WO2024201274A1 - Esketamine for use in the treatment of depression - Google Patents

Abstract

The present invention is directed to methods and dosing regimens for the treatment of treatment resistant depression in a patient that has had 2 or more prior treatment failures and is experiencing inadequate symptom relief from the combination of an antidepressant and adjunctive treatment with quetiapine.

Description

ESKETAMINE FOR USE IN THE TREATMENT OF DEPRESSION

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the priority of U.S. Provisional Patent Application Nos. 63/454,516, filed March 24, 2023, and 63/508,219, filed June 14, 2023, the disclosures of which are incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention is directed to methods and dosing regimens for the treatment of treatment resistant depression in a patient that has had 2 or more, or preferably 3 or more, prior treatment failures and is experiencing inadequate symptom relief from the combination of an antidepressant and adjunctive treatment with quetiapine comprising ceasing to administering quetiapine and administering esketamine, preferably intranasal esketamine, in conjunction with the antidepressant or preferably esketamine, preferably intranasal esketamine, and a newly initiated antidepressant, preferably a selective serotonin reuptake inhibitor and/or a selective norepinephrine reuptake inhibitor, preferably for a total treatment period of at least 32 weeks.

BACKGROUND OF THE INVENTION

[0003] Major Depressive Disorder is defined as the presence of one of more major depressive episodes that are not better accounted for psychotic disorder or bipolar disorder. A major depressive episode is characterized by meeting five or more of the following criteria during the same 2 week period which represent a change in functioning and include at least depressed/sad mood or loss of interest and pleasure, indifference or apathy, or irritability and is usually associated with a change in a number of neurovegetative functions, including sleep patterns, appetite and body weight, motor agitation or retardation, fatigue, impairment in concentration and decision making, feelings of shame or guilt, and thoughts of death or dying (Harrison's Principles of Internal Medicine, 2000). Symptoms of a depressive episode include depressed mood; markedly diminished interest or pleasure in all, or almost all, activities most of the day; weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day; insomnia or hypersomnia nearly every day; psychomotor agitation or retardation nearly every day; fatigue or loss of energy nearly every day; feelings of worthlessness or excessive or inappropriate guilt nearly every day; diminished ability to think or concentrate, or indecisiveness, nearly every day; recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide. Further, the symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, American Psychiatric Association, 1994)

[0004] Current treatment options for unipolar depression include monotherapy or combination therapy with various classes of drugs including mono-amine oxidase inhibitors (MAOI), tricyclic antidepressants (TCA), serotonin specific reuptake inhibitors (SSRI), serotonin noradrenergic reuptake inhibitors (SNRI), noradrenaline reuptake inhibitor (NRI), "natural products" (such as Kava- Kava, St. John's Wort), dietary supplement (such as s-adenosylmethionine) and others. More specifically, drugs used in the treatment of depression include, but are not limited to imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, chlomipramine, fluoxetine, citalopram, sertraline, paroxetine, tianeptine, nefazadone, venlafaxine, desvenlafaxine, duloxetine, reboxetine, mirtazapine, phenelzine, tranylcypromine, and/or moclobemide. Several of these agents including, but not limited to, serotonin reuptake inhibitors are also used when depression and anxiety co-exist, such as in anxious depression.

[0005] In the clinic, 40-50% of depressed patients who are initially prescribed antidepressant therapy do not experience a timely remission of depression symptoms. This group typifies level 1 treatment-resistant depression, that is, a failure to demonstrate an "adequate" response to an "adequate" treatment trial (that is, sufficient intensity of treatment for sufficient duration) of an antidepressant. Moreover, about approximately 30% of depressed patients remain partially or totally treatment-resistant to at least two antidepressant treatments including combination treatments). Increasingly, treatment of treatment-resistant depression includes augmentation strategies including treatment with pharmacological agents such as, antipsychotics (such as quetiapine, aripiprazole, olanzapine, risperidone, and the like), lithium, carbamazepine, and triiodothyronine, and the like; adjunctive electroconvulsive therapy; adjunctive transcranial magnetic stimulation; etc.

[0006] Treatment resistant depression (TRD) is defined by the European Medicines Agency as non-response to >2 consecutive treatments in the current depressive episode (of an adequate dosage for an adequate duration). Patients with TRD experience low rates of remission and high rates of relapse. In fact, the greater the number of treatment failure a patient suffers the more resistant they are to adequately responding to subsequent treatment. Patients >3 prior treatment failure are particularly difficult to adequately treat with standard adjunctive therapies. [0007] There remains a need to provide an effective alternative treatment for depression, more particularly treatment resistant depression patients with >2 or >3 prior treatment failures (or PTFs) wherein patients do not find adequate relief from standard adjunctive therapy such as quetiapine, because of the inherent difficulty in treating these patient population.

SUMMARY OF THE INVENTION

[0008] The present invention is directed to a method for the treatment of treatment resistant depression in a patient that has had >2 or >3 prior treatment failures and is experiencing inadequate symptom relief from the combination of an antidepressant and adjunctive treatment with quetiapine comprising: ceasing to administer quetiapine and administering conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone or administering conjunctively with a new a therapeutically effective amount of a new antidepressant wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone is administered in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and the new antidepressants comprises a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor.

BRIEF DESCRIPTION OF THE FIGURES

[0009] FIG. 1 illustrates the study disposition of a 32 week comparison between patients who were treated with either esketamine plus a selective serotonin reuptake inhibitor and/or a selective norepinephrine reuptake inhibitor and patients who were treated with quetiapine plus a selective serotonin reuptake inhibitor and/or a selective norepinephrine reuptake inhibitor. In this figure, Full analysis set (included all randomized patients). The study included an 8-week acute phase followed by a 24-week maintenance phase. Patients who terminated the trial before Day 64 were considered to have discontinued the study by Week 8. Percentages were based on the number of patients in the indicated population. ^a'Other' included: discontinuation of underlying SSRI/SNRI treatment, lost to follow-up, minimal required study treatment dose could not be tolerated, non-compliance with study treatment, physician decision, pregnancy, and other. AE: adverse event; NS: nasal spray; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release. [0010] FIG. 2 illustrates primary and secondary endpoints of the study measured at week eight and week 32. In this figure, Percentages were based on the number of patients in the full analysis set (included all randomized patients). Remission was defined as a MADRS total score of <10 and no treatment or study discontinuation before Week 8. ^aMissing data for patients continuing study treatment were imputed using LOCF; patients who discontinued were imputed as non-responders; ^bTreatment groups were compared using a Cochran-Mantel-Haenszel chi-square test, adjusted for age group (18-64 years; >65 years) and total number of treatment failures (2; >3); ^cWeek-32 endpoint is defined as a participant achieving remission at Week 8 and having no relapse within the consecutive 24 weeks and completed both the treatment and the trial. Cl: confidence interval; LOCF: last observation carried forward; MADRS: Montgomery-Asberg Depression Rating Scale; NS: nasal spray; OR: odds ratio; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release.

[0011] FIG. 3 illustrates response and remission rates over time, from week one to week 32. In this figure, Full analysis set: includes all randomised patients; data were missing for 1 patient in the quetiapine XR+SSRI/SNRI at Baseline. Percentages are based on the number of patients at each timepoint, using LOCF for missing data. Remission was defined as a MADRS total score of <10; ^bResponse was defined as >50% improvement in MADRS total score from baseline or MADRS total score <10. Tested at a two-sided 0.05 significance level without adjustment for multiple testing. **p<0.01; ***p<0.001. LOCF: last observation carried forward; MADRS: Montgomery-Asberg Depression Rating Scale; NS: nasal spray; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release.

[0012] FIG. 4 illustrates the ESCAPE-TRD study design. In this figure, AD: antidepressant; CGI-C: Clinical Global Impression - Change; MADRS: Montgomery-Asberg Depression Rating Scale; MDD: major depressive disorder; NS: nasal spray; Q4W: every 4 weeks; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TRD: treatment resistant depression; XR: extended release.

[0013] FIG. 5 illustrates the change in MADRS score over time from week one to week 32. In this figure, Full analysis set (included all randomized patients). LS Means and SE were based on a repeated measures mixed effects ANCOVA model with treatment, age group, number of treatment failures, time, time by treatment and Baseline value as covariates. It was modelled with an unstructured covariance structure. ANCOVA: analysis of covariance; LS: least squares; MADRS: Montgomery-Asberg Depression Rating Scale; NS: nasal spray; OC: observed case; SE: standard error; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release.

[0014] FIG 6. is a Kaplan-Meier plot comparing the rate of MADRS score reduction to 10 or lower for subjects treated with quetiapine XR plus an oral antidepressant and subjects treated with Esketamine NS plus an oral antidepressant.

[0015] FIG. 7 is a Kaplan-Meier plot comparing the rate of MADRS score reduction to 10 or lower for subjects treated with quetiapine XR plus an oral antidepressant and subjects treated with Esketamine NS plus an oral antidepressant, wherein the number of prior treatment failures is 2.

