19-nor C3,3-disubstituted C21-N-pyrazolyl steroids for the treatment of major depressive disorder

Abstract

The present disclosure relates to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) administering to the subject an initial treatment course comprising administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof; and (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering a therapeutically effective amount of compound (1) or a pharmaceutically acceptable salt thereof upon recurrence of depressive symptoms. The 0, 1, or 2 subsequent treatment courses can be administered over a period of 12 months from the start of the initial treatment course.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 162,501, filed March 17, 2021, and U.S. Provisional Patent Application No. 63 / 284,592, filed November 30, 2021. The entire contents of the aforementioned applications are incorporated by reference herein in their entirety.

[0002] FIELD OF THEINVENTION The present disclosure relates to a method of treating Major Depressive Disorder (MDD) in a subject in need thereof, comprising: (i) administering to the subject an initial treatment course comprising administration of a therapeutically effective amount of Compound (1) or a pharma- ceutically acceptable salt thereof; and (ii) administering to the subject zero, one, or two subsequent treatment courses, each subsequent treatment course comprising administering a therapeutically effective amount of Compound (1) or a pharma- ceutically acceptable salt thereof responsive to a recurrence of depressive symptoms, wherein the zero, one, or two subsequent treatment courses are administered over a period of twelve months from the start of the initial treatment course. [Background technology]

[0003] background Up to 40% of neurons in the brain utilize γ-aminobutyric acid, GABA, as a neurotransmitter, so GABA exerts a profound effect on overall brain excitability. GABA promotes the flow of chloride ions into the cell down the electrochemical gradient of the GRC by interacting with a recognition site on the GRC (GABA receptor complex). An intracellular increase in the level of this anion causes hyperpolarization of the transmembrane potential, making the neuron less sensitive to excitatory inputs (i.e., less excitable). In other words, the higher the concentration of chloride ions in the neuron, the lower the brain's excitability (level of arousal). It is well documented that GRCs are involved in mediating anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZ), e.g., Valium®) exert their therapeutically useful effects by interacting with specific regulatory sites on the GRC. Accumulating evidence suggests that the GRC contains distinct sites for neuroactive steroids (Lan, NC et al., Neuwchem. Res. 16:347-356 (1991). Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one, metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, MD et al., Science 232:1004-1007 (1986); Harrison, NL et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Lan, N.C. et al., Neuwchem. Res. 16:347-356 (1991) [Non-Patent Document 2] Majewska, MD et al., Science 232:1004-1007(1986) [Non-Patent Document 3] Harrison, N.L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987) Summary of the Invention [Means for solving the problem]

[0005] Summary of the Invention 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] administering to the subject an initial treatment course comprising administration of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering a therapeutically effective amount of compound (1) in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0006] 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] administering to the subject an initial treatment course comprising administering a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1) in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0007] In some embodiments of these aspects, 0 or 1 subsequent course of treatment is administered. In some embodiments, 1 subsequent course of treatment is administered.

[0008] In some embodiments, there is at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of the initial treatment course and the beginning of the subsequent treatment course. In some embodiments, there is at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of the initial treatment course and the beginning of the subsequent treatment course.

[0009] In some embodiments, the recurrence of depressive symptoms is indicated by subject assessment using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Patient Health Questionnaire (PHQ-9), or a combination thereof. In some embodiments, the recurrence of depressive symptoms in a subject is indicated by a PHQ-9 score of 10 or more or a HAM-D score of 20 or more.

[0010] In some embodiments, the duration of the initial treatment course is about 2 weeks or about 14 days. In some embodiments, the duration of each subsequent treatment course is about 2 weeks or about 14 days. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once a day for about 14 days in the initial treatment course. In some embodiments, compound (1) or a pharmaceutically acceptable salt of compound (1) is administered once a day for about 14 days in each subsequent treatment course.

[0011] In some embodiments, compound (1) is administered in a dose of about 20 mg to about 55 mg. In some embodiments, compound (1) is administered in a dose of about 30 mg to about 50 mg. In some embodiments, compound (1) is administered in a dose of about 50 mg. In some embodiments, compound (1) is administered in a dose of about 40 mg. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 20 mg to about 55 mg of the free base compound. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 30 mg to about 50 mg of the free base compound. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 50 mg of the free base compound. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 40 mg of the free base compound.

[0012] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, buccally, sublingually, rectally, topically, by inhalation, intranasally, or transdermally. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered with food. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day at night.

[0013] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks at 2θ between 9.7 and 10.1 degrees (inclusive), 2θ between 11.6 and 12.0 degrees (inclusive), 2θ between 13.2 and 13.6 degrees (inclusive), 2θ between 14.2 and 14.6 degrees (inclusive), 2θ between 14.6 and 15.0 degrees (inclusive), 2θ between 16.8 and 17.2 degrees (inclusive), 2θ between 20.5 and 20.9 degrees (inclusive), 2θ between 21.3 and 21.7 degrees (inclusive), 2θ between 21.4 and 21.8 degrees (inclusive), and 2θ between 22.4 and 22.8 degrees (inclusive). In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks at 2θ between 9.3 and 9.7 degrees (inclusive), 2θ between 10.6 and 11.0 degrees (inclusive), 2θ between 13.0 and 13.4 degrees (inclusive), 2θ between 14.7 and 15.1 degrees (inclusive), 2θ between 15.8 and 16.2 degrees (inclusive), 2θ between 18.1 and 18.5 degrees (inclusive), 2θ between 18.7 and 19.1 degrees (inclusive), 2θ between 20.9 and 21.3 degrees (inclusive), 2θ between 21.4 and 21.8 degrees (inclusive), and 2θ between 23.3 and 23.7 degrees (inclusive). 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 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. 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.

[0014] In some embodiments, the subject is treatment naive.

[0015] In some embodiments, the subject has been taking an additional antidepressant stably for at least 60 days prior to the start of the initial treatment course.

[0016] In another 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] administering to the subject an initial treatment course comprising administration of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering a therapeutically effective amount of compound (1) in response to a recurrence of depressive symptoms. Including, wherein 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course; The method includes wherein the subject is treatment naive.

[0017] In another 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] administering to the subject an initial treatment course comprising administering a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1) in response to a recurrence of depressive symptoms. Including, wherein 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course; The method includes wherein the subject is treatment naive.

[0018] In some embodiments of these aspects, 0 or 1 subsequent course of treatment is administered. In some embodiments, 1 subsequent course of treatment is administered.

[0019] In some embodiments, there is at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of the initial treatment course and the beginning of the subsequent treatment course. In some embodiments, there is at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of the initial treatment course and the beginning of the subsequent treatment course.

[0020] In some embodiments, the recurrence of depressive symptoms is indicated by subject assessment using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Patient Health Questionnaire (PHQ-9), or a combination thereof. In some embodiments, the recurrence of depressive symptoms in a subject is indicated by a PHQ-9 score of 10 or more or a HAM-D score of 20 or more.

[0021] In some embodiments, the duration of the initial treatment course is about 2 weeks or about 14 days. In some embodiments, the duration of each subsequent treatment course is about 2 weeks or about 14 days. In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered once a day for about 14 days in the initial treatment course. In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered once a day for about 14 days in each subsequent treatment course. In some embodiments, compound (1) is administered at a dose of about 20 mg to about 55 mg. In some embodiments, compound (1) is administered at a dose of about 30 mg to about 50 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. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered at a dose equivalent to about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered in a dose equivalent to about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered in a dose equivalent to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered in a dose equivalent to about 40 mg of the free base compound.

[0022] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, buccally, sublingually, rectally, topically, by inhalation, intranasally, or transdermally. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered with food. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day at night.

[0023] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks at 2θ between 9.7 and 10.1 degrees (inclusive), 2θ between 11.6 and 12.0 degrees (inclusive), 2θ between 13.2 and 13.6 degrees (inclusive), 2θ between 14.2 and 14.6 degrees (inclusive), 2θ between 14.6 and 15.0 degrees (inclusive), 2θ between 16.8 and 17.2 degrees (inclusive), 2θ between 20.5 and 20.9 degrees (inclusive), 2θ between 21.3 and 21.7 degrees (inclusive), 2θ between 21.4 and 21.8 degrees (inclusive), and 2θ between 22.4 and 22.8 degrees (inclusive). In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks at 2θ between 9.3 and 9.7 degrees (inclusive), 2θ between 10.6 and 11.0 degrees (inclusive), 2θ between 13.0 and 13.4 degrees (inclusive), 2θ between 14.7 and 15.1 degrees (inclusive), 2θ between 15.8 and 16.2 degrees (inclusive), 2θ between 18.1 and 18.5 degrees (inclusive), 2θ between 18.7 and 19.1 degrees (inclusive), 2θ between 20.9 and 21.3 degrees (inclusive), 2θ between 21.4 and 21.8 degrees (inclusive), and 2θ between 23.3 and 23.7 degrees (inclusive). 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 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. 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.

[0024] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 30 mg to about 50 mg of compound (1): [ka] administering to the subject an initial treatment course comprising administration of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering to the subject about 30 mg to about 50 mg of compound (1) in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0025] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1), in a dose equivalent to about 30 mg to about 50 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising administering a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering to the subject a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 30 mg to about 50 mg of the free base compound in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0026] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 30 mg to about 50 mg of compound (1): [ka] administering to the subject an initial treatment course comprising once daily for about 14 days a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering to the subject about 30 mg to about 50 mg of compound (1) once daily for about 14 days in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0027] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1), in a dose equivalent to about 30 mg to about 50 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising once daily for about 14 days a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering to the subject once daily for about 14 days a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 30 mg to about 50 mg of the free base compound in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0028] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 30 mg to about 50 mg of compound (1): [ka] administering to the subject an initial treatment course comprising once daily administration of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each of which comprises administering to the subject about 30 mg to about 50 mg of compound (1) once per day for about 14 days in response to the recurrence of depressive symptoms, provided that there is an interval of at least about 6 weeks between the end of the initial treatment course and the start of the subsequent treatment course. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0029] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1), in a dose equivalent to about 30 mg to about 50 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising once daily for about 14 days a pharma- ceutically acceptable salt of (ii) administering to the subject zero, one, or two subsequent treatment courses, each of which comprises administering to the subject a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 30 mg to about 50 mg of the free base compound once daily for about 14 days in response to a recurrence of depressive symptoms, provided that there is an interval of at least about six weeks between the end of the initial treatment course and the beginning of the subsequent treatment course. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0030] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 30 mg to about 50 mg of compound (1): [ka] administering to the subject an initial treatment course comprising once-daily administration for about 14 days of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering to the subject about 30 mg to about 50 mg of compound (1) once daily for about 14 days in response to a recurrence of depressive symptoms. Including, wherein 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course; The method includes wherein the subject has been taking an additional antidepressant medication stably for at least 60 days.

[0031] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1), in a dose equivalent to about 30 mg to about 50 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising once daily for about 14 days a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering to the subject once daily for about 14 days a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 30 mg to about 50 mg of the free base compound in response to a recurrence of depressive symptoms. Including, wherein 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course; The method includes wherein the subject has been taking an additional antidepressant medication stably for at least 60 days.

[0032] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 45 mg to about 55 mg of compound (1): [ka] administering to the subject an initial treatment course comprising administration of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering to the subject about 45 mg to about 55 mg of compound (1) in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0033] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1), in a dosage equivalent to about 45 mg to about 55 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising administering a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering to the subject a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 45 mg to about 55 mg of the free base compound in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0034] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 45 mg to about 55 mg of compound (1): [ka] administering to the subject an initial treatment course comprising once-daily administration for about 14 days of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering to the subject about 45 mg to about 55 mg of compound (1) once daily for about 14 days in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0035] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1), in a dosage equivalent to about 45 mg to about 55 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising once daily for about 14 days a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering to the subject a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 45 mg to about 55 mg of the free base compound once daily for about 14 days in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0036] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 45 mg to about 55 mg of compound (1): [ka] administering to the subject an initial treatment course comprising once daily administration of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each of which comprises administering to the subject about 45 mg to about 55 mg of compound (1) once daily for about 14 days in response to a recurrence of depressive symptoms, provided that there is an interval of at least about 6 weeks between the end of the initial treatment course and the start of the subsequent treatment course. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0037] In another aspect, the present disclosure provides a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1) in a dosage equivalent to about 45 mg to about 55 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising once daily for about 14 days of a pharma- ceutically acceptable salt of (ii) administering to the subject zero, one, or two subsequent treatment courses, each of which comprises administering to the subject, in response to a recurrence of depressive symptoms, a pharma- ceutically acceptable salt of Compound (1) at a dose equivalent to about 45 mg to about 55 mg of the free base compound once daily for about 14 days, provided that there is an interval of at least about six weeks between the end of the initial treatment course and the beginning of the subsequent treatment course. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0038] In some embodiments of these aspects, 0 or 1 subsequent course of treatment is administered.

[0039] In some embodiments, the recurrence of depressive symptoms is indicated by subject assessment using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Patient Health Questionnaire (PHQ-9), or a combination thereof. In some embodiments, the recurrence of depressive symptoms in a subject is indicated by a PHQ-9 score of 10 or more or a HAM-D score of 20 or more.

[0040] In some embodiments, compound (1) is administered in a dose of about 50 mg, or a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 50 mg of the free base compound. In some embodiments, compound (1) is administered in a dose of about 40 mg, and a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 40 mg of the free base compound.

[0041] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, buccally, sublingually, rectally, topically, by inhalation, intranasally, or transdermally. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered with food. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day at night.

[0042] In some embodiments, the subject is treatment naive. [Brief description of the drawings]

[0043] [Figure 1] FIG. 1 is an outline of the clinical trial of Example 1.

[0044] [Diagram 2] FIG. 2 is a depiction of the eligibility criteria for the clinical trial of Example 1.

[0045] [Diagram 3] FIG. 3 is a flow chart of the dosing cohorts.

[0046] [Figure 4A] FIG. 4A is a schematic of the flow of subjects (30 mg cohort).

[0047] [Figure 4B] FIG. 4B is a schematic of subject flow (50 mg cohort).

[0048] [Diagram 5] FIG. 5 shows the LS mean change in HAM-D total score from baseline over time for the 30 mg and 50 mg cohorts.

[0049] [Figure 6A]FIG. 6A is a bar graph of HAMD-17 responses at specific time points for the 30 mg and 50 mg cohorts.

[0050] [Figure 6B] FIG. 6B is a bar graph of HAMD-17 remission at specific time points for the 30 mg and 50 mg cohorts.

[0051] [Figure 7] FIG. 7 is a bar graph of the change in HAM-D total score over time—Study Period 1 (Safety Analysis Population).

[0052] [Figure 8] FIG. 8 shows box plots of period-specific change from baseline in HAM-D total score at day 15 in each treatment cycle by antidepressant use (yes / no) at period-specific baseline - low-dose cohort (safety analysis set for cycle 1, full analysis set for cycles C2-5).

[0053] [Figure 9] FIG. 9 shows box plots of the change from baseline HAM-D total score on day 15 in each treatment cycle (safety population for treatment cycle 1, FAS for C2-C5).

[0054] [Figure 10] FIG. 10 shows box plots of period-specific change from baseline in HAM-D total score at day 15 in each treatment cycle by antidepressant use (yes / no) at period-specific baseline - low-dose cohort (safety population for treatment cycle 1, FAS for C2-C5).

[0055] [Figure 11] FIG. 11 is a bar chart of HAM-D response over time - Study Period 1 (safety population).

