Esketamine for the treatment of depression

Abstract

The present invention provides a method for maintaining stable remission or stable response achieved by a patient with depression after administration of a therapeutically effective amount of esketamine during an initial dosing period, comprising continuing administration of a therapeutically effective amount of esketamine for at least five months during subsequent dosing periods. The present invention also provides a method for long-term treatment of depression in a patient, comprising administering to a patient in need of treatment a therapeutically effective amount of esketamine that has been proven clinically safe and clinically effective for at least six months. In some embodiments, the depression is major depressive disorder or treatment-resistant depression.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 755,905, filed November 5, 2018, U.S. Provisional Patent Application No. 62 / 675,846, filed May 24, 2018, U.S. Provisional Patent Application No. 62 / 667,406, filed May 4, 2018, U.S. Provisional Patent Application No. 62 / 663,206, filed April 26, 2018, U.S. Provisional Patent Application No. 62 / 663,219, filed April 26, 2018, and U.S. Provisional Patent Application No. 62 / 609,504, filed December 22, 2017, all of which are incorporated herein by reference in their entireties.

[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 methods are useful for treating treatment-refractory or treatment-resistant depression. In other embodiments, the methods are useful for treating suicidal ideation. The present invention comprises administering to a patient in need thereof a therapeutically effective amount of esketamine, proven clinically safe, as monotherapy or in combination with at least one antidepressant. [Background technology]

[0003] Major depressive disorder (MDD) affects approximately 7–15% of the general population. MDD is associated with significant morbidity and mortality and is a leading cause of disability worldwide. Approximately one-third of patients fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression (TRD). Such patients who benefit from oral antidepressants (AD) have a high relapse rate despite continued treatment.

[0004] The impact of TRD on patients' lives is difficult to adequately describe. Many patients experience depressive episodes that last for years. Severely depressed patients lose the will to continue living their lives, 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 even engage in self-care, neglecting caregiving duties such as parenting or spousal care. This affects not only the patients themselves, but also their families and those who depend on them. They also lose the ability to find pleasure in doing things they previously enjoyed, robbing people of the essence and motivation of life. In effect, their lives are taken away from them by TRD. These effects are theorized to be related to dysregulation of the glutamate pathway.

[0005] Glutamate is the major excitatory neurotransmitter in the mammalian brain and plays a prominent role in synaptic plasticity, learning, and memory. At high levels, glutamate is a potent neuroexcitotoxin that can induce rapid or delayed neurotoxicity. Over the years, interest in the role of glutamate in the pathophysiology of depression has grown, as abnormal activity of the glutamatergic system likely contributes to the impaired synaptic plasticity observed in depressed patients. The classical anesthetic ketamine has demonstrated activity not only in animal models of depression but also in small-scale clinical trials in patients with major depressive disorder, including those with treatment-resistant depression. At subanesthetic doses administered intravenously, ketamine exhibits robust antidepressant effects in patients, which last for several days after a single administration and can be maintained for several weeks via repeated infusions.

[0006] Ketamine (a racemic mixture of the corresponding S- and R-enantiomers) is a nonselective antagonist at the phencyclidine binding site of glutamate N-methyl-D-aspartate (NMDA) receptors, but this may not primarily mediate its antidepressant effects. The enantiomer S-ketamine (esketamine) exhibits approximately 3-4 times higher affinity for glutamate NMDA receptors in vitro than R-ketamine. A major concern with ketamine and esketamine is the potential for neurotoxicity associated with long-term use and whether repeated administration of ketamine / esketamine over time can maintain significant antidepressant efficacy (Molero, et al., "Antidepressant Efficacy and Tolerability of Ketamine and Esketamine: A Critical Review," CNS Drugs (2018) 32:411-420). Specifically, previous studies have shown that esketamine, in contrast to R-ketamine, failed to elicit sustained antidepressant effects in rodent models (C. Yang et al., "R-Ketamine: a rapid onset and sustained antidepressant without psychotomimetic side effects," Transl. Psychiatry (2015) 5:1-11). Furthermore, compared with R-ketamine, esketamine exhibited more undesirable psychotomimetic side effects, including a significant reduction in PV-positive cells in the brain, which is associated with psychiatric and cognitive impairment (ibid.). The literature does not provide guidance regarding the cumulative effects or tolerability of long-term administration of esketamine. Summary of the Invention [Problem to be solved by the invention]

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

[0008] The present invention is directed to a method for the treatment of depression (e.g., major depressive disorder), comprising administering to a patient in need of treatment a therapeutically effective amount of esketamine that has been proven clinically safe.

[0009] The present invention is further directed to a method for the treatment of depression (e.g., major depressive disorder), comprising administering to a patient in need thereof a combination therapy with a clinically proven safe and therapeutically effective amount of esketamine and at least one antidepressant, as defined herein.

[0010] The present invention is also directed to a method of maintaining stable remission or stable response achieved by a patient with depression after administration of a therapeutically effective amount of esketamine during an initial dosing period, comprising continuing to administer a therapeutically effective amount of esketamine for at least five months during subsequent dosing periods. In some embodiments, the depression is major depressive disorder or treatment-resistant depression.

[0011] The present invention is further directed to a method for the long-term treatment of depression in a patient, comprising administering to a patient in need of treatment a therapeutically effective amount of esketamine that has been proven clinically safe and / or proven clinically effective for at least six months. In some embodiments, the depression is major depressive disorder or treatment-resistant depression.

[0012] Methods of treatment include long-term treatment, which includes a duration of at least about 6 months. In some embodiments, treatment may be for a duration of at least about 1 year, at least about 18 months, or at least about 2 years. For example, long-term treatment may include a duration ranging from about 6 months to about 2 years. Treatment may extend for much longer periods, to the extent that the patient benefits from the treatment.

[0013] In some embodiments, the at least one antidepressant is independently selected from the group consisting of monoamine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic-specific serotonergic agents, noradrenaline reuptake inhibitors, natural products, dietary supplements, neuropeptides, compounds that target neuropeptide receptors, and hormones.

[0014] In another embodiment, a method for the treatment of depression (e.g., major depressive disorder) is provided, comprising administering to a patient in need thereof a clinically proven safe and therapeutically effective amount of esketamine in combination with an irreversible MAOI (phenezine, tranylcypromine), a reversible (MOAI) monoamine oxidase inhibitor (MOI), such as moclobemide, or a combination thereof. inhibitors (MAOIs), tricyclics such as imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, tetracyclics such as maprotiline, acyclics such as nomifensine, triazolopyridines such as trazodone, anticholinergics (e.g., scopolamine), serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, serotonin receptor antagonists such as nefazadone, tianeptine, serotonin receptor antagonists such as venlafaxine, desvenlafaxine, milnacipran, levomilnacipran, etc. The present invention also includes administering in combination with one or more compounds selected from the group consisting of noradrenergic reuptake inhibitors, noradrenergic and specific serotonergic agents such as mirtazapine, noradrenaline reuptake inhibitors such as reboxetine, atypical antipsychotics such as bupropion, lithium, triple reuptake inhibitors, natural products such as kava and St. John's wort, dietary supplements such as s-adenosylmethionine, and neuropeptides such as thyrotropin-releasing hormone, compounds targeting neuropeptide receptors such as neurokinin receptor antagonists, and hormones such as triiodothyronine.

[0015] In another embodiment, a method for treating depression (e.g., major depressive disorder) is provided, comprising administering to a patient in need of treatment a clinically safe and therapeutically effective amount of esketamine in combination with one or more compounds selected from the group consisting of monoamine oxidase inhibitors, tricyclics, tetracyclics, acyclics, triazolopyridines, serotonin reuptake inhibitors, serotonin receptor antagonists, serotonin noradrenergic reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic-specific serotonergic agents, noradrenaline reuptake inhibitors, atypical antipsychotics, natural products, dietary supplements, neuropeptides, compounds targeting neuropeptide receptors, and hormones. Preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of monoamine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic-specific serotonergic agents, atypical antipsychotics, and / or adjunctive therapy with antipsychotics (e.g., risperidone, olanzapine, quetiapine, aripiprazole, and ziprapadone). More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of monoamine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors.

[0016] In still a further embodiment, a method for the treatment of depression (e.g., major depressive disorder) is provided, comprising administering to a patient in need of treatment a clinically proven safe and therapeutically effective amount of esketamine in combination with one or more compounds selected from the group consisting of phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, bupropion, thyrotropin-releasing hormone, and triiodothyronine.

[0017] Preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of lithium, riluzole, phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, levomilnacipran, mirtazapine, and bupropion. More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine. More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine.

[0018] In yet a further embodiment, a method for the treatment of depression (e.g., major depressive disorder) is provided, comprising administering to a patient in need of treatment a clinically safe and therapeutically effective amount of esketamine in combination with one or more compounds selected from the group consisting of neuropeptides, such as thyrotropin-releasing hormone, compounds that target neuropeptide receptors, such as neurokinin receptor antagonists, and hormones, such as triiodothyronine.

[0019] In another embodiment, a method for the treatment of depression (e.g., major depressive disorder) is provided, comprising administering to a patient in need thereof a clinically safe and therapeutically effective combination therapy of esketamine, at least one antidepressant, and at least one atypical antipsychotic, as defined herein.

[0020] In a further embodiment, a method for the treatment of depression (e.g., major depressive disorder) is provided, comprising administering to a patient in need thereof a clinically safe and therapeutically effective amount of combination therapy with esketamine, at least one antidepressant, and at least one atypical antipsychotic selected from the group consisting of quetiapine, aripiprazole, brexipirazole, olanzapine, lurasidone, risperidone, and paliperidone.

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

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

[0023] The present invention is further directed to esketamine for use in a method for the treatment of depression (e.g., major depressive disorder), preferably treatment-refractory or treatment-resistant depression, in a subject in need of treatment.

[0024] In another embodiment, a composition comprising esketamine for the treatment of depression (e.g., major depressive disorder) is provided. In some embodiments, the composition is for the treatment of treatment-refractory or treatment-resistant depression. In other embodiments, the agent is for the treatment of suicidal behavior and / or suicidal ideation. [Brief explanation of the drawings]

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

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

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

[0026] The present invention is directed to methods comprising administering a clinically safe and therapeutically effective amount of esketamine to a patient in need of treatment for depression (e.g., major depressive disorder). In some embodiments, the method is for treating treatment-refractory or treatment-resistant depression. In other embodiments, the agent is for treating suicidal ideation.

[0027] These methods advantageously allow for the tailoring of effective regimens to patients with depression, including those already diagnosed with MDD, TRD, suicidal tendencies, or who are otherwise untreated for depression.

[0028] Also described are methods for maintaining stable remission or stable response achieved by a patient with depression after administering a therapeutically effective amount of esketamine during an initial dosing period, comprising continuously administering a therapeutically effective amount of esketamine for at least five months during subsequent dosing periods.

[0029] Thus, methods for the long-term treatment of depression in a patient are also provided. These methods involve administering to a patient in need of treatment a therapeutically effective amount of esketamine, which has been proven clinically safe and clinically effective, for at least six months. Desirably, the patient's cognitive performance remains stable based on baseline measurements after six months of treatment. In some embodiments, treatment may last at least about one year, at least about 18 months, or at least about two years. For example, long-term treatment may range in duration from about six months to about two years. Treatment may also be continued for longer periods, including, but not limited to, four, five, six, seven, eight, nine, ten years or more, as determined by the treating physician. In some embodiments, esketamine is initially administered twice weekly for up to four weeks during an induction period, and then administered less frequently than twice weekly thereafter.

[0030] In certain embodiments of the invention, esketamine may be administered in combination with one or more antidepressants, preferably in combination with 1 to 3 antidepressants, and more preferably in combination with 1 to 2 antidepressants, as described herein.

[0031] In certain embodiments of the present invention, esketamine may be administered in combination with one or more antidepressants, further in combination with one or more atypical antipsychotics, as described herein.

[0032] In embodiments, the invention is directed to a combination therapy comprising esketamine and one or more antidepressants, where esketamine is administered as an acute treatment. In another embodiment, the invention is directed to a combination therapy comprising esketamine and one or more antidepressants, where esketamine is administered as an acute treatment and one or more antidepressants are administered as a chronic treatment.

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

[0034] Some of the quantitative expressions set forth herein are not modified by the term "about." Whether or not the term "about" is explicitly used, all amounts set forth herein are understood to refer to their actual indicated values, and also to refer to approximations of such indicated values ​​that would be reasonably estimated based on ordinary skill in the art, including approximations based on experimental and / or measurement conditions of such indicated values.

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

[0036] [ka] Also known as (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone. "Esketamine" is also intended to mean a salt, for example a chloride salt, such as the hydrochloride salt, of the (S)-enantiomer of ketamine, i.e., the compound of formula (II):

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

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

[0039] [ka]

[0040] In other embodiments, the esketamine contains less than about 10% by weight of the (R)-enantiomer of ketamine, based on the weight of the esketamine sample. In further embodiments, the esketamine contains less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.005, or 0.001% by weight of the (R)-enantiomer of ketamine, based on the weight of the esketamine sample. In yet other embodiments, the esketamine contains from about 0.001 to about 10% by weight of the (R)-enantiomer of ketamine, based on the weight of the esketamine sample. In still further embodiments, the esketamine contains about 0.001 to about 10%, about 0.001 to about 5%, about 0.001 to about 1, about 0.001 to about 0.5, about 0.001 to about 0.1, about 0.1 to about 5, about 0.1 to about 1, about 0.1 to about 5, or about 0.5 to about 5% by weight of the (R)-enantiomer of esketamine, based on the weight of the esketamine sample.

[0041] The term "esketamine" may also include other pharmaceutically acceptable salts thereof, which may be readily selected by one skilled in the art. A "pharmaceutically acceptable salt" is intended to mean a salt of esketamine that is non-toxic, biologically tolerated, or otherwise biologically suitable for administration to a subject. See generally G.S. Paulekuhn, "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database," J. Med. Chem., 2007, 50:6665-72; S.M. Berge, "Pharmaceutical Salts," J. Pharm Sci., 1977, 66:1-19; and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are salts that are pharmacologically effective and suitable for administration to a patient without undue toxicity, irritation, or allergic response.

[0042] Examples of other pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide (such as hydrobromide), iodide (such as hydroiodide), acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1, 4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate salts. In particular, the salt of esketamine is the hydrochloride salt.

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

[0044] In certain embodiments of the invention, esketamine is administered intranasally as a solution containing 161.4 mg / mL esketamine hydrochloride (equivalent to 140 mg / mL esketamine base), 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL citric acid in water at a pH of 4.5. In certain embodiments of the invention, esketamine is administered intranasally, and intranasal delivery is by administering 100 μL of a solution containing 161.4 mg / mL esketamine hydrochloride (equivalent to 140 mg / mL esketamine base), 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL citric acid in water at a pH of 4.5. In one particular embodiment, esketamine is delivered intranasally using a nasal spray pump that delivers 100 μL of a solution containing 161.4 mg / mL esketamine hydrochloride (equivalent to 140 mg / mL esketamine base), 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL citric acid at a pH of 4.5 in water.

[0045] Generally, one pump from the nasal spray device may be configured to deliver about 50 μL to about 200 μL (including about 60 μL, about 70 μL, about 80 μL, about 90 μL, about 100 μL, about 110 μL, about 120 μL, about 130 μL, about 140 μL, about 150 μL, about 160 μL, about 170 μL, about 180 μL, and about 200 μL) of esketamine solution to a subject's nostril. Thus, two pumps would deliver about 100 μL to about 400 μL to a subject.

[0046] In certain embodiments of the present invention, the patient in need of treatment with a clinically proven safe and therapeutically effective amount of esketamine is a patient suffering from an episode of depression (e.g., major depressive disorder). In certain embodiments of the present invention, the patient in need of treatment is suffering from an episode of depression (e.g., major depressive disorder), where the episode of depression (e.g., major depressive disorder) has not responded to treatment with at least two oral antidepressants (i.e., the 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 an episode of depression (e.g., major depressive disorder), where the episode of depression (e.g., major depressive disorder) has not responded to treatment with two oral antidepressants (i.e., the elderly patient has not responded to treatment with two oral antidepressants).

[0047] In certain embodiments of the invention, the patient in need of treatment is suffering from depression (e.g., major depressive disorder), for example, a patient having a score of 18 or greater as measured by the MADRS or a score of 4 or greater on the CGI scale.

[0048] As used herein, the term "depression" includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, menstrual cycle disorder, situational depression, anhedonia, melancholia, mid-life depression, late-life depression, depression due to an identifiable stressor, treatment-resistant depression, or combinations thereof. In certain embodiments, the depression is major depressive disorder. In other embodiments, major depressive disorder is accompanied by depressive features or anxiety distress. In further embodiments, the depression is treatment-resistant depression.

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

[0050] As used herein, the term "episode of major depressive disorder" means a continuous period (e.g., about 2 weeks or more) during which a patient has sufficient symptoms of major depressive disorder to meet the criteria for major depression as specified in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM 5).

[0051] As used herein, "suicide" is "the act of taking one's own life." See http: / / en.wikipedia.org / wiki / Suicide-cite_note-7. Suicide includes suicide attempts or non-fatal suicidal behavior, which is self-injury involving the desire to end one's life and does not result in death. A suicide attempt is a self-initiated sequence of actions by an individual who, at the time of initiation, anticipates that the series of actions will lead to their death.

[0052] As used herein, "suicidal ideation" refers to thoughts about or an abnormal preoccupation with suicide, or thoughts of taking one's own life or not wanting to live any longer, but not necessarily making any active attempt to do so. Suicidal ideation ranges from transient to chronic and progresses to detailed planning, role-playing, and failed attempts, which may be deliberately constructed to fail or be discovered, or may be fully intended to result in death. In some embodiments, a patient is classified as "suicidal" when the patient has an average baseline MADRS total score of about 38 or greater. In other embodiments, a patient is classified as suicidal when the patient has an average baseline BBSS score of 22 or greater. In further embodiments, a patient is classified as suicidal when the patient has a score of 6 or greater on the SIBAT Clinical Global Assessment of Suicide Risk. In still other embodiments, a patient has a combination of one or more of these scores.

[0053] As used herein, the terms "concomitant therapy," "combination therapy," "adjunctive therapy," "combination treatment," and "co-administration" refer to the treatment of a patient in need thereof by administering esketamine in combination with one or more antidepressants, wherein the esketamine and antidepressant(s) are administered by any suitable means. In some embodiments, esketamine is administered in a regimen with one to five antidepressants. In other embodiments, esketamine is administered in a regimen with one, two, three, four, or five antidepressants. In other embodiments, esketamine is administered in a regimen with one or two antidepressants. In further embodiments, esketamine is administered in a regimen with an antidepressant currently administered to the patient. In other embodiments, esketamine is administered in a regimen with a different antidepressant. In yet further embodiments, esketamine is administered in a regimen with an antidepressant not previously administered to the patient. In yet other embodiments, esketamine is administered in a regimen with an antidepressant previously administered to the patient. When esketamine and the antidepressant(s) are administered in separate dosage forms, the number of daily doses administered for each compound can be the same or different, and more typically different. The antidepressant may be administered as prescribed by the treating physician and / or according to its label, and esketamine is administered as described herein. Typically, the patient is under concurrent treatment with both an antidepressant and esketamine, both of which are administered according to their prescribed dosing regimens.

[0054] Esketamine and the antidepressant(s) may be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intranasal (in), intramuscular (im), subcutaneous (sc), transdermal, buccal, and rectal. In some embodiments, esketamine is administered intranasally. As used herein, unless otherwise specified, the term "antidepressant" refers to any medication that can be used to treat depression. Suitable examples include, but are not limited to, monoamine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic-specific serotonergic agents, or atypical antipsychotics. Other examples include monoamine oxidase inhibitors such as phenelzine, tranylcypromine, and moclobemide; tricyclics such as imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, and amoxapine; tetracyclics such as maprotiline; acyclics such as nomifensine; triazolopyridines such as trazodone; serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine; serotonin receptor antagonists such as nefazadone; venlafaxine, milnacipran, and desben. These include, but are not limited to, serotonin-norepinephrine reuptake inhibitors such as lafaxine, duloxetine, levomilnacipran, noradrenergic and specific serotonergic agents such as mirtazapine, noradrenaline reuptake inhibitors such as reboxetine and edivoxetine, atypical antipsychotics such as bupropion, natural products such as kava and St. John's wort, dietary supplements such as s-adenosylmethionine, and neuropeptides such as thyrotropin-releasing hormone, compounds targeting neuropeptide receptors such as neurokinin receptor antagonists, and hormones such as triiodothyronine.In some embodiments, the antidepressant is imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, kavakava, St. John's wort, s-adenosylmethionine, thyroid hormone-releasing hormone, neurokinin receptor antagonist, or triiodothyronine. Preferably, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine, and sertraline.

[0055] Therapeutically effective amounts / dosage levels and dosing regimens for antidepressants (e.g., monoamine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin-noradrenaline reuptake inhibitors, noradrenergic-specific serotonergic agents, noradrenaline reuptake inhibitors, natural products, dietary supplements, neuropeptides, compounds targeting neuropeptide receptors, hormones, and pharmaceuticals described herein) may be readily determined by one of skill in the art. For example, therapeutic dosages and regimens for pharmaceuticals approved for sale are generally available and are listed, for example, on package labels, standard dosing guidelines, standard medication references such as the Physician's Desk Reference (Medical Economics Company or online at http: / / www.pdrel.com), or other sources.

[0056] As used herein, the term "antipsychotic" includes, but is not limited to: (a) Typical or conventional antipsychotics, such as phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin), thioxanthenes (e.g., thiothixene, flupentixol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), substituted benzamides (e.g., sulpride, amisulpride), and the like; and (b) Atypical antipsychotics and mood stabilizers, such as paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, ORG-5222 (Organon), etc.; and others, such as sonepiprazole, aripiprazole, nemonapride, SR-31742 (Sanofi), CX-516 (Cortex), SC-111 (Scotia), NE-100 (Taisho), etc.

[0057] In embodiments, the "atypical antipsychotic" is selected from the group consisting of aripiprazole, quetiapine, olanzapine, risperidone, and paliperidone. In another embodiment, the atypical antipsychotic is selected from the group consisting of aripiprazole, quetiapine, olanzapine, and risperidone, preferably, the atypical antipsychotic is selected from the group consisting of aripiprazole, quetiapine, and olanzapine.

[0058] As used herein, the term "treatment-refractory or treatment-resistant depression" and the abbreviation "TRD" are defined as major depressive disorder in patients who have not responded adequately to at least two different antidepressants, preferably two to five antidepressants, in their current depressive episode. In another embodiment, TRD is defined as major depressive disorder in patients who have not responded adequately to at least two oral antidepressants at adequate doses and durations in their current depressive episode.

[0059] Those skilled in the art will recognize that non-response to a given series of suitable antidepressants can be determined retrospectively or prospectively. In an embodiment, at least one of the non-response to a given series of suitable antidepressants is determined prospectively. In another embodiment, at least two of the non-response to a given series of suitable antidepressants is determined prospectively. In another embodiment, at least one of the non-response to a given series of suitable antidepressants is determined retrospectively. In another embodiment, at least two of the non-response to a given series of suitable antidepressants is determined retrospectively in the current depressive episode.

[0060] The "at least two oral antidepressants" or "at least two different oral antidepressants" are administered to the patient at appropriate doses, which may be determined by the patient's physician. Similarly, the antidepressants are administered for a suitable duration, which may be determined by the patient's physician.

[0061] As used herein, unless otherwise indicated, the terms "treat" and "treatment" and the like include the management and care of subjects or patients (preferably mammals, more preferably humans) for the purpose of treating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the occurrence of symptoms or complications, alleviate symptoms or complications, or eliminate the disease, condition, or disorder.