[0016] FIG. 8 is a Kaplan-Meier plot comparing the rate of MADRS score reduction to 10 or lower for subjects treated with quetiapine XR plus an oral antidepressant and subjects treated with Esketamine NS plus an oral antidepressant, wherein the number of prior treatment failures is 3 or more.

[0017] FIG. 9 is a Kaplan-Meier plot comparing the rate of MADRS score reduction to 10 or lower or MADRS score reduction by 50% for subjects treated with quetiapine XR plus an oral antidepressant and subjects treated with Esketamine NS plus an oral antidepressant.

[0018] FIG. 10 is a Kaplan-Meier plot comparing the rate of MADRS score reduction to 10 or lower or MADRS score reduction by 50% for subjects treated with quetiapine XR plus an oral antidepressant and subjects treated with Esketamine NS plus an oral antidepressant, wherein the number of prior treatment failures is 2.

[0019] FIG. 11 is a Kaplan-Meier plot comparing the rate of MADRS score reduction to 10 or lower or MADRS score reduction by 50% for subjects treated with quetiapine XR plus an oral antidepressant and subjects treated with Esketamine NS plus an oral antidepressant, wherein the number of prior treatment failures is 3 or more.

DETAILED DESCRIPTION OF THE INVENTION

[0020] The invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks.

In some embodiments, in methods of the invention wherein adjunctive treatment with quetiapine is discontinued, the treatment with the antidepressant that was administered with quetiapine is continued; that is, "the antidepressant" administered in conjunction with (S)-2-(2- chlorophenyl)-2-(methylamino)cyclohexanone is the same antidepressant as previously used in the combination with adjunctive treatment with quetiapine.

[0021] In another embodiment, the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same prior major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks.

[0022] In another embodiment, the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks, wherein treatments are administered twice weekly during weeks 1-4, weekly during weeks 5-8 and weekly or every 2 weeks during weeks 9-32.

[0023] In another embodiment, the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks, wherein the induction dosage is about 56 mg or about 84 mg, and the maintenance dosage is about 56 mg or about 84 mg. [0024] In another embodiment, the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks, wherein the depression is major depressive disorder.

[0025] In another embodiment, the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks, wherein the (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone is administered as its corresponding hydrochloride salt during the induction phase and maintenance phase.

[0026] In another embodiment, the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and conjunctively with a new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks; wherein new antidepressant comprises a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor.

[0027] In another embodiment, the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and conjunctively with a new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks; wherein new antidepressant comprises a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks.

[0028] In another embodiment, the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and conjunctively with a new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks; wherein new antidepressant comprises a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks, wherein treatments are administered twice weekly during weeks 1-4, weekly during weeks 5-8 and weekly or every 2 weeks during weeks 9-32.

[0029] In another embodiment, the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and conjunctively with a new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks; wherein new antidepressant comprises a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks, wherein the induction dosage is about 56 mg or about 84 mg, and the maintenance dosage is about 56 mg or about 84 mg.

[0030] In another embodiment, the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and conjunctively with a new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks; wherein new antidepressant comprises a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks, wherein the depression is major depressive disorder. [0031] In another embodiment, the invention comprises a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and conjunctively with a new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and conjunctively with the new antidepressant intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks; wherein new antidepressant comprises a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks, wherein the (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone is administered as its corresponding hydrochloride salt during the induction phase and maintenance phase.

[0032] In an embodiment of the invention: the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone to the patient in an amount in the range of from about 28 mg to about 84 mg, during a period of about four weeks, at a frequency of twice per week.

[0033] In an embodiment of the invention: the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks.

[0034] In an embodiment of the invention: the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same prior major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks.

[0035] In an embodiment of the invention: the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks, wherein treatments are administered twice weekly during weeks 1-4, weekly during weeks 5-8 and weekly or every 2 weeks during weeks 9-32.

[0036] In an embodiment of the invention: the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks, wherein the induction dosage is about 56 mg or about 84 mg, and the maintenance dosage is about 56 mg or about 84 mg. [0037] In an embodiment of the invention: the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the or one or more prior same major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks, wherein the depression is major depressive disorder.

[0038] In an embodiment of the invention: the invention is a method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing quetiapine; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks, wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone is administered as its corresponding hydrochloride salt during the induction phase and maintenance phase.

[0039] Suicide, also known as completed suicide, is the "act of taking one's own life". Attempted suicide or non-fatal suicidal behavior is self-injury with the desire to end one's life that does not result in death. Suicidal ideation is the medical term for thoughts about or an unusual preoccupation with suicide, or thoughts of ending one's life or not wanting to live anymore but not necessarily taking any active efforts to do so.

[0040] Scales used in the evaluation of suicidal ideation include Beck Scale for Suicide Ideation (BSS), Columbia Suicide Severity Rating Scale (C-SSRS), Suicidal Ideation and Behavioral Assessment Tool (SIBAT) and The Kessler Psychological Distress Scale (K10, which test does not measure suicidal ideation directly, but there may be value in its administration as an early identifier of suicidal ideation. High scores of psychological distress are also, in some cases associated with suicidal ideation.

[0041] There are also several psychiatric disorders that appear to be comorbid with suicidal ideation or considerably increase the risk of suicidal ideation. The following disorders have been shown to be the strongest predictors of suicidal ideation/disorders in which risk is increased to the greatest extent: major depressive disorder (MDD), dysthymia, bipolar disorder. The main treatments for suicidality and/or suicidal ideation include: hospitalization, outpatient treatment, and medication. Hospitalization allows the patient to be in a secure, supervised environment to prevent their suicidal ideation from turning into suicide attempts. In most cases, individuals have the freedom to choose which treatment they see fit for themselves. However, there are several circumstances in which individuals can be hospitalized involuntarily, per state law including circumstances where an individual poses danger to self or others and where an individual is unable to care for one's self. One skilled in the art will recognize that the maintenance phase of the dosing regimens of the present invention will continue until further treatment is not required, for example as determined by a clinician, physician, psychiatrist, psychologist, or other suitable medical professional, and as indicated by for example, prolonged remission of the depression (including for example, the remission of one or more symptoms associated with the depression), social and/or occupational functional improvement(s) to normal or premorbid levels, or other known measures of depression.

[0042] One skilled in the art will further recognize that in the methods and dosing regimens of the present invention, the maintenance of the antidepressant response in a patient may be determine by for example, a clinician, physician, psychiatrist, psychologist, or other suitable medical professional. Additionally, maintenance of the antidepressant response may be established by for example, an absence of relapse of the depression (or one or more symptoms of the depression), an absence of the need for additional or alternate treatment(s) for the depression, an absence of the worsening of the depression, an absence of the need for hospitalization for a suicidal attempt or to prevent suicide, or, when evaluated by MADRS score, by maintenance of a MADRS score less than about 22 and/or the absence of a MADRS score above 22 for any continuous two week period.

[0043] As used herein, the term "depression" shall be defined to include major depressive disorder and treatment resistant depression. Preferably, the depression is treatment resistant depression.

[0044] In an embodiment, the present invention is directed to methods and dosing regimens for the treatment of depression in suicidal patients. One skilled in the art will recognize that the term "depression in suicidal patients" shall include any type of depression as herein defined, when diagnosed in a patient that also exhibits at least one symptom of suicidality, for example suicidal ideations and/or behaviors (e.g. intent, planning, etc.). Thus, "depression in suicidal patients" includes, but is not limited to, major depressive disorder in suicidal patients, unipolar depression in suicidal patients, treatment resistant depression in suicidal patients, depression with anxious distress in suicidal patients, bipolar depression in suicidal patients and dysthymia in suicidal patients. Preferably, the "depression in suicidal patients" is selected from the group consisting of major depressive disorder in suicidal patients, unipolar depression in suicidal patients and treatment resistant depression in suicidal patients. More preferably, the "depression in suicidal patients" is treatment resistant depression in suicidal patients.

[0045] As used herein, the term "treatment-refractory or treatment-resistant depression" and the abbreviation "TRD" shall be defined as a major depressive disorder that does not respond to a least two antidepressant regimens or treatments.

[0046] As used herein, unless otherwise noted, the term "antidepressant" shall mean any pharmaceutical agent which can be used to treat depression. Suitable examples include, but are not limited to mono-amine oxidase inhibitors such as phenelzine, tranylcypromine, moclobemide, and the like; tricyclics such as imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, chlomipramine, amoxapine, and the like; tetracyclics such as maprotiline, and the like; non-cyclics such as nomifensine, and the like; triazolopyridines such as trazodone, and the like; serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, escitolapram, fluvoxamine, and the like; serotonin receptor antagonists such as nefazadone, and the like; serotonin noradrenergic reuptake inhibitors such as venlafaxine, milnacipran, desvenlafaxine, duloxetine and the like; noradrenergic and specific serotonergic agents such as mirtazapine, and the like; noradrenaline reuptake inhibitors such as reboxetine, edivoxetine and the like; atypical antidepressants such as bupropion, and the like; natural products such as Kava-Kava, St. John's Wort, and the like; dietary supplements such as s-adenosylmethionine., and the like; and neuropeptides such as thyrotropinreleasing hormone and the like; compounds targeting neuropeptide receptors such as neurokinin receptor antagonists and the like; and hormones such as triiodothyronine, and the like. Preferably, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine and sertraline.

