Neuroactive steroids for treating CNS-related disorders

Abstract

The present disclosure relates to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof with a combination of compound (1) and an additional antidepressant, followed by continued administration of the additional antidepressant. An embodiment of the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising: (i) administering a combination comprising about 40 mg to about 50 mg of compound (1), or a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound, and a therapeutically effective amount of an additional antidepressant; and (ii) administering a second treatment comprising a therapeutically effective amount of an additional antidepressant.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 310,581, filed February 16, 2022, U.S. Provisional Application No. 63 / 337,828, filed May 3, 2022, and U.S. Provisional Application No. 63 / 482,200, filed January 30, 2023. The entire contents of the above-mentioned applications are hereby incorporated by reference in their entirety.

[0002] FIELD OF THEINVENTION The present invention relates to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof with Compound (1) and an additional antidepressant. [Background technology]

[0003] background The World Health Organization (WHO) has identified depression as the leading cause of disability worldwide and as a major contributor to the overall global burden of disease (http: / / www.who.int / mediacentre / factsheets / fs369 / en / ). Worldwide, depression is estimated to affect approximately 260 million people.

[0004] In the United States, the economic burden of depression, including workplace costs, direct costs, and costs associated with suicide, was estimated at $210.5 billion in 2010. According to WHO statistics, over 700,000 people die by suicide each year, making it the fourth leading cause of death among people aged 15-29. The proportion of U.S. adults who attempt suicide has increased (from 0.62% in 2004-2005 to 0.79% in 2012-2013), with increased suicide attempts among young adults (42% to 50%, respectively) and those with depressive disorders (26% to 54%, respectively).

[0005] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, American Psychiatric Association 2013) provides diagnostic criteria for Major Depressive Disorder (MDD), including the presence of at least five of nine depressive symptoms (depressed mood and / or loss of interest or pleasure, as well as other changes affecting appetite or weight, sleep, psychomotor activity, energy levels, guilt, concentration, and suicidality) during the same two-week period, representing a change from previous functioning.

[0006] Antidepressants are the mainstay of pharmacological treatment of depressive disorders. Selective serotonin uptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and other compounds that affect monoaminergic neurotransmission, such as mirtrazapine and bupropion, are the major classes of antidepressants. Although antidepressants are widely used, large-scale studies have demonstrated their limited efficacy, including low remission rates and untreated symptoms. Furthermore, these drugs may take 4-8 weeks to demonstrate full clinical efficacy, and for the most commonly prescribed classes, namely SSRIs and SNRIs, titration to the appropriate therapeutic range may be hindered by common side effects, including weight gain, GI symptoms, and sexual dysfunction.

[0007] In the largest study evaluating the efficacy of depression treatments in patients with MDD, patients' time to remission after treatment ranged from 5.4 to 7.4 weeks, with almost half of the patients who eventually achieved remission doing so after 6 weeks, and 40% of those who achieved remission required 8 weeks or more to achieve remission. Even after remission, many patients report residual symptoms that are often associated with reduced positive emotions, such as loss of interest in activities once considered enjoyable, fatigue, loss of energy, and disturbances in sleep and appetite / weight. Thus, patients may remain symptomatic for up to two months while waiting for the current standard drug therapy to take full effect. Patients may also have to deal with unwanted side effects and residual symptoms. These aspects highlight the need for more novel fast-acting treatments.

[0008] Thus, there is a need for symptomatic relief during the acute phase of a major depressive episode while waiting for pharmacotherapy to take effect. Summary of the Invention [Means for solving the problem]

[0009] Summary of the Invention An embodiment of the present disclosure is a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising: (i) about 40 mg to about 50 mg of compound (1), or a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound. [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0010] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1) or a pharma- ceutically acceptable salt thereof; [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant; wherein the subject is treatment naive.

[0011] In some embodiments, the subject is treatment naive.

[0012] In some embodiments, the subject has not received any antidepressant treatment within at least 30 days before the start of the first treatment.In some embodiments, the subject has not received additional antidepressant treatment within at least 30 days before the start of the first treatment.In some embodiments, the subject has not received additional antidepressant treatment within at least 60 days before the start of the first treatment.

[0013] In some embodiments, in the first treatment, the combination is administered for about 14 days. In some embodiments, in the second treatment, the additional antidepressant is administered for at least 28 days. In some embodiments, in the second treatment, the additional antidepressant is administered for at least 28 days. In some embodiments, in the second treatment, the additional antidepressant is administered for at least 28 days.

[0014] In some embodiments, the additional antidepressant is administered at the same dose in the first and second treatments. In some embodiments, the additional antidepressant is administered at different doses in the first and second treatments.

[0015] In some embodiments, Compound (1), or a pharma- ceutically acceptable salt thereof, is not administered to the subject in the second treatment.

[0016] In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the initial treatment are administered in separate dosage forms. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the initial treatment are administered simultaneously. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the initial treatment are administered at different times.

[0017] In some embodiments, the additional antidepressant is administered at the same dose in the first and second treatments. In some embodiments, the additional antidepressant is administered at different doses in the first and second treatments.

[0018] In some embodiments, the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the first treatment.

[0019] In some embodiments, the combination of Compound (1) or a pharma- ceutically acceptable salt thereof and an additional antidepressant is re-administered to the subject upon recurrence of depressive symptoms. In some embodiments, there is an interval of at least 6 weeks between the last dose of the initial treatment and the first dose of the re-administration.

[0020] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising: A therapeutically effective amount of compound (1) or a pharma- ceutically acceptable salt thereof. [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0021] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a treatment-naive subject in need thereof, comprising administering a therapeutically effective amount of Compound (1) or a pharma- ceutical acceptable salt thereof. [ka] and simultaneously commencing administration of a combination comprising a therapeutically effective amount of an additional antidepressant.

[0022] In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to treatment. In some embodiments, the subject has not received additional antidepressant treatment within at least 30 days prior to treatment. In some embodiments, the subject has not received additional antidepressant treatment within at least 60 days prior to treatment.

[0023] In some embodiments, the combination is administered for about 14 days.

[0024] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant are administered in separate dosage forms. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant are administered simultaneously. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant are administered at different times.

[0025] In some embodiments, the treatment further comprises a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. In some embodiments, in the second treatment, the additional antidepressant is administered for at least 28 days. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof is not administered to the subject in the second treatment.

[0026] In some embodiments, the additional antidepressant is administered in the second treatment at the same dose as in the combination.In some embodiments, the additional antidepressant is administered in the second treatment at a different dose compared to the dose administered in the combination.In some embodiments, the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the combination.

[0027] In some embodiments, the subject has MDD. In some embodiments, the subject has MDD with elevated anxiety. In some embodiments, the subject is experiencing a major depressive episode. In some embodiments, the subject has elevated anxiety during the majority of days of the major depressive episode. In some embodiments, the subject has a HAM-D Anxiety / Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17, at least 18, at least 19, or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.

[0028] In some embodiments, the subject has PPD. In some embodiments, the subject has PPD with elevated anxiety. In some embodiments, the subject has experienced a major depressive episode with perinatal onset. In some embodiments, the subject has elevated anxiety during the majority of days of the major depressive episode with perinatal onset. In some embodiments, the subject has a HAM-D Anxiety / Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17, at least 18, at least 19, or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.

[0029] In some embodiments, administration of the combination reduces treatment-emergent gastrointestinal adverse events. In some embodiments, treatment-emergent gastrointestinal adverse events include nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof. In some embodiments, treatment-emergent gastrointestinal adverse events include nausea and / or diarrhea. In some embodiments, treatment-emergent gastrointestinal adverse events include nausea. In some embodiments, treatment-emergent gastrointestinal adverse events include diarrhea. In some embodiments, treatment-emergent gastrointestinal adverse events are due to treatment with an additional antidepressant.

[0030] In some embodiments, the combination of Compound (1) or a pharma- ceutically acceptable salt thereof and an additional antidepressant is re-administered to the subject upon recurrence of depressive symptoms. In some embodiments, there is an interval of at least 6 weeks between the last dose administered and the first dose administered.

[0031] In some embodiments, compound (1) is administered. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered.

[0032] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and about 40 mg to about 50 mg of Compound (1): [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0033] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound. [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0034] In one aspect, the disclosure provides a method of treating major depressive disorder with elevated anxiety (MDD) or postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and about 40 mg to about 50 mg of Compound (1): [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0035] In one aspect, the disclosure provides a method of treating major depressive disorder with elevated anxiety (MDD) or postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound. [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0036] In some embodiments, the subject is treatment naive.

[0037] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound; [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0038] In one aspect, the present disclosure provides a method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof, comprising: (i) about 40 mg to about 50 mg of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0039] In one aspect, the present disclosure provides a method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof, comprising: (i) a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound; [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0040] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0041] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0042] In one aspect, the present disclosure provides a method of reducing gastrointestinal adverse events emerging under treatment with an antidepressant drug in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0043] In one aspect, the present disclosure provides a method of reducing gastrointestinal adverse events emerging under treatment with an antidepressant drug in a subject in need thereof, comprising: (i) a therapeutically effective amount of [ka] and a therapeutically effective amount of an additional antidepressant; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0044] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine for about 14 days; thereafter (ii) administering for at least 28 days a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. The present invention is directed to a method, comprising:

[0045] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine for about 14 days; thereafter (ii) administering for at least 28 days a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. The present invention is directed to a method, comprising:

[0046] In one aspect, the present disclosure provides a method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine for about 14 days; thereafter (ii) administering for at least 28 days a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. The present invention is directed to a method, comprising:

[0047] In one aspect, the present disclosure provides a method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine for about 14 days; thereafter (ii) administering for at least 28 days a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. The present invention is directed to a method, comprising:

[0048] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) (a) about 50 mg of compound (1): [ka] and (b) providing an initial treatment comprising co-administering a therapeutically effective amount of an additional antidepressant for about 14 days, wherein compound (1) is administered once daily, and compound (1) and the additional antidepressant in the initial treatment are administered in separate dosage forms; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant for at least 28 days. The present invention is directed to a method, comprising:

[0049] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) (a) a pharma- ceutically acceptable salt of compound (1) in an amount equivalent to about 50 mg of the free base compound; [ka] and (b) providing an initial treatment comprising co-administering a therapeutically effective amount of an additional antidepressant for about 14 days, wherein the pharma- ceutically acceptable salt of Compound (1) is administered once daily, and the pharma-ceutically acceptable salt of Compound (1) and the additional antidepressant in the initial treatment are administered in separate dosage forms; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant for at least 28 days. The present invention is directed to a method, comprising:

[0050] In some embodiments, the subject is experiencing major depressive episode.In some embodiments, the subject has elevated anxiety during the majority of days of major depressive episode.In some embodiments, the subject has a HAM-D anxiety / somatization subscale score of at least 7 at baseline.In some embodiments, the subject has a HAM-A total score of at least 17 or at least 20 at baseline.

[0051] In some embodiments, administering the combination reduces treatment-emergent gastrointestinal adverse events. In some embodiments, administering the first treatment reduces treatment-emergent gastrointestinal adverse events.

[0052] In some embodiments, the treatment-emergent gastrointestinal adverse events include nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof. In some embodiments, the treatment-emergent gastrointestinal adverse events include nausea and / or diarrhea. In some embodiments, the treatment-emergent gastrointestinal adverse events are due to treatment with an additional antidepressant.

[0053] In some embodiments, the subject is treatment naive. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received additional antidepressant treatment within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received additional antidepressant treatment within at least 60 days prior to the start of the first treatment.

[0054] In some embodiments, the combination is administered for about 14 days in the first treatment. In some embodiments, the additional antidepressant is administered for at least 28 days in the second treatment. In some embodiments, the additional antidepressant is administered at the same dose in the first treatment and the second treatment. In some embodiments, the additional antidepressant is administered at different doses in the first treatment and the second treatment. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is not administered to the subject in the second treatment.

[0055] In some embodiments, Compound (1) or a pharmaceutically acceptable salt thereof and the additional antidepressant in the first treatment are administered in separate dosage forms. In some embodiments, Compound (1) or a pharmaceutically acceptable salt thereof and the additional antidepressant in the first treatment are administered simultaneously. In some embodiments, Compound (1) or a pharmaceutically acceptable salt thereof and the additional antidepressant in the first treatment are administered at different times.

[0056] In some embodiments, the additional antidepressant is administered in the same dose in (i) and (ii). In some embodiments, the additional antidepressant is administered in different doses in (i) and (ii). In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is not administered to the subject in (ii). In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) and the additional antidepressant in (i) are administered. In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) and the additional antidepressant in (i) are administered simultaneously. In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) and the additional antidepressant in (i) are administered at different times. In some embodiments, the additional antidepressant administered in (ii) is the same as the additional antidepressant administered in (i).

[0057] In some embodiments, the combination of Compound (1) or a pharma- ceutically acceptable salt of Compound (1) and an additional antidepressant is re-administered to the subject upon recurrence of depressive symptoms. In some embodiments, there is an interval of at least 6 weeks between the last dose of the initial treatment and the first dose of the re-administration.

[0058] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0059] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0060] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0061] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0062] In one aspect, the disclosure provides a method for reducing gastrointestinal adverse events occurring under treatment with an antidepressant in a subject in need thereof, comprising administering a therapeutically effective amount of Compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0063] In one aspect, the disclosure provides a method for reducing gastrointestinal adverse events emerging under treatment with an antidepressant in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0064] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine. wherein the subject is treatment naive.

[0065] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a therapeutically effective amount of a pharma- ceutically acceptable salt of Compound (1) to a subject in need thereof for about 14 days. [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine. wherein the subject is treatment naive.

[0066] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject from about 40 mg to about 50 mg of Compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. The method includes:

[0067] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a medicament for use in treating major depressive disorder (MDD) in a subject in need thereof a medicament for use in treating major depressive disorder in a subject in need thereof, the method comprising administering to a subject a medicament for use in treating major depressive disorder in a subject in need thereof ..., [ka] and administering a therapeutically effective amount of an additional antidepressant. The present invention relates to a method comprising:

[0068] In some embodiments, the subject is experiencing major depressive episode.In some embodiments, the subject has elevated anxiety during the majority of days of major depressive episode.In some embodiments, the subject has a HAM-D anxiety / somatization subscale score of at least 7 at baseline.In some embodiments, the subject has a HAM-A total score of at least 17 or at least 20 at baseline.

[0069] In some embodiments, administering the combination reduces treatment-emergent adverse gastrointestinal events. In some embodiments, administering the combination reduces treatment-emergent adverse gastrointestinal events. In some embodiments, treatment-emergent adverse gastrointestinal events include nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof. In some embodiments, treatment-emergent adverse gastrointestinal events include nausea and / or diarrhea. In some embodiments, treatment-emergent adverse gastrointestinal events are due to treatment with an additional antidepressant.

[0070] In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of treatment.In some embodiments, the subject has not received additional antidepressant treatment within at least 30 days prior to the start of treatment.In some embodiments, the subject has not received additional antidepressant treatment within at least 60 days prior to the start of treatment.

[0071] In some embodiments, the treatment involves administering the combination for about 14 days.

[0072] In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the combination are administered in separate dosage forms. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the combination are administered simultaneously. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the combination are administered at different times.

[0073] In some embodiments, the treatment further comprises a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. In some embodiments, the second treatment administers the additional antidepressant for at least 28 days. In some embodiments, the additional antidepressant is administered in the second treatment at the same dose as in the combination. In some embodiments, the additional antidepressant is administered in a different dose in the second treatment compared to the dose administered in the combination. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is not administered to the subject in the second treatment. In some embodiments, the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the combination.

[0074] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and about 40 mg to about 50 mg of Compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0075] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound. [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0076] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and about 40 mg to about 50 mg of Compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0077] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound. [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0078] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of Compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. Subjects are treatment naive and subject to the method.

[0079] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. Subjects are treatment naive and subject to the method.

[0080] In one aspect, the disclosure provides a method for reducing gastrointestinal adverse events occurring under treatment with an antidepressant in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0081] In one aspect, the disclosure provides a method for reducing gastrointestinal adverse events emerging under treatment with an antidepressant in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0082] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of Compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. Of interest herein is the method, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine.

[0083] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. Of interest herein is the method, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine.

[0084] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of Compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. Of interest herein is the method, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine.

[0085] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. Of interest herein is the method, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine.

[0086] In some embodiments, the subject is experiencing major depressive episode.In some embodiments, the subject has elevated anxiety during the majority of days of major depressive episode.In some embodiments, the subject has a HAM-D anxiety / somatization subscale score of at least 7 at baseline.In some embodiments, the subject has a HAM-A total score of at least 17 or at least 20 at baseline.

[0087] In some embodiments, co-administration reduces treatment-emergent adverse gastrointestinal events. In some embodiments, co-administration reduces treatment-emergent adverse gastrointestinal events. In some embodiments, treatment-emergent adverse gastrointestinal events include nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof. In some embodiments, treatment-emergent adverse gastrointestinal events include nausea and / or diarrhea. In some embodiments, treatment-emergent adverse gastrointestinal events are due to treatment with an antidepressant.

[0088] In some embodiments, the subject is treatment-naive. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of co-administration. In some embodiments, the subject has not received additional antidepressant treatment within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received additional antidepressant treatment within at least 60 days prior to the start of the first treatment.

[0089] In some embodiments, the antidepressant continues to be administered for at least an additional 28 days after day 14 of treatment. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is not administered to the subject after day 14 of treatment.

[0090] In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and antidepressant in co-administration are administered in separate dosage forms. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and antidepressant in co-administration are administered simultaneously. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and antidepressant in co-administration are administered at different times. In some embodiments, the antidepressant is administered at the same dose from day 1 of treatment to about day 14 of treatment and after day 14 of treatment. In some embodiments, the antidepressant is administered at the same dose from day 1 of treatment to about day 14 of treatment and after day 14 of treatment.

[0091] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a treatment-naive subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] and simultaneously initiating administration of a combination comprising a therapeutically effective amount of an antidepressant.

[0092] In each of the embodiments described herein, the methods directed to the treatment of MDD are also directed to the treatment of postpartum depression (PPD). [Brief description of the drawings]

[0093] [Figure 1] FIG. 1 is a schematic study design of the clinical study of Example 1.

[0094] [Diagram 2] FIG. 2 shows the patient disposition for the study of Example 2.

[0095] [Diagram 3] Figure 3 is a bar graph showing the change from baseline (CFB) in HAM-D total score on day 3. Data are presented for the full analysis set using a mixed effects model for repeated measures. *p<0.05.

[0096] [Figure 4] Figure 4 is a bar graph showing the CFB of HAM-D total score over the blinded treatment period (14 days on treatment; with equal weighting for days 3, 8, 12, and 15). Data are presented for the full analysis set using a mixed effects model for repeated measures. Changes from baseline in HAMD-17 total score over the blinded treatment period were estimated using equal weighting for scheduled visits on days 3, 8, 12, and 15. *p<0.05.

[0097] [Diagram 5] Figure 5 is a line graph showing least squares means (LSM) (±SE) of change from baseline in HAM-D total score over time. Data are presented for the full analysis set using a mixed effects model for repeated measures. Day 3 is the primary endpoint. All other time points were not adjusted for multiplicity and p values ​​are considered nominal. *p<0.05. The dashed line represents the end of the treatment period and final assessment of the primary endpoint.

[0098] [Figure 6] Figure 6 is a forest plot of treatment differences in HAMD-17 total score on day 3. Data are shown for the full analysis set.

[0099] [Figure 7A] FIG. 7A shows a bar graph of HAM-D response (≧50% reduction from baseline in HAMD-17) at various time points. Data are shown for the full analysis set. Endpoints were not adjusted for multiplicity and p values ​​are considered nominal. *p<0.05.

[0100] [Figure 7B] Figure 7B shows a bar graph of HAM-D remission (HAMD-17 <= 7) at various time points. Data are shown for the full analysis set. Endpoints were not adjusted for multiplicity and p values ​​are considered nominal. *p<0.05.

[0101] [Figure 8] Figure 8 shows a line graph showing the LSM (±SE) of the change from baseline in MADRS total score. Data are presented for the full analysis set using a mixed effects model for repeated measures. These endpoints were not adjusted for multiplicity and p values ​​are considered nominal. *p<0.05.

[0102] [Figure 9]Figure 9 shows a bar graph of CGI-I response by study visit. Data are presented for the full analysis set. Response was defined as a CGI-I score of "very large improvement" or "large improvement." These endpoints were not adjusted for multiplicity and p values ​​are considered nominal. *p<0.05.

[0103] [Figure 10A] Figure 10A is a line graph showing the change from baseline in HAM-D total score over time in patients with MDD with elevated anxiety. Data is shown for the full analysis set. *p<0.05 for significant nominal differences. p values ​​were not adjusted for multiplicity. The term "elevated anxiety" is used only in reference to or as a symptom of depression.

[0104] [Figure 10B] Figure 10B shows a subgroup analysis of the change from baseline in HAMD-17 total score in patients with MDD with elevated anxiety. Patients with MDD with elevated anxiety were defined as having a baseline HAM-A total score of ≧20. Data are presented for the full analysis set using a mixed-effects model for repeated measures. The term "elevated anxiety" is used only when referring to or as a symptom of depression. These endpoints were not adjusted for multiplicity and p values ​​are considered nominal. *p<0.05.

[0105] [Figure 10C] Figure 10C is a line graph showing the change from baseline in HAM-D total score over time in patients with MDD without elevated anxiety. Data are shown for the full analysis set. p values ​​were not adjusted for multiplicity.

[0106] [Figure 11] FIG. 11 is a line graph showing the LSM (±SE) of change from baseline in HAM-A over time. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0107] Detailed Description definition

[0108] As used herein, “compound (1)” refers to a compound having the formula (or structure): [ka] It refers to a compound having the formula:

[0109] Compound (1) is also known as zuranolone, i.e., 3α-hydroxy-3β-methyl-21-(4-cyanopyrazol-1-yl)-5β-19-norpregnan-20-one, and by its IUPAC name: 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (CAS Registry Number 1632051-40-1). Methods for chemically synthesizing compound (1) are described in U.S. Pat. No. 9,512,165 and PCT Publication No. WO2014 / 169833, the entire contents of which are incorporated herein by reference in their entirety. Some crystalline forms of compound (1) and methods for preparing said forms are described in U.S. Patent No. 11,236,121; and PCT Publication No. WO2018 / 039378, the entire contents of which are incorporated herein by reference in their entirety. Pharmaceutical compositions of compound (1) and methods for preparing said compositions are described in PCT Publication No. WO2022 / 020363A9 and U.S. Application No. 17 / 579,541, the entire contents of which are each incorporated herein by reference in their entirety. Some deuterated forms of compound (1) and methods for preparing said forms are described in PCT Publication No. WO2019 / 113494 and U.S. Application No. 17 / 545,290, the entire contents of which are incorporated herein by reference in their entirety.

[0110] Compound (1) inhibits synaptic and extrasynaptic GABA receptors. A GABA Receptor Targeting A Compound (1) is a neuroactive steroid that has been shown to be a positive allosteric modulator of the GABA receptor. A As a positive allosteric modulator of the receptor, it serves as a therapeutic agent to treat CNS-related disorders such as depression, postpartum depression and major depressive disorder, as well as to treat neurological conditions such as essential tremor, epilepsy and Parkinson's disease.

[0111] As used herein, "crystalline" refers to a solid phase of a given chemical entity that has a well-defined three-dimensional structural order. The atoms, ions and / or molecules are arranged in a regular, periodic manner in a repeating three-dimensional lattice. In various embodiments, a crystalline material may include one or more discreet crystalline forms.

[0112] As used herein, the terms "crystalline form," "crystalline solid form," "crystalline form," "solid form," and related terms herein refer to crystalline modifications of a given substance (e.g., Compound (1)), including single-component and multi-component crystalline forms, including, but not limited to, polymorphs, solvates, hydrates, and salts.

[0113] The term "substantially crystalline" refers to a form that may be crystalline to at least a certain weight percent. The certain weight percentage may include 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%. In certain embodiments, the certain weight percentage of crystallinity is at least 90%. In certain other embodiments, the certain weight percentage of crystallinity is at least 95%. In some embodiments, Compound (1) may be a substantially crystalline sample of any of the crystalline forms described herein (e.g., crystalline forms A and C) and / or PCT Publication No. WO2018 / 039378, the entire contents of which are incorporated herein by reference in their entirety.