[0062] As used herein, unless otherwise indicated, the term "clinically proven" (used independently or to modify the terms "safe" and / or "effective") means evidence established by Phase III clinical trials sufficient to meet the approval criteria of the U.S. Food and Drug Administration or similar studies for market authorization by the EMEA. Preferably, esketamine trials use appropriately sized, randomized, double-blind, controlled trials to clinically prove the efficacy of esketamine. Most preferably, this will be a randomized, double-blind, active-controlled trial of flexibly administered intranasal esketamine (28 mg, 56 mg, or 84 mg ± 20%) co-administered with a newly started or currently started oral antidepressant compared to a newly started or currently started oral antidepressant (active comparator) plus intranasal placebo to clinically demonstrate the efficacy of esketamine for treating major depressive disorder, e.g., treatment-resistant depression, with patient status assessed by techniques described herein, such as the MADRS, Hamilton, CGI, Beck Depression Rating Scale, QIDS, or PHQ-9, including assessments on days 1 through 28 as well as during subsequent dosing periods as described herein.

[0063] As used herein, unless otherwise specified, the term "clinically proven effective" means that the effectiveness of the treatment has been proven statistically significant by a Phase III clinical trial, i.e., the clinical trial results are unlikely to be attributable to an alpha level of less than 0.05, or the clinical effectiveness results are sufficient to meet the approval standards of the U.S. Food and Drug Administration or similar tests for market approval by the EMEA. For example, esketamine, administered flexibly intranasally at a therapeutically effective dose of 28 mg, 56 mg, or 84 mg (±25%), has been proven clinically effective for treating patients with major depressive disorder, e.g., treatment-resistant depression, when administered as part of a dosing regimen including an induction phase and a maintenance phase as described herein, and when co-administered with a newly initiated or currently initiated oral antidepressant, in reducing a patient's MADRS score by at least about 50% for patients with a baseline MADRS score, as specifically described in the Examples.

[0064] As used herein, unless otherwise specified, the term "safe" when referring to a pharmaceutical treatment (therapy) or combination therapy shall mean free from undue adverse side effects (such as toxicity, irritation, or allergic reaction) and, when used in the manner of the present invention, is commensurate with a reasonable benefit / risk ratio.

[0065] As used herein, unless otherwise specified, the term "clinically proven safe" means that a Phase III clinical trial has demonstrated the safety of the treatment through analysis of the test data and results, establishing that the treatment is devoid of excessive side effects and commensurate with a statistically significant clinical benefit (efficacy) sufficient to meet the approval criteria of the U.S. Food and Drug Administration or similar trials for market authorization by the EMEA. For example, esketamine, administered flexibly intranasally at therapeutically effective doses of 28 mg, 56 mg, or 84 mg (±25%), has been proven clinically safe for the treatment of patients with major depressive disorder, e.g., treatment-resistant depression, when administered as part of a dosing regimen including an induction and maintenance phase as described herein, and when co-administered with a newly initiated or currently initiated oral antidepressant, as specifically described in the Examples.

[0066] As used herein, the term "therapeutically effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal, or human, that is desired by a researcher, veterinarian, physician, or other clinician, including alleviation of the symptoms of the disease or disorder being treated. Desirably, a therapeutically effective amount is an amount that has been clinically proven to be safe and clinically effective. In some embodiments, an antidepressant is utilized in a therapeutically effective amount as determined by the attending physician. In other embodiments, esketamine is utilized in a therapeutically effective amount.

[0067] A therapeutically effective amount of esketamine and / or an antidepressant may be administered during the early stage(s) and / or late stage(s), as described herein. In some embodiments, the therapeutically effective amount of esketamine is about 20 to about 100 mg. In other embodiments, the therapeutically effective amount of esketamine is about 30 to about 90 mg. In further embodiments, the therapeutically effective amount of esketamine is about 40 to about 80 mg. In still other embodiments, the therapeutically effective amount of esketamine is about 14, 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, 41, 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, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, In yet further embodiments, the therapeutically effective amount is about 28 mg, about 56 mg, or about 84 mg. In other embodiments, the therapeutically effective amount is about 56 mg or about 84 mg. In yet further embodiments, the therapeutically effective amount of esketamine is about 28 mg. In other embodiments, the therapeutically effective amount of esketamine is about 56 mg. In a further embodiment, the therapeutically effective amount is about 84 mg of esketamine.

[0068] As used herein, unless otherwise indicated, the terms "subject" and "patient" refer to an animal, preferably a mammal, and most preferably a human, who has been subjected to treatment, observation, or experiment. Preferably, a subject or patient is experiencing and / or exhibiting at least one symptom of the disease or disorder to be treated and / or prevented.

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

[0070] In other embodiments, the subject or patient is elderly or geriatric. As used herein, the terms "elderly" and "elderly" are used interchangeably to refer to human subjects aged about 65 years or older. Elderly patients aged >65 to <75 years are likely to respond better to treatment than patients aged >75 years.

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

[0072] As used herein, the term "composition" is intended to encompass a product containing specified ingredients in specified amounts, as well as any product that results directly or indirectly from combining specified amounts of specified ingredients.

[0073] As used herein, "stable remission" refers to a patient having a MADRS total score of 12 or less for at least three of the past four weeks after the patient achieved a substantially complete response to esketamine during the induction phase. In certain exemplified embodiments herein, patients in "stable remission" include patients with a single deviation in the MADRS total score of greater than 12 or a single missed MADRS assessment at week 13 or 14 following the induction phase. In other embodiments, patients in "stable remission" include patients with a MADRS total score of 12 or less at weeks 15 and 16 following the induction phase.

[0074] As used herein, "stable response" refers to a patient who has experienced a 50% or greater reduction in the MADRS total score from baseline (Day 1 of the induction period, pre-randomization / pre-first intranasal dose) in each of the last two weeks after the patient achieved a substantially complete response to esketamine during the induction period, but does not meet the criteria for stable remission.

[0075] As described above, a method for treating depression in a patient is described. The method includes administering esketamine in one, two, or optionally three phases, i.e., an initial and subsequent administration phases. In some embodiments, the phases include an initial induction phase, an extended induction phase, a maintenance phase, or any combination thereof. Accordingly, an effective amount of esketamine is administered in each phase. A physician can evaluate the patient's condition and determine the most beneficial initial / induction and maintenance doses for the patient from the dosage ranges and administration frequencies specified herein. The effective amount of esketamine in each phase may be the same or different.

[0076] The methods described herein allow for the optimization of esketamine dosages for administration to patients with or susceptible to depression during an "optimization phase." Optimization can be considered part of the maintenance phase following the induction phase. In some embodiments, the methods described herein do not require adjustment of the esketamine dosage. Indeed, esketamine can be administered at the lowest dosing frequency during the phases described herein (e.g., induction and maintenance phases) at which an esketamine response is observed and maintained in the patient. An effective dose of esketamine has been found to be about 28 to about 84 mg.

[0077] As used herein, an "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 long enough to achieve a robust and stable reduction in depressive symptoms. The induction phase may depend on factors including, but not limited to, the particular patient and / or the patient's gender, age, weight, administration time, administration frequency, and concomitant illnesses. The induction phase may include an initial induction phase and an extended induction phase. The total induction period (initial and extended periods combined) can be about 4 to about 12 weeks, about 4 to about 11 weeks, about 4 to about 10 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 about 7 weeks, about 5 to about 6 weeks, about 6 to about 12 weeks, about 6 to about 11 weeks, about 6 to about 10 weeks, about 6 to about 9 weeks, about 6 to about 8 weeks, about 7 to about 12 weeks, about 7 to about 11 weeks, about 7 to about 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 about 4 to about 8 weeks.

[0078] During the initial induction period, the patient is administered a therapeutically effective amount of esketamine at a given frequency of at least twice a week. In some embodiments, the patient is administered a therapeutically effective amount of esketamine at a given frequency of three times a week. As long as the administration is three times a week, administration occurs on days 1, 3, and 5 ± 1 of the week. The initial induction period is typically a period during which the patient demonstrates responsiveness to treatment but is not ready to progress to the maintenance period. At that time, the patient's response is assessed by a skilled artisan. In some embodiments, the patient's response is assessed daily. In other embodiments, the patient's response is assessed twice a week. In further embodiments, the patient's response is assessed every other day. In still other embodiments, the patient's response is assessed at the end of the initial induction period. Typically, the patient's response can be assessed using techniques and tests known to those skilled in the art. In some embodiments, the patient's MADRS score is determined and used to determine whether the initial induction period has ended. The initial induction period is desirably long enough to achieve a reduction in depressive symptoms. In some embodiments, the initial induction period is about 1 to about 4 weeks in duration. In other embodiments, the induction period is up to about 1 week, up to about 2 weeks, up to about 3 weeks, or up to about 4 weeks in duration. In further embodiments, the initial induction 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 weeks, 1 week, 2 weeks, 3 weeks, 4 weeks, up to 1 week, up to 2 weeks, up to 3 weeks, or up to 4 weeks. The effective amount of esketamine administered during the initial induction period can be determined by the attending physician. In some embodiments, the effective amount of esketamine administered during the initial induction period is about 28 mg. In some embodiments, the effective amount of esketamine administered during the initial induction period is about 56 mg. In other embodiments, the effective amount of esketamine administered during the initial induction period is about 84 mg.

[0079] As used herein, the term "twice weekly" refers to a frequency of twice in a one-week (7-day) period. For example, "twice weekly" can refer to the administration of esketamine herein. "Twice weekly" can also refer to the frequency of monitoring a patient in one or more phases discussed herein. In some embodiments, twice weekly refers to a frequency that is days 1 and 2 of the week. In other embodiments, twice weekly refers to a frequency that is days 1 and 3 of the week. In further embodiments, twice weekly refers to a frequency that is days 1 and 4 of the week. In still other embodiments, twice weekly refers to a frequency that is days 1 and 5 of the week. "Day 1" may be any day of the week, including Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, or Saturday. Typically, with respect to the administration of esketamine, twice weekly refers to a frequency that is days 1 and 4 of the week. To the extent there is an erroneous administration, the dose may be taken as soon as possible thereafter, and the prescribed regimen may then be continued.

[0080] In some patient populations (such as the elderly), the reduction in depressive symptoms during the initial induction period is insufficient, necessitating an extended induction period. The extended initial induction period involves continuous administration of a therapeutically effective amount of esketamine at a given frequency of at least twice weekly. At that point, the patient's response is again assessed by a skilled artisan. In some embodiments, the patient's response is assessed daily. In other embodiments, the patient's response is assessed twice weekly. In further embodiments, the patient's response is assessed every other day. Typically, the patient's response can be assessed using techniques and tests known to those skilled in the art. In some embodiments, the patient's MADRS score is determined and used to determine whether the extended induction period has ended. The extended induction period is desirably long enough to achieve a substantial reduction in depressive symptoms, and thus a substantially complete response to esketamine.

[0081] As used herein, the term "substantially complete response to esketamine" refers to a patient having a reduction in their MADRS score from baseline to at least a 50% improvement from baseline. In some embodiments, a substantially complete response to esketamine refers to a patient having either at least a 50% improvement from baseline or a MADRS score that is about -20 lower than the patient's baseline score. In other embodiments, a substantially complete response includes a reduction in the MADRS score of about -20 or less, -19 or less, -18 or less, -17 or less, -16 or less, -15 or less, -14 or less, -13 or less, -12 or less, -11 or less, or -10 or less. In further embodiments, a substantially complete response results in a patient having a reduction of about -15 to about -20 from their MADRS baseline score. A substantially complete response to esketamine may also be obtained if the patient's MADRS score is reduced by about 50% from the MADRS score at the start of treatment. Such a substantially complete response may be observed at any time during esketamine treatment. In some embodiments, a substantially complete response is observed when the patient has a reduction in the MADRS total score from baseline 4 hours after treatment, hi other embodiments, a substantially complete response is observed when the patient has a reduction in the MADRS total score from baseline 2 days after treatment.

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

[0083] Administration may further include an optimization / maintenance phase following the induction phase, wherein after the patient achieves a substantially complete response to esketamine during the induction phase, esketamine is administered less frequently than twice weekly during the optimization / maintenance phase, hi some embodiments, the administration frequency during the optimization / maintenance phase is once weekly, once every two weeks, once monthly, or a combination thereof.

[0084] At any stage during one or more of the induction, optimization, or maintenance phases, the patient's response to treatment can be assessed using the techniques described herein. This assessment may be performed until the patient is deemed by one of skill in the art to have achieved a suitable response to the treatment regimen. In some embodiments, the induction period can be said to be complete when the patient's MADRS score is reduced by ≥ 50% from baseline, or from about 20 to about 13. In other embodiments, the patient's MADRS score can be about 19, about 18, about 17, about 16, about 15, about 14, or about 13. Patients with a MADRS score ≤ 12 are considered to be in remission and should be moved to or maintained in the maintenance phase if stable for 4 weeks.

[0085] At the end of the induction phase or extended induction phase, the treating physician should evaluate the patient to optimize the dosage and frequency of any subsequent administration phase, such as a "maintenance phase" or "long-term therapy phase." It is expected that the frequency of intranasal treatment during subsequent administration, such as a maintenance phase, will be reduced from the frequency during the induction phase or extended induction phase (at least twice weekly) to once weekly administration over a period of at least four weeks. In some embodiments, subsequent administration, such as a maintenance phase, is for at least about four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, thirteen weeks, seventeen weeks, eighteen weeks, nineteen weeks, twenty weeks, six months, seven months, eight months, nine months, ten months, eleven months, one year, or two years. In some embodiments, the continued administration of esketamine during the subsequent administration phase is for at least six months. In other embodiments, the continued administration of esketamine during the subsequent administration phase is for at least one year. In further embodiments, the dosing frequency during the subsequent dosing phase is once weekly, or once every two weeks, or a combination thereof. In yet other embodiments, the dosing frequency and effective amount of esketamine during the subsequent dosing phase is the minimum frequency and amount to maintain stable remission or stable response.

[0086] Subsequent administrations, such as maintenance periods, may include longer periods depending on the patient's condition. In some embodiments, these longer periods may be at least about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, or more than about 10 years, including indefinitely. For example, for patients diagnosed with TRD, treatment may be indefinite. In other embodiments, the treatment frequency is reduced to every other week. In further embodiments, the treatment frequency is reduced to every three weeks. In yet other embodiments, the treatment frequency is reduced to once a month. The patient is maintained on schedule until the patient achieves remission, maintains a response, or fails treatment. If the patient achieves remission or maintains a response with weekly treatment for at least four weeks, the frequency of intranasal treatment sessions can be reduced to a biweekly maintenance dose based on the severity of depressive symptoms; in some patient populations, the treatment frequency can be reduced to about once every three or four weeks, as described above.

[0087] Those skilled in the art will understand that the maintenance phase described herein can continue until further treatment is no longer necessary, as indicated, for example, by long-term remission of depression (e.g., including remission of one or more symptoms associated with depression), improvement in social and / or occupational functioning to normal or pre-morbid levels, or other known measures of depression.

[0088] An effective amount of esketamine is administered to the patient during the maintenance phase. As described above, the amount of esketamine administered during the maintenance phase is an amount that induces a biological or medical response in the tissue systems described above with respect to the induction phase. In certain embodiments, the effective amount of esketamine is an amount that maintains the pharmacodynamic steady state of esketamine achieved during the induction phase. In other embodiments, if depressive symptoms begin to worsen with biweekly, every three weeks, or every four weeks treatment, the administration of esketamine is increased to stabilize the patient. For example, if a patient is being administered every two weeks and their symptoms begin to worsen, esketamine can be administered once a week during the maintenance phase to maintain response. Again, the patient's response can be reassessed at any time during the maintenance phase.

[0089] In elderly patients, the recommended dose of esketamine is about 28 to about 84 mg. It is recommended that the initial dose (in the first treatment session) be about 28 mg of esketamine. Based on the efficacy and tolerability of the about 28 mg dose, the dose in the next treatment session may remain at about 28 mg or may be increased to about 56 mg. Depending on the efficacy and tolerability of the about 56 mg dose, the dose in subsequent treatment sessions may remain at about 56 mg, may be increased to about 84 mg, or may be reduced to about 28 mg. Depending on the tolerability of the about 84 mg dose, the dose in subsequent treatment sessions may remain at about 84 mg or may be reduced to about 56 mg.

[0090] In patients with hepatic impairment, the recommended dose of esketamine is about 28 to about 56 mg. The initial dose (in the first treatment session) is recommended to be about 28 mg of esketamine. Based on the efficacy and tolerability of the about 28 mg dose, the dose in subsequent treatment sessions may remain at about 28 mg or may be increased to about 56 mg. Because esketamine is extensively metabolized in the liver, physicians should regularly monitor patients with hepatic impairment for drug tolerance.

[0091] In treating patients with major depressive disorder who have suicidal ideation and are at imminent risk of suicide, administration is more aggressive due to the severity of the condition. This method involves administering esketamine during one or two phases: an initial induction phase, and optionally, in certain circumstances, a maintenance phase. Due to the imminent risk to the patient's life, the initial dose of esketamine is administered at the highest effective dose that the patient can tolerate twice weekly during the induction phase. In some embodiments, the patient continues treatment with an existing (i.e., currently initiated) antidepressant simultaneously with the initiation of treatment with esketamine during the induction phase. In other embodiments, the patient begins treatment with a new antidepressant simultaneously with the initiation of treatment with esketamine during the induction phase. In a further embodiment, the patient continues treatment with a previously administered antidepressant simultaneously with the initiation of treatment with esketamine during the induction phase. The antidepressant should be administered in a manner appropriate to the patient's condition / health and as labeled for the treatment of MDD. The induction period should be about 4 to about 8 weeks, about 4 to about 7 weeks, or about 4 to about 6 weeks, most preferably about 4 weeks. At the end of the induction period, if the patient responds adequately to treatment or is in remission, esketamine administration should be discontinued. The patient should be monitored to ensure that the patient remains stable or is in remission on antidepressant medication alone. If the patient does not stabilize on the first combination of esketamine and an antidepressant, or fails treatment with an antidepressant started with esketamine after esketamine administration is discontinued, a second induction period may be initiated.

[0092] During the second induction period, the patient is restarted with esketamine at the highest tolerated dose and concurrently with a second new antidepressant. Alternatively, the patient is restarted with esketamine at the highest tolerated dose and concurrently with the same antidepressant used during the previous induction period. Esketamine is administered twice weekly. The antidepressant is administered as indicated for the treatment of MDD in a manner appropriate to the patient's condition / health. The second induction period should last from about 4 to about 8 weeks, from about 4 to about 7 weeks, or from about 4 to about 6 weeks, most preferably about 4 weeks. At the end of the second induction period, if the patient responds adequately to treatment or is in remission, esketamine administration should be discontinued, and the patient should be monitored to ensure that the patient remains stable and / or is in stable remission on the antidepressant alone. If the patient does not stabilize or fails treatment with the antidepressant started with esketamine after esketamine administration is discontinued, a third induction period may be initiated.

[0093] During the third induction period, the patient is restarted with esketamine at the highest tolerated dose and simultaneously with a third new antidepressant. Alternatively, the patient is restarted with esketamine at the highest tolerated dose and simultaneously with the same antidepressant used during the second induction period. Esketamine is administered twice weekly. The antidepressant is administered in a manner appropriate to the patient's condition / health and as labeled for the treatment of MDD. The third induction period should last from about 4 to about 8 weeks, from about 4 to about 7 weeks, from about 4 to about 6 weeks, and most preferably about 4 weeks. At the end of the third induction period, the patient is now identified as a TRD patient and therefore proceeds to a maintenance period designated for TRD. The methods described herein enable optimization of the esketamine dosage for administration to patients with or susceptible to depression. In some embodiments, the methods described herein do not require adjustment of the esketamine dosage.

[0094] Generally, patients may be restarted with the highest tolerated dose of esketamine, simultaneously with the same antidepressant used during any previous induction period (including antidepressants with which the patient was not stabilized or otherwise failed treatment). For example, in a method for treating treatment-resistant depression in a patient in which the patient has not responded to at least two oral antidepressants in the current depressive episode, the patient may be administered esketamine alone or at least twice weekly with a first oral antidepressant that is the same or different from the previously ineffective oral antidepressant in the first induction period. To the extent that the patient does not achieve a substantially complete response to esketamine, the patient may be restarted with the highest tolerated dose of esketamine alone or simultaneously with a second oral antidepressant that is the same or different from the first oral antidepressant in the second induction period. To the extent that the patient achieves a substantially complete response to esketamine during the second induction period, the patient may then be administered a therapeutically effective amount of esketamine less than twice weekly during the subsequent maintenance period.

[0095] If one or more (e.g., two) doses of esketamine are missed during any of the periods described herein, the next dose will be scheduled when possible based on the dosing frequency regimen. If more than two doses are missed according to clinical judgment, an adjustment of the esketamine dose or frequency may be necessary.

[0096] In the preferred pharmaceutical composition of the present invention, S-ketamine hydrochloride as the active ingredient is thoroughly mixed with a pharmaceutical carrier, preferably water, according to conventional pharmaceutical compounding techniques, which may take a 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 these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the British Pharmaceutical Association.

[0097] Methods for formulating pharmaceutical compositions are described in many publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al., published by Marcel Dekker, Inc.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al.

[0098] One suitable aqueous formulation of S-ketamine comprises water and S-ketamine, wherein the S-ketamine is present in an amount ranging from about 25 mg / mL to about 250 mg / mL, preferably from about 55 mg / mL to about 250 mg / mL, or from about 100 mg / mL to about 250 mg / mL, based on the total volume of the pharmaceutical composition, or any amount or range therein. Preferably, the S-ketamine is present in an amount ranging from about 150 mg / mL to about 200 mg / mL, or any amount or range therein. More preferably, the S-ketamine is present in an amount ranging from about 150 mg / mL to about 175 mg / mL, or any amount or range therein. More preferably, the S-ketamine is present in an amount ranging from about 160 mg / mL to about 163 mg / mL, for example, about 161.4 mg / mL.

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

[0100] The pharmaceutical composition suitable for use in the present invention is preferably an aqueous formulation.As used herein, unless otherwise specified, the term "aqueous" means that the main liquid component of the formulation is water.Preferably, water comprises more than about 80% by weight of the liquid component of the pharmaceutical composition, more preferably more than about 90% by weight, more preferably more than about 95% by weight, more preferably about 98% by weight.

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

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

[0103] In another pharmaceutical composition for use in the present invention, the water content of the composition is in the range of 95±4.75 wt.%, more preferably 95±4.5 wt.%, even more preferably 95±4 wt.%, still more preferably 95±3.5 wt.%, most preferably 95±3 wt.%, and especially 95±2.5 wt.%, based on the total weight of the composition.

[0104] In another pharmaceutical composition for use in the present invention, the water content of the composition is in the range of 75 to 99.99 wt %, more preferably 80 to 99.98 wt %, even more preferably 85 to 99.95 wt %, even more preferably 90 to 99.9 wt %, most preferably 95 to 99.7 wt %, and especially 96.5 to 99.5 wt %, based on the total weight of the composition.

[0105] In another pharmaceutical composition for use in the present invention, the composition further comprises one or more buffering agents and / or buffering systems (ie, conjugate acid-base pairs).

[0106] As used herein, the term "buffering agent" refers to any solid or liquid composition (preferably an aqueous liquid composition) that, when added to an aqueous formulation, adjusts the pH of the formulation. Those skilled in the art will recognize that a buffering agent can adjust the pH of an aqueous formulation in any direction (toward a more acidic, more basic, or more neutral pH). Preferably, the buffering agent is pharmaceutically acceptable.

[0107] Suitable examples of buffering agents that may be used in the aqueous formulations of the present invention include, but are not limited to, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, malic acid, lactic acid, fumaric acid, etc. Preferably, the buffering agent or buffering system is selected from the group consisting of NaOH, citric acid, sodium dihydrogen phosphate, and disodium hydrogen phosphate.

