Compositions and methods for the treatment of depression

Abstract

The disclosure provides a method of treating depression comprising intranasally administering an effective amount of esketamine to a patient in need thereof, wherein the patient is identified as having a positive biomarker signature if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 298,067, filed January 10, 2022, which is incorporated by reference in its entirety.

[0002] FIELD OF THEINVENTION The present disclosure relates to methods of treating depression using esketamine, where a patient is identified as having a positive biomarker signature. [Background technology]

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

[0004] The impact of TRD on patients' lives is difficult to adequately describe. Many patients have depressive episodes that last for years. Severely depressed patients lose the will to continue with their lives and suicide attempts increase seven-fold. Life expectancy is reduced by 10 years. In extreme cases, they are unable to manage basic personal needs such as bathing or feeding or caring for themselves, leaving these care entirely to their parents, spouses, etc. This affects not only the patients themselves, but also their families and those who depend on them. They also lose the ability to find pleasure in doing things they previously enjoyed, which robs people of the essence of life and what drives it. In effect, their life is taken away from them by TRD.

[0005] There remains a need for improved treatments for patients with depression, particularly those with TRD. Summary of the Invention

[0006] In some aspects, the disclosure relates to a method for treating depression, comprising intranasally administering an effective amount of esketamine to a patient in need thereof, wherein the patient is identified as having a positive biomarker signature if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level. In certain embodiments, the method has an induction phase and optionally a maintenance phase, wherein the induction phase comprises induction phase treatment sessions at a given frequency, and the maintenance phase comprises maintenance phase treatment sessions administered to the patient less frequently.

[0007] In further embodiments, the methods include administering to the patient intranasally about 28 mg to about 84 mg of esketamine per induction phase treatment session, where the induction phase treatment sessions occur twice weekly during the induction phase, and optionally administering to the patient intranasally about 56 mg to about 84 mg of esketamine per maintenance phase treatment session, where the maintenance phase treatment sessions occur weekly or biweekly. In certain embodiments, the induction phase has a duration of about 4 weeks.

[0008] In certain embodiments, about 56 or about 84 mg of esketamine is administered per induction phase treatment session, hi further embodiments, about 56 or about 84 mg of esketamine is administered per maintenance phase treatment session.

[0009] In some embodiments, esketamine is delivered from the intranasal device in two or more sprays during the induction and / or maintenance phases. In certain aspects, the method further comprises administering to the patient a therapeutically effective amount of an oral antidepressant during the induction and / or maintenance phases. In certain aspects, esketamine is administered as its corresponding hydrochloride salt during the induction and / or maintenance phases.

[0010] In yet a further aspect, the depression comprises major depressive disorder. In a particular aspect, the major depressive disorder is major depressive disorder accompanied by suicidal thoughts or behavior. In a further aspect, the major depressive disorder is treatment-resistant depression.

[0011] In certain aspects, a patient is identified as having a positive biomarker signature if a biological sample obtained from the patient is identified as having at least one of: (a) a CRP level higher than a reference CRP level; and (b) (i) a TNF-α level higher than a reference TNF-α level; and (ii) a sIL6R level higher than a reference sIL6R level.

[0012] In a particular embodiment, the reference CRP level is about 3 mg / L. In a further embodiment, the reference TNF-α level is about 4 pg / mL. In yet a further embodiment, the reference sIL6R level is about 25 ng / mL. [Brief description of the drawings]

[0013] [Figure 1] Clinical trial design of Example 1. Upon entry into the study, enrolled non-responder subjects continued to receive the same oral antidepressant that was initiated in the ESKETINTRD3005 study. New oral ADs were for direct entry subjects only. [Diagram 2] 1 shows the mean MADRS total score over time in the IND and OP / MA phases based on observed case data from Example 1. [Diagram 3] Responses of patients with a response of > 50% reduction from baseline and a remission of MADRS < 12 are shown. [Figure 4] 1 shows the mean PHQ-9 total score over time in the IND and OP / MA phases based on the observed case data of Example 1. [Diagram 5]The effect of 3MM across various clinical trials is shown. For ESKETINTRD2003, only subjects who received consistent treatment across the two double-blind phases were considered. The ClinicalTrials.gov identifiers for each of the illustrated trials are as follows: 54135419SUI3001 (NCT03039192); 54135419SUI3002 (NCT03097133), ESKETINSUI2001 (NCT02133001), 54135419TRD2005 (NCT02918318), ESKETINTRD2003 (NCT01998958), ESKETINTRD3001 (NCT02417064), and ESKETINTRD3002 (NCT02418585). [Figure 6] The different clinical trials are shown for 3MM biomarker signature positive subjects (TE signature positive), biomarker signature negative subjects (TE signature negative), and the difference between subtypes (signature benefit). Overall, the treatment effect in 3MM+ patients in the final DB was 7.8 MADRS points, significantly greater than the treatment effect of 2.0 MADRS points in 3MM- patients (p<0.01). The effect was evident in three of the four TRD studies. In ESKETINTRD2003, only subjects who received consistent treatment over the two double-blind phases were considered. [Figure 7A] Graph showing change in MADRS for placebo (PBO) vs. treatment (TRT) biomarker signature positive patients in the ESKETINTRD2003 study. [Figure 7B] Graph showing change in MADRS for placebo (PBO) vs. treatment (TRT) biomarker signature negative patients in the ESKETINTRD2003 study. [Figure 8A] Shows the effect of 2MM across various clinical trials. [Figure 8B]Shows the effect of 3MM across various clinical trials. High,Diff(PBO-TRT) refers to TE signature positive subjects, Other,Diff(PBO-TRT) refers to TE signature negative subjects, and High,Diff-Other,Diff(PBO-TRT) refers to signature benefit. ClinicalTrials.gov identifiers for each of the illustrated trials are as follows: CNTO136MDD2001 (NCT02473289); 67953964MDD2001 (NCT03559192), 42847922MDD2001 (NCT03227224), 42847922MDD2002 (NCT03321526), ​​54135419SUI3001 (NCT03039192), 54135419SUI300 2 (NCT03097133), ESKETINSUI2001 (NCT02133001), 54135419TRD2005 (NCT02918318), ESKETINTRD2003 (NCT01998958), ESKETINTRD3001 (NCT02417064), and ESKETINTRD3002 (NCT02418585). [Figure 9] CRP effect across various clinical trials is shown. High,Diff(PBO-TRT) refers to TE signature positive subjects, Other,Diff(PBO-TRT) refers to TE signature negative subjects, and High,Diff-Other,Diff(PBO-TRT) refers to signature advantage. ClinicalTrials.gov identifiers for each of the illustrated trials are as follows: CNTO136MDD2001 (NCT02473289); 67953964MDD2001 (NCT03559192), 42847922MDD2001 (NCT03227224), 42847922MDD2002 (NCT03321526), ​​54135419SUI3001 (NCT03039192), 54135419SUI300 2 (NCT03097133), ESKETINSUI2001 (NCT02133001), 54135419TRD2005 (NCT02918318), ESKETINTRD2003 (NCT01998958), ESKETINTRD3001 (NCT02417064), and ESKETINTRD3002 (NCT02418585). Detailed Description of the Invention

[0014] The present invention relates to a method comprising administering a therapeutically effective amount of esketamine to a patient in need of treatment for depression (e.g., major depressive disorder). In some embodiments, the method is for treating treatment-refractory or treatment-resistant depression. In other embodiments, the agent is for treating suicidal ideation. These methods advantageously allow for tailoring an effective regimen to patients with depression. Such patients include those who have already been diagnosed with MDD, TRD, have suicidal tendencies, or are otherwise untreated for depression. For example, the method is intended for patients with major depressive disorder accompanied by suicidal ideation or behavior.

[0015] In one aspect of the invention, a method of treating depression is provided comprising, consisting of, or consisting essentially of intranasally administering an effective amount of esketamine to a patient in need thereof, wherein the patient is identified as having a positive biomarker signature if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

[0016] In a further aspect of the present invention, there is provided a method of treating depression comprising, consisting of, or consisting essentially of intranasally administering an effective amount of esketamine to a patient in need thereof, wherein the patient has a positive biomarker signature, and the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

[0017] Further described herein is esketamine for use in the treatment of depression, comprising, consisting of, or consisting essentially of intranasally administering an effective amount of esketamine to a patient in need thereof, wherein the patient is identified as having a positive biomarker signature, and wherein the patient is identified as having a positive biomarker signature if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

[0018] Further described herein is esketamine for use in the treatment of depression, comprising, consisting of, or consisting essentially of intranasally administering an effective amount of esketamine to a patient in need thereof, wherein the patient is biomarker signature positive, and the patient is biomarker signature positive if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

[0019] In certain embodiments, the patient is identified as having a positive biomarker signature.

[0020] In certain aspects, a patient is identified as having a positive biomarker signature if a biological sample obtained from the patient is identified as having at least one of: (a) a CRP level higher than a reference CRP level; and (b) (i) a TNF-α level higher than a reference TNF-α level; and (ii) a sIL6R level higher than a reference sIL6R level.

[0021] In certain embodiments, a method is described herein for identifying a patient as a candidate for treatment with esketamine if the subject has a positive biomarker signature, wherein the patient is identified as having a positive biomarker signature if a biological sample obtained from the patient is identified as having at least one of: (a) a level of CRP higher than a reference CRP level; and (b) (i) a level of TNF-α higher than a reference TNF-α level; and (ii) a level of sIL6R higher than a reference sIL6R level. In certain embodiments, the method further comprises administering an effective amount of esketamine to the patient.

[0022] In certain embodiments, the biomarker signature is an inflammatory biomarker signature ("3MM") with a positive status defined by CRP>3mg / L and (TNFα>4pg / mL or sIL6R>25ng / mL). In the disclosed methods utilizing the 3MM biomarker signature, a patient is identified as having a positive biomarker signature if a biological sample obtained from the patient is identified as having at least one of: (a) a level of CRP higher than a reference CRP level; and (b) (i) a level of TNF-α higher than a reference TNF-α level; and (ii) a level of sIL6R higher than a reference sIL6R level. In certain embodiments, a patient identified as having a positive biomarker signature exhibits an improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, a patient identified as having a positive biomarker signature exhibits an improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, a patient identified as having a positive biomarker signature exhibits an improvement in MADRS points compared to a comparison population of patients administered esketamine but not having a positive biomarker signature. In certain embodiments, patients identified as having a positive biomarker signature exhibit an improvement of about 7.8 MADRS points compared to a comparison population of patients administered esketamine but who do not have a positive biomarker signature.