[0114] The term "substantially pure" refers to a composition of a particular crystalline form (e.g., a crystalline form of Compound (1)) that may be free of impurities and / or other solid forms at least a particular weight percentage. The particular weight percentage may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In certain embodiments, Compound (1) may be a substantially pure sample of any of the crystalline forms (e.g., crystalline forms A and C) described herein. In certain embodiments, Compound (1) may be substantially pure form A. In certain embodiments, Compound (1) may be substantially pure form C.

[0115] As used herein, "XRPD" refers to X-ray powder diffraction. An XRPD pattern is an xy graph with 2Q (diffraction angle) plotted on the x-axis and intensity plotted on the y-axis. There are diffraction peaks that can be used to characterize crystalline materials. Diffraction peaks are usually represented and referenced by their position on the x-axis, rather than their intensity on the y-axis, because diffraction peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255- 257 (2003)). Thus, intensity is not usually used by those skilled in the art to characterize crystalline materials. As with any data measurement, XRPD data can have variability. In addition to variability in diffraction peak intensity, there can also be variability in the position of the diffraction peaks on the x-axis. However, this variability can usually be taken into account when reporting the position of the diffraction peaks for characterization purposes. Such variability in the position of the diffraction peaks along the x-axis can derive from several sources. One such source may be sample preparation. Samples of the same crystalline material prepared under different conditions may produce slightly different diffractograms. Factors such as particle size, moisture content, solvent content, temperature and orientation may all affect how a sample diffracts X-rays. Another source of variability is due to instrument parameters. Different X-ray powder diffractometers may operate using different parameters, resulting in slightly different diffraction patterns from the same crystalline material. Similarly, different software packages process XRPD data differently, which may also result in variability. These and other sources of variability are known to those skilled in the art. Due to such sources of variability, the value of each X-ray diffraction peak may be preceded by the term "about" or followed by an appropriate range (e.g., ±0.1°, ±0.2°, ±0.3°, ±0.4°, ±0.5°, etc.) that defines the experimental variability.

[0116] The term "characteristic peaks," when describing peaks in an XRPD pattern of a crystalline form of a given chemical entity (e.g., a crystalline form of Compound (1)), refers to a particular collection of diffraction peaks whose values, taken as a whole, span a range of 2θ values ​​(e.g., from 0° to 40°) that is characteristic of that particular crystalline form.

[0117] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government, or a corresponding agency in a country other than the United States, for use in animals, or more particularly in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias.

[0118] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharma- ceutically acceptable and that possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and inorganic or organic base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl ... or (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or is coordinated to an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, salts of non-toxic organic or inorganic acids, such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, salts of hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmacologically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.

[0119] Chemical elements are identified according to the Periodic Table of the Elements (CAS version) on the inside cover of Handbook of Chemistry and Physics, 75th Edition, and specific functional groups are defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0120] As used herein, the term "about," when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated limit of a stated value or range.

[0121] As used herein, the term "modulation" refers to the A Refers to the inhibition or activation of receptor function. "Modulators" (e.g., GABA A The compound or a pharma- ceutically acceptable salt thereof that modulates the function of a GABA receptor is, for example, AIt may be an agonist, partial agonist, antagonist or partial antagonist of the receptor.

[0122] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is afflicted with a particular disease, disorder, or condition, which actions reduce the severity of the disease, disorder, or condition (or any symptoms thereof) or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate prophylactic actions taken before a subject begins to suffer from a particular disease, disorder, or condition.

[0123] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0124] As used herein, "treatment naive" refers to a subject who has not been previously treated with additional antidepressants within the scope of the current depressive episode. "Treatment naive" also refers to a subject who has not taken any antidepressant within at least 30 days prior to the start of treatment (i.e., day 1). In some embodiments, the subject has not taken any antidepressant within at least 60 days prior to the start of treatment (i.e., day 1).

[0125] The Hamilton Rating Scale for Depression, sometimes abbreviated as "HRSD", "HDRS", "HAMD" or "HAM-D", is a multi-item questionnaire used to provide an index of depression. The original scale / version, published by Max Hamilton in 1960, contains 17 items for rating, with other versions available containing up to 29 items. As used herein, "HAMD-17" or "17-HAM-D" refers to the 17-item Hamilton Rating Scale for Depression. In some embodiments, "HAM-D total score" and "HAMD-17 total score" are used interchangeably and refer to the total score obtained using the 17-item Hamilton Rating Scale for Depression. In some embodiments, "HAM-D" followed by a subscale or single item score, such as the HAM-D Anxiety / Somatization subscale, refers to a subscale or single item score using the 17-item Hamilton Rating Scale for Depression.

[0126] The term "elevated anxiety" is used when referring to or as a symptom of depression. "MDD with elevated anxiety" or "MDD with anxiety distress" are used interchangeably and refer to a subject with MDD who exhibits elevated anxiety as a symptom of their depression. In some embodiments, MDD with elevated anxiety is characterized by a HAM-D Anxiety / Somatization subscale score of at least 7 at baseline. In some embodiments, MDD with elevated anxiety is characterized by a HAM-D Anxiety / Somatization subscale standardized or normalized score of at least 39 at baseline. In some embodiments, a HAM-D Anxiety / Somatization subscale standardized or normalized score of at least 39 is equivalent to a HAM-D Anxiety / Somatization subscale (raw) score of at least 7. In some embodiments, MDD with elevated anxiety is characterized by a HAM-A total score of at least 17 at baseline (i.e., before administration of compound (1) or a pharma- ceutically acceptable salt thereof). In some embodiments, MDD with elevated anxiety is characterized at baseline by a HAM-A total score of at least 18. In some embodiments, MDD with elevated anxiety is characterized at baseline by a HAM-A total score of at least 20. In some embodiments, MDD with elevated anxiety is defined according to the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition, which is MDD with the anxious distress specifier.

[0127] In other embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items and the somatic items. In some embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety, somatic anxiety, GI somatic symptoms, and / or general somatic symptoms. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D anxiety / somatization subscale score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D Anxiety / Somatization subscale score based primarily on items assessing the anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the anxiety symptoms of depression.

[0128] "PPD with elevated anxiety," "PPD with anxiety distress," or "MDD with perinatal onset and anxiety distress" are used interchangeably and refer to a subject with PPD that presents with elevated anxiety as a symptom of the subject's depression. In some embodiments, PPD with elevated anxiety is defined in accordance with the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition, which is MDD with a specifier of perinatal onset and with a specifier of anxiety distress. In some embodiments, PPD with elevated anxiety is characterized by a HAM-D anxiety / somatization subscale score, a HAM-A total score, and / or a MADRS score, as described herein.

[0129] As used herein, the "effective amount" of a compound (or its pharmaceutically acceptable salt) refers to an amount sufficient to elicit a desired biological response, for example, to treat sexual dysfunction, for example, to treat treatment-induced sexual dysfunction.As recognized by those skilled in the art, the effective amount of the compound of the present invention (or its pharmaceutically acceptable salt) can vary depending on factors such as the desired biological end point, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health and condition of the subject.The effective amount includes therapeutic and prophylactic treatments.

[0130] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound (or a pharma- ceutically acceptable salt thereof) is an amount sufficient to realize a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound (or a pharma- ceutically acceptable salt thereof) refers to the amount of a therapeutic agent, alone or in combination with other therapies, that realizes a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0131] In an alternative embodiment, the present invention contemplates administering the compound of the present invention, or its pharma- ceutically acceptable salt or pharma-ceutically acceptable composition, as a prophylaxis before a subject begins to suffer from a particular disease, disorder or condition.As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition, or to prevent its recurrence.A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that achieves a prophylactic benefit in the prevention of a disease, disorder or condition.The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0132] A "subject" or "patient" is a human (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent), or an adult subject (e.g., young adult, middle-aged adult, or geriatric adult)).

[0133] As used herein, the term "dose equivalent" refers to a biologically equivalent dose. For example, the dose equivalent of a 50 mg dose of a pharma- ceutically acceptable salt of Compound (1) is the amount (by weight) of a pharma- ceutically acceptable salt required to produce a dose biologically equivalent to a 50 mg dose of the free base of Compound (1).

[0134] As used herein, the term "unit dosage form" is defined to refer to the form in which Compound (1) is administered to a patient. Specifically, the unit dosage form can be, for example, a pill, a capsule or a tablet. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form is a tablet.

[0135] As used herein, "solid dosage form" means a pharmaceutical dose(s) in solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalation formulations and chewables.

[0136] As used herein, the terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, into or onto a subject.

[0137] As used herein, "co-administration" or administration of a "combination" refers to administration of selected therapeutic agents to a single patient and includes treatment regimens in which the agents are administered by the same or different routes of administration, or at the same time or at different times. In some embodiments, the agents are in a fixed dose combination. In some embodiments, the agents are not in a fixed dose. In some embodiments, the agents are administered simultaneously. In some embodiments, the agents are administered sequentially. In some embodiments, the agents are not in a fixed dose and are administered at the same time or at different times.

[0138] Treatment

[0139] The present disclosure is directed to methods of treating major depressive disorder (MDD) or postpartum depression. The diagnosis and severity of MDD or PPD treated by the methods described herein may be determined according to the Diagnostic and Statistical Manual of Mental Disorders, 5 th It can be characterized as defined by the DSM-5 Edition (DSM-5).

[0140] Depressive disorder

[0141] Depressive disorders include major mood dysregulation disorder, major depressive disorder (including major depressive episodes), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder. The common feature of all of these disorders is the presence of a sad, empty, or irritable mood accompanied by physical and cognitive changes that significantly affect an individual's ability to function. What differs between them is the matter of duration, timing, or presumed etiology.

[0142] Major depressive disorder represents the classic presentation in this group of disorders. It is characterized by discrete episodes of at least 2 weeks duration (although most episodes last much longer) with distinct changes in affect, cognition and autonomic nervous system function and remissions between episodes. Discrete episodes of major depressive disorder may be called "major depressive episodes" or "depressive episodes".

[0143] Major depressive disorder

[0144] Major depressive disorder is generally known in the art.

[0145] In some embodiments, MDD, also known as depression or clinical depression, is a mood disorder that causes persistent feelings of sadness and loss of interest.MDD affects how a subject feels, thinks and acts, and can result in a variety of emotional and physical problems.

[0146] In some embodiments, MDD is defined and diagnosed according to DSM-5, for example, MDD is diagnosed according to diagnostic criterion A, as described below.

[0147] Diagnostic Criteria A. Five (or more) of the following symptoms appear during the same two-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1. Depressed mood for most of the day, almost every day, as indicated by either subjective report (e.g., feeling sad, empty, hopeless) or observation made by others (e.g., appearing tearful) (Note: in children and adolescents, irritable mood is possible). 2. Markedly diminished interest or pleasure in all or almost all activities for most of the day, almost every day (as indicated by either subjective description or observation). 3. Significant weight loss or gain when not on a diet (e.g., more than a 5% change in body weight in one month) or decreased or increased appetite on most days (Note: in children, consider that this may not be expected weight gain). 4. Having insomnia or excessive sleep almost every day. 5. Psychomotor agitation or retardation (observable by others, not just a subjective feeling of restlessness or slowness) almost every day. 6. Feeling fatigued or inactive almost every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) almost every day (not just remorse or guilt about being ill). 8. Poor ability to think or concentrate, or indecisiveness almost every day (either subjectively described or observed by others). 9. Recurrent thoughts of death (not just the fear of death), recurrent suicidal thoughts without a specific plan, or a specific plan to attempt or commit suicide.

[0148] Diagnostic criteria B through E described below are further explanations of MDD and may be considered explanations or diagnoses of MDD, but are not required.

[0149] Diagnostic Criterion B. Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0150] Criterion C. The episode cannot be attributed to the physiological effects of a substance or to another medical condition.

[0151] Criteria A-C may represent a major depressive episode.

[0152] Diagnostic Criterion D. The occurrence of a major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder or other specified and unspecified schizophrenia spectrum and other psychotic disorders.

[0153] Diagnostic Criterion E. Never had a manic or hypomanic episode.

[0154] In some embodiments, a major depressive episode (MDE) is a period characterized by the symptoms of MDD listed above.

[0155] In some embodiments, MDD is a clinical pathway characterized by one or more major depressive episodes (MDEs) in a subject.

[0156] In some embodiments, MDD is diagnosed according to diagnostic criteria A through C, as described above. In some embodiments, MDD is diagnosed according to diagnostic criteria A through E, as described above.

[0157] Diagnostic Features

[0158] The diagnostic criteria symptoms of major depressive disorder, except for weight change and suicidal ideation, must be present almost every day to be considered present. In addition to being present almost every day, depressed mood must be present for a large portion of the day. Often, insomnia or fatigue is the presenting complaint, leading to underdiagnosis if the patient fails to investigate the accompanying depressive symptoms. Sadness may be initially denied, but may be elicited by interview or inferred from facial expression and demeanor. For individuals who focus on somatic complaints, the clinician should determine whether the distress resulting from the complaint is related to a specific depressive symptom. Fatigue and sleep disturbance are present in a high percentage of cases. Psychomotor disorders are less common but are indicators of greater overall severity, as are delusional or delusional feelings of guilt.

[0159] The essential feature of a major depressive episode is a period of at least 2 weeks during which there is either a depressed mood or a loss of interest or pleasure in almost all activities (criterion A above). In children and adolescents, the mood may be irritable rather than sad. The individual must also experience at least four additional symptoms drawn from a list including: changes in appetite or weight, sleep and psychomotor activity; decreased motivation; feelings of worthlessness or guilt; difficulty thinking, concentrating or making decisions; or recurrent thoughts of death or suicidal ideation or suicide plans or suicide attempts. To count as a major depressive episode, the symptoms must be new or have clearly worsened compared with the person's pre-episode state. Symptoms must persist for most of the day, almost every day, for at least 2 consecutive weeks. The episode must be accompanied by clinically significant distress or impairment in social, occupational or other important areas of functioning. For some individuals with mild episodes, functioning may appear normal but requires significantly increased effort.

[0160] Sleep disturbances may take the form of either difficulty sleeping or excessive sleeping (criterion A4). When insomnia is present, it usually takes the form of intermediate insomnia (i.e., difficulty getting back to sleep after waking during the night) or end-stage insomnia (i.e., waking too early and not being able to get back to sleep). Early-stage insomnia (e.g., difficulty falling asleep) may also occur. Individuals with hypersomnia (excessive sleep) may experience longer sleep episodes at night or increased daytime sleepiness.

[0161] In some embodiments, MDD may have specifiers defined by DSM-5, such as "anxiety distress" or "elevated anxiety."

[0162] Major depressive disorder with anxiety distress

[0163] The DSM-5-defined identifier "anxiety distress" for MDD indicates the presence of at least two of the following symptoms during most days of a major depressive episode or persistent depressive disorder (dysthymia): 1. Feeling excited or nervous. 2. Feeling unusually restless. 3. Worrying makes it hard to concentrate. 4. You are afraid that something terrible might happen. 5. I feel like I'm losing control.

[0164] Severity is defined as follows: Mild: 2 symptoms. Moderate: 3 symptoms. Moderate to severe: 4 or 5 symptoms. Severe: Four or five symptoms with motor agitation.

[0165] "Anxiety distress" and "elevated anxiety" are used interchangeably herein.

[0166] Anxiety distress has been documented as a prominent feature of both bipolar disorder and major depressive disorder in both primary care and specialty mental health settings. High levels of anxiety have been associated with a higher suicide risk, longer duration of illness, and a higher likelihood of not responding to treatment.

[0167] Treatment-emergent gastrointestinal adverse events (TEAEs) are frequently observed in patients with major depressive disorder (MDD) while taking antidepressants and can lead to discontinuation of treatment. For example, one study (Oliva V. et al. Prog Neuropsychopharmacol Biol Psychiatry. 2021 Jul 13;109:110266) found that escitalopram and sertraline were the least tolerated antidepressants for the gastrointestinal tract, with all possible TEAEs (nausea / vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite and dry mouth) except for constipation and increased appetite.

[0168] Postpartum depression

[0169] In some embodiments, each of the methods described herein is also directed to a method of treating postpartum depression (PPD).

[0170] Postpartum depression (PPD), also called depression after childbirth, is a type of mood disorder that accompanies childbirth. Postpartum depression (PPD) is commonly known in the art.

[0171] PPD has been identified as the most common psychopathological illness occurring during the postpartum period (O'Hara MW, Wisner KL. Best Pract Res Clin Obstet Gynaecol. 2014;28(1):3-12); PPD can occur during the third trimester or after birth. If untreated, PPD can have devastating consequences for the woman and her family. In some embodiments, PPD is characterized by significant maternal functional impairment due to sadness and depressed mood, loss of interest in daily activities, changes in eating and sleeping habits, fatigue, and reduced motivation, inability to concentrate, and feelings of worthlessness, shame, or guilt. Postpartum depression also carries an increased risk for suicide, which is the leading cause of maternal death after childbirth in developed countries.

[0172] Professional health organizations vary in their definitions of PPD occurrence. For example, the American Psychiatric Association characterizes PPD as having an onset during pregnancy or within 4 weeks of delivery (DSM-5). The American College of Obstetricians and Gynecologists characterizes PPD as having an onset during pregnancy or within 12 months after delivery (ACOG, updated December 2021). The World Health Organization characterizes PPD as having an onset within 12 months after delivery (International Classification of Diseases 10 th edition (ICD-10). Thus, in some embodiments, a diagnosis of PPD treated by the methods described herein can be characterized as defined by DSM-5. In some embodiments, a diagnosis of PPD treated by the methods described herein can be characterized as defined by ACOG. In some embodiments, a diagnosis of PPD treated by the methods described herein can be characterized as defined by ICD-10.

[0173] In some embodiments, the diagnosis of PPD and / or PPD with elevated anxiety treated by the methods described herein is based on the criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders, 5 th It can be characterized as MDD with perinatal onset, as defined by the DSM-5 Edition (DSM-5), i.e., as described above.

[0174] In the case of perinatal onset (DSM-5 designator of depressive disorder)

[0175] This designation can be applied to a recent major depressive episode if the full diagnostic criteria are currently not met for a major depressive episode, or if the onset of mood symptoms occurred during pregnancy or within 4 weeks after delivery.

[0176] Mood episodes may have an occurrence either during pregnancy or after birth. Depending on the duration of postpartum follow-up, estimates vary, but 3% to 6% of women experience an occurrence of a major depressive episode during pregnancy or in the weeks or months after birth. Fifty percent of "postpartum" major depressive episodes actually begin before birth. These episodes are therefore collectively referred to as perinatal episodes. Women with perinatal major depressive episodes often have severe anxiety and even panic attacks. Prospective studies have demonstrated that mood and anxiety symptoms during pregnancy, as well as the "baby blues," increase the risk of a postpartum major depressive episode. Mood episodes occurring perinatally may manifest with or without psychiatric features. Infanticide is most often associated with a postpartum psychiatric episode characterized by command hallucinations to kill the infant or delusions that the infant is possessed, although psychiatric symptoms may also occur in severe postpartum mood episodes without such specific delusions or hallucinations.

[0177] Treatment An embodiment of the present disclosure is a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising: (i) about 40 mg to about 50 mg of compound (1), or a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound. [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0178] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1) or a pharma- ceutically acceptable salt thereof; [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant; wherein the subject is treatment naive.

[0179] In some embodiments, the subject is treatment naive.

[0180] In some embodiments, the subject has not received any antidepressant treatment within at least 30 days before the start of the first treatment.In some embodiments, the subject has not received additional antidepressant treatment within at least 30 days before the start of the first treatment.In some embodiments, the subject has not received additional antidepressant treatment within at least 60 days before the start of the first treatment.

[0181] In some embodiments, in the first treatment, the combination is administered for about 14 days. In some embodiments, in the second treatment, the additional antidepressant is administered for at least 28 days. In some embodiments, in the second treatment, the additional antidepressant is administered for at least 28 days. In some embodiments, in the second treatment, the additional antidepressant is administered for at least 28 days.

[0182] In some embodiments, the additional antidepressant is administered at the same dose in the first and second treatments. In some embodiments, the additional antidepressant is administered at different doses in the first and second treatments.

[0183] In some embodiments, Compound (1), or a pharma- ceutically acceptable salt thereof, is not administered to the subject in the second treatment.

[0184] In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the initial treatment are administered in separate dosage forms. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the initial treatment are administered simultaneously. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the initial treatment are administered at different times.

[0185] In some embodiments, the additional antidepressant is administered at the same dose in the first and second treatments. In some embodiments, the additional antidepressant is administered at different doses in the first and second treatments.

[0186] In some embodiments, the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the first treatment.

[0187] In some embodiments, the combination of Compound (1) or a pharma- ceutically acceptable salt thereof and an additional antidepressant is re-administered to the subject upon recurrence of depressive symptoms. In some embodiments, there is an interval of at least 6 weeks between the last dose of the initial treatment and the first dose of the re-administration.

[0188] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising: A therapeutically effective amount of compound (1) or a pharma- ceutically acceptable salt thereof. [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0189] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a treatment-naive subject in need thereof, comprising administering a therapeutically effective amount of Compound (1) or a pharma- ceutical acceptable salt thereof. [ka] and simultaneously commencing administration of a combination comprising a therapeutically effective amount of an additional antidepressant.

[0190] In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the treatment. In some embodiments, the subject has not received additional antidepressant treatment within at least 30 days prior to the treatment. In some embodiments, the subject has not received additional antidepressant treatment within at least 60 days prior to the treatment. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of the treatment. In some embodiments, the subject has not received additional antidepressant treatment within at least 30 days prior to the start of the treatment. In some embodiments, the subject has not received additional antidepressant treatment within at least 60 days prior to the start of the treatment.

[0191] In some embodiments, the combination is administered for about 14 days.

[0192] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant are administered in separate dosage forms. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant are administered simultaneously. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant are administered at different times.

[0193] In some embodiments, the treatment further comprises a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. In some embodiments, in the second treatment, the additional antidepressant is administered for at least 28 days. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof is not administered to the subject in the second treatment.

[0194] In some embodiments, the additional antidepressant is administered in the second treatment at the same dose as in the combination.In some embodiments, the additional antidepressant is administered in the second treatment at a different dose compared to the dose administered in the combination.In some embodiments, the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the combination.

[0195] In some embodiments, the subject has MDD. In some embodiments, the subject has MDD with elevated anxiety. In some embodiments, the subject is experiencing a major depressive episode. In some embodiments, the subject has elevated anxiety during the majority of days of the major depressive episode. In some embodiments, the subject has a HAM-D Anxiety / Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17, at least 18, at least 19, or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.

[0196] In some embodiments, the subject has PPD. In some embodiments, the subject has PPD with elevated anxiety. In some embodiments, the subject has experienced a major depressive episode with perinatal onset. In some embodiments, the subject has elevated anxiety during the majority of days of the major depressive episode with perinatal onset. In some embodiments, the subject has a HAM-D Anxiety / Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17, at least 18, at least 19, or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.

[0197] In some embodiments, administration of the combination reduces treatment-emergent gastrointestinal adverse events. In some embodiments, treatment-emergent gastrointestinal adverse events include nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof. In some embodiments, treatment-emergent gastrointestinal adverse events include nausea and / or diarrhea. In some embodiments, treatment-emergent gastrointestinal adverse events include nausea. In some embodiments, treatment-emergent gastrointestinal adverse events include diarrhea. In some embodiments, treatment-emergent gastrointestinal adverse events are due to treatment with an additional antidepressant.

[0198] In some embodiments, the combination of Compound (1) or a pharma- ceutically acceptable salt thereof and an additional antidepressant is re-administered to the subject upon recurrence of depressive symptoms. In some embodiments, there is an interval of at least 6 weeks between the last dose administered and the first dose administered.

[0199] In some embodiments, compound (1) is administered. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered.

[0200] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and about 40 mg to about 50 mg of Compound (1): [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0201] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound. [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0202] In one aspect, the disclosure provides a method of treating major depressive disorder with elevated anxiety (MDD) or postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and about 40 mg to about 50 mg of Compound (1): [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0203] In one aspect, the disclosure provides a method of treating major depressive disorder with elevated anxiety (MDD) or postpartum depression with elevated anxiety (PPD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound. [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0204] In some embodiments, the subject is treatment naive.