[0108] In embodiments, the buffering agent is selected to adjust the pH of the S-ketamine hydrochloride pharmaceutical compositions of the invention (e.g., aqueous formulations described herein) to about pH 3.5 to about pH 6.5, or any amount or range therein. Preferably, the buffering agent is selected to adjust the pH of the S-ketamine hydrochloride compositions of the invention to about pH 4.0 to about pH 5.5, or any amount or range therein, more preferably about pH 4.5 to about pH 5.0, or any amount or range therein.

[0109] Preferably, the concentrations of the buffer and buffer system, preferably NaOH, respectively, are adjusted to provide sufficient buffering capacity.

[0110] In embodiments, the present invention is directed to a pharmaceutical composition comprising S-ketamine hydrochloride, water, and a buffering agent or buffering system, preferably NaOH, wherein the buffering agent or buffering system is present in an amount sufficient to provide a formulation having a pH in the range of about pH 4.0 to about pH 6.0, or any amount or range therein.

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

[0112] As used herein, unless otherwise specified, the terms "antimicrobial preservative" and "preservative" preferably refer to any substance typically added to a pharmaceutical composition to preserve against microbial degradation or microbial growth. In this regard, microbial growth typically plays an essential role; that is, the preservative serves the primary purpose of avoiding microbial contamination. In some aspects, it may be desirable to avoid any microbial effects on the active ingredient and excipients, respectively, i.e., to avoid microbial degradation.

[0113] Representative examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmethyl nitrate, propylene glycol, sodium propionate, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, sorbic acid, and potassium sorbate.

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

[0115] As used herein, the terms "penetration agent," "penetration enhancer," and "penetrant" refer to any substance that increases or promotes the absorption and / or bioavailability of an active ingredient (e.g., S-ketamine hydrochloride) of a pharmaceutical composition. Preferably, the penetrant increases or promotes the absorption and / or bioavailability of an active ingredient (e.g., S-ketamine hydrochloride) of a pharmaceutical composition following nasal administration (i.e., increases or promotes the absorption and / or bioavailability of the active ingredient across a mucous membrane).

[0116] Suitable examples include, but are not limited to, tetradecyl maltoside, sodium glycolcholate, tauroursodeoxycholic acid (TUDCA), lecithin, chitosan (and salts), and surface active ingredients such as benzalkonium chloride, sodium dodecyl sulfate, sodium dodecylate, polysorbate, laureth-9, oxytoxinol, sodium deoxycholate, polyarginine, etc. Preferably, the penetrating agent is tauroursodeoxycholic acid (TUDCA).

[0117] Penetrants may act through any mechanism, including, for example, increasing membrane fluidity, forming transient hydrophilic pores in epithelial cells, reducing the viscosity of the mucus layer, or opening tight junctions. Some penetrants (e.g., bile salts and fusidic acid derivatives) can also inhibit enzymatic activity in membranes, thereby improving the bioavailability of active ingredients.

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

[0119] In one embodiment of the present invention, the osmotic agent is selected to increase penetration (absorption and / or bioavailability of S-ketamine hydrochloride) without nasal irritation. In another embodiment of the present invention, the osmotic agent is selected to improve absorption and / or bioavailability of S-ketamine hydrochloride and further to enhance uniform dosing effectiveness.

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

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

[0122] Pharmaceutical compositions for use in the present invention may further contain one or more additional excipients, such as wetting agents, surfactant components, solubilizing agents, thickening agents, coloring agents, antioxidant components, and the like.

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

[0124] Solubilizers and emulsifiers can be included to promote more uniform dispersion of active ingredients or other excipients that are not generally soluble in liquid carriers.Suitable emulsifiers include, but are not limited to, gelatin, cholesterol, acacia, tragacanth, pectin, methylcellulose, carbomer, and mixtures thereof, if used.Suitable solubilizers include, but are not limited to, polyethylene glycol, glycerin, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof.

[0125] Preferably, the solubilizing agent comprises glycerin. The solubilizing agent or emulsifying agent is generally present in an amount sufficient to dissolve or disperse the active ingredient, i.e., S-ketamine, in the carrier. Typical amounts of the solubilizing or emulsifying agent, when present, are from about 1% to about 80% by weight, preferably from about 20% to about 65% by weight, and more preferably from about 25% to about 55% by weight of the total weight of the composition.

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

[0127] Suspending or thickening agents can be added to the pharmaceutical compositions of the present invention, for example, to increase retention time in the nose. Suitable examples include, but are not limited to, hydroxypropyl methylcellulose, carmellose sodium, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salts, gellan gum, poloxamer, polyvinylpyrrolidone, xanthan gum, etc.

[0128] Advantageously, esketamine may be administered in a single daily dose, or the total daily dose may be administered in divided doses two, three, or four times daily, preferably twice daily. Typically, the divided doses should be administered more closely spaced in time. In some embodiments, the divided doses are administered within about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, or about 1 minute of each other. Additionally, flexible dosing regimens allow patients to receive daily, twice weekly, weekly, biweekly, or monthly doses. For example, one dose of esketamine is administered on day 1 and another 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 and 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 in intranasal form via topical use of a suitable intranasal vehicle, such as a nasal spray pump.

[0129] As described, the method of administering esketamine to a patient results in a maximum plasma concentration (C) of esketamine of about 45 to about 165 ng / mL. max Those skilled in the art will appreciate that ranges or individual C max It will be understood that any of the values ​​may vary by ±30%. max is about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 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. max is about 50 to about 150, about 50 to about 125, about 50 to about 100, about 50 to about 75, about 75 to about 150, about 75 to about 125, or about 75 to about 100 ng / mL. maxis about 45 to about 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 when about 28 mg of esketamine is administered. max is about 65 to about 120, about 70 to about 120, about 70 to about 110, about 70 to about 100, about 70 to about 90, about 70 to about 80, about 80 to about 120, about 80 to about 110, about 80 to about 90, about 90 to about 120, or about 90 to about 110 ng / mL when about 56 mg of esketamine is administered. max When about 84 mg of esketamine is administered, the doses are about 90 to about 165, about 95 to about 165, about 95 to about 155, about 95 to about 145, about 95 to about 135, about 95 to about 125, about 95 to about 115, about 105 to about 165, about 105 to about 155, about 105 to about 145, about 105 to about 135, about 105 to about 125, and about 105 to about 1 15, about 115 to about 165, about 115 to about 155, about 115 to about 145, about 115 to about 135, about 115 to about 125, about 125 to about 165, about 125 to about 155, about 125 to about 145, about 125 to about 135, about 135 to about 165, about 135 to about 155, about 135 to about 145, or about 145 to about 165 ng / mL.

[0130] Similarly, the method of administering esketamine to a patient may include administering from about 125 to about 490 mg of esketamine at time 0. * The last quantifiable concentration (AUC last As used herein, the term "AUC" last " 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 start of the intended dose. For example, in Example 1, which relates to intranasal administration, time 0 is defined as the time of administration of the first intranasal spray into one nostril from the first intranasal device. To the extent that the intended dose requires administration of two oral tablets, time 0 is the time of administration of the first tablet. Those skilled in the art will appreciate that ranges or individual AUC lastIt will be understood that any of the values ​​may vary ±30%. In some 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 490 ng * h / mL. In another embodiment, the AUC last is about 150 to about 450, about 200 to about 400, about 250 to about 350, about 150 to about 350, or about 200 to about 300 ng * h / mL. In a further embodiment, the AUC last When about 28 mg of esketamine is administered, the average daily dose is about 125 to about 185, about 130 to about 180, about 135 to about 175, about 140 to about 170, about 145 to about 165, or about 150 to about 160 ng. * h / mL. In yet another embodiment, the AUC last When about 56 mg of esketamine is administered, the average daily dose is about 210 to about 320, about 220 to about 310, about 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 is about 305 to about 490, about 310 to about 480, about 320 to about 470, about 330 to about 460, about 340 to about 450, about 350 to about 450, about 360 to about 440, about 370 to about 430, about 380, about 420, or about 390 to about 410 ng when about 84 mg of esketamine is administered. * h / mL.

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

[0132] A representative nasal spray device is disclosed in U.S. Patent No. 6,321,942, which is incorporated herein by reference. For example, the methods disclosed herein can be practiced using a disposable sprayer for delivering successive partial discharges as a spray. Typically, such devices allow for spraying medication into both nostrils of a patient in two successive strokes. The device, in which medication is delivered from a media container, is ready for immediate use. The device typically separates the first discharge stroke from the second to prevent complete emptying of the media container in a single motion. The device can take the form of a dual-stroke disposable pump, which is discarded after a single use and allows for individual partial discharges with high dosing accuracy and reliability.

[0133] In one embodiment, the nasal spray device is a single-use device that delivers a total of 28 mg of esketamine in two sprays (one spray per nostril). The device may be operated by the patient under the supervision of a medical professional. Regarding dosage, one device may be used for a 28 mg dose, two devices for a 56 mg dose, or three devices for an 84 mg dose. It is also preferable to have a 5-minute interval between the use of each device. As described in Example 1, time 0 is defined as the time of administration of the first intranasal spray from the first intranasal device into one nostril.

[0134] Aspects of the disclosure The present disclosure relates to and includes at least the following aspects: 1. A method for treating major depressive disorder, comprising intranasally administering to a patient in need thereof a therapeutically effective amount of esketamine, which has been proven clinically safe and clinically effective; The method, wherein the patient in need thereof is a human patient having a major depressive episode, and the patient has 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; A patient in need thereof is having a major depressive episode, and the patient has not responded to at least two oral antidepressants in the current depressive episode; Esketamine is administered intranasally, The method wherein the therapeutically effective amount of esketamine administered to the patient is clinically proven safe and effective. 3. A method for treating major depressive disorder in a human patient, comprising: (a) diagnosing the human patient by determining the patient's baseline MADRS score; (b) intranasally administering to the human patient a therapeutically effective amount of esketamine that has been clinically proven safe and effective; a therapeutically effective amount that improves the MADRS score by at least 50% relative to a measured baseline MADRS score; esketamine is administered at predetermined intervals; (c) following step (b), re-evaluating the human patient at regular intervals to determine relative efficacy; The reassessment includes measuring the MADRS score of the human patient. 4. The method of aspect 1, 2, or 3, wherein the major depressive disorder is treatment-refractory or treatment-resistant depression. 5. The method of aspect 1, 2, 3, or 4, wherein a therapeutically effective amount of at least one antidepressant is co-administered with esketamine. 6. The method of embodiment 5, wherein the combination therapy comprises esketamine and one to two antidepressants. 7. The method of aspect 5, wherein each antidepressant is independently selected from the group consisting of imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, kavacava, St. John's wort, s-adenosylmethionine, thyroid hormone-releasing hormone, neurokinin receptor antagonists, and triiodothyronine. 8. The method of aspect 5, wherein each antidepressant is independently selected from the group consisting of a monoamine oxidase inhibitor, a tricyclic, a serotonin reuptake inhibitor, a serotonin noradrenergic reuptake inhibitor, a noradrenergic-specific serotonergic agent, and an atypical antidepressant. 9. The method of aspect 5, wherein each antidepressant is independently selected from the group consisting of phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, and bupropion. 10. The method of aspect 5, wherein the combination therapy comprises esketamine and one to two antidepressants independently selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine, and sertraline. 11. The method of aspect 5, wherein the combination therapy comprising esketamine and at least one antidepressant further comprises an atypical antidepressant. 12. The method of aspect 11, wherein the atypical antidepressant is selected from the group consisting of aripiprazole, quetiapine, olanzapine, risperidone, and paliperidone. 13. The method of aspect 12, wherein the atypical antidepressant is selected from the group consisting of aripiprazole, quetiapine, and olanzapine. 14. A pharmaceutical composition for the treatment of treatment-refractory or treatment-resistant depression comprising esketamine, optionally at least one antidepressant, and at least one pharmaceutically acceptable carrier. 15. Use of esketamine in the preparation of a medicament for the treatment of treatment-refractory or treatment-resistant depression in a patient in need thereof. 16. Esketamine for use in a method for the treatment of treatment-refractory or treatment-resistant depression in a patient in need thereof. 17. A composition comprising esketamine for the treatment of treatment-refractory or treatment-resistant depression. 18. A pharmaceutical product comprising esketamine for administration to a patient suffering from treatment-resistant depression, wherein the esketamine is administered intranasally to the patient in an amount clinically proven to be safe and effective. 19. A method for maintaining stable remission or stable response achieved by a patient with depression after administration of a therapeutically effective amount of esketamine during an initial dosing period, comprising continuing to administer a therapeutically effective amount of esketamine for at least five months during subsequent dosing periods. 20. The method of aspect 19, wherein the depression is treatment-resistant depression. 21. The method of aspect 19 or 20, wherein the therapeutically effective amount of esketamine is administered intranasally, intramuscularly, subcutaneously, transdermally, orally, or rectally in the initial and subsequent administration phases. 22. The method of aspect 21, wherein the administration is intranasal. 23. The method of any one of aspects 19-22, wherein a therapeutically effective amount of at least one antidepressant is co-administered with esketamine during the initial and subsequent administration phases. 24. The method of embodiment 23, wherein esketamine is co-administered with one to two antidepressants. 25. The method of aspect 24, wherein each antidepressant is independently imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, kavakava, St. John's wort, s-adenosylmethionine, thyroid hormone-releasing hormone, neurokinin receptor antagonist, or triiodothyronine. 26. The method of any one of aspects 23-25, wherein each antidepressant is independently a monoamine oxidase inhibitor, a tricyclic, a serotonin reuptake inhibitor, a serotonin noradrenergic reuptake inhibitor, a noradrenergic-specific serotonergic agent, or an atypical antidepressant. 27. The method of any one of aspects 23-26, wherein each antidepressant is independently phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, or bupropion. 28. The method of any one of aspects 23-27, wherein each antidepressant is independently fluoxetine, imipramine, bupropion, venlafaxine, or sertraline. 29. The method of aspect 23, wherein at least one antidepressant is an atypical antidepressant. 30. The method of aspect 29, wherein the atypical antidepressant is aripiprazole, quetiapine, olanzapine, risperidone, or paliperidone. 31. The method of aspect 30, wherein the atypical antidepressant is aripiprazole, quetiapine, or olanzapine. 32. The method of any one of aspects 19-31, wherein the initial administration phase comprises an induction phase in which esketamine is administered at least twice weekly. 33. The method of embodiment 32, wherein the frequency is twice a week. 34. The method of aspect 32 or 33, further comprising assessing patient response during the induction period. 35. The method of any one of aspects 32-34, wherein the initial administration phase further comprises an optimization phase following an induction phase, and after the patient achieves a substantially complete response to esketamine during the induction phase, esketamine is administered less frequently than twice weekly during the optimization phase. 36. The method of embodiment 35, further comprising assessing patient response during the optimization phase to achieve stable remission or stable response, and adjusting the dosing frequency during the optimization phase based on the response. 37. The method of embodiment 36, wherein the administration frequency during the optimization phase is once every week, once every two weeks, or a combination thereof. 38. The method of any one of aspects 19-37, wherein the effective amount of esketamine is 28 mg, 56 mg, or 84 mg during the initial and subsequent administration phases. 39. The method of any one of aspects 32-38, wherein the continued administration of esketamine during the subsequent administration period is for at least 6 months. 40. The method of any one of aspects 32-39, wherein the continued administration of esketamine during the subsequent administration period is for at least 1 year. 41. The method of any one of aspects 32-40, wherein the dosing frequency during the subsequent dosing phase is once every week or once every two weeks, or a combination thereof. 42. The method of any one of aspects 32-41, wherein the effective amount of esketamine during the subsequent administration period is 56 mg or 84 mg. 43. The method of any one of aspects 32-42, wherein the administration frequency and effective amount of esketamine during subsequent administration periods is the minimum frequency and amount to maintain stable remission or stable response. 44. The method of any one of aspects 19-43, wherein the therapeutically effective amount of esketamine is an amount that has been clinically proven to be safe and clinically proven to be effective. 45. A method for the long-term treatment of depression in a patient, comprising administering to a patient in need of treatment a therapeutically effective amount of esketamine that has been proven clinically safe and clinically effective 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 of any one of aspects 45-47, wherein the depression is treatment-resistant depression. 49. The method of any one of aspects 45-47, wherein the esketamine is administered intranasally. 50. The method of any one of aspects 45-48, wherein a therapeutically effective amount of at least one antidepressant is co-administered with esketamine. 51. The method of embodiment 50, wherein esketamine is co-administered with one to two antidepressants. 52. The method of aspect 51, wherein each antidepressant is independently imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, kavakava, St. John's wort, s-adenosylmethionine, thyroid hormone-releasing hormone, neurokinin receptor antagonist, or triiodothyronine. 53. The method of any one of aspects 50-52, wherein each antidepressant is independently a monoamine oxidase inhibitor, a tricyclic, a serotonin reuptake inhibitor, a serotonin noradrenergic reuptake inhibitor, a noradrenergic-specific serotonergic agent, or an atypical antidepressant. 54. The method of any one of aspects 50-53, wherein each antidepressant is independently phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, or bupropion. 55. The method of any one of aspects 50-54, wherein each antidepressant is independently fluoxetine, imipramine, bupropion, venlafaxine, or sertraline. 56. The method of embodiment 55, wherein at least one antidepressant is an atypical antidepressant. 57. The method of aspect 56, wherein the atypical antidepressant is aripiprazole, quetiapine, olanzapine, risperidone, or paliperidone. 58. The method of aspect 57, wherein the atypical antidepressant is aripiprazole, quetiapine, or olanzapine. 59. The method of any one of aspects 45-58, wherein esketamine is initially administered twice weekly for up to 4 weeks during an induction period, and then administered less frequently than twice weekly thereafter. 60. The method of embodiment 59, wherein esketamine is administered once a week or once every two weeks following the induction period. 61. The method of any one of aspects 45-60, wherein the therapeutically effective amount of esketamine is 28 mg, 56 mg, or 84 mg. 62. The method of any one of aspects 45-61, wherein the patient's cognitive performance remains stable based on baseline measurements after 6 months of treatment. 63. A method for treating major depressive disorder in an elderly patient, comprising: administering a therapeutically effective amount of esketamine at least twice weekly during an initial induction period of defined duration to a patient in need of treatment for major depressive disorder; assessing patient response following an initial induction period; and continuing to administer the esketamine at a frequency of at least twice weekly during the extended induction period based on an assessment of whether the patient has achieved a substantially complete response to esketamine. 64. The method of embodiment 63, wherein the elderly patient has not responded to at least two oral antidepressants in the current depressive episode. 65. The method of embodiment 64, wherein the therapeutically effective amount of esketamine is administered intranasally, intramuscularly, subcutaneously, transdermally, orally, or rectally. 66. The method of any one of aspects 63-65, wherein administration is intranasal. 67. The method of any one of aspects 63-66, wherein the initial induction period is up to 2 weeks. 68. The method of any one of aspects 63-66, wherein the initial induction period is up to 3 weeks. 69. The method of any one of aspects 63-66, wherein the initial induction period is up to 4 weeks. 70. The method of any one of aspects 63-66, wherein the extended induction period is up to 8 weeks. 71. The method of any one of aspects 63-70, wherein the effective amount is 28 mg, 56 mg, or 84 mg. 72. The method of any one of aspects 63-71, wherein after the elderly patient achieves a substantially complete response to esketamine, esketamine is thereafter administered no more frequently than once a week during an optimization phase. 73. The method of embodiment 72, further comprising evaluating the patient's response periodically during the optimization phase. 74. The method of any one of aspects 63-73, wherein the frequency of the initial induction phase, the extended induction phase, or a combination thereof is twice a week. 75. The method of any one of aspects 63-74, wherein the major depressive disorder is treatment-refractory depression or treatment-resistant depression. 76. The method of any one of aspects 63-75, wherein a therapeutically effective amount of at least one antidepressant is co-administered with esketamine. 77. The method of any one of aspects 63-76, wherein the combination therapy comprises esketamine and one to two antidepressants. 78. The method of aspect 77, wherein each antidepressant is independently imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, kavakava, St. John's wort, s-adenosylmethionine, thyroid hormone-releasing hormone, neurokinin receptor antagonist, or triiodothyronine. 79. The method of aspect 77 or 78, wherein each antidepressant is independently a monoamine oxidase inhibitor, a tricyclic, a serotonin reuptake inhibitor, a serotonin noradrenergic reuptake inhibitor, a noradrenergic-specific serotonergic agent, or an atypical antidepressant. 80. The method of any one of aspects 77-79, wherein each antidepressant is independently phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, or bupropion. 81. The method of any one of aspects 77-80, comprising one or two antidepressants that are independently fluoxetine, imipramine, bupropion, venlafaxine, or sertraline. 82. The method of embodiment 79, wherein at least one antidepressant is an atypical antidepressant. 83. The method of aspect 82, wherein the atypical antidepressant is aripiprazole, quetiapine, olanzapine, risperidone, or paliperidone. 84. The method of aspect 82 or 83, wherein the atypical antidepressant is aripiprazole, quetiapine, or olanzapine. 85. The method of any one of aspects 63-84, wherein the patient is at least 65 years old. 86. A method for treating a patient having major depressive disorder, comprising administering to a patient in need of treatment for major depressive disorder a therapeutically effective amount of esketamine that has been proven clinically safe and clinically effective. 87. The method of embodiment 86, wherein the patient has not responded to at least two oral antidepressants at adequate doses and durations in the current depressive episode. 88. The method of aspect 86 or 87, wherein the patient has been diagnosed with treatment-refractory or treatment-resistant depression. 89. The method of embodiment 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. The method of any one of aspects 86-92, wherein esketamine is administered intranasally, intramuscularly, subcutaneously, transdermally, orally, or rectally. 94. The method of any one of aspects 86-93, wherein the esketamine is administered intranasally. 95. The method of any one of aspects 86-94, wherein a therapeutically effective amount of at least one antidepressant is co-administered with esketamine. 96. The method of embodiment 95, wherein esketamine is co-administered with one to two antidepressants. 97. The method of aspect 95 or 96, wherein each antidepressant is independently imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, kavakava, St. John's wort, s-adenosylmethionine, thyroid hormone-releasing hormone, neurokinin receptor antagonist, or triiodothyronine. 98. The method of aspect 95 or 96, wherein each antidepressant is independently a monoamine oxidase inhibitor, a tricyclic, a serotonin reuptake inhibitor, a serotonin noradrenergic reuptake inhibitor, a noradrenergic-specific serotonergic agent, or an atypical antidepressant. 99. The method of any one of aspects 95-98, wherein each antidepressant is independently phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, or bupropion. 100. The method of any one of aspects 96-99, wherein each antidepressant is independently fluoxetine, imipramine, bupropion, venlafaxine, or sertraline. 101. The method of embodiment 95, wherein at least one antidepressant is an atypical antidepressant. 102. The method of aspect 101, wherein the atypical antidepressant is aripiprazole, quetiapine, olanzapine, risperidone, or paliperidone. 103. The method of aspect 101 or 102, wherein the atypical antidepressant is aripiprazole, quetiapine, or olanzapine. 104. A pharmaceutical composition for the treatment of major depressive disorder comprising esketamine, optionally at least one antidepressant, and at least one pharmaceutically acceptable carrier. 105. A pharmaceutical composition for the treatment of treatment-refractory or treatment-resistant depression comprising esketamine, optionally at least one antidepressant, and at least one pharmaceutically acceptable carrier. 106. A pharmaceutical composition for the treatment of suicidal ideation comprising esketamine, optionally at least one antidepressant, and at least one pharmaceutically acceptable carrier. 107. Use of esketamine in the preparation of a medicament for the treatment of major depressive disorder in patients requiring treatment. 108. The use according to aspect 107, wherein the patient suffers from treatment-refractory or treatment-resistant depression. 109. The use according to aspect 107, wherein the patient is suffering from suicidal thoughts. 110. Esketamine for use in a method for the treatment of major depressive disorder in a patient in need of treatment. 111. Esketamine according to aspect 110, wherein the patient is suffering from treatment-refractory or treatment-resistant depression. 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. A composition comprising esketamine for the treatment of treatment-refractory or treatment-resistant depression. 115. A composition comprising esketamine for the treatment of suicidal ideation. 116. A pharmaceutical product comprising esketamine for administration to a patient suffering from major depressive disorder, wherein the esketamine is administered intranasally to the patient in an amount clinically proven to be safe and effective. 117. The pharmaceutical product according to aspect 116, wherein the patient suffers from treatment-refractory or treatment-resistant depression. 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 method includes a first phase lasting from about one week to about four weeks, in which about 28 mg to about 84 mg of esketamine is administered to the patient twice a week, and has been proven clinically safe. 120. The method of embodiment 119, wherein about 28 mg of esketamine is administered. 121. The administration of esketamine results in a maximum plasma concentration (Cmax) of esketamine of approximately 45 to approximately 75 ng / mL, and a maximum plasma concentration (Cmax) of approximately 125 to approximately 185 ng / mL. * 121. The method of embodiment 119 or 120, wherein the area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUClast) in h / mL is achieved, or a combination thereof. 122. The method of any one of aspects 119-121, wherein esketamine is administered intranasally. 123. The method of embodiment 122, wherein about 28 mg of esketamine is administered in at least two sprays. 124. The method of embodiment 123, wherein about 28 mg of esketamine is administered via one spray in each nostril. 125. The method of embodiment 119, wherein about 56 mg of esketamine is administered. 126. The administration of esketamine results in a maximum plasma concentration (Cmax) of esketamine of approximately 65 to approximately 120 ng / mL, and a maximum plasma concentration (Cmax) of approximately 210 to approximately 320 ng / mL. * 126. The method of embodiment 119 or 125, wherein the area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUClast) in h / mL is achieved, or a combination thereof. 127. The method of aspect 125 or 126, wherein esketamine is administered intranasally. 128. The method of embodiment 127, wherein about 56 mg of esketamine is administered in at least four sprays. 129. The method of embodiment 128, wherein esketamine is administered via one spray in each nostril at time 0 for a total of about 28 mg, and repeated about 5 minutes later for a total of about 56 mg. 130. The method of embodiment 119, wherein about 84 mg of esketamine is administered. 131. The administration of esketamine results in a maximum plasma concentration (Cmax) of esketamine of approximately 90 to approximately 165 ng / mL, and a maximum plasma concentration (Cmax) of approximately 305 to approximately 490 ng / mL. * 131. The method of embodiment 119 or 130, wherein the area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUClast) in h / mL is achieved, or a combination thereof. 132. The method of aspect 130 or 131, wherein esketamine is administered intranasally. 133. The method of embodiment 132, wherein about 84 mg of esketamine is administered in at least 6 sprays. 134. The method of embodiment 133, wherein esketamine is administered via one spray in each nostril at time 0 for a total of about 28 mg, repeated about 5 minutes later for a total of about 56 mg, and repeated again about 5 minutes later at about 10 minutes for a total of about 84 mg. 135. The method of any one of aspects 119-134, wherein the first phase is about 4 weeks in duration. 136. The method of any one of aspects 119-135, further comprising a second phase following the first phase, the second phase having a duration of about 1 to about 4 weeks, wherein about 56 mg to about 84 mg of esketamine is administered to the patient at a frequency of once per week. 137. The method of embodiment 136, wherein about 56 mg of esketamine is administered to the patient once per week during the second period. 138. The method of embodiment 136, wherein about 84 mg of esketamine is administered to the patient once per week during the second period. 139. The method of any one of aspects 136-138, wherein esketamine is administered intranasally in the second period. 140. The method of any one of aspects 136-139, wherein the second phase is about 4 weeks in duration. 141. The method of any one of aspects 119-140, further comprising a third phase following the second phase of at least about 1 week duration, wherein about 56 mg to about 84 mg of esketamine is administered to the patient every two weeks or once per week. 142. The method of embodiment 141, wherein about 56 mg of esketamine is administered to the patient every two weeks or once per week during the third period. 143. The method of embodiment 141, wherein about 84 mg of esketamine is administered to the patient every two weeks or once per week during the third period. 144. The method of any one of aspects 141-143, wherein esketamine is administered intranasally during the third period. 145. The method of any one of aspects 141-144, wherein the third phase is at least about 1 month in duration. 146. The method of any one of aspects 141-144, wherein the third stage is at least about 2 months in duration. 147. The method of any one of aspects 141-144, wherein the third phase is at least about 3 months in duration. 148. The method of any one of aspects 141-144, wherein the third stage is at least about 4 months in duration. 149. The method of any one of aspects 141-144, wherein the third stage is at least about 5 months in duration. 150. The method of any one of aspects 141-144, wherein the third stage is at least about 6 months in duration. 151. The method of any one of aspects 141-144, wherein the third stage is at least about 1 year in duration. 152. The method of any one of aspects 141-144, wherein the third stage is at least about 2 years in duration. 153. The method of any one of aspects 119-152, wherein the method further comprises co-administering an antidepressant, and wherein the method has been proven clinically effective in treating major depressive disorder. 154. The method of embodiment 153, wherein the antidepressant is administered orally. 155. The method of aspect 153 or 154, wherein the major depressive disorder is treatment-resistant depression. 156. A pharmaceutical product comprising one or more intranasal spray devices, wherein one or more devices contain an esketamine composition, and wherein the one or more devices are configured to administer about 28 to about 84 mg of esketamine, and wherein the pharmaceutical product has been clinically proven safe and / or clinically proven effective for treating major depressive disorder. 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 pharmaceutical product of aspect 156, wherein the device is configured to administer esketamine in two or more sprays. 160. The pharmaceutical product of aspect 158 ​​or 159, wherein the device contains about 28 mg of esketamine. 161. The pharmaceutical product of aspect 156, wherein the product comprises two or more devices, each device containing about 28 mg of esketamine. 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. The pharmaceutical product of any one of aspects 156-163, further comprising instructions for performing any one of the methods according to aspects 119-155. 165. A method for treating major depressive disorder accompanied by suicidal ideation, comprising: esketamine administered twice weekly at the highest tolerated dose during a first induction period of defined duration; administering a first oral antidepressant concurrently with esketamine; and and evaluating the patient to determine whether a substantially complete response to esketamine has been achieved. 166. The method of embodiment 165, wherein treatment is discontinued when the patient achieves a substantially complete response to esketamine. 167. The method of embodiment 166, wherein the patient is monitored to ensure that the patient remains stable or in remission on the first oral antidepressant alone. 168. The method of embodiment 165, wherein if a substantially complete response is not achieved during the first induction period, a second induction period is initiated. 169. The method of aspect 168, wherein the patient is restarted on the highest tolerated dose of esketamine during a second induction period, and concurrently with the second oral antidepressant. 170. The method of aspect 169, wherein the second oral antidepressant is the same as the first oral antidepressant. 171. The method of aspect 169, wherein the second oral antidepressant is different from the first oral antidepressant. 172. The method of any one of aspects 169-171, wherein the patient is monitored to ensure that the patient remains stable or in remission on the second oral antidepressant alone. 173. The method of any one of aspects 169-172, wherein if a substantially complete response is not achieved during the second induction period, a third induction period is initiated. 174. The method of aspect 173, wherein the patient is restarted on the highest tolerated dose of esketamine during a third induction period, and concurrently with a third oral antidepressant. 175. The method of aspect 174, wherein the third oral antidepressant is the same as the second oral antidepressant. 176. The method of aspect 174, wherein the third oral antidepressant is different from the second oral antidepressant. 177. The method of any one of aspects 165-176, further comprising administering a therapeutically effective amount of esketamine to the patient less than twice per week during a subsequent maintenance phase. 178. The method of any one of aspects 165-177, wherein the first, second, and third induction periods are independently at least 4 weeks. 179. A method for treating treatment-resistant depression in a patient, wherein the patient has not responded to at least two oral antidepressants in a current depressive episode; administering to the patient a first oral antidepressant; administering esketamine to the patient at least twice weekly during a first induction period of defined duration; assessing the patient during a first induction period; If the patient fails to achieve a substantially complete response to esketamine, restarting the patient on the highest tolerated dose of esketamine, concurrently with the second oral depressant, in a second induction period of defined duration. 180. The method of embodiment 179, wherein the first oral antidepressant is the same as at least one of the at least two oral antidepressants. 181. The method of aspect 179, wherein the first oral antidepressant is different from at least one of the at least two oral antidepressants. 182. The method of embodiment 179, wherein the first oral antidepressant is different from the at least two oral antidepressants. 183. The method of any one of aspects 179-182, wherein if the patient does not achieve a substantially complete response to esketamine during the second induction period, the patient is restarted on esketamine and concurrently with the third oral depressant in a third induction period of defined duration. 184. The method of aspect 183, wherein the third oral antidepressant is the same as the second oral antidepressant. 185. The method of aspect 183, wherein the third oral antidepressant is different from the second oral antidepressant. 186. The method of any one of aspects 179-185, further comprising administering a therapeutically effective amount of esketamine to the patient up to once a week during a subsequent maintenance phase when the patient achieves a substantially complete response to esketamine. 187. The method of any one of aspects 179-186, wherein the first, second, and third induction periods are independently at least 4 weeks. 188. A method of treating treatment-resistant depression in a patient, the method comprising: administering to said patient a therapeutically effective amount of an oral antidepressant; administering a therapeutically effective amount of esketamine intranasally to said patient at least twice weekly during an induction period of at least four weeks; administering a therapeutically effective amount of esketamine intranasally to the patient up to once weekly during a subsequent maintenance phase; The method is clinically proven to be safe and / or clinically proven to be effective. 189. The method of embodiment 188, wherein esketamine is administered once every two weeks during a subsequent maintenance phase. 190. The method of embodiment 188, wherein the administration frequency can be adjusted during the induction phase and / or the maintenance phase. 191. The method of embodiment 188, wherein the therapeutically effective amount of esketamine administered during the induction period is from about 28 mg to about 84 mg. 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 method of embodiment 191, wherein the therapeutically effective amount of esketamine is about 56 mg at the start of the induction period and is adjusted to about 84 mg during the induction period. 196. The method of embodiment 192, wherein the patient is 65 years of age or older. 197. The method of aspect 188, wherein the therapeutically effective amount of esketamine administered during the maintenance phase is about 56 mg or about 84 mg. 198. The method of any one of aspects 188-197, wherein the therapeutically effective amount of esketamine during the induction and maintenance phases is delivered in two or more sprays from the intranasal administration device. 199. The method of any one of aspects 188-198, wherein treatment continues for at least 6 months. 200. The method of any one of aspects 188-198, wherein treatment continues for up to two years.

