drive for 24 hours after the last dose of intranasal study drug on each dosing day. or work with machinery.

[0226] Oral antidepressants Beginning on day 1, all subjects were initiated on new open-label oral antidepressant treatment. Oral antidepressants were administered for the duration of this period. one of the following: cetin, escitalopram, sertraline, or venlafaxine XR Antidepressants were assessed based on the MGH-ATRQ and related information review regarding previous antidepressant treatment. Based on the view, the investigator assigned the In the study, patients were not previously non-responders, were not previously intolerant (lifetime), and were available in participating countries. It was something that was possible.

[0227] 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.

[0228] [Table 5]

[0229] 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: Phosphorus (50 mg / day), venlafaxine XR (150 mg / day), escitalopram ( 10 mg / day), and duloxetine (60 mg / day). Subjects requiring lower doses were Although such subjects were able to continue in the study and complete the double-blind run-in phase, they were not included in the efficacy study E Participate in SKETINTRD3003 maintenance and follow-up after completion of the double-blind run-in phase was not eligible to advance to the next term.

[0230] All subjects were to ensure there was 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.

[0231] Study site personnel will administer oral anti-inflammatory drugs supplied during the double-blind run-in phase for home use. Subjects were instructed on how to administer and store the medication.

[0232] In the intranasal treatment session, oral antidepressant treatment was administered at night and at the same time during the double-blind run-in 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

[0233] 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. After meeting the inclusion and exclusion criteria on Day 1, subjects' pre-dose systolic blood pressure (SBP) was ≥ 160mmHg and / or diastolic blood pressure (DBP) was ≥ 100mmHg If this occurs, it is recommended that blood pressure measurements be repeated after the subject has rested for 10 minutes in a sitting or lying position. Pre-administration SBP ≥ 160mmHg and / or DBP ≥ 100mmHg If so, dosing was postponed and the subject was scheduled to return the next day or within a given visit period. If elevated blood pressure persists at this visit, the subject should consult a cardiologist or primary care physician before further administration. A consultation with the treating physician was scheduled.

[0234] 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. Ta.

[0235] As long as the subject is approved to continue on the study after evaluation by a cardiologist or primary care physician, If pre-dose blood pressure is within acceptable limits at the next scheduled visit, the subject will continue with intranasal administration. I was able to do this.

[0236] SBP ≥ 200 mmHg and / or DBP ≥ 200 mmHg at any time point after administration on the day of administration If the mean blood pressure was ≥ 120 mmHg, the subject was to discontinue further administration and return to the follow-up assessment. For this reason, patients were referred to a cardiologist or their primary care physician.

[0237] During the double-blind run-in period, SBP was ≥ 160 mmHg at 1.5 hours post-dose; and / or DBP was ≥ 100mmHg, SBP < 160mmHg and Subject receives appropriate medical care until DBP < 100 mmHg or if clinically indicated Evaluations must continue every 30 minutes until the patient is referred to the ER.

[0238] Follow-up period Patients who received at least one dose of intranasal study drug during the double-blind run-in period but did not receive any subsequent maintenance clinical Subjects who did not enter the ESKETINTRD3003 study will be followed up at 24 weeks. The patients proceeded to the nasal study phase. No intranasal study drug was administered during this phase.

[0239] At the start of the follow-up period, further clinical / standard care for the treatment of depression was initiated by the investigator. The patient's oral antidepressant medication was administered during this period and arranged by the attending physician and / or the patient's treating physician. The decision to continue was at the discretion of the investigator, but was based on potential withdrawal symptoms from the intranasal study drug. For better evaluation, oral antidepressants should be administered without prescription unless clinically appropriate. It was recommended that the study be continued for at least the first 2 weeks of the follow-up period.

[0240] Treatment compliance The investigator or designated study site personnel must ensure that all intranasal treatments are distributed and returned. They were required to maintain a log of study medication and oral antidepressants. Each subject's medication supply was kept confidential throughout the study. The entire body was managed in a list.

[0241] Subjects were instructed to comply with oral antidepressant treatment. Designated study site personnel will monitor any subject to ensure compliance with oral antidepressant medication. served to provide additional instruction for retraining the

[0242] 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.

[0243] Antidepressant treatment compliance during the double-blind run-in phase was assessed by pill counts (i.e., co- This was assessed by conducting a compliance check and investigational drug management.

[0244] 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.

[0245] 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.

[0246] 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 treatments were recorded at the start of the screening / prospective observation period. Antidepressant choice (i.e., duloxetine, escitalopram, sertraline, and benzamidine) Information on any history of intolerance to either cefotaxime (e.g., cefotaxime XR) or cefotaxime XR was also obtained.

[0247] 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. A follow-up period beyond this time was obtained only in conjunction with new or worsening adverse events.

[0248] Subjects were taking permitted concomitant medications (e.g., antihypertensives) on their regular schedule. However, restrictions were placed on the use of oral antihypertensive drugs, and Table 6 below was taken into consideration. If oral antihypertensive drugs are taken in the morning, the morning dose Please note that the dose is taken on the day of intranasal administration.