[0205] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 40 mg to about 50 mg of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0206] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound; [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0207] In one aspect, the present disclosure provides a method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof, comprising: (i) about 40 mg to about 50 mg of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0208] In one aspect, the present disclosure provides a method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof, comprising: (i) a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound; [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0209] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0210] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0211] In one aspect, the present disclosure provides a method of reducing gastrointestinal adverse events emerging under treatment with an antidepressant drug in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0212] In one aspect, the present disclosure provides a method of reducing gastrointestinal adverse events emerging under treatment with an antidepressant drug in a subject in need thereof, comprising: (i) a therapeutically effective amount of [ka] and a therapeutically effective amount of an additional antidepressant; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The present invention is directed to a method, comprising:

[0213] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine for about 14 days; thereafter (ii) administering for at least 28 days a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. The present invention is directed to a method, comprising:

[0214] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine for about 14 days; thereafter (ii) administering for at least 28 days a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. The present invention is directed to a method, comprising:

[0215] In one aspect, the present disclosure provides a method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine for about 14 days; thereafter (ii) administering for at least 28 days a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. The present invention is directed to a method, comprising:

[0216] In one aspect, the present disclosure provides a method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine for about 14 days; thereafter (ii) administering for at least 28 days a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. The present invention is directed to a method, comprising:

[0217] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) (a) about 50 mg of compound (1): [ka] and (b) providing an initial treatment comprising co-administering a therapeutically effective amount of an additional antidepressant for about 14 days, wherein compound (1) is administered once daily, and compound (1) and the additional antidepressant in the initial treatment are administered in separate dosage forms; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant for at least 28 days. The present invention is directed to a method, comprising:

[0218] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) (a) a pharma- ceutically acceptable salt of compound (1) in an amount equivalent to about 50 mg of the free base compound; [ka] and (b) providing an initial treatment comprising co-administering a therapeutically effective amount of an additional antidepressant for about 14 days, wherein the pharma- ceutically acceptable salt of Compound (1) is administered once daily, and the pharma-ceutically acceptable salt of Compound (1) and the additional antidepressant in the initial treatment are administered in separate dosage forms; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant for at least 28 days. The present invention is directed to a method, comprising:

[0219] In some embodiments, the subject is experiencing a major depressive episode. In some embodiments, the subject has elevated anxiety during the majority of days of the major depressive episode. In some embodiments, the subject has a HAM-D anxiety / somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 18 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.

[0220] In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 18 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 19 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 20 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-D anxiety / somatization subscale score of at least 7 at baseline.

[0221] In some embodiments, administering the combination reduces treatment-emergent gastrointestinal adverse events. In some embodiments, administering the first treatment reduces treatment-emergent gastrointestinal adverse events.

[0222] In some embodiments, the treatment-emergent gastrointestinal adverse events include nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof. In some embodiments, the treatment-emergent gastrointestinal adverse events include nausea and / or diarrhea. In some embodiments, the treatment-emergent gastrointestinal adverse events are due to treatment with an additional antidepressant.

[0223] In some embodiments, the subject is treatment naive. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received additional antidepressant treatment within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received additional antidepressant treatment within at least 60 days prior to the start of the first treatment.

[0224] In some embodiments, the combination is administered for about 14 days in the first treatment. In some embodiments, the additional antidepressant is administered for at least 28 days in the second treatment. In some embodiments, the additional antidepressant is administered at the same dose in the first treatment and the second treatment. In some embodiments, the additional antidepressant is administered at different doses in the first treatment and the second treatment. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is not administered to the subject in the second treatment.

[0225] In some embodiments, Compound (1) or a pharmaceutically acceptable salt thereof and the additional antidepressant in the first treatment are administered in separate dosage forms. In some embodiments, Compound (1) or a pharmaceutically acceptable salt thereof and the additional antidepressant in the first treatment are administered simultaneously. In some embodiments, Compound (1) or a pharmaceutically acceptable salt thereof and the additional antidepressant in the first treatment are administered at different times.

[0226] In some embodiments, the additional antidepressant is administered in the same dose in (i) and (ii). In some embodiments, the additional antidepressant is administered in different doses in (i) and (ii). In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is not administered to the subject in (ii). In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) and the additional antidepressant in (i) are administered. In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) and the additional antidepressant in (i) are administered simultaneously. In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) and the additional antidepressant in (i) are administered at different times. In some embodiments, the additional antidepressant administered in (ii) is the same as the additional antidepressant administered in (i).

[0227] In some embodiments, the combination of Compound (1) or a pharma- ceutically acceptable salt of Compound (1) and an additional antidepressant is re-administered to the subject upon recurrence of depressive symptoms. In some embodiments, there is an interval of at least 6 weeks between the last dose of the initial treatment and the first dose of the re-administration.

[0228] In each of the embodiments described herein, the methods directed to the treatment of MDD are also directed to the treatment of postpartum depression (PPD).

[0229] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0230] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0231] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0232] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0233] In one aspect, the disclosure provides a method for reducing gastrointestinal adverse events occurring under treatment with an antidepressant in a subject in need thereof, comprising administering a therapeutically effective amount of Compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0234] In one aspect, the disclosure provides a method for reducing gastrointestinal adverse events emerging under treatment with an antidepressant in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0235] In one aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine. wherein the subject is treatment naive.

[0236] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a therapeutically effective amount of a pharma- ceutically acceptable salt of Compound (1) to a subject in need thereof for about 14 days. [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine. wherein the subject is treatment naive.

[0237] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject from about 40 mg to about 50 mg of Compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. The method includes:

[0238] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a medicament for use in treating major depressive disorder (MDD) in a subject in need thereof a medicament for use in treating major depressive disorder in a subject in need thereof, the method comprising administering to a subject a medicament for use in treating major depressive disorder in a subject in need thereof ..., [ka] and administering a therapeutically effective amount of an additional antidepressant. The present invention relates to a method comprising:

[0239] In some embodiments, the subject is experiencing a major depressive episode. In some embodiments, the subject has elevated anxiety during the majority of days of the major depressive episode. In some embodiments, the subject has a HAM-D anxiety / somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 18 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.

[0240] In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 18 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 19 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 20 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-D anxiety / somatization subscale score of at least 7 at baseline.

[0241] In some embodiments, administering the combination reduces treatment-emergent adverse gastrointestinal events. In some embodiments, administering the combination reduces treatment-emergent adverse gastrointestinal events. In some embodiments, treatment-emergent adverse gastrointestinal events include nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof. In some embodiments, treatment-emergent adverse gastrointestinal events include nausea and / or diarrhea. In some embodiments, treatment-emergent adverse gastrointestinal events are due to treatment with an additional antidepressant.

[0242] In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of treatment.In some embodiments, the subject has not received additional antidepressant treatment within at least 30 days prior to the start of treatment.In some embodiments, the subject has not received additional antidepressant treatment within at least 60 days prior to the start of treatment.

[0243] In some embodiments, the treatment involves administering the combination for about 14 days.

[0244] In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the combination are administered in separate dosage forms. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the combination are administered simultaneously. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the combination are administered at different times.

[0245] In some embodiments, the treatment further comprises a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. In some embodiments, the second treatment administers the additional antidepressant for at least 28 days. In some embodiments, the additional antidepressant is administered in the second treatment at the same dose as in the combination. In some embodiments, the additional antidepressant is administered in a different dose in the second treatment compared to the dose administered in the combination. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is not administered to the subject in the second treatment. In some embodiments, the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the combination.

[0246] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and about 40 mg to about 50 mg of Compound (1): [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0247] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound. [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0248] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and about 40 mg to about 50 mg of Compound (1): [ka] , and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0249] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound. [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0250] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of Compound (1): [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, The antidepressant will continue to be administered after the 14th day of treatment. Subjects are treatment naive and subject to the method.

[0251] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. Subjects are treatment naive and subject to the method.

[0252] In one aspect, the disclosure provides a method for reducing gastrointestinal adverse events occurring under treatment with an antidepressant in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0253] In one aspect, the disclosure provides a method for reducing gastrointestinal adverse events emerging under treatment with an antidepressant in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Methods are covered wherein the antidepressant is administered continuously after the 14th day of treatment.

[0254] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of Compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. Of interest herein is the method, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine.

[0255] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. Of interest herein is the method, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine.

[0256] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of Compound (1): [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. Of interest herein is the method, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine.

[0257] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and, wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. Of interest herein is the method, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine.

[0258] In some embodiments, the subject is experiencing a major depressive episode. In some embodiments, the subject has elevated anxiety during the majority of days of the major depressive episode. In some embodiments, the subject has a HAM-D anxiety / somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 18 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.

[0259] In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 18 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 19 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 20 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-D anxiety / somatization subscale score of at least 7 at baseline.

[0260] In some embodiments, co-administration reduces treatment-emergent adverse gastrointestinal events. In some embodiments, co-administration reduces treatment-emergent adverse gastrointestinal events. In some embodiments, treatment-emergent adverse gastrointestinal events include nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof. In some embodiments, treatment-emergent adverse gastrointestinal events include nausea and / or diarrhea. In some embodiments, treatment-emergent adverse gastrointestinal events are due to treatment with an antidepressant.

[0261] In some embodiments, the subject is treatment-naive. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of co-administration. In some embodiments, the subject has not received additional antidepressant treatment within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received additional antidepressant treatment within at least 60 days prior to the start of the first treatment.

[0262] In some embodiments, the antidepressant continues to be administered for at least an additional 28 days after day 14 of treatment. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is not administered to the subject after day 14 of treatment.

[0263] In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and antidepressant in co-administration are administered in separate dosage forms. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and antidepressant in co-administration are administered simultaneously. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and antidepressant in co-administration are administered at different times. In some embodiments, the antidepressant is administered at the same dose from day 1 of treatment to about day 14 of treatment and after day 14 of treatment. In some embodiments, the antidepressant is administered at the same dose from day 1 of treatment to about day 14 of treatment and after day 14 of treatment.

[0264] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a treatment-naive subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] and simultaneously initiating administration of a combination comprising a therapeutically effective amount of an antidepressant.

[0265] In each of the embodiments described herein, the methods directed to the treatment of MDD are also directed to the treatment of postpartum depression (PPD).

[0266] The severity of the disorder treated by the methods described herein, for example, moderate or severe, can be characterized by methods known to those skilled in the art. These methods can include, but are not limited to, the following scales / assessments: Hamilton Depression Score (HAM-D), Hamilton Anxiety Score (HAM-A), Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression (CGI) scale, Clinical Global Impression-Improvement Scale (CGI-I), Clinical Global Impression-Severity of Illness (CGI-S), Clinical Global Impression-Change (CGI-C), Sheehan Disability Scale (SDS), 9-item Patient Health Questionnaire (PHQ-9) and Short Form 36 Health Survey version 2 (SF-36v2). Scoring for each of the above scales / assessments is based on each of the assessment measurements, and the results can be reported as total scores, subscale scores and / or single item scores.

[0267] The safety and tolerability of Compound (1) can be evaluated by methods known to those skilled in the art. These methods may include, but are not limited to, collection and summary of adverse events (AEs), clinical laboratory measures, vital signs, and 12-lead electrocardiography. Emergent suicidal thoughts and behaviors can be assessed using the Columbia Suicide Severity Rating Scale (C-SSRS). Sedation / sleeping can be assessed using the Stanford Sleepiness Scale (SSS). The Physician Withdrawal Checklist-20 total score (PWC-20) can be used to monitor the presence of potential withdrawal symptoms following cessation of treatment with Compound (1).

[0268] In some embodiments, the method provides a therapeutic effect. In some embodiments, the therapeutic effect is observed within about 42 (±3) days, about 35 (±3) days, about 28 (±3) days, about 21 (±1) days, about 18 (±1) days, about 15 (±1) days, about 12 (±1) days, about 8 (±1), about 3 (±1) days or about 1 day, as measured by a decrease in HAM-D total score. In some embodiments, the therapeutic effect is a decrease from baseline in HAM-D total score at the end of the first treatment period or the combination administration of compound (1) and an additional antidepressant, i.e., at the end of 14 days of administration of compound (1) and an additional antidepressant. In some embodiments, the therapeutic effect is a decrease from baseline in HAM-D total score at the end of the second treatment period. In some embodiments, the reduction in HAM-D total score from baseline is from severe (e.g., HAM-D total score of 24 or higher, or a score of 26 or higher) to asymptomatic, i.e., remission of depression (e.g., HAM-D total score of 7 or less). In some embodiments, the reduction in HAM-D total score from baseline is from severe (e.g., HAM-D total score of 24 or higher, or a total score of 26 or higher) to normal or mild depression (e.g., HAM-D total score of 7 or less, or a HAM-D total score of 18-13). In some embodiments, the change from baseline in HAM-D total score on day 3 (LS mean) is at least about 8-10. In some embodiments, the change from baseline in HAM-D total score on day 3 (LS mean) is at least about 8. In some embodiments, the change from baseline in HAM-D total score on day 3 (LS mean) is at least about 9. In some embodiments, the change from baseline (LS Mean) in HAM-D total score during the treatment period (i.e., first treatment or combination administration or co-administration) is at least about 11. In some embodiments, the change from baseline (LS Mean) in HAM-D total score during the treatment period (i.e., first treatment or combination administration or co-administration) is at least about 11.5.In some embodiments, the change from baseline (LS Mean) in HAM-D total score during the treatment period (ie, initial treatment or combination administration or co-administration) is at least about 12.

[0269] In some embodiments, the method provides a therapeutic benefit within about 42 (±3) days, about 35 (±3) days, about 28 (±3) days, about 21 (±1) days, about 18 (±1) days, about 15 (±1) days, about 12 (±1) days, about 8 (±1), about 3 (±1) days, or about 1 day, as measured by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (relating to outward sadness, verbal sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, lethargy, inability to feel, pessimistic thoughts, and suicidal thoughts) that psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. 0-6 indicates normal / no symptoms, 7-19 indicates mild depression, 20-34 indicates moderate depression, and >34 indicates severe depression. In some embodiments, the therapeutic effect is a reduction in MADRS total score from baseline at the end of a first treatment period or at the end of the combined administration of compound (1) and an additional antidepressant, i.e., at the end of 14 days of administration of compound (1) and an additional antidepressant. In some embodiments, the therapeutic effect is a reduction in MADRS total score from baseline at the end of a second treatment period. In some embodiments, the reduction in MADRS score from baseline is from severe (e.g., MADRS score of 30 or higher) to asymptomatic (e.g., MADRS score of 20 or less). In some embodiments, the change from baseline in MADRS total score at day 8 (LS mean) is at least about 12-14. In some embodiments, the change from baseline in MADRS total score at day 15 (LS mean) is at least about 16-18.

[0270] In some embodiments, the method provides a therapeutic effect within about 42 (±3) days, about 35 (±3) days, about 28 (±3) days, about 21 (±1) days, about 18 (±1) days, about 15 (±1) days, about 12 (±1) days, about 8 (±1), about 3 (±1) days, or about 1 day, as measured by a reduction in the Hamilton Anxiety Score (HAM-A). The HAM-A is scored, where <17 indicates mild severity, 18-24 indicates mild to moderate severity, and 25-30 indicates moderate to severe. In some embodiments, the therapeutic effect is a reduction in the HAM-A score from baseline at the end of the initial treatment period or at the end of the combined administration of compound (1) and the additional antidepressant, i.e., at the end of 14 days of administration of compound (1) and the additional antidepressant. In some embodiments, the therapeutic effect is a reduction in HAM-A score from baseline at the end of the second treatment period. In some embodiments, the reduction in HAM-A score from baseline is from severe (e.g., HAM-A score of 25 or higher) to asymptomatic (e.g., HAM-A score of 17 or lower). In some embodiments, the reduction in HAM-A score from baseline is from severe (e.g., HAM-A score of 25 or higher) to mild (e.g., HAM-A score of 24 or lower). In some embodiments, the change from baseline in HAM-A total score at day 3 (LS mean) is at least about 9. In some embodiments, the change from baseline in HAM-A total score at day 8 (LS mean) is at least about 11. In some embodiments, the change from baseline in HAM-A total score at day 15 (LS mean) is at least about 14.

[0271] Additional antidepressants

[0272] In some embodiments, the antidepressant in the first and second treatments, or combination, or co-administration is a selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), serotonin modulators and stimulators (SMS), serotonin antagonists and reuptake inhibitors (SARI), norepinephrine reuptake inhibitors (NRI), norepinephrine dopamine reuptake inhibitors (NDRI), tricyclic antidepressants (TCA), tetracyclic antidepressants (TeCA), monoamine oxidase inhibitors (MAOI), atypical antipsychotics, agomelatine, esketamine, tianeptine, ketamine, alpha-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademetionine, hypericum perforatum, oxytriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine or tranylcypromine and trifluoperazine.

[0273] In some embodiments, the antidepressant in the first and second treatment, or combination, or co-administration is 4-chlorokynurenine (AV-101), apimostinel (NRX-1074), arketamine (PCN-101, HR-071603), dextromethadone (REL-1017), MIJ-821, lisrenemdaz (CERC-301, MK-0657), TAK-653 (NBI-1065845), OPC-64005, PDC-1421 (BLI-1005), Toludesvenlafaxine, Hypidone (YL-0919), TGBA01AD (FKB01MD), Vortioxetine, Lisdexamfetamine, Midomafetamine, Aramisulpride / esamisulpride (85:15 ratio) (SEP-4199), Gepirone, Pramipexole, Psilocybin, Briraloxazine, Cariprazine , lumateperone, lurasidone, pimavanserin, ademetionine, 3β-methoxypregnenolone (MAP-4343), PH-10-vomeropherin, aticaplant, BTRX-335140 (BTRX-140), buprenorphine / samidorphan, BTRX-246040 (LY-2940094), scopolamine (DPI-386), JNJ-39393406, onabotulinumtoxinA, JNJ-61393215, celtrexant, BI-135889 4, crisdesalazine, elteberel, JNJ-54175446, NSI-189, NV-5138, SNG-12, TS-121, WIP-DF17, tramadol, bupropion / dextromethorphan (AXS-05; Auvelity™), carbidopa / oxytriptan (EVX-101), cycloserine / lurasidone (NRX-101; Cyclerad) or deuxomethorphan / quinidine (AVP-786, CTP-786).

[0274] In some embodiments, the antidepressant in the first or second treatment, or combination, or co-administration is SSRI.In some embodiments, the SSRI is sertraline, escitalopram, citalopram, fluvoxamine, paroxetine, fluoxetine, indalpine or zimelidine.In some embodiments, the SSRI is sertraline.In some embodiments, the SSRI is escitalopram.In some embodiments, the SSRI is citalopram.

[0275] In some embodiments, the antidepressant in the first or second treatment, or combination, or co-administration is an SNRI.In some embodiments, the SNRI is duloxetine, desvenlafaxine, levomilnacipran, milnacipran or venlafaxine.In some embodiments, the SNRI is duloxetine.In some embodiments, the SNRI is desvenlafaxine.

[0276] In some embodiments, the antidepressant in the first or second treatment, or in the combination, or in co-administration, is an SMS, hi some embodiments, the SMS is vilazodone or vortioxetine.

[0277] In some embodiments, the antidepressant in the first or second treatment, or in the combination, or in co-administration, is a SARI, hi some embodiments, the SARI is nefazodone, trazodone, or etoperidone.

[0278] In some embodiments, the antidepressant in the first or second treatment, or in the combination, or in co-administration, is an NRI, hi some embodiments, the NRI is reboxetine, teniloxazine, viloxazine, or atomoxetine.

[0279] In some embodiments, the antidepressant in the first or second treatment, or in the combination, or in co-administration, is a NDRI. In some embodiments, the NDRI is bupropion, amphetamine, methylphenidate, modafinil, amineptine, or nomifensine.

[0280] In some embodiments, the antidepressant in the first or second treatment, or combination, or co-administration is a TCA. In some embodiments, the TCA is amitriptyline, amitriptyline oxide, clomipramine, desipramine, dibenzazepine, dimethacrine, dosluepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, notriptyline, noxiptyline, opipramol, pipofezin, protriptyline, trimipramine, butriptyline, demexiptyline, fluacizine, imipramine oxide, iprindole, metapramine, propizepine, quinupramine, thiazesim or tofenacin.

[0281] In some embodiments, the antidepressant in the first or second treatment, or in the combination, or in co-administration, is TeCA. In some embodiments, the TeCA is amoxapine, maprotiline, mianserin, mirtazapine, or setiptiline.

[0282] In some embodiments, the antidepressant in the first or second treatment, or combination, or co-administration is an MAOI. In some embodiments, the MAOI is isocarboxazid, phenelzine, tranylcypromine, benmoxine, iproclozide, iproniazid, mebanazine, nialamide, octamoxine, pheniprazine, phenoxypropazine, pibhydrazine, safrazine, selegiline, caroxazone, metralindole, moclobemide, pirlindole, eprobemide, minaprine, toloxatone, or bifemelane.

[0283] In some embodiments, the antidepressant in the first or second treatment, or combination, or co-administration is an atypical antipsychotic.In some embodiments, the atypical antipsychotic is amisulpride, lumateperone, lurasidone, quetiapine, aripiprazole, brexpiprazole, lumateperone, lurasidone, olanzapine, quetiapine, or risperidone.

[0284] In some embodiments, the antidepressant in the first or second treatment, or combination, or co-administration is agomelatine, esketamine, tianeptine, ketamine, alpha-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademethionine, hypericum perforatum, oxytriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine, or tranylcypromine and trifluoperazine.

[0285] In some embodiments, the antidepressant in the first or second treatment, or in the combination, or co-administration, is administered according to its labeled prescribing information.

[0286] In some embodiments, co-administration refers to the simultaneous initiation of administration of said compound (1), or a pharma- ceutically acceptable salt; and said antidepressant.

[0287] In some embodiments, the SSRI is sertraline and is administered at a dose of about 50 mg to about 200 mg, or about 50 mg to about 100 mg, or about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg. In some embodiments, the dose of sertraline is increased by about 25 to about 50 mg per day of administration. In some embodiments, sertraline is administered at a dose of about 50 mg. In some embodiments, sertraline is administered at a dose of about 100 mg. In some embodiments, sertraline is administered at a dose of about 150 mg. In some embodiments, sertraline is administered at a dose of about 200 mg.

[0288] In some embodiments, the SSRI is citalopram and is administered at a dose of about 10 mg to about 40 mg, or about 15 mg to about 30 mg, or about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg. In some embodiments, citalopram is administered at a dose of about 20 mg. In some embodiments, citalopram is administered at a dose of about 30 mg. In some embodiments, citalopram is administered at a dose of about 40 mg.

[0289] In some embodiments, the SSRI is escitalopram and is administered at a dose of about 10 mg to about 40 mg, or about 15 mg to about 30 mg, or about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg. In some embodiments, the escitalopram is administered at a dose of about 10 mg. In some embodiments, the escitalopram is administered at a dose of about 15 mg. In some embodiments, the escitalopram is administered at a dose of about 20 mg.

[0290] In some embodiments, the SNRI is duloxetine and is administered at a dose of about 40 mg to about 120 mg, or about 60 mg to about 100 mg, or about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg. In some embodiments, duloxetine is administered at a dose of about 40 mg. In some embodiments, duloxetine is administered at a dose of about 60 mg.

[0291] In some embodiments, the SNRI is desvenlafaxine and is administered at a dose of about 10 mg to about 100 mg, or about 20 mg to about 50 mg, or about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg. In some embodiments, desvenlafaxine is administered at a dose of about 50 mg.

[0292] Dosage

[0293] In some embodiments, compound (1) is administered. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered. In some embodiments, compound (1) is present in a non-deuterated form. In some embodiments, compound (1) is present in a deuterated form. In some embodiments, the deuterated form of compound (1) is as disclosed and described in PCT Publication No. WO2019 / 113494 and U.S. Application No. 17 / 545,290, the entire contents of which are incorporated herein by reference in their entirety.

[0294] In some embodiments, compound (1) is administered at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) is administered at a dose of about 15 mg to about 75 mg. In some embodiments, compound (1) is administered at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg. In some embodiments, compound (1) is administered at a dose of about 50 mg. In some embodiments, compound (1) is administered at a dose of about 40 mg.

[0295] In some embodiments, compound (1) is administered once daily at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) is administered once daily at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) is administered once daily at a dose of about 50 mg. In some embodiments, compound (1) is administered once daily at a dose of about 40 mg.