[0135] As used herein, AD = antidepressant, AE = adverse event, ESK = esketamine nasal spray, PBO = placebo nasal spray, PHQ-9 = Patient Adherence Questionnaire, SDS = Sheehan Disability Scale, CGI-S = Clinical Global Impression-Severity, MADRS = Montgomery-Åsberg Depression Rating Scale, SD = standard deviation, SNRI = serotonin and norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, LS = least squares, SE = standard error, BMI = body mass index, BPIC-SS = bladder pain / interstitial cystitis symptom score, BPRS+ = 4-item positive symptom subscale of the Brief Psychiatric Rating Scale, C = clinic visit, CADSS = clinician-administered dissociative status rating scale, CGADR = clinical global assessment of discharge readiness, 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, glycosylated hemoglobin assay, HRUQ = healthcare resource utilization questionnaire, HVLT-R = Hopkins Verbal Learning Test-Revised, IDS-C 30= Depressive Symptoms Scale, a 30-item clinician-rated scale; LOE = lack of validity; MDD = major depressive disorder; LTF = lost to follow-up; MGH-ATRQ = Massachusetts General Hospital-Antidepressant Treatment History Questionnaire; MGH-Female RLHQ = Massachusetts General Hospital Hospital-Female Reproductive Cycle / Hormones Questionnaire, MINI = Mini International Neuropsychiatric Interview, MOAA / S = Modified Observer Assessment of Alertness / Sedation, NS = Not Statistically Significant, OL = Open Label, OTH = Other Reasons for Withdrawal, PAQ, Patient Adherence Questionnaire, PHQ-9 = Patient Health Questionnaire-9, PWC-20 = Physician Withdrawal Checklist, 20-item 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, Three P's Law, STOP-Bang = Snoring, Tiredness, Observed Apnea, High Blood Pressure, Body Mass Index, Age, Neck Circumference circumference), Gender (questionnaire), TRD=treatment-resistant depression, TSH=thyroid-stimulating hormone, RA=remote assessment only, LOCF=last observation carried forward, WBP=patient withdrawal, WD=withdrawal.

[0136] The following examples are provided to aid in the understanding of the present invention and are not intended to, and should not be construed to, limit in any way the invention set forth in the claims appended hereto.

[0137] Example 1: Efficacy of intranasal esketamine for treating treatment-resistant depression (TRD), a phase 3 clinical trial The ability of esketamine to treat treatment-refractory or treatment-resistant depression (TRD) was evaluated via the clinical trial described below, which was conducted to evaluate the efficacy, safety, and tolerability of flexibly administered intranasal esketamine plus a newly initiated oral antidepressant in adult subjects with TRD. This study served as a pivotal Phase 3 short-term efficacy and safety study supporting regulatory requirements for registration of intranasal esketamine for the treatment of TRD.

[0138] The hypothesis of this study was that in adult subjects with TRD, switching from a failing antidepressant treatment to intranasal esketamine plus a newly initiated oral antidepressant would be superior to switching to a newly initiated oral antidepressant treatment (active comparator) plus intranasal placebo in improving depressive symptoms.

[0139] The primary objective of this study was to evaluate the effectiveness of switching adult subjects with TRD from their previous antidepressant treatment (who were not responding) to flexibly administered intranasal esketamine (28 mg, 56 mg, or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo in improving depressive symptoms as assessed by change from baseline in MADRS total score from Day 1 (pre-randomization) to the end of a 4-week double-blind induction phase.

[0140] Key secondary objectives were to evaluate the effect of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo on the following parameters in adult subjects with TRD: (a) depressive symptoms (subject-reported), (b) onset of clinical response by day 2, and (c) functioning and associated disability. Additional secondary objectives included (a) depression response rate, (b) depression remission rate, (c) global severity of depression, (d) anxiety symptoms, and (e) health-related quality of life and well-being.

[0141] To investigate the safety and tolerability of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo in adult subjects with TRD, the following parameters were also measured: (a) TEAEs, including AEs of special interest; (b) topical nasal tolerability; (c) effects on 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; (h) potential effects on suicidal ideation / behavior; (i) potential treatment-emergent symptoms of cystitis and / or lower urinary tract symptoms; (j) potential withdrawal and / or rebound symptoms after cessation of intranasal esketamine treatment; and (k) potential effects on smell.

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

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

[0144] The placebo solution was supplied as a clear, colorless intranasal solution in water for injection, with the addition of a bittering agent (denatonium benzoate [Bitrex®] at a final concentration of 0.001 mg / mL) to simulate the taste of the intranasal solution with the active drug. The placebo solution was provided in a matching nasal spray pump device. Benzalkonium chloride was added at a concentration of 0.3 mg / mL as a preservative. Each individual nasal spray pump (device) contained two doses of spray solution.

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

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

[0147] Sertraline 50 mg and 25 mg (where applicable) were obtained from commercial stocks and provided under the responsibility of the sponsor. Please refer to package insert / SmPC for physical description and list of excipients.

[0148] Venlafaxine 75 mg and 37.5 mg (where applicable) were obtained from commercial stocks and provided under the responsibility of the sponsor. Please refer to package insert / SmPC for physical description and list of excipients.

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

[0150] Screening / prospective observation period (4 weeks duration) This phase prospectively assessed the subject's treatment response to their 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 an independent remote rater) were eligible to proceed to the double-blind induction phase. Site investigators were blinded to the study criteria for non-response.

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

[0152] Because new oral antidepressants were initiated on day 1 of the double-blind induction phase, eligible subjects who did not require tapering off their antidepressant(s) proceeded immediately to the double-blind induction phase.

[0153] Double-blind induction period (4 weeks duration) This study included 227 randomized subjects (n = 98 subjects per treatment arm) who were randomly assigned in a 1:1 ratio to receive double-blind treatment with either intranasal esketamine or intranasal placebo (four of whom did not receive the intranasal and / or oral AD study medication and were therefore not included in the analysis population). Intranasal treatment sessions (esketamine or placebo) were conducted twice weekly. In addition, all subjects started a new open-label oral antidepressant on Day 1, which was taken daily for the duration of this period. The assigned oral antidepressant was one of four oral antidepressants (duloxetine, escitalopram, sertraline, or venlafaxine extended-release [XR]) for which the subject had no prior non-response in the current depressive episode, no prior intolerance (lifetime), and which were available in the participating country.

[0154] At the end of the induction period, subjects who were responders (defined as a ≥ 50% reduction in MADRS total score from baseline [pre-randomization on Day 1] to the end of the 4-week double-blind induction period) were eligible to participate in the follow-on study, ESKETINTRD3003, if they met all other study entry criteria (ESKETINTRD3003 is a longer-term efficacy maintenance study with repeated treatment sessions of intranasal esketamine).

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

[0156] Follow-up period (24-week duration) This phase included all subjects who were ineligible or elected not to participate in the maintenance efficacy study ESKETINTRD 3003 and who had received at least one dose of intranasal study drug during the double-blind induction phase. There were no intranasal treatment sessions administered during this phase.

[0157] At the start of the follow-up period, further clinical / standard care for the treatment of depression was arranged by the investigator and / or the subject's treating physician. The decision to continue oral antidepressants during this period was at the investigator's discretion, but to better assess potential withdrawal symptoms from the intranasal study medication, it was recommended that oral antidepressants be continued for at least the first 2 weeks of the follow-up period unless deemed clinically appropriate.

[0158] The follow-up phase also allowed for the collection of additional information data to assess the course of the subjects' major depressive episode over a 6-month period.

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

[0160] Study population The inclusion criteria for enrolling subjects in this study were as follows: Each potential subject met all of the following criteria to be enrolled in this study. 1. Subjects were men and women aged 18 years (or 19 years or older if the minimum legal age for consent in the country where the study is being conducted is higher) to 64 years at the time of signing the informed consent form (ICF). 2. At the start of the screening / prospective observation period, subjects met DSM-5 diagnostic criteria for single-episode MDD (for single-episode MDD, duration was ≥ 2 years) or recurrent MDD without psychotic features based on clinical assessment and confirmed by MINI. 3. At the start of the screening / prospective observation period, subjects had a history of non-response to two or more but not more than five oral antidepressant medications in the current depressive episode, as assessed using the MGH-ATRQ and confirmed by documented medical history and pharmacy / prescription records. Subjects were receiving oral antidepressant therapy without response at the start of the screening / prospective observation period. As documented by the PAQ, subjects adhered to their continuous oral antidepressant medication(s) (without dosage adjustments) throughout the screening / prospective observation period. Missing antidepressant medication for four or more days in the previous two-week period was considered inadequate adherence. Subjects who were non-responders to their current oral antidepressant(s) from the screening / prospective observation period (as assessed by an independent remote rater) were eligible for randomization if all other entry criteria were met. 4. At the start of the screening / prospective observation period, subjects must meet the IDS-C 30 had a total score ≥34. 5. The subject's current major depressive episode and antidepressant treatment response in the current depressive episode were confirmed using an independent institutional eligibility assessment. 6. Subjects were medically stable based on physical examination, medical history, vital signs (including blood pressure), pulse oximetry, and a 12-lead ECG performed during the screening / prospective observation period. If any abnormalities not specified in the inclusion and exclusion criteria were present, a determination of clinical significance was made by the investigator and recorded on the subject's source documentation and initialed by the investigator. 7. Subjects were medically stable based on laboratory tests performed during the screening / prospective observation period. If serum chemistry panel, hematology, or urinalysis results were outside the normal reference range, subjects were included only if the investigator determined the abnormality or deviation from normal to be not clinically significant or appropriate and reasonable for the population under study. This determination was recorded on the subject's source documentation and initialed by the investigator. Subjects with a pre-existing history of thyroid disease / disorder treated with thyroid hormone were on a stable dose for 3 months prior to the start of the screening / prospective observation period and had thyroid-stimulating hormone (TSH) within the normal range during the screening / prospective observation period. 8. Subject was comfortable self-administering intranasal medication and was able to follow the intranasal administration instructions provided. 9. Prior to the start of the screening / prospective phase, female subjects were either: (a) not of childbearing potential: postmenopausal (age >45 years with amenorrhea for at least 12 months, or any age with amenorrhea for at least 6 months and a serum follicle stimulating hormone (FSH) level >40 IU / L), permanently infertile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy), or otherwise unable to conceive, or (b) of childbearing potential and practicing established use of highly effective methods of contraception, e.g., oral, injected, or implanted hormonal contraception, intrauterine device, consistent with local regulations regarding the use of contraception for subjects participating in clinical trials. placement of an intrauterine system (IUD, IUD) or intrauterine system; barrier methods (e.g., condoms with spermicidal foam / gel / film / cream / suppositories or occlusive caps [diaphragm or cervical / vaginal vault cap] with spermicidal foam / gel / film / cream / suppositories); sterilization of the male partner (the vasectomized partner should be the subject's only partner); or true abstinence (if this is consistent with the subject's preferred usual lifestyle). If fertility changed after the start of the study (e.g., a woman who was not heterosexually active became active), female subjects were initiated on highly effective contraceptive methods, as described above. Women agreed to continue using these contraceptive methods throughout the study and for at least 6 weeks after the last dose of intranasal study drug. 10. Women of childbearing potential had a negative serum (β-human chorionic gonadotropin [β-hCG]) at the start of the screening / prospective observation period and a negative urine pregnancy test on day 1 of the double-blind induction period before randomization. 11. Non-vasectomized men who were sexually active with women of childbearing potential agreed to use a barrier method of contraception, e.g., condoms with spermicidal foam / gel / film / cream / suppository, or their partner used an occlusive cap (diaphragm or cervical / vaginal vault cap) with spermicidal foam / gel / film / cream / suppository, from Day 1 of the double-blind induction period (before randomization) until 3 months after the last dose of intranasal study drug. Alternatively, the female partner of childbearing potential could practice a highly effective method of contraception, e.g., established use of oral, injection, or implanted hormonal methods; placement of an intrauterine device (IUD) or intrauterine system; or sterilization of the male partner. If childbearing potential changed after the start of the study, the female partner of the male subject initiated a highly effective method of contraception, as described above. 12. The subject was willing and able to comply with the prohibitions and restrictions specified in the clinical trial protocol. 13. Each subject signed an ICF indicating that they understood the purpose of the study and the procedures involved and were willing to participate in the study.