[0056] [Figure 12] FIG. 12 shows a bar chart of HAM-D response over time in Study Period 1 by antidepressant use at baseline (safety analysis population).

[0057] [Figure 13] FIG. 13 is a bar chart of HAM-D response at day 15 in each treatment cycle by period-specific baseline antidepressant use - low dose cohort (safety population).

[0058] [Figure 14] FIG. 14 is a bar chart of HAM-D remission over time - Study Period 1 (safety population).

[0059] [Figure 15] FIG. 15 shows a bar chart of HAM-D remission over time in Study Period 1 by antidepressant use at baseline (safety analysis population).

[0060] [Figure 16] FIG. 16 shows bar charts of HAM-D remission at day 15 in each treatment cycle by period-specific baseline antidepressant use - low dose cohort.

[0061] [Figure 17] FIG. 17 shows a line graph of LS mean (±SE) change from baseline for subjects with a baseline HAM-D score ≧24—Study Period 1 (Safety Population).

[0062] [Figure 18] FIG. 18 is a bar chart of HAM-D response over time during Study Period 1 for subjects with a baseline HAM-D score ≧24 (safety analysis population).

[0063] [Figure 19]FIG. 19 is a bar chart of HAM-D remission over time for subjects with a baseline HAM-D score ≧24—Study Period 1 (Safety Population).

[0064] [Figure 20] FIG. 20 shows a line graph of LS mean (±SE) change from baseline for subjects with a baseline HAM-D ≧26—Study Period 1 (Safety Population).

[0065] [Figure 21] FIG. 21 is a bar chart of HAM-D response over time in Study Period 1 for subjects with a baseline HAM-D score ≧26—Study Period 1 (Safety Population).

[0066] [Figure 22] FIG. 22 is a bar chart of HAM-D remission over time for subjects with a baseline HAM-D score ≧26—Study Period 1 (Safety Population).

[0067] [Diagram 23] FIG. 23 provides box plots of the time to retreatment by treatment cycle.

[0068] [Figure 24] FIG. 24 is a bar chart of HAM-D responders / non-responders with percent of responders in previous cycle - low dose cohort (FAS).

[0069] [Diagram 25] FIG. 25 is a bar chart of HAM-D responders / non-responders with percentage of non-responders in previous cycle - low dose cohort (FAS). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0070] Detailed Description I. Definition

[0071] As used herein, “compound (1)” refers to a compound having the following formula (or structure): [ka] .

[0072] Compound (1) is also known as zuranolone, 3α-hydroxy-3β-methyl-21-(4-cyanopyrazol-1-yl)-5β-19-norpregnan-20-one, and 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 chemical synthesis of compound (1) were described in U.S. Patent No. 9,512,165 and PCT Application Publication No. WO2014 / 169833 (the entire contents of the aforementioned applications are incorporated herein by reference in their entirety). Some crystalline forms of compound (1) and methods for preparing said forms have been described in U.S. Patent No. 11,236,121; U.S. Patent Application Publication No. 2019 / 0177359; and PCT Application Publication No. WO2018 / 039378 (the entire contents of the aforementioned applications are incorporated herein by reference in their entirety). Pharmaceutical compositions of compound (1) and methods for preparing said compositions have been described in PCT Application Publication No. WO2022 / 020363 and U.S. Patent Application No. 17 / 579,541 (the entire contents of the aforementioned applications are incorporated herein by reference in their entirety).

[0073] Compound (1) is GABA A Synaptic Receptors and GABA A Targeting extrasynaptic receptors, GABA A It is a neuroactive steroid that has been shown to be a positive allosteric modulator of the GABA receptor. AAs a positive allosteric modulator of the receptor, compound (1) is useful as a therapeutic agent for treating CNS-related disorders (e.g., depression, postpartum depression, and major depressive disorder) and for treating neurological conditions (e.g., essential tremor, epilepsy, and Parkinson's disease).

[0074] As used herein, "crystal" 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 comprise one or more discreet crystalline forms.

[0075] As used herein, the terms "crystalline form," "crystalline solid form," "crystalline form," "solid form," and related terms 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.

[0076] The term "substantially crystalline" refers to a form that can be crystalline to at least one particular weight percentage. The particular weight percentage can 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 some embodiments, the particular weight percentage of crystallinity is at least 90%. In some embodiments, the particular weight percentage of crystallinity is at least 95%. In some embodiments, Compound (1) can be a substantially crystalline sample of any of the crystalline forms described herein (e.g., crystalline forms A and C) and / or PCT Application Publication No. WO2018 / 039378 (the entire contents of the aforementioned application are incorporated herein by reference in their entirety).

[0077] The term "substantially pure" refers to a composition of a specific crystalline form (e.g., a crystalline form of Compound (1)) that may be free of at least a specific weight percentage of contaminants and / or other solid forms. The specific weight percentage may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some embodiments, Compound (1) may be a substantially pure sample of any crystalline form described herein (e.g., crystalline forms A and C). In some embodiments, Compound (1) may be substantially pure form A. In some embodiments, Compound (1) may be substantially pure form C.

[0078] As used herein, "XRPD" refers to powder X-ray diffraction. XRPD patterns are xy graphs with 2Q (diffraction angle) plotted on the x-axis and intensity plotted on the y-axis. There are diffraction peaks present that can be used to characterize crystalline materials. Diffraction peaks are usually expressed and referenced by their position on the x-axis rather than their intensity on the y-axis, since the intensity of the diffraction peaks is particularly sensitive to the orientation of the sample (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Thus, intensity is not typically 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 the diffraction peak intensities, there can also be variability in the positions of the diffraction peaks on the x-axis. However, this variability can typically be accounted for when reporting the positions of the diffraction peaks for characterization. Such variability in the positions of the diffraction peaks along the x-axis can come from several sources. One such source can be sample preparation. Samples of the same crystalline material prepared under different conditions may yield slightly different diffractograms. Factors such as particle size, water content, solvent content, temperature, and orientation can all affect the X-ray diffraction of a sample. Another source of variability comes from instrument parameters. Different X-ray powder diffractometers use different parameters for operation, which may result 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. For such sources of variability, the value of each X-ray diffraction peak can be preceded by the term "about" or an appropriate range (e.g., ±0.1°, ±0.2°, ±0.3°, ±0.4°, ±0.5°, etc.) that defines the experimental variability.

[0079] The term "characteristic peaks," when referring to 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 set of specific diffraction peaks whose values ​​collectively span a range of 2θ values ​​(e.g., 0°-40°) that is specific to that specific crystalline form.

[0080] "Pharmaceutically acceptable" means approved or approvable by a regulatory authority of a federal or state government, or a corresponding authority in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more specifically, in humans.

[0081] "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 can be inorganic or organic acid addition salts and inorganic or organic base addition salts. Specifically, such salts include: (1) salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts formed with organic acids, such as 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, and the like. or (2) salts formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and, where the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as 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.

[0082] The definition of specific functional groups and chemical terms is explained in detail below. Chemical elements are identified according to the Periodic Table of Elements (CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover), and specific functional groups are generally defined as described therein. In addition, the general rules of organic chemistry, as well as specific functional moieties and reactivity, 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.

[0083] When the term "about" is used before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically indicated otherwise. As used herein, unless specifically indicated or implied, the term "about" refers to a ±10% variation from the nominal value.

[0084] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0085] As used herein, the term "equivalent dose" refers to a biologically equivalent dose. For example, the equivalent dose 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 provide a biologically equivalent dose of the free base of Compound (1) in a dose of 50 mg.

[0086] As used herein, an "effective amount" of a compound (or a pharma- ceutically acceptable salt thereof) refers to an amount sufficient to induce a desired biological response, such as an amount sufficient to treat depression (e.g., major depressive disorder (MDD)). As will be appreciated by those skilled in the art, the effective amount of a compound (or a pharma- ceutically acceptable salt thereof) of the present invention may vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount includes therapeutic and prophylactic treatments.

[0087] As used herein, an "episodic dosing regimen" is a dosing regimen in which a compound or a composition comprising a compound is administered to a subject for a finite period of time in response to a diagnosis of a disorder or a symptom thereof, e.g., a diagnosis or symptom of depression, or an episode of major depressive disorder. In some embodiments, the major depressive disorder is a moderate major depressive disorder. In some embodiments, the major depressive disorder is a severe major depressive disorder. In some embodiments, the compound is formulated as an individual dosage unit, each unit comprising Compound 1 and one or more suitable pharmaceutical excipients. In some embodiments, the episodic dosing regimen has a duration of multiple weeks, e.g., about 8 weeks. In contrast to chronic administration as defined herein, episodic dosing of a compound is administered for a finite period of time, e.g., about 2 weeks to about 8 weeks, in response to a diagnosis or recurrence of a disorder, e.g., depression, or a symptom thereof. In some embodiments, episodic dosing is administered once per day for multiple weeks, e.g., about 2 weeks to about 6 weeks. In one embodiment, episodic dosing has a duration of 2 weeks. In some embodiments, a subject is administered more than one episodic dosing regimen but no more than three episodic dosing regimens (eg, two or more episodic regimens administered over a 12 month period).

[0088] As used herein, the term "modulation" refers to the A Refers to the inhibition or enhancement of receptor function. "Modulators" (e.g., GABA A The compound that modulates the function of a GABA receptor or a pharma- ceutically acceptable salt thereof is, for example, A It can be an agonist, partial agonist, antagonist, or partial antagonist of the receptor.

[0089] As used herein, "administering" an initial and / or subsequent treatment course refers to the act of carrying out a treatment course. In some embodiments, administering an initial and / or subsequent treatment course refers to starting administration of Compound (1) or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, administering an initial and / or subsequent treatment course refers to completing a treatment course (e.g., administering Compound (1) or a pharmaceutically acceptable salt thereof) to a subject for a specific period of time (e.g., about 2 weeks or about 14 days).

[0090] As used herein, "safety analysis population" refers to all subjects administered compound (1) in the clinical trial of Example 1. As used herein, "full analysis population" refers to all subjects in the safety analysis population who have a HAM-D response on day 15 of treatment cycle 1 (e.g., initial treatment course) and whose study discontinuation date (if any) is after the end of treatment cycle 1 (e.g., initial treatment course). Responders are subjects who have at least a 50% reduction from baseline in the HAM-D total score on day 15 of the treatment cycle. If the HAM-D total score on day 15 of the treatment cycle is missing, the subject is considered a non-responder.

[0091] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound (or a pharma- ceutically acceptable salt thereof) is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound (or a pharma- ceutically acceptable salt thereof) means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, an amount that reduces or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic efficacy of another therapeutic agent.

[0092] In an alternative embodiment, the present invention contemplates administration of the compound of the present invention or its pharma- ceutically acceptable salt or pharma- ceutically acceptable composition as a prophylactic agent before a subject begins to suffer from a particular disease, disorder, or condition.As used herein, 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 the disease, disorder, or condition, or to prevent its recurrence.A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease, disorder, or condition.The term "prophylactically effective amount" can include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic efficacy of another prophylactic agent.

[0093] As used herein, "solid dosage form" means a pharmaceutical dose in solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalants, and chewables.

[0094] A "subject" or "patient" is a human (e.g., male or female of any age group, e.g., a juvenile subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)).

[0095] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is suffering from a particular disease, disorder, or condition, which 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.

[0096] As used herein, a "treatment course" refers to the administration of Compound (1) or a pharma- ceutically acceptable salt thereof for a specific period of time to treat major depressive disorder (MDD) in a subject in need of such treatment. For example, a treatment course can be administered Compound (1) or a pharma- ceutically acceptable salt thereof for about 2 weeks or about 14 days. A "treatment course" begins on the day that the first dose of Compound (1) or a pharma- ceutically acceptable salt thereof is administered and continues until the day that the last dose is administered. A subject who is receiving a treatment course for the first time within 12 months is receiving an "initial treatment course".

[0097] The "treatment course" can be repeated, provided that there is a time interval between each treatment course when compound (1) or a pharma- ceutically acceptable salt thereof is not administered (e.g., at least 4 weeks, at least 6 weeks, or at least 8 weeks from the end of the initial treatment course). A "subsequent treatment course" refers to a treatment course (e.g., a repeat of the treatment course) administered to a subject after the initial treatment course. In some embodiments, 0, 1, or 2 subsequent treatment courses are administered over 12 months from the start of the initial treatment course. Thus, in some embodiments, the methods provided herein may administer 1, 2, or 3 treatment courses to a subject over 12 months from the start of the initial treatment course. In certain embodiments, the treatment course (e.g., subsequent treatment course) may be repeated in response to a recurrence of depressive symptoms. The recurrence of depressive symptoms may be indicated by subject evaluation using the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), the Patient Health Questionnaire (PHQ-9), or a combination thereof. For example, recurrence of depressive symptoms in a subject may be indicated by a PHQ-9 score of 10 or greater and / or a HAM-D score of 20 or greater. In some embodiments, depressive symptoms may be assessed every 14 days for 12 months from the end of the initial treatment course.

[0098] As used herein, "treatment naive" refers to a subject who has not been previously treated with additional antidepressants in the current depressive episode. Also, "treatment naive" refers to a subject who has not taken any antidepressants within at least 60 days before the initial treatment course. In some embodiments, the subject is a "naive patient". The term "naive patient" refers to two specific categories: i) patients who have not been previously therapeutically exposed to a type or category of medicine for treating depression ("primary naive"), and ii) patients who have been previously exposed to medicine for treating depression, but with an appropriate length of withdrawal period based on the practitioner's judgment ("secondary naive").

[0099] As used herein, the term "unit dosage form" is defined to refer to the form in which Compound (1) is administered to a patient. In some embodiments, the unit dosage form may be, for example, a pill, a capsule, or a tablet. In some embodiments, the unit dosage form is a capsule. In some embodiments, a typical amount of Compound (1) in a unit dosage form useful in the present disclosure is about 10 mg to about 100 mg, about 20 mg to about 55 mg, or about 30 mg to about 50 mg (e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, or about 55 mg).

[0100] In some embodiments, the administration of compound (1) improves cognitive function. In some embodiments, cognitive function refers to a set of mental tasks and functions, including but not limited to memory (e.g., semantic, episodic, procedural, priming, or working memory); orientation; language; problem solving; vision, construction, and integration; planning; organizational skills; selective attention; inhibitory control; and the ability to mentally manipulate information. In one embodiment, cognitive function is one or more selected from the group consisting of memory (e.g., semantic, episodic, procedural, priming, or working memory); orientation; language; problem solving; vision, construction, and integration; planning; organizational skills; selective attention; inhibitory control; and the ability to mentally manipulate information. Measures of cognitive function include, for example, assessment tools designed to measure (a) general intelligence, (b) non-verbal intelligence, (c) academic achievement, (d) attention / executive function, (e) memory and learning, (f) visual-motor function and motor function, and (g) language.

[0101] For example, any change in cognitive function over time or with treatment can be monitored by using one or more of these well-established tests at two or more time points and comparing the results.The phrase "improve cognitive function" as referred to herein means the positive change in the ability of a subject to carry out symbolic operations (e.g., recognize, remember, create mental images, think clearly, notice, reason, think, or judge).Positive change can be measured using any of the aforementioned tests for two or more events (e.g., a first event to measure baseline cognitive function and a second event to measure cognitive function after a period of time during which treatment may be performed).

[0102] II. Treatment Method

[0103] The present disclosure relates to a method for treating major depressive disorder (MDD). The diagnosis and severity of major depressive disorder treated by the methods described herein can be characterized as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).