[0023] In certain embodiments, the biomarker signature is CRP>3 mg / L and sIL6R>25 ng / mL. In the disclosed methods utilizing the 2MM biomarker signature, a patient is identified as having a positive biomarker signature if a biological sample obtained from the patient is identified as having a level of CRP higher than a reference CRP level and a level of sIL6R higher than a reference sIL6R level. In certain embodiments, patients identified as having a positive biomarker signature exhibit an improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, patients identified as having a positive biomarker signature exhibit an improvement in MADRS points compared to a comparison population of patients administered esketamine but not having a positive biomarker signature.

[0024] In certain embodiments, the biomarker signature is an inflammatory biomarker signature ("CRP") with a positive status defined by CRP>3mg / L. In the disclosed methods utilizing a CRP biomarker signature, a patient is identified as having a positive biomarker signature if a biological sample obtained from the patient is identified as having a level of CRP higher than a reference CRP level. In certain embodiments, patients identified as having a positive biomarker signature exhibit an improvement in MADRS points compared to a comparison population of patients treated with a placebo. In certain embodiments, patients identified as having a positive biomarker signature exhibit an improvement in MADRS points compared to a comparison population of patients administered esketamine but not having a positive biomarker signature.

[0025] In any of the disclosed embodiments, the reference CRP level is about 3 mg / L.

[0026] In any of the disclosed embodiments, the reference TNF-α level is about 4 pg / mL.

[0027] In any of the disclosed embodiments, the reference sIL6R level is about 25 ng / mL.

[0028] In any of the disclosed embodiments, reference CRP, TNF-α, sIL6R and / or dynorphin reference levels may be calculated according to the methods disclosed in the Examples.

[0029] In any of the disclosed embodiments, biomarker correlates with any of the biomarkers may be used, for example, biomarker correlates with CRP, TNF-α, sIL6R, or dynorphin. As used herein, a "biomarker correlate" with a biomarker is another marker whose level or activity correlates with the level or activity of the biomarker. For example, if a biomarker is X and the level of Y correlates with the level of X, then Y is a biomarker correlate of X.

[0030] As used herein, "CRP" refers to C-reactive protein. In certain embodiments, CRP has the UniProtKB / Swiss-Prot number P02741.

[0031] As used herein, "TNF-α" refers to tumor necrosis factor alpha. In certain embodiments, TNF-α has the UniProtKB / Swiss-Prot number P01375.

[0032] As used herein, "IL6R" refers to the interleukin 6 receptor. In certain embodiments, IL6R has the UniProtKB / Swiss-Prot number P08887. As used herein, "sIL6R" refers to the soluble form of IL6R.

[0033] It will be understood that for each of the methods of treatment described herein, the method of treatment may also be configured as a method of manufacturing a medicament for the treatment of the described indication, or as esketamine for use in treating the described indication.

[0034] Methods of maintaining a stable remission or stable response achieved by a patient with depression after administration of a therapeutically effective amount of esketamine during an initial dosing phase are also described, comprising continuously administering a therapeutically effective amount of esketamine for at least five months during a subsequent dosing phase.

[0035] In embodiments of any of the foregoing treatment methods, the method has an induction phase, optionally followed by a maintenance phase, where the induction phase includes induction phase treatment sessions at a given frequency, and the maintenance phase includes maintenance phase treatment sessions administered to the patient less frequently.

[0036] In some embodiments, methods for long-term treatment of depression in a patient may also be provided. These methods include administering a therapeutically effective amount of esketamine to a patient in need of treatment for at least 6 months. Desirably, the patient's cognitive performance remains stable based on baseline measurements after 6 months of treatment. In some embodiments, the treatment may be for a duration of at least about 1 year, at least about 18 months, or at least about 2 years. For example, long-term treatment may include a duration range of about 6 months to about 2 years. Treatment may also be continued for longer periods of time, including, but not limited to, 4, 5, 6, 7, 8, 9, 10 years or more, as determined by the attending physician. In some embodiments, esketamine is initially administered twice weekly for up to 4 weeks during an induction phase, and then administered less frequently than twice weekly.

[0037] In further embodiments, the methods include administering to the patient intranasally about 28 mg to about 84 mg of esketamine per induction phase treatment session, where the induction phase treatment sessions occur twice weekly during the induction phase, and optionally administering to the patient intranasally about 56 mg to about 84 mg of esketamine per maintenance phase treatment session, where the maintenance phase treatment sessions occur weekly or biweekly. In certain embodiments, the induction phase has a duration of about 4 weeks.

[0038] In certain embodiments, about 56 or about 84 mg of esketamine is administered per induction phase treatment session, hi further embodiments, about 56 or about 84 mg of esketamine is administered per maintenance phase treatment session.

[0039] In certain embodiments, esketamine may be administered in combination with one or more antidepressants, preferably in combination with 1-3 antidepressants, and more preferably in combination with 1-2 antidepressants, as described herein.

[0040] In certain embodiments, esketamine may be administered in combination with one or more antidepressants, further in combination with one or more atypical antipsychotics, as described herein.

[0041] In further embodiments, the disclosure relates to combination therapies comprising esketamine and one or more antidepressants, where esketamine is administered as an acute treatment. In another embodiment, the disclosure relates to combination therapies comprising esketamine and one or more antidepressants, where esketamine is administered as an acute treatment and one or more antidepressants are administered as a chronic treatment.

[0042] In other embodiments, such as during the induction phase, esketamine may be used as a monotherapy and may not be used in combination with any other active compounds.

[0043] Some of the quantitative expressions given herein are not modified by the term "about". Regardless of whether the term "about" is explicitly used or not, it is understood that all quantities given herein are meant to refer to the actual given value, and also to the approximation of such given value that is reasonably estimated based on ordinary skill in the art, including the approximation of such given value by experimental and / or measurement conditions.

[0044] As used herein, unless otherwise specified, the term “esketamine” refers to the (S)-enantiomer of ketamine, i.e., the compound of formula (I):

[0045] [ka] "Esketamine" also refers to a salt, e.g., a chloride salt, such as the hydrochloride salt, of the (S)-enantiomer of ketamine, i.e., the compound of formula (II):

[0046] [ka] Also includes chloride salts, such as the hydrochloride of the compound, which is also known as (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride.

[0047] In some embodiments, esketamine is the (R)-enantiomer of ketamine, i.e., formula (III):

[0048] [ka] The compound is substantially free of

[0049] In other embodiments, the esketamine contains less than about 10% by weight of the (R)-enantiomer of ketamine based on the weight of the esketamine sample. In further embodiments, the esketamine contains less than about 10%, less than about 9%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.1%, less than about 0.005%, or less than about 0.001% by weight of the (R)-enantiomer of esketamine based on the weight of the esketamine sample. In yet other embodiments, the esketamine contains from about 0.001 to about 10% by weight of the (R)-enantiomer of ketamine based on the weight of the esketamine sample. In still further embodiments, the esketamine contains about 0.001 to about 10%, about 0.001 to about 5%, about 0.001 to about 1, about 0.001 to about 0.5, about 0.001 to about 0.1, about 0.1 to about 5, about 0.1 to about 1, about 0.1 to about 5, or about 0.5 to about 5% by weight of the (R)-enantiomer of esketamine based on the weight of the esketamine sample.

[0050] The term "esketamine" may also include other pharma- ceutically acceptable salts thereof, which may be readily selected by one of ordinary skill in the art. A "pharma-ceutically acceptable salt" is intended to mean a salt of esketamine that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally, GS Paulekuhn, "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database", J.Med.Chem., 2007, 50:6665-72; SM Berge, "Pharmaceutical Salts", J Pharm Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharma- ceutically acceptable salts are salts that are pharmacologically effective and suitable for administration to a patient without undue toxicity, irritation, or allergic response.

[0051] Examples of other pharma- ceutically acceptable salts include sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, bromide (e.g., hydrobromide), iodide (e.g., hydroiodide), acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate, 1-methylbut ... Examples of suitable salts of esketamine include 1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate. In particular, the salts of esketamine are chloride salts, such as the hydrochloride salt.

[0052] In certain embodiments, esketamine is administered intranasally. In other embodiments, esketamine is administered intranasally as its corresponding hydrochloride salt. In further embodiments, esketamine is administered intranasally as its corresponding hydrochloride salt in a 16.14% weight / volume solution (corresponding to 14% weight / volume of esketamine base).

[0053] In some embodiments, esketamine is delivered from the intranasal device in two or more sprays during the induction and / or maintenance phases. In certain aspects, the method further comprises administering to the patient a therapeutically effective amount of an oral antidepressant during the induction and / or maintenance phases. In certain aspects, esketamine is administered as its corresponding hydrochloride salt during the induction and / or maintenance phases.

[0054] In certain embodiments, esketamine is administered intranasally in a solution containing 161.4 mg / mL esketamine hydrochloride (equivalent to 140 mg / mL esketamine base), 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL citric acid at a pH of 4.5 in water. In other embodiments, esketamine is administered intranasally, with intranasal delivery of 100 μL of a solution containing 161.4 mg / mL esketamine hydrochloride (equivalent to 140 mg / mL esketamine base), 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL citric acid at a pH of 4.5 in water. In certain embodiments, esketamine is delivered intranasally using a nasal spray pump that delivers 100 μL of a solution containing 161.4 mg / mL esketamine hydrochloride (equivalent to 140 mg / mL esketamine base), 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA), and 1.5 mg / mL citric acid at a pH of 4.5 in water.

[0055] Generally, a single pump from the nasal spray device may be configured to deliver about 50 μL to about 200 μL of esketamine solution to a subject's nostril, including about 60 μL, about 70 μL, about 80 μL, about 90 μL, about 100 μL, about 110 μL, about 120 μL, about 130 μL, about 140 μL, about 150 μL, about 160 μL, about 170 μL, about 180 μL, and about 200 μL. Thus, two pumps deliver about 100 μL to about 400 μL to a subject.

[0056] In yet a further aspect, the depression comprises major depressive disorder. In a particular aspect, the major depressive disorder is major depressive disorder accompanied by suicidal thoughts or behavior. In a further aspect, the major depressive disorder is treatment-resistant depression.