[0296] In some embodiments, compound (1) is administered at a dose of about 50 mg once a day for less than two weeks. In some embodiments, compound (1) is administered at a dose of about 50 mg once a day for about 14 days. In some embodiments, compound (1) is administered at a dose of about 40 mg once a day for less than two weeks. In some embodiments, compound (1) is administered at a dose of about 40 mg once a day for about 14 days.

[0297] In some embodiments, the patient is administered Compound (1) at night. In some embodiments, the patient is administered Compound (1) within 1 hour before the patient goes to sleep. In some embodiments, the patient is administered Compound (1) within 15 minutes before the patient goes to sleep.

[0298] In some embodiments, compound (1) is administered with food. In some embodiments, compound (1) is administered with a fat-containing meal. Examples of fat-containing meals include nuts, peanut butter, avocado, eggs and cheese. In some embodiments, compound (1) is administered with a fat-containing meal at night (e.g., within 1 hour of a fat-containing dinner or with a fat-containing snack).

[0299] In some embodiments, Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalation, intranasally, or transdermally. In some embodiments, Compound (1) is administered orally.

[0300] In some embodiments, Compound (1) is administered in one or more capsules. In some embodiments, the therapeutically effective amount is administered over two capsules. In some embodiments, the therapeutically effective amount is administered over three capsules. In some embodiments, the therapeutically effective amount is administered over two capsules, with at least one capsule containing about 20 mg of Compound (1). In some embodiments, the therapeutically effective amount is administered over two capsules, with at least one capsule containing about 25 mg of Compound (1). In some embodiments, the therapeutically effective amount is administered over two capsules, with at least one capsule containing about 30 mg of Compound (1). In some embodiments, the therapeutically effective amount is administered over two capsules, with each capsule containing about 20 mg of Compound (1). In some embodiments, the therapeutically effective amount is administered over two capsules, with each capsule containing about 25 mg of Compound (1). In some embodiments, the therapeutically effective amount is administered over two capsules, one capsule containing about 30 mg of Compound (1) and another capsule containing about 20 mg of Compound (1).

[0301] In other embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 15 mg to about 75 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 40 mg of the free base compound.

[0302] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 40 mg of the free base compound.

[0303] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 50 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 50 mg of the free base compound for about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for about 14 days.

[0304] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at night. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered within 1 hour before the subject goes to sleep. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered within 15 minutes before the subject goes to sleep.

[0305] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered with food. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered with a fat-containing meal. Examples of fat-containing meals include nuts, peanut butter, avocado, eggs and cheese. In some embodiments, Compound (1) is administered with a fat-containing meal at night (e.g., within 1 hour of a fat-containing dinner or with a fat-containing snack).

[0306] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalation, intranasally, or transdermally. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered orally.

[0307] In some embodiments, a pharma- ceutically acceptable salt of Compound (1) is administered chronically.

[0308] In some embodiments, the initial treatment involves administering the combination of Compound (1), or a pharma- ceutically acceptable salt thereof, and an additional antidepressant for about 14 days.

[0309] In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the initial treatment are administered in separate dosage forms. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the initial treatment are administered simultaneously. In some embodiments, compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the initial treatment are administered at different times.

[0310] In some embodiments, in the second treatment, the additional antidepressant is administered for at least 28 days.

[0311] In some embodiments, the additional antidepressant is administered at the same dose in the first and second treatments. In some embodiments, the additional antidepressant is administered at different doses in the first and second treatments.

[0312] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is not administered to the subject in the second treatment.

[0313] In some embodiments, the combination of Compound (1) or a pharma- ceutically acceptable salt of Compound (1) and an additional antidepressant is re-administered to the subject upon recurrence of depressive symptoms. In some embodiments, there is an interval of at least 6 weeks between the last dose of the initial treatment and the first dose of the re-administration.

[0314] In some embodiments, the combination of Compound (1) or a pharma- ceutically acceptable salt thereof and an additional antidepressant may be administered in combination with another drug. The administration in combination with another drug may proceed by any technique apparent to one skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0315] In some embodiments, in the second treatment, the additional antidepressant may be administered in combination with another drug. The administration in combination with another drug may proceed by any technique that is obvious to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration and alternating administration.

[0316] Crystal form of compound (1)

[0317] In some embodiments, compound (1) is in a crystalline form. In some embodiments, the crystalline form of compound (1) is any of the crystalline forms disclosed in PCT Publication No. WO2018 / 039378, the entire contents of which are incorporated herein by reference.

[0318] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.7 and 10.1 degrees 2θ (inclusive), between 11.6 and 12.0 degrees 2θ (inclusive), between 13.2 and 13.6 degrees 2θ (inclusive), between 14.2 and 14.6 degrees 2θ (inclusive), between 14.6 and 15.0 degrees 2θ (inclusive), between 16.8 and 17.2 degrees 2θ (inclusive), between 20.5 and 20.9 degrees 2θ (inclusive), between 21.3 and 21.7 degrees 2θ (inclusive), between 21.4 and 21.8 degrees 2θ (inclusive), and between 22.4 and 22.8 degrees 2θ (inclusive). In some embodiments, compound (1) is in a crystalline form having an XRPD pattern that includes peaks between 9.7 and 10.1 degrees 2θ (inclusive), between 14.6 and 15.0 degrees 2θ (inclusive), between 16.8 and 17.2 degrees 2θ (inclusive), between 20.5 and 20.9 degrees 2θ (inclusive), and between 21.3 and 21.7 degrees 2θ (inclusive).

[0319] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ (inclusive), between 10.6 and 11.0 degrees 2θ (inclusive), between 13.0 and 13.4 degrees 2θ (inclusive), between 14.7 and 15.1 degrees 2θ (inclusive), between 15.8 and 16.2 degrees 2θ (inclusive), between 18.1 and 18.5 degrees 2θ (inclusive), between 18.7 and 19.1 degrees 2θ (inclusive), between 20.9 and 21.3 degrees 2θ (inclusive), between 21.4 and 21.8 degrees 2θ (inclusive), and between 23.3 and 23.7 degrees 2θ (inclusive). In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ (inclusive), between 10.6 and 11.0 degrees 2θ (inclusive), between 13.0 and 13.4 degrees 2θ (inclusive), between 18.7 and 19.1 degrees 2θ (inclusive), and between 21.4 and 21.8 degrees 2θ (inclusive).

[0320] In some embodiments, the crystalline form of Compound (1) comprises a mixture of two or more crystalline forms.

[0321] Pharmaceutical Compositions

[0322] Another aspect of the present disclosure provides a pharmaceutical composition comprising Compound (1) (also referred to as "active ingredient") and a pharma- ceutically acceptable excipient for use in the combinations and methods described herein. In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharma- ceutically acceptable salt of the active ingredient and a pharma- ceutically acceptable excipient for use in the combinations and methods described herein. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient, or a pharma- ceutically acceptable salt of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient, or a pharma- ceutically acceptable salt of the active ingredient. In some embodiments, the pharmaceutical composition of Compound (1) is any of the pharmaceutical compositions disclosed in PCT Publication No. WO2022 / 020363A9, the entire contents of which are incorporated herein by reference in their entirety.

[0323] The pharmaceutical compositions provided herein can be administered by various routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM) and intranasal. In some embodiments, the pharmaceutical composition is administered orally.

[0324] The pharmaceutical composition of the present invention may further be delivered using various dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, for example, to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic level of the active ingredient desired throughout the body, for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., by IV drip) allows for a much faster delivery that quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example, by IV drip, to achieve the maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still other embodiments, the pharmaceutical composition may be administered first as a bolus dose and then as a continuous infusion.

[0325] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, compositions are supplied in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in combination with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules, and the like, for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

[0326] The above components of the orally administrable, injectable or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0327] The compositions of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0328] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to all kinds of animals.It is well understood that modifying pharmaceutical compositions suitable for administration to humans to make the composition suitable for administration to various animals is possible, and a skilled veterinary pharmacologist can use routine experimentation to design and / or carry out such modifications.General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.

[0329] kit

[0330] Another embodiment of the present disclosure provides a kit comprising a pharmaceutical composition comprising Compound (1), an additional antidepressant, and an instruction set describing the methods for treating major depressive episode (MDD) or postpartum depression (PPD) as described herein.

[0331] In one aspect, the disclosure provides a kit comprising a pharmaceutical composition comprising about 40 mg to about 50 mg of Compound (1), an additional antidepressant, and a set of instructions describing a method for treating major depressive episode (MDD) or postpartum depression (PPD), the method resulting in (i) a first treatment comprising administration of a combination of a pharmaceutical composition comprising Compound (1) and an additional antidepressant, and (ii) a second treatment comprising administration of the additional antidepressant.

[0332] In one aspect, the disclosure provides a kit comprising a pharmaceutical composition comprising Compound (1) and a combination of an additional antidepressant, as well as a set of instructions describing how to use the combination to treat major depressive episode (MDD) or postpartum depression (PPD) in a treatment-naive subject.

[0333] Another aspect of the disclosure includes a kit comprising a plurality of therapeutically effective dosages of Compound (1), a plurality of therapeutically effective dosages of an additional antidepressant, and a set of instructions describing how to administer the dosages to treat major depressive episode (MDD) or postpartum depression (PPD) in a treatment-naive subject. In some embodiments, the method of administering the dosages is any one of the methods described herein.

[0334] In some embodiments, the dosage of Compound (1) is an individual dosage unit of Compound (1). In some embodiments, the individual dosage unit contains about 20 mg to about 30 mg of Compound (1). In some embodiments, the individual dosage unit contains about 20 mg of Compound (1). In some embodiments, the individual dosage unit contains about 25 mg of Compound (1). In some embodiments, the individual dosage unit contains about 30 mg of Compound (1). In some embodiments, the individual dosage unit of Compound (1) is a capsule or tablet. In some embodiments, the individual dosage unit of Compound (1) is a capsule. In some embodiments, the individual dosage unit of Compound (1) is a capsule of size 1, 2, 3 or 4. In some embodiments, the capsule is size 1. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the capsule further comprises a specified amount of Compound (1) (e.g., 20 mg, 25 mg, or 30 mg) plus croscarmellose sodium, mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, and sodium stearyl fumarate. In some embodiments, a plurality of therapeutically effective dosages of Compound (1) comprises two capsules. In some embodiments, a plurality of therapeutically effective dosages of Compound (1) comprises three capsules.

[0335] In some embodiments, the dosage of the additional antidepressant is an individual dosage unit of the additional antidepressant. In some embodiments, the additional antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. In some embodiments, the individual dosage units of the additional antidepressant are packaged and labeled by a commercial manufacturer.

[0336] In some embodiments, the additional antidepressant is sertraline. In some embodiments, the dosage of the additional antidepressant is an individual dosage unit of sertraline. In some embodiments, the individual dosage unit of sertraline is a tablet. In some embodiments, the individual dosage unit of sertraline contains about 25 mg, 50 mg, or 100 mg of sertraline. In some embodiments, the individual dosage unit of sertraline is a container containing a liquid concentrate, where each 1 mL of concentrate is equivalent to 20 mg of sertraline. In some embodiments, the additional antidepressant is escitalopram. In some embodiments, the dosage of the additional antidepressant is an individual dosage unit of escitalopram. In some embodiments, the individual dosage unit of escitalopram is a tablet. In some embodiments, the individual dosage unit of escitalopram contains about 5 mg, 10 mg, or 20 mg of escitalopram. In some embodiments, the additional antidepressant is citalopram. In some embodiments, the dosage of the additional antidepressant is an individual dosage unit of citalopram. In some embodiments, the individual dosage unit of citalopram is a tablet. In some embodiments, the individual dosage unit of citalopram contains about 10 mg, 20 mg, or 40 mg of citalopram. In some embodiments, the additional antidepressant is duloxetine. In some embodiments, the dosage of the additional antidepressant is an individual dosage unit of duloxetine. In some embodiments, the individual dosage unit of duloxetine is a capsule. In some embodiments, the individual dosage unit of duloxetine contains about 20 mg, 30 mg, or 60 mg of duloxetine. In some embodiments, the additional antidepressant is desvenlafaxine. In some embodiments, the dosage of the additional antidepressant is an individual dosage unit of desvenlafaxine. In some embodiments, the individual dosage unit of desvenlafaxine is a tablet. In some embodiments, individual dosage units of desvenlafaxine contain about 25 mg, 50 mg, or 100 mg of desvenlafaxine.

[0337] In some embodiments, the instruction set is printed on a suitable material.

[0338] Other embodiments The embodiments of the subject matter disclosed herein may be advantageous alone or in combination with one or more other embodiments. Without limiting the above description, certain non-limiting embodiments of the present disclosure are presented below, namely numbered 1 to 258. Upon reading this disclosure, it will be clear to one skilled in the art that each individually numbered embodiment may be used or combined with any of the individually numbered embodiments before or after it. This is intended to provide support for all such combinations of embodiments, and is not limited to the combinations of embodiments explicitly presented below.

[0339] Embodiments of the present disclosure:

[0340] Embodiment 1. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 40 mg to about 50 mg of compound (1) [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject. (ii) providing a second treatment, comprising administering a therapeutically effective amount of an additional antidepressant. A method comprising:

[0341] Embodiment 2. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound; [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The method includes:

[0342] Embodiment 3. A method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof, comprising: (i) about 40 mg to about 50 mg of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The method includes:

[0343] Embodiment 4. A method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof, comprising: (i) a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound; [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The method includes:

[0344] Embodiment 5. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0345] Embodiment 6. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0346] Embodiment 7. A method of reducing gastrointestinal adverse events emerging under treatment with an antidepressant in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant to the subject; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The method includes:

[0347] Embodiment 8. A method of reducing gastrointestinal adverse events emerging under treatment with an antidepressant in a subject in need thereof, comprising: (i) a therapeutically effective amount of [ka] and a therapeutically effective amount of an additional antidepressant; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant. The method includes:

[0348] Embodiment 9. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine for about 14 days; thereafter (ii) administering for at least 28 days a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. The method includes:

[0349] Embodiment 10. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine for about 14 days; thereafter (ii) administering for at least 28 days a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. The method includes:

[0350] Embodiment 11. A method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine for about 14 days; thereafter (ii) administering for at least 28 days a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. The method includes:

[0351] Embodiment 12. A method of treating major depressive disorder with elevated anxiety (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine for about 14 days; thereafter (ii) administering for at least 28 days a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine. The method includes:

[0352] Embodiment 13. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) (a) about 50 mg of compound (1): [ka] and (b) providing an initial treatment comprising co-administering a therapeutically effective amount of an additional antidepressant for about 14 days, wherein compound (1) is administered once daily, and compound (1) and the additional antidepressant in the initial treatment are administered in separate dosage forms; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant for at least 28 days. The method includes:

[0353] Embodiment 14. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) (a) a pharma- ceutically acceptable salt of compound (1) in an amount equivalent to about 50 mg of the free base compound; [ka] and (b) providing an initial treatment comprising co-administering a therapeutically effective amount of an additional antidepressant for about 14 days, wherein the pharma- ceutically acceptable salt of Compound (1) is administered once daily, and the pharma-ceutically acceptable salt of Compound (1) and the additional antidepressant in the initial treatment are administered in separate dosage forms; and (ii) providing a second treatment comprising administering a therapeutically effective amount of an additional antidepressant for at least 28 days. The method includes:

[0354] Embodiment 15. The method of any one of embodiments 1, 2, 9 or 10, wherein the subject is experiencing a major depressive episode.

[0355] Embodiment 16. The method of embodiment 15, wherein the subject has elevated anxiety during most days of a major depressive episode.

[0356] Embodiment 17. The method of any one of embodiments 3, 4, 11, or 12, wherein the subject has a HAM-D Anxiety / Somatization subscale score of at least 7 at baseline.

[0357] Embodiment 18. The method of any one of embodiments 3, 4, 11 or 12, wherein the subject has a HAM-A total score of at least 17 or at least 20 at baseline.

[0358] Embodiment 19. The method of any one of embodiments 1-6 or 9-12, wherein administering the combination reduces treatment-emergent gastrointestinal adverse events.

[0359] Embodiment 20. The method of embodiment 13 or 14, wherein administering the initial treatment reduces treatment-emergent gastrointestinal adverse events.

[0360] Embodiment 21. The method of any one of embodiments 7, 8, 19, or 20, wherein the treatment-emergent gastrointestinal adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.

[0361] Embodiment 22. The method of embodiment 21, wherein the treatment-emergent gastrointestinal adverse events comprise nausea and / or diarrhea.

[0362] Embodiment 23. The method of any one of embodiments 7, 8, or 19-22, wherein the treatment-emergent gastrointestinal adverse event is due to treatment with an additional antidepressant.

[0363] Embodiment 24. The method of any one of embodiments 1-4 or 7-23, wherein the subject has not undergone treatment.

[0364] Embodiment 25. The method of any one of embodiments 1-4 or 7-23, wherein the subject has not received any antidepressant treatment within at least 30 days prior to the start of the first treatment.

[0365] Embodiment 26. The method of any one of embodiments 1-4 or 7-23, wherein the subject has not received additional antidepressant treatment within at least 30 days prior to the start of the first treatment.

[0366] Embodiment 27. The method of any one of embodiments 1-4 or 7-23, wherein the subject has not received additional antidepressant treatment within at least 60 days prior to the start of the first treatment.

[0367] Embodiment 28. The method of any one of embodiments 1-8, wherein the initial treatment involves administering the combination for about 14 days.

[0368] Embodiment 29. The method of any one of embodiments 1-8, wherein in the second treatment, an additional antidepressant is administered for at least 28 days.

[0369] Embodiment 30. The method of any one of embodiments 1-8, wherein the additional antidepressant is administered at the same dose in the first treatment and the second treatment.

[0370] Embodiment 31. The method of any one of embodiments 1-8, wherein the additional antidepressant is administered at different doses in the first treatment and the second treatment.

[0371] Embodiment 32. The method of any one of embodiments 1-8, wherein Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is not administered to the subject in the second treatment.

[0372] Embodiment 33. The method of any one of embodiments 1-8, wherein the compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the initial treatment are administered in separate dosage forms.

[0373] Embodiment 34. The method of embodiment 33, wherein the compound (1) or a pharma- ceutically acceptable salt thereof in the initial treatment and the additional antidepressant are administered simultaneously.

[0374] Embodiment 35. The method of embodiment 33, wherein the compound (1), or a pharma- ceutically acceptable salt thereof, in the initial treatment and the additional antidepressant are administered at different times.

[0375] Embodiment 36. The method of any one of embodiments 9-14, wherein the additional antidepressant is administered in (i) and (ii) at the same dose.

[0376] Embodiment 37. The method of any one of embodiments 9-14, wherein the additional antidepressant is administered in (i) and (ii) at different doses.

[0377] Embodiment 38. The method of any one of embodiments 9-14, wherein compound (1) or a pharma- ceutically acceptable salt of compound (1) is not administered to the subject in (ii).

[0378] Embodiment 39. The method of any one of embodiments 9-14, wherein compound (1) or a pharma- ceutically acceptable salt thereof in (i) and the additional antidepressant are administered in separate dosage forms.

[0379] Embodiment 40. The method of embodiment 39, wherein compound (1) or a pharma- ceutically acceptable salt thereof in (i) and the additional antidepressant are administered simultaneously.

[0380] Embodiment 41. The method of embodiment 39, wherein compound (1) or a pharma- ceutically acceptable salt thereof in (i) and the additional antidepressant are administered at different times.

[0381] Embodiment 42. The method of any one of embodiments 1-41, wherein the additional antidepressant administered in (ii) is the same as the additional antidepressant administered in (i).

[0382] Embodiment 43. The method of any one of embodiments 1-12, wherein compound (1), or a pharma- ceutically acceptable salt thereof, is administered once daily.

[0383] Embodiment 44. The method of any one of embodiments 5, 7, 9, or 11, wherein Compound (1) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg.

[0384] Embodiment 45. The method of any one of embodiments 1, 3, or 44, wherein compound (1) is administered at a dose of about 50 mg.

[0385] Embodiment 46. The method of any one of embodiments 1, 3, or 44, wherein compound (1) is administered at a dose of about 40 mg.

[0386] Embodiment 47. The method of embodiment 45, wherein compound (1) is administered once a day at a dose of about 50 mg.

[0387] Embodiment 48. The method of embodiment 46, wherein compound (1) is administered once a day at a dose of about 40 mg.

[0388] Embodiment 49. The method of any one of embodiments 6, 8, 10, 12, wherein a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of the free base compound.

[0389] Embodiment 50. The method of any one of embodiments 2, 4, or 49, wherein a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 50 mg of the free base compound.

[0390] Embodiment 51. The method of any one of embodiments 2, 4, or 49, wherein a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 40 mg of the free base compound.

[0391] Embodiment 52. The method of embodiment 50, wherein a pharma- ceutically acceptable salt of compound (1) is administered once daily in a dose equivalent to about 50 mg of the free base compound.

[0392] Embodiment 53. The method of embodiment 51, wherein a pharma- ceutically acceptable salt of compound (1) is administered once daily in a dose equivalent to about 40 mg of the free base compound.

[0393] Embodiment 54. The method of any one of embodiments 1 to 53, wherein Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalation, intranasally, or transdermally.

[0394] Embodiment 55. The method of embodiment 54, wherein Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally.

[0395] Embodiment 56. The method of any one of embodiments 1-55, wherein Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered with food.

[0396] Embodiment 57. The method of any one of embodiments 1-56, wherein Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once daily in the evening.

[0397] Embodiment 58. The method of any one of embodiments 1 to 57, wherein the combination of Compound (1) or a pharma- ceutically acceptable salt of Compound (1) and an additional antidepressant is re-administered to the subject upon recurrence of depressive symptoms.

[0398] Embodiment 59. The method of embodiment 58, wherein there is an interval of at least 6 weeks between the final dose of the initial treatment and the first dose of the readministration.

[0399] Embodiment 60. The method of any one of embodiments 1, 3, 5, 7, 9, 11, or 13, wherein compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.7 and 10.1 degrees 2θ [inclusive], between 11.6 and 12.0 degrees 2θ [inclusive], between 13.2 and 13.6 degrees 2θ [inclusive], between 14.2 and 14.6 degrees 2θ [inclusive], between 14.6 and 15.0 degrees 2θ [inclusive], between 16.8 and 17.2 degrees 2θ [inclusive], between 20.5 and 20.9 degrees 2θ [inclusive], between 21.3 and 21.7 degrees 2θ [inclusive], between 21.4 and 21.8 degrees 2θ [inclusive], and between 22.4 and 22.8 degrees 2θ [inclusive].

[0400] Embodiment 61. The method of any one of embodiments 1, 3, 5, 7, 9, 11, or 13, wherein compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ [inclusive], between 10.6 and 11.0 degrees 2θ [inclusive], between 13.0 and 13.4 degrees 2θ [inclusive], between 14.7 and 15.1 degrees 2θ [inclusive], between 15.8 and 16.2 degrees 2θ [inclusive], between 18.1 and 18.5 degrees 2θ [inclusive], between 18.7 and 19.1 degrees 2θ [inclusive], between 20.9 and 21.3 degrees 2θ [inclusive], between 21.4 and 21.8 degrees 2θ [inclusive], and between 23.3 and 23.7 degrees 2θ [inclusive].

[0401] Embodiment 62. The method of any one of embodiments 1, 3, 5, 7, 9, 11, or 13, wherein compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.7 and 10.1 degrees 2θ [inclusive], between 14.6 and 15.0 degrees 2θ [inclusive], between 16.8 and 17.2 degrees 2θ [inclusive], between 20.5 and 20.9 degrees 2θ [inclusive], and between 21.3 and 21.7 degrees 2θ [inclusive].

[0402] Embodiment 63. The method of any one of embodiments 1, 3, 5, 7, 9, 11, or 13, wherein compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ [inclusive], between 10.6 and 11.0 degrees 2θ [inclusive], between 13.0 and 13.4 degrees 2θ [inclusive], between 18.7 and 19.1 degrees 2θ [inclusive], and between 21.4 and 21.8 degrees 2θ [inclusive].

[0403] Embodiment 64. The additional antidepressant in (i) and (ii) is a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), a serotonin modulator and stimulator (SMS), a serotonin antagonist and reuptake inhibitor (SARI), a norepinephrine reuptake inhibitor (NRI), a norepinephrine dopamine reuptake inhibitor (NDRI), a tricyclic antidepressant (TCA), a tetracyclic antidepressant (TeCA), a monoamine oxidase inhibitor (MAOI), an atypical antipsychotic, agomelatine, esketamine, tianeptine, ketamine, alpha-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademetionine, hypericum The method of any one of embodiments 1-63, wherein the agonist is benzodiazepine, benzocaine, benzodiazepine, benzocaine, benzoyl perforatum, oxytriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine or tranylcypromine and trifluoperazine.