[0161] The exclusion criteria for enrolling subjects in this study were as follows: Any potential subject who met any of the following criteria was excluded from participating in this study. 1. The subject's depressive symptoms have previously shown non-response to (a) esketamine or ketamine in the current major depressive episode according to clinical judgment, or (b) all oral antidepressant treatment options available in the respective country (i.e., duloxetine, escitalopram, sertraline, and venlafaxine XR) during the double-blind induction phase in the current major depressive episode (based on the MGH-ATRQ), or (c) an adequate course of unilateral electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least seven treatments with ECT. 2. Subject had an implant for vagal nerve stimulation (VNS) or was receiving deep brain stimulation (DBS) in the current depressive episode. 3. Subject had a current or previous DSM-5 diagnosis of psychotic disorder or MDD with psychotic, bipolar or related disorder (confirmed by MINI), comorbid obsessive-compulsive disorder, intellectual disability (DSM-5 diagnosis code 319 only), borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder. 4. Subjects had homicidal ideation / intent according to the investigator's clinical judgment, or had suicidal ideation with some intent to act within 6 months prior to the start of the Screening / Prospective Observation Period according to the investigator's clinical judgment or based on the C-SSRS (corresponding to a "yes" response to item 4 (active suicidal ideation with some intent to act without a specific plan) or item 5 (active suicidal ideation with a specific plan and intent) on the C-SSRS regarding suicidal ideation, or a history of suicidal behavior in the year prior to the start of the Screening / Prospective Observation Period). Subjects who reported suicidal ideation or suicidal behavior with intent to act before the start of the double-blind induction period were excluded. 5. Subjects had a history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria, excluding nicotine or caffeine, within 6 months prior to the start of the screening / prospective observation period. Lifetime history of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3,4-methylenedioxy-methamphetamine (MDMA) hallucination-related use disorder was excluded. 6. Subject had a current or past history of seizures (uncomplicated childhood febrile seizures without sequelae are not excluded). 7. Subject had a UPSIT total score ≦18 during the screening / prospective observation period, indicating anemia. 8. Subject had one of the following cardiovascular-related conditions: (a) cerebrovascular disease with a history of stroke or transient ischemic attack; (b) aneurysmal vascular disease (including the intracranial, thoracic, or abdominal aorta, or peripheral arterial vessels); (c) coronary artery disease with myocardial infarction, unstable angina, or revascularization procedure (e.g., coronary angioplasty or bypass graft surgery) within 12 months prior to the start of the screening / prospective observation period; (d) hemodynamically significant valvular heart disease, such as mitral regurgitation, aortic stenosis, or aortic regurgitation; or (e) New York Heart Association (NYHA) Class III-IV heart failure of any cause. 9. Subjects had a history of uncontrolled hypertension at the start of the screening / prospective observation period despite diet, exercise, or antihypertensive therapy, or a past history of hypertensive emergency, or ongoing evidence of uncontrolled hypertension, defined as a supine systolic blood pressure (SBP) >140 mmHg or a diastolic blood pressure (DBP) >90 mmHg during the screening / prospective observation period (and persisting above this range on repeated testing during this period). Subjects were also excluded if they had a supine SBP >140 mmHg or DBP >90 mmHg on Day 1 of the double-blind induction period before randomization. Potential subjects may have their current antihypertensive medication regimen adjusted during the screening / prospective observation period and then reevaluated to assess blood pressure control. Subjects were on a stable regimen for at least 2 weeks prior to Day 1 of the double-blind induction period. 10. Subject had a current or past history of significant pulmonary insufficiency / condition or an arterial oxygen saturation (SpO2) of <93% at the start of the screening / prospective observation period or on Day 1 prior to randomization. 11. Subjects had clinically significant ECG abnormalities defined as (a) QT interval corrected according to the Fridericia formula (QTcF): ≥ 450 msec, (b) second- and third-degree AV block with a PR interval > 200 msec, or evidence of first-degree AV block, left bundle branch block (LBBB), or right bundle branch block (RBBB), (c) new ischemic features, or (d) arrhythmias (excluding premature atrial contractions (PACs) and premature ventricular contractions (PVCs)) at the start of the screening / prospective observation period or on Day 1 of the double-blind induction period prior to randomization. 12. Subject had a history of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome) or use of concomitant medications that prolong the QT interval / corrected QT (QTc) interval. 13. Subjects had a history of liver cirrhosis (e.g., esophageal varices, ascites, and elevated prothrombin time), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥ 2 times the upper limit of normal during the screening / prospective observation period, or total bilirubin > 1.5 times the ULN. Subjects were eligible to participate in the study if, in the opinion of the investigator and with consent from sponsor medical staff, the elevated bilirubin was consistent with Gilbert's disease. 14. Subjects had positive test result(s) for a drug of abuse (including barbiturates, methadone, opiates, cocaine, phencyclidine, and amphetamine / methamphetamine) at the start of the screening / prospective observation period or on Day 1 of the double-blind induction period prior to randomization. Subjects with a positive test result at screening for prescription / over-the-counter opiates, barbiturates, or amphetamines were allowed to continue into the screening / prospective observation period if medication was discontinued for at least 1 week or 5 half-lives, whichever was longer, before Day 1 of the double-blind induction period (prior to randomization), subject to the restrictions presented to the investigator and reproduced in Table 6 below. Day 1 (prior to randomization) test results for a drug of abuse were required to be negative for subjects to be randomized. Retesting for positive test result(s) was not permitted, except for the reasons stated above. Previous intermittent use of cannabinoids before the start of the screening / prospective observation period was not excluded unless the subject met criteria for a substance use disorder. However, a positive test result for cannabinoids before dosing on Day 1 of the double-blind induction period was excluded. 15. Subject had uncontrolled diabetes mellitus or secondary diabetes mellitus as evidenced by HbA1c >9% during the Screening / Prospective Observation Period or history of severe hypoglycemia with diabetic ketoacidosis, hyperglycemic coma, or loss of consciousness in the 3 months prior to the start of the Screening / Prospective Observation Period. 16. Subject had untreated glaucoma, current penetrating or perforating eye injury, brain injury, hypertensive encephalopathy, intrathecal therapy with a ventricular shunt, or any other condition related to elevated intracranial or intraocular pressure or planned eye surgery. 17. Subject had any anatomical or medical condition that could interfere with the delivery or absorption of intranasal investigational drug (e.g., significant structural or functional abnormality of the nose or upper respiratory tract, obstruction or mucosal lesion of the nasal cavity or nasal passages, sinus surgery in the past 2 years). 18. Subject had an abnormal or unrepaired deviated nasal septum with any one or more of the following symptoms: (a) obstruction of one or both nostrils within the past few months that may affect study participation, (b) nasal congestion (especially on one side), (c) frequent nosebleeds, (d) frequent sinus infections, or (e) wheezing during sleep. 19. Subject had a history of malignancy within 5 years prior to the start of the screening / prospective observation period (with the exception of squamous cell and basal cell carcinoma of the skin and carcinoma in situ of the cervix, or a malignancy that, in the opinion of the investigator and in agreement with the sponsor's medical monitor, was deemed cured with minimal risk of recurrence). 20. Subject had a known allergy, hypersensitivity, intolerance, or contraindication to esketamine / ketamine and / or its excipients, or to any of the available oral antidepressant treatment options for the double-blind induction phase. 21. Subject was receiving any prohibited therapy that would not be allowed to be administered on Day 1, as outlined in the section entitled Pre-Study and Concomitant Therapy, and in Table 6. 22. Subject was taking a total daily dose of benzodiazepines greater than the equivalent of 6 mg / day of lorazepam at the start of the screening / prospective observation period. 23. Subjects had a score of ≥ 5 on the STOP-Bang questionnaire, in which case obstructive sleep apnea had to be excluded (e.g., apnea-hypopnea index [AHI] < 30). Subjects with obstructive sleep apnea could be included if they were using a positive airway pressure device or other treatment / therapy that effectively treated their sleep apnea. 24. Subject has received an investigational drug (including an investigational vaccine) or used an invasive investigational medical device within 60 days prior to the start of the screening / prospective observation period, or has participated in two or more clinical intervention trials for MDD or other psychiatric conditions in the year prior to the start of the screening / prospective observation period, or is currently enrolled in a clinical trial. 25. Subject was a woman who was pregnant, nursing, or planning to become pregnant while enrolled in this study or within 6 weeks after the last dose of intranasal study drug. 26. Subjects had a diagnosis of acquired immunodeficiency syndrome (AIDS). Human immunodeficiency virus (HIV) testing was not required for this study. 27. The subject had any condition or situation / circumstances in which, in the opinion of the investigator, participation would not be in the subject's best interest (compromise their well-being) or which could interfere with, limit, or confound protocol-specified assessments. 28. Subject had undergone major surgery (e.g., requiring general anesthesia) within 12 weeks prior to the start of the screening / prospective observation period, or had not fully recovered from surgery, or had surgery planned during the time the subject was expected to enter the study. Subjects scheduled for a surgical procedure performed under local anesthesia were allowed to participate. 29. Subjects were employees of the investigator or the testing facility who were directly involved in the proposed study or other studies under the direction of the investigator or testing facility, as well as family members of such employees or investigators.

[0162] The investigator ensured that all study entry criteria were met. If a subject's condition changed (including receipt of laboratory results or additional medical records) before the first dose of study drug was administered such that the subject could no longer meet all eligibility criteria, the subject would be excluded from study participation.

[0163] Additionally, to be eligible to participate, potential subjects had to be willing and able to adhere to the following prohibitions and restrictions during the course of the study. 1. Inclusion and Exclusion Criteria, 2. Preliminary testing and concomitant therapy restrictions, including a list of prohibited concomitant medications for intranasal investigational drugs. 3. A positive urine drug screen for phencyclidine (PCP), 3,4-methylenedioxy-methamphetamine (MDMA), or cocaine use from Day 1 of the induction phase through the final visit in the double-blind induction phase will lead to discontinuation. 4. Subjects were required to abstain from alcohol for 24 hours before and after each intranasal treatment session. Dosing should not be administered if the subject appears intoxicated. 5. On all intranasal study drug administration days, all subjects were required to remain at the clinical trial site until study procedures were completed and the subject was ready to be released, and to be accompanied by a responsible adult when released from the clinical trial site. Subjects were not to drive or work with machinery for 24 hours after study drug administration. 6. Subjects were not to consume grapefruit juice, Seville oranges, or quinine for 24 hours prior to receiving an intranasal dose of study drug. 7. ECT, DBS, transcranial magnetic stimulation (TMS), and VNS were prohibited from study entry until the end of the double-blind induction period. 8. Subjects receiving psychiatric therapy were allowed to continue receiving this therapy as long as this therapy had been stable in terms of frequency over the past 6 months prior to the screening / prospective observation period and did not change until the end of the double-blind induction period.

[0164] Treatment assignment, randomization, and blinding This study employed central randomization. Subjects were randomly assigned to treatment group 1 or 2 in a 1:1 ratio based on a computer-generated randomization schedule prepared by the sponsor or under the sponsor's supervision prior to the study. Randomization was balanced by using randomly permuted blocks and stratified by country and the class of oral antidepressant (SNRI or SSRI) initiated during the double-blind induction period. The interactive web response system (IWRS) assigned unique treatment codes that determined subjects' treatment assignments and matching study drug kits. After the investigator selected the oral antidepressant treatment for the double-blind induction period, the site entered this information into the IWRS. When requesters contacted the IWRS, they used their user identification and personal identification number to obtain relevant subject details to uniquely identify the subject.

[0165] The investigators were not provided with a randomization code, which was maintained within the IWRS and had the functionality to allow the investigator to unblind individual subjects.

[0166] Data that could potentially be unblinded to treatment assignment (e.g., intranasal investigational drug plasma concentrations, treatment assignment) were handled with particular care to ensure that the integrity of the blinding was maintained and the potential for bias was minimized. This could include making exceptions, as appropriate, such as ensuring that the investigator, clinical team, or others could not see the data until the database was time-locked and unblinded.

[0167] Under normal circumstances, the blind should not be broken until all subjects had completed the study and the database was finalized. Otherwise, the blind could be broken only if knowledge of the subject's treatment status indicated a specific emergency treatment / course of action. In such cases, the investigator could determine the identity of the treatment in an emergency by contacting the IWRS. Before breaking the blind, investigators were encouraged to contact the sponsor or its designee, if possible, to discuss the specific situation. Telephone contact with the sponsor or its designee was available 24 hours a day, 7 days a week. If the blind was broken, the sponsor was notified as soon as possible. The date and time of unblinding were documented by the IWRS, and the reason for unblinding was documented by the electronic case report form (eCRF) and in the source documents. Documentation indicating code unblinding received from the IWRS was retained with the subject's source documents in a secure manner.

[0168] Subjects whose treatment assignments were unblinded were to continue returning for scheduled early withdrawal and follow-up visits.

[0169] In general, randomization codes were fully disclosed only once the trial was completed and the clinical database was closed. For interim analyses, the randomization codes, and, where necessary, their translation into treatment and control groups, were disclosed to authorized personnel only for subjects included in the interim analysis.

[0170] At the end of the double-blind induction phase, the database was locked for analysis and reporting of this phase. Subjects' treatment assignment was revealed only to the sponsor's study staff. Investigators and site personnel were blinded to treatment assignment until all subjects completed study participation through the follow-up phase.

[0171] To maintain blinding of the intranasal study medication, the esketamine and placebo intranasal devices were indistinguishable.

[0172] A total of 227 subjects were randomized in the study. Of these, 3 subjects did not receive either study drug (intranasal or oral AD), and 1 subject did not receive both intranasal and oral AD study drugs.

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

[0174] [Table 1-1]

[0175] [Table 1-2]

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

[0177] [Table 2]

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

[0179] [Table 3-1]

[0180] [Table 3-2]

[0181] Dosage and Administration Screening / prospective observation period At the start of the screening / prospective observation period, subjects were on oral antidepressant treatment and non-responders at the start of the screening / prospective observation period, and continued this same treatment for the duration of this period to confirm non-response. Sites and investigators were blinded to the study criteria for non-response. Antidepressant treatment adherence was assessed during this period using the PAQ.

[0182] After completion of 4 weeks of prospective antidepressant treatment and assessment of antidepressant treatment response, antidepressants were tapered and discontinued over a period of up to 3 weeks according to local prescribing information or clinical judgment (e.g., antidepressant treatment with a short half-life, such as paroxetine and venlafaxine XR, or tolerability concerns).

[0183] Double-blind induction period During this phase, subjects self-administered double-blind intranasal treatment with esketamine (56 mg or 84 mg) or placebo twice weekly for 4 weeks on a flexible dosing regimen at the study site. In addition, subjects concurrently started a new open-label oral antidepressant (i.e., duloxetine, escitalopram, sertraline, or venlafaxine XR) on Day 1 and continued it for the duration of this phase.

[0184] Intranasal investigational drug For all intranasal treatment sessions, a physician, nurse, or other appropriate member of site staff with recent (i.e., within 1 year) training in cardiopulmonary resuscitation (CPR) was present with the subject during the intranasal treatment session and post-administration observation period. In addition, supportive ventilation and resuscitation equipment was available. Table 4 below describes how each intranasal treatment session was administered during the double-blind induction period.

[0185] [Table 4]

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

[0187] All subjects self-administered intranasal study medication (esketamine or placebo) at the study site for two treatment sessions per week for four weeks. The first treatment session occurred on Day 1. Intranasal treatment sessions were not administered on consecutive days.

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

[0189] Food was restricted for at least 2 hours before each administration of study medication. Drinking any fluids was restricted for at least 30 minutes before the first nasal spray.

[0190] If subjects had nasal congestion on the day of dosing, they were encouraged to delay the dosing day (according to the allowed visit duration). Doses were not to be administered on consecutive days. If intranasal decongestant was used to reduce nasal congestion, it could not be used within 1 hour before intranasal study drug administration.

[0191] For all intranasal treatment sessions, subjects remained at the clinical site until study procedures were completed and the subjects were ready to be released, and were accompanied by a responsible adult when released from the clinical trial site. Subjects were not to drive or work with machinery for 24 hours after the last dose of intranasal study medication on each dosing day.

[0192] Oral antidepressants Beginning on Day 1, new open-label oral antidepressant treatment was initiated in all subjects and continued for the duration of this phase. The oral antidepressant was one of four oral antidepressants (duloxetine, escitalopram, sertraline, or venlafaxine XR). The antidepressant was assigned by the investigator based on review of the MGH-ATRQ and related information regarding previous antidepressant treatment, was not previously non-responsive to the subject in their current depressive episode, was not previously intolerant (lifetime), and was available in the participating country.

[0193] Oral antidepressant administration began on day 1 and was titrated up to the maximum tolerated dose according to the local prescribing information for each product. The protocol-specified titration schedule was as presented in Table 5 below.

[0194] [Table 5]

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

[0196] All subjects were provided with an additional 4-week supply of oral antidepressants to ensure no interruption of antidepressant therapy during transition to further clinical / standard care.

[0197] Study site personnel instructed subjects on how to administer and store the oral antidepressant treatment provided during the double-blind induction period for home use.

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

[0199] Guidelines for blood pressure monitoring on the day of intranasal administration: Considering the possibility of treatment-emergent transient increases in systolic and diastolic blood pressure, the following guidelines were followed on intranasal dosing days.

[0200] After meeting the inclusion and exclusion criteria on Day 1, if the subject's pre-dose systolic blood pressure (SBP) was ≥ 160 mmHg and / or diastolic blood pressure (DBP) was ≥ 100 mmHg, it was recommended that the subject rest for 10 minutes in a sitting or recumbent position for a repeat blood pressure measurement. If the repeat pre-dose SBP was ≥ 160 mmHg and / or DBP was ≥ 100 mmHg, dosing was postponed and the subject was scheduled to return the next day or within a given visit period. If elevated blood pressure persisted at the next visit, the subject was scheduled for a consultation with a cardiologist or primary care physician before further dosing.

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

[0202] As long as the subject was approved to continue on the study after evaluation by a cardiologist or attending physician, subjects could continue intranasal dosing if their pre-dose blood pressure was within acceptable limits at the next scheduled visit.

[0203] If SBP was ≥ 200 mmHg and / or DBP was ≥ 120 mmHg at any time after dosing on the dosing day, the subject was to discontinue further dosing and be referred to a cardiologist or primary care physician for follow-up evaluation.

[0204] During the double-blind induction period, if SBP is ≥ 160 mmHg and / or DBP is ≥ 100 mmHg at 1.5 hours post-dose, assessments must continue every 30 minutes until blood pressure is SBP < 160 mmHg and DBP < 100 mmHg, or if clinically indicated, until the subject is referred to appropriate medical care.

[0205] Follow-up period Subjects who received at least one dose of intranasal study drug during the double-blind induction phase but did not enter the subsequent maintenance clinical trial, ESKETINTRD3003, proceeded to a 24-week follow-up phase. Intranasal study drug was not administered during this phase.

[0206] At the start of the follow-up period, further clinical / standard care for the treatment of depression was arranged by the investigator and / or the subject's treating physician. The decision to continue oral antidepressants during this period was at the investigator's discretion, but to better assess potential withdrawal symptoms from the intranasal study medication, it was recommended that oral antidepressants be continued for at least the first 2 weeks of the follow-up period unless deemed clinically appropriate.

[0207] Treatment compliance The investigator or designated study site personnel were required to maintain a log of all dispensed and returned intranasal study medications and oral antidepressants. Each subject's medication supply was inventoried and managed throughout the study.

[0208] Subjects received instructions for compliance with oral antidepressant treatment. During the course of the study, the investigator or designated study site personnel was responsible for providing additional instructions to re-educate any subjects to ensure compliance with oral antidepressant medication.

[0209] Antidepressant treatment adherence during the screening / prospective observation period was assessed using the PAQ. Missing antidepressant medication for 4 or more days during the previous 2-week period was considered inadequate adherence.

[0210] Antidepressant treatment compliance during the double-blind induction period was assessed by conducting pill counts (i.e., compliance checks) and study drug administration.

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

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

[0213] All antidepressant treatment(s), including adjunctive treatments for MDD, taken during the current depressive episode (i.e., including those taken >30 days before the start of the screening / prospective observation period) were recorded at the start of the screening / prospective observation period. In addition, information was obtained regarding any history of intolerance to any of the four antidepressant choices (i.e., duloxetine, escitalopram, cetrile, and venlafaxine XR).

[0214] Concomitant therapy was recorded throughout the study, beginning with the signing of the informed consent and continuing until the last follow-up visit. Information on concomitant therapy was also obtained beyond this time, along with any new or worsening adverse events, simply until resolution of the events.

[0215] Subjects continued to take permitted concomitant medications (e.g., antihypertensives) on their regular schedule, subject to restrictions and considerations in Table 6 below. Note that if an oral antihypertensive was taken in the morning, the morning dose would be taken on intranasal administration days.

[0216] Subjects receiving psychotropic therapy were allowed to continue receiving this therapy provided that this therapy had been stable in terms of frequency over the past 6 months prior to the screening / prospective observation period and had not changed after completion of the double-blind induction period.

[0217] All treatments different from the investigational product were recorded, including prescription or over-the-counter medications, vaccines, vitamins, herbal supplements, psychiatric treatments, electrical stimulation, acupuncture, special diets, and non-pharmacological therapies such as exercise regimens. Modifications of active existing treatments should not be made for the express purpose of enrolling the subject in the study, unless permitted by the protocol (e.g., adjustment of blood pressure medications).

[0218] Rescue medication Rescue medications were not provided by the sponsor. In the event of a treatment-emergent adverse event that was not alleviated by discontinuing further administration of intranasal esketamine / placebo, the following rescue medications could be considered: For agitation or anxiety: Midazolam (maximum dose 2.5 mg orally or IM) or short-acting benzodiazepines as needed For nausea: Ondansetron 8 mg sublingually, metoclopramide (10 mg orally or IV or IM), or dimenhydrinate (25 to 50 mg IV or IM) as needed

[0219] It was recommended that transient increases in blood pressure not be treated, as blood pressure typically returns to pre-dose values ​​within 2 hours. The effects of any treatment may result in hypotension.

[0220] Prohibited drugs A (non-exhaustive) list of prohibited medications was provided for the investigator's general guidance and is reproduced below in Table 6. The sponsor was notified in advance (or as soon thereafter as possible) of any instances in which prohibited therapy would be administered.

[0221] [Table 6-1]

[0222] [Table 6-2]

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

[0224] [Table 7]

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

[0226] [Table 8]

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

[0228] [Table 9]

[0229] Test evaluation The time and event schedule is shown in Tables 10 and 11 below, summarizing the frequency and timing of efficacy, PK, biomarker, pharmacogenomic, healthcare resource utilization, health economics, and safety measurements applicable to this study.

[0230] [Table 10-1]

[0231] [Table 10-2]

[0232] [Table 10-3]

[0233] [Table 10-4]

[0234] [Table 11-1]

[0235] [Table 11-2]

[0236] With the exception of post-dose assessments, visit-specific subject-reported outcome assessments were conducted or completed before any tests, procedures, or other visits to avoid influencing subject perception. A recommended sequence of study procedures was provided. Actual assessment dates and times were recorded on source documents and eCRFs.

[0237] The approximate total volume of blood drawn from each subject was 123.5 mL (see Table 12 below). Repeat or unscheduled samples could be drawn for safety reasons or due to technical problems with the sample. If deemed necessary by the investigator or required by local regulations, additional serum or urine pregnancy tests could be performed to confirm that the subject was not pregnant at any time during their participation in the study.

[0238] [Table 12]

[0239] Screening / prospective observation period Before any study procedures were performed, the investigator (or designated study personnel) reviewed and explained the written ICF to each subject. After signing the ICF, subjects between the ages of 18 (or 19 or older if the minimum legal age of consent in the country where the study is being conducted is >18) and 64 years of age were screened to determine their eligibility for study participation.

[0240] Subjects were required to meet DSM-5 diagnostic criteria for single-episode MDD (for single-episode MDD, duration was ≥ 2 years) or recurrent MDD without psychotic features, based on clinical assessment and confirmed by the MINI. In addition, at the start of the screening / prospective observation period, subjects were required to complete the IDS-C 30 Must have a total score ≥ 34.

[0241] At the start of this period, subjects must have a history of non-response to ≥2 but ≤5 oral antidepressant medications in the current depressive episode, as assessed using the MGH-ATRQ and confirmed by documented medical history and pharmacy / prescription records. Subjects were receiving oral antidepressant therapy without response at entry, and this treatment was continued at the same dose for the duration of this period to prospectively confirm non-response. Antidepressant treatment adherence was assessed using the PAQ. Missing antidepressant medication for ≥4 days in the previous 2-week period was considered inadequate adherence.