[0249] Subjects receiving psychotropic therapy were asked to report that this therapy had been discontinued prior to the screening / prospective observation period. It was stable in frequency over 6 months and did not change after the completion of the double-blind run-in period. They were allowed to continue receiving psychiatric treatment on the condition that they did not have any

[0250] All therapies other than the study drug (prescriptions including vaccines, vitamins, and herbal nutritional supplements) Non-pharmacological treatments such as medications or over-the-counter medications, psychotherapy, electrical stimulation, acupuncture, special diets, and exercise regimens Modification of existing effective treatments was not permitted by the protocol. Unless otherwise specified (e.g., adjustment of blood pressure medication), it is done for the express purpose of enrolling the subject in the study. It shouldn't be.

[0251] 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) 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.

[0252] 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)

[0253] [Table 6-1]

[0254] [Table 6-2]

[0255] The number of doses of intranasal study drug is summarized in Table 7 below.

[0256] [Table 7]

[0257] A summary of the mean, mode, and final doses of intranasal study drug is summarized in Table 8 below.

[0258] [Table 8]

[0259] On day 25 of the double-blind run-in period, 66 of 99 (66 / 7%) subjects were of esketamine. Of the 115 subjects treated with intranasal esketamine, Eleven (9.6%) subjects had their dose reduced during the double-blind phase. The duration of exposure to the study drug was as summarized in Table 9 below.

[0260] [Table 9-1]

[0261] [Table 9-2]

[0262] 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.

[0263] [Table 10-1]

[0264] [Table 10-2]

[0265] [Table 10-3]

[0266] [Table 10-4]

[0267] [Table 10-5]

[0268] [Table 11-1]

[0269] [Table 11-2]

[0270] With the exception of post-administration assessments, visit-specific subject-reported outcome assessments did not influence subject perceptions. performed or completed before any test, procedure, or other examination to prevent A recommended test sequence was provided. Actual evaluation dates and times were determined based on source documentation and This was recorded in the eCRF.

[0271] 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 preliminary Unspecified samples could be collected if deemed necessary by the investigator. or, if required by local regulations, perform an additional serum or urine pregnancy test. Ensure that subjects are not pregnant at any time during their participation in the study. This was possible.

[0272] [Table 12]

[0273] 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 screened at age 18 (or when the study was conducted). 19 years or older if the minimum legal age of consent in the country where the drug is used is >18 years old) to 64 years or older Subjects below were screened to determine eligibility for study participation.

[0274] Subjects were diagnosed with single-episode MDD based on clinical assessment and confirmed by MINI. (For single-episode MDD, duration was ≥2 years) or recurrent episodes without psychotic features Patients were required to meet the DSM-5 diagnostic criteria for onset MDD. At the start of the prospective observation period, subjects must have an IDS-C30 total score ≥ 34 It won't happen.

[0275] At the start of this period, patients were assessed using the MGH-ATRQ and a documented medical history was obtained. and ≥2 types in a current eligible episode of depression confirmed by pharmacy / prescription records. Subjects must have a history of non-response to ≤5 oral antidepressant medications. , non-responders receiving oral antidepressant treatment at entry and continuing this treatment for the duration of this period Patients were continued at the same dose and prospectively confirmed non-response. Treatment adherence was assessed. Patients were assessed for whether antidepressants had been taken for ≥4 days in the previous 2-week period. Failure to do so was considered inadequate adherence.

[0276] Subject's current major depressive episode and any antidepressants used during the current depressive episode Antidepressant treatment response to antidepressant therapy was confirmed using an independent institutional eligibility assessment. Ta.

[0277] 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 run-in phase. Eligible non-responders (by a remote blinded assessor) were blinded to the specific details of the study. (to be determined) are current antidepressants and any other prohibited psychotropic drugs (adjunctive atypical Antipsychotics were discontinued. Benzodiazepine or non-benzodiazepine hypnotics were continued. was allowed, but with specific restrictions regarding administration time for intranasal treatment sessions. .

[0278] All other subjects who did not proceed to the double-blind run-in phase terminated study participation at this point. No further study visits or follow-up were required.

[0279] Optional antidepressant tapering period All non-responder subjects had started a new oral antidepressant during the double-blind run-in 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 based on local prescribing information or clinical judgment. Patients were allowed to taper and discontinue their current oral antidepressants according to the guidelines.

[0280] 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.

[0281] Double-blind run-in period During this period, subjects received either esketamine (56 mg or 84 mg) or placebo. Double-blind intranasal treatment was self-administered twice weekly for 4 weeks as a variable-dose regimen Additionally, subjects were concurrently started on a new open-label oral antidepressant.

[0282] Study subjects (with TRD) were randomly assigned to one of two groups in a 1:1 ratio (approximately 98 per group): Patients 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. Antidepressants (duloxetine, escitalopram, sertraline, or venlafaxine X) The antidepressant was one of the following: (MGH-ATRQ and related previous antidepressants) assigned by the investigator (based on review of medication information) and the subject's current No previous non-response in a seizure episode, no previous intolerance (lifetime), participating Oral antidepressants were administered starting on day 1 and Doses were titrated to the maximum tolerated dose according to the local prescribing information for each product. The titration schedule for the oral antidepressants administered was as presented in Table 5 above.