[0404] Embodiment 65. The method of embodiment 64, wherein the additional antidepressant in (i) and (ii) is an SSRI.

[0405] Embodiment 66. The method of embodiment 65, wherein the SSRI is sertraline, escitalopram, citalopram, fluvoxamine, paroxetine, fluoxetine, indalpine or zimelidine.

[0406] Embodiment 67. The method of embodiment 66, wherein the SSRI is sertraline.

[0407] Embodiment 68. The method of embodiment 66, wherein the SSRI is escitalopram.

[0408] Embodiment 69. The method of embodiment 66, wherein the SSRI is citalopram.

[0409] Embodiment 70. The method of embodiment 64, wherein the additional antidepressant in (i) and (ii) is an SNRI.

[0410] Embodiment 71. The method of embodiment 70, wherein the SNRI is duloxetine, desvenlafaxine, levomilnacipran, milnacipran or venlafaxine.

[0411] Embodiment 72. The method of embodiment 71, wherein the SNRI is duloxetine.

[0412] Embodiment 73. The method of embodiment 71, wherein the SNRI is desvenlafaxine.

[0413] Embodiment 74. The method of embodiment 64, wherein the additional antidepressant in (i) and (ii) is SMS.

[0414] Embodiment 75. The method of embodiment 74, wherein the SMS is vilazodone or vortioxetine.

[0415] Embodiment 76. The method of embodiment 64, wherein the additional antidepressant in (i) and (ii) is a SARI.

[0416] Embodiment 77. The method of embodiment 76, wherein the SARI is nefazodone, trazodone or etoperidone.

[0417] Embodiment 78. The method of embodiment 64, wherein the additional antidepressant in (i) and (ii) is an NRI.

[0418] Embodiment 79. The method of embodiment 78, wherein the NRI is reboxetine, teniloxazine, viloxazine or atomoxetine.

[0419] Embodiment 80. The method of embodiment 64, wherein the additional antidepressant in (i) and (ii) is an NDRI.

[0420] Embodiment 81. The method of embodiment 80, wherein the NDRI is bupropion, amphetamine, methylphenidate, modafinil, amineptine or nomifensine.

[0421] Embodiment 82. The method of embodiment 64, wherein the additional antidepressant in (i) and (ii) is a TCA.

[0422] Embodiment 83. The method of embodiment 82, wherein the TCA is amitriptyline, amitriptyline oxide, clomipramine, desipramine, dibenzazepine, dimethacrine, dosulepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, notriptyline, noxiptyline, opipramol, pipofezin, protriptyline, trimipramine, butriptyline, demexiptyline, fluacidine, imipramineoxide, iprindole, metapramine, propizepine, quinupramine, thiazesim or tofenacin.

[0423] Embodiment 84. The method of embodiment 64, wherein the additional antidepressant in (i) and (ii) is TeCA.

[0424] Embodiment 85. The method of embodiment 84, wherein the TeCA is amoxapine, maprotiline, mianserin, mirtazapine or setiptiline.

[0425] Embodiment 86. The method of embodiment 64, wherein the additional antidepressant in (i) and (ii) is an MAOI.

[0426] Embodiment 87. The method of embodiment 86, wherein the MAOI is isocarboxazid, phenelzine, tranylcypromine, benmoxine, iproclozide, iproniazid, mebanazine, nialamide, octamoxin, pheniprazine, phenoxypropazine, pibhydrazine, safrazine, selegiline, caroxazone, metralindole, moclobemide, pirlindole, eprobemide, minaprine, toloxatone, or bifemelane.

[0427] Embodiment 88. The method of embodiment 64, wherein the additional antidepressant in (i) and (ii) is an atypical antipsychotic.

[0428] Embodiment 89. The method of embodiment 88, wherein the atypical antipsychotic is amisulpride, lumateperone, lurasidone, quetiapine, aripiprazole, brexpiprazole, lumateperone, lurasidone, olanzapine, quetiapine or risperidone.

[0429] Embodiment 90. The method of embodiment 64, wherein the additional antidepressant in (i) and (ii) is agomelatine, esketamine, tianeptine, ketamine, alpha-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademethionine, hypericum perforatum, oxytriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine, or tranylcypromine and trifluoperazine.

[0430] Embodiment 91. The additional antidepressant in (i) and (ii) is 4-chlorokynurenine (AV-101), apimostinel (NRX-1074), arketamine (PCN-101, HR-071603), dextromethadone (REL-1017), MIJ-821, lisrenemdaz (CERC-301, MK-0657), TAK-653 (NBI-1065845), OPC-64005, PDC-1421 (BLI-1005), tol. Desvenlafaxine, Hypidone (YL-0919), TGBA01AD (FKB01MD), vortioxetine, lisdexamfetamine, midomafetamine, aramisulpride / esamisulpride (85:15 ratio) (SEP-4199), gepirone, pramipexole, psilocybin, briraloxazine, cariprazine, lumateperone, lurasidone, pimavanserin, ademetionine, 3β-methoxypregnenolone (MAP -4343), PH-10-vomeropherin, Aticaplant, BTRX-335140 (BTRX-140), Buprenorphine / Samidolphan, BTRX-246040 (LY-2940094), Scopolamine (DPI-386), JNJ-39393406, OnabotulinumtoxinA, JNJ-61393215, Celtrexant, BI-1358894, Crisdesalazine, Elteberel, JNJ-54175 446, NSI-189, NV-5138, SNG-12, TS-121, WIP-DF17, tramadol, bupropion / dextromethorphan (AXS-05), carbidopa / oxytriptan (EVX-101), cycloserine / lurasidone (NRX-101; Cyclerad) or deuxomethorphan / quinidine (AVP-786, CTP-786).

[0431] Embodiment 92. The method of any one of embodiments 1-91, wherein the additional antidepressant is administered in accordance with its labeled prescribing information.

[0432] Embodiment 93. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0433] Embodiment 94. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0434] Embodiment 95. A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0435] Embodiment 96. A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0436] Embodiment 97. A method for reducing gastrointestinal adverse events manifested under antidepressant treatment in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of Compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0437] Embodiment 98. A method for reducing gastrointestinal adverse events manifested under antidepressant treatment in a subject in need thereof, comprising administering a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. wherein the subject is treatment naive.

[0438] Embodiment 99. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine. wherein the subject is treatment naive.

[0439] Embodiment 100. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a therapeutically effective amount of a pharma- ceutically acceptable salt of Compound (1) to a subject in need thereof for about 14 days. [ka] and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine. wherein the subject is treatment naive.

[0440] Embodiment 101. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject from about 40 mg to about 50 mg of Compound (1): [ka] and administering a therapeutically effective amount of an additional antidepressant. The method includes:

[0441] Embodiment 102. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a medicament comprising administering to said subject a medicament comprising a medicament comprising administering to said subject a medicament a medicament comprising administering to said subject a medicament a medicament [ka] and administering a therapeutically effective amount of an additional antidepressant. The method includes:

[0442] Embodiment 103. The method of any one of embodiments 93, 94, or 99-102, wherein the subject is experiencing a major depressive episode.

[0443] Embodiment 104. The method of embodiment 103, wherein the subject has elevated anxiety during the majority of days of a major depressive episode.

[0444] Embodiment 105. The method of any one of embodiments 95, 96, or 104, wherein the subject has a HAM-D Anxiety / Somatization subscale score of at least 7 at baseline.

[0445] Embodiment 106. The method of any one of embodiments 95, 96, or 104, wherein the subject has a HAM-A total score of at least 17 or at least 20 at baseline.

[0446] Embodiment 107. The method of any one of embodiments 93-96 or 99-102, wherein administering the combination reduces treatment-emergent gastrointestinal adverse events.

[0447] Embodiment 108. The method of embodiment 97 or 98, wherein administering the combination reduces treatment-emergent gastrointestinal adverse events.

[0448] Embodiment 109. The method of any one of embodiments 97, 98, 107, or 108, wherein the treatment-emergent gastrointestinal adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.

[0449] Embodiment 110. The method of embodiment 109, wherein the treatment-emergent gastrointestinal adverse events comprise nausea and / or diarrhea.

[0450] Embodiment 111. The method of any one of embodiments 97, 98, or 107-110, wherein the treatment-emergent gastrointestinal adverse event is due to treatment with an additional antidepressant.

[0451] Embodiment 112. The method of any one of embodiments 93-111, wherein the subject has not received any antidepressant treatment within at least 30 days prior to the initiation of treatment.

[0452] Embodiment 113. The method of any one of embodiments 93-111, wherein the subject has not received additional antidepressant treatment within at least 30 days prior to initiating treatment.

[0453] Embodiment 114. The method of any one of embodiments 93-111, wherein the subject has not received additional antidepressant treatment within at least 60 days prior to initiating treatment.

[0454] Embodiment 115. The method of any one of embodiments 93-98 or 101-102, wherein the treatment comprises administering the combination for about 14 days.

[0455] Embodiment 116. The method of any one of embodiments 93-102, wherein compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the combination are administered in separate dosage forms.

[0456] Embodiment 117. The method of embodiment 116, wherein compound (1), or a pharma- ceutically acceptable salt thereof, and the additional antidepressant in the combination are administered simultaneously.

[0457] Embodiment 118. The method of embodiment 116, wherein compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant in the combination are administered at different times.

[0458] Embodiment 119. The method of any one of embodiments 93-118, wherein the treatment further comprises a second treatment comprising administering a therapeutically effective amount of an additional antidepressant.

[0459] Embodiment 120. The method of embodiment 119, wherein the second treatment comprises administering an additional antidepressant for at least 28 days.

[0460] Embodiment 121. The method of embodiment 119, wherein the additional antidepressant is administered in the second treatment at the same dose as in the combination.

[0461] Embodiment 122. The method of embodiment 119, wherein the additional antidepressant is administered in a different dose in the second treatment compared to the dose administered in the combination.

[0462] Embodiment 123. The method of embodiment 119, wherein compound (1) or a pharma- ceutically acceptable salt of compound (1) is not administered to the subject in the second treatment.

[0463] Embodiment 124. The method of any one of embodiments 119-123, wherein the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the combination.

[0464] Embodiment 125. The method of any one of embodiments 93-102, wherein compound (1) or a pharma- ceutically acceptable salt thereof is administered once a day.

[0465] Embodiment 126. The method of any one of embodiments 93, 95, 97, or 99, wherein Compound (1) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg.

[0466] Embodiment 127. The method of any one of embodiments 101 or 126, wherein compound (1) is administered at a dose of about 50 mg.

[0467] Embodiment 128. The method of any one of embodiments 101 or 126, wherein compound (1) is administered at a dose of about 40 mg.

[0468] Embodiment 129. The method of embodiment 127, wherein compound (1) is administered once a day at a dose of about 50 mg.

[0469] Embodiment 130. The method of embodiment 128, wherein compound (1) is administered once a day at a dose of about 40 mg.

[0470] Embodiment 131. The method of any one of embodiments 94, 96, 98, or 100, wherein a pharma- ceutically acceptable salt of Compound (1) is administered in a dose equivalent to about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of the free base compound.

[0471] Embodiment 132. The method of any one of embodiments 102 or 131, wherein a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 50 mg of the free base compound.

[0472] Embodiment 133. The method of embodiment 102 or 131, wherein a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 40 mg of the free base compound.

[0473] Embodiment 134. The method of embodiment 132, wherein a pharma- ceutically acceptable salt of compound (1) is administered once daily in a dose equivalent to about 50 mg of the free base compound.

[0474] Embodiment 135. The method of embodiment 133, wherein a pharma- ceutically acceptable salt of compound (1) is administered once daily in a dose equivalent to about 40 mg of the free base compound.

[0475] Embodiment 136. The method of any one of embodiments 93 to 135, wherein compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalation, intranasally, or transdermally.

[0476] Embodiment 137. The method of embodiment 136, wherein Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally.

[0477] Embodiment 138. The method of any one of embodiments 93-137, wherein Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered with food.

[0478] Embodiment 139. The method of any one of embodiments 93-138, wherein Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once daily in the evening.

[0479] Embodiment 140. The method of any one of embodiments 93-139, wherein the combination of Compound (1) or a pharma- ceutically acceptable salt of Compound (1) and an additional antidepressant is re-administered to the subject upon recurrence of depressive symptoms.

[0480] Embodiment 141. The method of embodiment 140, wherein there is an interval of at least 6 weeks between the last dose of the initial treatment and the first dose of the readministration.

[0481] Embodiment 142. 102. The method of any one of embodiments 93, 95, 97, 99, or 101, wherein compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.7 and 10.1 degrees 2θ [inclusive], between 11.6 and 12.0 degrees 2θ [inclusive], between 13.2 and 13.6 degrees 2θ [inclusive], between 14.2 and 14.6 degrees 2θ [inclusive], between 14.6 and 15.0 degrees 2θ [inclusive], between 16.8 and 17.2 degrees 2θ [inclusive], between 20.5 and 20.9 degrees 2θ [inclusive], between 21.3 and 21.7 degrees 2θ [inclusive], between 21.4 and 21.8 degrees 2θ [inclusive], and between 22.4 and 22.8 degrees 2θ [inclusive].

[0482] Embodiment 143. The method of any one of embodiments 93, 95, 97, 99, or 101, wherein compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ [inclusive], between 10.6 and 11.0 degrees 2θ [inclusive], between 13.0 and 13.4 degrees 2θ [inclusive], between 14.7 and 15.1 degrees 2θ [inclusive], between 15.8 and 16.2 degrees 2θ [inclusive], between 18.1 and 18.5 degrees 2θ [inclusive], between 18.7 and 19.1 degrees 2θ [inclusive], between 20.9 and 21.3 degrees 2θ [inclusive], between 21.4 and 21.8 degrees 2θ [inclusive], and between 23.3 and 23.7 degrees 2θ [inclusive].

[0483] Embodiment 144. The method of any one of embodiments 93, 95, 97, 99, or 101, wherein compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.7 and 10.1 degrees 2θ [inclusive], between 14.6 and 15.0 degrees 2θ [inclusive], between 16.8 and 17.2 degrees 2θ [inclusive], between 20.5 and 20.9 degrees 2θ [inclusive], and between 21.3 and 21.7 degrees 2θ [inclusive].

[0484] Embodiment 145. The method of any one of embodiments 93, 95, 97, 99, or 101, wherein compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ [inclusive], between 10.6 and 11.0 degrees 2θ [inclusive], between 13.0 and 13.4 degrees 2θ [inclusive], between 18.7 and 19.1 degrees 2θ [inclusive], and between 21.4 and 21.8 degrees 2θ [inclusive].

[0485] Embodiment 146. The additional antidepressant in the combination and in the second treatment is a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), a serotonin modulator and stimulator (SMS), a serotonin antagonist and reuptake inhibitor (SARI), a norepinephrine reuptake inhibitor (NRI), a norepinephrine dopamine reuptake inhibitor (NDRI), a tricyclic antidepressant (TCA), a tetracyclic antidepressant (TeCA), a monoamine oxidase inhibitor (MAOI), an atypical antipsychotic, agomelatine, esketamine, tianeptine, ketamine, alpha-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozan, pivagabine, ademetionine, hypericum The method of any one of embodiments 93-145, wherein the agonist is benzodiazepine, benzocaine, benzodiazepine, benzocaine, benzoyl perforatum, oxytriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine or tranylcypromine and trifluoperazine.

[0486] Embodiment 147. The method of embodiment 146, wherein the additional antidepressant in the combination and second treatment is an SSRI.

[0487] Embodiment 148. The method of embodiment 147, wherein the SSRI is sertraline, escitalopram, citalopram, fluvoxamine, paroxetine, fluoxetine, indalpine or zimelidine.

[0488] Embodiment 149. The method of embodiment 148, wherein the SSRI is sertraline.

[0489] Embodiment 150. The method of embodiment 148, wherein the SSRI is escitalopram.

[0490] Embodiment 151. The method of embodiment 148, wherein the SSRI is citalopram.

[0491] Embodiment 152. The method of embodiment 146, wherein the additional antidepressant in the combination and second treatment is an SNRI.

[0492] Embodiment 153. The method of embodiment 152, wherein the SNRI is duloxetine, desvenlafaxine, levomilnacipran, milnacipran or venlafaxine.

[0493] Embodiment 154. The method of embodiment 153, wherein the SNRI is duloxetine.

[0494] Embodiment 155. The method of embodiment 153, wherein the SNRI is desvenlafaxine.

[0495] Embodiment 156. The method of embodiment 146, wherein the additional antidepressant in the combination and second treatment is SMS.

[0496] Embodiment 157. The method of embodiment 156, wherein the SMS is vilazodone or vortioxetine.

[0497] Embodiment 158. The method of embodiment 146, wherein the additional antidepressant in the combination and second treatment is a SARI.

[0498] Embodiment 159. The method of embodiment 158, wherein the SARI is nefazodone, trazodone or etoperidone.

[0499] Embodiment 160. The method of embodiment 146, wherein the additional antidepressant in the combination and second treatment is an NRI.

[0500] Embodiment 161. The method of embodiment 160, wherein the NRI is reboxetine, teniloxazine, viloxazine or atomoxetine.

[0501] Embodiment 162. The method of embodiment 146, wherein the additional antidepressant in the combination and second treatment is an NDRI.

[0502] Embodiment 163. The method of embodiment 162, wherein the NDRI is bupropion, amphetamine, methylphenidate, modafinil, amineptine or nomifensine.

[0503] Embodiment 164. The method of embodiment 146, wherein the additional antidepressant in the combination and second treatment is a TCA.

[0504] Embodiment 165. The method of embodiment 164, wherein the TCA is amitriptyline, amitriptyline oxide, clomipramine, desipramine, dibenzazepine, dimethacrine, dosulepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, notriptyline, noxiptyline, opipramol, pipofezin, protriptyline, trimipramine, butriptyline, demexiptyline, fluacidine, imipramineoxide, iprindole, metapramine, propizepine, quinupramine, thiazesim or tofenacin.

[0505] Embodiment 166. The method of embodiment 146, wherein the additional antidepressant in the combination and second treatment is TeCA.

[0506] Embodiment 167. The method of embodiment 166, wherein the TeCA is amoxapine, maprotiline, mianserin, mirtazapine or setiptiline.

[0507] Embodiment 168. The method of embodiment 146, wherein the additional antidepressant in the combination and second treatment is an MAOI.

[0508] Embodiment 169. The method of embodiment 168, wherein the MAOI is isocarboxazid, phenelzine, tranylcypromine, benmoxine, iproclozide, iproniazid, mebanazine, nialamide, octamoxin, pheniprazine, phenoxypropazine, pibhydrazine, safrazine, selegiline, caroxazone, metralindole, moclobemide, pirlindole, eprobemide, minaprine, toloxatone, or bifemelane.

[0509] Embodiment 170. The method of embodiment 146, wherein the additional antidepressant in the combination and second treatment is an atypical antipsychotic.

[0510] Embodiment 171. The method of embodiment 170, wherein the atypical antipsychotic is amisulpride, lumateperone, lurasidone, quetiapine, aripiprazole, brexpiprazole, lumateperone, lurasidone, olanzapine, quetiapine or risperidone.

[0511] Embodiment 172. The method of embodiment 146, wherein the additional antidepressant in the combination and second treatment is agomelatine, esketamine, tianeptine, ketamine, alpha-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademethionine, hypericum perforatum, oxytriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine or tranylcypromine and trifluoperazine.

[0512] Embodiment 173. The additional antidepressant in the combination and in the second treatment is 4-chlorokynurenine (AV-101), apimostinel (NRX-1074), arketamine (PCN-101, HR-071603), dextromethadone (REL-1017), MIJ-821, lisrenemdaz (CERC-301, MK-0657), TAK-653 (NBI-1065845), OPC-64005, PDC-1421 (BLI-1005), Tordesvenlafaxine, hypidone (YL-0919), TGBA01AD (FKB01MD), vortioxetine, lisdexamfetamine, midomafetamine, aramisulpride / esamisulpride (85:15 ratio) (SEP-4199), gepirone, pramipexole, psilocybin, briraloxazine, cariprazine, lumateperone, lurasidone, pimavanserin, ademetionine, 3β-methoxypregnenolone (MA P-4343), PH-10-vomeropherin, Aticaplant, BTRX-335140 (BTRX-140), Buprenorphine / Samidolphan, BTRX-246040 (LY-2940094), Scopolamine (DPI-386), JNJ-39393406, OnabotulinumtoxinA, JNJ-61393215, Celtrexant, BI-1358894, Crisdesalazine, Elteberel, JNJ-541754 46, NSI-189, NV-5138, SNG-12, TS-121, WIP-DF17, tramadol, bupropion / dextromethorphan (AXS-05), carbidopa / oxytriptan (EVX-101), cycloserine / lurasidone (NRX-101; Cyclerad) or deuxomethorphan / quinidine (AVP-786, CTP-786).

[0513] Embodiment 174. The method of any one of embodiments 93-173, wherein the additional antidepressant is administered in accordance with its labeled prescribing information.

[0514] Embodiment 175. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and about 40 mg to about 50 mg of Compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; The method wherein the antidepressant is administered continuously after the 14th day of treatment.

[0515] Embodiment 176. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound. [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; The method wherein the antidepressant is administered continuously after the 14th day of treatment.

[0516] Embodiment 177. A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and about 40 mg to about 50 mg of Compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; The method wherein the antidepressant is administered continuously after the 14th day of treatment.

[0517] Embodiment 178. A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 40 mg to about 50 mg of the free base compound. [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; The method wherein the antidepressant is administered continuously after the 14th day of treatment.

[0518] Embodiment 179. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of Compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. The subject was treatment naive, method.

[0519] Embodiment 180. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. The subject was treatment naive, method.

[0520] Embodiment 181. A method for reducing gastrointestinal adverse events manifested under treatment with an antidepressant in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; The method wherein the antidepressant is administered continuously after the 14th day of treatment.

[0521] Embodiment 182. A method of reducing gastrointestinal adverse events manifested under treatment with an antidepressant in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; The method wherein the antidepressant is administered continuously after the 14th day of treatment.

[0522] Embodiment 183. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of Compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. The method, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.

[0523] Embodiment 184. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. The method, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.

[0524] Embodiment 185. A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. The method, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.

[0525] Embodiment 186. A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1): [ka] and the co-administration occurs from about day 1 of treatment to about day 14 of treatment; Antidepressants will be administered continuously after the 14th day of treatment. The method, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.

[0526] Embodiment 187. The method of any one of embodiments 175-176, 179-180, or 183-184, wherein the subject is experiencing a major depressive episode.

[0527] Embodiment 188. The method of embodiment 187, wherein the subject has elevated anxiety during most days of a major depressive episode.

[0528] Embodiment 189. The method of any one of embodiments 177-178, 185-186, or 188, wherein the subject has a HAM-D Anxiety / Somatization subscale score of at least 7 at baseline.

[0529] Embodiment 190. The method of any one of embodiments 177-178, 185-186, or 188, wherein the subject has a HAM-A total score of at least 17 or at least 20 at baseline.

[0530] Embodiment 191. The method of any one of embodiments 175-180 or 183-186, wherein the co-administration reduces treatment-emergent gastrointestinal adverse events.

[0531] Embodiment 192. The method of embodiment 181 or 182, wherein the co-administration reduces treatment-emergent gastrointestinal adverse events.

[0532] Embodiment 193. The method of any one of embodiments 181, 182, 191, or 192, wherein the treatment-emergent gastrointestinal adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.

[0533] Embodiment 194. The method of embodiment 193, wherein the treatment-emergent gastrointestinal adverse events comprise nausea and / or diarrhea.

[0534] Embodiment 195. The method of any one of embodiments 181, 182, or 192-194, wherein the treatment-emergent gastrointestinal adverse event is attributable to treatment with an antidepressant.

[0535] Embodiment 196. The method of any one of embodiments 175-178 or 181-195, wherein the subject has not been treated.

[0536] Embodiment 197. The method of any one of embodiments 175-178 or 181-195, wherein the subject has not received any antidepressant treatment within at least 30 days prior to the start of co-administration.