[0057] In certain embodiments, the patient in need of treatment with a therapeutically effective amount of esketamine is a patient suffering from an episode of depression (e.g., major depressive disorder). In other embodiments, the patient in need of treatment is suffering from an episode of depression (e.g., major depressive disorder), and the episode of depression (e.g., major depressive disorder) has not responded to treatment with at least two oral antidepressants (i.e., the patient has not responded to treatment with at least two oral antidepressants). In other embodiments, the elderly patient in need of treatment is suffering from an episode of depression (e.g., major depressive disorder), and the episode of depression (e.g., major depressive disorder) has not responded to treatment with two oral antidepressants (i.e., the elderly patient has not responded to treatment with two oral antidepressants).

[0058] In certain embodiments, the patient in need of treatment suffers from depression (e.g., major depressive disorder), for example, a patient having a score of 18 or greater as measured by the MADRS or a score of 4 or greater on the CGI scale.

[0059] As used herein, the term "depression" includes major depressive disorder, persistent depressive disorder, seasonal affective disorder, postpartum depression, premenstrual dysphoric disorder, situational depression, anhedonia, melancholia, midlife depression, late-life depression, depression due to an identifiable stressor, treatment-resistant depression, or combinations thereof. In certain embodiments, the depression is major depressive disorder. In other embodiments, the major depressive disorder is accompanied by depressive features or anxiety distress. In further embodiments, the depression is treatment-resistant depression.

[0060] As used herein, the term "non-responder" refers to a patient who does not fully recover (eg, 25% or less change from baseline in total MADRS score) with an antidepressant.

[0061] As used herein, the term "episode of major depressive disorder" refers to a period in which a patient experiences a major depressive disorder episode that is more severe than the symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. th Major depressive disorder refers to a continuous period (e.g., about 2 weeks or more) during which a person has sufficient symptoms of major depressive disorder to meet the criteria for major depression as defined in the DSM-5 (DSM-5 Edition).

[0062] As used herein, "suicide" is "the act of taking one's own life." See http: / / en.wikipedia.org / wiki / Suicide-cite_note-7. Suicide includes suicide attempts or non-fatal suicidal behavior, which is self-injury involving a desire to end one's life and does not result in death. A suicide attempt is a self-initiated sequence of actions by an individual who, at the time of initiation, expects that the series of actions will lead to their own death.

[0063] As used herein, "suicidal ideation" refers to thoughts about or abnormal obsession with suicide, or thoughts of wanting to end one's life or not wanting to live any longer, but not necessarily making any active attempts to do so. Suicidal ideation ranges from transient to chronic and progression to detailed planning, role-playing, and failed attempts, which may be deliberately constructed to fail or be discovered, or may be fully intended to result in death. In some embodiments, a patient is classified as "suicidal" when the patient has an average baseline MADRS total score of about 38 or greater. In other embodiments, a patient is classified as suicidal when the patient has an average baseline BBSS score of 22 or greater. In further embodiments, a patient is classified as suicidal when the patient has a score of 6 or greater on the SIBAT Clinical Global Assessment of Suicide Risk. In still other embodiments, a patient has a combination of one or more of these scores.

[0064] As used herein, the terms "concomitant therapy," "combination therapy," "adjunctive therapy," "adjunctive therapy," "combination treatment," and "concomitant administration" are intended to mean treatment of a patient in need thereof by administering esketamine in combination with one or more antidepressants, wherein the esketamine and antidepressants are administered by any suitable means. In some embodiments, esketamine is administered in a regimen with one to five antidepressants. In other embodiments, esketamine is administered in a regimen with one, two, three, four, or five antidepressants. In other embodiments, esketamine is administered in a regimen with one or two antidepressants. In further embodiments, esketamine is administered in a regimen with an antidepressant currently administered to the patient. In other embodiments, esketamine is administered in a regimen with a different antidepressant. In still further embodiments, esketamine is administered in a regimen with an antidepressant not previously administered to the patient. In still other embodiments, esketamine is administered in a regimen with an antidepressant previously administered to the patient. When esketamine and antidepressant are administered in separate dosage forms, the number of doses administered per day for each compound may be the same or different, and more typically, different.The antidepressant may be administered as prescribed by the attending physician and / or by its label, and esketamine is administered as described herein.Typically, the patient is under concurrent treatment with both an antidepressant and esketamine, both of which are administered according to their prescribed dosing regimen.

[0065] The esketamine and the antidepressant may be administered via the same or different routes of administration. Examples of suitable methods of administration include, but are not limited to, oral, intravenous (iv), intranasal (in), intramuscular (im), subcutaneous (sc), transdermal, buccal, or rectal. In some embodiments, the esketamine is administered intranasally.

[0066] As used herein, unless otherwise specified, the term "antidepressant" refers to any pharmaceutical agent that can be used to treat depression. Suitable examples include, but are not limited to, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic and specific serotonergic agents, or atypical antipsychotics. Other examples include monoamine oxidase inhibitors such as irreversible MAOIs (phenelzine, tranylcypromine), reversible MAOIs (moclobemide), and the like; tricyclic antidepressants such as imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine; tetracyclic antidepressants such as maprotiline; acyclics such as nomifensine; triazolopyridines such as trazodone; serotonin reuptake inhibitors such as fluoxetine, sertraline, paroxetine, citalopram, escitrapram, fluvoxamine, and the like, serotonin receptor antagonists such as nefazadone, tianeptine; venlafaxine, milnacipran, desalination, and the like. These include, but are not limited to, serotonin noradrenergic reuptake inhibitors such as venlafaxine, duloxetine, and levomilnacipran; noradrenergic and specific serotonergic agents such as mirtazapine; noradrenaline reuptake inhibitors such as reboxetine and edivoxetine; anticholinergic drugs, e.g., scopolamine; lithium; triple reuptake inhibitors; atypical antipsychotics such as bupropion; natural products such as kava kava and hypericum perforatum; dietary supplements such as s-adenosylmethionine; and neuropeptides such as thyrotropin releasing hormone; compounds targeting neuropeptide receptors such as neurokinin receptor antagonists; and hormones such as triiodothyronine.In some embodiments, the antidepressant is imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, maprotiline, amoxapine, trazodone, bupropion, clomipramine, fluoxetine, duloxetine, escitalopram, citalopram, sertraline, paroxetine, fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mirtazapine, phenelzine, tranylcypromine, moclobemide, kavakava, hypericum perforatum, s-adenosylmethionine, thyroid hormone releasing hormone, neurokinin receptor antagonist, or triiodothyronine. Preferably, the antidepressant is selected from the group consisting of fluoxetine, imipramine, bupropion, venlafaxine, and sertraline. Preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic-specific serotonergic drugs, atypical antipsychotics, and / or adjunctive therapy with antipsychotics (e.g., risperidone, olanzapine, quetiapine, aripiprazole, and ziprapradone). More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors. More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors. In other embodiments, the antidepressant is phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, mirtazapine, bupropion, thyroid stimulating hormone, and triiodothyronine.In further embodiments, the antidepressant is lithium, riluzole, phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paraxetine, citalopram, fluvoxamine, venlafaxine, milnacipran, levomilnacipran, mirtazapine, and bupropion. More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of phenelzine, tranylcypromine, moclobemide, imipramine, amitriptyline, desipramine, nortriptyline, doxepin, protriptyline, trimipramine, clomipramine, amoxapine, fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine. More preferably, esketamine is administered in combination with one or more compounds selected from the group consisting of fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine.

[0067] Therapeutically effective amount / dosage levels and dosing regimens of antidepressants (e.g., monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors, serotonin noradrenergic reuptake inhibitors, noradrenergic-specific serotonergic drugs, noradrenaline reuptake inhibitors, natural products, dietary supplements, neuropeptides, compounds targeting neuropeptide receptors, hormones, and other pharmaceutical agents disclosed herein) may be readily determined by one of skill in the art. For example, therapeutic dosages and regimens for pharmaceutical agents approved for sale are generally available and are listed, for example, on package labels, standard dosing guidelines, standard dosing references such as the Physician's Desk Reference (Medical Economics Company or online at http: / / / www.pdrel.com), or other sources.

[0068] As used herein, the term "antipsychotic" includes, but is not limited to: (a) typical or conventional antipsychotics, such as phenothiazines (e.g., chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, levomepromazin), thioxanthenes (e.g., thiothixene, flupentixol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), substituted benzamides (e.g., sulpride, amisulpride), and the like; (b) Atypical antipsychotics and mood stabilizers, such as paliperidone, clozapine, risperidone, olanzapine, quetiapine, zotepine, ziprasidone, iloperidone, perospirone, blonanserin, sertindole, ORG-5222 (Organon), and others, such as sonepiprazole, aripiprazole, nemonapride, SR-31742 (Sanofi), CX-516 (Cortex), SC-111 (Scotia), NE-100 (Taisho), divalproate (mood stabilizer), and the like.

[0069] In one embodiment, the "atypical antipsychotic" is selected from the group consisting of aripiprazole, quetiapine, olanzapine, risperidone, and paliperidone. In another embodiment, the atypical antipsychotic is selected from the group consisting of aripiprazole, quetiapine, olanzapine, brexpiprazole, lurasidone, and risperidone, preferably, the atypical antipsychotic is selected from the group consisting of aripiprazole, quetiapine, and olanzapine.

[0070] As used herein, the term "treatment-refractory or treatment-resistant depression" and the abbreviation "TRD" are intended to be defined as major depressive disorder in patients who have not responded adequately to at least two different antidepressants, preferably 2-5 antidepressants, during their current depressive episode. In another embodiment, TRD is defined as major depressive disorder in patients who have not responded adequately to at least two oral antidepressants of adequate dose and duration during their current depressive episode.

[0071] In other embodiments, the methods for the treatment of depression can be combined with adjunctive therapies, such as antipsychotic therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or combinations thereof.

[0072] Those skilled in the art will recognize that non-response to a given set of suitable antidepressants can be determined retrospectively or prospectively. In an embodiment, at least one of the non-response to the suitable set of antidepressants is determined prospectively. In another embodiment, at least two of the non-response to the suitable set of antidepressants is determined prospectively. In another embodiment, at least one of the non-response to the suitable set of antidepressants is determined retrospectively. In another embodiment, at least two of the non-response to the suitable set of antidepressants is determined retrospectively in the current depressive episode.

[0073] The "at least two oral antidepressants" or "at least two different oral antidepressants" are administered to the patient at appropriate doses, which may be determined by the attending physician. Similarly, the antidepressants are administered for a suitable duration, which may be determined by the attending physician.