[0283] If the information was obtained by telephone, the call should be transcribed for review against the source document. During telephone contact with subjects by site personnel, adverse events and Additionally, specific clinician dosing assessments were performed by appropriately qualified staff. This was carried out by F.

[0284] At the end of the double-blind run-in period, subjects who were responders (baseline [pre-randomization on Day 1] ] to the end of the 4-week double-blind run-in period as a ≥ 50% reduction in the MADRS total score (as defined) to enter a subsequent maintenance clinical trial (Study ESKETINTRD3003). To maintain the blindness of the study, an active comparator (i.e., oral antidepressant plus nasal All responder subjects, including those responding to intravenous placebo, will be included in Study ESKETINTRD. Participation in ESKETINTRD3003 was a double-blind The study began immediately after the completion of the run-in phase. Subjects received oral antidepressants and were followed up at the next study visit (i.e., The first study visit of the stabilization period in Study ESKETINTRD3003 was I was instructed to continue taking my oral antidepressants.

[0285] Subjects who did not enter study ESKETINTRD3003 progressed to the follow-up period .

[0286] Early withdrawal Early withdrawal if a subject withdraws before the end of the double-blind run-in period for reasons other than withdrawal of consent The visit took place within one week of the discontinuation date and followed 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 a duplicate assessment was performed. was not required.

[0287] Further clinical / standard care for the treatment of depression may be recommended by the investigator and / or the subject's treating physician. The investigator and / or treating physician decided to continue the current oral antidepressant medication. decided whether to do it or not.

[0288] If applicable, subjects who withdrew received additional oral antidepressants early and if not clinically appropriate. Oral resistance therapy should be continued for at least the first 2 weeks of the follow-up period unless otherwise deemed necessary. It was recommended that she continue taking her medication.

[0289] Follow-up period Patients who received at least one dose of intranasal study drug during the double-blind run-in phase and subsequently received 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 conducted as specified in the time and event schedule. During this period, the study included potential withdrawal symptoms after discontinuation of intranasal esketamine. Safety and tolerability were assessed. Additionally, subjects were assessed for their current major depressive episodes over a 6-month period. Data were collected to assess the progression of the episodes.

[0290] Further clinical / standard care for the treatment of depression may be recommended by the investigator and / or the subject's treating physician. Intranasal study medication was not administered during this period. To better assess potential withdrawal symptoms, unless deemed clinically appropriate, It is recommended that oral antidepressants be continued for at least the first 2 weeks of the follow-up period. The decision to continue antidepressants was at the discretion of the investigator.

[0291] If information is obtained by telephone, transcribe the call for review against the source document. The records were made available.

[0292] 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 nature of the adverse events and special reporting circumstances, all adverse events and special reporting circumstances will be reported to the subject's last study-related procedure. was reported to completion.

[0293] Efficacy assessment It was recommended that various subject-reported outcome assessments be completed before any other procedures.

[0294] 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. designed for use in subjects with MDD to detect changes due to The MADRS scale has been validated as a primary measure to determine its effectiveness in major depression. The primary efficacy measure of this study was It was used as such.

[0295] 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 The test exhibits high inter-rater reliability.

[0296] 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 by the end of the run-in period was

[0297] In this study, subjects in one of two treatment groups who responded to the investigational drug (i.e., Respondents) will be assessed from baseline (day 1 before randomization) to the end of the 4-week double-blind run-in period. Subjects who met criteria for response, defined as a ≥ 50% reduction in MADRS total score Defined.

[0298] In addition to being the primary efficacy measure, the MADRS also correlated with the duration of the double-blind run-in phase. 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

[0299] MADRS also assessed subjects with response and remission at the end of the 4-week double-blind run-in period. Subgroup analysis to assess the proportion of subjects (defined as subjects with a MADRS total score ≤ 12) The data were used to assess the secondary objectives.

[0300] Key secondary efficacy assessments (clinician-completed) MADRS was the clinical response by day 2 that was maintained for the duration of the double-blind run-in 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

[0301] 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 over the duration of the double-blind run-in phase.

[0302] 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 the severity of mental retardation. 5 Each of the nine symptom domains of the MDD criteria was scored, and 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). These were added to provide a total score (ranging from 0 to 27), with higher scores indicating more severe depression. Symptoms were observed. The recall period was 2 weeks.

[0303] The Sheehan Disability Scale (SDS) was used to assess functional impact and The secondary objective of associated disability was assessed. The SDS is a subject-reported outcome measure and is It is a widely used and accepted five-item questionnaire for assessing disability and related disorders. The first three items were rated on a 0-10 scale, and were divided into (1) work / school, (2) social life, and and (3) assessing the disruption of family life / family responsibilities. The scores for the first three items were added together to arrive at a total of 0. A total score of ~30 was created, with higher scores indicating greater impairment. It also has 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.

[0304] 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. Provides an overall clinician-determined summary measure of the subject's illness severity. The IS assesses the severity of psychopathology on a scale of 0 to 7. Taking into account the entire clinical experience, subjects The severity of mental illness at the time of assessment was assessed as follows: 0 = not assessed; 1 = not assessed; = normal (not ill at all), 2 = borderline psychotic, 3 = mildly ill 4 = moderately ill, 5 = significantly ill, 6 = severely ill, 7 = very ill The CGI-S allows for a global assessment of a subject's condition at a given time. do.