[0537] Embodiment 198. The method of any one of embodiments 175-178 or 181-195, wherein the subject has not received additional antidepressant treatment within at least 30 days prior to the start of the first treatment.

[0538] Embodiment 199. The method of any one of embodiments 175-178 or 181-195, wherein the subject has not received additional antidepressant treatment within at least 60 days prior to the start of the first treatment.

[0539] Embodiment 200. The method of any one of embodiments 175-199, wherein the antidepressant is continuously administered for at least an additional 28 days after the 14th day of treatment.

[0540] Embodiment 201. The method of any one of embodiments 175-199, wherein compound (1) or a pharma- ceutically acceptable salt of compound (1) is not administered to the subject after day 14 of the treatment.

[0541] Embodiment 202. The method of any one of embodiments 175-201, wherein the compound (1), or a pharma- ceutically acceptable salt thereof, and the antidepressant in co-administration are administered in separate dosage forms.

[0542] Embodiment 203. The method of embodiment 203, wherein the compound (1), or a pharma- ceutically acceptable salt thereof, and the antidepressant in co-administration are administered simultaneously.

[0543] Embodiment 204. The method of embodiment 203, wherein the compound (1), or a pharma- ceutically acceptable salt thereof, and the antidepressant in co-administration are administered at different times.

[0544] Embodiment 205. The method of any one of embodiments 175-204, wherein the antidepressant is administered at the same dose from day 1 of treatment to about day 14 of treatment and after day 14 of treatment.

[0545] Embodiment 206. The method of any one of embodiments 175-204, wherein the antidepressant is administered at the same dose from day 1 of treatment to about day 14 of treatment, and after day 14 of treatment.

[0546] Embodiment 207. The method of any one of embodiments 175-206, wherein compound (1), or a pharma- ceutically acceptable salt thereof, is administered once daily.

[0547] Embodiment 208. The method of any one of embodiments 179, 181, 183, and 185, wherein Compound (1) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg.

[0548] Embodiment 209. The method of any one of embodiments 175, 177, or 208, wherein compound (1) is administered at a dose of about 50 mg.

[0549] Embodiment 210. The method of any one of embodiments 175, 177, or 208, wherein compound (1) is administered at a dose of about 40 mg.

[0550] Embodiment 211. The method of embodiment 209, wherein compound (1) is administered once a day at a dose of about 50 mg.

[0551] Embodiment 212. The method of embodiment 210, wherein compound (1) is administered once a day at a dose of about 40 mg.

[0552] Embodiment 213. The method of any one of embodiments 180, 182, 184, and 186, wherein a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of the free base compound.

[0553] Embodiment 214. The method of embodiment 176, 178 or 213, wherein a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 50 mg of the free base compound.

[0554] Embodiment 215. The method of embodiment 176, 178 or 213, wherein a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 40 mg of the free base compound.

[0555] Embodiment 216. The method of embodiment 214, wherein a pharma- ceutically acceptable salt of compound (1) is administered once daily in a dose equivalent to about 50 mg of the free base compound.

[0556] Embodiment 217. The method of embodiment 215, wherein a pharma- ceutically acceptable salt of compound (1) is administered once daily in a dose equivalent to about 40 mg of the free base compound.

[0557] Embodiment 218. The method of any one of embodiments 175 to 217, wherein Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalation, intranasally, or transdermally.

[0558] Embodiment 219. The method of embodiment 218, wherein Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally.

[0559] Embodiment 220. The method of any one of embodiments 175-219, wherein Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered with food.

[0560] Embodiment 221. The method of any one of embodiments 175-220, wherein Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once daily in the evening.

[0561] Embodiment 222. The method of any one of embodiments 175-222, wherein the co-administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1) and an antidepressant is readministered to the subject upon recurrence of depressive symptoms.

[0562] Embodiment 223. The method of embodiment 222, wherein there is an interval of at least 6 weeks between the last dose of the initial treatment and the first dose of the readministration.

[0563] Embodiment 224. The compound (1) is a compound having a 2θ between 9.7 and 10.1 degrees [endpoints included], a 2θ between 11.6 and 12.0 degrees [endpoints included], a 2θ between 13.2 and 13.6 degrees [endpoints included], a 2θ between 14.2 and 14.6 degrees [endpoints included], a 2θ between 14.6 and 15.0 degrees [endpoints included], a 2θ between 16.8 and 17.2 degrees [endpoints included], a 2θ between 20.5 and 21. The method of any one of embodiments 175, 177, 179, 181, 183, or 185, wherein the crystalline form has an XRPD pattern comprising peaks between 20.9 degrees 2θ [endpoints included], between 21.3 and 21.7 degrees 2θ [endpoints included], between 21.4 and 21.8 degrees 2θ [endpoints included], and between 22.4 and 22.8 degrees 2θ [endpoints included].

[0564] Embodiment 225. The compound (1) is a compound having a 2θ between 9.3 and 9.7 degrees [endpoints included], a 2θ between 10.6 and 11.0 degrees [endpoints included], a 2θ between 13.0 and 13.4 degrees [endpoints included], a 2θ between 14.7 and 15.1 degrees [endpoints included], a 2θ between 15.8 and 16.2 degrees [endpoints included], a 2θ between 18.1 and 18.5 degrees [endpoints included], a 2θ between 18.7 and 1 The method of any one of embodiments 175, 177, 179, 181, 183, or 185, wherein the compound is in a crystalline form having an XRPD pattern comprising peaks between 9.1 degrees 2θ [endpoints included], between 20.9 and 21.3 degrees 2θ [endpoints included], between 21.4 and 21.8 degrees 2θ [endpoints included], and between 23.3 and 23.7 degrees 2θ [endpoints included].

[0565] Embodiment 226. The method of any one of embodiments 175, 177, 179, 181, 183, or 185, wherein compound (1) is in a crystalline form having an XRPD pattern comprising peaks between 9.7 and 10.1 degrees 2θ [inclusive], between 14.6 and 15.0 degrees 2θ [inclusive], between 16.8 and 17.2 degrees 2θ [inclusive], between 20.5 and 20.9 degrees 2θ [inclusive], and between 21.3 and 21.7 degrees 2θ [inclusive].

[0566] Embodiment 227. The method of any one of embodiments 175, 177, 179, 181, 183, or 185, wherein compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ [inclusive], between 10.6 and 11.0 degrees 2θ [inclusive], between 13.0 and 13.4 degrees 2θ [inclusive], between 18.7 and 19.1 degrees 2θ [inclusive], and between 21.4 and 21.8 degrees 2θ [inclusive].

[0567] Embodiment 228. The antidepressant is a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), a serotonin modulator and stimulator (SMS), a serotonin antagonist and reuptake inhibitor (SARI), a norepinephrine reuptake inhibitor (NRI), a norepinephrine dopamine reuptake inhibitor (NDRI), a tricyclic antidepressant (TCA), a tetracyclic antidepressant (TeCA), a monoamine oxidase inhibitor (MAOI), an atypical antipsychotic, agomelatine, esketamine, tianeptine, ketamine, alpha-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozan, pivagabine, ademetionine, hypericum The method of any one of embodiments 175-227, wherein the agonist is benzodiazepine, benzocaine, benzoyl perforatum, oxytriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine or tranylcypromine and trifluoperazine.

[0568] Embodiment 229. The method of embodiment 228, wherein the antidepressant is an SSRI.

[0569] Embodiment 230. The method of embodiment 229, wherein the SSRI is sertraline, escitalopram, citalopram, fluvoxamine, paroxetine, fluoxetine, indalpine or zimelidine.

[0570] Embodiment 231. The method of embodiment 230, wherein the SSRI is sertraline.

[0571] Embodiment 232. The method of embodiment 230, wherein the SSRI is escitalopram.

[0572] Embodiment 233. The method of embodiment 230, wherein the SSRI is citalopram.

[0573] Embodiment 234. The method of embodiment 228, wherein the antidepressant is an SNRI.

[0574] Embodiment 235. The method of embodiment 234, wherein the SNRI is duloxetine, desvenlafaxine, levomilnacipran, milnacipran or venlafaxine.

[0575] Embodiment 236. The method of embodiment 235, wherein the SNRI is duloxetine.

[0576] Embodiment 237. The method of embodiment 235, wherein the SNRI is desvenlafaxine.

[0577] Embodiment 238. The method of embodiment 228, wherein the antidepressant is SMS.

[0578] Embodiment 239. The method of embodiment 238, wherein the SMS is vilazodone or vortioxetine.

[0579] Embodiment 240. The method of embodiment 228, wherein the antidepressant is a SARI.

[0580] Embodiment 241. The method of embodiment 240, wherein the SARI is nefazodone, trazodone or etoperidone.

[0581] Embodiment 242. The method of embodiment 228, wherein the antidepressant is an NRI.

[0582] Embodiment 243. The method of embodiment 242, wherein the NRI is reboxetine, teniloxazine, viloxazine or atomoxetine.

[0583] Embodiment 244. The method of embodiment 228, wherein the antidepressant is an NDRI.

[0584] Embodiment 245. The method of embodiment 244, wherein the NDRI is bupropion, amphetamine, methylphenidate, modafinil, amineptine or nomifensine.

[0585] Embodiment 246. The method of embodiment 228, wherein the antidepressant is a TCA.

[0586] Embodiment 247. The method of embodiment 246, wherein the TCA is amitriptyline, amitriptyline oxide, clomipramine, desipramine, dibenzazepine, dimethacrine, dosulepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, notriptyline, noxiptyline, opipramol, pipofezin, protriptyline, trimipramine, butriptyline, demexiptyline, fluacidine, imipramineoxide, iprindole, metapramine, propizepine, quinupramine, thiazesim or tofenacin.

[0587] Embodiment 248. The method of embodiment 228, wherein the antidepressant is TeCA.

[0588] Embodiment 249. The method of embodiment 248, wherein the TeCA is amoxapine, maprotiline, mianserin, mirtazapine or setiptiline.

[0589] Embodiment 250. The method of embodiment 228, wherein the antidepressant is an MAOI.

[0590] Embodiment 251. The method of embodiment 250, wherein the MAOI is isocarboxazid, phenelzine, tranylcypromine, benmoxine, iproclozide, iproniazid, mebanazine, nialamide, octamoxin, pheniprazine, phenoxypropazine, pibhydrazine, safrazine, selegiline, caroxazone, metralindole, moclobemide, pirlindole, eprobemide, minaprine, toloxatone, or bifemelane.

[0591] Embodiment 252. The method of embodiment 228, wherein the antidepressant is an atypical antipsychotic.

[0592] Embodiment 253. The method of embodiment 252, wherein the atypical antipsychotic is amisulpride, lumateperone, lurasidone, quetiapine, aripiprazole, brexpiprazole, lumateperone, lurasidone, olanzapine, quetiapine or risperidone.

[0593] Embodiment 254. The method of embodiment 228, wherein the antidepressant is agomelatine, esketamine, tianeptine, ketamine, alpha-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademethionine, hypericum perforatum, oxytriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine, or tranylcypromine and trifluoperazine.

[0594] Embodiment 255. The antidepressant is selected from the group consisting of 4-chlorokynurenine (AV-101), apimostinel (NRX-1074), arketamine (PCN-101, HR-071603), dextromethadone (REL-1017), MIJ-821, lisrenemdaz (CERC-301, MK-0657), TAK-653 (NBI-1065845), OPC-64005, PDC-1421 (BLI-1005), tordesvenlafaxine, hypidosporine, serotonin ... (YL-0919), TGBA01AD (FKB01MD), vortioxetine, lisdexamfetamine, midomafetamine, aramisulpride / esamisulpride (85:15 ratio) (SEP-4199), gepirone, pramipexole, psilocybin, briraloxazine, cariprazine, lumateperone, lurasidone, pimavanserin, ademetionine, 3β-methoxypregnenolone (MAP-4343), PH- 10-Vomeropherin, Aticaplant, BTRX-335140 (BTRX-140), Buprenorphine / Samidolphan, BTRX-246040 (LY-2940094), Scopolamine (DPI-386), JNJ-39393406, OnabotulinumtoxinA, JNJ-61393215, Celtrexant, BI-1358894, Crisdesalazine, Elteberel, JNJ-54175446, NSI The method of any one of embodiments 175 to 227, wherein the agonist is selected from the group consisting of bupropion / dextromethorphan (AXS-05), carbidopa / oxytriptan (EVX-101), cycloserine / lurasidone (NRX-101; Cyclerad) or deuxomethorphan / quinidine (AVP-786, CTP-786).

[0595] Embodiment 256. The method of any one of embodiments 175-255, wherein the antidepressant is administered in accordance with its labeled prescribing information.

[0596] Embodiment 257. The method of any one of embodiments 13, 14, and 175 to 255, wherein the co-administration is the simultaneous initiation of administration of said compound (1) or a pharma- ceutically acceptable salt; and said antidepressant.

[0597] Embodiment 258. A method of treating major depressive disorder (MDD) in a treatment-naive subject in need thereof, comprising administering to a subject a therapeutically effective amount of compound (1): [ka] and simultaneously initiating administration of a combination comprising a therapeutically effective amount of an antidepressant. EXAMPLES

[0598] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are presented to illustrate the methods provided herein and should not be construed as limiting the scope thereof in any way.

[0599] Example 1 Research protocol for a randomized, double-blind, Phase 3 study comparing the efficacy and safety of compound (1) plus an antidepressant versus placebo plus an antidepressant in adults with major depressive disorder (CORAL).

[0600] [Table 14-1] [Table 14-2]

[0601] Introduction

[0602] Major depressive disorder (MDD) is a mental health disorder associated with significant mortality, severe functional disability, and reduced quality of life (QoL). Often a relapsing condition, the global prevalence of MDD has increased worldwide in recent decades and has further increased during the COVID-19 pandemic. The majority of patients with MDD are untreated or often undertreated. In fact, less than one-third of people living with depression in the United States receive adequate treatment.

[0603] Standard of care (SOC) antidepressant treatments (ADTs), such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), are effective, but improvement in depressive symptoms typically takes weeks or months, which may lead to increased risk of suicide and discontinuation of treatment.

[0604] In the Sequenced Treatment Alternatives to Relieve Depression study, the mean time to remission for patients with MDD receiving SOC ADT ranged from 5.4 to 7.4 weeks. Furthermore, the likelihood of remission after acute treatment decreased, and relapse rates increased with each acute ADT treatment step. Existing SOC ADT may also not be suitable for some patients with MDD due to commonly reported adverse events (AEs), which may lead to non-adherence and reduced QoL. Thus, given the limitations of currently available treatments for some patients with MDD, new treatment options that deliver rapid responses with tolerable AE profiles are needed.

[0605] In the search for novel treatments, various mechanisms of depression have been investigated, especially the disturbance of the balance between excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) signaling. Available drugs exert their effects through GABAergic / glutamatergic balance and contribute to the restoration of brain networks. Neuroactive steroids (NAS) are hypothesized to rapidly restore network balance in brain regions dysregulated in depression by binding to GABAA receptors. Compound (1) is a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and is a NAS in clinical development (as monotherapy or adjunctive therapy) for adults with MDD and PPD, respectively, in the LANDSCAPE and NEST clinical development programs as an oral, once-daily, 14-day treatment course. As part of the LANDSCAPE program, the ongoing SHORELINE study (NCT03864614) was designed to evaluate the safety and tolerability of a 14-day treatment course of 30 mg or 50 mg of compound (1), as well as the need for up to a total of five treatment courses over a period of one year or less. Interim results from the SHORELINE study showed that nearly 80% of patients who responded to the first course of 50 mg of compound (1) and continued beyond day 28 received a total of one or two treatment courses over a treatment follow-up period of up to one year. Another completed study showed that 50 mg of compound (1) resulted in improvement in depressive symptoms at day 15 compared with placebo, with onset of effect observed as early as day 2 or 3 in patients with MDD or PPD, despite the concomitant stable SOC ADT. However, the efficacy and safety of compound (1) initiated simultaneously with SOC ADT was not investigated in the aforementioned study.

[0606] It is important to understand that Compound (1) may rapidly improve depression symptoms, including when started simultaneously with ADT, because previous literature has shown that individuals with MDD who achieve an early treatment response are more likely to achieve a better outcome than those who do not achieve an early response or whose symptoms persist or do not resolve. Furthermore, the possibility of a 14-day treatment course of Compound (1) may lead to greater compliance. Because NAS has a mechanism of action that is different from that of other ADTs, the simultaneous initiation of Compound (1) with SOC ADT may also improve efficiency.

[0607] There is an unmet need for new therapies that minimize the adverse effects commonly associated with ADT and do not require long-term treatment.

[0608] Given the widespread use of SSRI and SNRI ADT, this study provides a useful clinical context in which a more rapid response may be achieved by switching from treatment with delayed, chronically administered ADT to the co-initiated administration of compound (1) with SOC ADT.

[0609] Objectives and Endpoints

[0610] The primary objective of this study was to evaluate the efficacy of compound (1) and antidepressants compared to placebo and antidepressants in the treatment of MDD. Secondary objectives were to evaluate patient-reported outcome (PRO) measures as they relate to depressive symptoms and to assess the safety and tolerability of compound (1) and antidepressants. Other objectives were to evaluate PRO measures as they relate to health-related quality of life and to evaluate the PK of compound (1) using population PK methods.

[0611] Endpoints

[0612] The primary endpoint was the change from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total score at day 3.

[0613] The key secondary endpoint was the change from baseline (CFB) in HAM-D total score over the blinded treatment period (using equal weighting for scheduled visits on days 3, 8, 12, and 15). Other secondary endpoints were change from baseline in HAM-D total score at days 15 and 42, change from baseline in HAM-D total score near the end of blinded treatment (using equal weighting for scheduled visits on days 12, 15, and 18), HAM-D response at days 15 and 42, HAM-D remission at days 15 and 42, change from baseline in Clinical Global Impression-Severity (CGI-S) at day 15, and the score for "much improved" or "very much improved" at days 3 and 15. These included CGI-I response defined, change from baseline in MADRS total score at day 15, MADRS response at day 15 (≥50% decrease from baseline in MADRS total score), MADRS remission at day 15 (MADRS total score ≤10), change from baseline in HAM-A total score at day 15, time to first HAM-D response, change from baseline in depressive symptoms at day 15 as assessed by PHQ-9, and incidence and severity of treatment-emergent adverse events (TEAEs).

[0614] Other endpoints included change from baseline to day 15 in PRO measures of health-related quality of life assessed by response to the SF-36v2, change from baseline to day 15 in PRO measures (as they relate to functioning assessed by the Sheehan Disability Scale (SDS)), change from baseline in clinical laboratory measures, vital signs and electrocardiogram (ECG), suicidal thoughts and behaviors using the Columbia Suicide Severity Scale (C-SSRS), potential withdrawal symptoms using the 20-item Physician Withdrawal Checklist (PWC-20), and pharmacokinetic (PK) parameters (e.g., clearance) and exposure estimates (e.g., area under the curve over the dosing interval, maximum plasma concentration) assessed by population PK methods.

[0615] Overall study design

[0616] This was a randomized, double-blind, parallel-group, placebo-controlled study in adults with MDD. Diagnosis of MDD was made according to the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Clinical Trial Version (SCID 5-CT), administered by a qualified health care professional.

[0617] The study consisted of a maximum 28-day screening period, a 14-day double-blind treatment period, and a 28-day ADT duration period. The screening period began with signing of an informed consent form (ICF) at the screening visit. Preliminary screening procedures to determine eligibility included completion of the MGH-ATRQ and HAM-D.

[0618] Participants were randomized to receive either blinded compound (1) 50 mg or placebo to be administered every evening from Day 1 through Day 14. In addition, all participants received one of two classes of ADT: selective serotonin reuptake inhibitors (SSRIs; sertraline, escitalopram, citalopram) or serotonin-norepinephrine reuptake inhibitors (SNRIs; duloxetine or desvenlafaxine) on an open-label basis from Day 1 through the end of the study. ADT was administered according to the label prescribing information. Investigators assigned one of five ADTs based on clinical standard of care, and participants must not have been previously treated with the assigned ADT within the current depressive episode and must not have taken any ADT within the 30 days prior to Day 1 (or fluoxetine within the 60 days prior to Day 1). Randomization was stratified by ADT class (SSRI or SNRI).

[0619] After the double-blind treatment period, ADT was continued every evening for the remainder of the study (ADT duration). During this period (weeks 3-6), ADT dosing could be modified based on individual response, at the investigator's discretion and in accordance with the labeled prescribing information.

[0620] Between screening and completion of the Day 42 assessment / end of study visit, initiation of other antidepressants or any other medications that may have had the potential to affect efficacy or safety endpoints was not permitted.

[0621] Participants self-administered blinded investigational drug (IP) once daily at approximately 8 PM with a fat-containing meal (e.g., within 1 hour of a fat-containing dinner or with a fat-containing snack) on an outpatient basis for 14 days. ADT and Compound (1) / placebo were administered simultaneously for the treatment period. Participants assigned to duloxetine also received ADT in the morning as part of a split dose for the first 7 days (2 doses per day). Participants returned to the study site as outlined in the schedule of assessments (Table 1).

[0622] During the treatment period, participants were allowed to receive Compound (1) / placebo unless there were dose-limiting safety / tolerability concerns. Participants who could not tolerate Compound (1) / placebo 50 mg received 40 mg for the remainder of the treatment period. Participants who, in the opinion of the investigator, could not tolerate a dose of Compound (1) / placebo 40 mg were allowed to discontinue Compound (1) / placebo at the investigator's discretion. If blinded IP was discontinued, ADT was allowed to continue at the investigator's discretion.

[0623] Upon completion of this study, eligible participants had the opportunity to participate in a long-term, open-label study of Compound (1).

[0624] Eligibility

[0625] Inclusion criteria Participants signed the ICF before any study-specific procedures were performed. Participants were male or female, aged between 18 and 64 years (inclusive). Participants were in good physical health and had no clinically significant findings on physical examination, 12-lead ECG or laboratory tests as determined by the investigator. Participants agreed to comply with the study requirements. Participants had a diagnosis of MDD as diagnosed by the SCID-5-CT, including symptoms that had been present for a period of at least 4 weeks. Participants had a HAMD-17 total score of ≥ 24 at screening and on Day 1 (pre-medication). Participants were willing to delay initiation of any antidepressants (unless per protocol), anxiolytics, anti-insomnia medications, psychostimulants, prescription opioid regimens, or new psychological therapies (including cognitive behavioral therapy for insomnia [CBT-I]) until after completion of the study. Participants accepting psychological therapy must have been receiving treatment on a regular schedule for at least 60 days prior to Day 1 and intended to maintain that schedule for the duration of the study. Female participants agreed to use at least one highly effective method of contraception (see below) during their participation in the study and for 30 days after their final dose of IP, unless they were postmenopausal (at least 12 months of spontaneous amenorrhea without another medical cause and confirmed follicle-stimulating hormone >40 mIU / mL) and / or surgically sterile (bilateral oophorectomy, hysterectomy, and / or bilateral salpingectomy) or engaged in sexual activities that placed them at risk for pregnancy (not including abstinence). Female participants who were breastfeeding at screening or on Day 1 (prior to administration of Compound (1)) must be willing to temporarily discontinue breastfeeding their child from immediately prior to receiving Compound (1) on Day 1 until 7 days after the final dose of Compound (1) / placebo. Male participants agreed to use an approved, effective method of contraception for the duration of the study and for 5 days after receiving compound (1), except when engaging in sexual activity that poses a risk of pregnancy. Male participants were willing to refrain from sperm donation during the treatment period and for 5 days after receiving their final dose of Compound (1). Participants agreed to abstain from drug and alcohol abuse for the duration of the study; and Participants were willing, able, and eligible to take at least one of the five protocol-specified ADTs (eligible ADTs were those that had not been taken during the current depressive episode and that the participant had no contraindications to; furthermore, if escitalopram had been taken during the current depressive episode, participants were not eligible for citalopram and vice versa).