[0104] Depressive disorders

[0105] 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 these disorders is the presence of a sad, empty, or irritable mood accompanied by physical and cognitive changes that significantly affect the individual's ability to function. What differs between them is the issue of duration, timing, or presumed etiology.

[0106] Major depressive disorder represents the classic state in this group of disorders. It is characterized by discrete episodes of at least two weeks (although most episodes last much longer) that include distinct changes in affective, cognitive, and autonomic functioning, and remissions between episodes. Discrete episodes of major depressive disorder may be referred to as "major depressive episodes" or "depressive episodes."

[0107] Major Depressive Disorder (MDD)

[0108] Major depressive disorder is commonly known in the art.

[0109] In some embodiments, MDD, also known as depression or clinical depression, is a mood disorder characterized by persistent sadness and loss of interest. MDD affects how a subject feels, thinks, and acts, and can cause a variety of emotional and physical problems.

[0110] In some embodiments, MDD is defined and diagnosed according to DSM-5, for example, MDD is diagnosed according to criterion A below.

[0111] Criterion A. Five (or more) of the following symptoms occur simultaneously over a 2-week period and are associated with a change in functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or enjoyment: 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feelings of sadness, emptiness, hopelessness) or by observation by others (e.g., appearing to be in tears). (Note: In children and adolescents, this may be irritable mood. 2. A marked decrease in interest or pleasure in all or almost all activities for most of the day, on most days, every day (as indicated by either subjective description or observation). 3. Significant weight loss or weight gain when not dieting (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 failure to gain weight as expected). 4. Near-daily insomnia or hypersomnia. 5. Near-daily psychomotor agitation or slowness (observable by others, not merely subjective feelings of restlessness or slowness). 6. Fatigue or loss of energy almost every day. 7. Near-daily feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) (not simply self-blame or guilt about illness). 8. Diminished ability to think or concentrate or indecisiveness nearly every day (either subjectively described or observed by others). 9. Recurrent thoughts about death (not simply fear of death), recurrent suicidal thoughts without a specific plan, or suicide attempts or specific plans for suicide.

[0112] Criteria B through E below are further explanations of MDD and may, but are not required to, be considered for the explanation or diagnosis of MDD.

[0113] Criterion B. Symptoms cause clinically significant distress or impairment in social, workplace, or other important areas of functioning.

[0114] Criterion C. The episode is not attributable to the physiological effects of a substance or another medical condition.

[0115] Criteria A-C may indicate a major depressive episode.

[0116] Criterion D. The occurrence of a major depressive episode is not adequately explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders.

[0117] Criterion E. No previous manic or hypomanic episodes.

[0118] In some embodiments, a major depressive episode (MDE) is a period characterized by the symptoms of MDD listed above.

[0119] In some embodiments, MDD is a clinical course characterized by one or more major depressive episodes (MDEs) in a subject.

[0120] In some embodiments, MDD is diagnosed according to criteria A through C above. In some embodiments, MDD is diagnosed according to diagnostics A through E above.

[0121] Diagnostic Features

[0122] Criteria symptoms for major depressive disorder must be present nearly every day to be considered present, except for weight change and suicidal ideation. Depressed mood must be present for nearly all of the day, in addition to being present nearly every day. Insomnia or fatigue are frequent presenting complaints that would be underdiagnosed if the associated depressive symptoms could not be explored. Sadness may be initially denied, but may be elicited from the interview or inferred from facial expression and demeanor. In individuals noted for physical complaints, the clinician should determine whether the distress from the complaint is related to a specific depressive symptom. Fatigue and sleep disturbances are present in a high percentage of cases; psychomotor disorders are much rarer but indicate a greater overall severity, as does the presence of delusions or near-delusional feelings of guilt.

[0123] The essential feature of a major depressive episode is the presence of either a depressed mood or loss of interest or pleasure in nearly all activities for at least 2 weeks (criterion A above). In children and adolescents, the mood may be more irritable than sad. The individual must also experience at least four additional symptoms taken from a list including: changes in appetite or weight, sleep, and psychomotor activity; decreased energy; 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 qualify as a major depressive episode, the symptoms must be new or clearly worse than the person's previous episode. The symptoms must be present nearly all day, nearly every day, and continue for two consecutive weeks. The episode must involve clinically significant distress or impairment in functioning in society, at work, or other important areas. For some individuals with milder episodes, functioning may appear normal but requires significant effort.

[0124] Sleep disorders can take the form of either difficulty sleeping or hypersomnia (Criterion A4). When insomnia is present, it typically takes the form of intermediate insomnia (i.e., difficulty getting back to sleep after waking in the middle of the night) or end-stage insomnia (i.e., waking too early and not being able to get back to sleep). Early-stage insomnia (i.e., difficulty falling asleep) can also occur. Individuals who present with hypersomnia (hypersomnia) may experience prolonged nighttime sleep episodes or increased daytime sleep. Sometimes, the reason individuals seek treatment is because of a sleep disorder.

[0125] Accordingly, one aspect of the present invention is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] administering to the subject an initial treatment course comprising administration of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering a therapeutically effective amount of compound (1) in response to a recurrence of depressive symptoms. Including, Provided herein are methods in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0126] Another aspect of the present invention is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] administering to the subject an initial treatment course comprising administering a pharma- ceutically acceptable salt of (ii) administering to the subject zero, one, or two subsequent courses of treatment, each of which comprises administering a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1) in response to a recurrence of depressive symptoms. Including, Provided herein are methods in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0127] In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0128] In some embodiments, 0 or 1 subsequent course of treatment is administered. In some embodiments, no subsequent course of treatment is administered (e.g., 0). In some embodiments, 1 subsequent course of treatment is administered. In some embodiments, 2 subsequent courses of treatment are administered.

[0129] In some embodiments, the method comprises administering a total of one, two, or three treatment courses over a 12-month period. In some embodiments, the method comprises administering a total of two treatment courses over a 12-month period from the start of an initial (first) treatment course. In some embodiments, the method comprises administering a total of three treatment courses over a 12-month period from the start of an initial (first) treatment course.

[0130] In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks. In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by at least about 4 weeks. In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by at least about 6 weeks. In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by at least about 8 weeks.

[0131] In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by about 4 weeks, about 6 weeks, or about 8 weeks. In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by about 4 weeks. In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by about 6 weeks. In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by about 8 weeks.

[0132] In embodiments in which two subsequent treatment courses are administered, the time interval between each subsequent treatment course is the same as the time interval between the initial and subsequent treatment courses (e.g., at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of the first subsequent treatment course and the start of the second subsequent treatment course). In some embodiments, there is about 4 weeks, about 6 weeks, or about 8 weeks between the end of the first subsequent treatment course and the start of the second subsequent treatment course.

[0133] In some embodiments, the recurrence of depressive symptoms is indicated by the subject's assessment using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Patient Health Questionnaire (PHQ-9), or a combination thereof.In some embodiments, the recurrence of depressive symptoms in the subject is indicated by a PHQ-9 score of 10 or more.In some embodiments, the recurrence of depressive symptoms in the subject is indicated by a HAM-D score of 20 or more.In some embodiments, the recurrence of depressive symptoms in the subject is indicated by a PHQ-9 score of 10 or more or a HAM-D score of 20 or more.

[0134] In some embodiments, the duration of the initial treatment course is about 2 weeks or about 14 days. In some embodiments, the duration of the initial treatment course is about 2 weeks. In some embodiments, the duration of the initial treatment course is about 14 days. In some embodiments, the duration of the initial treatment course is 2 weeks or 14 days.

[0135] In some embodiments, the duration of each subsequent treatment course is about 2 weeks or about 14 days. In some embodiments, the duration of each subsequent treatment course is about 2 weeks. In some embodiments, the duration of each subsequent treatment course is about 14 days. In some embodiments, the duration of each subsequent treatment course is 2 weeks or 14 days.

[0136] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about two weeks or about fourteen days in the initial treatment course. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about two weeks in the initial treatment course. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about fourteen days in the initial treatment course.

[0137] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about two weeks or about fourteen days in each subsequent course of treatment. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about two weeks in each subsequent course of treatment. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about fourteen days in each subsequent course of treatment.

[0138] 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 to about 55 mg. In some embodiments, compound (1) is administered at a dose of about 30 mg to about 50 mg. In some embodiments, compound (1) is administered at a dose of about 45 mg to about 55 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.

[0139] In some embodiments, compound (1) is administered once a day at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) is administered once a day at a dose of about 15 mg to about 75 mg. In some embodiments, compound (1) is administered once a day at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) is administered once a day at a dose of about 20 mg to about 55 mg. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg to about 50 mg. In some embodiments, compound (1) is administered once a day at a dose of about 45 mg to about 55 mg. In some embodiments, compound (1) is administered once a day 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 once a day at a dose of about 50 mg. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg.

[0140] In some embodiments, compound (1) is administered at a dose of about 20 mg to about 50 mg once a day for about 2 weeks or about 14 days. In some embodiments, compound (1) is administered at a dose of about 30 mg to about 50 mg once a day for about 2 weeks or about 14 days. In some embodiments, compound (1) is administered at a dose of about 45 mg to about 55 mg once a day for about 2 weeks or about 14 days. In some embodiments, compound (1) is administered at a dose of about 50 mg once a day for less than 2 weeks. In some embodiments, compound (1) is administered at a dose of about 50 mg once a day for about 2 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 2 weeks. In some embodiments, compound (1) is administered at a dose of about 40 mg once a day for about 2 weeks. In some embodiments, compound (1) is administered at a dose of about 40 mg once a day for about 14 days.

[0141] In other embodiments, the pharma- ceutically acceptable salt of compound (1) is administered in an equivalent dose 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 in an equivalent dose 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 in an equivalent dose 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 in an equivalent dose of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered in an equivalent dose of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered in an equivalent dose of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent 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 of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent dose of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent dose of about 40 mg of the free base compound.

[0142] In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered once a day at an equivalent dose 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 a day at an equivalent dose 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 once a day at an equivalent dose 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 a day at an equivalent dose of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered once a day at an equivalent dose of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered once a day at an equivalent dose of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered once a day at an equivalent 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 of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered once a day at an equivalent dose of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered once a day at an equivalent dose of about 40 mg of the free base compound.

[0143] In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered at an equivalent dose of about 30 mg to about 50 mg of the free base compound once a day for about 2 weeks or about 14 days. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered at an equivalent dose of about 45 mg to about 55 mg of the free base compound once a day for about 2 weeks or about 14 days. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered at an equivalent dose of about 50 mg of the free base compound once a day for less than 2 weeks. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered at an equivalent dose of about 50 mg of the free base compound once a day for about 2 weeks. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered at an equivalent dose of about 50 mg of the free base compound once a day for about 14 days. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent dose of about 40 mg of the free base compound once a day for less than two weeks. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent dose of about 40 mg of the free base compound once a day for about two weeks. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent dose of about 40 mg of the free base compound once a day for about 14 days.

[0144] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, bucally, sublingually, rectally, topically, as an inhalation, intranasally, or transdermally. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally.

[0145] In some embodiments, Compound (1), or a pharma- ceutically acceptable salt of Compound (1), is administered chronically.

[0146] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered in one or more capsules. In some embodiments, a therapeutically effective amount is administered over two capsules. In some embodiments, a therapeutically effective amount is administered over three capsules.

[0147] In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered with food containing fat. Examples of food containing fat include nuts, peanut butter, avocado, eggs, and cheese. In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered with food containing fat at night (e.g., within 1 hour after a dinner containing fat or with a snack containing fat).

[0148] In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) at night. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) within 1 hour before the patient goes to bed. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) within 15 minutes before the patient goes to bed. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) once a day at night. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) once a day within 1 hour before the patient goes to bed. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) once a day within 15 minutes before the patient goes to bed.

[0149] In some embodiments, compound (1) is in a crystalline form. In some embodiments, the crystalline form of compound (1) is any crystalline form disclosed in PCT Application Publication No. WO2018 / 039378 (the entire contents of the aforementioned application are incorporated herein by reference in their entirety).

[0150] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks at 2θ between 9.7 and 10.1 degrees (inclusive), 2θ between 11.6 and 12.0 degrees (inclusive), 2θ between 13.2 and 13.6 degrees (inclusive), 2θ between 14.2 and 14.6 degrees (inclusive), 2θ between 14.6 and 15.0 degrees (inclusive), 2θ between 16.8 and 17.2 degrees (inclusive), 2θ between 20.5 and 20.9 degrees (inclusive), 2θ between 21.3 and 21.7 degrees (inclusive), 2θ between 21.4 and 21.8 degrees (inclusive), and 2θ between 22.4 and 22.8 degrees (inclusive). 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 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.

[0151] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks at 2θ between 9.3 and 9.7 degrees (inclusive), 2θ between 10.6 and 11.0 degrees (inclusive), 2θ between 13.0 and 13.4 degrees (inclusive), 2θ between 14.7 and 15.1 degrees (inclusive), 2θ between 15.8 and 16.2 degrees (inclusive), 2θ between 18.1 and 18.5 degrees (inclusive), 2θ between 18.7 and 19.1 degrees (inclusive), 2θ between 20.9 and 21.3 degrees (inclusive), 2θ between 21.4 and 21.8 degrees (inclusive), and 2θ between 23.3 and 23.7 degrees (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.

[0152] In some embodiments, the crystalline form of Compound (1) comprises a mixture of two or more crystalline forms.

[0153] 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 initial treatment course. In some embodiments, the subject has not received any antidepressant treatment within at least 60 days prior to the start of the initial treatment course.

[0154] In some embodiments, the subject has been taking an additional antidepressant stably for at least 60 days prior to the start of the initial treatment course.

[0155] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] administering to the subject an initial treatment course comprising administration of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering a therapeutically effective amount of compound (1) in response to a recurrence of depressive symptoms. Including, wherein 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course; The method includes wherein the subject is treatment naive.

[0156] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) a therapeutically effective amount of compound (1): [ka] administering to the subject an initial treatment course comprising administering a pharma- ceutically acceptable salt of (ii) administering to the subject zero, one, or two subsequent courses of treatment, each of which comprises administering a therapeutically effective amount of a pharma- ceutically acceptable salt of compound (1) in response to a recurrence of depressive symptoms. Including, wherein 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course; The method includes wherein the subject is treatment naive.

[0157] In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0158] In some embodiments, 0 or 1 subsequent course of treatment is administered. In some embodiments, no subsequent course of treatment is administered (e.g., 0). In some embodiments, 1 subsequent course of treatment is administered. In some embodiments, 2 subsequent courses of treatment are administered.

[0159] In some embodiments, the method comprises administering a total of one, two, or three treatment courses over a 12-month period. In some embodiments, the method comprises administering a total of two treatment courses over a 12-month period from the start of an initial (first) treatment course. In some embodiments, the method comprises administering a total of three treatment courses over a 12-month period from the start of an initial (first) treatment course.

[0160] In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks. In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by at least about 4 weeks. In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by at least about 6 weeks. In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by at least about 8 weeks.

[0161] In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by about 4 weeks, about 6 weeks, or about 8 weeks. In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by about 4 weeks. In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by about 6 weeks. In some embodiments, the end of the initial treatment course and the start of the subsequent treatment course are spaced apart by about 8 weeks.