[0074] As used herein, unless otherwise indicated, the terms "treat", "treatment" and the like are intended to include the management and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound described herein to prevent the occurrence of symptoms or complications, alleviate symptoms or complications, or eliminate the disease, condition, or disorder.

[0075] As used herein, the term "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue system, animal or human, as desired by a researcher, veterinarian, physician or other clinician, including alleviation of the symptoms of the disease or disorder being treated. In some embodiments, antidepressants are utilized in a therapeutically effective amount as determined by the attending physician. In other embodiments, esketamine is utilized in a therapeutically effective amount.

[0076] A therapeutically effective amount of esketamine and / or an antidepressant may be administered during the early and / or late phases, as described herein. In some embodiments, the therapeutically effective amount of esketamine is about 20 to about 100 mg. In other embodiments, the therapeutically effective amount of esketamine is about 30 to about 90 mg. In further embodiments, the therapeutically effective amount of esketamine is about 40 to about 80 mg. In yet other embodiments, a therapeutically effective amount of esketamine is about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101, about 102, about 103, about 104, about 105, about 106, about 107, about 108, about 109, about 10 5, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, or about 100 mg. In further embodiments, the therapeutically effective amount is about 28 mg, about 56 mg, or about 84 mg. In other embodiments, the therapeutically effective amount is about 56 mg or about 84 mg. In yet a further embodiment, the therapeutically effective amount of esketamine is about 28 mg. In other embodiments, the therapeutically effective amount of esketamine is about 56 mg. In yet a further embodiment, the therapeutically effective amount of esketamine is about 84 mg. Unless otherwise specified, the amount of esketamine corresponds to the free base of esketamine.

[0077] As used herein, unless otherwise specified, the terms "subject" and "patient" refer to an animal, preferably a mammal, and most preferably a human, who is being subjected to treatment, observation or experiment. Preferably, a subject or patient is experiencing and / or exhibiting at least one symptom of the disease or disorder to be treated and / or prevented.

[0078] In some embodiments, the subject or patient is an adult. As used herein, the term "adult" as used herein refers to a human who is between about 18 and about 65 years of age.

[0079] In other embodiments, the subject or patient is aged or elderly. As used herein, the terms "aged" and "elderly" are used interchangeably to refer to a human subject aged about 65 years or older. Elderly patients aged ≧65 to ≦75 years are likely to respond better to treatment than patients aged ≧75 years.

[0080] In a further embodiment, the subject or patient is a pediatric subject. As used herein, the term "pediatric" refers to a human subject younger than about 18 years of age.

[0081] 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 resulting directly or indirectly from combining the specified ingredients in the specified amounts.

[0082] As used herein, "stable remission" refers to a patient having a MADRS total score of 12 or less for at least three of the last four weeks after the patient achieves a substantially complete response to esketamine during the induction phase. In certain exemplified embodiments herein, patients in "stable remission" include patients with one deviation in MADRS total score of greater than 12 or one missed MADRS assessment at week 13 or 14 following the induction phase. In other embodiments, patients in "stable remission" include patients with a MADRS total score of 12 or less at weeks 15 and 16 following the induction phase.

[0083] As used herein, "stable response" refers to a patient's MADRS total score decreasing by 50% or more from baseline (Run-in Day 1; pre-randomization / pre-first nasal dose) in each of the final 2 weeks, whereafter the patient has demonstrated a substantially complete response to esketamine during the run-in phase but does not meet the criteria for stable remission.

[0084] As mentioned above, a method for treating depression in a patient is described. The method includes administering esketamine in one, two, or optionally three phases, i.e., initial and subsequent administration phases. In some embodiments, the phases include an initial induction phase, an extended induction phase, a maintenance phase, or any combination thereof. Thus, an effective amount of esketamine is administered in each phase. A physician can evaluate the patient's condition and determine the most beneficial initial / induction and maintenance dose for the patient from the dosage range and administration frequency specified herein. The effective amount of esketamine can be the same or different in each phase.

[0085] The methods described herein allow for optimizing the dosage of esketamine for administration to patients with or susceptible to depression during the "optimization phase." Optimization can be considered part of the maintenance phase following the induction phase. In some embodiments, the methods described herein do not require adjustment of the esketamine dosage. Indeed, esketamine may be administered at the lowest dosing frequency at which an esketamine response is observed and maintained in the patient during the phases described herein (e.g., induction and maintenance phases). An effective amount of esketamine has been found to be about 28 to about 84 mg.

[0086] As used herein, an "induction phase" or "acute administration phase" is the period during which esketamine is first administered to a patient. In some embodiments, the induction phase is long enough to achieve a robust and stable reduction in depressive symptoms. The induction phase may depend on factors including, but not limited to, the particular patient and / or the patient's gender, age, weight, administration time, administration frequency, and associated diseases. The induction phase may include an initial induction phase and an extended induction phase. The total induction period (initial and extended periods combined) may be about 4 to about 12 weeks, about 4 to about 11 weeks, about 4 to about 10 weeks, about 4 to about 9 weeks, about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, about 5 to about 12 weeks, about 5 to about 11 weeks, about 5 to about 10 weeks, about 5 to about 9 weeks, about 5 to about 8 weeks, about 5 to about 7 weeks, about 5 to about 6 weeks, about 6 to about 12 weeks, about 6 to about 11 weeks, about 6 to about 10 weeks, about 6 to about 9 weeks, about 6 to about 8 weeks, about 7 to about 12 weeks, about 7 to about 11 weeks, about 7 to about 10 weeks, about 7 to about 9 weeks, about 8 to about 12 weeks, about 8 to about 11 weeks, or about 8 to about 10 weeks. In some embodiments, the total induction period is about 4 to about 8 weeks.

[0087] In the initial induction period, the patient is administered a therapeutically effective amount of esketamine at a given frequency of at least twice a week. In some embodiments, the patient is administered a therapeutically effective amount of esketamine at a given frequency of three times a week. As long as the administration is three times a week, the administration is performed on days 1, 3, and 5 ± 1 of the week. The initial induction phase is typically a period during which the patient is shown to be responsive to treatment but is not ready to progress to the maintenance phase. At a point therein, the patient's response is evaluated by a person skilled in the art. In some embodiments, the patient's response is evaluated daily. In other embodiments, the patient's response is evaluated twice a week. In further embodiments, the patient's response is evaluated every other day. In yet other embodiments, the patient's response is evaluated at the end of the initial induction phase. Typically, the patient's response can be evaluated using techniques and tests known to those skilled in the art. In some embodiments, the patient's MADRS score is determined and used as a determination as to whether the initial induction phase has ended. The initial induction phase is of such length that it desirably achieves a reduction in depressive symptoms. In some embodiments, the initial induction phase is about 1 to about 4 weeks in duration. In other embodiments, the induction phase is up to about 1 week, up to about 2 weeks, up to about 3 weeks, or up to about 4 weeks in duration. In further embodiments, the initial induction period is about 1 to about 3 weeks, about 1 to about 2 weeks, about 2 to about 4 weeks, about 2 to about 3 weeks, about 3 to about 4 weeks, 1 week, 2 weeks, 3 weeks, 4 weeks, up to 1 week, up to 2 weeks, up to 3 weeks, or up to 4 weeks. The effective amount of esketamine administered during the initial induction phase can be determined by the attending physician. In some embodiments, the effective amount of esketamine administered during the initial induction phase is about 28 mg. In some embodiments, the effective amount of esketamine administered during the initial induction phase is about 56 mg. In other embodiments, the effective amount of esketamine administered during the initial induction phase is about 84 mg.

[0088] As used herein, the term "twice weekly" refers to a frequency of two times in a one week (7 day) period. For example, "twice weekly" may refer to the administration of esketamine herein. "Twice weekly" may also refer to a frequency of monitoring a patient in one or more phases discussed herein. In some embodiments, twice weekly refers to a frequency that is the first and second days of the week. In other embodiments, twice weekly refers to a frequency that is the first and third days of the week. In further embodiments, twice weekly refers to a frequency that is the first and fourth days of the week. In yet other embodiments, twice weekly refers to a frequency that is the first and fifth days of the week. "Day 1" may be any day of the week, including Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, or Saturday. Typically, with respect to the administration of esketamine, twice weekly refers to a frequency that is the first and fourth days of the week. To the extent there is an erroneous administration, a dose may be taken as soon as possible thereafter, and the prescribed regimen may then be continued.

[0089] In some patient populations (such as the elderly), the reduction of depressive symptoms during the initial induction phase is insufficient, necessitating an extended induction phase. In the extended initial induction phase, continuous administration of a therapeutically effective amount of esketamine is performed at a given frequency of at least twice a week. At a point therein, the patient's response is again evaluated by a person skilled in the art. In some embodiments, the patient's response is evaluated daily. In other embodiments, the patient's response is evaluated twice a week. In further embodiments, the patient's response is evaluated every other day. Typically, the patient's response can be evaluated using techniques and tests known to those skilled in the art. In some embodiments, the patient's MADRS score is determined and used as a determination as to whether the extended induction phase has ended. The extended induction phase is desirably of such length to achieve a substantial reduction in depressive symptoms, thus achieving a substantially complete response to esketamine.

[0090] As used herein, the term "substantially complete response to esketamine" refers to a patient having a reduction in MADRS score from baseline to at least a 50% improvement from baseline. In some embodiments, a substantially complete response to esketamine refers to a patient having either an at least 50% improvement from baseline or a MADRS score of about -20 below the patient baseline score. In other embodiments, a substantially complete response includes a reduction in MADRS score of about -20 or less, -19 or less, -18 or less, -17 or less, -16 or less, -15 or less, -14 or less, -13 or less, -12 or less, -11 or less, or -10 or less. In further embodiments, a substantially complete response results in a patient having a reduction of about -15 to about -20 from the MADRS baseline score. A substantially complete response to esketamine may also be obtained when the patient's MADRS score is reduced by about 50% from the MADRS score at the start of treatment. Such a substantially complete response may be observed at any time during esketamine treatment. In some embodiments, a substantially complete response is observed when the patient has a reduction in the MADRS total score from baseline 4 hours after treatment, hi other embodiments, a substantially complete response is observed when the patient has a reduction in the MADRS total score from baseline 2 days after treatment.