[0305] Anxiety symptoms were assessed using the 7-item subject-report Generalized Anxiety Disorder 7-item Scale (GAD-7). 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. Recall period was 2 weeks.

[0306] 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, daily activities, These include management, usual activities, pain / discomfort, and anxiety / depression. Level of perceived problems (Level 1 indicates no problems, Level 2 indicates slight problems, Level 3 indicates Level 3 indicates moderate problems, level 4 indicates severe problems, and level 5 indicates extreme problems) It is divided.

[0307] Subjects were asked to answer each of the five items, considering the response that best matched their health "today." A descriptive system was used to describe health status. EQ-VAS self-ratings were completed. Respondents' own assessment of their health status at the time of completion was recorded on a scale of 0 to 100.

[0308] 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 run-in period.

[0309] 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.

[0310] 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 investigational medication were included. As shown, the results of the change in MADRS total score were significantly higher with oral AD than with intranasal placebo. Intranasal esketamine plus oral AD was favored. (Figure 2 shows the double-blind comparison based on MMRM analysis.) Least squares mean change from baseline in MADRS total score over time at the study period (± Mean changes from baseline (SD) at day 28 were observed with esketamine. + oral AD was −21.4 (12.32) and active comparator was −17.0 (13 Treatment, day, country, oral antidepressant class, and treatment per day were factors. Based on the MMRM model with baseline values ​​as covariates, The least squares mean difference (SE) between Min+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.

[0311] 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.

[0312] [Table 13]

[0313] Secondary endpoints The first key secondary endpoint was subject-reported depression using the PHQ-9 total score. Depressive symptoms from baseline (Day 1 before randomization) to the end of the 4-week double-blind run-in period This was the change up to now.

[0314] The second key secondary endpoint was maintained through the end of the 4-week double-blind run-in period The percentage of subjects demonstrating an onset of clinical response by day 2. Onset of clinical response was measured at 4 weeks post-treatment. The day after taking the first dose of double-blind study drug [Day 2], which continued until the end of the double-blind run-in period defined as a ≥ 50% reduction in the MADRS total score before the end of the double-blind run-in period. Subjects who discontinued the study were not considered to have maintained a clinical response.

[0315] 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 from baseline to the end of the double-blind run-in period. Ta.

[0316] Other secondary efficacy endpoints included: (a) response at the end of the 4-week double-blind run-in 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 2-week double-blind run-in period, and c) CGI-S, anxiety symptoms, and EQ-5D-5L as measured by GAD-7 Baseline measures 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 run-in period were included. .

[0317] Secondary endpoint results Initiation of clinical response At each visit, subjects were assessed for 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 days 8, 15, or 22. However, the score must show at least a 25% improvement. Subjects who did not meet the required criteria or who discontinued the study for any reason before Day 28 were , considered non-responders, assigned a value of "no," and did not meet the criteria for the initiation of a clinical response. It means there wasn't.

[0318] As shown in Table 14 below, 7.9% of subjects in the esketamine + oral AD group experienced a significant improvement in the active A clinical response was achieved in 4.6% of subjects in the control group. The difference between the treatment groups was 0.05 at a one-sided level of 0.05. 025 was not statistically significant. Therefore, the pre-defined secondary endpoints of interest were Based on the test sequence, the SDS total score and PHQ-9 total score were formally assessed. I couldn't do it.

[0319] [Table 14]

[0320] 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) as presented in Table 15 and Figures 3 to 5 It was.

[0321] [Table 15]

[0322] Sheehan Disability Scale (SDS) The SDS is a subject-reported outcome measure widely used to assess functional impairment and related disorders. It is a commonly used and accepted five-item questionnaire. The first three items are rated on a 0-10 scale. Use the degree to manage disruptions in (1) work / school, (2) social life, and (3) family life / home responsibilities. The scores for the first three items are added together to create a total score between 0 and 30, and the Higher scores indicate greater impairment.

[0323] 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 .

[0324] 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.

[0325] [Table 16]

[0326] 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.

[0327] 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 .

[0328] 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

[0329] [Table 17]

[0330] 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:

[0331] Adverse events Adverse events will be reported to the subject (or, where appropriate, caregiver, surrogate, or Adverse events were reported by the investigator. TEAEs of special interest were examined separately.

[0332] 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.

[0333] The following tests were performed by a central laboratory unless otherwise noted.

[0334] [Table 18]

[0335] [Table 19]

[0336] [Table 20]

[0337] 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. Female subjects will be screened for blood tests only if necessary to demonstrate they are not of childbearing potential. Serum follicle-stimulating hormone (FSH) level test (referring to inclusion criterion No. 0)

[0338] Single 12-lead ECG During ECG collection, subjects were asked to sit quietly and without distractions (e.g., television, cell phone). The subject should be in a supine position and resting for at least 5 minutes before ECG collection. and should refrain from talking or moving their arms or legs.

[0339] 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.

[0340] 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.