[0162] In embodiments in which two subsequent treatment courses are administered, the time interval between each subsequent treatment course is the same as the time interval between the initial and subsequent treatment courses (e.g., at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of the first subsequent treatment course and the start of the second subsequent treatment course). In some embodiments, there is about 4 weeks, about 6 weeks, or about 8 weeks between the end of the first subsequent treatment course and the start of the second subsequent treatment course.

[0163] In some embodiments, the recurrence of depressive symptoms is indicated by the subject's assessment using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Patient Health Questionnaire (PHQ-9), or a combination thereof.In some embodiments, the recurrence of depressive symptoms in the subject is indicated by a PHQ-9 score of 10 or more.In some embodiments, the recurrence of depressive symptoms in the subject is indicated by a HAM-D score of 20 or more.In some embodiments, the recurrence of depressive symptoms in the subject is indicated by a PHQ-9 score of 10 or more or a HAM-D score of 20 or more.

[0164] In some embodiments, the duration of the initial treatment course is about 2 weeks or about 14 days. In some embodiments, the duration of the initial treatment course is about 2 weeks. In some embodiments, the duration of the initial treatment course is about 14 days. In some embodiments, the duration of the initial treatment course is 2 weeks or 14 days.

[0165] In some embodiments, the duration of each subsequent treatment course is about 2 weeks or about 14 days. In some embodiments, the duration of each subsequent treatment course is about 2 weeks. In some embodiments, the duration of each subsequent treatment course is about 14 days. In some embodiments, the duration of each subsequent treatment course is 2 weeks or 14 days.

[0166] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about two weeks or about fourteen days in the initial treatment course. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about two weeks in the initial treatment course. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about fourteen days in the initial treatment course.

[0167] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about two weeks or about fourteen days in each subsequent course of treatment. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about two weeks in each subsequent course of treatment. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about fourteen days in each subsequent course of treatment.

[0168] 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 to about 55 mg. In some embodiments, compound (1) is administered at a dose of about 30 mg to about 50 mg. In some embodiments, compound (1) is administered at a dose of about 45 mg to about 55 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.

[0169] In some embodiments, compound (1) is administered once a day at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) is administered once a day at a dose of about 15 mg to about 75 mg. In some embodiments, compound (1) is administered once a day at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) is administered once a day at a dose of about 20 mg to about 55 mg. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg to about 50 mg. In some embodiments, compound (1) is administered once a day at a dose of about 45 mg to about 55 mg. In some embodiments, compound (1) is administered once a day 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 once a day at a dose of about 50 mg. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg.

[0170] In some embodiments, compound (1) is administered at a dose of about 20 mg to about 50 mg once a day for about 2 weeks or about 14 days. In some embodiments, compound (1) is administered at a dose of about 30 mg to about 50 mg once a day for about 2 weeks or about 14 days. In some embodiments, compound (1) is administered at a dose of about 45 mg to about 55 mg once a day for about 2 weeks or about 14 days. In some embodiments, compound (1) is administered at a dose of about 50 mg once a day for less than 2 weeks. In some embodiments, compound (1) is administered at a dose of about 50 mg once a day for about 2 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 2 weeks. In some embodiments, compound (1) is administered at a dose of about 40 mg once a day for about 2 weeks. In some embodiments, compound (1) is administered at a dose of about 40 mg once a day for about 14 days.

[0171] In other embodiments, the pharma- ceutically acceptable salt of compound (1) is administered in an equivalent dose 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 in an equivalent dose 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 in an equivalent dose 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 in an equivalent dose of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered in an equivalent dose of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered in an equivalent dose of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent 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 of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent dose of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent dose of about 40 mg of the free base compound.

[0172] In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered once a day at an equivalent dose 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 a day at an equivalent dose 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 once a day at an equivalent dose 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 a day at an equivalent dose of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered once a day at an equivalent dose of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered once a day at an equivalent dose of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered once a day at an equivalent 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 of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered once a day at an equivalent dose of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered once a day at an equivalent dose of about 40 mg of the free base compound.

[0173] In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered at an equivalent dose of about 30 mg to about 50 mg of the free base compound once a day for about 2 weeks or about 14 days. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered at an equivalent dose of about 45 mg to about 55 mg of the free base compound once a day for about 2 weeks or about 14 days. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered at an equivalent dose of about 50 mg of the free base compound once a day for less than 2 weeks. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered at an equivalent dose of about 50 mg of the free base compound once a day for about 2 weeks. In some embodiments, a pharma- ceutically acceptable salt of compound (1) is administered at an equivalent dose of about 50 mg of the free base compound once a day for about 14 days. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent dose of about 40 mg of the free base compound once a day for less than two weeks. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent dose of about 40 mg of the free base compound once a day for about two weeks. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent dose of about 40 mg of the free base compound once a day for about 14 days.

[0174] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, bucally, sublingually, rectally, topically, as an inhalation, intranasally, or transdermally. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally.

[0175] In some embodiments, Compound (1), or a pharma- ceutically acceptable salt of Compound (1), is administered chronically.

[0176] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered in one or more capsules. In some embodiments, a therapeutically effective amount is administered over two capsules. In some embodiments, a therapeutically effective amount is administered over three capsules.

[0177] In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered with food containing fat. Examples of food containing fat include nuts, peanut butter, avocado, eggs, and cheese. In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered with food containing fat at night (e.g., within 1 hour after a dinner containing fat or with a snack containing fat).

[0178] In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) at night. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) within 1 hour before the patient goes to bed. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) within 15 minutes before the patient goes to bed. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) once a day at night. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) once a day within 1 hour before the patient goes to bed. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) once a day within 15 minutes before the patient goes to bed.

[0179] In some embodiments, compound (1) is in a crystalline form. In some embodiments, the crystalline form of compound (1) is any crystalline form disclosed in PCT Application Publication No. WO2018 / 039378 (the entire contents of the aforementioned application are incorporated herein by reference in their entirety).

[0180] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks at 2θ between 9.7 and 10.1 degrees (inclusive), 2θ between 11.6 and 12.0 degrees (inclusive), 2θ between 13.2 and 13.6 degrees (inclusive), 2θ between 14.2 and 14.6 degrees (inclusive), 2θ between 14.6 and 15.0 degrees (inclusive), 2θ between 16.8 and 17.2 degrees (inclusive), 2θ between 20.5 and 20.9 degrees (inclusive), 2θ between 21.3 and 21.7 degrees (inclusive), 2θ between 21.4 and 21.8 degrees (inclusive), and 2θ between 22.4 and 22.8 degrees (inclusive). 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 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.

[0181] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks at 2θ between 9.3 and 9.7 degrees (inclusive), 2θ between 10.6 and 11.0 degrees (inclusive), 2θ between 13.0 and 13.4 degrees (inclusive), 2θ between 14.7 and 15.1 degrees (inclusive), 2θ between 15.8 and 16.2 degrees (inclusive), 2θ between 18.1 and 18.5 degrees (inclusive), 2θ between 18.7 and 19.1 degrees (inclusive), 2θ between 20.9 and 21.3 degrees (inclusive), 2θ between 21.4 and 21.8 degrees (inclusive), and 2θ between 23.3 and 23.7 degrees (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.

[0182] In some embodiments, the crystalline form of Compound (1) comprises a mixture of two or more crystalline forms.

[0183] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 30 mg to about 50 mg of compound (1): [ka] administering to the subject an initial treatment course comprising administration of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering to the subject about 30 mg to about 50 mg of compound (1) in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0184] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1), in a dose equivalent to about 30 mg to about 50 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising administering a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering to the subject a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 30 mg to about 50 mg of the free base compound in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0185] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 30 mg to about 50 mg of compound (1): [ka] administering to the subject an initial treatment course comprising once daily for about 14 days a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering to the subject about 30 mg to about 50 mg of compound (1) once daily for about 14 days in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0186] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1), in a dose equivalent to about 30 mg to about 50 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising once daily for about 14 days a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering to the subject once daily for about 14 days a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 30 mg to about 50 mg of the free base compound in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0187] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 30 mg to about 50 mg of compound (1): [ka] administering to the subject an initial treatment course comprising once daily administration of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each of which comprises administering to the subject about 30 mg to about 50 mg of compound (1) once per day for about 14 days in response to the recurrence of depressive symptoms, provided that there is an interval of at least about 6 weeks between the end of the initial treatment course and the start of the subsequent treatment course. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0188] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1), in a dose equivalent to about 30 mg to about 50 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising once daily for about 14 days a pharma- ceutically acceptable salt of (ii) administering to the subject zero, one, or two subsequent treatment courses, each of which comprises administering to the subject a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 30 mg to about 50 mg of the free base compound once daily for about 14 days in response to a recurrence of depressive symptoms, provided that there is an interval of at least about six weeks between the end of the initial treatment course and the beginning of the subsequent treatment course. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0189] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 30 mg to about 50 mg of compound (1): [ka] administering to the subject an initial treatment course comprising once-daily administration for about 14 days of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering to the subject about 30 mg to about 50 mg of compound (1) once daily for about 14 days in response to a recurrence of depressive symptoms. Including, wherein 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course; The method includes wherein the subject has been taking an additional antidepressant medication stably for at least 60 days.

[0190] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1), in a dose equivalent to about 30 mg to about 50 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising once daily for about 14 days a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering to the subject once daily for about 14 days a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 30 mg to about 50 mg of the free base compound in response to a recurrence of depressive symptoms. Including, wherein 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course; The method includes wherein the subject has been taking an additional antidepressant medication stably for at least 60 days.

[0191] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 45 mg to about 55 mg of compound (1): [ka] administering to the subject an initial treatment course comprising administration of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering to the subject about 45 mg to about 55 mg of compound (1) in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0192] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1), in a dosage equivalent to about 45 mg to about 55 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising administering a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering to the subject a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 45 mg to about 55 mg of the free base compound in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0193] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 45 mg to about 55 mg of compound (1): [ka] administering to the subject an initial treatment course comprising once-daily administration for about 14 days of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering to the subject about 45 mg to about 55 mg of compound (1) once daily for about 14 days in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0194] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1), in a dosage equivalent to about 45 mg to about 55 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising once daily for about 14 days a pharma- ceutically acceptable salt of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each subsequent treatment course comprising administering to the subject a pharma- ceutically acceptable salt of Compound (1) in a dose equivalent to about 45 mg to about 55 mg of the free base compound once daily for about 14 days in response to a recurrence of depressive symptoms. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0195] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) about 45 mg to about 55 mg of compound (1): [ka] administering to the subject an initial treatment course comprising once daily administration of (ii) administering to the subject 0, 1, or 2 subsequent treatment courses, each of which comprises administering to the subject about 45 mg to about 55 mg of compound (1) once daily for about 14 days in response to a recurrence of depressive symptoms, provided that there is an interval of at least about 6 weeks between the end of the initial treatment course and the start of the subsequent treatment course. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0196] Another aspect of the present disclosure is a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) Compound (1) in a dosage equivalent to about 45 mg to about 55 mg of the free base compound: [ka] administering to the subject an initial treatment course comprising once daily for about 14 days of a pharma- ceutically acceptable salt of (ii) administering to the subject zero, one, or two subsequent treatment courses, each of which comprises administering to the subject, in response to a recurrence of depressive symptoms, a pharma- ceutically acceptable salt of Compound (1) at a dose equivalent to about 45 mg to about 55 mg of the free base compound once daily for about 14 days, provided that there is an interval of at least about six weeks between the end of the initial treatment course and the beginning of the subsequent treatment course. Including, Herein, methods are included in which 0, 1, or 2 subsequent treatment courses are administered over a 12 month period from the start of the initial treatment course.

[0197] In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0198] In some embodiments, 0 or 1 subsequent course of treatment is administered. In some embodiments, no subsequent course of treatment is administered (e.g., 0). In some embodiments, 1 subsequent course of treatment is administered. In some embodiments, 2 subsequent courses of treatment are administered.

[0199] In some embodiments, the method comprises administering a total of one, two, or three treatment courses over a 12-month period. In some embodiments, the method comprises administering a total of two treatment courses over a 12-month period from the start of an initial (first) treatment course. In some embodiments, the method comprises administering a total of three treatment courses over a 12-month period from the start of an initial (first) treatment course.

[0200] In some embodiments, the recurrence of depressive symptoms is indicated by the subject's assessment using the Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Patient Health Questionnaire (PHQ-9), or a combination thereof.In some embodiments, the recurrence of depressive symptoms in the subject is indicated by a PHQ-9 score of 10 or more.In some embodiments, the recurrence of depressive symptoms in the subject is indicated by a HAM-D score of 20 or more.In some embodiments, the recurrence of depressive symptoms in the subject is indicated by a PHQ-9 score of 10 or more or a HAM-D score of 20 or more.

[0201] 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 to about 55 mg. In some embodiments, compound (1) is administered at a dose of about 30 mg to about 50 mg. In some embodiments, compound (1) is administered at a dose of about 45 mg to about 55 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.

[0202] In other embodiments, the pharma- ceutically acceptable salt of compound (1) is administered in an equivalent dose 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 in an equivalent dose 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 in an equivalent dose 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 in an equivalent dose of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered in an equivalent dose of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) is administered in an equivalent dose of about 45 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent 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 of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent dose of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at an equivalent dose of about 40 mg of the free base compound.

[0203] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, bucally, sublingually, rectally, topically, as an inhalation, intranasally, or transdermally. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally.

[0204] In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered with food. In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered with food containing fat. Examples of food containing fat include nuts, peanut butter, avocado, eggs, and cheese. In some embodiments, compound (1) or a pharma- ceutically acceptable salt of compound (1) is administered with food containing fat at night (e.g., within 1 hour after a dinner containing fat or with a snack containing fat).

[0205] In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) at night. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) within 1 hour before the patient goes to bed. In some embodiments, the subject is administered Compound (1) or a pharma- ceutically acceptable salt of Compound (1) within 15 minutes before the patient goes to bed.

[0206] 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 initial treatment course. In some embodiments, the subject has not received any antidepressant treatment within at least 60 days prior to the start of the initial treatment course.

[0207] III. Pharmaceutical Compositions

[0208] Another aspect of the present disclosure provides a pharmaceutical composition comprising Compound (1) (also referred to as "active ingredient") for use in the methods described herein, and a pharma- ceutically acceptable excipient. In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharma- ceutically acceptable salt of the active ingredient for use in the methods described herein, and a pharma- ceutically acceptable excipient. 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 pharmaceutical composition disclosed in PCT Application Publication No. WO2022 / 020363 (the entire contents of the aforementioned application are incorporated herein by reference in their entirety).

[0209] The pharmaceutical compositions provided herein may be administered by a variety of 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.

[0210] The pharmaceutical composition of the present invention can also be delivered using various dosing methods. For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, for the purpose of raising 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 (for example, by IV infusion) allows for a faster delivery, which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by IV infusion, to provide the maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still other embodiments, the pharmaceutical composition can be administered as a bolus dose initially, followed by a continuous infusion.

[0211] Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, compositions are provided 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 together with suitable pharmaceutical excipients. Typical unit dosage forms include premeasured, prefilled ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like in the case of 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 serve to form the desired dosage form.

[0212] The ingredients described above for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0213] The compositions of the invention can 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.

[0214] 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 any type of animal. Modifications of pharmaceutical compositions suitable for administration to humans to make the compositions suitable for administration to various animals are well understood, and veterinary pharmacologists of ordinary skill can design and / or perform such modifications using routine experimentation. 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.