[0047] Therapeutically effective dosage levels and dosage regimens for antidepressants (for example, mono-amine oxidase inhibitors, tricyclics, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic and specific serotonergic agents, noradrenaline reuptake inhibitor, natural products, dietary supplements, neuropeptides, compounds targeting neuropeptide receptors, hormones and other pharmaceutical agents disclosed herein), may be readily determined by one of ordinary skill in the art. For example, therapeutic dosage amounts and regimens for pharmaceutical agents approved for sale are publicly available, for example as listed on packaging labels, in standard dosage guidelines, in standard dosage references such as the Physician's Desk Reference (Medical Economics Company or online at http://www.pdrel.com) or other sources.

[0048] As used herein the term "antipsychotic" includes, but is not limited to:

[0049] (a) typical or 1st generation 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

[0050] (b) atypical or 2nd generation antipsychotics, such as paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, ORG-5222 (Organon), and the like; and others such as sonepiprazole, aripiprazole, brexpiprazole, nemonapride, SR-31742 (Sanofi), CX-516 (Cortex), SC-111 (Scotia), NE-100 (Taisho), and the like.

[0051] In an embodiment, the "atypical antipsychotic" is selected from the group consisting of aripiprazole, brexpiprazole, 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. [0052] One skilled in the art will recognize that wherein the present invention is directed to methods or dosing regimens for the treatment and/or prevention of suicidality, said methods and dosing regimens include, but are not limited to, the prevention of suicidal ideations, suicidal behaviors, suicidal attempts and/or suicide.

[0053] As used herein, unless otherwise noted, the term "esketamine" shall mean the (S)- enantiomer of ketamine, a its corresponding hydrochloride salt, a compound of formula (I)

also known as (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride.

[0054] As used herein, unless otherwise noted, the terms "treating", "treatment" and the like, shall include the management and care of a subject or patient (preferably mammal, more preferably human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder.

[0055] As used herein, unless otherwise noted, the term "prevention" shall include (a) reduction in the frequency of one or more symptoms; (b) reduction in the severity of one or more symptoms; (c) the delay or avoidance of the development of additional symptoms; and/or (d) delay or avoidance of the development of the disorder or condition.

[0056] One skilled in the art will recognize that wherein the present invention is directed to methods of prevention, a subject in need of thereof (i.e. a subject in need of prevention) shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least one symptom of the disorder, disease or condition to be prevented. Further, a subject in need thereof may additionally be a subject (preferably a mammal, more preferably a human) who has not exhibited any symptoms of the disorder, disease or condition to be prevented, but who has been deemed by a physician, clinician or other medical profession to be at risk of developing said disorder, disease or condition. For example, the subject may be deemed at risk of developing a disorder, disease or condition (and therefore in need of prevention or preventive treatment) as a consequence of the subject's medical history, including, but not limited to, family history, pre-disposition, co-existing (comorbid) disorders or conditions, genetic testing, and the like. [0057] As used herein, unless otherwise noted, the terms "subject" and "patient" refer to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject or patient has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. One skilled in the art will further recognize that the methods of treatment or prevention and the dosing regimens of the present invention are directed to subjects or patients in need of such treatment, prevention or dosing regimen, more particularly to subjects or patients diagnosed with or exhibiting at least one symptom of depression (preferably, meeting the criteria for major depressive disorder or episode) regardless of type or underlying cause.

[0058] In an embodiment of the present invention, the subject or patient in need thereof is a subject or patient that has been diagnosed with or exhibits at least one symptom of depression (preferably, meeting the criteria for major depressive disorder or episode) and who has further been diagnosed with or exhibits at least one symptom of suicidality (e.g. suicidal ideations and/or behaviors).

[0059] In some embodiments, an inadequate response is a non-response. In some embodiments, an inadequate response is defined as >0% - <25% improvement of symptoms.

[0060] In some embodiments, an adequate dose is the maximum therapeutic dose of said treatment. In some embodiments, an adequate duration is >6 weeks.

[0061] The term "therapeutically effective amount" as used herein, (for example, in describing monotherapy with intranasal esketamine) means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

[0062] Wherein the present invention is directed to therapy with a combination of agents, "therapeutically effective amount" shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response. For example, the therapeutically effective amount of combination therapy comprising esketamine and a serotonin reuptake inhibitor would be the amount of esketamine and the amount of the serotonin reuptake inhibitor that when taken together or sequentially have a combined effect that is therapeutically effective, more preferably where the combined effect is synergistic. Further, it will be recognized by one skilled in the art that in the case of combination therapy with a therapeutically effect amount, the amount of each component of the combination individually may or may not be therapeutically effective. [0063] Wherein the present invention is directed to the administration of a combination, the compounds may be co-administered simultaneously, sequentially, separately or in a single pharmaceutical composition. Where the compounds are administered separately, the number of dosages of each compound given per day, may not necessarily be the same, e.g. where one compound may have a greater duration of activity, and will therefore, be administered less frequently. Further, the compounds may be administered via the same or different routes of administration, and at the same or different times during the course of the therapy, concurrently in divided or single combination forms. The instant invention is therefore understood as embracing all regimens of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

[0064] As used herein, the terms "co-therapy", "combination therapy", "adjunctive treatment", "adjunctive therapy" "administered in conjunction with" and "combined treatment" shall mean treatment of a patient in need thereof by administering esketamine in combination with one or more antidepressant(s), and further, optionally in combination with one or more atypical antipsychotics wherein the esketamine and the antidepressant(s) are administered by any suitable means, simultaneously, sequentially, separately or in a single pharmaceutical formulation. Where the esketamine and the antidepressant(s) are administered in separate dosage forms, the number of dosages administered per day for each compound may be the same or different. The 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), sublingual, transdermal, and rectal. Compounds may also be administered directly to the nervous system including, but not limited to, intracerebral, intraventricular, intracerebroventricular, intrathecal, intracisternal, intraspinal and/or peri-spinal routes of administration by delivery via intracranial or intravertebral needles and/or catheters with or without pump devices. The esketamine and the antidepressant(s) may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.

[0065] Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound or compounds used, the mode of administration, the strength of the preparation and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient's sex, age, weight, diet, time of administration and concomitant diseases, will result in the need to adjust dosages. [0066] One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and/or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

[0067] One skilled in the art will further recognize that human clinical trials including first-in- human, dose ranging and efficacy trials, in healthy patients and/or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.

[0068] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

[0069] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.

[0070] To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that wherein a range is recited, the range is not limited to the recited upper and lower bounds, but rather includes the full range from about amount X through about amount Y, or any amount or range therein.

[0071] For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric add, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

[0072] Representative acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2- dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(lS)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy- ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D- gluconic acid, D-glucoronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)- L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-l,5-disulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino- salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.

[0073] Representative bases which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2- (diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H- imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, l-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

[0074] Pharmaceutical formulations of esketamine are described in US 11,446,260 B2 hereby incorporated by reference herein. In an embodiment, the present invention is directed to an aqueous formulation of S-ketamine, comprising water and S-ketamine; wherein the (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone hydrochloride is present in a concentration in range of from about 150 mg/ml to about 200 mg/ml, preferably in the range of from about 126 mg/ml to about 162 mg/ml, more preferably in the range of from about 160 mg/ml to about 163 mg/m, based on the total volume of the pharmaceutical composition and may contain one or more additional excipients for example, wetting agents, surfactant components, solubilizing agents, thickening agents, colorant agents, antioxidant components, and the like.

[0075] Examples of a suitable antioxidant component, if used, include, but are not limited to one or more of the following: sulfites; ascorbic acid; ascorbates, such as sodium ascorbate, calcium ascorbate, or potassium ascorbate; ascorbyl palmitate; fumaric acid; ethylene diamine tetraacetic acid (EDTA) or its sodium or calcium salts; tocopherol; gallates, such as propyl gallate, octyl gallate, or dodecyl gallate; vitamin E; and mixtures thereof. The antioxidant component provides long term stability to the liquid compositions. Addition of the antioxidant component can help enhance and ensure the stability of the compositions and renders the compositions stable even after six months at 40° C. A suitable amount of the antioxidant component, if present, is about 0.01 wt.-% to about 3 wt.-%, preferably about 0.05 wt.-% to about 2 wt.-%, of the total weight of the composition.

[0076] Solubilizing and emulsifying agents can be included to facilitate more uniform dispersion of the active ingredient or other excipient that is not generally soluble in the liquid carrier. Examples of a suitable emulsifying agent, if used, include, but are not limited to, for example, gelatin, cholesterol, acacia, tragacanth, pectin, methyl cellulose, carbomer, and mixtures thereof. Examples of a suitable solubilizing agent include polyethylene glycol, glycerin, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof.