[0341] Tympanic temperature was recommended. Automated equipment was used to measure respiratory rate.

[0342] 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.

[0343] 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 subject is referred to appropriate medical care if clinically indicated. Pulse oximetry was performed every 5 minutes until the patient was discharged.

[0344] 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

[0345] 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. The aim was to exclude any subjects that were likely to be affected.

[0346] Subsequent examinations include nasal stenosis for nasal erythema, rhinorrhea, rhinitis, capillary / vascular breakdown, and nosebleeds. 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.

[0347] nasal symptom questionnaire Subjects completed a nasal symptom questionnaire to assess nasal tolerance after intranasal administration of the study drug. The questionnaire asks about nasal symptoms and is evaluated by the subjects. Rated by subjects as none, mild, moderate, or severe based on how they feel at times. It was determined.

[0348] 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 can be conducted 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.

[0349] 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.

[0350] 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, 16-1 Participants' experiences were divided into two categories: memory loss (items 14, 15, and 22). Responses were coded on a 5-point scale (0 = not at all to 4 = extremely). It has inter-subject reliability and internal consistency.

[0351] BPRS+ Four items of the BPRS were administered to assess potential treatment-emergent psychotic symptoms. The BPRS is a measure of psychotic symptoms and affect, assessed both by subject observation and by subject self-report. It is an 18-item rating scale used to assess a range of symptoms. It provides rapid and efficient assessment of treatment response in drug trials and clinical settings. The four-item positive symptom subscale of the BPRS+ (i.e., suspiciousness, hallucinations, abnormal thought content, and Only the variances (i.e., the number of items and conceptual confusion) were used, which are highly sensitive to change and are not affected by training and standard interventions. Good interrater reliability can be achieved using interview procedures.

[0352] 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 (general anesthesia); Corresponding to the ASA continuum) ~5 = Responds easily to name spoken in a normal tone (alertness, (corresponding to the ASA continuum of minimal sedation).

[0353] 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 score was dropped. The MOAA / S was performed every 5 min until the AA reached 4 (at which point t = post-dose + 1). (Subjects may resume every 15 minutes for up to 5 hours.) Subjects will be administered at t = +1.5 hours post-dose. Subjects were further monitored if they did not have a score of at least 5. For subjects with a score of 3 or less, the assessment was repeated every 15 minutes. Assessments were repeated every 5 minutes until the score returned to 5, or if clinically indicated, the subject was reassigned. I referred him to the appropriate medical facility.

[0354] CGADR The CGADR is used to measure the current clinical status of the subject and will be used to determine the The clinician's assessment of the subject's overall clinical status (e.g., readiness to Patients considered ready for discharge based on their clinical status (e.g., sedation, blood pressure, and other adverse events) They answered "yes" or "no" to the question "Can you do this?"

[0355] 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 Repeat assessment every 15 minutes until subject is referred to appropriate medical care if clinically indicated. No subjects were discharged before the 1.5 hour time point. On the day of the screening, the subject will be kept at the clinical site until study procedures are completed and the subject is ready for discharge. It stayed.

[0356] PWC-20 Conduct the 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.

[0357] 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.

[0358] BPIC-SS BPIC-SS is a suitable bladder screening program for clinical trials evaluating new treatments for bladder pain syndrome. It is a subject-reported outcome measure developed to identify the bladder pain syndrome / interstitial cystitis population. do.

[0359] 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 pain and / or pressure in the bladder, including urinary frequency, were identified by subjects with BPS. Subjects responded to items using a 5-point scale (based on frequency). For the question, 0 = never, 1 = rarely, 2 = occasionally, 3 = most of the time, 4 = always. and for items regarding symptom-related hassle, 0 = not at all, 1 = a little, 2 = somewhat; Question 8 asks participants to rate their experiences over the past seven days using a 0-10 numeric rating scale. The worst bladder pain is recorded. Add this number to the response option selected by the subject. The scale's likelihood score ranges from 0 to 38. A total score of 19 or greater demonstrated good sensitivity / specificity and indicated no significant bladder symptoms or bladder pain. was considered as a relevant cutoff for distinguishing from flame.

[0360] If any item was missing, a total score could not be calculated.

[0361] In the current study, subjects had a score >18 on the BPIC-SS scale and were screened by urinalysis and microscopy. If there was no evidence of a urinary tract infection based on the examination, the subject was referred to a specialist for further evaluation. Therefore, in addition to the urine test, the BPIC-SS score was obtained on the applicable test day. If >18, a urine culture was obtained.

[0362] 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 was scored using the arcsine transformation of the percentage of correct responses. Startup test Working memory (n-back); score correct response rate (log10 transformed response rate of correct responses) average over time) Executive Function; Maze / Sequencing Test (scored for total number of errors)

[0363] All measures have been validated against traditional neuropsychological tests and are associated with alcohol and High accuracy in assessing the effects of various drugs, including benzodiazepines, on cognitive performance. Completion of the battery requires approximately 25 minutes.

[0364] 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 study included a 20-minute delayed recall trial (including a 20-minute word sequence), and a computer-assisted delayed recall trial. The tester is prompted, and instructions and a 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.