[0091] The extended induction phase is a period of time that results in a substantially complete response to esketamine. In some embodiments, the extended induction phase is from about 1 to about 8 weeks. In other embodiments, the extended induction phase is for a period of up to about 1 week, up to about 2 weeks, up to about 3 weeks, up to about 4 weeks, up to about 5 weeks, up to about 6 weeks, up to about 7 weeks, or up to about 8 weeks. In further embodiments, the extended induction period is about 1 to about 8 weeks, about 1 to about 7 weeks, about 1 to about 6 weeks, about 1 to about 5 weeks, about 1 to about 4 weeks, about 1 to about 3 weeks, about 2 to about 8 weeks, about 2 to about 7 weeks, about 2 to about 7 weeks, about 2 to about 6 weeks, about 2 to about 5 weeks, about 2 to about 4 weeks, about 3 to about 8 weeks, about 3 to about 7 weeks, about 3 to about 6 weeks, about 3 to about 5 weeks, about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, about 5 to about 8 weeks, about 5 to about 7 weeks, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, or about 8 weeks. The effective amount of esketamine administered during the extended induction period can be determined by the attending physician. In some embodiments, the effective amount of esketamine administered during the extended induction period is about 56 mg. In other embodiments, the effective amount of esketamine administered during the extended induction phase is about 84 mg.

[0092] Administration may further include an optimization / maintenance phase following the induction phase, where after the patient achieves a substantially complete response to esketamine during the induction phase, esketamine is administered less frequently than twice weekly during the optimization / maintenance phase, in some embodiments, the frequency of administration during the optimization / maintenance phase is once weekly, once every two weeks, once monthly, or a combination thereof.

[0093] At any stage during one or more of the induction, optimization, or maintenance phases, the patient's response to treatment may be evaluated using the techniques described herein. This evaluation may be performed until the patient is deemed by those skilled in the art to have achieved a suitable response to the treatment regimen. In some embodiments, the induction period may be said to be complete when the patient's MADRS score is reduced by 50% or more from baseline, or from about 20 to about 13. In other embodiments, the patient's MADRS score may be about 19, about 18, about 17, about 16, about 15, about 14, or about 13. Patients with a MADRS score of 12 or less are considered to be in remission and should be moved to or maintained in the maintenance phase if stable for 4 weeks.

[0094] At the end of the induction phase or extended induction phase, the treating physician should evaluate the patient to optimize the dosage and frequency of any subsequent administration phase, such as the "maintenance phase" or "long-term therapy phase." It is expected that the frequency of intranasal treatment during the subsequent administration, such as the maintenance phase, will be reduced from the frequency during the induction phase or extended induction phase (at least twice a week) to once a week administration for at least 4 weeks. In some embodiments, the subsequent administration, such as the maintenance phase, is for at least about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, 1 year, or about 2 years. In some embodiments, the continued administration of esketamine during the subsequent administration phase is for at least 6 months. In other embodiments, the continued administration of esketamine during the subsequent administration phase is for at least 1 year. In further embodiments, the frequency of administration during the subsequent dosing phase is once every week, or once every two weeks, or a combination thereof. In yet other embodiments, the frequency and effective amount of administration of esketamine during the subsequent dosing phase is the minimum frequency and amount to maintain stable remission or stable response.

[0095] Subsequent administrations, such as maintenance periods, may include longer periods depending on the patient's condition. In some embodiments, these longer periods may be at least about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, or more than about 10 years, including indefinitely. For example, for patients diagnosed with TRD, treatment may be indefinite. In other embodiments, the treatment frequency is reduced to every other week. In further embodiments, the treatment frequency is reduced to every 3 weeks. In yet other embodiments, the treatment frequency is reduced to once a month. The patient is maintained on schedule until the patient achieves remission, maintains response, or fails treatment. If the patient achieves remission or maintains response with weekly treatment for at least 4 weeks, the frequency of intranasal treatment sessions can be reduced to a biweekly maintenance dose based on the severity of depressive symptoms, and in some patient populations, the treatment frequency can be reduced to about once every 3 or 4 weeks as described above.

[0096] One of ordinary skill in the art will appreciate that the maintenance phase described herein may continue until further treatment is no longer necessary, as indicated, for example, by long-term remission of depression (e.g., including remission of one or more symptoms associated with depression), improvement in social and / or occupational functioning to normal or pre-morbid levels, or other known measures of depression.

[0097] An effective amount of esketamine is administered to the patient during the maintenance phase. As described above, the amount of esketamine administered during the maintenance phase is an amount that causes a biological or pharmaceutical response in the tissue systems described above with respect to the induction phase. In certain embodiments, the effective amount of esketamine is an amount that maintains the pharmacodynamic steady state of esketamine achieved in the induction phase. In other embodiments, if depressive symptoms begin to worsen with biweekly, 3-weekly, or 4-weekly treatment, the administration of esketamine will be increased to stabilize the patient. For example, if a patient is receiving biweekly administration and their symptoms begin to worsen, esketamine can be administered once a week during the maintenance phase to maintain response. Again, the patient's response can be reassessed at any time during the maintenance phase.

[0098] In elderly patients, the recommended dose of esketamine is about 28 to about 84 mg. It is recommended that the initial dose (in the first treatment session) be about 28 mg of esketamine. Based on the efficacy and tolerability of the about 28 mg dose, the dose in the next treatment session may remain at about 28 mg or may be increased to about 56 mg. Depending on the efficacy and tolerability of the about 56 mg dose, the dose in the subsequent treatment session may remain at about 56 mg or may be increased to about 84 mg, or may be reduced to about 28 mg. Depending on the tolerability of the about 84 mg dose, the dose in the subsequent treatment session may remain at about 84 mg or may be reduced to about 56 mg.

[0099] In patients with hepatic impairment, the recommended dose of esketamine is about 28 to about 56 mg. The initial dose (in the first treatment session) is recommended to be about 28 mg of esketamine. Based on the efficacy and tolerability of the about 28 mg dose, the dose in the next treatment session may remain at about 28 mg or may be increased to about 56 mg. Because esketamine is extensively metabolized in the liver, physicians should regularly monitor patients with hepatic impairment for drug tolerance.

[0100] In the treatment of patients with major depressive disorder who have suicidal ideation and are at imminent risk of suicide, dosing is more aggressive due to the severity of the condition. This method includes administering esketamine during one or two phases, namely an initial induction phase, and optionally in certain circumstances a maintenance phase. Due to the imminent risk to the patient's life, the initial dose of esketamine is administered at the highest effective dose of esketamine that the patient can tolerate twice a week during the induction phase. In some embodiments, the patient continues existing (i.e., currently initiated) antidepressant therapy simultaneously with the initiation of esketamine therapy during the induction phase. In other embodiments, the patient begins a new antidepressant therapy simultaneously with the initiation of esketamine therapy during the induction phase. In further embodiments, the patient continues previously administered antidepressant therapy simultaneously with the initiation of esketamine therapy during the induction phase. Antidepressants should be administered in a manner appropriate to the patient's condition / health and as described on the label for the treatment of MDD. The induction phase should be about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, and most preferably about 4 weeks. At the end of the induction phase, if the patient is responding adequately to treatment or is in remission, esketamine administration should be discontinued. The patient should be monitored to ensure that the patient remains stable or is in remission on the antidepressant alone. If the patient is not stabilized on the first combination of esketamine and antidepressant or fails treatment with the antidepressant initiated with esketamine after cessation of esketamine administration, a second induction phase may be initiated.

[0101] In the second induction phase, the patient is restarted with esketamine at the highest tolerated dose and simultaneously with a second new antidepressant. Alternatively, the patient is restarted with esketamine at the highest tolerated dose and simultaneously with the same antidepressant used during the previous induction phase. Esketamine is administered twice weekly. The antidepressant is administered in a manner appropriate to the patient's condition / health and as directed on the label for the treatment of MDD. The second induction phase should be about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, and most preferably about 4 weeks. At the end of the second induction phase, if the patient is responding adequately to treatment or in remission, esketamine administration should be discontinued and the patient should be monitored to ensure that the patient remains stable / or is in stable remission on the antidepressant alone. If the patient does not stabilize or fails treatment with the antidepressant initiated with esketamine after cessation of esketamine administration, a third induction phase may be initiated.

[0102] In the third induction phase, the patient is restarted with esketamine at the highest tolerated dose and simultaneously with a third new antidepressant. Alternatively, the patient is restarted with esketamine at the highest tolerated dose and simultaneously with the same antidepressant used during the second induction phase. Esketamine is administered twice weekly. The antidepressant is administered in a manner appropriate to the patient's condition / health and as directed on the label for the treatment of MDD. The third induction phase should be about 4 to about 8 weeks, about 4 to about 7 weeks, about 4 to about 6 weeks, and most preferably about 4 weeks. At the end of the third induction phase, the patient is now certified as a TRD patient, and therefore the patient proceeds to the maintenance phase designated for TRD. The methods described herein allow for optimizing the dosage of esketamine for administration to patients with depression or susceptible to depression. In some embodiments, the methods described herein do not require adjustment of the esketamine dosage.

[0103] In general, the patient may be resumed with the highest tolerated dose of esketamine and at the same time with the same antidepressant used during any previous induction phase (including the antidepressant with which the patient did not stabilize or otherwise failed treatment). For example, in a method for treating treatment-resistant depression in a patient in which the patient has not responded to at least two oral antidepressants in a current depressive episode, the patient may be administered esketamine alone or at least twice a week with a first oral antidepressant that is the same or different from the oral antidepressant that was previously ineffective in the first induction phase. To the extent that the patient does not achieve a substantially complete response to esketamine, the patient may be resumed with the highest tolerated dose of esketamine alone or at the same time with a second oral antidepressant that is the same or different from the first oral antidepressant in the second induction phase. To the extent that the patient achieves a substantially complete response to esketamine during the second induction phase, the patient may then be administered a therapeutically effective amount of esketamine less than twice a week during the subsequent maintenance phase.

[0104] If one or more (e.g., two) doses of esketamine are not administered during any of the phases described herein, the next dose will be scheduled when possible based on the dosing frequency regimen. If more than two doses are not administered according to clinical judgment, an adjustment in the dose or frequency of esketamine may be necessary.

[0105] The preferred pharmaceutical composition, S-ketamine hydrochloride as the active ingredient, is thoroughly mixed with a pharmaceutical carrier, preferably water, according to conventional pharmaceutical compounding techniques, which may take a wide variety of forms depending on the form of preparation desired for administration. Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the British Pharmaceutical Association.

