Neuroactive steroids for use in the treatment of major depressive disorder and postpartum depression in breastfeeding women

Abstract

The present disclosure relates to compound (1), or a pharma- ceutically acceptable salt thereof, for use in a method of treating postpartum depression (PPD) in a human female subject during the postpartum period, wherein the subject is breastfeeding a child during the treatment period. TIFF2024515830000052.tif2559 The disclosure also relates to compound (1), or a pharma- ceutically acceptable salt thereof, for use in a method of treating major depressive disorder (MDD) in a human female subject, wherein the subject is breastfeeding a child during the treatment period.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 181,807, filed April 29, 2021. The entire contents of the above-mentioned application are hereby incorporated by reference in their entirety.

[0002] FIELD OF THEINVENTION The present disclosure is directed to a method of treating postpartum depression (PPD) in a human female subject during the postpartum period, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof during the treatment period, wherein the subject is breastfeeding a child during the treatment period. The present disclosure is also directed to a method of treating major depressive disorder (MDD) in a human female subject, comprising administering to the subject a therapeutically effective amount of Compound (1) or a pharmaceutically acceptable salt thereof during the treatment period, wherein the subject is breastfeeding a child during the treatment period. [Background technology]

[0003] background Progesterone and its metabolites have been demonstrated to have profound effects on brain excitability (Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130: 19-24 (1985); Pfaff, D. W and McEwen, BS, Science 219:808-814 (1983); Gyermek et al, J Med Chem. 11: 117 (1968); Lambert, J. et al., Trends Pharmacol. Sci. 8:224-227 (1987)). The levels of progesterone and its metabolites vary with the phase of the menstrual cycle. It is well established that the levels of progesterone and its metabolites decline prior to the onset of menstruation. It is also well established that certain physical symptoms prior to the onset of menstruation recur monthly. These symptoms have been associated with premenstrual syndrome (PMS) and include stress, anxiety and migraines (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). Subjects with PMS experience monthly recurring symptoms that are present before menstruation and absent after menstruation.

[0004] A syndrome associated with low progesterone levels is postpartum depression (PND), or postpartum depression (PPD). Immediately after delivery, progesterone levels fall dramatically, resulting in the development of PND. Symptoms of PND range from mild depression to psychiatric disorders requiring hospitalization. PND has also been associated with severe anxiety and irritability. PND-related depression is not amenable to treatment with classical antidepressants, and women experiencing PND show increased incidence of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). There is growing evidence supporting the use of neuroactive steroids, such as those described herein, such as Compound (1), in the treatment and prevention of postpartum depression. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130: 19-24 (1985) [Non-Patent Document 2] Pfaff, D. W and McEwen, B. S., Science 219:808-814 (1983) [Non-Patent Document 3] Gyermek et al, J Med Chem. 11: 117 (1968) [Non-Patent Document 4] Lambert, J. et al., Trends Pharmacol. Sci. 8:224-227 (1987) [Non-Patent Document 5] Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984) Summary of the Invention [Means for solving the problem]

[0006] Summary of the Invention In one aspect, the disclosure provides a method of treating postpartum depression (PPD) in a human female subject during the postpartum period of the subject, comprising administering to the subject a therapeutically effective amount of Compound (1): [ka] administering wherein said subject is breastfeeding a child during said treatment period.

[0007] In one aspect, the disclosure provides a method of treating postpartum depression (PPD) in a human female subject during the postpartum period of the subject, comprising administering to the subject during the treatment period a therapeutically effective amount of a pharma- ceutically acceptable salt of Compound (1): [ka] administering wherein said subject is breastfeeding a child during said treatment period.

[0008] In one aspect, the disclosure provides a method of treating postpartum depression (PPD) associated with elevated anxiety in a human female subject during the postpartum period of the subject, comprising administering to the subject a therapeutically effective amount of Compound (1): [ka] administering wherein said subject is breastfeeding a child during said treatment period.

[0009] In one aspect, the disclosure provides a method of treating postpartum depression (PPD) associated with elevated anxiety in a human female subject during the postpartum period of the subject, comprising administering to the subject during the treatment period a therapeutically effective amount of a pharma- ceutically acceptable salt of Compound (1): [ka] administering wherein said subject is breastfeeding a child during said treatment period.