[0242] The subject's current major depressive episode and antidepressant treatment response to antidepressant therapy used during the current depressive episode were confirmed using an independent institutional eligibility assessment.

[0243] An independent blinded rater performed remote MADRS assessments to evaluate depressive symptoms during this period. Investigators and study sites were blinded to specific details regarding the response criteria for entry into the double-blind induction period. Eligible non-responders (as determined by the remote blinded rater) discontinued their current antidepressant(s) and any other prohibited psychotropic medications (including adjunctive atypical antipsychotics). Benzodiazepine or non-benzodiazepine hypnotics were allowed to be continued, but with specific restrictions regarding administration time for intranasal treatment sessions.

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

[0245] Optional antidepressant tapering period Because all non-responder subjects had started a new oral antidepressant during the double-blind induction phase, no drug-free or non-drug period was required after discontinuing current antidepressant treatment; however, an optional additional period of up to 3 weeks was allowed to tapere and discontinue current oral antidepressants according to local prescribing information or clinical judgment.

[0246] The tapering period did not begin until after completion of 4 weeks of prospective antidepressant treatment and assessment of antidepressant treatment response.

[0247] Double-blind induction period During this period, subjects self-administered double-blind intranasal treatment with esketamine (56 mg or 84 mg) or placebo twice weekly for 4 weeks as a flexible dosing regimen. In addition, subjects simultaneously started a new open-label oral antidepressant.

[0248] Study subjects (with TRD) were randomly assigned in a 1:1 ratio (approximately 98 per group) 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. The oral antidepressant was one of four oral antidepressants (duloxetine, escitalopram, sertraline, or venlafaxine XR). The antidepressant was assigned by the investigator (based on review of the MGH-ATRQ and relevant previous antidepressant treatment information), was not previously non-responsive, was not previously intolerant (lifetime), and was available in the participating country in the current depressive episode. Oral antidepressant administration began on Day 1 and was titrated to the maximum tolerated dose according to the local prescribing information for each product. The titration schedule for the selected oral antidepressants was as presented in Table 5 above.

[0249] For information obtained by telephone, a transcript of the call was made available for review with the source documents. Adverse event and concomitant medication information was obtained during telephone contact with the subject by site personnel. Additionally, certain clinician administration assessments were performed by appropriately certified staff.

[0250] At the end of the double-blind induction phase, subjects who were responders (defined as a ≥ 50% reduction in the MADRS total score from baseline [pre-randomization on Day 1] to the end of the 4-week double-blind induction phase) were eligible to enter the subsequent maintenance clinical trial (Study ESKETINTRD3003). To maintain the study blind, all responder subjects, including those who responded to the active comparator (i.e., oral antidepressant + intranasal placebo), were eligible to enter Study ESKETINTRD3003. Participation in ESKETINTRD3003 began immediately after the completion of the double-blind induction phase. Subjects received oral antidepressants and were instructed to continue taking their oral antidepressants until the next study visit (i.e., the first study visit of the stabilization phase in Study ESKETINTRD3003).

[0251] Subjects who did not enter study ESKETINTRD3003 progressed to the follow-up phase.

[0252] Early withdrawal If a subject withdrew before the end of the double-blind induction period for reasons other than withdrawal of consent, an early withdrawal visit was conducted within 1 week of the date of discontinuation, followed by the follow-up period. If the early withdrawal visit occurred on the same day as a scheduled visit, the early withdrawal visit was conducted on the same day and did not require a duplicate assessment.

[0253] Further clinical / standard care for the treatment of depression was arranged by the investigator and / or the subject's treating physician, who decided whether or not to continue current oral antidepressants.

[0254] If applicable, subjects who withdrew were encouraged to receive an additional oral antidepressant early and to continue taking oral antidepressants for at least the first 2 weeks of the follow-up period unless deemed clinically appropriate.

[0255] Follow-up period All subjects who received at least one dose of intranasal study drug during the double-blind induction phase and did not subsequently enter the ESKETINTRD3003 study proceeded to a 24-week follow-up phase. Clinic and remote assessment visits were conducted as specified in the time and event schedule. During this phase, safety and tolerability were assessed, including potential withdrawal symptoms after discontinuation of intranasal esketamine. Additionally, data were collected to assess the course of the subject's current major depressive episode over a 6-month period.

[0256] Further clinical / standard care for the treatment of depression was arranged by the investigator and / or the subject's treating physician. Intranasal study medication was not administered during this phase. To better assess potential withdrawal symptoms from intranasal medication, oral antidepressants were recommended to be continued for at least the first 2 weeks of the follow-up phase unless deemed clinically appropriate. The decision to continue antidepressants was at the investigator's discretion.

[0257] Where information was obtained via telephone contact, transcripts of the calls were made available for review with the source documents.

[0258] Any clinically significant abnormalities persisting at the end of the study were followed by the investigator until resolution or until a clinically stable endpoint was reached. All adverse events, whether serious or non-serious, and special reporting circumstances were reported until the subject's completion of the last study-related procedure.

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

[0260] Primary efficacy evaluation The primary efficacy outcome was the MADRS total score. The MADRS was administered by an independent remote rater during the study. The MADRS, a 10-item clinician-administered, clinician-rated scale, was designed for use in subjects with MDD to measure the overall severity of depressive symptoms, including depression severity, and to detect changes with antidepressant treatment. The MADRS scale was used as the primary efficacy measure in this study because it is validated, reliable, and acceptable to regulatory health authorities as a primary measure for determining efficacy in major depression.

[0261] The MADRS scale consists of 10 items, each scored from 0 (absence of item or normal) to 6 (severe or persistent presence of symptoms), for a total possible score of 60. Higher scores represent more severe illness. The MADRS assesses apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, fatigue, interest level, pessimistic thoughts, and thoughts of suicide. The test exhibits high inter-rater reliability.

[0262] The primary efficacy endpoint was the change in MADRS total score from baseline (day 1 before randomization) to the end of the 4-week double-blind induction period.

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

[0264] In addition to being the primary efficacy measure, the MADRS was also used to assess the key secondary efficacy endpoint of the onset of clinical response (i.e., antidepressant effect) by day 2 that was maintained for the duration of the double-blind induction phase. The onset of clinical response was defined as a ≥ 50% improvement in the MADRS total score by day 2 (i.e., the day after taking the first dose of double-blind intranasal medication) that continued until the end of the double-blind phase.

[0265] The MADRS was also used to evaluate the secondary objective of assessing the proportion of subjects with a response and in remission (defined as subjects with a MADRS total score ≦12) at the end of the 4-week double-blind induction period.

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

[0267] The MADRS with a 24-hour recall period was used on Day 2. The feasibility of this shortened recall period was confirmed by patients and physicians, and there is data supporting the psychometric properties of this shortened recall period. The MADRS with a 7-day recall was used for all subsequent MADRS assessments used for the key secondary efficacy assessment (maintenance of the clinical response achieved on Day 2 for the duration of the double-blind induction period).

[0268] Key secondary efficacy measures (patient-reported outcomes) The Patient Health Questionnaire (PHQ-9) is a nine-item subject-reported outcome measure used to assess depressive symptoms. This scale scores each of the nine symptom domains of the DSM-5 MDD criteria and has been used both as a screening tool and as a measure of response to treatment for depression. Each item was rated on a 4-point scale (0 = not at all, 1 = several days, 2 = more than half the days, 3 = almost every day). Subjects' item responses were summed to provide a total score (ranging from 0 to 27), with higher scores indicating more severe depressive symptoms. The recall period was 2 weeks.

[0269] The secondary objectives of functional impact and associated disability were assessed using the Sheehan Disability Scale (SDS). The SDS is a subject-reported outcome measure, a five-item questionnaire widely used and accepted for assessing functional impairment and associated disability. The first three items assess disruptions to (1) work / school, (2) social life, and (3) family life / household responsibilities using a 0-10 rating scale. Scores on the first three items were added to create a total score ranging from 0 to 30, with higher scores indicating greater disability. The SDS also includes one item regarding days missed from school or work and one item regarding days of reduced productivity. The recall period for this study was 7 days.

[0270] The Clinical Global Impression-Severity Scale (CGI-S) provides an overall clinician-determined summary measure of the severity of a subject's illness, taking into account all available information, including the subject's medical history, psychosocial situation, symptoms, behavior, and the impact of symptoms on the subject's ability to function. The CGI-S assesses the severity of psychopathology on a scale of 0 to 7. Taking into account all clinical experience, subjects rated the severity of their psychiatric illness at the time of assessment according to the following: 0 = not assessed, 1 = normal (not ill at all), 2 = borderline psychotic, 3 = mildly ill, 4 = moderately ill, 5 = significantly ill, 6 = severely ill, and 7 = most severely ill. The CGI-S allows for a global assessment of the subject's condition at a given time.

[0271] The seven-item subject-reported Generalized Anxiety Disorder 7-Item Scale (GAD-7) was used to measure secondary objectives of anxiety symptoms. The GAD-7 is a brief and validated measure of overall anxiety. Each item was rated on a 4-point scale (0 = not at all, 1 = several days, 2 = more than half the days, and 3 = almost every day). Item responses were summed to obtain a total score ranging from 0 to 21. Higher scores indicated greater anxiety. The recall period was 2 weeks.

[0272] The Euro-Qol-5 Item-5 Level (EQ-5D-5L) is a standardized instrument for use as a health outcome measure, primarily designed for self-completion by respondents. It consists of the EQ-5D-5L descriptor system and the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptor system includes five items: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each of the five items is divided into five levels of perceived problem (level 1 indicates no problem, level 2 indicates slight problem, level 3 indicates moderate problem, level 4 indicates severe problem, and level 5 indicates extreme problem).

[0273] Subjects selected an answer for each of the five items, considering the response that best matched their health "today." A descriptive system was used to describe health status. The EQ-VAS self-rating recorded respondents' own assessment of their health status at the time of completion on a scale of 0 to 100.

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

[0275] Primary endpoint results: A serial gatekeeping (fixed order) approach was applied to adjust for multiplicity and to robustly control type I error for the primary efficacy endpoint and three key secondary efficacy endpoints (onset of clinical response, change in SDS total score, and change in PHQ-9 total score). The three key secondary endpoints were analyzed sequentially and considered statistically significant at the one-sided 0.025 level only if the endpoint was individually significant at the one-sided 0.025 level and the previous endpoint in the hierarchy (including the primary endpoint) was significant at the one-sided 0.025 level. If the primary endpoint was statistically significant, the selected secondary endpoints were evaluated in the following order: onset of clinical response, change in SDS total score, and change in PHQ-9 total score.

[0276] The primary efficacy endpoint was the change in MADRS total score from baseline to Day 28. The MADRS total score ranges from 0 to 60. The primary efficacy analysis was performed on the full analysis set, which included all randomized subjects who received at least one dose of intranasal study drug and one dose of oral antidepressant study drug. As shown in Table 13 below, the results of the change in MADRS total score favored intranasal esketamine plus oral AD over oral AD plus intranasal placebo. (Figure 2 presents the least-squares mean change (±SE) from baseline in MADRS total score over time during the double-blind phase based on MMRM analysis.) The mean change from baseline (SD) at Day 28 was -21.4 (12.32) for esketamine plus oral AD and -17.0 (13.88) for the active comparator. Based on an MMRM model with treatment, day, country, oral antidepressant class, and treatment per day as factors and baseline value as a covariate, the least squares mean difference (SE) between esketamine plus oral AD and the active comparator was -4.0 (1.69). The difference between the treatment groups was statistically significant (one-sided p = 0.010). The MMRM analysis was considered the primary analysis for all non-EU dossiers.

[0277] Results based on an ANCOVA model for change in MADRS total score from baseline to endpoint (DB) using treatment, country, and oral antidepressant class as factors and baseline value as a covariate were consistent with the MMRM analysis, with the least squares mean difference (SE) between esketamine plus oral AD and the active comparator being -3.5 (1.63), one-sided p = 0.017.

[0278] [Table 13]

[0279] Secondary endpoints The first key secondary endpoint was the change from baseline (day 1 pre-randomization) to the end of the 4-week double-blind induction period in subject-reported depressive symptoms using the PHQ-9 total score.

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

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

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

[0283] Secondary endpoint results Initiation of clinical response Subjects were defined as having a clinical response if, at each visit, there was at least a 50% improvement from baseline in the MADRS total score with an onset by Day 2 that was maintained through Day 28. Subjects were allowed one deviation (non-response) on Days 8, 15, or 22, but the score must show at least a 25% improvement. Subjects who did not meet such criteria or who discontinued during the study for any reason before Day 28 were considered non-responders and assigned a value of "no," meaning they did not meet the criteria for the onset of a clinical response.

[0284] As shown in Table 14 below, 7.9% of subjects in the esketamine + oral AD group achieved a clinical response compared to 4.6% of subjects in the active comparator group. The difference between the treatment groups was not statistically significant at the one-sided level of 0.025. Therefore, based on the default testing sequence of the key secondary endpoints, the SDS total score and the PHQ-9 total score could not be formally assessed.

[0285] [Table 14]

[0286] Response and remission rates based on MADRS total score The response rates (≧50% improvement from baseline in MADRS total score) and remission rates (MADRS total score≦12) were as presented in Table 15 and Figures 3-5.

[0287] [Table 15]

[0288] Sheehan Disability Scale (SDS) The SDS is a subject-reported outcome measure, a five-item questionnaire that is widely used and accepted for assessing functional impairment and related disabilities. The first three items assess disruptions to (1) work / school, (2) social life, and (3) family life / home responsibilities using a rating scale of 0 to 10. Scores on the first three items are added to create a total score ranging from 0 to 30, with higher scores indicating greater impairment.

[0289] As shown in Table 16 below, the results for change in SDS total score favored intranasal esketamine plus oral AD over oral AD plus intranasal placebo. The mean change from baseline (SD) at day 28 was -13.3 (8.22) for esketamine plus oral AD and -9.5 (8.38) for the active comparator. Based on an MMRM model using treatment, day, country, oral antidepressant class, and treatment per day as factors and baseline value as a covariate, the least squares mean difference (SE) between esketamine plus oral AD and the active comparator was -3.6 (1.18). Based on the predefined testing sequence for the key secondary endpoint, there was no statistically significant difference between the treatment groups for the onset of clinical response, so the SDS total score could not be formally assessed. Nominal one-sided p-value = 0.001.

[0290] Results based on ANCOVA models for change in SDS total score from baseline to endpoint (DB) with factors for treatment, country, and class of oral antidepressant, and baseline value as covariates, were consistent with the MMRM analysis.

[0291] [Table 16]

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

[0293] As shown in Table 17 below, the results for change in PHQ-9 total score favored intranasal esketamine plus oral AD over oral AD plus intranasal placebo. The mean change from baseline (SD) at day 28 was -12.8 (6.43) for esketamine plus oral AD and -10.2 (7.84) for the active comparator. Based on an MMRM model using treatment, day, country, oral antidepressant class, and day of treatment as factors and baseline value as a covariate, the least squares mean difference (SE) between esketamine plus oral AD and the active comparator was -2.2 (0.89). Based on the predefined test sequence for the key secondary endpoint, there was no statistically significant difference between the treatment groups for the onset of clinical response, so the PHQ-9 total score cannot be formally assessed. Nominal one-sided p-value = 0.006.

[0294] Results based on the ANCOVA model for change in PHQ-9 total score from baseline to endpoint (DB), with factors for treatment, country, and class of oral antidepressant and baseline value as a covariate, were consistent with the MMRM analysis (see Appendix 3).

[0295] [Table 17]

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

[0297] Adverse events Adverse events were reported by the subject (or, where appropriate, by a caregiver, surrogate, or legally acceptable representative of the subject) for the duration of the study. Adverse events were tracked by the investigator. TEAEs of special interest were examined separately.

[0298] Laboratory tests Blood samples for serum chemistry and hematology and urine samples for urinalysis were collected. The investigator reviewed laboratory reports, documented this review, and recorded any clinically relevant changes that occurred during the study in the adverse events section of the eCRF. Laboratory reports were submitted with source documentation. If initiation of treatment or safety follow-up was time-critical and central laboratory results were not expected to be available before dosing needed to begin, or if action needed to be taken for safety reasons, use of local laboratories was permitted.

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

[0300] [Table 18]

[0301] [Table 19]

[0302] [Table 20]

[0303] The following tests were performed at the times specified in the time and event schedule. 1. Lipid panel: total cholesterol, low density lipoprotein (LDL) cholesterol, low density lipoprotein (HDL) cholesterol, and triglycerides 2. Serum and urine pregnancy tests (for women of childbearing potential only) 3. Urine Drug Screen: Barbiturates, methadone, opiates, cocaine, cannabinoids (cannabinoids will only be tested pre-dose on Day 1), phencyclidine, and amphetamine / methamphetamine 4. Alcohol breath test 5. Thyroid-stimulating hormone (TSH) 6. Glycated hemoglobin (HbA1c) test 7. Serum follicle-stimulating hormone (FSH) level testing only if required to demonstrate that the female subject is not of childbearing potential (referring to inclusion criterion no. 0)

[0304] Single 12-lead ECG During ECG collection, subjects should be in a quiet environment free of distractions (e.g., television, cell phones). Subjects should rest in a supine position and refrain from talking or moving their arms or legs for at least 5 minutes before ECG collection.

[0305] All ECG tracings were sent to a central ECG laboratory. ECGs were read at scheduled time points and summarized by the central ECG laboratory. The principal investigator or co-investigator was required to review all ECGs at study visits to assess for evidence of any potential safety concerns or exclusions.

[0306] Vital signs (temperature, pulse / heart rate, respiratory rate, blood pressure) Blood pressure and pulse / heart rate measurements were assessed in the supine position using fully automated equipment. Manual techniques were used only if automated equipment was unavailable. Prior to blood pressure and pulse / heart rate measurements, subjects rested for at least 5 minutes in a quiet environment free from distractions (e.g., television, cell phones).

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

[0308] Pulse oximetry Arterial oxygen saturation was measured using pulse oximetry. On each dosing day, a device was attached to a finger, toe, or ear before the first nasal spray, and then monitored and documented after the first spray. Any arterial oxygen saturation (SpO2) <93% lasting longer than 2 minutes and confirmed by further manual measurement in another part of the body was reported as an adverse event.

[0309] On the day of the intranasal treatment session, pulse oximetry was performed every 15 minutes from pre-dose until t = 1.5 hours post-dose. If it was ≤ 93% at any time during the 1.5 hour post-dose interval, pulse oximetry was performed every 5 minutes until it returned to ≥ 93% or the subject was referred to appropriate medical care if clinically indicated.

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

[0311] Nose examination Nasal examination (including upper airway / throat) was performed by a certified medical practitioner. The purpose of the screening examination was to exclude any subjects with anatomical or medical conditions that may interfere with drug delivery or absorption.

[0312] Post-test consisted of visual inspection of the nares, nasal mucosa, and pharynx for nasal erythema, rhinitis, rhinitis, capillary / vascular breakdown, and nosebleeds, graded as absent, mild, moderate, or severe. Any treatment-emergent change or worsening from the baseline examination was recorded as an adverse event.

[0313] nasal symptom questionnaire Subjects completed a nasal symptom questionnaire. A nasal symptom questionnaire was developed to assess nasal tolerability following intranasal administration of the study drug. The questionnaire asked about nasal symptoms, which were rated by the subject as none, mild, moderate, or severe based on how they felt at the time of evaluation.

[0314] C-SSRS The C-SSRS was administered to assess potential suicidal ideation and behavior. The C-SSRS is a low-burden scale of the spectrum of suicidal ideation and behavior developed in the National Institute of Mental Health's treatment study of adolescent suicide attempters to assess severity and track suicidal events throughout any treatment. It is a clinical interview that provides an overview of both suicidal ideation and behavior and can be administered during any evaluation or risk assessment to identify the level and type of suicidality present. The C-SSRS can also be used during treatment to monitor clinical deterioration.

[0315] Two versions of the C-SSRS were used in this study: a baseline / screening version and a since-last-visit version. The baseline / screening version of the C-SSRS was used during the screening / prospective observation period. This version assessed suicidal ideation at two time points ("lifetime" and "within the past 6 months") and suicidal behavior at two time points ("lifetime" and "within the past year"). All subsequent C-SSRS assessments in this study used the since-last-visit version, which assessed suicidal ideation and behavior since the subject's last visit.

[0316] CADSS The CADSS is a current dissociative symptom measurement instrument administered to assess dissociative symptoms occurring during treatment. The CADSS consists of 23 subjective items divided into three components: depersonalization (items 3-7, 20, and 23), derealization (items 1, 2, 8-13, 16-19, and 21), and amnesia (items 14, 15, and 22). Participants' responses were coded on a 5-point scale (0 = not at all to 4 = extremely). The CADSS has excellent interrater reliability and internal consistency.

[0317] BPRS+ Four items from the BPRS were administered to assess psychotic symptoms emerging during potential treatment. The BPRS is an 18-item rating scale used to assess a range of psychotic and affective symptoms, assessed both by subject observation and self-report. It reportedly provides a rapid and efficient assessment of treatment response in clinical drug trials and clinical settings. This study used only the four-item positive symptom subscale of the BPRS+ (i.e., suspiciousness, hallucinations, unusual thought content, and conceptual disorganization). It is highly sensitive to change and, with training and standard interview procedures, can achieve excellent inter-rater reliability.

[0318] MOAA / S The MOAA / S was used to measure sedation occurring during treatment in correlation with the level of sedation defined by the American Society of Anesthesiologists (ASA) continuum. MOAA / S scores range from 0 = no response to pain stimuli (corresponding to the ASA continuum of general anesthesia) to 5 = readily responds to name spoken in a normal tone (awake, corresponding to the ASA continuum of minimal sedation).

[0319] On each intranasal administration day, the MOAA / S was performed every 15 minutes from pre-dose until t = +1.5 hours post-dose. If the score was ≦3 at any time during the 1.5-hour post-dose interval, the MOAA / S was performed every 5 minutes until a score of 4 was reached (at which point the frequency of every 15 minutes could be resumed until t = +1.5 hours post-dose). If the subject did not have a score of at least 5 at t = +1.5 hours post-dose, the subject was further monitored. For subjects with a score of 4, the assessment was repeated every 15 minutes. For subjects with a score ≦3, the assessment was repeated every 5 minutes until the score returned to 5, or the subject was referred to appropriate medical care if clinically indicated.

[0320] CGADR The CGADR was used to measure the subject's current clinical status and was a clinician's assessment of readiness to be released from the study site. Clinicians answered "yes" or "no" to the question, "Do you consider the subject ready to be released based on their overall clinical status (e.g., sedation, blood pressure, and other adverse events)?"

[0321] On each intranasal administration day, the CGADR was administered 1 hour and 1.5 hours post-dose. If the response was not "yes" at 1.5 hours post-dose, the assessment was repeated every 15 minutes until a "yes" response was achieved or, if clinically indicated, until the subject was referred to appropriate medical care. Subjects were not released prior to the 1.5 hour time point. On all intranasal treatment session days, subjects remained in the clinical facility until study procedures were completed and the subject was ready to be released.

[0322] PWC-20 The PWC-20 was administered to assess potential withdrawal symptoms after discontinuation of intranasal esketamine treatment. Assessments were performed on day 25 to establish a baseline before discontinuing intranasal esketamine treatment. To better assess potential withdrawal symptoms from intranasal medication, it was recommended that oral antidepressants be continued for at least the first 2 weeks of the follow-up period unless deemed clinically appropriate.

[0323] The PWC-20 is a 20-item, simple, and accurate method for assessing the potential development of discontinuation symptoms after cessation of an investigational drug. The PWC-20 is a reliable and sensitive instrument for the assessment of discontinuation symptoms. Discontinuation symptoms may occur early and resolve rather quickly, depending on the rate of tapering, the daily dose, and the drug elimination half-life.