[0106] Methods for formulating pharmaceutical compositions are described in many publications, such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al.; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al., all published by Marcel Dekker, Inc.

[0107] One suitable aqueous formulation of S-ketamine comprises water and S-ketamine, wherein S-ketamine is present in an amount ranging from about 25 mg / mL to about 250 mg / mL, preferably from about 55 mg / mL to about 250 mg / mL, or from about 100 mg / mL to about 250 mg / mL, or any amount or range therein, based on the total volume of the pharmaceutical composition. Preferably, S-ketamine is present in an amount ranging from about 150 mg / mL to about 200 mg / mL, or any amount or range therein. More preferably, S-ketamine is present in an amount ranging from about 150 mg / mL to about 175 mg / mL, or any amount or range therein. More preferably, S-ketamine is present in an amount ranging from about 160 mg / mL to about 163 mg / mL, for example, in an amount of about 161.4 mg / mL.

[0108] Another suitable aqueous formulation of S-ketamine comprises water and S-ketamine, wherein the S-ketamine is present in an amount ranging from about eq. 100 mg / mL equivalent to about eq. 250 mg / mL equivalent, or any amount or range therein, based on the total volume of the pharmaceutical composition. Preferably, the S-ketamine is present in an amount ranging from about eq. 125 mg / mL equivalent to about eq. 180 mg / mL equivalent, or any amount or range therein. More preferably, the S-ketamine is present in an amount ranging from about eq. 140 mg / mL equivalent to about eq. 160 mg / mL equivalent, or any amount or range therein, for example, about eq. 140 mg / mL equivalent.

[0109] The pharmaceutical composition suitable for use herein is preferably an aqueous formulation.As used herein, unless otherwise specified, the term "aqueous" means that the main liquid component of the formulation is water.Preferably, water comprises more than about 80% by weight of the liquid component of the pharmaceutical composition, more preferably more than about 90% by weight, more preferably more than about 95% by weight, more preferably about 98% by weight.

[0110] In pharmaceutical compositions suitable for use herein, the water content of the composition is in the range of 85±14% by weight, more preferably 85±12% by weight, even more preferably 85±10% by weight, most preferably 85±7.5% by weight, especially 85±5% by weight, based on the total weight of the composition.

[0111] In pharmaceutical compositions suitable for use herein, preferably the water content of the composition is in the range of 90±14% by weight, more preferably 90±12% by weight, even more preferably 90±10% by weight, most preferably 80±7.5% by weight, especially 90±5% by weight, based on the total weight of the composition.

[0112] In another pharmaceutical composition for use herein, the water content of the composition is within the range of 95±4.75% by weight, more preferably 95±4.5% by weight, even more preferably 95±4% by weight, still more preferably 95±3.5% by weight, most preferably 95±3% by weight, especially 95±2.5% by weight, based on the total weight of the composition.

[0113] In another pharmaceutical composition for use herein, the water content of the composition is in the range of 75 to 99.99% by weight, more preferably 80 to 99.98% by weight, even more preferably 85 to 99.95% by weight, still more preferably 90 to 99.9% by weight, most preferably 95 to 99.7% by weight, especially 96.5 to 99.5% by weight, based on the total weight of the composition.

[0114] In another pharmaceutical composition for use herein, the composition further comprises one or more buffering agents and / or buffering systems (ie, conjugate acid-base pairs).

[0115] As used herein, the term "buffering agent" is intended to mean any solid or liquid composition (preferably an aqueous liquid composition) that, when added to an aqueous formulation, adjusts the pH of the formulation. Those skilled in the art will recognize that a buffering agent may adjust the pH of an aqueous formulation in any direction (towards a more acidic, more basic, or more neutral pH). Preferably, the buffering agent is pharma- ceutically acceptable.

[0116] Suitable examples of buffers that may be used in the aqueous formulation may include, but are not limited to, citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, malic acid, lactic acid, fumaric acid, etc. Preferably, the buffer or buffer system is selected from the group consisting of NaOH, citric acid, sodium dihydrogen phosphate, and disodium hydrogen phosphate.

[0117] In embodiments, the buffering agent is selected to adjust the pH of the S-ketamine hydrochloride pharmaceutical composition (e.g., an aqueous formulation described herein) to a pH in the range of about pH 3.5 to about pH 6.5, or any amount or range therein. Preferably, the buffering agent is selected to adjust the pH of the S-ketamine hydrochloride composition to a pH in the range of about pH 4.0 to about pH 5.5, or any amount or range therein, more preferably, to a range of about pH 4.5 to about pH 5.0, or any amount or range therein.

[0118] Preferably, the concentrations of the buffer and buffer system, preferably NaOH, respectively, are adjusted to provide sufficient buffering capacity.

[0119] In embodiments, the present disclosure relates to a pharmaceutical composition comprising S-ketamine hydrochloride, water, and a buffering agent or buffering system, preferably NaOH, present in an amount sufficient to obtain a formulation having a pH in the range of about pH 4.0 to about pH 6.0, or any amount or range therein.

[0120] Optionally, the pharmaceutical composition may contain a preservative. As used herein, unless otherwise specified, the terms "antimicrobial preservative" and "preservative" preferably refer to any substance that is usually added to a pharmaceutical composition to protect the pharmaceutical composition against microbial degradation or microbial growth. In this regard, microbial growth typically plays an essential role. That is, the preservative serves the main purpose of avoiding microbial contamination. In one aspect, it may be desirable to avoid any microbial effect on the active ingredient and excipients, respectively, i.e., to avoid microbial degradation.

[0121] Representative examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben, benzylparaben, sorbic acid, and potassium sorbate.

[0122] Due to its preservative properties, it is preferred that preservatives in the pharmaceutical compositions used herein are completely absent when the content of S-ketamine hydrochloride is high enough so that the desired shelf life or stability in use can be achieved by the presence of the drug itself.Preferably, under these circumstances, the concentration of S-ketamine hydrochloride is at least eq.120 mg / mL equivalent, preferably in the range of about eq.120 mg / mL equivalent to about eq.175 mg / mL equivalent, or any amount or range therein, more preferably in the range of about eq.125 mg / mL equivalent to about eq.150 mg / mL equivalent, or any amount or range therein, such as about eq.126 mg / mL equivalent or about eq.140 mg / mL equivalent.

[0123] As used herein, the terms "penetration agent," "penetration enhancer," and "penetrant" refer to any substance that increases or enhances the absorption and / or bioavailability of an active ingredient (e.g., S-ketamine hydrochloride) of a pharmaceutical composition. Preferably, the penetrant increases or enhances the absorption and / or bioavailability of an active ingredient (e.g., S-ketamine hydrochloride) of a pharmaceutical composition following nasal administration (i.e., increases or enhances the absorption and / or bioavailability of the active ingredient through a mucous membrane).

[0124] Suitable examples include, but are not limited to, tetradecyl maltoside, sodium glycol cholate, tauroursodeoxycholic acid (TUDCA), lecithin, etc.; and chitosan (and salts), as well as surfactants such as benzalkonium chloride, sodium dodecyl sulfate, sodium dodecylate, polysorbate, laureth-9, oxytoxinol, sodium deoxycholate, polyarginine, etc. Preferably, the penetrating agent is tauroursodeoxycholic acid (TUDCA).

[0125] Penetrants may act through any mechanism, including, for example, increasing membrane fluidity, forming transient hydrophilic pores in epithelial cells, decreasing the viscosity of the mucus layer, or opening tight junctions. Some penetrants (e.g., bile salts and fusidic acid derivatives) may also inhibit enzymatic activity in membranes, thereby improving the bioavailability of active ingredients.

[0126] Preferably, the penetrant is selected to meet one or more, more preferably all, of the following general requirements: (a) is effective in increasing absorption (preferably nasal absorption) of the active ingredient, preferably in a temporary and / or reversible manner. (b) It is pharmacologically inactive. (c) being non-allergenic, non-toxic, and / or non-irritating; (d) Very potent (effective in small amounts). (e) be compatible with other ingredients of the pharmaceutical composition; (f) It is odorless, colorless, and / or tasteless. (g) is acceptable to a regulatory authority. (h) It is inexpensive and available in high purity.

[0127] In one embodiment, the penetrant is selected to increase penetration (absorption and / or bioavailability of S-ketamine hydrochloride) without nasal irritation, hi another embodiment, the penetrant is selected to improve absorption and / or bioavailability of S-ketamine hydrochloride and further enhance uniform dosing effectiveness.

[0128] In embodiments, the present disclosure relates to a pharmaceutical composition comprising S-ketamine and water, wherein the pharmaceutical composition does not contain an antimicrobial preservative, and the pharmaceutical composition further contains a penetration enhancer, preferably TUDCA.

[0129] In another embodiment, the present disclosure relates to a pharmaceutical composition comprising S-ketamine and water, wherein the pharmaceutical composition does not contain an antimicrobial preservative, and the pharmaceutical composition further comprises tauroursodeoxycholic acid (TUDCA), wherein the TUDCA is present at a concentration in the range of about 1.0 mg / mL to about 25.0 mg / mL, or any amount or range therein, preferably in the range of about 2.5 mg / mL to about 15 mg / mL, or any amount or range therein, preferably in the range of about 5 mg / mL to about 10 mg / mL, or any amount or range therein. In another embodiment, the present disclosure relates to a pharmaceutical composition, wherein the TUDCA is present at a concentration of about 5 mg / mL. In another embodiment, the present disclosure relates to a pharmaceutical composition, wherein the TUDCA is present at a concentration of about 10 mg / mL.

[0130] Pharmaceutical compositions for use herein may further contain one or more additional excipients, such as wetting agents, surfactant components, solubilizers, thickeners, colorants, antioxidant components, and the like.

[0131] Examples of suitable antioxidant components, when used, include, but are not limited to, one or more of the following: sulfites; ascorbic acid; ascorbate salts, such as sodium ascorbate, calcium ascorbate, or potassium ascorbate; ascorbyl palmitate; fumaric acid; ethylenediaminetetraacetic acid (EDTA) or its sodium or calcium salts; tocopherol; gallate salts, such as propyl gallate, octyl gallate, or dodecyl gallate; vitamin E; and mixtures thereof. The antioxidant component provides long-term stability to the liquid composition. The addition of the antioxidant component can help to enhance and ensure the stability of the composition, making the composition stable even after 6 months at 40°C. The suitable amount of the antioxidant component, when present, is about 0.01% to about 3% by weight, preferably about 0.05% to about 2% by weight, of the total weight of the composition.