[0215] In another aspect, the disclosure includes a method of treating major depressive disorder in a subject in need thereof, comprising administering to the subject a daily dose comprising 45 mg to 55 mg of Compound (1) using an episodic dosing regimen for treating major depressive disorder in the subject.

[0216] In one embodiment of this aspect, the duration of the episodic dosing regimen is about 2 to about 8 weeks. In another embodiment, the duration of the episodic dosing regimen is about 2 to about 6 weeks. In another embodiment, the duration of the episodic dosing regimen is about 2 to about 4 weeks. In a further embodiment, the duration of the episodic dosing regimen is about 2 weeks or 14 days. In yet a further embodiment, the duration of the episodic dosing regimen is 2 weeks.

[0217] In one embodiment, the subject responds to the episodic dosing regimen, where the response is indicated by a decrease in HAM-D score of about 50% or more from baseline. In one embodiment, the subject is evaluated for recurrence or re-emergence of depressive symptoms.

[0218] In some embodiments, the method comprises a multiple episodic dosing regimen. In one embodiment, the episodic dosing regimen is spaced at least 8 weeks apart. In another embodiment, the daily dose comprises 45 mg to 55 mg of Compound (1). In another embodiment, the daily dose comprises 48 mg to 52 mg of Compound (1). In a further embodiment, the daily dose comprises 50 mg of Compound (1).

[0219] In one embodiment, the daily dose is administered to the subject in the evening, hi another embodiment, the daily dose is administered to the subject in conjunction with or immediately after food intake.

[0220] In another aspect, the present disclosure provides a method of treating major depressive disorder in a subject in need thereof, comprising: (i) administering to the subject a daily dose containing 45 mg to 55 mg of compound (1) once daily for about two weeks; and (ii) in response to a recurrence of depressive symptoms, readministering to said subject a daily dose comprising 45 mg to 55 mg of compound (1) once per day for about two weeks, wherein there is an interval of at least 8 weeks between administering compound (1) to said subject and readministering compound (1) to said subject.

[0221] In one embodiment of this aspect, Compound (1) is re-administered to the subject for two weeks. In another embodiment, the interval between administering Compound (1) to the subject and re-administering Compound (1) to the subject is eight weeks. In a further embodiment, the major depressive disorder is moderate major depressive disorder. In another further embodiment, the major depressive disorder is severe major depressive disorder. In one embodiment, the subject has experienced a major depressive episode for about one year. In another embodiment, the subject is between about 18 and about 75 years of age. In another embodiment, the subject is between about 18 and about 65 years of age. In one embodiment, the daily dose comprises 48 mg to 52 mg of Compound (1). In a further embodiment, the daily dose comprises 50 mg of Compound (1). In another embodiment, the daily dose is administered to the subject in the evening. In another embodiment, the daily dose is administered to the subject in conjunction with or immediately after food intake. In one embodiment, the daily dose comprising Compound (1) is in the form of a capsule. In one embodiment, the method further comprises administering a second therapeutic agent to the subject.

[0222] In another aspect, the disclosure provides a method of treating major depressive disorder in a subject in need thereof using a kit, the kit comprising: a plurality of individual dosage units, each of which contains 45 mg to 55 mg of Compound (1); and An instruction set describing a method for administering dosage units to a subject using an episodic dosing regimen. The present invention includes a method comprising the steps of:

[0223] In another aspect, the disclosure provides a method of treating major depressive disorder in a subject in need thereof using a kit, the kit comprising: a plurality of individual dosage units, each of which contains 30 mg to 50 mg of compound (1); and A set of instructions describing a method for administering a dosage unit to a subject using an episodic dosing regimen. The present invention includes a method comprising the steps of:

[0224] In embodiments of these aspects, the duration of the episodic dosing regimen is about 2 to about 8 weeks. In one embodiment, the duration of the episodic dosing regimen is about 2 to about 6 weeks. In another embodiment, the duration of the episodic dosing regimen is about 2 to about 4 weeks. In a further embodiment, the duration of the episodic dosing regimen is about 2 weeks. In yet a further embodiment, the duration of the episodic dosing regimen is 2 weeks. In one embodiment, the subject has been diagnosed with major depressive disorder. In a further embodiment, the major depressive disorder is moderate major depressive disorder. In another further embodiment, the major depressive disorder is severe major depressive disorder. In one embodiment, each dosage unit contains 45 mg to 55 mg of compound (1). In one embodiment, each dosage unit contains 48 mg to 52 mg of compound (1). In a further embodiment, each dosage unit contains 50 mg of compound (1). In a further embodiment, each dosage unit contains 40 mg of compound (1). In one embodiment, the method in the instruction set includes instructions for administering the dosage unit in the evening, hi another embodiment, the method in the instruction set includes instructions for administering the dosage unit in conjunction with or immediately following food intake.

[0225] In another aspect, the disclosure includes a kit comprising a plurality of dosages, each of which comprises 45 mg to 55 mg of Compound (1), and an instruction set describing how to administer the dosages using an episodic dosing regimen for treating major depressive disorder. In one embodiment of this aspect, the dosages are individual dosage units of Compound (1). In a further embodiment, the individual dosage units comprise 48 mg to 52 mg of Compound (1). In yet a further embodiment, the individual dosage units comprise 50 mg of Compound (1). In one embodiment, the duration of the episodic dosing regimen is about 2 to about 8 weeks. In another embodiment, the duration of the episodic dosing regimen is about 2 to about 6 weeks. In a further embodiment, the duration of the episodic dosing regimen is about 2 to about 4 weeks. In a still further embodiment, the duration of the episodic dosing regimen is about 2 weeks or 14 days. In a still further embodiment, the duration of the episodic dosing regimen is 2 weeks. In one embodiment, the major depressive disorder is moderate major depressive disorder. In another embodiment, the major depressive disorder is severe major depressive disorder. In one embodiment, the instruction set is printed on a suitable material. In another embodiment, the individual dosage unit is a capsule or tablet. In a further embodiment, the individual dosage unit is a capsule. In some embodiments, the individual dosage unit is a size 1, size 2, size 3, or size 4 capsule. In one embodiment, the capsule is size 1.

[0226] In another aspect, the disclosure includes a kit including a plurality of dosages, each of which comprises 30 mg to 50 mg of Compound (1), and an instruction set describing how to administer the dosages using an episodic dosing regimen for treating major depressive disorder. In one embodiment of this aspect, the dosages are individual dosage units of Compound (1). In a further embodiment, the individual dosage units comprise 45 mg to 55 mg of Compound (1). In a further embodiment, the individual dosage units comprise 48 mg to 52 mg of Compound (1). In yet a further embodiment, the individual dosage units comprise 50 mg of Compound (1). In yet a further embodiment, the individual dosage units comprise 40 mg of Compound (1). In one embodiment, the duration of the episodic dosing regimen is about 2 to about 8 weeks. In another embodiment, the duration of the episodic dosing regimen is about 2 to about 6 weeks. In a further embodiment, the duration of the episodic dosing regimen is about 2 to about 4 weeks. In yet a further embodiment, the duration of the episodic dosing regimen is about 2 weeks or 14 days. In yet a further embodiment, the duration of the episodic dosing regimen is 2 weeks. In one embodiment, the major depressive disorder is moderate major depressive disorder. In another embodiment, the major depressive disorder is severe major depressive disorder. In one embodiment, the instruction set is printed on a suitable material. In another embodiment, the individual dosage unit is a capsule or tablet. In a further embodiment, the individual dosage unit is a capsule. In some embodiments, the individual dosage unit is a capsule size 1, 2, 3, or 4. In one embodiment, the capsule is size 1.

[0227] In some embodiments, the method improves cognitive function in a subject. In some embodiments, the method improves cognitive function in a subject after completion of an episodic dosing regimen. In some embodiments, the method does not cause cognitive impairment in the subject.

[0228] In another aspect, the present invention provides a method of treating major depressive disorder in a subject in need thereof, comprising: (i) administering to the subject an initial dosing cycle, wherein the initial dosing cycle is about 30 mg or about 50 mg of Compound (1): [ka] administering to said subject a daily dose comprising: (ii) administering to the subject 0, 1, 2, 3, or 4 subsequent administration cycles, each subsequent administration cycle consisting essentially of an administration period comprising administering to the subject a daily dose comprising about 30 mg or about 50 mg of Compound (1) once daily for 2 weeks, followed by a non-administration period comprising a period of at least 8 weeks during which the subject is not administered Compound (1). The present invention includes a method comprising the steps of:

[0229] In one embodiment of this aspect, the total time of the first administration cycle and all subsequent administration cycles is at most one year. In another embodiment, no more than four subsequent administration cycles are performed within one year. In some embodiments, an interval of eight weeks is provided between administering compound (1) to the subject and re-administering compound (1) to the subject. The administration of one or more subsequent administration cycles to a subject who has received a first administration cycle is interchangeably referred to as re-administration of compound (1) and interchangeably referred to as retreatment. In one embodiment, each subsequent administration cycle is performed in response to a recurrence of depressive symptoms after a non-administration period of the previous administration cycle. In another embodiment, the recurrence of depressive symptoms that requires a subsequent administration cycle is determined by assessing the subject using the Hamilton Depression Rating Scale (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), the Patient Health Questionnaire (PHQ-9), or a combination thereof. In another embodiment, the recurrence of depressive symptoms that requires a subsequent administration cycle is determined by a HAM-D score of 20 or more. In a further embodiment, the recurrence of depressive symptoms requiring a subsequent dosing cycle is further determined by a PHQ-9 score of 10 or more. In yet a further embodiment, the recurrence of depressive symptoms requiring a subsequent dosing cycle is further determined by a MADRS score of 28 or more. In one embodiment, the non-dosing period is at least 10 weeks, and the subject is administered no more than three subsequent dosing cycles. In another embodiment, the non-dosing period is at least 12 weeks, and the subject is administered no more than two subsequent dosing cycles. In another embodiment, the non-dosing period is at least 16 weeks, and the subject is administered no more than one subsequent dosing cycle. In another embodiment, the non-dosing period is at least 24 weeks, and the subject is administered no subsequent dosing cycles. In some embodiments, the depressive symptoms do not recur. In some embodiments, the first dosing cycle comprises a daily dose of 30 mg of Compound (1). In a further embodiment, each and every subsequent dosing cycle comprises a daily dose of 30 mg of Compound (1).In another embodiment, one or more subsequent dosing cycles include a daily dose of 50 mg of compound (1), and the remainder of the subsequent dosing cycles include a daily dose of 30 mg of compound (1). In another embodiment, each and every subsequent dosing cycle includes a daily dose of 50 mg of compound (1). In some embodiments, the first dosing cycle includes a daily dose of 50 mg of compound (1). In a further embodiment, each and every subsequent dosing cycle includes a daily dose of 50 mg of compound (1). In another embodiment, one or more subsequent dosing cycles include a daily dose of 30 mg of compound (1), and the remainder of the subsequent dosing cycles include a daily dose of 50 mg of compound (1). In another embodiment, each and every subsequent dosing cycle includes a daily dose of 30 mg of compound (1). In one embodiment, the subject is treatment naive to any form of medication for treating depression. In a further embodiment, the subject is primary naive. In a further embodiment, the subject is secondary naive. In one embodiment, the subject is currently or recently on antidepressant medication. In a further embodiment, the subject has been on a stable dose of antidepressant medication for at least 60 days prior to the start of the first administration period. In one embodiment, the major depressive disorder is moderate major depressive disorder. In another embodiment, the major depressive disorder is severe major depressive disorder. In one embodiment, the subject has been experiencing major depressive episodes for about one year. In one embodiment, the subject is between about 18 and about 75 years old. In a further embodiment, the subject is between about 18 and about 65 years old. In one embodiment, the daily dose of compound (1) is administered to the subject in the evening. In another embodiment, the daily dose is administered to the subject in conjunction with or immediately after food intake. In one embodiment, the daily dose containing compound (1) is in the form of a capsule. In another embodiment, the method further comprises administering to the subject a second therapeutic agent. EXAMPLES

[0230] Working Example Example 1. An open-label, 1-year Phase 3 study of the safety, tolerability, and necessity of retreatment with Compound (1) in adult subjects with major depressive disorder. [Table 33]

[0231] Primary Objective: To determine the safety and tolerability of initial treatment and retreatment with Compound 1 in adults with major depressive disorder (MDD) and currently experiencing a major depressive episode (MDE) over a one-year period.

[0232] Secondary objectives: To assess the need for re-treatment with Compound 1 after initial treatment in adults with MDD and currently experiencing MDE for one year, and to assess the response to initial treatment with Compound 1 and to re-treatment after an initial 2-week treatment period in adults with MDD and currently experiencing MDE for one year.

[0233] Primary endpoint: Safety and tolerability of initial treatment with compound (1) and retreatment with compound (1) as assessed by the incidence and severity of adverse events / serious adverse events, changes from baseline in clinical laboratory measures, vital signs, and electrocardiograms (ECGs); and suicidal ideation and behavior (using the Columbia Suicide Severity Scale (C-SSRS)) over one year. Safety and tolerability of initial treatment with compound (1) and retreatment with compound (1) as assessed by the incidence and severity of adverse events / serious adverse events, changes from baseline in clinical laboratory measures, vital signs, and electrocardiograms (ECGs); and suicidal ideation and behavior (using the Columbia Suicide Severity Scale (C-SSRS)).

[0234] Secondary endpoints: need for retreatment with Compound 1 as assessed by time to first retreatment (Kaplan-Meier curves); number of subjects who achieved the requirement for retreatment; number of cycles of retreatment for each subject; response to initial treatment and / or retreatment as assessed by change in 17-item Hamilton Rating Scale for Depression (HAM-D) total score from baseline at the end of each of the 14-day treatment (initial treatment and / or retreatment) periods; change in HAM-D score from baseline at the end of each of the 14-day treatment (initial treatment and / or retreatment) periods. HAM-D response, defined as a ≧50% decrease in core; HAM-D remission, defined as a HAM-D total score of ≦7 at the end of each of the 14-day treatment (initial treatment and / or retreatment) periods; Clinical Global Impression-Improvement (CGI-I) response, defined as "much improved" or "very much improved" at the end of each of the 14-day treatment (initial treatment and / or retreatment) periods; change from baseline in Clinical Global Impression-Severity (CGI-S) score at the end of each of the 14-day treatment (initial treatment and / or retreatment) periods.

[0235] Study Population: Subjects are 18-75 years of age and have a diagnosis of major depressive disorder (MDD) with a MADRS total score of 28 or greater and a HAM-D total score of 20 or greater at screening and Day 1 (pre-dose).

[0236] Treatment groups: 30 mg and 50 mg dose groups were divided according to the time of enrollment. The study consisted of two cohorts: a cohort using 30 mg of compound (1) as the starting dose (30 mg cohort; n=725) and an initial cohort using 50 mg of compound (1) as the starting dose (50 mg cohort; n=199). Patients receiving 30 mg of compound (1) could have their dose reduced to 20 mg, and patients receiving 50 mg of compound (1) could have their dose reduced to 40 mg (based on tolerability). In all cohorts, patients self-administered compound (1) as an oral treatment with food once at night for 14 days. Study design

[0237] The study will have a screening period of up to 28 days, a treatment period of 14 days, and follow-up of up to one year. Figure 1 provides an overview of the study.