[0365] The tests were administered in the following order: HVLT-R, computerized cognitive test; Battery, and HVLT-R (delayed).

[0366] 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 performed were as follows:

[0367] The UPSIT is the most widely used test in the world to assess a subject's ability to identify odors. This standardized test is derived from basic psychological test measurement theory and identifies odorants at suprathreshold levels. The UPSIT focuses on the comparative ability of the target. Each consisted of 10-5 pieces located on a brown strip at the bottom of the booklet pages. embedded in 0 μm polymer microcapsules, 10 “scratch-and-scratch” The instrument contains a "f" odorant. The internal consistency and test-retest reliability coefficients for this instrument are >0. 90. Many studies have shown that this and related tests are effective against viruses, head trauma, and other conditions. Sensitive to subtle changes in olfactory function associated with multiple etiologies, including those resulting from several neurodegenerative diseases This indicates that it is a feeling.

[0368] 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.

[0369] These tests were performed bilaterally (i.e., both nostrils simultaneously). This was done during the screening / prospective observation period to establish baseline sensitivity. The magnitude of change from baseline in the CI was determined over time. Rates served as the dependent measure for each subject at each test.

[0370] MINI Subjects were randomly assigned to a randomized controlled trial to confirm the diagnosis of MDD and to determine whether other psychiatric conditions were present. To do this, they underwent a MINI (Mini Structured Diagnostic Interview), which lasted approximately 1 The test has a 5-minute implementation time.

[0371] 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 degree of improvement is assessed on a scale of % (completely improved) to % (completely improved). It was completed in collaboration with

[0372] 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. and answer yes or no to questions about high blood pressure (these are (This is the "STOP" item in the G acronym.) This takes approximately one minute.

[0373] Test facility staff were asked to 2 (over 50?), 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.

[0374] 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).

[0375] 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. Independent facility selection by telephone during the screening / prospective observation period for all subjects A personality assessment was conducted.

[0376] 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.

[0377] 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

[0378] Menstrual cycle tracking (start date of last menstrual period) specified in time and event schedule The study visits were documented at the scheduled visits.

[0379] PAQ Subjects to their oral antidepressant treatment regimen during the screening / prospective observation period Adherence was assessed using the PAQ, which measures how often subjects take their antidepressant medication. Subjects were on an antidepressant treatment regimen or had made any change to an antidepressant treatment regimen in the past 2 weeks. to assess whether changes were made. This is a brief, two-item, subject-reported outcome measure developed in the c–f were calculated by adding the response choices (0 = adherence, 1 or more = non-adherence).

[0380] 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.

[0381] Target completion / exit completion Subjects were randomly assigned to the MAD at the end of the 4-week double-blind run-in period (i.e., Day 28 MADRS). Completion of the RS assessment was considered completion of the double-blind run-in phase of the study. Subjects who prematurely discontinue study treatment for any reason before completion of the enrollment period will be considered for study duplication. Subjects who entered the follow-up period were not considered to have completed the blinded run-in period. Completion of the MADRS assessment at week 24 of the uptake phase will be considered completion of this phase of the study. It was.

[0382] Withdrawal from the study Subjects were withdrawn from the study for any of the following reasons: 1. Lost to follow-up 2. Withdrawal of consent 3. Violation of protocol procedures (determined on a case-by-case basis) 4. The blind was lifted (double-blind run-in 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

[0383] 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 to

[0384] If a subject withdrew before completing the study, the reason for withdrawal was documented. The assigned investigational drug was not allocated to another subject. If a patient discontinues the study before the end of the double-blind run-in period for any reason, the early withdrawal visit will be held on the same day as the date of discontinuation. This was done within a week and followed by a follow-up period.

[0385] Safety analysis Safety data were analyzed for the double-blind run-in period using the safety analysis set.

[0386] Adverse events Verbatim terms used by investigators in eCRFs to identify adverse events All reported events with onset during the double-blind run-in 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 the given event was calculated. Adverse events occurring during the follow-up period were summarized separately.

[0387] 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.

[0388] Laboratory tests 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.

[0389] ECG Effects on cardiovascular variables were assessed by descriptive statistics and frequency summaries. These tables are , including observed values ​​and changes from baseline values.

[0390] 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.

[0391] 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.

[0392] Descriptive statistics of QTc interval and change from double-blind baseline were obtained at each scheduled time point. QTc <30 ms, 30-60 ms, or >60 ms from baseline The proportion of subjects with QTc intervals >450 msec, >480 msec, or >490 msec, as well as the proportion of subjects with increased intervals summarized the percentage of subjects with >500 ms.

[0393] 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).

[0394] 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.

[0395] Nose examination Changes in findings from baseline nasal examination (including upper airway / pharynx) were listed by treatment group. Examination of the nostrils and nasal mucosa for nasal erythema, rhinorrhea, 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.

[0396] nasal symptom questionnaire Scores from the nasal symptom questionnaire were summarized descriptively by treatment group for each scheduled time point. .

[0397] 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.

[0398] CADSS, BPRS+, and MOAA / S Descriptive statistics and change from pre-dose for each score were summarized at each scheduled time point.