[0132] Solubilizers and emulsifiers can be included to promote more uniform dispersion of active ingredients or other excipients that are not generally soluble in liquid carriers.Suitable examples of emulsifiers include, but are not limited to, gelatin, cholesterol, acacia, tragacanth, pectin, methylcellulose, carbomer, and mixtures thereof, if used.Suitable examples of solubilizers include polyethylene glycol, glycerin, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate, and mixtures thereof.

[0133] Preferably, the solubilizer comprises glycerin. The solubilizer or emulsifier is generally present in an amount sufficient to dissolve or disperse the active ingredient, i.e., S-ketamine, in the carrier. The typical amount of the solubilizer or emulsifier, if present, is about 1% to about 80% by weight, preferably about 20% to about 65% by weight, more preferably about 25% to about 55% by weight of the total weight of the composition.

[0134] Suitable tonicity agents, if used, include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, and mixtures thereof. If included, the suitable amount of tonicity agent is typically about 0.01% to about 15% by weight, more preferably about 0.3% to about 4% by weight, more preferably about 0.5% to about 3% by weight of the total weight of the composition.

[0135] For example, suspending or thickening agents can be added to the pharmaceutical composition to increase nasal retention time, suitable examples include, but are not limited to, hydroxypropylmethylcellulose, carmellose sodium, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salts, gellan gum, poloxamer, polyvinylpyrrolidone, xanthan gum, etc.

[0136] Advantageously, esketamine may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or four times a day, preferably two times a day. Typically, divided doses should be administered at shorter intervals. In some embodiments, divided doses are administered within about 20 minutes, about 15 minutes, about 10 minutes, about 5 minutes, about 4 minutes, about 3 minutes, about 2 minutes, about 1 minute, or less of each other. Additionally, in a flexible dosing regimen, patients may be administered daily, twice a week, once a week, once every other week, or once a month. For example, one dose of esketamine is administered on day 1 and another dose of esketamine is administered on day 2, or one dose of esketamine is administered on day 1 and another dose of esketamine is administered on day 3, or one dose of esketamine is administered on day 1 and another dose of esketamine is administered on day 4, or one dose of esketamine is administered on day 1 and another dose of esketamine is administered on day 5. Additionally, esketamine is preferably administered in intranasal form via topical use of a suitable intranasal vehicle, such as a nasal spray pump.

[0137] A representative nasal spray device is disclosed in U.S. Patent No. 6,321,942, which is incorporated herein by reference. For example, a disposable sprayer for discharging successive partial discharges as a spray can be utilized to carry out the methods disclosed herein. Typically, such a device allows for spraying of the medicament into both nostrils of a patient in two successive strokes. The container may be a ready-to-use device in which the medicament is discharged from a media container. The device may typically separate the first discharge stroke from the second discharge stroke to prevent complete emptying of the media container in a single motion. The device may take the form of a two-stroke disposable pump that is discarded after a single use and allows for individual partial discharges with high dosing accuracy and reliability.

[0138] In one embodiment, the nasal spray device is a single-use device that delivers a total of 28 mg of esketamine in two sprays (one spray per nostril). The device may be operated by the patient under the supervision of a medical professional. In terms of dosage, one device may be used for a 28 mg dose, two devices for a 56 mg dose, or three devices for an 84 mg dose. It is also preferred to have a 5 minute interval between the use of each device. As described in Example 1, time 0 is defined as the time of administration of the first intranasal spray from the first intranasal device into one nostril.

[0139] As used herein, AD = antidepressants, ESK = esketamine nasal spray, PHQ-9 = Patient Adherence Questionnaire, SDS = Sheehan Disability Scale, CGI-S = Clinical Global Impression-Severity, MADRS = Montgomery-Åsberg Depression Rating Scale, SD = standard deviation, C-SSRS = Columbia Suicide Severity Rating Scale, MDD = major depressive disorder, MGH-ATRQ = Massachusetts General Hospital-Antidepressant Treatment History Questionnaire, TRD = treatment-resistant depression.

[0140] The following examples are provided to aid in the understanding of the present invention and are not intended, and should not be construed, as in any way limiting the invention described in the claims appended hereto. Example 1

[0141] This is an open-label, multicenter, long-term study to evaluate the efficacy of intranasal esketamine plus a newly initiated oral antidepressant in subjects with TRD (ESKETINTRD3002 / NCT02418585).

[0142] Investigational Drug Information Esketamine was supplied as a clear, colorless intranasal solution of esketamine hydrochloride (16.14% weight / volume [w / v], equivalent to 14% w / v esketamine base) in a nasal spray pump. The solution consisted of 161.4 mg / mL esketamine hydrochloride (equivalent to 140 mg esketamine base) formulated in 0.12 mg / mL ethylenediaminetetraacetic acid (EDTA) and 1.5 mg / mL citric acid (pH 4.5) in water for injection. Provided in a nasal spray pump, the pump delivered 16.14 mg esketamine hydrochloride (14 mg esketamine base) per 100-μL spray. Each individual nasal spray pump (device) contained a total of 28 mg (i.e., two sprays).

[0143] The placebo solution was supplied as a clear, colorless intranasal solution in water for injection, with the addition of a bittering agent (denatonium benzoate [Bitrex®] at a final concentration of 0.001 mg / mL) to simulate the taste of an intranasal solution containing active drug. The placebo solution was provided in a matching nasal spray pump device. Benzalkonium chloride was added at a concentration of 0.3 mg / mL as a preservative. Each individual nasal spray pump (device) contained two doses of spray solution.

[0144] Intranasal investigational drugs Table 1 describes how each intranasal treatment session was administered.

[0145] [Table 1]

[0146] On day 1, subjects randomized to intranasal esketamine started at a dose of 56 mg. On day 4, the dose was increased to 84 mg or remained at 56 mg. On day 8, the dose was increased to 84 mg (if day 4 dose was 56 mg), remained the same, or decreased to 56 mg (if day 4 dose was 84 mg). On day 11, the dose was increased to 84 mg (if day 8 dose was 56 mg), remained the same, or decreased to 56 mg (if day 8 dose was 84 mg). On day 15, dose reduction from 84 mg to 56 mg was allowed if necessary for tolerability. Dose escalation was not allowed on day 15. After day 15, the dose remained stable (unchanged).

[0147] Oral antidepressants Duloxetine 30 mg, escitalopram 10 mg, sertraline 50 mg and 25 mg, and venlafaxine 75 mg and 37.5 mg were obtained commercially.

[0148] Treatment duration / trial duration Each subject participated in up to four periods: a screening period of up to 4 weeks (direct entry subjects only), a 4-week open-label induction (IND) period (direct entry subjects and transferred-in non-responder subjects), a 48-week open-label optimization / maintenance (OP / MA) period (all responder subjects from the open-label IND period of the current study and transferred-in responder subjects), and a 4-week follow-up period. The maximum duration of subject participation in the ESKETINTRD3004 study was 60 weeks for direct entry subjects, 56 weeks for transferred-in non-responder subjects, and 52 weeks for transferred-in responder subjects. A sample size of 750 was estimated with at least 300 subjects receiving intranasal esketamine for 6 months and at least 100 subjects receiving intranasal esketamine for 12 months. Additionally, transferred-in subjects were enrolled from the 3005 study to obtain 100 elderly subjects receiving esketamine. See Figure 1 for study design.

[0149] Efficacy analysis population Efficacy analyses were based on the full (IND) analysis set and the full (OP / MA) analysis set. The full (IND) analysis set was defined as all subjects receiving at least one dose of intranasal study drug or one dose of oral antidepressant during the open-label IND phase (for direct entry and enrolled non-responder subjects). The full (OP / MA) analysis set was defined as all subjects receiving at least one dose of intranasal study drug or one dose of oral antidepressant during the OP / MA phase. Efficacy variables included the 10-item MADRS covering all core depressive symptoms, with each item scored from 0 (no symptoms present or normal) to 6 (severe or persistent presence of symptoms). A total score (0-60) was calculated by adding the scores of all 10 items. Higher scores indicate more severe symptoms.

[0150] Subject and Treatment Information Eight hundred two subjects with a DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) diagnosis of MDD were enrolled. Of the 802 enrolled subjects, 691 were direct entry subjects and 111 were transfer subjects from study ESKETINTRD3005. Of the 779 direct entry or transfer non-responder subjects from the TRD3005 study in the full (IND) analysis population, 580 (74.5%) completed the IND period. Of the 603 subjects who entered the OP / MA period, 150 (24.9%) completed the OP / MA period. A total of 357 subjects entered the follow-up period, and 326 (91.3%) completed the follow-up period.

[0151] Of the 802 enrolled subjects, 1 subject did not receive intranasal study drug but received oral AD, and 1 subject received intranasal study drug but did not receive oral AD. These subjects are included in the All Enrolled Analysis Set. See Tables 2 and 3.

[0152] [Table 2]

[0153] [Table 3]

[0154] Subjects received variable-dose intranasal ESK for the first 2 weeks, followed by a fixed dose (28 mg in elderly subjects only, 56 mg or 84 mg in all age groups) plus the newly started oral antidepressant (sertraline, escitalopram, venlafaxine XR, or fluoxetine). Esketamine was administered twice weekly during the IND. In OP / MA, weekly administration occurred at weeks 5-8. During weeks 9-52 of the OP / MA phase, esketamine was administered weekly or biweekly depending on the MADRS score with the aim of having the lowest frequency to maintain remission. Switching to biweekly treatment (if the total MADRS score was ≦12) or returning to weekly treatment (if the total MADRS score was >12) was possible at 4-week intervals starting at week 8. From day 15 (patients <65 years old) or day 18 (patients ≧65 years old), the dose of esketamine nasal spray remained the same. After an initial period of dose titration, the oral antidepressant doses remained the same. Dose reductions based on tolerability were permitted for both agents. Baseline psychiatric history for the entire enrolled analysis population is presented in Table 4.

[0155] [Table 4-1]

[0156] [Table 4-2]

[0157] Extent of exposure The number of doses of intranasal investigational drug during the IND period is summarized in Table 5.

[0158] [Table 5]

[0159] A summary of the mean, mode, and final doses of intranasal study medication during the IND period are summarized in Table 6. On day 25 of the IND period, 28 of 675 (4.1%) received a 28 mg dose of esketamine, 298 of 675 (44.1%) received a 56 mg dose of esketamine, and 349 of 675 (51.7%) received an 84 mg dose of esketamine.