[0626] Exclusion criteria

[0627] Participants were ineligible to participate in the study if they met any of the following criteria: Participant was at significant risk of suicide or had attempted suicide in relation to a current episode of MDD, as determined by the investigator. Participants had a current occurrence of a depressive episode during pregnancy or within the 4 postpartum weeks, or participants had symptoms at screening during the 6-month postpartum period. Participants had a recent history or active clinically significant manifestations of a metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, cutaneous, genitourinary, neurological, or ocular, ear, nose and pharynx disorder, or any other acute or chronic condition, that, in the opinion of the investigator, would limit the participant's ability to complete or participate in this clinical trial. Participants with a BMI ≤ 18 or ≥ 45 kg / m2 were excluded, and those with a BMI between 40 and 44.9 kg / m2 (inclusive) at screening underwent a more extensive evaluation of medical comorbidities as described above. Participants had treatment-resistant depression, defined as persistent depressive symptoms despite being treated with adequate doses of antidepressants (excluding antipsychotics) within the scope of a current major depressive episode from two different classes for at least 4 weeks of treatment. The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ) was used for this purpose. Participants had vagus nerve stimulation, electroconvulsive therapy, or took ketamine within a current major depressive episode. Participants had received cognitive behavioral therapy for insomnia (CBT-I) within the 28 days prior to Day 1. Participants had a known allergy to compound (1), allopregnanolone, or related compounds. Participants had taken an antidepressant within 30 days prior to Day 1 and / or had taken fluoxetine within 60 days prior to Day 1. Female participants had a positive pregnancy test or were confirmed pregnant. Participants had a clinically significant abnormal 12-lead ECG at screening or baseline visit (mean QT interval calculated using the Fridericia method (QTcF) >450 msec in men or >470 msec in women was the criterion for exclusion from the study). Participants had active psychosis as assessed by the investigator. Participants had a medical history of seizures. Participants had a medical history of bipolar disorder, schizophrenia and / or schizoaffective disorder. Participants had a history of mild, moderate or severe substance use disorder (including benzodiazepines) diagnosed using DSM-5 criteria in the 12 months prior to screening OR participants had a history of mild or moderate substance use disorder not in sustained remission for at least 6 months prior to screening. Participant had exposure to another investigational drug or device within 30 days prior to screening. Participants had previously received brexanolone or had participated in a clinical trial of Compound (1) or SAGE-547 (brexanolone). Participants had used any known strong inhibitor of cytochrome P450 (CYP) 3A4 within 28 days or 5 half-lives (whichever was longer) or had consumed grapefruit juice, grapefruit or Seville orange, or products containing these within 14 days prior to Day 1. Participant used any strong CYP3A inducers such as rifampin, carbamazepine, enzalutamide, mitotane, phenytoin or hypericum perforatum within 28 days prior to Day 1. Participants had a positive drug and / or alcohol screen at screening or on Day 1 prior to medication. Participants were scheduled to undergo elective surgery prior to completing the Day 42 visit. Participants had been taking a benzodiazepine, barbiturate, or gamma-aminobutyric acid type A (GABAA) modulator (e.g., eszopiclone, zopiclone, zaleplon, and zolpidem) within 28 days prior to Day 1, or had used these medications daily or near daily (≥4 times per week) for more than 1 year. Participants had been taking either a benzodiazepine or a GABA modulator with a half-life of ≥48 hours (e.g., diazepam) for 60 days prior to Day 1. Participants were taking a non-GABA antiinsomnia medication (e.g., medications prescribed specifically for insomnia and / or over-the-counter sleep aids) or a first- or second-generation (typical / atypical) antipsychotic within 14 days prior to Day 1. Nonsedating antihistamines were permitted. Participants had been diagnosed with and / or treated for any type of cancer (excluding basal cell carcinoma and intraepidermal melanoma) within the past year prior to screening. Participants had a history of sleep apnea. Participants had gastric bypass surgery, had a gastric sleeve or lap-band, or had any related procedure that interfered with gastrointestinal transit. Participants were taking stimulants (e.g., methylphenidate, amphetamines) or opioids on a regular or as-needed basis within the 28 days prior to Day 1. Participants were family members of sponsor, investigator, investigator's representative, or study site personnel. Participants were expected to work the night shift during the 14-day treatment period, or Participants had detectable hepatitis B surface antigen, anti-hepatitis C virus (HCV) and positive HCV viral load, or human immunodeficiency virus (HIV) antibodies at screening.

[0628] Dosage and Mode of Administration

[0629] Compound (1) was available as a hard gelatin capsule for oral administration. Multiple capsules were provided (30 mg or 20 mg dose strengths) for a total dose of 50 mg, with the option to reduce to 40 mg based on tolerability.

[0630] A blinded placebo was provided for oral administration in a hard gelatin capsule matched in appearance to Compound (1).

[0631] Sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine were administered according to the labeled prescribing information.

[0632] Sertraline was administered according to the labeled prescribing information, starting at 50 mg every evening for week 1, and this dose was recommended to be increased to 100 mg every evening for week 2.

[0633] Citalopram was administered according to the labeled prescribing information, with a recommended starting dose of 20 mg / day.

[0634] Escitalopram was administered according to the labeled prescribing information, with a recommended starting dose of 10 mg / day.

[0635] Duloxetine was administered according to the labeled prescribing information, with a recommended starting dose of 40 mg / day or 60 mg / day (divided as 20 mg or 30 mg, respectively, twice daily for the first 7 days).

[0636] Desvenlafaxine was administered according to the labeled prescribing information, with a recommended starting dose of 50 mg / day.

[0637] Duration of treatment

[0638] Blinded compound (1) or placebo was administered once daily for 14 days, and open-label ADT was administered according to labeled prescribing information for 42 days.

[0639] Dosage Justification

[0640] Results of a large multi-center study of Compound (1) 20 mg and 30 mg in MDD (217-MDD-301) support the need for higher steady-state concentrations of Compound (1) to allow participants to experience the full antidepressant and anxiolytic benefits. Compound (1) was administered as a 14-day regimen of 50 mg evening doses, with dose reduction to 40 mg, if necessary, based on tolerability. Compound (1) at a dose of 50 mg was expected to show a favorable benefit-risk profile in relation to the results of previous Compound (1) studies that utilized a dose of 30 mg, identified as the minimally effective dose. Compound (1) was expected to maintain an acceptable tolerability profile based on the current safety database of over 2000 participants exposed across different doses / concentrations.

[0641] Sertraline is a commercially available SSRI indicated for the treatment of MDD and other psychiatric disorders. The dosage and administration of sertraline as described in the approved US Prescribing Information (PI) recommends a starting dose of 50 mg per day in patients with MDD, with weekly increases in dose increments of 25-50 mg per day to a maximum dose of 200 mg per day if there is an inadequate response to the starting dose. In this study, a starting dose of 50 mg per day was recommended for 7 days, followed by an increase to 100 mg per day.

[0642] Both citalopram and escitalopram are commercially available SSRIs indicated for acute and maintenance treatment of MDD. Escitalopram is also indicated for the treatment of generalized anxiety disorder. The starting dosage for MDD in the US PI is 20 mg / day for citalopram and 10 mg / day for escitalopram, with maximum amounts of 40 mg / day and 20 mg / day, respectively. In this study, the starting dose for the first 14 days was recommended to be 20 mg / day for citalopram and 10 mg / day for escitalopram. Subsequent dose escalation could be considered, except for participants >60 years old taking citalopram.

[0643] Duloxetine is a commercially available SNRI indicated for the treatment of MDD, generalized anxiety disorder, and pain disorder. The starting dosage for MDD in the US PI is 40-60 mg / day. The maximum dosage is 120 mg / day, but there is no evidence that dosages greater than 60 mg / day provide any additional benefit. In this study, a starting dose of 40 or 60 mg / day was recommended (divided as 20 mg or 30 mg, respectively, twice daily for the first 7 days).

[0644] Desvenlafaxine is a commercially available SNRI indicated for the treatment of MDD. The recommended dosage in the US PI is 50 mg / day. In this study, a dose of 50 mg / day was recommended. There is no evidence that doses greater than 50 mg / day provide any additional benefit.

[0645] Treatment Allocation

[0646] Participants were assigned to blinded IP (Compound (1) or placebo) according to the randomization schedule on Day 1. The investigator assigned one of five ADTs based on clinical standard of care. The ADT assigned to the participant could not have been taken previously by the participant during the current depressive episode. Furthermore, if escitalopram had been taken during the current depressive episode, citalopram could not be assigned, and vice versa.

[0647] Randomization was stratified by antidepressant class (SSRI or SNRI).

[0648] Dose adjustment criteria

[0649] During the treatment period, participants were allowed to receive Compound (1) / placebo unless there were dose-limiting safety / tolerability concerns. Participants who could not tolerate 50 mg (as determined by the investigator) received 40 mg for the remainder of the treatment period.

[0650] At the investigator's discretion, participants who were unable to tolerate the 40 mg dose at any time were allowed to discontinue medication. These participants should be followed up according to the evaluation schedule and complete the evaluations.

[0651] Between weeks 3 and 6, ADT dosing could be modified based on individual response, at the investigator's discretion and per the labeled prescribing information.

[0652] Previous and Concomitant Medications and / or Supplements

[0653] The start and end dates, route, dose / units, frequency, and indication for all medications and / or supplements taken within 30 days prior to screening and throughout the study period were recorded. Additionally, psychotropic medications taken within 6 months prior to screening were recorded.

[0654] Any medications and / or supplements deemed necessary for the participant's welfare could be administered at any time during the study, at the discretion of the investigator.

[0655] Prohibited Medicines

[0656] The following specific classes of medicines were banned: · Starting any new psychotropic medications until the Day 42 visit. · Initiating new antidepressant treatment 30 days prior to Day 1 (60 days for fluoxetine) through Visit Day 42. Use of any benzodiazepine, barbiturate, GABAA modulator, or GABA-containing medication from day -28 (or from day -60 for benzodiazepines or GABA modulators with a half-life of ≥48 hours) through visit day 42. · -Long-term or as-needed neurostimulants (e.g., methylphenidate, amphetamine) or opioids from visit day 28 through visit day 42. · First-generation (typical) antipsychotics (e.g., haloperidol, perphenazine) and second-generation (atypical) antipsychotics (e.g., aripiprazole, quetiapine) from day -14 through visit day 42. Use any non-GABA antiinsomnia medication (e.g., medications prescribed specifically for insomnia and / or over-the-counter sleep aids) from Day -14 through Day 1. Non-sedating antihistamines were permitted. Exposure to another investigational drug or device from 30 days prior to screening through visit Day 42. Any known strong inhibitors of CYP3A4, beginning on Day -28 or 5 half-lives prior to Day 1 (whichever is longer) and continuing throughout the treatment period. Use of any strong CYP3A inducer, such as rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, or Hypericum perforatum, from Day -28 through the treatment period; or Any contraindications per the labeled prescribing information for the assigned SSRI / SNRI.

[0657] Other Restrictions

[0658] Any specific restrictions regarding concomitant medications for the assigned SSRI / SNRI were considered in accordance with the labeled prescribing information.

[0659] Consumption of grapefruit juice, grapefruit or Seville orange, or products containing these was prohibited within 14 days prior to Day 1 and throughout the treatment period.

[0660] Consumption of alcohol or use of drugs of abuse was abstained throughout the study period.

[0661] Female participants who were breast-feeding or actively nursing were required to stop breast-feeding their infants beginning on Day 1 and continuing until 7 days after the final dose of Compound (1) / placebo.

[0662] Elective surgeries or procedures were prohibited until the day 42 visit.

[0663] Participants must not work the night shift during the treatment period.

[0664] Participants who felt sedated, drowsy and / or dizzy should have refrained from driving or engaging in any activity requiring alertness.

[0665] Participants receiving psychotherapy on a regular schedule for at least 60 days prior to Day 1 were allowed if they intended to continue that schedule through the follow-up period (Day 42). Initiation of new psychotherapy was prohibited until after completion of the study.

[0666] Randomization and blinding

[0667] Participants were randomized in a 1:1 ratio to receive Compound (1) or matching placebo. Participants, site personnel, and sponsors were blinded to treatment allocation. All participants also received unblinded ADT. Randomization was performed centrally by an interactive response technology (IRT) system. The randomization schedule was generated by an independent statistician. Allocation to blinded treatment (Compound (1) or placebo) was based on this randomization schedule. The randomization schedule was kept strictly confidential and accessible only to authorized personnel until the time of unblinding. The blinding of the study was made public after the database was locked.

[0668] Investigational Drug

[0669] Blinded Investigational Drug

[0670] Compound (1) was available as a hard gelatin capsule containing a white to off-white powder. Active Compound (1) capsules contained the specified amount of Compound (1) drug substance, as well as the excipients croscarmellose sodium, mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, and sodium stearyl fumarate. Capsules were available in dosage strengths of 20 mg and 30 mg.

[0671] Blinded placebo was provided as a hard gelatin capsule matched in appearance to Compound (1).

[0672] Open-label investigational drug

[0673] Sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine, packaged and labeled by commercial manufacturers, were supplied by a third party supplier. Open-label IP were stored and administered according to the package insert. Open-label IP during this study were used only as directed in this protocol.

[0674] Blinded investigational product packaging and labeling

[0675] Compound (1) and placebo were provided to the clinic pharmacist and / or designated site personnel responsible for dispensing the blinded IP in participant-specific kits containing appropriately labeled, sealed unit doses. Each unit dose for the 40 mg and 50 mg dose levels consisted of two capsules. Additional information regarding packaging and labeling was provided in the pharmacy manual.

[0676] Labels for compound (1) and placebo were prepared by the sponsor containing all necessary information and complying with all applicable FDA Code of Federal Regulations and Good Manufacturing Practice / Good Clinical Practice guidelines.

[0677] Storage of blinded investigational products

[0678] Compound (1) and placebo should be stored securely and separately from other medications at room temperature (59-86°F; 15-30°C).

[0679] Blinded and open-label investigational drug administration

[0680] Blinded IP and open-label ADT were administered orally once daily at approximately 8 PM with a fat-containing meal (e.g., within 1 hour of a fat-containing dinner or with a fat-containing snack). Examples of fat-containing snacks include nuts, peanut butter, avocado, eggs, and cheese. Participants assigned to duloxetine also received duloxetine in the morning (two divided doses per day) for the first 7 days.

[0681] If a participant misses a dose of either the blinded or open-label IP, the participant should omit that dose (e.g., the participant should not take that dose in the morning) and take the next scheduled dose the following evening.

[0682] Efficacy and clinical pharmacology evaluation

[0683] Efficacy evaluation

[0684] Hamilton Rating Scale for Depression (HAM-D)

[0685] The primary outcome measure was change from baseline in the 17-item HAM-D total score on day 3. Every effort was made to have the same assessor administer all of the HAM-D assessments for each participant. At screening, an assessment window of the past 7 days (1 week) was used, and for all other visits, "since last visit" was used.

[0686] The 17-item HAM-D was used to grade the severity of depression in participants already diagnosed with depression. The 17-item HAM-D includes individual ratings related to the following symptoms: depressed mood (sadness, hopelessness, helplessness, worthlessness), guilt, suicidality, insomnia (early, middle, late), work and activities, retardation (slowness of thought and speech, poor concentration, reduced motor activity), agitation, anxiety (mental and physical), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, weight loss, and insight. The HAM-D total score was calculated as the sum of the 17 individual item scores.

[0687] In addition to the primary efficacy endpoint of change from baseline in HAM-D total score, several secondary efficacy endpoints were derived for HAM-D. Hamilton Rating Scale for Depression subscale scores were calculated as the sum of the items comprising each subscale. Hamilton Rating Scale for Depression response was defined as having a 50% or greater reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission was defined as having a HAM-D total score of ≦7.

[0688] Montgomery-Asberg Depression Rating Scale (MADRS)

[0689] The MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. The MADRS was designed as an adjunct to the HAM-D, which is more sensitive to changes brought about by antidepressants and other forms of treatment than the Hamilton scale. Higher MADRS scores indicate more severe depression, and each item is given a score from 0 to 6. The overall score ranges from 0 to 60. The MADRS total score was calculated as the sum of the scores of the 10 individual items.

[0690] Hamilton Anxiety Rating Scale (HAM-A)

[0691] The 14-item HAM-A is used to grade the severity of anxiety symptoms. Each of the 14 items is defined by a set of symptoms and measures both mental anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Scoring of the HAM-A is calculated by assigning a score from 0 (absent) to 4 (very severe), with a total score ranging from 0 to 56, where <17 indicates mild severity, 18 to 24 indicates mild to moderate severity, and 25 to 30 indicates moderate to severe severity. The HAM-A total score was calculated as the sum of the scores of the 14 individual items.

[0692] Clinical Global Impression (CGI)

[0693] The CGI is a validated scale that is often utilized in clinical studies to allow clinicians to integrate multiple sources of information into a single rating of a participant's condition. See, for example, Joan Busner and Steven D. Targum, "The Clinical Global Impressions Scale", Psychiatry (Edgmont). 2007 Jul; 4(7): 28-37. In general, the CGI has two components: CGI-Severity (SGI-S), which grades disease severity, and CGI-Improvement (CGI-I), which grades change from the start of treatment (baseline).

[0694] The CGI-S uses a 7-point Likert scale to rate the severity of the participant's illness at the time of assessment in comparison with the clinician's previous experience with participants with the same diagnosis. Taking into account the overall clinical experience, the participant is rated at the time of grading on the severity of their mental illness as follows: 1=normal, not at all ill, 2=borderline ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, and 7=extremely ill.

[0695] The CGI-I measures the overall improvement in a participant's condition after treatment using a 7-point Likert scale. Investigators grade the participant's overall improvement, whether or not it is entirely due to drug treatment. Response options include: 0=no rating, 1=very significant improvement, 2=significant improvement, 3=minimal improvement, 4=unchanged, 5=minimal worsening, 6=significant worsening, and 7=very significant worsening. The CGI-I was graded only at post-treatment assessments. By definition, all CGI-I assessments were assessed against baseline conditions. A CGI-I response was defined as having a CGI-I score of "very significant improvement" or "significant improvement."

[0696] Simplified Format 36 Version 2

[0697] The Medical Outcomes Study SF-36v2 is a 36-item measure of health status that has been validated in a number of different disease states. SF-36v2 encompasses eight health dimensions, including four physical health status domains (physical functioning, role participation with physical health problems [role-physical], bodily pain, and general health), and four mental health status domains (vitality, social functioning, role participation with emotional health problems [role-emotional], and mental health). In addition, two summary scores, a physical component summary and a mental component summary, are generated by taking a weighted linear combination of the eight individual domains. SF-36v2 is available with two recall periods: a standard recall period of four weeks and an acute recall period of one week. This study used the acute version, which asked patients to respond to questions about the past week. Higher SF-36v2 scores indicate better health status.

[0698] patient health questionnaire

[0699] The PHQ-9 is a participant-rated depression symptom severity scale. To monitor the severity over time in newly diagnosed or currently treated participants for depression, participants can complete the questionnaire at baseline and at regular intervals thereafter. Scoring is based on responses to specific questions as follows: 0=not at all, 1=several days, 2=more than half the days, and 3=almost every day.

[0700] The PHQ-9 total score is calculated as the sum of the scores of the nine individual items. PHQ-9 total scores are classified as follows: 1–4 = slight depression, 5–9 = mild depression, 10–14 = moderate depression, 15–19 = moderately severe depression; and 20–27 = severe depression.

[0701] Sheehan Disability Scale

[0702] The SDS is a participant-rated rating that measures the extent to which symptoms of psychiatric illness have interfered with work / school, social life, and home life or family responsibilities. SDS total scores range from a minimum of 0 to a maximum of 30. For the SDS total score, lower scores indicate better outcomes and higher scores indicate worse outcomes. A negative change from baseline (a decrease in score) is considered a better outcome and a positive change from baseline (an increase in score) is considered a worse outcome. The SDS contains three items. The total score is calculated as the sum of the scores of the three items.

[0703] Clinical Pharmacology Evaluation

[0704] Pharmacokinetic evaluation

[0705] Pharmacokinetic parameters (e.g., clearance) and exposure estimates (e.g., area under the curve over the dosing interval, maximum plasma concentrations) were assessed by population PK methods. Data from this study may be combined with data from other studies and reported separately to support this analysis.

[0706] Blood sample collection

[0707] Plasma samples for PK analysis will be collected according to the sampling schedule. The investigator or designee will arrange for plasma samples to be shipped as directed for bioanalysis.

[0708] Additional PK samples could be taken at any time if clinically indicated and at the investigator's discretion (e.g., unusual or severe AEs). In the case of dose adjustments, unscheduled PK samples should be taken immediately prior to the dose adjustment, if possible.

[0709] Each sample was marked with a unique identifier including at least the study number, participant number and visit date. The date and actual time the blood sample was taken was recorded on the case report form.

[0710] Sample analysis

[0711] Bioanalysis of plasma samples for the determination of compound (1) was performed in a qualified laboratory using a validated liquid chromatography-tandem mass spectrometry method.

[0712] Safety assessment

[0713] Columbia-Suicide Severity Rating Scale (C-SSRS)

[0714] Suicidality was monitored throughout the study using the C-SSRS. This scale consists of a baseline assessment assessing participants' lifetime experiences with suicidal thoughts and behaviors, and a post-baseline assessment looking at suicidality since the last study visit. The C-SSRS includes a "yes" or "no" response to an assessment of suicidal thoughts and behaviors, and a numerical rating (1-5, with 5 being the most severe) regarding the severity of suicidal thoughts, if any.

[0715] The “Baseline / Screening” C-SSRS forms were completed at screening (lifetime medical history and past 24 months). The “Since Last Visit” C-SSRS forms were all completed at later time points as outlined in Table 1.

[0716] Physician Withdrawal Checklist

[0717] The Penn Physician Withdrawal Checklist (PWC) consists of 35 items developed to measure benzodiazepine and benzodiazepine-like discontinuation symptoms. The PWC-20 is a simplified version of the PWC based on 20 items that provided the best discrimination from placebo in previous studies. The PWC-20 consists of a list of 20 symptoms (e.g., loss of appetite, nausea-vomiting, diarrhea, anxiety-nervousness, irritability, etc.) graded on a scale from 0 (none) to 3 (severe). The PWC-20 was used to monitor for the presence of potential withdrawal symptoms following discontinuation of compound (1).

[0718] Adverse events and serious adverse events

[0719] Definition of adverse events

[0720] An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a medicinal product that does not necessarily have a causal relationship to this treatment. Thus, an AE can be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease that is temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. In clinical studies, an AE can include any untoward medical condition that occurs at any time, including baseline or washout phases, even when no study treatment is administered.

[0721] A TEAE was defined as an AE with occurrence after initiation of IP or any worsening of a pre-existing medical condition / AE occurring after IP initiation and throughout the study. The term IP includes any Sage IP, comparator or placebo administered in the clinical study.

[0722] Laboratory abnormalities and changes from baseline in vital signs and ECGs were considered AEs if they led to discontinuation or interruption of study treatment, required therapeutic medical intervention, met protocol-specific criteria (if applicable), or the investigator considered them clinically important. Any abnormalities that met the criteria for an SAE should be reported promptly. Laboratory abnormalities and changes from baseline in vital signs and ECGs that were clearly attributable to another AE did not require separate reporting (e.g., electrolyte abnormalities in the setting of dehydration, chemistry and hematology abnormalities in the setting of sepsis).

[0723] All participants should report to Sage Therapeutics all AEs that occur after signing the informed consent and throughout the duration of the study, whether or not related to the study.

[0724] Participants who discontinued IP due to an AE should be followed until the event was resolved, deemed stable, or the investigator determined that the event was no longer clinically significant, regardless of causality as determined by the investigator. Any AE that had not resolved at the participant's last AE assessment during the study was followed by the investigator as long as medically indicated, but was not further recorded in the eCRF. The sponsor or its designee reserved the right to request additional information for any patient with an ongoing AE / SAE at the end of the study, if deemed necessary.

[0725] Definition of serious adverse events

[0726] An SAE was any of the following untoward medical occurrences at any dose: - Leading to death. Participants were at risk of imminent death (life-threatening events). However, this did not include events that could cause death if they occurred in a more severe form. · The need for hospitalization or the prolongation of an existing hospitalization. Caused a persistent or significant impairment or incapacity; or · Caused congenital anomalies or birth defects.

[0727] An SAE could be any other medically significant event that, in the opinion of the investigator, may put the participant at risk or require medical intervention to prevent one of the outcomes listed above (examples of such an event included an allergic bronchospasm requiring intensive treatment in an emergency room, or a seizure occurring at home that did not require hospitalization).

[0728] All SAEs that occurred after any participant signed the ICF and throughout the duration of the study, whether or not related to the study, must be recorded in an SAE report provided by Sage Therapeutics. Any SAEs occurring when the participant completed their last study visit were followed by the investigator until the event resolved, stabilized, returned to baseline status, or the participant died or was lost to follow-up.