[0324] BPIC-SS The BPIC-SS is a subject-reported outcome measure developed to identify appropriate bladder pain syndrome / interstitial cystitis populations for clinical trials evaluating new treatments for bladder pain syndrome.

[0325] The BPIC-SS was used to monitor subjects for potential symptoms of cystitis, bladder pain, and interstitial cystitis. The BPIC-SS includes eight questions with a seven-day recall period and addresses key symptoms identified by subjects with BPS, including symptom concepts of bladder pain and / or pressure and urinary frequency. Subjects responded to items using a five-point scale (0 = never, 1 = rarely, 2 = occasionally, 3 = most of the time, 4 = always for frequency-based questions, and 0 = not at all, 1 = slightly, 2 = somewhat, 3 = moderately, 4 = very much for symptom-related hassle items). Question 8 uses a 0-10 numeric rating scale to record the worst bladder pain in the past seven days. A total score was calculated by adding these numbers to the response option selected by the subject. The scale's possible scores range from 0 to 38. A total score of 19 or greater demonstrated good sensitivity / specificity and was considered a relevant cut-off for distinguishing from significant bladder symptoms or cystitis.

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

[0327] In the current study, if a subject had a score >18 on the BPIC-SS scale and there was no evidence of a urinary tract infection based on urinalysis and microscopy, the subject was referred to a specialist for further evaluation. Thus, in addition to urinalysis, a urine culture was obtained if the BPIC-SS score was >18 on the applicable study day.

[0328] Cognitive testing: Computerized cognitive battery and HVLT-R The computerized cognitive battery provides assessment of multiple cognitive domains, including attention, visual learning, and memory, as well as executive function. The test uses culture-neutral stimuli, allowing for use in multilingual / multicultural environments. The computerized battery includes: Simple reaction and choice reaction time tests, response speed scored (mean log10 transformed reaction time of correct responses) Visual episodic memory, a visual recall test scored using an arcsine transformation of the proportion of correct responses Working memory (n-back), correct response speed is scored (mean log10 transformed reaction time of correct responses) Executive function, maze / sequencing tests (scored for total number of errors)

[0329] All measures have been validated against traditional neuropsychological tests and are sensitive to the effects of various drugs on cognitive performance, including alcohol and benzodiazepines. Completion of the cognitive battery requires approximately 25 minutes.

[0330] The HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. Administration includes three learning trials, a 24-word recognition list (containing 12 target words and 12 foil words), and a delayed recall (20 min) trial. Administration is computer-assisted; instructions and word lists appear on the screen. The test administrator records each word correctly recalled and scores for learning, short-term, and delayed recall are generated via the testing software. The HVLT-R is a well-validated and widely used measure of verbal episodic memory.

[0331] Tests were administered in the following order: HVLT-R, computerized cognitive test battery, and HVLT-R (delayed).

[0332] UPSIT and Odor Threshold Test To assess any potential treatment-induced effects on olfactory function, olfactory function was assessed qualitatively and quantitatively using validated standard olfactory tests before and at designated time points during the study. The two tests administered were as follows:

[0333] The UPSIT assesses a subject's ability to identify odors. This standardized test, the most widely used in the world, is derived from basic psychological test measurement theory and focuses on subjects' comparative ability to identify odorants at suprathreshold levels. The UPSIT consists of four envelope-sized booklets, each containing 10 "scratch-and-sniff" odorants embedded in 10-50 μm polymer microcapsules positioned on a brown strip at the bottom of the booklet's pages. The instrument's internal consistency and test-retest reliability coefficients are >0.90. Extensive studies have shown that this test and related tests are sensitive to subtle changes in olfactory function associated with multiple etiologies, including those resulting from viruses, head trauma, and numerous neurodegenerative disorders.

[0334] The Odor Threshold Test assesses olfactory threshold using a binary single-step threshold procedure. This test quantifies the detection threshold for the rose-scented odorant phenyl ethyl alcohol (PEA). This odorant is used because it has minimal stimulant properties on the trigeminal nerve in the nose. This test is sensitive to olfactory impairments from a wide range of disorders.

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

[0336] MINI Subjects were administered the MINI (Mini Structured Diagnostic Interview) to confirm the diagnosis of MDD and to determine whether other psychiatric conditions were present, which took approximately 15 minutes to administer.

[0337] MGH-ATRQ Treatment resistance in MDD was determined using the MGH-ATRQ. The MGH-ATRQ assesses the appropriateness of the duration and dosage of all antidepressants used for the current major depressive episode. Additionally, the MGH-ATRQ assesses the degree of improvement on a scale of 0% (no improvement) to 100% (complete improvement). The MGH-ATRQ was completed by a clinician in collaboration with the subject.

[0338] STOP-Bang Questionnaire The STOP-Bang questionnaire is a brief, easy-to-use, validated, and sensitive screening tool for obstructive sleep apnea (OSA). The questionnaire has eight items that address important risk factors for obstructive sleep apnea: snoring, tiredness, observed breathing interruptions during sleep, high blood pressure, body mass index, age, neck size, and gender. The STOP-Bang questionnaire does not specify a recall period. Subjects answer yes or no to questions about snoring, tiredness, observed breathing interruptions, and high blood pressure (these are the "STOP" items in the STOP-BANG acronym). It takes approximately one minute.

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

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

[0341] Independent qualification of the facility An independent psychiatrist / psychologist conducted an independent site eligibility assessment by telephone during the screening / prospective observation phase for all subjects to confirm a diagnosis of depression and study eligibility.

[0342] IDS-C 30 30 items IDS-C 30The IDS-C is designed to assess the severity of depressive symptoms. The IDS assesses all criteria symptom domains specified by DSM-5 to diagnose a major depressive episode. While these assessments can be used to screen for depression, they are primarily used as a measure of symptom severity. A 7-day period prior to assessment is the usual time frame for assessing symptom severity. 30 The psychometric properties of the have been established in a variety of study samples.

[0343] Massachusetts General Hospital Female Reproductive Cycle and Hormones Questionnaire (MGH-Female RLHQ): Module I and Menstrual Cycle Tracking The MGH-Women's RLHQ Module I (fertility, menopausal status, and menstrual cycle) is a brief questionnaire aimed at standardizing the collection of minimally relevant information about reproductive hormones and status. It was completed by clinicians. This information could facilitate exploratory analyses of the influence of endogenous and exogenous reproductive hormones on the course of MDD treatment and potentially inform the care of women with MDD in the future.

[0344] Menstrual cycle follow-up (start date of last menstrual period) was documented at the study visits specified in the Time and Event Schedule.

[0345] PAQ Subjects' adherence to their oral antidepressant treatment regimen during the screening / prospective observation period was assessed using the PAQ, a brief, two-item subject-reported outcome measure developed at the University of Texas Southwestern Medical Center to assess how frequently subjects received their antidepressant treatment regimen and whether they had made any changes to their antidepressant treatment regimen in the past two weeks. A total score was calculated by adding the response selections for questions 1c–1f (0 = adherence, 1 or greater = nonadherence).

[0346] Sample collection and handling The exact date and time of sample collection was recorded on the eCRF or laboratory requisition form. When blood samples were collected via an indwelling cannula, an appropriate volume (1 mL) of serum fluid, slightly more than the free volume of the lock, was removed from the cannula and discarded before each blood sample was collected. After blood sample collection, the cannula was flushed with 0.9% sodium chloride, United States Pharmacopeia, USP (or equivalent) and filled to a volume equal to the free volume of the lock.

[0347] Subject Completion / Withdrawal completion Subjects were considered to have completed the double-blind induction phase of the study if they completed the MADRS assessment at the end of the 4-week double-blind induction phase (i.e., Day 28 MADRS). Subjects who prematurely discontinued study treatment for any reason prior to completion of the double-blind induction phase were not considered to have completed the double-blind induction phase of the study. Subjects who entered the follow-up phase were considered to have completed this phase of the study if they completed the MADRS assessment at Week 24 of the follow-up phase.

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

[0349] If a subject was lost to follow-up, all reasonable efforts were made by study site personnel to contact the subject and determine the reason for discontinuation / withdrawal.

[0350] If a subject withdrew before completing the study, the reason for withdrawal was documented. The study drug assigned to the withdrawn subject was not assigned to another subject. If a subject withdrew from the study before the end of the double-blind induction period for reasons other than withdrawal of consent, an early withdrawal visit was conducted within 1 week of the date of discontinuation, followed by the follow-up period.

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

[0352] Adverse events To identify adverse events, the verbatim terms used by the investigator in the eCRF were coded using MedDRA. All reported adverse events with onset during the double-blind induction period (i.e., TEAEs and adverse events that worsened after baseline) were included in the analysis. For each adverse event, the proportion of subjects experiencing at least one occurrence of the given event was summarized by treatment group. Adverse events occurring during the follow-up period were summarized separately.

[0353] TEAEs of special interest were examined separately. AEs of special interest were listed in the SAP. Subjects who died, discontinued treatment due to an adverse event, or experienced a severe or serious adverse event were summarized separately.

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

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

[0356] Electrocardiogram data were summarized by ECG parameters. Descriptive statistics were calculated at baseline, and observed values ​​and changes from baseline were calculated at each scheduled time point. Frequency counts of abnormalities were performed.

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

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

[0359] Any significant abnormalities in the ECG waveform that changed from the baseline reading were reported (eg, changes in T wave morphology or occurrence of U waves).

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

[0361] Nose examination Changes in findings from baseline nasal examination (including upper airway / pharynx) were listed by treatment group. The examination provided ratings (absent, mild, moderate, or severe) based on visual inspection of the nostrils, nasal mucosa, and pharynx for nasal erythema, rhinitis, rhinitis, capillary / vascular breakdown, and epistaxis. Shift tables for changes from double-blind baseline in each examination rating were presented by treatment group.

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

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

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

[0365] Clinical Global Assessment of Readiness for Release, PWC-20, BPIC-SS, UPSIT, and Odor Threshold Test Descriptive statistics for each score and the change and / or percent change from baseline were summarized at each scheduled time point.

[0366] Cognitive testing Descriptive statistics and change from baseline in cognitive domain scores were summarized at each scheduled time point.

[0367] Definitions and classification of adverse events An adverse event is any untoward medical occurrence in a clinical trial subject administered a medicinal product (investigational or non-investigational medicinal product). An adverse event does not necessarily have a causal relationship to treatment. Thus, an adverse event can be any untoward or unintended sign (including an abnormal finding), symptom, or disease that is temporally related to the use of a medicinal product (investigational or non-investigational medicinal product), whether or not related to the medicinal product (investigational or non-investigational medicinal product) (as defined by the International Conference on Harmonisation (ICH)). This includes any occurrence that is new onset or worsening in severity or frequency from a baseline condition, or an abnormal result of a diagnostic procedure, including an abnormal laboratory test.

[0368] A serious adverse event according to the ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for Human Use is any untoward medical occurrence, regardless of dose, of: Deadly Life-threatening (e.g., the subject was at risk of death at the time of the event. "Life-threatening" does not refer to an event that, if more severe, might have resulted in death.) -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 * * Medical and scientific judgment should also be exercised in determining whether other circumstances, such as significant medical events that may not be immediately life-threatening or result in death or hospitalization, may still endanger the subject or require intervention to prevent one of the other outcomes listed in the definition above. These should generally be considered serious.

[0369] If a serious unexpected adverse event occurred for which there was evidence suggesting a causal relationship between the investigational drug and the event (e.g., death due to anaphylaxis), the event was reported as a suspected serious unexpected adverse reaction, even if it was a component of a study endpoint (e.g., all-cause mortality).

[0370] An adverse event was considered unlisted if its nature or severity was not consistent with the applicable product standard safety information. For esketamine, the expected value of an adverse event was determined by whether it was listed in the standard safety information section of the investigator's pamphlet.

[0371] For duloxetine, escitalopram, sertraline, and venlafaxine XR, adverse event expectations were determined according to whether they were listed in the SmPC or US prescribing information.

[0372] An adverse event is considered to be related to the use of a drug if it is possible, probable, or very likely to be attributable according to the definitions of attribution listed below. Unrelated: Adverse events not related to drug use. Doubtful: Adverse event for which an alternative explanation is more likely, e.g., concomitant medication(s), comorbidity(ies), or time relationship suggests a causal relationship is unlikely. Possible: Adverse event that could be attributed to the use of the drug. Alternative explanations, e.g., concomitant medication(s), comorbidity(ies), are inconclusive. The time relationship is reasonable, therefore, a causal relationship could not be ruled out. High probability: Adverse event attributable to drug use. The time relationship was suggestive (e.g., confirmed by drug discontinuation). Alternative explanations, e.g., concomitant medication(s), comorbidity(ies), were unlikely. Likely: An adverse event listed as a possible adverse reaction and that could not be reasonably explained by an alternative explanation, e.g., concomitant medication(s), comorbidity(ies). The time relationship was highly suggestive (e.g., confirmed by interruption and resumption of medication).

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

[0374] Investigators used clinical judgment in assessing the severity of events not directly experienced by the subject (e.g., laboratory abnormalities).

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

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

[0377] Procedure: All adverse events All adverse events and special reporting circumstances, whether serious or non-serious, were reported from the time the signed and dated ICF was obtained until the completion of the subject's last study-related procedure, which may include safety follow-up contact. Serious adverse events, including those spontaneously reported to the investigator within 30 days after the last dose of study drug, were reported using the Serious Adverse Event Form. The sponsor evaluated any safety information spontaneously reported by the investigator beyond the protocol-specified timeframe.

[0378] All events that met the definition of a serious adverse event were reported as serious adverse events, regardless of whether they were protocol-specific. Expected events were recorded and reported.

[0379] All adverse events were recorded in source documents and eCRFs using medical terminology, regardless of seriousness, severity, or presumed relationship to study drug. Whenever possible, a diagnosis was given when signs and symptoms were attributable to a common etiology (e.g., cough, runny nose, sneezing, sore throat, and feeling of stuffiness in the head were reported as "upper respiratory tract infection"). The investigator recorded their opinion regarding the relationship of the adverse event to study therapy in the eCRF. All measurements necessary for adverse event management were recorded and reported in source documents.

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

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

[0382] Serious adverse events All serious adverse events occurring during the study were reported by study site personnel to the appropriate sponsor contact person within 24 hours of becoming aware of the event.

[0383] All serious adverse events that had not resolved by the end of the study or at the time of discontinuation of the subject's participation in the study were followed until one of the following occurred: The event was alleviated The event stabilized If baseline values / conditions are available, the event has returned to baseline The event could be attributed to a drug other than the investigational drug or to factors unrelated to the study. · It was unlikely that any additional information would be obtained (subject or healthcare professional declined to provide additional information or was lost to follow-up after expressing due diligence through follow-up efforts).

[0384] Suspected transmission of an infectious agent by a medicinal product was reported as a serious adverse event. Any event requiring hospitalization (or prolonged hospitalization) occurring during the course of a subject's participation in the study was reported as a serious adverse event, except for the following hospitalizations: Hospitalization not intended to treat an acute illness or adverse event (e.g., social reasons such as waiting for placement in a long-term care facility) Surgery or procedures planned before study entry (must be documented on the eCRF). Hospitalizations planned before signing of the ICF and without a worsening of the underlying condition for which the hospitalization was planned were not considered serious adverse events. Any adverse event that resulted in a prolongation of the originally planned hospitalization was to be reported as a new serious adverse event.

[0385] For convenience, investigators could choose to hospitalize subjects for the duration of the treatment period.

[0386] The cause of a subject's death in the study was considered to be a serious adverse event, regardless of whether the event was expected or related to the study drug.

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

[0388] Because the effect of the investigational drug on sperm is unknown, pregnancy in the partner of a male subject included in the study was to be reported by study site personnel within 24 hours of becoming aware of the event using the appropriate pregnancy notification form.

[0389] Follow-up information on the outcome of the pregnancy and the outcome of any postnatal sequelae of the infant was also required.

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

[0391] [Table 21]

[0392] FIG. 6 shows the proportion of subjects reporting problems at baseline and endpoint as determined by individual items of the EQ-5D-%L.

[0393] Treatment-emergent adverse events occurring during the double-blind period (≥ 5% of subjects in either treatment group) are summarized by treatment group for the safety analyses shown in Table 19 below. The most common (≥ 20%) TEAEs in the esketamine + oral AD group during the double-blind period were nausea (26.1%), vertigo (26.1%), dysgeusia (24.3%), and dizziness (20.9%). The most common TEAE in the active comparator group was headache (17.4%).

[0394] [Table 22]

[0395] Adverse events leading to withdrawal from the study drug There were nine subjects (eight in the esketamine + oral AD group and one in the active comparator) who discontinued the double-blind induction phase intranasal study medication due to treatment-emergent adverse events (Table 20). There were four subjects in the esketamine + oral AD group who discontinued the double-blind induction phase oral antidepressant study medication due to treatment-emergent adverse events (Table 21). Three subjects in the esketamine + oral AD group discontinued the double-blind period due to both intranasal and oral AD medications (summarized in both Tables 20 and 21).

[0396] [Table 23]

[0397] [Table 24]

[0398] Serious adverse events Two subjects experienced serious treatment-emergent adverse events during the double-blind phase. One subject in the active comparator group experienced postural vertigo, which was considered to have a suspected relationship to both the intranasal placebo and the oral AD. One subject in the esketamine + oral AD group experienced multiple injuries resulting from a motorcycle accident (subsequently died after formal database lock). This event was not related to esketamine and was considered to have a suspected relationship to the oral AD.

[0399] One subject in the esketamine + oral AD group experienced a cerebral hemorrhage during the 83-day follow-up period after the last intranasal dose of esketamine, which was considered to be of questionable relationship to esketamine and not related to oral AD.

[0400] blood pressure The transient blood pressure increase peaked approximately 40 minutes after administration in the esketamine group and returned to the normal range by 90 minutes. The maximum mean increase in systolic BP (across all dosing days) was 11.6 in the esketamine + oral AD group and 5.0 in the active comparator group. The maximum mean increase in diastolic BP (across all dosing days) was 8.1 in the esketamine group and 4.5 in the active comparator group. Figures 7 and 8 show the mean blood pressure measured over time by treatment group during the double-blind phase.

[0401] Clinician-Rated Dissociative Symptoms Scale (CADSS) The Clinician-Administered Assessment of Dissociative State Scale (CADSS) was administered prior to the start of each dose, and 40 minutes and 1.5 hours after administration. The CADSS is used to assess dissociative symptoms and perceptual changes that occurred during treatment, with a total score ranging from 0 to 92, with higher scores representing more severe symptoms. The dissociative symptoms and perceptual changes measured by the CADSS suggest that these symptoms developed soon after initiation of dosing and subsided by 1.5 hours after dosing (as shown in Figure 9).

[0402] Modified Observer Assessment of Arousal / Sedation (MOAA / S) The modified observer's assessment of alertness / sedation (MOAA / S) was used to measure sedation occurring during treatment, correlated with sedation levels defined by the American Society of Anesthesiologists (ASA) continuum. MOAA / S scores ranged from 0 ("none" response to pain stimuli, corresponding to the ASA continuum for general anesthesia) to 5 (immediate response to name spoken in a normal tone [alertness], corresponding to the ASA continuum for minimal sedation). Sedation, as measured by the MOAA / S, suggests that sedation had subsided by 1.5 hours post-administration (as shown in Figure 10).

[0403] Pharmacokinetics At the time points specified in the time and event schedule, approximately 2 mL venous blood samples were drawn for measurement of plasma concentrations of esketamine, noresketamine, and other metabolites (if warranted). The exact date and time of PK blood sampling was recorded.

[0404] Plasma samples were analyzed to determine the concentrations of esketamine (and, where warranted, noresketamine) using a specific achiral and sensitive liquid chromatography-tandem mass spectrometry (LC-MS / MS) method validated by or under the sponsor's supervision. Where appropriate, some plasma samples were analyzed to document the presence of other analytes (e.g., circulating metabolites or denatonium) using certified laboratory methods. Additionally, plasma PK samples could be stored for future analysis of metabolite profiles.

[0405] Pharmacokinetic parameters Esketamine (and, where warranted, noresketamine) plasma concentration-time data were analyzed using population PK modeling. Representative population values ​​for basic PK parameters (e.g., esketamine clearance volume of distribution) were estimated along with inter-individual variability. The effects of subject demographics, laboratory parameter values, and other covariates on esketamine PK were investigated.

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

[0407] Biomarker, pharmacogenomic (DNA), and expression (RNA) assessment Blood was collected for biomarker assessments during the study at the time points indicated in the time and event schedule. Biomarker blood samples were collected pre-dose. Subjects were encouraged to follow a low-fat diet on the day of sample collection.

[0408] Biomarkers (proteins, metabolites, and ribonucleic acid [RNA]) related to, but not limited to, immune system activity, hypothalamic-pituitary-adrenal (HPA) axis activation, neurotrophic factors, and metabolic factors were investigated in the blood. Biomarkers were added or removed based on scientific information or technological innovation, under conditions that did not increase the total blood volume collected.

[0409] Blood samples for DNA analysis were collected at the time points indicated in the time and event schedule for evaluation of genetic and epigenetic variations in genes in pathways related to depression (e.g., HPA axis, inflammation, growth factors, monoamine transporters, ion channels, and circadian rhythms). Genotyping was performed on screening samples only. Pharmacogenomic and epigenetic evaluations could be performed on any / all collected samples.

[0410] DNA samples were used in research related to esketamine, oral antidepressants, TRD, or MDD. They could also be used to develop tests / assays related to esketamine, oral antidepressants, TRD, or MDD. Pharmacogenomic studies consisted of analysis of one or more candidate genes, or (as appropriate) genome-wide genetic markers, related to esketamine, oral antidepressants, TRD, or MDD clinical endpoints.

[0411] Medical resource utilization Healthcare resource utilization data related to visits were collected during the follow-up phase of the study. Protocol-defined procedures, tests, and visits were excluded. The collected data allowed for exploratory economic analyses, including: (a) the number and duration of medical visits, including surgeries, and other selected procedures (inpatient and outpatient); (b) length of hospital stay (total number of days of stay, including duration by unit (e.g., intensive care unit)); (c) the number and characteristics of diagnostic and therapeutic tests and procedures; and / or (d) outpatient medical visits and treatments (including physician or emergency room visits, tests and procedures, and medications).

[0412] Pharmacokinetic analysis Plasma esketamine (and, where justified, noresketamine) concentrations were listed for all subjects. Esketamine (and, where justified, noresketamine) plasma concentration-time data were analyzed using population PK modeling. Data may be combined with data from other selected studies to support relevant structural models. Representative population values ​​for basic PK parameters were estimated along with interindividual variability. The effects of subject demographics, laboratory parameter values, and other covariates on esketamine PK were investigated.

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

[0414] Biomarker and Pharmacogenomic Analysis Baseline biomarker values ​​and changes from baseline biomarker values ​​to time points specified in the time and event schedule were summarized. Exploratory analyses may include comparison of biomarker measurements between treatment groups, correlation to baseline, and change from baseline biomarker values ​​in efficacy and other measurements. Further exploratory analyses may also include relationship between baseline and change from baseline to clinical response in biomarker measurements, maintenance / stabilization of response, relapse, and non-response.

[0415] Pharmacogenomic analysis may also include candidate gene analysis or genome-wide association analysis for treatment response, maintained / stabilized response, relapse, non-response, and MDD / TRD. Expression analysis may include examination of known messenger RNA / microRNA (mRNA / miRNA) transcripts or transcriptome-wide analysis associated with antidepressant treatment response and MDD / TRD.

[0416] Statistical methods used in the analysis A general description of the statistical methods used to analyze efficacy and safety data is outlined below. At the end of the double-blind induction period, the database was locked for analysis and reporting of this period. Subjects' treatment assignment was revealed only to the sponsor's study staff. Investigators and site personnel were blinded to treatment assignment until all subjects completed study participation through the follow-up period.