[0077] Preferably, the solubilizing agent includes glycerin. The solubilizing or emulsifying agent is/are generally present in an amount sufficient to dissolve or disperse the active ingredient, i.e. S- ketamine, in the carrier. Typical amounts when a solubilizing or an emulsifier are included are from about 1 wt.-% to about 80 wt.-%, preferably about 20 wt.-% to about 65 wt.-%, and more preferably about 25 wt.-% to about 55 wt.-%, of the total weight of the composition.

[0078] A suitable isotonizing agent, if used, includes sodium chloride, glycerin, D-mannitol, D- sorbitol, glucose, and mixtures thereof. A suitable amount of the isotonizing agent, when included, is typically about 0.01 wt.-% to about 15 wt.-%, more preferably about 0.3 wt.-% to about 4 wt.-%, and more preferably about 0.5 wt.-% to about 3 wt.-%, of the total weight of the composition.

[0079] A Suspending agent or viscosity increasing agent can be added to the pharmaceutical compositions of the present invention, to for example, increase the residence time in the nose. Suitably examples include, but are not limited to, hydroxypropyl methylcellulose, sodium carmellose, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salts, gellan gum, poloxamer, polyvinyl pyrrolidone, xanthan gum, and the like.

[0080] Preferably the aqueous pharmaceutical composition will contain (S)-2-(2- chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride is present in a concentration in the range of from about eq. 160 mg/ml to about eq. 163 mg/ml, based on the total volume of the pharmaceutical composition, and the pharmaceutical composition further comprises citric acid, EDTA, and sodium hydroxide, wherein the pH of the pharmaceutical composition is in the range of from about 4.0 to about 5.5. The most preferred formulation is as provided in the approved FDA SPRAVATO label.

[0081] ESCAPE-TRD (NCT04338321) was the first phase I II b randomized trial to compare esketamine NS with the antipsychotic augmentation agent, quetiapine extended release (XR), both in conjunction with a continuing selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI).

[0082] The primary goal of acute treatment for major depressive disorder (MDD) is remission leading to full recovery, whereafter maintenance treatment aims to prevent relapse.^{1, 2} Up to two thirds of patients may not achieve remission with initial antidepressant (AD) treatment, and many who do achieve remission relapse within a year.^{3, 4} Treatment resistant depression (TRD) is commonly defined as non-response to >2 antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode (MDE).⁵ TRD, affecting 10-30% of patients with MDD, is associated with increased hospitalisation rates, comorbidities, mortality, and suicide.^{3, 6-9}

[0083] Antidepressant treatments approved for MDD, including oral ADs and adjunctive medications, are used in various physician-defined strategies to treat TRD.^10-12 There is a severe unmet need for effective treatment options approved specifically for TRD, with diverse strategies used in clinical practice.¹⁰ Quetiapine extended release (XR), a guideline-supported antipsychotic augmentation agent approved by the FDA and EMA for patients with MDD who have experienced sub-optimal response to AD monotherapy, is one of the most commonly used TRD treatments.^13-16

[0084] Unlike most AD treatments that primarily target the monoamine pathways, esketamine primarily targets the glutamatergic pathway.^{17, 18} Esketamine, administered as a nasal spray (NS) in conjunction with a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI), is the only treatment approved specifically for TRD, and is also approved for acute treatment of psychiatric emergency due to MDD.¹⁹ Esketamine NS can reduce depressive symptoms and risk of relapse versus placebo, when both are given in combination with a newly initiated SSRI/SNRL^19-22 [0085] Here, we report findings from ESCAPE-TRD (NCT04338321); the first open-label randomized clinical trial to compare flexibly-dosed esketamine NS with quetiapine XR, an active comparator, both in conjunction with a continuing SSRI/SNRI, in patients with TRD.

[0086] Patients were randomized 1:1 to flexibly-dosed esketamine NS (56/84 mg; twice weekly, weekly, or every 2 weeks) or quetiapine XR (150-300 mg/day), both in conjunction with SSRI/SNRI. The primary endpoint was remission rate at Week 8 (Montgomery-Asberg Depression Rating Scale [MADRS] total score <10). The key secondary endpoint was rate of relapse-free through Week 32 after remission at Week 8 (adjusted for age and treatment failures). All patients were analysed; treatment discontinuation was considered a negative outcome for both endpoints.

[0087] The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.

[0088] Example 1 Treatment of treatment resistant depression comprising administering intranasal esketamine, plus a selective serotonin reuptake inhibitor and/or a selective norepinephrine reuptake inhibitor ESCAPE-TRD (NCT04338321) Clinical Trials

METHODS

PATIENTS

[0089] Adult patients (aged 18-74 years) with TRD were eligible for inclusion (Table 1).

Patients met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for MDD, with Inventory of Depressive Symptomatology Clinician-rated, 30-item scale (IDS-C30) score >34. In the current MDE, patients had previously failed (or not-responded; <25% symptom improvement) to 2-<6 treatments, including the current treatment, from >2 different classes. Patients were receiving a current AD treatment that included an SSRI/SNRI, which had also resulted in non-response after treatment at an adequate dosage for >6 weeks and having been up-titrated to the maximum tolerated dose. The current SSRI/SNRI treatment continued while all other AD treatments, including augmentation agents, were stopped. Patients already receiving quetiapine (XR or immediate-release) at <50 mg/day at screening were allowed to participate following a >7-day wash-out.

Table 1 Key inclusion and exclusion criteria

Key Inclusion Criteria Key Exclusion Criteria

Sex Male or female ,, , Age at onset of first episode of MDD

Age 18 -74 years (inclusive) >55 years

Current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related . . _r . . disorders, obsessive compulsive

Meets DSM-5 criteria for single- . . . .. . disorder (current only), intellectual Diagnosis episode or recurrent MDD, without .. . ...

. . _r disability, autism spectrum disorder, psychotic features . . .. .. borderline personality disorder, antisocial personality disorder, histrionic personality disorder or narcissistic personality disorder

Disease Severity IDS-C30 total score >34

Non-response^b to a current AD _. ,

Treatment wi_i t_l h quetiapine XR (at treatment that includes an , , , . , doses >50 mg/day), esketamine or

SSRI/SNRI at the maximum tolerated . ketamine for the curren .t. . M. dDrE¬

Current Treatment dose for >6 weeks

No signs of clinical improvement at all

Must be on a single oral SSRI/SNRI on curren .t A _A D . treatment on Day 1 prior to randomisation

Non-response to >7 consecutive treatments at an adequate dosage for Current AD treatment was

Previous immediately preceded by . . . . depressive episode Treatments non-response to >1 but <5 different consecutive treatments

Received vagal nerve or deep brain stimulation in the current MDE ^aThe minimum age could be older if the legal minimum age of consent in the country in which the study took place was >18 years; ^bNon-response was defined as >0%-<25% improvement of symptoms. cSSRI/SNRI was continued following randomisation. AD: antidepressant; DSM-5: The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; IDS-C30: Inventory of Depressive Symptomatology Clinician-rated, 30-item scale; MDD: major depressive disorder; MDE: major depressive episode; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release.

TRIAL DESIGN AND OVERSIGHT

[0090] ESCAPE-TRD was a randomized, open-label, rater-blinded, active-controlled, international, study across 171 sites comprising hospitals, inpatient and outpatient clinics and research centres in 24 countries. The study aimed to evaluate the efficacy, safety, and tolerability of esketamine NS versus quetiapine XR, both in conjunction with a continuing SSRI/SNRI, in patients with TRD.

[0091] ESCAPE-TRD comprised an up-to-14-day screening phase, an 8-week acute treatment phase, a 24-week maintenance phase, and a safety follow-up 2 weeks after the last dose of study treatment (FIG 4). Patients were randomized 1:1 to esketamine NS or quetiapine XR, based on a computer-generated schedule prepared before the study using randomly permuted blocks, stratified by age (18-<64 years; 65-<75 years) and total number of prior treatment failures (2; >3). Patients who discontinued study treatment remained in the study for all follow-up visits through Week 32.