[0729] Elective or elective or routinely scheduled procedures were not considered SAEs, even if the participant was hospitalized. Facilities had to document all of the following: The elective or routine elective procedure was scheduled (or was on a waiting list) before the participant consented to participate in the study; and · A condition requiring a planned or elective procedure or routinely planned procedure, in the opinion of the investigator, was pre-existing and had not worsened or progressed between the participant's consent to participate in the study and the time of the procedure or procedure.

[0730] Relationship with investigational drug

[0731] For each AE, the investigator had to determine whether it was related to the IP (not related, related). The following definitions should be considered when assessing the relationship of AEs and SAEs to the IP:

[0732] Unrelated – An AE was considered "unrelated" to the use of an IP if there was not a reasonable possibility that the event was caused by the IP. Factors that led to this assessment included, but were not limited to, no temporal relationship between administration of the IP and the event, an implausible biological association between the product and the AE, or another more likely explanation for the AE.

[0733] Related - An AE was considered "related" to the use of the IP if there was a reasonable possibility that the event could have been caused by the product under study. Factors that led to this assessment included, but were not limited to, a positive rechallenge, a plausible temporal sequence between administration of the drug and the event, a known response pattern for the suspected drug, improvement after discontinuation or dose reduction, a biologically plausible relationship between the drug and the AE, or the absence of an alternative explanation for the AE.

[0734] Recording of adverse events

[0735] Adverse events spontaneously reported by participants and / or reported in response to open questions from study personnel or evident by observation were recorded at the study site during the study. AE terms should be reported in standard medical terminology when possible. For each AE, the investigator assessed and reported onset (date and time), resolution (date and time), intensity, causality, actions taken, outcome and seriousness (if applicable), and whether the participant discontinued IP or withdrew early from the study.

[0736] Strength was assessed according to the following scale: Mild: Symptoms that were barely noticeable or did not bother the participant; did not affect performance or function; did not typically require prescription medication to relieve symptoms. Moderate: Symptoms severe enough to cause discomfort to the participant; impact on carrying out daily activities; participant is able to continue in the study; treatment for symptoms may be required. Severe: Symptoms cause severe discomfort; Symptoms cause incapacitation or significantly affect the participant's daily life; Severity may cause cessation of treatment with the IP; Treatment for symptoms may be administered and / or the participant may be hospitalized.

[0737] It is important to distinguish between serious and severe AEs. Severity is a measure of intensity, while seriousness is defined by the criteria described herein. AEs of severe intensity may not necessarily be considered serious.

[0738] Overdose

[0739] Overdoses were considered AEs and recorded as such on the eCRF, regardless of the presence of associated clinical manifestations (e.g., headache, abnormal laboratory values). Any clinical manifestations of an overdose must also be recorded as an AE on the eCRF. In addition, all overdoses must be recorded on an Overdose Form and sent to Sage or designee within 24 hours of the site becoming aware of the overdose.

[0740] [Table 1-1] [Table 1-2] Abbreviations AE=adverse event; CGI-I=Clinical Global Impression-Improved; CGI-S-Clinical Global Impression-Severity; C-SSRS=Columbia Suicide Severity Scale; D=day; EOT=end of treatment; ET=early discontinuation; ECG=electrocardiogram; FSH=follicle-stimulating hormone; HAM-A=Hamilton Anxiety Scale; HAM-D=Hamilton Rating Scale for Depression, 17 items; HIV=human immunodeficiency virus; IP=investigational drug; MADRS=Montgomery-Asberg Depression Rating Scale; MGH ATRQ=Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; PHQ-9=9-item Patient Health Questionnaire; PWC-20=20-item Physician Withdrawal Checklist; O=as needed; PK=pharmacokinetics; SCID-5-CT=Structured Clinical Interview for Clinical Trials Version, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; SDS=Sheehan Disability Scale; SF-36v2=36-item Short Form Questionnaire, version 2; V=visit. a Participants who discontinue treatment early should return to the site for an end of treatment (EOT) visit as soon as possible, preferably on the same day after discontinuation of treatment. If necessary, if a participant discontinues IP and terminates the study on the same day of the visit, the EOT and ET visits can be on the same day. In this case, all EOT visit assessments should be performed. b Participants will be asked to authorize the entry of a unique participant identifier into a registry (www.subjectregistry.com) for the purpose of identifying participants who may meet exclusion criteria due to their participation in another clinical study. c Serum FSH testing will be performed at screening of non-surgically sterile female participants to determine whether those with spontaneous amenorrhea for ≥12 months meet the protocol-defined criteria for postmenopause. d Participants will be trained by site personnel in the use of software applications and devices necessary to conduct the study. eA full physical exam will be performed at screening, followed by a shortened physical exam. The full physical exam will include evaluation of the body systems (e.g., head, eyes, ears, nose and throat; heart; lungs; abdomen; and extremities). The shortened physical exam will include a brief medical history followed by a targeted physical exam. f Safety laboratory tests included hematology, serum chemistry, coagulation and urinalysis. g Urine toxicology for selected drugs of abuse and breath testing for alcohol. h Serum pregnancy test at screening and subsequent urine pregnancy test for female participants who are not surgically sterile and do not meet protocol-defined criteria for postmenopausal status. i Optional blood samples for exploratory hormone and biochemistry testing (if consent is given). j Genetic samples as needed for exploratory biomarker testing (if consent is obtained). k If vital signs are scheduled for the same time as blood draw, they will be obtained first. Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). After the participant has rested for 5 minutes, heart rate and blood pressure will then be collected in the supine position at all scheduled times after approximately 3 minutes in the standing position. Vital signs may be repeated at the discretion of the investigator as clinically indicated. l ECGs are collected in triplicate. ECG and PK sampling is performed on the same day, with a 12-lead ECG performed prior to PK sampling. m The "Baseline / Screening" C-SSRS form will be completed at screening. The "Since Last Visit" C-SSRS form will be completed at all subsequent time points. n The HAM-D should be completed as soon as possible during the visit. oThe assessment time frame for the HAM-D scale refers to the past 7 days (1 week) at screening and "since last visit" for all other visits. The assessment time frame for the HAM-A scale refers to the past 7 days (1 week) at all visits. p Blood samples for PK analysis will be taken at any time during the visit. In the case of dose adjustments, unscheduled PK samples should be taken immediately prior to the dose adjustment, if possible. The date and time of sample collection and the date and time of administration of the final dose must be recorded. ECG and PK sampling will be performed on the same day, with a 12-lead ECG performed prior to PK sampling. q IP administration will be monitored by a smartphone-based medication adherence monitoring platform to verify IP intake. IP adherence will not be captured after participants discontinue IP. r ADT is administered according to the labeled prescribing information. s AEs will be collected beginning at the time of informed consent and throughout the participant's participation in the study. t Past medications will be collected at screening, and concomitant medications and / or procedures will be collected at each subsequent visit.

[0741] Example 2 Results for the Study of Example 1

[0742] summary

[0743] This was a randomized, double-blind, parallel-group, active / placebo-controlled Phase 3 study (NCT04476030) in participants with major depressive disorder (MDD) as described in Example 1. The study evaluated the efficacy and safety of coadministration of Compound (1) with standard of care (SOC) antidepressants (ADT, SSRI or SNRI). Compound (1) was taken for only 14 days, while ADT was continued until the end of the study (42 days). Figure 1 is a schematic diagram of the clinical study design. Briefly, the study period consisted of a screening period of up to 28 days, followed by a 14-day double-blind treatment course (treatment period), followed by a 28-day open-label follow-up period with continuation of SOC ADT treatment.

[0744] The study met its objectives, achieving its primary and key secondary endpoints by demonstrating rapid and statistically significant reductions in depressive symptoms on day 3 and over the two-week treatment period, as assessed by change from baseline in the 17-item Hamilton Rating Scale for Depression (HAMD-17). This significance was demonstrated when Compound (1) 50 mg was initiated concomitantly with open-label standard of care antidepressant (ADT) at the first measurement time point, day 3. The study also met its key secondary endpoints, demonstrating that Compound (1) initiated concomitantly with standard of care ADT resulted in statistically significant improvements in depressive symptoms compared to ADT initiated concomitantly with placebo, as measured using equal weighting over the two-week treatment period.

[0745] Compound (1) was generally well tolerated, and no new safety signals were identified that were attributed to compound (1). This study supports that, upon achievement of prespecified objectives, compound (1) may accelerate the benefit of treating depression when co-initiated with standard of care compared with ADT treatment alone.

[0746] A total of 440 participants were randomized 1:1 to Compound (1) + ADT or placebo + ADT treatment groups. A total of 430 participants received at least one dose of blinded treatment (safety set): 212 in Compound (1) + ADT and 218 in placebo + ADT.

[0747] statistical analysis

[0748] The safety population included all patients who received blinded study drug.The Full Analysis Set (FAS) included all randomized patients in the safety population with an effective baseline and a postbaseline total score of ≥1 on at least one of the efficacy assessments (HAMD-17, Hamilton Rating Scale for Anxiety [HAM-A], Montgomery-Asberg Depression Scale, or the 9-item Patient Health Questionnaire), or with an effective baseline and a postbaseline value of ≥1 on the Clinical Global Impression-Improvement score and / or Clinical Global Impression-Severity score.

[0749] A sample size of 382 e...

Claims

1. 1. A method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising: (i) about 40 mg to about 50 mg of compound (1) 【Chemistry 128】 or a combination comprising a dose equivalent to about 40 mg to about 50 mg of the free base compound of a pharma- ceutically acceptable salt of Compound (1) and a therapeutically effective amount of an additional antidepressant; (ii) providing a second treatment comprising administering a therapeutically effective amount of said additional antidepressant. A method comprising:

2. 1. A method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1). 【Chemistry 129】 or a pharma- ceutically acceptable salt thereof and a therapeutically effective amount of an additional antidepressant; (ii) providing a second treatment comprising administering a therapeutically effective amount of said additional antidepressant. Including, The method, wherein said subject is treatment naive.

3. The method of claim 1 , wherein the subject is treatment naive.

4. a. the subject has not received any antidepressant treatment within at least 30 days prior to the start of the first treatment; b. the subject has not been treated with an additional antidepressant within at least 30 days prior to the start of the first treatment; or c. the subject has not been treated with the additional antidepressant within at least 60 days prior to the start of the first treatment; The method according to any one of claims 1 to 3.

5. The method of any one of claims 1 to 4, wherein the initial treatment comprises administering the combination for about 14 days.

6. The method of any one of claims 1 to 5, wherein the second treatment comprises administering the additional antidepressant for at least 28 days.

7. a. the additional antidepressant is administered at the same dose in the first treatment and in the second treatment; or b. the additional antidepressant is administered at different doses in the first treatment and the second treatment; The method according to any one of claims 1 to 6.

8. The method of any one of claims 1 to 7, wherein compound (1) or a pharma- ceutically acceptable salt thereof is not administered to the subject in the second treatment.

9. a. compound (1) or a pharma- ceutically acceptable salt thereof in the first treatment and the additional antidepressant are administered in separate dosage forms; and / or b. Compound (1) or a pharma- ceutically acceptable salt thereof in the first treatment and the additional antidepressant are administered simultaneously; or c. Compound (1) or a pharma- ceutically acceptable salt thereof in the first treatment and the additional antidepressant are administered at different times; The method according to any one of claims 1 to 8.

10. The additional antidepressant a. at the same dose in the first treatment and in the second treatment, or b. at different doses in the first and second treatments The method according to any one of claims 1 to 9, wherein the

11. The method of any one of claims 1 to 10, wherein the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the first treatment.

12. A method for treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of compound (1). 【Chemistry 130】 or a pharma- ceutically acceptable salt thereof and a therapeutically effective amount of an additional antidepressant; The method, wherein said subject is treatment naive.

13. A method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a treatment-naive subject in need of such treatment, comprising administering a therapeutically effective amount of compound (1) or a pharma- ceutical acceptable salt thereof. 【Chemistry 131】 and simultaneously commencing administration of a combination comprising a therapeutically effective amount of an additional antidepressant.

14. a. the subject has not received any antidepressant treatment within at least 30 days prior to said treatment; b. the subject has not been treated with an additional antidepressant within at least 30 days prior to the treatment; or c. the subject has not been treated with an additional antidepressant within at least 60 days prior to the treatment; 14. The method according to claim 12 or 13.

15. The method of any one of claims 12 to 14, wherein the combination is administered for about 14 days.

16. a. Compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant are administered in separate dosage forms; and / or b. Compound (1) or a pharma- ceutically acceptable salt thereof and the additional antidepressant are administered simultaneously; or c. Compound (1), or a pharma- ceutically acceptable salt thereof, and the additional antidepressant are administered at different times; The method according to any one of claims 12 to 15.

17. the treatment further comprises a second treatment comprising administering a therapeutically effective amount of an additional antidepressant; Optionally, the second treatment comprises administering the additional antidepressant for at least 28 days; 17. The method of any one of claims 12 to 16, optionally wherein compound (1), or a pharma- ceutically acceptable salt thereof, is not administered to the subject in the second treatment.

18. a. the additional antidepressant is administered in the second treatment at the same dosage as in the combination b. the additional antidepressant is administered at a different dose in the second treatment compared to the dose administered in the combination; 18. The method of claim 17, optionally wherein the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the combination.

19. the subject has MDD, Optionally, the subject has MDD with elevated anxiety; Optionally, the subject is experiencing a major depressive episode, and optionally, the subject has elevated anxiety during a majority of days of the major depressive episode; Optionally, the subject has a HAM-D Anxiety / Somatization subscale score of at least 7 at baseline, and / or Optionally, the subject has a HAM-A total score of at least 17 or at least 20 at baseline.

19. The method according to any one of claims 1 to 18.

20. the subject has PPD, Optionally, the subject has PPD accompanied by elevated anxiety; Optionally, the subject has experienced a major depressive episode with perinatal onset, and optionally, the subject has elevated anxiety during a majority of days of the major depressive episode with perinatal onset; Optionally, the subject has a HAM-D Anxiety / Somatization subscale score of at least 7 at baseline, and / or Optionally, the subject has a HAM-A total score of at least 17 or at least 20 at baseline.

21. administering the combination reduces treatment-emergent gastrointestinal adverse events; Optionally, said treatment-emergent gastrointestinal adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite or dry mouth, or any combination thereof; Optionally, said treatment-emergent gastrointestinal adverse events include nausea and / or diarrhea, and / or 21. The method of any one of claims 1 to 20, optionally wherein said treatment-emergent gastrointestinal adverse event is attributable to treatment with said additional antidepressant.

22. The method according to any one of claims 1 to 21, wherein compound (1) or a pharma- ceutically acceptable salt thereof is administered once a day.

23. The method according to any one of claims 1 to 22, wherein compound (1) is administered.

24. Compound (1) is a. at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg; b. At a dose of about 50 mg, c. at a dose of about 40 mg d. once daily at a dose of about 50 mg; or e. Once a day at a dose of about 40 mg The method according to any one of claims 2 to 22, wherein the

25. The method according to any one of claims 1 to 22, wherein a pharma- ceutically acceptable salt of compound (1) is administered.

26. A pharma- ceutically acceptable salt of compound (1) is a. at a dose equivalent to about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of the free base compound; b. at a dose equivalent to about 50 mg of the free base compound, c. at a dose equivalent to about 40 mg of the free base compound, d. once daily at a dose equivalent to about 50 mg of the free base compound; or e. once daily at a dose equivalent to approximately 40 mg of the free base compound The method according to any one of claims 2 to 22, wherein the

27. Compound (1) or a pharma- ceutically acceptable salt thereof is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalation, intranasally or transdermally; Optionally, compound (1) or a pharma- ceutically acceptable salt thereof is orally administered; Optionally, compound (1) or a pharma- ceutically acceptable salt thereof is administered with food, and / or Optionally, compound (1) or a pharma- ceutically acceptable salt thereof is administered once daily in the evening; The method according to any one of claims 1 to 26.

28. the combination of compound (1), or a pharma- ceutically acceptable salt thereof, and the additional antidepressant is readministered to the subject upon recurrence of depressive symptoms; Optionally, there is an interval of at least 6 weeks between the final dose of said initial treatment and the first dose of said re-administration. The method according to any one of claims 1 to 11.

29. the combination of compound (1), or a pharma- ceutically acceptable salt thereof, and the additional antidepressant is readministered to the subject upon recurrence of depressive symptoms; Optionally, there is an interval of at least 6 weeks between the last dose of said administration and the first dose of said re-administration. The method according to any one of claims 12 to 18.

30. a. Compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.7 and 10.1 degrees 2θ [including endpoints], between 11.6 and 12.0 degrees 2θ [including endpoints], between 13.2 and 13.6 degrees 2θ [including endpoints], between 14.2 and 14.6 degrees 2θ [including endpoints], between 14.6 and 15.0 degrees 2θ [including endpoints], between 16.8 and 17.2 degrees 2θ [including endpoints], between 20.5 and 20.9 degrees 2θ [including endpoints], between 21.3 and 21.7 degrees 2θ [including endpoints], between 21.4 and 21.8 degrees 2θ [including endpoints], and between 22.4 and 22.8 degrees 2θ [including endpoints]; b. Compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ [including endpoints], between 10.6 and 11.0 degrees 2θ [including endpoints], between 13.0 and 13.4 degrees 2θ [including endpoints], between 14.7 and 15.1 degrees 2θ [including endpoints], between 15.8 and 16.2 degrees 2θ [including endpoints], between 18.1 and 18.5 degrees 2θ [including endpoints], between 18.7 and 19.1 degrees 2θ [including endpoints], between 20.9 and 21.3 degrees 2θ [including endpoints], between 21.4 and 21.8 degrees 2θ [including endpoints], and between 23.3 and 23.7 degrees 2θ [including endpoints]; c. Compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.7 and 10.1 degrees 2θ [inclusive], between 14.6 and 15.0 degrees 2θ [inclusive], between 16.8 and 17.2 degrees 2θ [inclusive], between 20.5 and 20.9 degrees 2θ [inclusive], and between 21.3 and 21.7 degrees 2θ [inclusive]; or 30. The method of any one of claims 1-24 or 27-29, wherein compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ [inclusive], between 10.6 and 11.0 degrees 2θ [inclusive], between 13.0 and 13.4 degrees 2θ [inclusive], between 18.7 and 19.1 degrees 2θ [inclusive], and between 21.4 and 21.8 degrees 2θ [inclusive].

31. The additional antidepressant is a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), a serotonin modulator and stimulator (SMS), a serotonin antagonist and reuptake inhibitor (SARI), a norepinephrine reuptake inhibitor (NRI), a norepinephrine dopamine reuptake inhibitor (NDRI), a tricyclic antidepressant (TCA), a tetracyclic antidepressant (TeCA), a monoamine oxidase inhibitor (MAOI), an atypical antipsychotic, agomelatine, esketamine, tianeptine, ketamine, alpha-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademetionine, hypericum 31. The method of any one of claims 1 to 30, wherein the active ingredient is selected from the group consisting of amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine, or tranylcypromine and trifluoperazine.

32. The additional antidepressant a. SSRIs Optionally, the SSRI is sertraline, escitalopram, citalopram, fluvoxamine, paroxetine, fluoxetine, indalpine, or zimelidine; Optionally, the SSRI is sertraline; Optionally, the SSRI is escitalopram; Optionally, the SSRI is citalopram. SSRIs, b. An SNRI Optionally, the SNRI is duloxetine, desvenlafaxine, levomilnacipran, milnacipran, or venlafaxine; Optionally, the SNRI is duloxetine; Optionally, the SNRI is desvenlafaxine. SNRI, c. SMS, optionally wherein the SMS is vilazodone or vortioxetine; d. a SARI, optionally wherein the SARI is nefazodone, trazodone, or etoperidone; e. an NRI, optionally wherein the NRI is reboxetine, teniloxazine, viloxazine, or atomoxetine; f. an NDRI, optionally wherein the NDRI is bupropion, amphetamine, methylphenidate, modafinil, amineptine, or nomifensine; g. a TCA, optionally wherein the TCA is amitriptyline, amitriptyline oxide, clomipramine, desipramine, dibenzazepine, dimethacrine, dosulepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, notriptyline, noxiptyline, opipramol, pipofezin, protriptyline, trimipramine, butriptyline, demexiptyline, fluacizine, imipramineoxide, iprindole, metapramine, propizepine, quinupramine, thiazesim, or tofenacin; h. TeCA, optionally wherein the TeCA is amoxapine, maprotiline, mianserin, mirtazapine or setiptiline; i. an MAOI, optionally wherein said MAOI is isocarboxazid, phenelzine, tranylcypromine, benmoxine, iproclozide, iproniazid, mebanazine, nialamide, octamoxin, pheniprazine, phenoxypropazine, pibhydrazine, safrazine, selegiline, caroxazone, metralindole, moclobemide, pirlindole, eprobemide, minaprine, toloxatone or bifemelane; j. an atypical antipsychotic, optionally wherein the atypical antipsychotic is amisulpride, lumateperone, lurasidone, quetiapine, aripiprazole, brexpiprazole, lumateperone, lurasidone, olanzapine, quetiapine, or risperidone; k. agomelatine, esketamine, tianeptine, ketamine, alpha-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademethionine, hypericum perforatum, oxytriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine or tranylcypromine and trifluoperazine; or l. 4-Chlorokynurenine (AV-101), apimostinel (NRX-1074), arketamine (PCN-101, HR-071603), dextromethadone (REL-1017), MIJ-821, lisrenemdaz (CERC-301, MK-0657), TAK-653 (NBI-1065845), OPC-64005, PDC-1421 (BLI-1005), tordesvenlafaxine, hirudin Pydone (YL-0919), TGBA01AD (FKB01MD), vortioxetine, lisdexamfetamine, midomafetamine, aramisulpride / esamisulpride (85:15 ratio) (SEP-4199), gepirone, pramipexole, psilocybin, briraloxazine, cariprazine, lumateperone, lurasidone, pimavanserin, ademetionine, 3β-methoxypregnenolone (MAP -4343), PH-10-vomeroferrin, Aticaplant, BTRX-335140 (BTRX-140), buprenorphine / samidolphan, BTRX-246040 (LY-2940094), scopolamine (DPI-386), JNJ-39393406, onabotulinumtoxinA, JNJ-61393215, celtrexant, BI-1358894, crisdesalazine, ertebele le, JNJ-54175446, NSI-189, NV-5138, SNG-12, TS-121, WIP-DF17, tramadol, bupropion / dextromethorphan (AXS-05), carbidopa / oxytriptan (EVX-101), cycloserine / lurasidone (NRX-101; Cyclerad), or deuxtromethorphan / quinidine (AVP-786, CTP-786). and Optionally, the additional antidepressant is administered in accordance with its labeled prescribing information.

32. The method according to any one of claims 1 to 31.

33. 1. A method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of an antidepressant and about 40 mg to about 50 mg of compound (1): 【Chemistry 132】 and said co-administration occurring from about day 1 of treatment to about day 14 of treatment; The antidepressant is administered continuously after the 14th day of treatment. method.

34. A method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need of such treatment, comprising administering to a subject a therapeutically effective amount of an antidepressant and a dose equivalent to about 40 mg to about 50 mg of the free base compound of compound (1). 【Chemistry 133】 with a pharma- ceutically acceptable salt of said co-administration occurring from about day 1 of treatment to about day 14 of treatment; The antidepressant is administered continuously after the 14th day of treatment. method.

35. 1. A method of treating major depressive disorder with elevated anxiety (MDD) or postpartum depression with elevated anxiety (PPD) in a subject in need of such treatment, comprising administering to a subject a therapeutically effective amount of an antidepressant and about 40 mg to about 50 mg of compound (1): 【Chemistry 134】 and said co-administration occurring from about day 1 of treatment to about day 14 of treatment; The antidepressant is administered continuously after the 14th day of treatment. method.

36. 1. A method for treating major depressive disorder with elevated anxiety (MDD) or postpartum depression with elevated anxiety (PPD) in a subject in need of such treatment, comprising administering to a subject a therapeutically effective amount of an antidepressant and a dose equivalent to about 40 mg to about 50 mg of the free base compound of compound (1). 【Chemistry 135】 with a pharma- ceutically acceptable salt of said co-administration occurring from about day 1 of treatment to about day 14 of treatment; The antidepressant is administered continuously after the 14th day of treatment. method.

37. The method of any one of claims 33 to 36, wherein the subject is treatment naive.

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