[0417] The primary efficacy and safety analysis populations were as follows: Full analysis population: All randomized subjects who received at least one dose of intranasal study drug and one dose of oral antidepressant during the double-blind induction period. Safety Analysis Population: All randomized subjects who received at least one dose of intranasal study drug or one dose of oral antidepressant during the double-blind induction period.

[0418] The maximum planned sample size for this study was calculated assuming a double-blind induction-phase treatment difference of 6.5 points in MADRS total score between esketamine and the active comparator, a standard deviation of 12, a one-sided significance level of 0.0125, and a dropout rate of 25%. A maximum of approximately 98 subjects should be randomized to each treatment group to achieve 90% power using a fixed design with no interim analyses. The treatment difference and standard deviation used in this calculation were based on the results of Panel A of the ESKETINTRD2003 study and clinical judgment.

[0419] Interim analysis for sample size re-estimation or stopping for futility One open-label interim analysis was conducted 4 weeks after randomization of 66 subjects in the study (approximately 33 subjects per treatment arm). At that time, approximately 50 subjects in the full analysis set were expected to have completed the double-blind induction phase of the study (approximately 25 subjects per treatment group). Dropout rates were monitored to ensure that a sufficient number of subjects were included in the interim analysis. The purpose of the interim analysis was either to reestimate the sample size or to stop the study due to futility. The sample size could be adjusted to achieve the desired statistical power while maintaining control of overall type I error. The maximum sample size planned for this study was 98 per treatment group.

[0420] Based on the interim data and how the analysis was performed, a rigorous interim statistical analysis plan (SAP) and protocol was developed detailing the algorithm for sample size re-estimation. The IDMC performed the interim analysis and made recommendations for any sample size adjustments based on the rules defined in the interim SAP. Any changes to the sample size were communicated by the IDMC (or a statistician from the statistical support group) to the IWRS vendor to ensure an adequate number of subjects were enrolled in the study. None of the esketamine team members or staff members at the investigational sites that conducted the clinical trial were aware of the results of the interim analysis or any adjustments made to the sample size.

[0421] Procedures were in place to ensure that the results of the interim analysis would not influence the study, investigator, or subject behavior.

[0422] Efficacy analysis Efficacy analyses were performed on the full analysis set, which included all randomized subjects who received at least one dose of intranasal study drug and one dose of oral antidepressant study drug during the double-blind induction phase.

[0423] The primary efficacy variable, change from baseline in MADRS total score at week 4 of the double-blind induction phase, was analyzed using MMRM. The model included baseline MADRS total score as a covariate and treatment, country, antidepressant class (SNRI or SSRI), day, and treatment-per-day interactions as fixed effects, as well as a random subject effect. Comparisons of esketamine plus oral antidepressant with oral antidepressant plus intranasal placebo were performed using appropriate contrasts.

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

[0425] Subject to regulatory acceptance of the PHQ-9 as a key secondary endpoint, the first of three key secondary efficacy endpoints, the change from baseline in the PHQ-9 total score at week 4 of the double-blind induction phase, was analyzed using the same model described above for the MADRS total score.

[0426] For analysis of the second key secondary efficacy endpoint, the proportion of subjects demonstrating an onset of clinical response by Day 2 that was maintained for the duration of the double-blind induction phase in the esketamine plus oral antidepressant arm was compared with the oral antidepressant plus intranasal placebo arm using a Cochran-Mantel-Haenszel chi-squared test adjusting for country and antidepressant class (SNRI or SSRI). Clinical response was defined as a ≥50% improvement in the MADRS total score by Day 2 (i.e., the day after taking the first dose of double-blind intranasal medication) that continued through the end of the double-blind phase. Subjects who discontinued the study before the end of the double-blind induction phase were not considered to have maintained a clinical response.

[0427] The third key secondary efficacy endpoint, change from baseline in SDS total score at week 4 of the double-blind induction phase, was analyzed using ANCOVA. The model included factors for treatment, country, and oral antidepressant class (SNRI or SSRI), with baseline SDS total score as a covariate. Comparisons of each intranasal esketamine plus oral antidepressant arm with oral antidepressant plus intranasal placebo were performed using appropriate contrasts. Responses to questions H1–H3 were summarized separately.

[0428] A tandem gatekeeping (fixed order) approach was applied to adjust for multiplicity and to robustly control type I error on the primary efficacy endpoint and three key secondary efficacy endpoints (change in PHQ-9 total score, onset of clinical response, and change in SDS total score).

[0429] Response and remission rates were summarized at each visit.

[0430] The change from baseline in the GAD-7 total score and the rank of the change from baseline in the CGI-S score at the end of the double-blind induction period were analyzed based on the LOCF data using an ANCOVA model with country and antidepressant class (SNRI or SSRI) as factors and each baseline score (unranked score in the case of the CGI-S) as a covariate.

[0431] EQ-5D-5L data, health status index, and global health status score item scores were summarized over time.

[0432] Additionally, scores for all efficacy endpoints were summarized for all visits during the double-blind induction phase. Summaries were provided to demonstrate consistency of effect between relevant subgroups (e.g., antidepressant classes SNRI and SSRI).

[0433] US Subpopulation Analysis - Clinical Efficacy and Safety In the overall analysis, ESK+AD demonstrated a statistically significant and clinically meaningful advantage over AD+PBO in the primary efficacy endpoint (i.e., change from baseline in MADRS total score (Montgomery, British Journal of Psychiatry. 1979;134:382-389)). In this analysis, the efficacy and safety of these treatment groups were analyzed in US patients only, and differences in efficacy and safety between the US population and the overall study population were evaluated.

[0434] A. Results For clinician-rated assessments, the MADRS was administered at baseline and on days 2 (approximately 24 hours after administration), 8, 15, 22, and 28. Similarly, the Clinical Global Impression-Severity (CGI-S) scale (Guy W. ECDEU Assessment Manual for Psychopharmacology (028 Clinical Global Impressions [CGI]). 1976:218-222) was administered at baseline, days 4, 8, 11, 15, 22, and at the 4-week double-blind endpoint.

[0435] For patient assessment, the 9-item Patient Health Questionnaire-9 (PHQ-9) (Spitzer, JAMA. 1999;282(18):1737-1744) and the Sheehan Disability Scale (SDS) (Sheehan DV. The Anxiety Disease. A Leading Psychiatrist Offers New Hope for Victims of Severe Anxiety. New York, NY: Charles Scribner & Sons; 1983) were administered at baseline, day 15, and day 28.

[0436] B. Patient Demographics / Disease Characteristics Inclusion criteria included adults aged 18–64 years (including borderline) who met DSM-5 diagnostic criteria for MDD confirmed by the Mini International Neuropsychiatric Interview and had a 30-item total score ≥34 (moderate–severe depression) on the Clinician-Rated Depressive Symptoms Scale.

[0437] Patients must have TRD and non-response at the end of the screening period, defined as a ≦25% improvement in MADRS total score from weeks 1 to 4 and a MADRS total score ≧28 at weeks 2 and 4.

[0438] Of the 91 US patients, 46 received ESK + AD, 44 received AD + PBO, and 1 did not. Baseline patient demographics and disease characteristics were generally similar between the two treatment groups. See Table 22. The overall mean age was 44.1 years, approximately two-thirds (61.1%) of patients were female, and the majority (83.3%) of patients were white. The mean age of MDD diagnosis was 27.5 years, with an average history of depression exceeding 15 years. Baseline MADRS, CGI-S, and PHQ-9 scores were consistent with the population with TRD.

[0439] [Table 25]

[0440] C. Effectiveness Efficacy was determined by measuring the MADRS total score, SDS score, PHQ-9 score, and CGI-S score. For the MADRS total score, SDS score, and PHQ-9 score, tests of treatment effect were based on a mixed-effects model for repeated measures (MMRM) with change from baseline as the response variable and fixed-effect model terms for treatment (ESK+AD, AD+PBO), day, oral antidepressant class (serotonin and norepinephrine reuptake inhibitor [SNRI] or selective serotonin reuptake inhibitor [SSRI]), and treatment per day, and baseline value as a covariate. For the CGI-S score, tests of treatment effect were based on the rank of change from baseline as the response variable and an analysis of covariance (ANCOVA) model with last observation carried forward (LOCF) for factors for treatment (ESK+AD, AD+PBO) and oral antidepressant (SNRI or SSRI), and baseline value (unranked) as a covariate. For each analysis, a negative difference favored esketamine nasal spray plus new oral AD.

[0441] The results show that the least squares (LS) mean change in MADS total score decreased in both treatment groups during the 4-week double-blind induction period. See Figure 11.

[0442] The treatment effect favored the ESK+AD group at approximately 24 hours (Day 2) and 28 days after administration, with the difference reaching statistical significance at Day 28. See Table 23. The LS mean difference (SE) was -1.6 (2.15, P=0.225) at approximately 24 hours (Day 2) after administration and -5.5 (2.58, P=0.017) at Day 28.

[0443] [Table 26]

[0444] A statistically significant difference in improvement in depression severity, as measured by CGI-S, was observed between the two treatment groups on day 4 (P=0.015). This difference approached significance 4 weeks after the first dose (P=0.070). See Table 24.

[0445] [Table 27]

[0446] Patient-rated severity of depression decreased in both treatment groups, but the degree of decrease was greater in the ESK+AD group at day 28. See Figure 12. The mean PHQ-9 score at baseline was 20.2 in the ESK+AD group and 20.9 in the AD+PBO group. At day 28, the mean PHQ-9 total scores were 8.0 and 11.7, respectively. The LS mean difference (SE) in PHQ-9 was -3.1 (1.52, P = 0.024).

[0447] Functional disability decreased in both treatment groups, but the degree of improvement was greater in the ESK+AD group at day 28. See Figure 13. The mean SDS score at baseline was 23.4 in the ESK+AD group and 24.1 in the AD+PBO group. At day 28, the mean derived SDS total scores were 9.7 and 16.7, respectively. The LS mean difference (SE) in SDS total score was -5.2 (2.13, P = 0.009).

[0448] D. Safety Safety was assessed via treatment-emergent adverse events (TEAEs), serious AEs, vital signs, psychiatric symptoms assessed by the Brief Psychiatric Rating Scale (BPRS), dissociation measured by the Clinician-Administered Dissociation Status Scale (CADSS), and readiness to release.

[0449] Overall, TEAEs were observed in 91.3% of patients in the ESK+AD group and 77.3% of patients in the AD+PBO group. See Table 25A. There were no deaths. One patient in the ESK+AD group experienced an SAE (cerebral hemorrhage on day 98) during the follow-up period. Four patients were withdrawn from nasal spray (n=3 ESK, n=1 PBO), and no patients were withdrawn from new oral AD.

[0450] The most common TEAEs (≥5% in either treatment group) are shown in Table 4. The incidence of TEAEs was similar between US patients and the overall study population. AEs observed during the study were mostly mild to moderate in severity and transient in nature.

[0451] As observed in the overall population, current dissociative symptoms and transient sensory effects, as measured by CADSS total score, spontaneously resolved during the post-infusion observation period (within 60-90 minutes after infusion) before release. The majority (>90%) of patients in each treatment group were ready for release by 1.5 hours after infusion. Vital signs and BPRS findings were consistent with the overall population.

[0452] [Table 28]

[0453] E. Summary These results demonstrated that ESK+AD provided a rapid onset of efficacy that lasted for 4 weeks and was generally well tolerated in US patients with TRD. These observations were consistent with those from the overall study population, indicating that the US population did not differ significantly in efficacy. In STAR-D Level 3 (i.e., patients with MDD who did not achieve remission with Level 1 or Level 2 treatment), achievement of the primary outcome (17-item Hamilton Depression Rating Scale score ≤ 7) occurred in 8-12% of patients at approximately 6 weeks. See Rush, CNS Drugs. 2009;23(8):627-647. In comparison, 4 weeks after the first dose, ESK+AD resulted in improvements in LS mean change in MADRS total score, patient-rated severity of depression, and functional impairment.

[0454] Furthermore, statistically significant improvements in clinician-rated severity of depression were observed 24 hours after ESK+AD administration. Improvements in clinician-rated and patient-rated efficacy measures were observed in the ESK+AD and AD+PBO treatment groups.

[0455] ESK+AD compared with AD+PBO (active comparator) in US patients with TRD provided evidence of clinically meaningful, statistically significant, and rapid reductions in depressive symptoms. Significant improvements in clinician-rated severity of depression were observed as early as 24 hours after dosing in some patients. Improvements in LS mean change in MADRS total score, patient-rated severity of depression, and functional impairment were observed 4 weeks after the first dose.

[0456] Overall, safety and response / remission outcomes for US patients were similar to those seen for the overall population.

[0457] Final Analysis of the US Subpopulation - Response, Remission, and Safety As described above for the overall analysis, ESK+AD demonstrated a statistically significant and clinically meaningful advantage compared to AD+PBO in the primary efficacy endpoint (i.e., change from baseline in MADRS total score). See Montgomery, cited above. In this analysis, response, remission, and safety of these treatment groups were analyzed in U.S. patients only, and differences in efficacy and safety between the U.S. population and the overall study population were evaluated.

[0458] A. Results For clinician-rated assessments, the MADRS was administered at baseline and on days 2 (approximately 24 hours after administration), 8, 15, 22, and 28. Similarly, the Clinical Global Impression-Severity (CGI-S) scale (Guy W. ECDEU Assessment Manual for Psychopharmacology (028 Clinical Global Impressions [CGI]). 1976:218-222) was administered at baseline, days 4, 8, 11, 15, 22, and at the 4-week double-blind endpoint.

[0459] For patient assessment, the 9-item Patient Health Questionnaire-9 (PHQ-9) (Spitzer, JAMA. 1999;282(18):1737-1744) and the Sheehan Disability Scale (SDS) (Sheehan DV. The Anxiety Disease. A Leading Psychiatrist Offers New Hope for Victims of Severe Anxiety. New York, NY: Charles Scribner & Sons; 1983) were administered at baseline, day 15, and day 28.

[0460] B. Patient Demographics / Disease Characteristics Inclusion criteria included adults aged 18–64 years (including borderline) who met DSM-5 diagnostic criteria for MDD confirmed by the Mini International Neuropsychiatric Interview and had a 30-item total score ≥34 (moderate–severe depression) on the Clinician-Rated Depressive Symptoms Scale.

[0461] Patients must have TRD and non-response at the end of the screening period, defined as a ≦25% improvement in MADRS total score from weeks 1 to 4 and a MADRS total score ≧28 at weeks 2 and 4.

[0462] Of the 91 US patients, 46 received ESK + AD, 44 received AD + PBO, and 1 did not. Baseline patient demographics and disease characteristics were generally similar between the two treatment groups. See Table 22. The overall mean age was 44.1 years, approximately two-thirds (61.1%) of patients were female, and the majority (83.3%) of patients were white. The mean age of MDD diagnosis was 27.5 years, with an average history of depression exceeding 15 years. Baseline MADRS, CGI-S, and PHQ-9 scores were consistent with the population with TRD.

[0463] C. Effectiveness Efficacy was assessed by measuring response, remission, and change in clinician-rated symptom severity. Patients were considered responsive if they had a ≥ 50% reduction in their MADRS baseline score. Patients were classified as "in remission" if their clinician-rated MADRS score was ≤ 12 and their patient-rated PHQ-9 score was < 5. Finally, patients were considered to have a change in clinician-rated symptom severity if they had a ≥ 1-point reduction in the CGI-S and a ≥ 2-point reduction in the CGI-S.

[0464] Approximately 24 hours after administration (Day 2), 11 of 43 patients (25.6%) in the ESK+AD group and 9 of 40 patients (22.5%) in the AD+PBO group achieved a response. At Day 28, 26 of 40 patients (65.0%) in the ESK+AD group responded compared with 15 of 38 patients (39.5%) in the AD+PBO group. See Figure 14. Similarly, approximately 24 hours after administration (Day 2), 6 of 43 patients (14.0%) in the ESK+PBO group and 4 of 40 patients (10.0%) in the AD+PBO group achieved clinician-rated remission.

[0465] Clinician-assessed remission rates at day 28 were 18 of 40 (45.0%) patients in the ESK+AD group and 9 of 38 (23.7%) patients in the AD+PBO group. See Figure 15.

[0466] The frequency distribution of PHQ-9 severity categories on days 15 and 28 is shown in Figure 16. At day 15, the proportion of patients in remission (i.e., a score <5) was 11.4% in the ESK+AD group and 19.5% in the AD+PBO group. Four weeks after the first dose, the proportion of patients in remission (i.e., a score <5) was 23.8% in the ESK+AD group and 18.4% in the AD+PBO group. Furthermore, four weeks after the first dose, the proportion of patients with severe depression (i.e., a score of 20-27) was more than 10 times higher in the AD+PBO group (26.3%) than in the ESK+AD group (2.4%).

[0467] Furthermore, on Day 4, a ≥1-point decrease in the CGI-S was observed in nearly twice as many patients in the ESK + AD group compared with those in the PBO + AD group (47.6 vs. 26.3%). On Day 28, the rates were 77.5 and 63.9%, respectively. See Figure 17. The rate of patients with a ≥2-point decrease in the CGI-S was nearly twice as high in the ESK + AD group compared with the PBO + AD group on Day 4 (14.3 vs. 7.9%). On Day 28, the rates were 52.5 vs. 44.4%, respectively.

[0468] D. Safety Safety was assessed via treatment-emergent adverse events (TEAEs), serious AEs, vital signs, psychiatric symptoms assessed by the Brief Psychiatric Rating Scale (BPRS), dissociation measured by the Clinician-Administered Dissociative State Scale (CADSS), and readiness for release. See Table 25B, which shows the clinical global assessment of readiness for release, assessed based on overall clinical status (including sedation, sensory changes, blood pressure, and other adverse events).

[0469] [Table 29]

[0470] Overall, TEAEs were observed in 91.3% of patients in the ESK+AD group and 77.3% of patients in the AD+PBO group. See Table 23. There were no deaths. One patient in the ESK+AD group experienced an SAE (cerebral hemorrhage on day 98) during the follow-up period. Four patients were withdrawn from nasal spray (n=3 ESK, n=1 PBO), but no patients were withdrawn from new oral AD.

[0471] The most common TEAEs (≥5% in either treatment group) are shown in Table 23. The incidence of TEAEs was similar between US patients and the overall study population. AEs observed during the study were mostly mild to moderate in severity and transient in nature.

[0472] As observed in the overall population, current dissociative symptoms and transient sensory effects, as measured by CADSS total score, spontaneously resolved during the post-infusion observation period (within 60-90 minutes after infusion) before release. The majority (>90%) of patients in each treatment group were ready for release by 1.5 hours after infusion. Vital signs and BPRS findings were consistent with the overall population.

[0473] E. Conclusion These results demonstrated that ESK+AD, compared with AD+PBO, provided a rapid onset of efficacy lasting 4 weeks and was generally well tolerated in US patients with TRD. These results also demonstrated that ESK+AD demonstrated clinically meaningful improvements in depressive symptom response and remission and had a favorable safety profile in US patients with TRD. Specifically, ESK+AD demonstrated improvements in clinician-rated (CGI-S) and patient-rated (PHQ-9) assessments. Again, these observations were consistent with those from the overall study population, indicating no significant differences in efficacy in the US population.

[0474] However, in STAR-D Level 3, which includes patients with MDD who did not remit on Level 1 or Level 2 treatment, the overall acute response rate (based on Brief Depressive Symptom Scale-self report administered at each acute treatment visit) was 16.8%, and the overall acute remission rate was 13.7%. See Rush, American Journal of Psychiatry. 2006;163(11):1905-1917 and Howland RH. Journal of Psychosocial Nursing and Mental Health Services. 2008;46(10):21-24. In comparison, the response and remission rates observed with ESK+AD four weeks after initial administration were much higher (45% and 65.0%, respectively, as assessed by the MADRS).

[0475] Example 2: Efficacy of intranasal esketamine for treating treatment-resistant depression (TRD) in elderly patients, a phase 3 clinical trial The ability of esketamine to treat treatment-refractory or treatment-resistant depression (TRD) was evaluated via the clinical trial described below, which was conducted to evaluate the efficacy, safety, and tolerability of flexibly administered intranasal esketamine plus a newly initiated oral antidepressant in elderly subjects with TRD. This study served as a pivotal Phase 3 short-term efficacy and safety study supporting regulatory requirements for registration of intranasal esketamine for the treatment of TRD. Figure 18 outlines the study design.

[0476] The hypothesis of this study was that in elderly subjects with TRD, switching from a failing antidepressant treatment to intranasal esketamine plus a newly initiated oral antidepressant would be superior to switching to a newly initiated oral antidepressant treatment (active comparator) plus intranasal placebo in improving depressive symptoms.

[0477] The primary objective of this study was to evaluate the effectiveness of switching elderly subjects with treatment-resistant depression (TRD) from their previous antidepressant treatment (to which the subject was not responding) to flexibly administered intranasal esketamine (28 mg, 56 mg, or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant plus intranasal placebo in improving depressive symptoms as assessed by change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from Day 1 (pre-randomization) to the end of a 4-week double-blind induction phase.

[0478] Key secondary objectives were to evaluate the effect of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus an intranasal placebo on the following parameters in elderly subjects with TRD: (a) depressive symptoms (subject-reported), (b) onset of clinical response by day 2, and (c) functioning and associated disability. Additional secondary objectives included (a) depression response rate, (b) depression remission rate, (c) global severity of depression, (d) anxiety symptoms, and (e) health-related quality of life and well-being.

[0479] To investigate the safety and tolerability of intranasal esketamine plus a ...

Claims

1. 1. A pharmaceutical composition for use in a method for treating treatment-resistant depression in a patient, comprising: The pharmaceutical composition comprises esketamine, The patient has not responded to at least two oral antidepressants in the current depressive episode; The method comprises: administering to the patient a first oral antidepressant; administering esketamine intranasally to the patient at least twice weekly during a first induction period of at least four weeks; assessing the patient during a first induction period; wherein the patient does not achieve a substantially complete response to esketamine, and the pharmaceutical composition comprises resuming intranasal administration of esketamine at a maximum tolerated dose to the patient at least twice weekly during a second induction period of at least four weeks, concurrently with a second oral antidepressant, wherein the first oral antidepressant and the second oral antidepressant are the same.

2. 10. The pharmaceutical composition of claim 1, wherein the first oral antidepressant is the same as at least one of the at least two oral antidepressants.

3. 10. The pharmaceutical composition of claim 1, wherein the first oral antidepressant is different from at least one of the at least two oral antidepressants.

4. 10. The pharmaceutical composition of claim 1, wherein the first oral antidepressant is different from the at least two oral antidepressants.

5. 5. The pharmaceutical composition of any one of claims 1 to 4, wherein when the patient achieves a substantially complete response to esketamine, the method further comprises administering a therapeutically effective amount of esketamine to the patient up to once weekly during a subsequent maintenance phase.

6. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein esketamine is administered intranasally once every week, once every two weeks, or a combination thereof during a subsequent maintenance phase.

7. 7. The pharmaceutical composition of claim 1, wherein the amount of esketamine administered is from about 28 mg to about 84 mg.

8. The amount of esketamine administered (a) about 28 mg, about 56 mg, or about 84 mg; (b) about 56 mg, or about 84 mg; (c) about 28 mg, (d) about 56 mg, or (e) Approximately 84 mg The pharmaceutical composition according to any one of claims 1 to 7, wherein

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the patient is 65 years of age or older.

10. 10. The pharmaceutical composition of any one of claims 1-9, wherein the esketamine is administered via a single-use nasal spray device that delivers a total of 28 mg of esketamine in two sprays (one spray per nostril).

11. (a) One device is used for the 28 mg dose; (b) two devices are used for the 56 mg dose, or (c) Three devices are used for the 84 mg dose; The pharmaceutical composition of claim 10.

12. 12. The pharmaceutical composition of claim 11, wherein there is a 5 minute interval between each use of the device.

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