[0238] The screening period begins with the signing of an informed consent form (ICF) at the screening visit; signing of the ICF must occur prior to beginning any screening activities. A diagnosis of MDD must be made according to the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), clinical trial version (SCID-5-CT) administered by a qualified health professional. Subjects undergo preliminary screening procedures (including completion of the MADRS, HAM-D, and CGI-S) at the screening visit to determine eligibility.

[0239] Antidepressants were permitted if subjects had been on a stable dose for at least 60 days prior to Day 1 and agreed to continue on a stable dose throughout the follow-up period (Day 42). Initiation of new antidepressants or any other medications that could potentially affect efficacy or safety endpoints was not permitted between screening and completion of the Day 42 assessment.

[0240] Eligible subjects took Compound (1) at home in the evening with a meal. Subjects who achieved at least a 50% reduction in HAM-D total score on Day 15 (i.e., responders in treatment cycle 1) were allowed to continue on the study; other subjects were terminated after 14 days of follow-up (Day 28).

[0241] Subjects who continued through the observation period were monitored remotely with PHQ-9 assessments every 2 weeks. If the PHQ-9 score was 10 or greater at any assessment, the PHQ-9 assessments were switched to weekly until the score fell below 10, or the subject was administered Compound (1) in a subsequent cycle, whichever occurred first. Subjects were to return to the site for a HAM-D assessment within 1 week of a PHQ-9 score of 10 or greater; if the HAM-D total score was 20 or greater and at least 56 days had elapsed since the last dose of Compound (1), another cycle of Compound (1) administration was to be initiated. If neither of these criteria were met, the subject could not be treated with Compound (1) at that time. Subjects were to return to the clinic every 8 weeks if there was no visit trigger of a PHQ-9 of 10 or greater. Subjects could receive a maximum of 5 cycles of treatment within a year. Figure 2 describes the study eligibility criteria.

[0242] FIG. 3 is a flow chart of the dosing cohorts.

[0243] At the 50 mg lead-in time, subjects treated with 30 mg in the previous cycle were switched to 50 mg in the next treatment cycle.

[0244] Dose reductions from 30 mg to 20 mg or from 50 mg to 40 mg were permitted in any treatment cycle if safety and / or tolerability for the subject warranted. Additionally, if a subject's dose was reduced from 50 mg to 40 mg in any cycle, the investigator had the option to start the subject at 50 mg or 40 mg in the next treatment cycle. Subjects whose dose was reduced from 30 mg to 20 mg still started at 30 mg in the next treatment cycle.

[0245] The use of antidepressants can be modified during treatment cycles according to specific rules established in the protocol.

[0246] Main inclusion criteria: Female and male patients aged 18-75 years with symptoms for ≥4 weeks and a diagnosis of MDD with a HAM-D17 total score ≥20 and MADRS total score ≥28 at screening and on Day 1 (pre-dose). Patients taking antidepressants must have been taking these medications at the same dose for ≥60 days prior to Day 1 if they intended to continue through the first treatment cycle.

[0247] Main exclusion criteria: active psychosis, suicide attempt or risk associated with the current episode of MDD, history of bipolar disorder, schizophrenia, and / or schizoaffective disorder, or treatment-resistant depression defined as persistent depressive symptoms despite treatment with sufficient doses of two different classes of antidepressants (excluding antipsychotics) within the current MDD for at least 4 weeks of treatment.

[0248] Sample Size Determination: The sample size was not based on a formal sample size calculation. A sample size of 900 subjects was selected to ensure that at least 450 subjects would complete the 24-week study and at least 150 subjects would complete the 56-week study.

[0249] Cohorts regarding the different doses that subjects received were defined as follows:

[0250] 50 mg cohort: This cohort included subjects who initiated treatment at 50 mg and underwent retreatment at 50 mg only.

[0251] 30 mg cohort: This cohort includes subjects who initiated treatment at 30 mg, regardless of the dose administered at retreatment.

[0252] Low Dose Cohort: This cohort includes subjects who initiated treatment at 30 mg and underwent retreatment at 30 mg only.

[0253] Dose Switching Cohort: This cohort includes subjects who received initial treatment with 30 mg and at least one subsequent retreatment with 50 mg.

[0254] Test period X: starting on the day of the first administration of compound (1) in cycle X and continuing until one day before the first administration of the next cycle. In some embodiments, X is any number from 1 to 5.

[0255] Treatment period X: starting on the day of the first administration of compound (1) in cycle X and continuing until one day after the last administration of cycle X. In some embodiments, X is any number from 1 to 5.

[0256] Treatment cycle X: Beginning on the day of the first administration of compound (1) in cycle X and continuing until 14 days after the last administration of cycle X. Treatment cycles may be designated C1 to C5.

[0257] Observation period X: Starts the day after the end of treatment cycle X and continues until one day before the start of the next treatment cycle. In some embodiments, X is any number from 1 to 5.

[0258] Using the above, the 30 mg cohort was essentially identical to the combined low-dose and dose-switching cohorts for Study Period 1. 725 subjects were dosed in the 30 mg cohort (n=645 in the low-dose cohort and n=80 in the dose-switching cohort) and 199 subjects were dosed in the 50 mg cohort. The 30 mg cohort had completed one year of follow-up.

[0259] Analysis Sets: The safety analysis set was defined as all subjects who received the study drug. Period-specific safety analysis sets included subjects in the safety analysis set who received the study drug in the corresponding treatment cycle. The full analysis set (FAS) was defined as all subjects in the safety analysis set who had a HAM-D response on day 15 of treatment cycle 1, with discontinuation from the study date, if any, after the end of treatment cycle 1. (Treatment cycle X responders were subjects in the safety analysis set who showed at least a 50% reduction from baseline in the HAM-D total score on day 15 of treatment cycle X. Subjects were considered non-responders if they lacked a HAM-D total score on day 15 of treatment cycle X).

[0260] The dose switch cohort was defined as all subjects in the safety analysis population who received 30 mg on day 1 of treatment cycle 1 and then 50 mg on day 1 of the retreatment cycle.

[0261] statistical analysis

[0262] Whenever possible, data is presented for all cohorts separately, in addition to all cohorts being combined as Compound (1) overall cohort.For dose-switching cohorts, data is presented by study period, by dose administered on day 1 of treatment cycle X per dose distribution in a specific period, and for Compound (1) overall (regardless of the dose administered).All presentations are presented based on the treatment received, without considering treatment schedule.

[0263] Subject characteristics are provided, including the number of subjects dosed in each cycle and the number of subjects dosed in exactly X number of treatment cycles. For subjects dosed in treatment cycle 1 (safety population), descriptive statistics for HAM-D total score, HAM-D response, and remission for treatment cycle 1 are provided. FAS is used for the remaining analyses of HAM-D total score for subjects dosed in each treatment cycle. Line graphs of LS mean change from baseline in HAM-D total score for each study period are provided based on mixed effects repeated measures models (MMRM) for each study period and each dose cohort separately; the models include period-specific baseline scores, antidepressant use (yes or no) at baseline, and each of the assessment time points as explanatory variables. A summary of HAM-D for dose-switched cohorts by first dose in each cycle is provided. Additionally, a summary of HAM-D total score for subjects dosed in cycle X for current and past treatment cycles is provided. Responses at day 15 for past cycles for subjects who are non-responders in the current cycle are provided.Bar charts for HAM-D response and remission by study period are provided.

[0264] For safety analyses, period-specific safety analysis populations are used in addition to dose-switching cohorts, as appropriate. A treatment period is defined as the first dose date to the last dose date +1 day during the study period. A treatment cycle is defined as the first dose date to 14 days after the last dose date during the study period. Adverse events are analyzed by dose cohort for:

[0265] 1. Summary of treatment-emergent adverse events (including number and percentage of subjects with TEAEs, TEAEs for treatment cycle period, on-treatment period, and post-treatment period, TEAEs to maximum severity, TEAEs leading to discontinuation of study drug or dose reduction, serious TEAEs - overall and by study period).

[0266] 2. Treatment cycle duration AEs by SOC and PT - by study period and by first dose in study period using dose switching cohorts.

[0267] 3. Treatment cycle-period AEs and maximum severity by SOC / PT - by study period and by first dose in study period using dose-switching cohorts.

[0268] 4. TEAEs leading to study drug discontinuation by SOC / PT.

[0269] 5. TEAEs leading to dose reduction of investigational drug by SOC / PT.

[0270] 6. Serious TEAEs during treatment cycle by SOC / PT - by study period and by first dose in study period using dose switching cohorts.

[0271] Example 2. Results from Example 1 - Most important results.

[0272] The data used in this Example 2 was the data with a cutoff date that was the study completion date of the last subject who started the study with a dose of 30 mg. All subjects in the 50 mg cohort had completed the 28-day treatment cycle 1 as of this cutoff date, but some had not been in the study long enough to be eligible for any retreatment. As of this data cutoff date, only one subject in the 50 mg cohort had been administered treatment cycle 3 (including the first cycle).

[0273] The diagrams in Figures 4A and 4B provide an overview of the subject flow.

[0274] result

[0275] Primary endpoint - Safety

[0276] The proportion of subjects reporting treatment-emergent adverse events (TEAEs) was similar across dose cohorts: 50 mg cohort: 62.8% (125 / 199); 30 mg cohort: 68.0% (493 / 725); low-dose cohort: 67.6% (436 / 645); dose-switching cohort: 71.3% (57 / 80)

[0277] TEAEs occurring in greater than 5% of subjects in any dose cohort are provided in the table below.

[0278] [Table 1]

[0279] The overall safety findings in subjects receiving 50 mg of Compound (1) to date are comparable to the safety findings observed with 30 mg and do not deviate from the known safety profile of Compound (1).

[0280] The majority of TEAEs were mild to moderate in all dose cohorts, with similar incidence across all dose cohorts.

[0281] [Table 2]

[0282] The percentage of subjects reporting TEAEs leading to study drug discontinuation was 6.5% (13 / 199) in the 50 mg cohort, 2.8% (18 / 645) in the low-dose cohort, and 1.3% (1 / 80) in the dose-switching cohort.

[0283] The percentage of subjects reporting TEAEs leading to withdrawal from the study was 7.0% (14 / 199) in the 50 mg cohort, 4.8% (31 / 645) in the low-dose cohort, and 1.3% (1 / 80) in the dose-switching cohort.

[0284] The percentage of subjects reporting TEAEs leading to dose reduction was 17.1% (34 / 199) in the 50 mg cohort, all but 2 in cycle 1, and 2 / 26 in cycle 2. In the low-dose cohort, the respective percentages were 5.0% (32 / 645) overall: 3.4% (22 / 645) in cycle 1, 4.4% (9 / 206) in cycle 2, 2.3% (2 / 86) in cycle 3, 0 (0 / 43) in cycle 4, and 10% (2 / 20) in cycle 5. In the dose-switching cohort, the overall percentages were 15.0% (12 / 80): 2.5% (3 / 80) in each of cycles 1 and 2 receiving 30 mg; 4.2% (3 / 71) in cycle 3, 3.8% (2 / 53) in cycle 4, and 17.4% (4 / 23) in cycle 5 switching to 50 mg. Somnolence, dizziness, sedation, and headache were the most common AEs leading to dose reductions.

[0285] Secondary endpoint - Efficacy

[0286] [Table 3] * All subjects enrolled (HAM-D ≥ 20, MADRS ≥ 28) and treated

[0287] For the 30 mg cohort at day 15, the mean change from baseline was -15.2 ± 7.1 (n = 687); 505 (73.5%) patients achieved a response and 276 (40.2%) achieved remission (HAM-D ≤ 7). At day 15 of the initial treatment course in the 50 mg cohort, the mean HAM-D change from baseline was -16 ± 6.0; 149 / 185 (80.5%) achieved a response and 80 / 185 (43.2%) achieved remission. Change in HAM-D total score over time - Study Period 1 (safety population) is shown in Figure 5. Initial HAM-D response and remission are shown in Figures 6A and 6B, respectively.

[0288] Table 4 provides an overview of retreatments in the safety analysis population.

[0289] [Table 4] [1] Eligible for retreatment means that a subject completed treatment cycle 1 and did not discontinue the study within 56 days after the date of the last dose. [2] Eligible for retreatment means that the subject was eligible for retreatment and had a pre-retreatment HAM-D total score of 20 or greater. [3] Percentages use the number of subjects eligible for retreatment as the denominator.

[0290] [Table 5]

[0291] As shown in Table 5, the majority of patients (68.5%) received only one or two treatments with Compound (1) over the 12-month follow-up period in the 30 mg cohort.

[0292] The mean (range) number of retreatments over 1 year of follow-up per subject was 0.8 (0-4) for the low-dose cohort and 2.8 (1-4) for the dose-switched cohort. Overall, in the 30 mg cohort, the mean number of retreatments was 1.2 (0-4). Retreatment rates in the presence and absence of existing antidepressant treatment were similar. At the time of this report, none of the subjects in the 50 mg cohort had been on study for more than 6 months, the majority (n=114) had less than 3 months of follow-up, and only one subject had had more than one retreatment.

[0293] [Table 6]

[0294] The time lag (in days) between retreatments by baseline antidepressant use in the previous treatment cycle is shown in Table 7. The length of time between retreatments did not differ significantly by antidepressant use.

[0295] [Table 7]

[0296] Response rates by treatment cycle in the low-dose cohort were as follows: treatment cycle 2: 59.3% (118 / 199) overall response rate; treatment cycle 3: 57.8% (48 / 83) overall response rate, of which 75% (36 / 48) subjects were responders in treatment cycle 2 and the remainder were responders in treatment cycle 3; 25% (12 / 483) were non-responders in treatment cycle 2 who responded to retreatment; treatment cycle 4: 51.2% (22 / 43) overall response rate, of which 81.8% (18 / 22) subjects were responders in treatment cycle 3, 63.6% (14 / 22) subjects were responders in treatment cycle 2 and the remainder were responders in treatment cycle 4. 18.2% (4 / 22) of subjects were non-responders in treatment cycle 3 and 36.4% (8 / 22) were non-responders in treatment cycle 2 who responded to retreatment in treatment cycle 4. Treatment cycle 5: Overall response rate of 50.0% (10 / 20), of which 90% (9 / 10) in treatment cycle 4, 80% (8 / 10) in treatment cycle 3, and 70% (7 / 10) in treatment cycle 2 were responders, with the remainder responding in treatment cycle 5. 1% (1 / 10), 20.0% (2 / 10), and 30% (3 / 10) of subjects were non-responders in treatment cycle 4, treatment cycle 3, and treatment cycle 2 who responded to retreatment in treatment cycle 5, respectively.

[0297] Figure 7 provides a bar graph of HAM-D response / non-response at Day 15 by treatment cycle (low dose cohort only (FAS)). The inner bar indicates the percentage of responders in the previous cycle.

[0298] FIG. 8 provides box plots of HAM-D total score change from period-specific baseline on day 15 in each treatment cycle by antidepressant use (yes / no) at period-specific baseline - low-dose cohort (safety population for treatment cycle 1, FAS for treatment cycles 2-5).

[0299] Example 3. Results from Example 1 - Full Analysis Set.

[0300] Subject characteristics

[0301] The data used in this Example 3 were from the study of Example 1 with a cutoff date that was the study completion date of the last subject who began the study with the 30 mg dose. This Example presents additional results from Example 2.

[0302] A total of 924 subjects were treated with Compound (1) in treatment cycle 1 (C1), with 725 subjects treated in the 30 mg cohort (645 subjects in the low-dose cohort and 80 subjects in the dose-switched cohort) and 199 subjects treated in the 50 mg cohort.