[0092] Esketamine NS and quetiapine XR were dosed as per label.^{19, 23} Patients self-administered esketamine NS under supervision at their treatment sites and vital signs were monitored from 40 minutes post-administration until considered stable. The starting dose of esketamine NS was dependent on age and ancestry and was flexibly dosed (adult patients [18-<64 years]: commencing at 56 mg and flexibly dosed at 56 or 84 mg from Day 4; elderly patients [65-74 years] and adults of Japanese ancestry: commencing at 28 mg, increasing to 56 mg from Day 4 and flexibly dosed at 56 or 84 mg at subsequent visits). Treatments were administered twice weekly during Weeks 1-4, weekly during Weeks 5-8 and weekly or every 2 weeks during Weeks 9-32.²⁴

[0093] Quetiapine XR was provided as tablets and self-administered by patients at home before bedtime. Quetiapine XR was flexibly dosed (adult patients: 50 mg/day commencing on Day 1, increasing to >150 mg/day by the end of Week 2 but <300 mg/day, based on individual patient evaluation; elderly patients: same schedule, except the increase to <300 mg/day occurred no earlier than Day 22).¹³

[0094] The study was conducted in accordance with the Declaration of Helsinki and country specific ethics review boards provided approval.²⁵ All patients provided written informed consent. STUDY PROCEDURES AND EVALUATIONS

EFFICACY

[0095] Efficacy was assessed according to the Montgomery-Asberg Depression Rating Scale (MADRS), performed on-site by independent blinded raters. Efficacy analyses included all randomized patients. The primary endpoint assessed short-term efficacy, and was the proportion of patients who achieved remission (defined as MADRS score <10, ²⁶ and no treatment or study discontinuation) at Week 8. The key secondary endpoint assessed long-term efficacy and was the proportion of patients who were relapse-free through Week 32 (without treatment discontinuation) after remission at Week 8. [0096] Relapse was defined as any one of: an increase to MADRS score >22, confirmed by one additional MADRS score >22 within the next 5-15 days; hospitalization for worsening depression, suicide or suicidal ideation; prevention of suicide attempt or suicide attempt; completed suicide; or any other event determined by the investigator's clinical judgment as indicative of a relapse.

[0097] Analysis of rates of remission (irrespective of treatment discontinuation) and response (>50% improvement in MADRS total score from baseline or MADRS total score <10) rates and change from baseline (CfB) in MADRS total score are also reported.

ADDITIONAL PRE-SPECIFIED ENDPOINTS

[0098] Additional secondary endpoints were CfB in clinician-rated and patient-reported scales/questionnaires. Additional clinician-rated assessments evaluated overall severity of depressive illness, comprising Clinical Global Impression - Change (CGI-C) and Clinical Global Impression - Severity (CGI-S) ratings. Patient-reported outcomes assessed depressive symptoms, functional impairment, health-related quality of life and work productivity, comprising Patient Health Questionnaire 9-ltem score (PHQ-9), European Quality of Life Group, 5-Dimension, 5-Level questionnaire (EQ-5D-5L), Quality of Life in Depression Scale (QLDS), 36-item Short-Form Health Survey (SF-36), Work Productivity and Activity Impairment: Depression questionnaire (WPAI:D), and the Sheehan Disability Scale (SDS).

[0099] The primary and key secondary endpoints were also evaluated using an alternative remission threshold of MADRS total score <12 (and no treatment or study discontinuation before Week 8, as per the standard definition), prespecified in the Health Technology Assessment Statistical Analysis Plan for Germany. This definition of remission has been employed in numerous phase III trials of esketamine NS,^{20, 22, 27, 28} thus facilitating direct comparison to prior studies, and represents a commonly utilized threshold within studies of patients with TRD, owing to the typically higher basal MADRS total score in this population.^{38, 39} The handling of missing data and the statistical analyses performed were done so as described in the main body of the manuscript for each respective outcome.

SAFETY

[00100] Safety analysis included data from all randomized patients who received >1 dose of study treatment. An adverse event (AE) was considered a treatment-emergent AE (TEAE) if it started between taking the first dose and completion of the safety follow-up visit (14 days after last dose of study intervention), or up to 30 days after the last dose if it was a serious AE. Safety evaluations were carried out throughout the study. [00101] Prespecified TEAEs of special interest were grouped by Medical Dictionary for Regulatory Activities (MedDRA, versions 23-25)-based groups of preferred terms comprising sedation, dissociation, suicidality, suggestive of abuse potential, cystitis, and hepatic impairment. STATISTICAL ANALYSIS

[00102] Based on previous trial data, the study was powered for both the primary endpoint with 90% power (estimated Week 8 remission rate using non-responder imputation [N Rl] : 41.25% for esketamine NS+SSRI/SNRI; 28.88% for quetiapine XR+SSRI/SNRI) and the key secondary endpoint with 80% power (estimated Week 32 rate of relapse-free after remission using NRI: 25.99% for esketamine NS+SSRI/SNRI; 16.17% for quetiapine XR+SSRI/SNRI) at a 2-sided significance level of 0.05 when using chi-square tests. Thus, 311 patients per arm (622 patients in total) for the primary endpoint and 270 patients per arm (540 patients in total) for the key secondary endpoint gives sufficient power to detect between-treatment differences.

[00103] Both the primary and key secondary endpoints were analysed using NRI, whereby stopping treatment was considered a negative outcome. Missing Week 8 data for patients with no treatment discontinuation were imputed using last observation carried forward (LOCF). Treatments were compared using Cochran-Mantel-Haenszel (CMH) chi-square tests, adjusted for age (18-<64 years; 65-<75 years) and total number of previous treatment failures (2; >3). Additional analyses of the primary and key secondary endpoints were performed by applying a commonly used alternative remission threshold of MADRS <12.^{20, 22, 27} • ²⁸

[00104] Rates of remission and response over time (LOCF) were compared using unadjusted CMH tests. CfB in MADRS total score at each visit was assessed using a mixed model for repeated measures (with an unstructured covariance structure) based on observed cases (for on-study-treatment visits only). The model included baseline score as a covariate, and study intervention, stratification factors, visit, and visit-by-study-intervention interaction as fixed effects. RESULTS

PATIENT DISPOSITION AND BASELINE CHARACTERISTICS

[00105] Between 26 August 2020 and 5 November 2021, 811 patients were screened; 676 patients were subsequently randomized to esketamine NS+SSRI/SNRI (n=336) or quetiapine XR+SSRI/SNRI (n=340; FIG 1). Baseline demographic and psychiatric characteristics were generally similar between study treatments (Table 2) and participants were representative of the TRD/MDD population with respect to age, sex, race, and ethnic group (Table 3). Over the full treatment phase, rates of discontinuation were higher in patients receiving quetiapine XR+SSRI/SNRI than esketamine NS+SSRI/SNRI (FIG 1).

Table 2 Demographic and psychiatric characteristics at baseline

Esketamine NS + Quetiapine XR +

SSRI/SNRI SSRI/SNRI

N=336 N=340

Age, years

Mean (SD) 44.3 (13.6) 45.7 (13.4)

Median 45.0 47.0

Range 18; 72 18; 74

18-64, n (%) 317 (94.3) 322 (94.7)

>65, n (%) 19 (5.7) 18 (5.3)

Sex, n (%)

Male 111 (33.0) 118 (34.7)

Female 225 (67.0) 222 (65.3)

BMI, kg/m2

Underweight (<18.5) 6 (2.1) 5 (1.7)

Normal (18.5— <25) 110 (39.0) 90 (31.0)

Overweight (25-<30) 100 (35.5) 102 (35.2)

Obese (>30) 66 (23.4) 93 (32.1)

Employment status, n (%)

Employed 179 (53.3) 178 (52.4)

Unemployed 156 (46.4) 162 (47.6)

Other 1 (0.3) 0 (0.0)

Treatment failures, n (%)

2 204 (60.7) 211 (62.1)

>3 132 (39.3) 129 (37.9)

Age when diagnosed with MDD, years³

Mean (SD) 33.5 (11.77) 34.9 (11.71)

Median 33.0 35.0

Range 10; 54 10; 55

Duration of current episode, weeks³

Mean (SD) 68.5 (84.31) 64.6 (65.96)

Median 43.0 38.0

Range 12; 780 13; 449

Total number of depressive episodes³

Mean (SD) 3.4 (2.44) 3.5 (4.10)

Median 3.0 3.0

Range 1; 21 1; 60 MADRS Total Score^b

Mean(SD) 31.4(6.06) 31.0(5.83)

Median 31.0 31.0

Range 6; 52 12; 51

IDS-C30 Total Score

Mean (SD) 44.6 (6.58) 45.0 (6.87)

Median 44.0 45.0

Range 17; 66 28; 71

CGI-S Score

Mean(SD) 4.8(0.62) 4.9(0.70)

Median 5.0 5.0

Range 3; 7 3; 6

Full analysis set (included all randomized patients). ^aBaseline psychiatric history data were missing for 6 patients (2 for esketamine NS and 4 for quetiapine XR); ^bBaseline MADRS score data were missing for 1 quetiapine XR patient. BMI: body mass index; CGI-S: Clinical Global Impression - Severity; IDS-C30: Inventory of Depressive Symptomatology - Clinician-rated, 30-item scale; MADRS: Montgomery-Asberg Depression Rating Scale; MDD: major depressive disorder; NS: nasal spray; SD: standard deviation; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release.

Table 3 Representation of study Participants

MDD: major depressive disorder; MDE: major depressive disorder; TRD: treatment resistant depression.