[0399] Clinical Global Assessment of Discharge Readiness, PWC-20, BPIC-SS, UPSIT, and Olfaction 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.

[0400] Cognitive testing Descriptive statistics and changes from baseline in cognitive domain scores were collected at each scheduled time point. We agreed.

[0401] 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). (defined according to the International Conference on Harmonisation (ICH)) This may include new onset or an increase in severity or severity from baseline. is a deterioration in frequency of any episode or abnormality in diagnostic procedures, including abnormalities in laboratory tests This includes results that are

[0402] 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. "Threatening to life" does not refer to events that, if more severe, might have resulted in death. stomach.) -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 *

[0403] * Is likely to endanger the subject even if it is not immediately life-threatening or results in death or hospitalization Interventions to prevent one of the other consequences listed in the definition above Expedited reporting is also appropriate in other situations, such as serious medical events, where this may be necessary. Medical and scientific judgment must be exercised in determining whether to It must be considered serious.

[0404] 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.

[0405] 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.

[0406] 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.

[0407] 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.

[0408] Unrelated: Adverse events not related to drug use.

[0409] Doubtful: Adverse event for which an alternative explanation is more likely, e.g., concomitant medications, intercurrent illnesses, Or the time relationship suggests that a causal relationship is unlikely.

[0410] Possible: Adverse event that can be attributed to the use of the drug. Alternative explanations, e.g., concomitant medications, Onset is inconclusive. The time relationship is reasonable, and therefore causation cannot be ruled out. I was unable to do this.

[0411] High probability: Adverse event that can be attributed to drug use. The time relationship was suggestive (e.g. (Confirmed by discontinuation of drug administration, if any). Alternative explanations, e.g., concomitant medications, comorbidities, The possibility was low.

[0412] Likely: Listed as a possible adverse reaction and alternative explanations, e.g., concomitant medications, Adverse events that could not be reasonably explained by onset. The time relationship is highly suggestive. was effective (e.g., as evidenced by interruption and resumption of drug administration).

[0413] 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 functio...

Claims

1. 1. A method of treating depression, comprising: A subject suffering from depression is administered an approved formulation that contains esketamine. administering the compound in the amount prescribed on the label.

2. 10. The method of claim 1, wherein the depression is treatment-resistant depression.

3. 3. The method of claim 1 or 2, wherein a therapeutically effective amount of an oral antidepressant is co-administered with the esketamine. The method described.

4. The method of any one of claims 1 to 3, wherein the esketamine is delivered intranasally.

5. The esketamine is administered to the subject at least twice weekly during a lead-in period of at least four weeks. The method according to any one of claims 1 to 4, wherein the

6. 6. The method of claim 5, wherein the subject is evaluated after the induction period to determine the need for continued treatment. The method described.

7. The esketamine is administered to the subject up to once a week during a subsequent maintenance phase. Item 7. The method according to item 5 or 6.

8. 8. The method of claim 7, wherein the esketamine is administered once every two weeks during the subsequent maintenance phase. How to.

9. The administration frequency can be adjusted during the induction phase and / or the maintenance phase.

9. The method according to any one of claims 8 to 9.

10. The amount of esketamine administered during the induction phase is from about 28 mg to about 84 mg. The method according to any one of claims 5 to 9.

11. 11. The method of claim 10, wherein the amount of esketamine is about 28 mg.

12. 11. The method of claim 10, wherein the amount of esketamine is about 56 mg.

13. 11. The method of claim 10, wherein the amount of esketamine is about 84 mg.

14. the amount of esketamine is about 56 mg at the beginning of the induction phase and The method of claim 10, wherein the dosage is adjusted to about 84 mg.

15. 12. The method of claim 11, wherein the patient is 65 years of age or older.

16. The amount of esketamine administered during the maintenance phase is about 56 mg or about 84 mg. The method according to any one of claims 7 to 15,

17. 12. The method of claim 1, wherein the amount of esketamine is delivered in two or more sprays from an intranasal administration device.

17. The method according to any one of claims 1 to 16.

18. 20. The method of claim 17, wherein the intranasal device is a single-use device.

19. 20. The method of claim 18, wherein the single-use device comprises about 28 mg of the esketamine. 。

20. After approximately 16 weeks of treatment and improvement in depressive symptoms, the treatment was used to reduce the risk of relapse. The method according to any one of claims 1 to 19, wherein the step of

21. 20. The method of claim 1, wherein the treatment is continued for at least 6 months after improvement of depressive symptoms.

2. The method according to any one of claims 1 to 11.

22. The method of any one of claims 1 to 19, wherein the treatment continues for up to one year.

23. The method of any one of claims 1 to 19, wherein the treatment is continued for up to two years.

24. A method of selling an approved drug product containing esketamine, comprising selling said drug product. and the formulation label of the reference listed drug product includes instructions for treating depression. Law.

25. 1. A method of offering for sale a formulation comprising esketamine, comprising: and performing a step of administering to said patient a drug product reference-listed on the drug product label for treating depression. The method includes:

26. The drug product is an ANDA drug product, a supplemental new drug application drug product, or a section 505(b)(2) drug product. The method of claim 24 or 25, wherein the

27. The method according to any one of claims 24 to 26, wherein the depression is treatment-resistant depression. Law.

28. The formulation label includes instructions for co-administering the esketamine with an oral antidepressant. The method according to any one of claims 24 to 27.