[0303] Of 725 subjects initially treated with 30 mg, 202 (31.3%) subjects withdrew from the study early or during treatment cycle 1. Of the 202 subjects, 146 (72.3%) discontinued the study because they did not meet a 50% reduction in HAM-D on day 15. 523 (72.1%) subjects completed treatment cycle 1.

[0304] As shown in Table 8, of 725 subjects initially treated with 30 mg, 413 (57%) subjects prematurely withdrew from the study prior to completing one year in the 30 mg cohort. Of these 413 subjects, 173 (41.9%) withdrew due to failure to meet criteria for responder in treatment cycle 1. Of these 173 subjects, 146 discontinued within treatment cycle 1 due to non-compliance with the protocol, and 27 additional subjects discontinued after completion of treatment cycle 1 due to non-responder in treatment cycle 1 (for a total of 173).

[0305] Of the 725 subjects initially treated with 30 mg, 489 (67.4%) of the 725 subjects (409 subjects in the low-dose cohort and 80 subjects in the dose-switched cohort) were responders in treatment cycle 1; therefore, responders who completed treatment cycle 1 were included in the FAS.

[0306] Of the 80 subjects in the dose-switching cohort, 10 subjects switched to 50 mg in treatment cycle 2, 21 subjects in treatment cycle 3, 38 subjects in treatment cycle 4, and 11 subjects in treatment cycle 5. Two of the subjects who switched to 50 mg in treatment cycle 3 began treatment cycle 4, where the dose was reduced to 40 mg. Four subjects in this cohort withdrew from the study during the cycle when they switched to 50 mg - one discontinued study treatment during treatment cycle 2 and withdrew by physician decision; one discontinued treatment during treatment cycle 5 and withdrew due to an adverse event; one withdrew consent during treatment cycle 4, and one completed treatment cycle 5 but withdrew because scheduling conflicts prevented them from completing the end-of-study visit.

[0307] Of the 199 subjects dosed in the 50 mg cohort, 64 (32.2%) subjects had discontinued the study by the data cutoff date. Of the 64 subjects who discontinued the study, 35 (54.7%) did so because they did not meet a 50% reduction in HAM-D on day 15, and 14 (21.9%) did so because of adverse events. Of the 199 subjects initially treated with 50 mg, 146 (73.4%) were counted in the FAS (responders in treatment cycle 1 who did not discontinue the study during treatment cycle 1).

[0308] [Table 8]

[0309] Demographics and baseline characteristics

[0310] Demographics and baseline characteristics of subjects enrolled in the study were well balanced between the 30 mg and 50 mg cohorts. Overall, approximately 68% were female, 81% were white, and the mean age was 45 years (SD: 14.13 years). Approximately 42% of subjects were using antidepressants at baseline. 82% of subjects had a baseline HAMD of 22 or higher.

[0311] [Table 9]

[0312] [Table 10]

[0313] Efficacy Results

[0314] 1.HAM-D total score

[0315] [Table 11] [1] Baseline rows show mean ± SD of HAM-D total score.

[0316] FIG. 5 provides a line graph of the LS mean (±SE) change from baseline in HAM-D total score for Study Period 1.

[0317] FIG. 9 provides box plots of the change from baseline HAM-D total score on day 15 in each treatment cycle (safety population for treatment cycle 1, FAS for C2-C5).

[0318] FIG. 10 provides box plots of HAM-D total score change from period-specific baseline on day 15 for each treatment cycle by antidepressant use (yes / no) at period-specific baseline - low-dose cohort (safety population for treatment cycle 1, FAS for C2-5).

[0319] 2 HAM-D response

[0320] [Table 12]

[0321] Figure 11 provides a bar chart of HAM-D response over time - Study Period 1 (Safety Population). Figure 12 provides a bar chart of HAM-D response over time in Study Period 1 by baseline antidepressant use (Safety Population). Figure 13 provides a bar chart of HAM-D response at Day 15 in each treatment cycle by period-specific baseline antidepressant use - Low Dose Cohort (Safety Population).

[0322] 3 HAM-D remission

[0323] [Table 13]

[0324] Figure 14 provides a bar chart of HAM-D remission over time - Study Period 1 (Safety Population). Figure 15 provides a bar chart of HAM-D remission over time in Study Period 1 by baseline antidepressant use (Safety Population). Figure 16 provides a bar chart of HAM-D remission at Day 15 in each treatment cycle by period-specific baseline antidepressant use - Low Dose Cohort.

[0325] 4 Subjects with a baseline HAM-D score ≥ 24 (total score, response, and remission)

[0326] Tables 14, 15, and 16 show the HAM-D total score, response, and remission, respectively, at various time points for subjects with a baseline HAM-D score of 24 or greater. Figure 17 provides a line graph of the LS mean (±SE) change from baseline for subjects with a baseline HAM-D score of 24 or greater - Study Period 1 (Safety Population). Figures 18 and 19 provide bar charts of HAM-D response and remission, respectively, for subjects with a baseline HAM-D score of 24 or greater - Study Period 1 (Safety Population).

[0327] [Table 14] [1] Baseline rows show mean ± SD of HAM-D total score.

[0328] [Table 15]

[0329] [Table 16]

[0330] 5 Subjects with a baseline HAM-D score ≥ 26 (total score, response, and remission)

[0331] Tables 17, 18, and 19 show the HAM-D total score, response, and remission, respectively, at various time points for subjects with a baseline HAM-D score of 26 or greater. Figure 20 provides a line graph of the LS mean (±SE) change from baseline for subjects with a baseline HAM-D score of 26 or greater - Study Period 1 (Safety Population). Figures 21 and 22 provide bar charts of HAM-D response and remission, respectively, for subjects with a baseline HAM-D score of 26 or greater - Study Period 1 (Safety Population).

[0332] [Table 17] [1] Baseline rows show mean ± SD of HAM-D total score.

[0333] [Table 18]

[0334] [Table 19]

[0335] 6 Retreatment

[0336] The mean (range) number of retreatments per subject was 0.8 (0-4) for the low-dose cohort and 2.8 (1-4) for the dose-switched cohort. Overall, in the 30 mg cohort, the mean number of retreatments was 1.2 (0-4). At the time of this report, none of the subjects in the 50 mg cohort had been on study for more than 6 months, the majority (n=114) had been on study for less than 3 months, and only one subject had received more than one retreatment.

[0337] [Table 20] [1] Eligible for retreatment means that a subject completed treatment cycle 1 and did not discontinue the study within 56 days after the date of the last dose. [2] Eligible for retreatment means that the subject was eligible for retreatment and had a pre-retreatment HAM-D total score of 20 or greater. [3] Percentages use the number of subjects eligible for retreatment as the denominator.

[0338] [Table 21] [1] Percentage based on number of subjects administered C1 [2] Percentage based on number of subjects in the FAS

[0339] [Table 22]

[0340] [Table 23] [1] N = number of FAS subjects eligible for dosing in cycle X; n = number of FAS subjects eligible for and dosing in cycle X.

[0341] [Table 24]

[0342] FIG. 23 provides box plots of the time to retreatment by treatment cycle.

[0343] 7 Efficacy in responders vs. non-responders

[0344] [Table 25] + The denominator of the percentage is the number of subjects dosed in the current cycle. * The denominator of the percentage is the number of responders or non-responders in the current cycle.

[0345] FIG. 24 provides a bar chart of HAM-D responders / non-responders with the percentage of responders in the previous treatment cycle - low dose (FAS) (the inner bar indicates the percentage of responders in the previous cycle).

[0346] FIG. 25 provides a bar chart of HAM-D responders / non-responders with the percentage of non-responders in the previous treatment cycle - low dose (FAS) (the inner bar indicates the percentage of non-responders in the previous cycle).

[0347] 8. HAM-D total score in current and past cycles

[0348] Low-dose cohort

[0349] [Table 26] * n = number of subjects on which the calculation is based.

[0350] Dose switching cohort

[0351] [Table 27] * n = number of subjects on which the calculation is based. The dose switching cohort included subjects who began the study at a dose of 30 mg but switched to 50 mg in a subsequent treatment cycle.

[0352] Safety Results (Adverse Events)

[0353] Similar proportions of subjects reported treatment-emergent adverse events (TEAEs) across the three cohorts: 60.5% (46 / 76) in the 50 mg cohort, 66.6% (451 / 677) in the low-dose cohort, and 77.1% (37 / 48) in the dose-switching cohort subjects.

[0354] [Table 28] Treatment-period TEAEs are those that occur +1 day between the first and last doses of Compound (1). Treatment-cycle-period TEAEs are those that occur between the first and 14 days after the last dose of Compound (1).

[0355] TEAEs occurring in greater than 5% of subjects in any dose cohort are provided in Table 29.

[0356] [Table 29]

[0357] The majority of TEAEs were mild to moderate in all dose cohorts, with similar incidence across all dose cohorts.

[0358] [Table 30]

[0359] The overall safety findings in subjects receiving Compound (1) 50 mg were comparable to those observed at 30 mg and did not deviate from the known safety profile of Compound (1). Similar adverse events were reported in subjects with and without existing antidepressant treatment. No events of loss of consciousness were reported as of the cutoff date.

[0360] During treatment cycle 1, 2.5% (5 / 199) of subjects reported SAEs in the 50 mg cohort and 0.9% (6 / 645) in the lower dose cohort. In the 50 mg cohort, three of the five SAEs were deemed likely related to the study drug; subjects were withdrawn from the drug and discontinued in each of the following cases: one subject presenting with confusion, one subject presenting with asthenia, and one subject presenting with delirium. In the 50 mg cohort, two of the five SAEs deemed not related to the study drug were a suicide attempt and intentional self-harm; both of these resolved within 7 days.

[0361] In the low-dose cohort (30 mg only), no SAEs were considered likely or probably related to the study drug. Although five of the six SAEs were considered severe in intensity, only one (intracranial aneurysm) led to discontinuation of the study.

[0362] [Table 31]

[0363] The percentage of subjects reporting TEAEs leading to withdrawal from the study was 7.0% (14 / 199) in the 50 mg cohort, 4.8% (31 / 645) in the low-dose cohort, and 1.3% (1 / 80) in the dose-switching cohort.

[0364] The percentage of subjects reporting TEAEs leading to dose reduction was 17.1% (34 / 199) in the 50 mg cohort, all but 2 in cycle 1, and 2 / 26 in cycle 2. In the low-dose cohort, the respective percentages were 5.0% (32 / 645) overall: 3.4% (22 / 645) in cycle 1, 4.4% (9 / 206) in cycle 2, 2.3% (2 / 86) in cycle 3, 0 (0 / 43) in cycle 4, and 10% (2 / 20) in cycle 5. In the dose-switching cohort, the overall percentages were 15.0% (12 / 80): 2.5% (3 / 80) in each of cycles 1 and 2 receiving 30 mg; 4.2% (3 / 71) in cycle 3, 3.8% (2 / 53) in cycle 4, and 17.4% (4 / 23) in cycle 5 switching to 50 mg. Somnolence, dizziness, sedation, and headache were the most common AEs leading to dose reductions.

[0365] [Table 32] Treatment period is defined as the first dose to the last dose +1 day. Treatment cycle is defined as the first dose to the end of 14 days follow-up after the last dose.

[0366] conclusion

[0367] The first course of Compound (1) 30 mg was generally well tolerated, with safety outcomes consistent with previous studies. In the 30 mg cohort, 68.5% of subjects did not receive more than one retreatment. In the low dose cohort (treated with 30 mg only), subjects received an average of 0.8 retreatments (i.e., 1.8 treatments in total). In the 30 mg cohort, subjects received an average of 1.2 retreatments (i.e., 2.2 treatments in total). Approximately 70% of patients in the 30 mg cohort who responded to the initial treatment course received at most one additional treatment course.

[0368] Initial response rates were 73.5% vs. 80.5% in the 30 mg and 50 mg cohorts, respectively.

[0369] The safety and tolerability profiles of Compound (1) 30 mg and Compound (1) 50 mg were consistent with those observed in previous clinical trials. No events of loss of consciousness were reported to date in either group. Most TEAEs in the 30 mg and 50 mg cohorts were mild or moderate.

[0370] Example 4. One-year follow-up of the 50 mg cohort

[0371] Introduction

[0372] Example 4 provides further data from the study described in Example 1 (an open-label, one-year Phase 3 study of the safety, tolerability, and need for retreatment with Compound (1) in adult subjects with major depressive disorder). Examples 2-3 present data through a time point that ends when the 30 mg cohort (n=725) has completed one year of follow-up. Some earlier data for the 50 mg cohort (available at the time the 30 mg cohort has completed one year of follow-up) is provided in Examples 2-3. Example 4 presents data through a later time point that ends when the 50 mg cohort (n=199) has completed one year of follow-up. Example 4 provides further data currently collected and analyzed for the 50 mg cohort, but does not change the data, results, or conclusions described for the 30 mg cohort in Examples 2-3.

[0373] The data used in Example 4 is the data with a cutoff date that was the study completion date of the last subject who started the study in the 50 mg cohort (n=199). In Examples 2-3, all subjects in the 50 mg cohort completed treatment cycle 1, but some did not participate in the study long enough to be eligible for any retreatment. As of the data cutoff date in Examples 2-3, only one subject in the 50 mg cohort had been administered treatment cycle 3. As of the data cutoff date in Example 4, all subjects in the 50 mg cohort had completed one year of follow-up.

[0374] result

[0375] The mean baseline HAMD score (±SD) for the 50 mg cohort at study entry was 25.1 ± 3.29 (n = 199). At baseline, 81 (40.7%) patients were continuing existing antidepressant treatment (ADT), while 118 (59.3%) were not receiving ADT.

[0376] Compound (1) 50 mg was generally well tolerated, and no new safety findings or trends were identified in the data available as of the cutoff date of Example 4 for 50 mg cohort subjects who received one or more treatment cycles and were followed for up to one year. Safety was evaluated during and between treatment cycles and across multiple treatment cycles to inform tolerability over time. 137 of 199 50 mg cohort subjects (68.8%) reported at least one adverse event, which was similar to the 30 mg cohort (68.0%). Most 50 mg cohort subjects reported treatment-emergent adverse events (TEAEs) with a maximum severity of mild to moderate. The most common (reported by at least 5%) treatment-emergent adverse events (TEAEs) were somnolence (32; 16.1%), dizziness (30; 15.1%), headache (25; 12.7%), sedation (20; 10.1%), insomnia (14; 7.0%), nausea (13; 6.5%), and tremor (11; 5.5%).

[0377] The types of TEAEs reported by 50 mg cohort subjects were similar to those reported by 30 mg cohort subjects. The frequency of adverse drug reactions such as somnolence, dizziness, sedation, and tremor was higher in the 50 mg cohort; however, the severity and outcomes of TEAEs were consistent with the 30 mg cohort and the overall safety profile of Compound (1). The percentage of 50 mg cohort subjects reporting TEAEs leading to discontinuation of study drug and withdrawal from the study was 6.5% (13 / 199) and 8.0% (16 / 199), respectively.

[0378] There were no indications of increased suicidal ideation or behavior compared to baseline in any study period or dose cohort, as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS).The overall adverse event profile from the 50 mg cohort was generally consistent with previously reported data, with the types of TEAEs reported being similar to those reported throughout the compound (1) clinical program.