PRIMARY ENDPOINT RESULTS

[00106] At Week 8, significantly more patients receiving esketamine NS+SSRI/SNRI achieved remission (MADRS score <10) with no treatment discontinuation (n=91 [27.1%]) than those receiving quetiapine XR+SSRI/SNRI (n=60 [17.6%]; adjusted p=0.003; FIG 2). The adjusted odds ratio (OR) and 95% confidence interval (Cl) was 1.74 (1.20, 2.52), consistent with the unadjusted sensitivity analysis (Table 4). The adjusted relative risk (RR [95% Cl]) was 1.54 (1.15, 2.06).

Table 4 Sensitivity analysis of primary endpoint

Remission was defined as a MADRS total score of <10 and no treatment or study discontinuation before Week 8. ^aPatients who did not have an available MADRS result at the Week 8 visit but did not discontinue study treatment or withdraw before Week 8 were considered non-responders; ^bTested using a Cochran-Mantel-Haenszel test at a two-sided 0.05 significance level without adjustment for multiple testing. Cl: confidence interval; LOCF: last observation carried forward; MADRS: Montgomery- Asberg Depression Rating Scale; NS: nasal spray; OR: odds ratio; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release.

KEY SECONDARY ENDPOINT RESULTS

[00107] Significantly more patients were relapse-free through Week 32 after remission at week 8, without treatment discontinuation, with esketamine NS+SSRI/SNRI treatment (n=73 [21.7%]) versus quetiapine XR+SSRI/SNRI treatment (n=48 [14.1%]; FIG 2). The adjusted OR (95% Cl) was 1.72, (1.15, 2.57; p=0.008); the adjusted RR (95% Cl) was 1.55 (1.12, 2.16).

OTHER SECONDARY ENDPOINT RESULTS

[00108] A greater percentage of patients receiving esketamine NS+SSRI/SNRI achieved remission and response at each timepoint through Week 32 than patients receiving quetiapine XR+SSRI/SNRI (Week 32 remission: 55.0% versus 37.0%, respectively; p<0.001; Week 32 response: 75.5% versus 55.5%, respectively; p<0.001; FIG 3). [00109] At all timepoints, patients receiving esketamine NS+SSRI/SNRI consistently demonstrated greater CfB in MADRS total score than patients receiving quetiapine XR+SSRI/SNRI (FIG 5). When the MADRS <12 remission threshold was applied, significantly more patients achieved each endpoint with esketamine NS+SSRI/SNRI versus quetiapine XR+SSRI/SNRI, however, ORs were greater than when using MADRS <10 (Table 5).

Table 5 Analysis of primary and key secondary endpoints using MADRS <12 remission threshold

Remission was defined as a MADRS total score of <12 and no treatment or study discontinuation before Week 8. ^aMissing data for patients continuing study treatment were imputed using LOCF; patients who discontinued were imputed as non-responders; ^bTreatment groups were compared using a Cochran-Mantel-Haenszel chi-square test, adjusted for age group (18-64 years; >65 years) and total number of treatment failures (2; >3); ^cWeek 32 endpoint is defined as a participant achieving remission at Week 8 and having no relapse within the consecutive 24 weeks and completed both the treatment and the trial. Cl: confidence interval; LOCF: last observation carried forward; NS: nasal spray; OR: odds ratio; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; XR: extended release

SAFETY

[00110] From Week 0-32, 307 (91.9%) esketamine-randomized and 262 (78.0%) quetiapine-randomized patients experienced >1 TEAE (Table 6). Serious TEAEs occurred in 19 (5.7%) patients in the esketamine NS+SSRI/SNRI arm and 17 (5.1%) patients in the quetiapine XR+SSRI/SNRI arm. Two esketamine-randomized patients had serious TEAEs considered treatment-related by the investigator: acute coronary syndrome (after 21 weeks of treatment) and dizziness (after 2 weeks of treatment). No quetiapine XR-randomized patients experienced serious TEAEs considered treatment-related. [00111] AEs leading to treatment discontinuation occurred in 14 (4.2%) patients receiving esketamine NS+SSRI/SNRI and 37 (11.0%) patients receiving quetiapine XR+SSRI/SNRI (Table 6; Table 7). Two suicide attempts occurred in patients randomized to esketamine NS and one in patients randomized to quetiapine XR; neither were considered treatment-related. Throughout the study, two deaths were reported: one in the esketamine NS+SSRI/SNRI arm from an undetermined cause at Week 9, and one in the quetiapine XR+SSRI/SNRI arm at Week 17, due to a cerebrovascular accident (Table 6); neither were considered treatment-related.

Table 6 Summary of most common TEAEs

Safety Analysis Set (included all randomized patients who received >1 dose of any study intervention). TEAEs are reported in the table if they occurred in >5% of patients in either treatment group. NS: nasal spray; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TEAE: treatment-emergent adverse event; XR: extended release.

Table 7 TEAEs leading to treatment discontinuation

Safety Analysis Set (included all randomized patients who received >1 dose of any study intervention). NS: nasal spray; SNRI: serotonin norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TEAE: treatment-emergent adverse event; XR: extended release

DISCUSSION

[00112] ESCAPE-TRD was the first study to compare esketamine NS against a commonly used, guideline-recommended antipsychotic augmentation treatment (quetiapine XR), both in conjunction with a continuing SSRI/SNRI during acute and maintenance treatment phases.^{15, 29} Previously, esketamine NS has only been compared with placebo NS, both with a newly initiated oral AD.^{20-22, 28, 30} In these studies, esketamine NS+SSRI/SNRI outperformed placebo+SSRI/SNRI during the acute phase, and demonstrated superiority for relapse prevention versus switching to placebo NS.

[00113] The goal of acute AD treatment of depression is remission and, ultimately, recovery.^{1, 31} Results from the STAR*D trial demonstrated that, while acute remission rates in patients with MDD were relatively high with first and second AD treatments (36.8% and 30.6%, respectively), the third and fourth treatments elicited notably lower rates of remission (13.7% and 13.0%, respectively).³ After achieving remission, maintenance treatment aims to prevent relapse; however, relapse risk increases with an increasing number of previous relapses and treatment failures.^{1-3, 32} ESCAPE-TRD was designed to be clinically relevant by aligning the primary and key secondary outcomes with the treatment goals for patients with TRD. Additionally, to meet these endpoints, patients had to still be receiving study treatment at the relevant timepoints, reflecting clinical practice where continuing treatment beyond the acute phase is recommended and discontinuation constitutes treatment failure.¹⁵ [00114] The remission rate at Week 8 was significantly higher in the esketamine NS arm than the quetiapine XR arm, and significantly more patients achieved remission at Week 8 and remained relapse-free through Week 32, without treatment discontinuation. These results favour esketamine NS treatment over an approved, common TRD treatment strategy, demonstrating superior short- and long-term efficacy in the TRD population.²⁹

[00115] Remission rates reported here are lower than those previously seen in phase III esketamine NS trials, reflecting the lower threshold for remission employed in ESCAPE-TRD (MADRS <10 versus MADRS <12).^{20, 22, 27} ' ²⁸ When additional analyses were undertaken using a MADRS <12 remission threshold, remission rates were more comparable with prior studies. The higher proportion of patients in ESCAPE-TRD who had experienced >3 prior treatment failures compared to other studies, suggesting a greater degree of treatment resistance, may further explain the differing remission rates.^{22, 27}

[00116] At all timepoints from Week 8, both the proportion of patients in remission and response was significantly greater with esketamine NS+SSRI/SNRI treatment than quetiapine XR+SSRI/SNRI treatment (threshold p<0.05). Rates of remission and response continued to increase in both treatment arms through Week 32. Concordantly, CfB in MADRS total score declined in both treatment arms through Week 32; however, CfB was greater at every timepoint with esketamine NS+SSRI/SNRI versus quetiapine XR+SSRI/SNRI. Consistently, when both were compared to placebo, a recent meta-analysis revealed a higher mean difference in CfB in MADRS score in patients treated with esketamine NS than add-on second-generation antipsychotics.³³ These data highlight the importance of long-term esketamine NS treatment in the TRD population to reach remission. However, more comparative data are needed to support clinical decision making and optimize patient outcomes.

[00117] TEAEs observed with esketamine NS were consistent with its established safety profile with no new safety signals identified.^{19, 20, 27, 30, 34} No treatment-related suicide attempt was reported during the study. Although TEAEs were more common with esketamine NS+SSRI/SNRI than quetiapine XR+SSRI/SNRI, TEAEs with esketamine NS were typically transient, mild, and occurred on the day of dosing.^{19, 35} More patients discontinued study treatment due to TEAEs or a lack of efficacy with quetiapine XR+SSRI/SNRI versus esketamine NS+SSRI/SNRI, whereas discontinuations due to patients refusing further study treatment were comparable. Thus, TEAEs arising from esketamine NS may be less burdensome for patients than those from quetiapine XR. LIMITATIONS [00118] An open-label design was used to better reflect real-world practice. The use of placebo would have increased the burden on patients through more frequent visits and procedures, with a concomitant risk of functional unblinding due to the distinctive profile of esketamine NS.