[0010] In some embodiments, the subject breastfeeds the child at least three times per day.

[0011] In some embodiments, the treatment period is about 2 weeks or about 14 days.

[0012] In some embodiments, compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered once a day for about 14 days, i.e., about two weeks. 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 50 mg. In some embodiments, compound (1) is administered at a dose of about 40 mg. In some embodiments, compound (1) is administered at a dose of about 30 mg.

[0013] In some embodiments, 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. 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. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered in a dose equivalent to about 30 mg of the free base compound.

[0014] In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally. In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered orally. In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered with food. In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered once a day in the evening.

[0015] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.7 and 10.1 degrees 2θ (inclusive), between 11.6 and 12.0 degrees 2θ (inclusive), between 13.2 and 13.6 degrees 2θ (inclusive), between 14.2 and 14.6 degrees 2θ (inclusive), between 14.6 and 15.0 degrees 2θ (inclusive), between 16.8 and 17.2 degrees 2θ (inclusive), between 20.5 and 20.9 degrees 2θ (inclusive), between 21.3 and 21.7 degrees 2θ (inclusive), between 21.4 and 21.8 degrees 2θ (inclusive), and between 22.4 and 22.8 degrees 2θ (inclusive).

[0016] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ (inclusive), between 10.6 and 11.0 degrees 2θ (inclusive), between 13.0 and 13.4 degrees 2θ (inclusive), between 14.7 and 15.1 degrees 2θ (inclusive), between 15.8 and 16.2 degrees 2θ (inclusive), between 18.1 and 18.5 degrees 2θ (inclusive), between 18.7 and 19.1 degrees 2θ (inclusive), between 20.9 and 21.3 degrees 2θ (inclusive), between 21.4 and 21.8 degrees 2θ (inclusive), and between 23.3 and 23.7 degrees 2θ (inclusive).

[0017] 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).

[0018] 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).

[0019] In some embodiments, the subject is treatment naive.

[0020] In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days or at least 60 days prior to the start of the treatment period.

[0021] In some embodiments, the subject's breast milk is monitored to determine the relative infant dose of Compound (1) or the pharma- ceutically acceptable salt of Compound (1) in the breast milk, and the daily dose of Compound (1) is adjusted to provide less than the maximum relative infant dose. In some embodiments, the maximum relative infant dose is at most about 0.5% of the daily dose administered to the subject. In some embodiments, the maximum relative infant dose is at most about 0.4% of the daily dose administered to the subject. In some embodiments, the maximum relative infant dose is at most about 0.357% of the daily dose administered to the subject.

[0022] In some embodiments, the child is monitored for abnormal behavior, hi some embodiments, the abnormal behavior is selected from the group consisting of agitation, irritability, lethargy, excessive sleepiness, poor appetite and poor weight gain.

[0023] In some embodiments, if the relative infant dose exceeds the maximum relative infant dose or if the child exhibits abnormal behavior, the daily dose administered to the subject is reduced by 10 mg.

[0024] Another aspect of the disclosure is a method of treating major depressive disorder (MDD) in a human female subject, comprising administering to the subject a therapeutically effective amount of Compound (1): [ka] administering wherein said subject is breastfeeding a child during said treatment period.

[0025] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a human female subject, comprising administering to the subject a therapeutically effective amount of a pharma- ceutically acceptable salt of Compound (1): [ka] administering wherein said subject is breastfeeding a child during said treatment period.

[0026] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a human female subject, comprising administering to the subject a therapeutically effective amount of Compound (1): [ka] administering wherein said subject is breastfeeding a child during said treatment period.

[0027] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) with elevated anxiety in a human female subject, comprising administering to the subject a therapeutically effective amount of a pharma- ceutically acceptable salt of Compound (1): [ka] administering wherein said subject is breastfeeding a child during said treatment period.

[0028] In some embodiments, the subject breastfeeds the child at least three times per day.

[0029] In some embodiments, the treatment period is about 2 weeks or about 14 days.