[0379] On day 15 (treatment cycle 1), the mean change in HAM-D from baseline for the 50 mg cohort was -16.0±6.04 (n=185). Approximately 149 subjects (74.9%) achieved a response (at least a 50% reduction in HAM-D from baseline), and 80 subjects (40.2%) achieved remission (HAM-D of 7 or less). Of the 149 responders, 3 subjects left the study before day 28, leaving 146 subjects in the study after day 28 (i.e., of the 199 subjects initially treated with 50 mg Compound (1), 146, or about 73.4%, were included in the FAS). Of the 146 subjects in the study after day 28, 79.5% received at most one additional Compound (1) treatment cycle. 54.8% (n=80) received a total of 1 treatment course; 24.7% (n=36) received a total of 2 treatment courses; 10.3% (n=15) received a total of 3 treatment courses; 6.8% (n=10) received a total of 4 treatment courses; 3.4% (n=5) received a total of 5 treatment courses. Approximately 79.5% of FAS subjects in the 50 mg cohort did not receive more than 1 retreatment.

[0380] The proportion of subjects in the 50 mg cohort who received 0 or at most 1 additional Compound (1) treatment cycle was similar regardless of baseline use of antidepressant medication.

[0381] Example 5. Subpopulations of patients in the study of Example 1

[0382] Example 5.1 - MDD and metabolic comorbidities

[0383] Example 5.1 provides data for MDD patients with metabolic comorbidities from the study described in Example 1.

[0384] Introduction

[0385] MDD patients with metabolic comorbidities face additional adverse events associated with antidepressants (e.g., weight gain, metabolic abnormalities) and often respond poorly. This example shows results from a post-hoc analysis of the clinical trial of Example 1 in patients with MDD and metabolic comorbidities.

[0386] method

[0387] In the clinical trial of Example 1, MDD patients aged 18-75 years with a HAMD-17 score of 20 or greater and a MADRS total score of 28 or greater were enrolled in one of two cohorts: a 30 mg cohort and a 50 mg cohort. HAMD-17 responders (≥50% reduction from baseline) at day 15 continued in the study and were evaluated for retreatment eligibility.

[0388] Patients with metabolic comorbidities were identified in the patient's medical history by the following code terms: obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, type 1 diabetes, impaired glucose tolerance, hypertriglyceridemia, dyslipidemia, metabolic syndrome, and / or diabetic dyslipidemia.

[0389] result

[0390] The trial of Example 1 enrolled 924 patients (30 mg cohort n=725; 50 mg cohort n=199). Of these, 253 / 924 (27.4%) patients had metabolic comorbidities (30 mg cohort 197 / 725; 27.2%; 50 mg cohort 56 / 199; 28.1%). Baseline demographics vs. total population: mean (SD) age 52.2 (12.4) vs. 45.0 (14.1) years; Hispanic 30.4% vs. 23.8%; antidepressant use 54.2% vs. 41.8%; mean (SD) kg / m 2 BMI 33.4 (6.7) vs. 30.0 (6.54).

[0391] Mean (SD) CFB in HAMD-17 (metabolic comorbidity subgroup vs. overall population) at day 15 of the first treatment cycle was -14.8 (7.10) vs. -15.4 (6.9); HAMD-17 response rate was 67.3% vs. 75.0%; HAMD-17 remission rate was 37.1% vs. 40.8%.

[0392] Of the 161 / 253 patients in the metabolic comorbidity subpopulation who responded to and completed the first treatment cycle, 90 (55.9%) did not require further treatment courses during the study period (vs. 43.7% overall); mean (range) number of total treatment courses was 1.9 (1-5) vs. 1.8 (1-5) overall.

[0393] The number of patients in the metabolic comorbidity subpopulation with ≥1 TEAE over the study period was 167 / 253 (66.0%); most were mild / moderate (148 / 167; 88.6%). Common (≥5%) TEAEs in this subpopulation vs. overall included headache (14.2% vs. 13.9%), somnolence (13.8% vs. 12.8%), dizziness (9.1% vs. 9.1%), diarrhea (6.7% vs. 6.3%), upper respiratory tract infection (5.9% vs. 6.3%), dry mouth (5.5% vs. 5.5%), and sedation (5.1% vs. 8.7%). TEAEs led to discontinuation of study drug in 8 / 253 (3.2%) patients; dose reduction in 19 / 253 (7.5%) patients; and withdrawal from study in 11 / 253 (4.3%) patients.

[0394] conclusion

[0395] Compound (1) was generally well tolerated in patients with MDD and metabolic comorbidities and demonstrated similar safety and efficacy outcomes as patients in the overall study population. These results support further development of compound (1) given its potential for treating MDD patients, including those with metabolic comorbidities, on an as-needed basis.

[0396] Example 5.2 - Postmenopausal Women with MDD

[0397] Example 5.2 provides data for patients from the study described in Example 1 who were classified as postmenopausal women with MDD.

[0398] Introduction

[0399] Hormonal changes during early menopause can often affect the metabolism of antidepressants (ADT). Postmenopausal / elderly women may not respond well to ADT. This example shows a post-hoc analysis of the study described in Example 1 in postmenopausal women with MDD.

[0400] method

[0401] The study described in Example 1 enrolled MDD patients aged 18-75 years with a HAMD-17 score of 20 or greater and a MADRS total score of 28 or greater into one of two cohorts: a 30-mg cohort and a 50-mg cohort. HAMD-17 responders (≥50% reduction from baseline) at day 15 continued in the study and were assessed for repeat treatment eligibility. Postmenopausal women aged 45 years or older were identified based on baseline follicle-stimulating hormone >40 (central laboratory data) and medical history code name including "menopausal."

[0402] result

[0403] The study described in Example 1 enrolled 924 patients (30 mg cohort n=725; 50 mg cohort n=199); 152 / 924 (16.5%) postmenopausal women received either Compound (1) 30 mg (110 / 725; 15.2%) or Compound (1) 50 mg (42 / 199; 21.1%) during the first 14-day treatment course. Other than age and sex, the baseline demographics of patients in this subpopulation were generally consistent with those of the overall study population: mean (SD) age, 58.7 (6.72) years vs. 45.0 (14.1) years; mean (SD) HAMD-17, 25.7 (3.92) vs. 25.3 (3.9); antidepressant use, 52.6% vs. 41.7%.

[0404] The mean (SD) CFB of HAMD-17 at day 15 (last day of the first treatment period) in postmenopausal patients was -16.0 (7.00) vs. -15.4 (6.9) (in the entire study population). The HAMD-17 response rate at day 15 was 75.7% vs. 75.0% (in the entire study population). The HAMD-17 remission rate at day 15 was 39.6% vs. 40.8% (in the entire study population).

[0405] Of the 106 / 152 postmenopausal patients who responded to and completed treatment cycle 1, 45 (42.5%) did not require further courses during the study; the mean (range) number of total treatment courses was 2.2 (1-5).

[0406] The number of postmenopausal patients with at least one TEAE over the study period was 102 / 152 (67.1%). The majority experienced mild or moderate TEAEs (90 / 102; 88.2%). Common (≥5%) TEAEs in postmenopausal patients (vs. overall population) included headache (13.2% vs. 13.9%), somnolence (12.5% ​​vs. 12.8%), dizziness (11.8% vs. 9.1%), diarrhea (7.9% vs. 6.3%), upper respiratory tract infection (7.9% vs. 6.3%), dry mouth (7.2% vs. 5.5%), sedation (6.6% vs. 8.7%), and insomnia (6.6% vs. 5.4%). TEAEs led to discontinuation of study drug in 8 / 152 (5.3%) patients; dose reduction in 16 / 152 (10.5%) patients; and withdrawal from study in 9 / 152 (5.9%) patients.

[0407] conclusion

[0408] Compound (1) was generally well tolerated in postmenopausal women with safety and efficacy results similar to those in the overall study population. These results support further development of compound (1) because of its potential for the on-demand treatment of MDD patients, including difficult-to-treat postmenopausal women.

[0409] Equivalence and Scope In the claims, articles (e.g., "a," "an," and "the") can mean one or more, unless indicated to the contrary or otherwise clear from the context. Unless indicated to the contrary or otherwise clear from the context, a claim or description including "or" between one or more members of a group is deemed to satisfy that one, more than one, or all group members are present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one or all group members are present in, used in, or otherwise relevant to a given product or process.

[0410] Moreover, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element may be removed from the group. In general, when the invention or an aspect of the invention is referred to as comprising certain elements and / or features, it should be understood that certain embodiments of the invention or an aspect of the invention consist of or consist essentially of such elements and / or features. For purposes of simplicity, those embodiments have not been expressly set forth herein in these exact words. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow for the inclusion of additional elements or steps. Where ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or subrange within the range set forth in various embodiments of the invention to the tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0411] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any incorporated reference and this specification, this specification shall control. Furthermore, any particular embodiment of the present invention that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Since such embodiments are deemed known to those skilled in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0412] Other embodiments Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but is as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description may be made without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. 1. A composition for use in a method for treating major depressive disorder (MDD) in a subject in need thereof, the composition comprising compound (1): 【Chemical Formula 39】 or a pharma- ceutically acceptable salt of compound (1), The method comprises: (i) administering to the subject an initial treatment course comprising administering a therapeutically effective amount of compound (1) or a pharma- ceutically acceptable salt of compound (1); and (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each subsequent course of treatment comprising administering a therapeutically effective amount of compound (1) or said pharma- ceutical acceptable salt of compound (1) in response to a recurrence of depressive symptoms. Including, wherein said 0, 1, or 2 subsequent treatment courses are administered over a period of 12 months from the start of said initial treatment course.

2. 1. A composition for use in a method for treating major depressive disorder (MDD) in a subject in need thereof, the composition comprising compound (1): 【Chemistry 40】 or a pharma- ceutically acceptable salt of compound (1), The method comprises: (i) administering to the subject an initial treatment course comprising administering a therapeutically effective amount of compound (1) or a pharma- ceutically acceptable salt of compound (1); and (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each subsequent course of treatment comprising administering a therapeutically effective amount of compound (1) or said pharma- ceutical acceptable salt of compound (1) in response to a recurrence of depressive symptoms. Including, wherein the 0, 1, or 2 subsequent treatment courses are administered over a period of 12 months from the start of the initial treatment course; The composition, wherein the subject is treatment naive. (A) there is an interval of at least about 4 weeks, at least about 6 weeks, or at least about 8 weeks between the end of the initial treatment course and the beginning of the subsequent treatment course; or (B) there is an interval of about 4 weeks, about 6 weeks, or about 8 weeks between the end of the initial treatment course and the start of the subsequent treatment course; The composition according to claim 1 or claim 2. (A) the duration of the initial treatment course is about 2 weeks or about 14 days; and / or (B) the duration of each subsequent treatment course is about 2 weeks or about 14 days; The composition according to any one of claims 1 to 3.

5. (A) Compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered once a day for about 14 days during the initial treatment course; and / or (B) Compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered once a day for about 14 days in each subsequent course of treatment; The composition according to any one of claims 1 to 4.

6. The composition according to any one of claims 1 to 5, wherein compound (1) is administered in a dose of about 20 mg to about 55 mg, or the pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 20 mg to about 55 mg of the free base compound.

7. Compound (1) is (A) an XRPD pattern that includes 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); (B) 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); (C) 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); or (D) XRPD patterns 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). The composition of any one of claims 1 to 6, in a crystalline form having the formula:

8. 1. A composition for use in a method for treating major depressive disorder (MDD) in a subject in need thereof, the composition comprising compound (1): 【Chemistry 43】 or a pharma- ceutically acceptable salt of compound (1), The method comprises: (i) administering to the subject an initial treatment course comprising administering to the subject from about 30 mg to about 50 mg of compound (1) or a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 30 mg to about 50 mg of the free base compound; and (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each of which comprises administering to the subject from about 30 mg to about 50 mg of Compound (1) or a dose equivalent to about 30 mg to about 50 mg of the free base compound, in response to a recurrence of depressive symptoms. Including, wherein said 0, 1, or 2 subsequent treatment courses are administered over a period of 12 months from the start of said initial treatment course.

9. 1. A composition for use in a method for treating major depressive disorder (MDD) in a subject in need thereof, the composition comprising compound (1): 【Chemistry 45】 or a pharma- ceutically acceptable salt of compound (1), The method comprises: (i) administering to the subject an initial treatment course comprising administering to the subject, once daily for about 14 days, about 30 mg to about 50 mg of compound (1), or a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 30 mg to about 50 mg of the free base compound; and (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each subsequent course comprising administering to the subject once daily for about 14 days about 30 mg to about 50 mg of Compound (1), or a dose equivalent to about 30 mg to about 50 mg of the free base compound, in response to a recurrence of depressive symptoms. Including, wherein the 0, 1, or 2 subsequent treatment courses are administered over a period of 12 months from the start of the initial treatment course; Optionally, there is an interval of at least about six weeks between the end of said initial treatment course and the beginning of said subsequent treatment course; or Optionally, the subject has been taking an additional antidepressant medication stably for at least 60 days. composition.

10. 1. A composition for use in a method for treating major depressive disorder (MDD) in a subject in need thereof, the composition comprising compound (1): 【Chemistry 51】 or a pharma- ceutically acceptable salt of compound (1), The method comprises: (i) administering to the subject an initial treatment course comprising administering to the subject from about 45 mg to about 55 mg of compound (1) or a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 45 mg to about 55 mg of the free base compound; and (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each subsequent course comprising administering to the subject from about 45 mg to about 55 mg of Compound (1), or a dose equivalent to about 45 mg to about 55 mg of the free base compound, in response to a recurrence of depressive symptoms. Including, wherein said 0, 1, or 2 subsequent treatment courses are administered over a period of 12 months from the start of said initial treatment course.

11. 1. A composition for use in a method for treating major depressive disorder (MDD) in a subject in need thereof, the composition comprising compound (1): 【Chemistry 53】 or a pharma- ceutically acceptable salt of compound (1), The method comprises: (i) administering to the subject an initial treatment course comprising administering to the subject, once daily for about 14 days, about 45 mg to about 55 mg of compound (1), or a pharma- ceutically acceptable salt of compound (1) in a dose equivalent to about 45 mg to about 55 mg of the free base compound; and (ii) administering to the subject 0, 1, or 2 subsequent courses of treatment, each subsequent course comprising administering to the subject, in response to a recurrence of depressive symptoms, from about 45 mg to about 55 mg of Compound (1), or a dose equivalent to about 45 mg to about 55 mg of a pharma- ceutically acceptable salt of Compound (1), once daily for about 14 days. Including, wherein the 0, 1, or 2 subsequent treatment courses are administered over a period of 12 months from the start of the initial treatment course; Optionally, there is an interval of at least about 6 weeks between the end of the initial treatment course and the beginning of the subsequent treatment course. composition.

12. Composition according to any one of claims 1 to 11, characterized in that 0 or 1 subsequent treatment course is carried out, or characterized in that 1 subsequent treatment course is carried out.

13. (A) Compound (1) is administered in a dose of about 50 mg, or the pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 50 mg of the free base compound, or (B) Compound (1) is administered in a dose of about 40 mg, or the pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 40 mg of the free base compound; The composition according to any one of claims 1 to 12.

14. The composition according to any one of claims 1 to 13, characterized in that compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, bucally, sublingually, rectally, topically, as an inhalation, intranasally, or transdermally.

15. The composition of claim 14, wherein compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered orally.

16. The composition according to any one of claims 1 to 15, wherein compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered with food.

17. The composition according to any one of claims 1 to 16, wherein compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered once a day at night.

18. The composition of any one of claims 1 or 3-17, wherein the subject is treatment naive.

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