[00119] To minimise potential bias, MADRS score was assessed by an independent blinded rater, who was not otherwise involved in the study. Additionally, no inclusion/exclusion criteria used a MADRS score cut-off, nor was MADRS score used to influence decisions of treatment continuation. In the esketamine NS arm, the absence of blinding and the more frequent clinical interactions, may have influenced perceptions of treatment efficacy; however, patients in the quetiapine XR arm had more frequent clinical interactions than real-world treatment would typically provide.³⁶ The treatment protocol for esketamine NS reflected real-world clinical practice, and thus provides appropriate guidance for prescribing physicians and patients.

[00120] Quetiapine XR was chosen as an active comparator due to its approval for, and frequent use as, an add-on treatment in patients with previous treatment failures.^{13, 29} However, real-world evidence shows considerable treatment heterogeneity and a lack of clinical consensus, with patients receiving multiple ADs during a single MDE, limiting the generalisability of these findings.^{10, 29, 37} CONCLUSIONS

[00121] ESCAPE-TRD was the first long-term study comparing esketamine NS to a commonly- used antipsychotic augmentation treatment, quetiapine XR, in patients with TRD. Building upon the existing body of evidence, esketamine NS, in conjunction with a continuing SSRI/SNRI, is a beneficial treatment option for patients with TRD, improving both short- and long-term rates of remission and response, in a population for whom treatment goals are rarely met.

[00122] It is unusual to combine a study that measures remission with a study that measures relapse. Our study measured remission data at week 8 as a primary endpoint and then followed all subjects until week 32. The subset of remitters at week 8 who did not experience relapse until week 32 were considered as having a positive outcome on the secondary endpoint. In the past, patients who did not respond at week 4 were not afforded the possibility of continued treatment. The current study continued to treat all patients until week 32 and surprisingly found clinical benefit in continuing treatment of patients (FIGS 3, 6-11) who failed the primary endpoint of the study.

[00123] While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents. [00124] All documents cited herein are incorporated by reference.

ADDITIONAL SUB ANALYSIS RESULTS

[00125] Of the randomised patients, 415 (61.4%; esketamine NS: 204, Q-XR: 211) and 261 (38.6%; esketamine NS: 132, Q-XR: 129) had experienced 2 and >3 RTFs, respectively.

[00126] Did Patients Achieve Remission?

[00127] Of patients with 2 PTFs, 54/204 (26.5%) esketamine NS-treated patients and 46/211 (21.8%) Q-XR-treated patients achieved remission at Wk8 (p=0.267). Of patients with >3 PTFs, 37/132 (28.0%) and 14/129 (10.9%) patients achieved remission at Wk8 in esketamine NS and Q-XR arms, respectively (p<0.001).

[00128] The week 8 data show that of the patients treated with quetiapine, those with three or more prior treatment failures fared worse (10.9% remission) than those with only two prior treatment failures (21.8% remission). It is generally recognized among patients with treatment resistant depression that a higher number of prior treatment failures is associated with a lower chance of remission with subsequent treatment.

[00129] Surprisingly, the week 8 data show that the esketamine NS treated patients not only fared better than the quetiapine treated patients for both two and three or more prior treatment failures, but the higher number of prior treatment failures did not correlate with a lower chance of remission within the esketamine NS treated group. Esketamine NS treated patients with two prior treatment failures achieved 26.5% remission, and those with 3 or more prior treatment failures achieved 28.0% remission.

[00130] How Durable is the Response?

[00131] Of patients with 2 and >3 PTFs, 49/204 (24.0%) and 24/132 (18.2%) of esketamine NS-treated patients and 38/211 (18.0%) and 10/129 (7.8%) of Q-XR-treated patients achieved remission at week 8 without relapse to Wk32 (p=0.133 and p=0.013), respectively.

[00132] How Quickly was the MADRS Lowered?

[00133] Esketamine NS significantly improved time to remission FIG 6, where remission is defined as MDRS score less than or equal to 10, with a greater effect compared to quetiapine in the >3 PTF subgroup (2 PTFs: HR=1.547 [95% confidence interval (Cl) 1.210-1.976] FIG 7; p<0.001 vs >3 PTFs: HR=2.066 [95% Cl 1.469-2.907] FIG 8; p<0.001). The same conclusion may be drawn where response is defined as MADRS score less than or equal to 10 or MADRS improvement greater than or equal to 50%, FIGs 9, 10, and 11. REFERENCES

1. Mendlewicz J. Towards achieving remission in the treatment of depression. Dialogues Clin Neurosci 2008;10:371-5.

2. Preventing recurrent depression: long-term treatment for major depressive disorder. Prim Care Companion J Clin Psychiatry 2007;9:214-23.

3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006;163:1905- 17.

4. Fekadu A, Wooderson SC, Markopoulo K, et al. What happens to patients with treatmentresistant depression? A systematic review of medium to long term outcome studies. J Affect Disord 2009;116:4-11.

5. European Medicines Agency. Guideline on clinical investigation of medicinal products in the treatment of depression. EMA/CHMP/185423/2010 Rev 2, 2013.

6. Jaffe DH, Rive B, Denee TR. The humanistic and economic burden of treatment-resistant depression in Europe: a cross-sectional study. BMC Psychiatry 2019;19:247.

7. Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient preference and adherence 2012;6:369-388.

8. Heerlein K, De Giorgi S, Degraeve G, et al. Real-world evidence from a European cohort study of patients with treatment resistant depression: Healthcare resource utilization. Journal of Affective Disorders 2022;298:442-450.

9. Lundberg J, Cars T, Ldov S-A, et al. Association of Treatment-Resistant Depression With Patient Outcomes and Health Care Resource Utilization in a Population-Wide Study. JAMA Psychiatry 2022.

10. Heerlein K, Perugi G, Otte C, et al. Real-world evidence from a European cohort study of patients with treatment resistant depression: Treatment patterns and clinical outcomes. J Affect Disord 2021;290:334-344.

11. Heerlein K, Perugi G, Otte C, et al. Real-world evidence from a European cohort study of patients with treatment resistant depression: Treatment patterns and clinical outcomes. Journal of Affective Disorders 2021;290:334-344.

12. lonescu DF, Rosenbaum JF, Alpert JE. Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues Clin Neurosci 2015;17:111-26.

13. European Medicines Agency. Seroquel SmPC, labelling and package leaflet. https://www.ema.europa.eu/en/documents/referral/seroquel-seroquel-xr-associated-names-article-30- referral-annex-iii en.pdf (Accessed 20 December 2020).

14. European Medicines Agency. Questions and answers on Seroquel, Seroquel XR and associated names (quetiapine), 2014.

15. Nationale Versorgungs Leitlinien. Nationale Versorgungs Leitlinie: Unipolare Depression, 2022. 16. Heerlein K, Godinov Y, Kambarov Y, et al. HSD28 Most Common Treatments in Patients With Treatment Resistant Depression Based on European Cohort Study Real-World Evidence. Value in Health 2022;25:S278-S279.

17. Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol 2015;23:1-21.

18. Salahudeen MS, Wright CM, Peterson GM. Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review. Therapeutic Advances in Drug Safety 2020;ll:2042098620937899.

19. European Medicines Agency. Esketamine Nasal Spray Summary of Product Characteristics, 2021.

20. Popova V, Daly EJ, Trivedi M, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry 2019;176:428-438.

21. Daly EJ, Turkoz I, Salvadore G, et al. The effect of esketamine in patients with treatmentresistant depression with and without comorbid anxiety symptoms or disorder. Depress Anxiety 2021;38:1120-1130.

22. Daly EJ, Trivedi MH, Janik A, et al. Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry 2019;76:893-903.

23. European Medicines Agency. Seroquel XR Summary of Product Characteristics.

24. European Medicines Agency. Spravato EPAR Product Characteristics.

25. Association WM. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. JAMA 2013;310:2191-2194.

26. Hawley CJ, Gale TM, Sivakumaran T. Defining remission by cut off score on the MADRS: selecting the optimal value. J Affect Disord 2002;72:177-84.

27. Wajs E, Aluisio L, Holder R, et al. Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2). J Clin Psychiatry 2020;81.

28. Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol 2019;22:616-630.

29. Heerlein K, Godinov Y, Kambarov Y, et al. Most Common Treatments in Patients with Treatment Resistant Depression Based on European Cohort Study Real-World Evidence. ISPOR EU, 2022.

30. Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-TRANSFORM-3. Am J Geriatr Psychiatry 2020;28:121-141. 31. Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP Task Force on response and remission in major depressive disorder. Neuropsychopharmacology 2006;31:1841-53.

32. Gautam S, Jain A, Gautam M, et al. Clinical Practice Guidelines for the management of Depression. Indian J Psychiatry 2017;59:S34-s50.

33. Dold M, Bartova L, Kasper S. Treatment Response of Add-On Esketamine Nasal Spray in Resistant Major Depression in Relation to Add-On Second-Generation Antipsychotic Treatment. Int J Neuropsychopharmacol 2020;23:440-445.

34. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry 2018;75:139-148.

35. Nikayin S, Murphy E, Krystal JH, et al. Long-term safety of ketamine and esketamine in treatment of depression. Expert Opin Drug Saf 2022;21:777-787.

36. Heerlein K, De Giorgi S, Degraeve G, et al. Real-World Evidence from a European Cohort Study of Patients with Treatment Resistant Depression: Healthcare Resource Utilization. Journal of Affective Disorders 2022;298:442-450.

37. Heerlein K, Young, AH, Otte, C, Frodl, T, Degraeve, G, Hagedoorn, W, Oliveira-Maia, AJ, Perez Sola, V, Rathod, S, Rosso, G. Real-world evidence from a European cohort study of patients with treatment resistant depression: Baseline patient characteristics. J Affect Disord 2021;283:115-122.

38. Schweitzer I, Burrows G, Tuckwell V, et al. Sustained response to open-label venlafaxine in drugresistant major depression. J Clin Psychopharmacol 2001;21:185-9.

39. Nierenberg AA, Feighner JP, Rudolph R, et al. Venlafaxine for treatment-resistant unipolar depression. J Clin Psychopharmacol 1994;14:419-23.

40. Adekkanattu P, Olfson M, Susser LC, et al. Comorbidity and healthcare utilization in patients with treatment resistant depression: A large-scale retrospective cohort analysis using electronic health records. Journal of Affective Disorders 2023;324:102-113.

41. Grigoriadis S, Robinson GE. Gender issues in depression. Ann Clin Psychiatry 2007;19:247-55.

42. Arias de la Torre J, Vilagut G, Ronaldson A, et al. Prevalence and age patterns of depression in the United Kingdom. A population-based study. J Affect Disord 2021;279:164-172.

43. Liu X, Mukai Y, Furtek Cl, et al. Epidemiology of Treatment-Resistant Depression in the United States. J Clin Psychiatry 2021;83.

44. Shao Z, Richie WD, Bailey RK. Racial and Ethnic Disparity in Major Depressive Disorder. J Racial Ethn Health Disparities 2016;3:692-705.

45. Bailey RK, Mokonogho J, Kumar A. Racial and ethnic differences in depression: current perspectives. Neuropsychiatric disease and treatment. Volume 15, 2019:603-609.

46. Lesser IM, Castro DB, Gaynes BN, et al. Ethnicity/race and outcome in the treatment of depression: results from STAR*D. Med Care 2007;45:1043-51. 47. Mekonen T, Chan GCK, Connor JP, et al. Estimating the global treatment rates for depression: A systematic review and meta-analysis. Journal of Affective Disorders 2021;295:1234-1242.

48. Organization WH. Depression and other common mental disorders: global health estimates: World Health Organization, 2017.

Claims

What is claimed is:

1. A method of treating major depressive disorder in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 previous other antidepressant treatments, given for an adequate duration at an adequate dose, within the same major depressive episode, the method comprising: discontinuing adjunctive treatment with quetiapine; and treating the patient with intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase in conjunction with a therapeutically effective amount of the antidepressant, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase.

2. The method of claim 1 wherein after the induction phase, treating the patient intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase in conjunction with a therapeutically effective amount of the antidepressant, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks.

3. The method of claim 2, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks.

4. The method of claim 3, wherein treatments are administered twice weekly during weeks 1-4, weekly during weeks 5-8 and weekly or every 2 weeks during weeks 9-32.

5. The method of claim 3 or 4, wherein the induction dosage is about 56 mg or about 84 mg, and the maintenance dosage is about 56 mg or about 84 mg.

6. The method of any one of claims 2 to 5, wherein the (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone is administered as its corresponding hydrochloride salt during the induction phase and maintenance phase.

7. The method of any preceding claim, wherein the patient in need of treatment has had an inadequate response to >3 other antidepressant treatments, given for an adequate duration at an adequate dose.

8. A method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same depressive episode, optionally within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and treating the patient with intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase in conjunction with a new antidepressant, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase.

9. The method of claim 8 wherein after the induction phase, treating the patient intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks; in conjunction with a therapeutically effective amount of the new antidepressant wherein new antidepressant comprises a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor.

10. The method of claim 9, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks.

11. The method of claim 10, wherein treatments are administered twice weekly during weeks 1- 4, weekly during weeks 5-8 and weekly or every 2 weeks during weeks 9-32.

12. The method of claim 10 or 11, wherein the induction dosage is about 56 mg or about 84 mg, and the maintenance dosage is about 56 mg or about 84 mg.

13. The method of any one of claims 9 to 12, wherein the (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone is administered as its corresponding hydrochloride salt during the induction phase and maintenance phase.

14. The method of any one of claims 8 to 13, wherein the patient in need of treatment has had an inadequate response to >3 other antidepressant treatments, given for an adequate duration at an adequate dose.

15. A method of treating depression in a human patient in need thereof, the patient having had an inadequate response to quetiapine as an adjunctive therapy with a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same depressive episode, optionally within the same major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: discontinuing treatment with quetiapine; and treating the patient with intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase in conjunction with a therapeutically effective amount of the selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks in conjunction with a therapeutically effective amount of the selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor.

16. The method of claim 15, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks.

17. The method of claim 16, wherein treatments are administered twice weekly during weeks 1- 4, weekly during weeks 5-8 and weekly or every 2 weeks during weeks 9-32.

18. The method of any one of claims 15 to 17, wherein the induction dosage is about 56 mg or about 84 mg, and the maintenance dosage is about 56 mg or about 84 mg.

19. The method of any one of claims 15 to 18, wherein the (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone is administered as its corresponding hydrochloride salt during the induction phase and maintenance phase.

20. The method of any one of claims 15 to 19, wherein the patient in need of treatment has had an inadequate response to >3 other antidepressant treatments, given for an adequate duration at an adequate dose.

21. A method of treating depression in a human patient in need thereof, the patient having had an inadequate response to the combination of an antidepressant and adjunctive treatment with quetiapine and said patient also having had an inadequate response to >2 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same depressive episode, optionally within the same major depressive episode, the method comprising: discontinuing the antidepressant and adjunctive treatment with quetiapine; and treating the patient with intranasally administering (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase.

22. The method of claim 21 wherein after the induction phase, treating the patient intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks.

23. The method of claim 21 or 22, wherein the (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone is administered in conjunction with a therapeutically effective amount of the new antidepressant.

24. The method of claim 22 or 23, wherein the maintenance dosage of (S)-2-(2-chlorophenyl)-2- (methylamino)cyclohexanone is administered in conjunction with a therapeutically effective amount of the new antidepressant.

25. The method of any one of claims 21 to 24, wherein the patient in need of treatment has had an inadequate response to >3 other antidepressant treatments, given for an adequate duration at an adequate dose.

26. A method of treating depression in a human patient in need thereof, the patient having had an inadequate response to >3 other antidepressant treatments, given for an adequate duration at an adequate dose, within the same depressive episode, optionally within the same major depressive episode, the method having an induction phase and a subsequent maintenance phase, comprising: administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in an induction dosage to the patient in an amount in the range of from about 28 mg to about 84 mg in the induction phase, optionally wherein the (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone is administered intranasally, wherein the induction phase comprises a treatment period of about four weeks, and the induction dosage is administered at a frequency of twice per week during the induction phase; and intranasally administering (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone in a maintenance dosage in an amount in the range of from about 56 mg to about 84 mg in the maintenance phase, wherein the maintenance dosage is administered at a frequency of once per week or once every two weeks, wherein the induction phase plus maintenance phase comprises a treatment period of at least 32 weeks.

27. The method of claim 26, wherein treatments are administered twice weekly during weeks 1- 4, weekly during weeks 5-8 and weekly or every 2 weeks during weeks 9-32.

28. The method of claim 26 or 27, wherein the induction dosage is about 56 mg or about 84 mg, and the maintenance dosage is about 56 mg or about 84 mg.

29. The method of any one of claims 8 to 28, wherein the depression is major depressive disorder.

30. The method of any one of claims 1 to 14 and 21 to 29, wherein the antidepressant in the combination of an antidepressant and adjunctive treatment with quetiapine comprises a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor.

31. The method of claims 8 and 23 to 25 wherein the new antidepressant comprises a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor.

32. The method of any one of claims 1 to 31, wherein at least one of the other antidepressant treatments was a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor.

33. The method of any preceding claim wherein the patient in need of treatment has had an inadequate response to <5 other antidepressant treatments, given for an adequate duration at an adequate dose.

34. The method of any preceding claim wherein the inadequate response is a >0% - <25% improvement of symptoms.

35. The method of any preceding claim wherein the adequate duration is >6 weeks.

36. The method of any preceding claim wherein the adequate dose is the maximum tolerated dose of said treatment.

37. The method of any preceding claim, wherein the other antidepressant treatments have been given for >6 weeks at the maximum tolerated dose of said treatment.