[0030] In some embodiments, compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered once a day for about 14 days, i.e., about two weeks. 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 50 mg. In some embodiments, compound (1) is administered at a dose of about 40 mg. In some embodiments, compound (1) is administered at a dose of about 30 mg.

[0031] In some embodiments, 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. 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. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered in a dose equivalent to about 30 mg of the free base compound.

[0032] In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally. In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered orally. In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered with food. In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered once a day in the evening.

[0033] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.7 and 10.1 degrees 2θ (inclusive), between 11.6 and 12.0 degrees 2θ (inclusive), between 13.2 and 13.6 degrees 2θ (inclusive), between 14.2 and 14.6 degrees 2θ (inclusive), between 14.6 and 15.0 degrees 2θ (inclusive), between 16.8 and 17.2 degrees 2θ (inclusive), between 20.5 and 20.9 degrees 2θ (inclusive), between 21.3 and 21.7 degrees 2θ (inclusive), between 21.4 and 21.8 degrees 2θ (inclusive), and between 22.4 and 22.8 degrees 2θ (inclusive).

[0034] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ (inclusive), between 10.6 and 11.0 degrees 2θ (inclusive), between 13.0 and 13.4 degrees 2θ (inclusive), between 14.7 and 15.1 degrees 2θ (inclusive), between 15.8 and 16.2 degrees 2θ (inclusive), between 18.1 and 18.5 degrees 2θ (inclusive), between 18.7 and 19.1 degrees 2θ (inclusive), between 20.9 and 21.3 degrees 2θ (inclusive), between 21.4 and 21.8 degrees 2θ (inclusive), and between 23.3 and 23.7 degrees 2θ (inclusive).

[0035] 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).

[0036] 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).

[0037] In some embodiments, the subject is treatment naive.

[0038] In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days or at least 60 days prior to the start of the treatment period.

[0039] In some embodiments, the subject's breast milk is monitored to determine the relative infant dose of Compound (1) or the pharma- ceutically acceptable salt of Compound (1) in the breast milk, and the daily dose of Compound (1) is adjusted to provide less than the maximum relative infant dose. In some embodiments, the maximum relative infant dose is at most about 0.5% of the daily dose administered to the subject. In some embodiments, the maximum relative infant dose is at most about 0.4% of the daily dose administered to the subject. In some embodiments, the maximum relative infant dose is at most about 0.357% of the daily dose administered to the subject.

[0040] In some embodiments, the child is monitored for abnormal behavior, hi some embodiments, the abnormal behavior is selected from the group consisting of agitation, irritability, lethargy, excessive sleepiness, poor appetite and poor weight gain.

[0041] In some embodiments, if the relative infant dose exceeds the maximum relative infant dose or if the child exhibits abnormal behavior, the daily dose administered to the subject is reduced by 10 mg.

[0042] In some embodiments, the method further comprises administration of a second therapeutic agent.

[0043] In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is re-administered to the subject upon recurrence of depressive symptoms after completion of the initial treatment period. In some embodiments, an interval of at least 6 weeks is provided between the last dose of the initial treatment period and the first dose of the re-administration.

[0044] In one aspect, the present disclosure provides a method of treating postpartum depression (PPD) in a human female subject during the postpartum period of the subject, comprising: a) administering to the subject about 30 mg to about 50 mg of Compound (1) for the treatment period: [ka] once daily for about 14 days. said subject nursing a child during said treatment period; b) comparing the relative infant dose of Compound (1) in the subject's breast milk to a predetermined maximum relative infant dose; c) reducing the daily dose administered to the subject if the relative infant dose of compound (1) in the subject's breast milk exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior. The present invention provides a method comprising:

[0045] In one aspect, the present disclosure provides a method of treating postpartum depression (PPD) in a human female subject during the postpartum period of the subject, comprising: a) administering to the subject, for the treatment period, a dose equivalent to about 30 mg to about 50 mg of the free base compound of a pharma- ceutically acceptable salt of Compound (1): [ka] once daily for about 14 days, said subject nursing a child during said treatment period; b) comparing said relative infant dose of compound (1) in said subject's breast milk to a predetermined maximum relative infant dose; and c) reducing the daily dose administered to the subject if the relative infant dose of compound (1) in the subject's breast milk exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior. The present invention provides a method comprising:

[0046] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a human female subject, comprising: a) administering to the subject about 30 mg to about 50 mg of Compound (1) for the treatment period: [ka] once daily for about 14 days. said subject nursing a child during said treatment period; b) comparing the relative infant dose of compound (1) in the subject's breast milk to a predetermined maximum relative infant dose; and c) reducing the daily dose administered to the subject if the relative infant dose of compound (1) in the subject's breast milk exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior. The present invention provides a method comprising:

[0047] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a human female, comprising: a) administering to a subject, for the treatment period, a dose equivalent to about 30 mg to about 50 mg of the free base compound of a pharma- ceutically acceptable salt of Compound (1): [ka] once daily for about 14 days, said subject nursing a child during said treatment period; b) comparing the relative infant dose of compound (1) in the subject's breast milk to a predetermined maximum relative infant dose; and c) reducing the daily dose administered to the subject if the relative infant dose of compound (1) in the subject's breast milk exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior. The present invention provides a method comprising:

[0048] In one aspect, the present disclosure provides a method of treating postpartum depression (PPD) in a human female subject during the postpartum period of the subject, comprising: a) administering to the subject about 30 mg to about 50 mg of Compound (1) for the treatment period: [ka] once daily for about 14 days. said subject nursing a child during said treatment period; b) collecting and testing a sample of said subject's breast milk to determine the relative infant dose of Compound (1) in said breast milk; c) comparing the relative infant dose determined in step b) with a predetermined maximum relative infant dose; d) monitoring the child for abnormal behavior; e) reducing the daily dose administered to the subject if the relative infant dose determined in step b) exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior; and f) repeating steps a) through e) daily for the duration of said treatment period. The present invention provides a method comprising:

[0049] In one aspect, the present disclosure provides a method of treating postpartum depression (PPD) in a human female subject during the postpartum period of the subject, comprising: a) administering to the subject, for the treatment period, a dose equivalent to about 30 mg to about 50 mg of the free base compound of a pharma- ceutically acceptable salt of Compound (1): [ka] once daily for about 14 days, said subject nursing a child during said treatment period; b) collecting and testing a sample of said subject's breast milk to determine the relative infant dose of said pharmacologic acceptable salt of Compound (1) in said breast milk; c) comparing the relative infant dose determined in step b) with a predetermined maximum relative infant dose; d) monitoring the child for abnormal behavior; e) reducing the daily dose administered to the subject if the relative infant dose determined in step b) exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior; and f) repeating steps a) through e) daily for the duration of said treatment period. The present invention provides a method comprising:

[0050] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a human female subject, comprising: a) administering to the subject about 30 mg to about 50 mg of Compound (1) for the treatment period: [ka] once daily for about 14 days. said subject nursing a child during said treatment period; b) collecting and testing a sample of said subject's breast milk to determine the relative infant dose of Compound (1) in said breast milk; c) comparing the relative infant dose determined in step b) with a predetermined maximum relative infant dose; d) monitoring the child for abnormal behavior; e) reducing the daily dose administered to the subject if the relative infant dose determined in step b) exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior; and f) repeating steps a) through e) daily for the duration of said treatment period. The present invention provides a method comprising:

[0051] In one aspect, the disclosure provides a method of treating major depressive disorder (MDD) in a human female subject, comprising: a) administering to a subject, for the treatment period, a dose equivalent to about 30 mg to about 50 mg of the free base compound of a pharma- ceutically acceptable salt of Compound (1): [ka] once daily for about 14 days, said subject nursing a child during said treatment period; b) collecting and testing a sample of said subject's breast milk to determine the relative infant dose of said pharmacologic acceptable salt of Compound (1) in said breast milk; c) comparing the relative infant dose determined in step b) with a predetermined maximum relative infant dose; d) monitoring the child for abnormal behavior; e) reducing the daily dose administered to the subject if the relative infant dose determined in step b) exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior; and f) repeating steps a) through e) daily for the duration of said treatment period. The present invention provides a method comprising:

[0052] In some embodiments, the PPD is PPD with elevated anxiety.In some embodiments, the MDD is MDD with elevated anxiety.