29. Claim 1, wherein the formulation label includes data regarding improvement in depressive symptoms versus placebo.

29. The method according to any one of claims 24 to 28.

30. An approved drug product having at least one approved indication, comprising esketamine , Approved Formulations.

31. The approved drug product is a NDA drug product, an ANDA drug product, a supplemental new drug application drug product, or a 505 31. The approved preparation of claim 30, which is a preparation under section (b)(2).

32. 32. The approved formulation of claim 31, wherein the reference list of approved formulations includes a formulation label. Preparations.

33. Claim 1, wherein the formulation label includes data regarding improvement in depressive symptoms versus placebo.

32. An approved formulation according to claim 32.

34. 34. Any of claims 30 to 33, wherein the formulation label includes instructions for frequency and duration of administration.

2. The approved formulation according to claim 1.

35. The esketamine has a maximum plasma concentration (C ｍａｘ ), and about 125 to about 490 ng ＊ h / mL from time 0 to the last quantifiable concentration (AUC ｌａｓｔ )'s blood 35. The method of claim 30, wherein the plasma concentration-time area under the curve is achieved, or a combination thereof. The approved drug product according to any one of claims 1 to 5.

36. The approved formulation has a maximum plasma concentration (C) of esketamine of about 45 to about 75 ng / mL. ｍ ａｘ ), about 125 to about 185 ng ＊ h / mL from time 0 to the last quantifiable concentration (AUC ｌａ ｓｔ ), or a combination thereof.

36. The approved formulation of claim 35, which contains ketamine.

37. The approved formulation contains about 56 mg of esketamine, and Administration results in a maximum plasma concentration (C) of esketamine of about 65 to about 120 ng / mL. ｍａｘ ), about 2 10 to about 320ng ＊ h / mL from time 0 to the last quantifiable concentration (AUC ｌａｓｔ ) plasma 36. The approved method of claim 35, wherein the method achieves a concentration-time area under the curve, or a combination thereof. Preparations.

38. The approved formulation contains about 84 mg of esketamine, and the administration of the esketamine to a patient Administration results in a maximum plasma concentration (C) of about 90 to about 165 ng / mL. ｍａｘ ), about 305 to about 490 ng ＊ h / mL from time 0 to the last quantifiable concentration (AUC ｌａｓｔ Plasma concentration-time curve of 36. The approved formulation of claim 35, which achieves a lower area, a lower area, or a combination thereof.

39. The method according to any one of claims 30 to 38, wherein the indication is treatment-resistant depression. Approved formulation.

40. The approved product includes one or more intranasal spray devices, and the one or more devices are wherein the one or more devices contain from about 28 to about 84 mg of esketamine. The approved product according to any one of claims 30 to 39, adapted for administration. How to use:

41. The one or more devices are configured to administer the esketamine in two or more sprays. The method of claim 40,

42. 42. The method of claim 40 or 41, wherein the one or more devices contain about 28 mg of esketamine. How to.

43. 4. The one or more devices each contain about 28 mg of esketamine.

3. The method according to any one of claims 2 to 3.

44. Any of claims 40 to 43, wherein each of the one or more devices is a single-use device.

13. The method according to claim 1.

45. A method according to any one of claims 40 to 44, wherein the product comprises three devices.

46. The method of any one of claims 40 to 45, wherein the esketamine is administered to a patient. Law.

47. 47. The method of claim 46, wherein the esketamine is administered to a patient under the supervision of a medical professional. The method described.

48. 48. The method of claim 47, wherein the esketamine is administered in two puffs from a single device. 。

49. 49. The method of claim 48, wherein one spray is administered to each nostril of the patient.

50. 50. The method of claim 49, wherein the single device is discarded after the second spray.

51. 6. The method of claim 5, wherein approximately five minutes elapse between any two uses of the one or more devices. The method according to claim 0.

52. A method for reducing the risk of misuse or abuse of esketamine, comprising administering to a subject an approved restricting distribution of the formulation to selected distributors, which distributors may then provide to the Drug Enforcement Administration is registered and provides the approved esketamine formulations only to pre-approved care facilities. To provide, a method.

53. The pre-approved care facility is a hospital, mental health clinic, doctor's office, or 53. The method of claim 52, which is an outpatient pharmacy.

54. The care facility has a Food and Drug Administration-approved risk assessment for esketamine. The method of claim 52 or 53, which is certified under Evaluation and Risk Mitigation Strategy (REMS). Law.

55. The REMS is characterized in that esketamine is self-administered by the patient under the supervision of a medical professional. The method of claim 54, further comprising determining:

56. The approved formulation of esketamine includes a nasal spray device. The method according to any one of claims 1 to 5.

57. The nasal spray device is a single-use device that delivers 28 mg of esketamine in only two sprays. a disposable device for use in a single-use application, wherein minimal residual esketamine remains after said second nebulization; 57. The method of claim 56.

58. 58. The method of claim 57, wherein the minimal remaining residual esketamine is less than about 4 mg. method.

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