[0160] [Table 6]

[0161] The extent of exposure to intranasal investigational drug during the combined IND and OP / MA periods is summarized in Table 7.

[0162] [Table 7]

[0163] The frequency of subjects with 6- and 12-month exposure to esketamine is shown in Table 8.

[0164] [Table 8]

[0165] A summary of the mean, mode, and final doses of intranasal study drug during the OP / MA period are summarized in Table 9.

[0166] [Table 9]

[0167] At week 48 of the OP / MA phase, 7 of 143 (4.9%), 69 of 143 (48.3%), 1 of 143 (0.7%), and 66 of 143 (46.2%) were receiving 28 mg, 56 mg, 70 mg, and 84 mg doses of esketamine, respectively. Beginning at week 4 (OP / MA), intranasal treatment session frequency was allowed to adjust (if applicable) at fixed 4-week intervals. Of the 603 subjects treated with intranasal esketamine during the OP / MA phase, 275 (47.6%) subjects switched from weekly to biweekly at week 4 (OP / MA). See Table 10.

[0168] [Table 10]

[0169] Table 11 shows the changes in dosing regimen during the OP / MA phase.

[0170] [Table 11]

[0171] Efficacy Analysis Efficacy analyses were performed on the full analysis set for the IND and OP / MA periods, which included all enrolled subjects who received at least one dose of intranasal investigational drug or one dose of oral antidepressant investigational drug in the respective periods.

[0172] Montgomery-Asberg Depression Rating Scale (MADRS) The mean change (SD) from baseline (IND) to endpoint (IND) in MADRS total score was -16.4 (8.76) for esketamine + oral AD. The mean change from baseline (OP / MA) to endpoint (OP / MA) in MADRS total score was 0.3 (8.12) for esketamine + oral AD. See Figure 2.

[0173] Response rates (≧50% improvement from baseline (IND) in MADRS total score) and remission rates (MADRS total score is ≦12) are presented in Tables 12 and 13 for the IND and OP / MA phases, respectively.

[0174] At the IND end point, the response rate was 78.4% and the remission rate was 47.2%. Of the responders progressing to the OP / MA end point, 76.5% were responders and 58.2% were remitters at end point. Following functional recovery as measured by SDS, there was some lag time after mood improvement. At the IND end point, the remission rate was measured by SDS at the IND end point (21.1%, observed cases). The remission rate doubled throughout the OP / MA end point (25.2% at week 4 to 51.1% at week 48, observed cases). See Figure 3.

[0175] [Table 12]

[0176] [Table 13]

[0177] Patient Health Questionnaire (PHQ-9) total score The mean change (SD) from baseline (IND) to endpoint (IND) in PHQ-9 total score was -8.9 (6.67) for esketamine + oral AD. The mean change from baseline (OP / MA) to endpoint (OP / MA) in PHQ-9 total score was -0.2 (5.65) for esketamine + oral AD. See Figure 4. Example 2

[0178] Venous blood samples were obtained from patients and healthy control subjects from the subjects described in Example 1 and other clinical trials referenced herein. Serum or plasma was prepared from the venous blood samples. Human CRP and IL-6-R measurements were performed in serum using an MSD Sector 6000 with kits #K151STD and K151ALC (MesoScale Discovery, Rockville, MD). Human TNFα was quantified in serum using a Simoa HD-1 analyzer with kit #143 (Quanterix, Lexington, MA). All measurements were performed according to the kit manufacturer's recommendations.

[0179] As used in the following biomarker assay analyses, treatment (TRT) refers to treatment with intranasal esketamine plus optional oral antidepressant, and placebo (PBO) refers to treatment with placebo plus optional oral antidepressant.

[0180] The following biomarker signatures were used: 3MM: Inflammatory biomarker signature with a positive status defined by CRP>3mg / L and (TNFα>4pg / mL or sIL6R>25ng / mL). 2MM: Inflammatory biomarker signature with a positive status defined by CRP>3mg / L and sIL6R>25ng / mL. CRP: Inflammatory biomarker signature with positive status defined by CRP>3mg / L.

[0181] The 3MM signature was tested in clinical trials for adjunctive MDD, including treatment-resistant MDD (TRD) and MDD with suicidal ideation (SUI). The effect of 3MM across clinical trials is shown in Figure 5. Significance was driven by the esketamine (ESK) TRD study. Esketamine TRD shows the most robust effect for high inflammatory biotypes (CRP>3mg / L and TNFα>4pg / mL or sIL6R>25ng / mL). In esketamine studies with suicidal ideation (SUI), 3MM status at baseline did not predict treatment effect. Nominally significant (post-hoc, uncorrected for multiple testing) differentiation was found in the esketamine TRD studies (see Figure 6). Colors represent the range of n for subjects, shapes represent p-values, and grey shaded areas indicate MADRS changes less than 3 points.

[0182] Across esketamine TRD trials, significantly greater treatment effects in biomarker signature-positive subjects were evident in three of four trials: 3MM biomarker signature-positive subjects (TE signature 陽性 , left panel of Figure 6 ) improved by 7.8 MADRS points versus placebo at the end of double-blind treatment, and biomarker signature-negative subjects (TE signature 陰性 This was a significantly larger (p<0.01) treatment effect than the Japanese subtypes (Signature advantage, Fig. 6, center panel), whereas biomarker signature-negative subjects improved by only 2 MADRS points, resulting in a 5.8-point difference between subtypes (Signature advantage, Fig. 6, right panel). A larger treatment effect of 11.69 points change in MADRS was also seen in TRD2003 in Japanese patients with a positive biomarker signature (albeit with a smaller n, Fig. 7A) compared with 2.83 points in Japanese patients with a negative biomarker signature (Fig. 7B).

[0183] The same trend was observed across studies when 3MM was reduced to 2MM by removing TNFα and considering only CRP and sIL6R. The following 2MM and CRP analyses also include clinical trials CNTO136MDD2001, 67953964MDD2001, 42847922MDD2001, and 42847922MDD2002, which included administration of sirukumab (CNTO136MDD2001), aticaplant (67953964MDD2001), and seltrexant (42847922MDD2001 and NCT03321526). The overall effect in the biomarker signature positive group (left panel of FIG. 8A and FIG. 8B) is a 4.2 point improvement in MADRS across all trials in 2MM (FIG. 8A) vs. 4.6 points in 3MM (FIG. 8B), compared to 1.1 points in the biomarker signature negative group in 2MM (center panel of FIG. 8A and FIG. 8B) and 1.0 point in 3MM, resulting in a signature advantage of 3 points in 2MM vs. 3.6 points in 3MM (right panel of FIG. 8A and FIG. 8B). Thus, including TNFα in the model optimizes the biomarker signature effect and also captures a larger n of patients. In FIG. 8A, TRD2003 and TRD2003 are trending rather than significant due to the inversion of the identity of one individual in each study.

[0184] When the model is reduced to CRP levels only, the treatment effects observed with 3MM or 2MM are weaker and more variable. The overall effect in the biomarker signature positive group (left panel of FIG. 9) is an improvement of 3.5 points (FIG. 9) vs. 4.6 points (FIG. 8B) in MADRS across all trials with CRP alone, compared to 1.2 points in the biomarker signature negative group with CRP alone (center panel of FIG. 9) and 1.0 point with 3MM, resulting in a signature advantage of only 2.3 points with CRP alone vs. 3.6 points with 3MM (right panel of FIG. 9). Thus, a single marker (CRP) is not as robust as using a combination of markers. In FIG. 9, TRD3002 is trending due to the difference in membership of 20 subjects compared to 3MM.

[0185] The foregoing specification, together with examples given for purposes of illustration, teaches the principles of the invention, but it will be understood that the practice of the invention encompasses all ordinary modifications, adaptations and / or alterations that come within the scope of the following claims and equivalents thereof.

Claims

1. A method for treating depression, comprising intranasally administering an effective amount of esketamine to a patient in need thereof, wherein the patient is identified as having a positive biomarker signature if a biological sample obtained from the patient is identified as having a level of at least one biomarker that is higher or lower than a reference biomarker level.

2. 10. The method of claim 1, wherein the method has an induction phase and optionally a maintenance phase, the induction phase including induction phase treatment sessions at a given frequency and the maintenance phase including maintenance phase treatment sessions administered to the patient less frequently.

3. and optionally, administering intranasally to said patient about 28 mg to about 84 mg of esketamine per induction phase treatment session, said induction phase treatment sessions occurring twice weekly during said induction phase.

3. The method of claim 2, comprising intranasally administering about 56 mg to about 84 mg of esketamine to the patient per maintenance treatment session, wherein the maintenance treatment session occurs once weekly or once every two weeks.

4. 4. The method of claim 2 or 3, wherein the induction phase has a duration of at least about 4 weeks.

5. The method of any one of claims 2 to 4, wherein about 56 or about 84 mg of esketamine is administered per induction phase treatment session.

6. 6. The method of claim 5, wherein about 56 or about 84 mg of esketamine is administered per maintenance treatment session.

7. 7. The method of any one of claims 2-6, wherein the esketamine is delivered from an intranasal device in two or more sprays during the induction phase and / or the maintenance phase.

8. 8. The method of any one of claims 1 to 7, further comprising administering to the patient a therapeutically effective amount of an oral antidepressant during the induction and / or maintenance phase.

9. 9. The method of any one of claims 2 to 8, wherein the esketamine is administered as its corresponding hydrochloride salt during the induction phase and / or the maintenance phase.

10. The method of any one of claims 1 to 9, wherein the depression comprises major depressive disorder.

11. 11. The method of claim 10, wherein the major depressive disorder is major depressive disorder accompanied by suicidal thoughts or behavior.

12. 11. The method of claim 10, wherein the major depressive disorder is treatment-resistant depression.

13. said biological sample obtained from said patient a. a level of CRP that is higher than a reference CRP level, and b. The following: i. a level of TNF-α that is higher than a reference TNF-α level, and ii. a level of sIL6R that is higher than a reference sIL6R level The method of claim 1, wherein the patient is identified as having a biomarker signature positive if the patient is identified as having at least one of:

14. 14. The method of claim 13, wherein the reference CRP level is about 3 mg / L.

15. The method of claim 13, wherein the reference TNF-α level is about 4 pg / mL.

16. 14. The method of claim 13, wherein the reference sIL6R level is about 25 ng / mL.

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