[0053] In some embodiments, 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. In some embodiments, 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. In some embodiments, compound (1) is administered in a dose of about 30 mg, or the pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 30 mg of the free base compound.

[0054] In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally. In some embodiments, Compound (1) or the pharma-ceutically acceptable salt of Compound (1) is administered orally.

[0055] In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered with food.

[0056] In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is administered once daily in the evening.

[0057] In some embodiments, the subject is treatment naive.

[0058] In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days or at least 60 days prior to the start of the treatment period.

[0059] In some embodiments, the method further comprises administration of a second therapeutic agent.

[0060] In some embodiments, Compound (1) or the pharma- ceutically acceptable salt of Compound (1) is re-administered to the subject upon recurrence of depressive symptoms after completion of an initial treatment period, with at least 6 weeks separating the last dose of the initial treatment period from the first dose of the re-administration.

[0061] In some embodiments, the maximum relative infant dose (RID) is up to about 0.5% of the daily dose administered to the subject. In some embodiments, the maximum relative infant dose (RID) is up to about 0.4% of the daily dose administered to the subject. In some embodiments, the maximum relative infant dose (RID) is up to about 0.357% of the daily dose administered to the subject.

[0062] In some embodiments, said abnormal behavior is selected from the group consisting of agitation, irritability, lethargy, excessive sleepiness, loss of appetite and poor weight gain. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0063] Detailed Description I. Definition

[0064] As used herein, “compound (1)” refers to a compound having the formula (or structure): [ka] It refers to a compound having the formula:

[0065] Compound (1) is also known as zuranolone, i.e., 3α-hydroxy-3β-methyl-21-(4-cyanopyrazol-1-yl)-5β-19-norpregnan-20-one, and by its IUPAC name: 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (CAS Registry Number 1632051-40-1). Methods for chemically synthesizing compound (1) are described in U.S. Pat. No. 9,512,165 and PCT Publication No. WO2014 / 169833, the entire contents of which are incorporated herein by reference in their entirety. Some crystalline forms of Compound (1) and methods for preparing said forms are described in U.S. Patent No. 11,236,121; U.S. Patent Application Publication No. US2019 / 0177359; and PCT Application Publication No. WO2018 / 039378, the entire contents of which are incorporated herein by reference in their entirety. Pharmaceutical compositions of Compound (1) and methods for preparing said compositions are described in PCT Application Publication No. WO2022 / 020363A9 and U.S. Application No. 17 / 579,541, the entire contents of which are incorporated herein by reference in their entirety.

[0066] Compound (1) is a neuroactive steroid that has been shown to be a positive allosteric modulator of GABAA receptors, targeting synaptic and extrasynaptic GABAA receptors.As a positive allosteric modulator of GABAA receptors, compound (1) acts as a therapeutic agent for treating CNS-related disorders, such as depression, postpartum depression and major depressive disorder, as well as treating neurological conditions, such as essential tremor, epilepsy and Parkinson's disease.

[0067] As used herein, "crystalline" refers to a solid phase of a given chemical entity that has a well-defined three-dimensional structural order. The atoms, ions and / or molecules are arranged in a regular, periodic manner in a repeating three-dimensional lattice. In various embodiments, a crystalline material may include one or more discreet crystalline forms.

[0068] 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.

[0069] The term "substantially crystalline" refers to a form that may be crystalline to at least a certain weight percent. The certain weight percentage may include 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%. In some embodiments, the certain weight percentage of crystallinity is at least 90%. In some embodiments, the certain weight percentage of crystallinity is at least 95%. In some embodiments, Compound (1) may be a substantially crystalline sample of any of the crystalline forms described herein (e.g., crystalline forms A and C) and / or PCT Publication No. WO2018 / 039378, the entire contents of which are incorporated herein by reference in their entirety.

[0070] The term "substantially pure" refers to a composition of a particular crystalline form (e.g., a crystalline form of Compound (1)) that may be free of impurities and / or other solid forms at least a particular weight percentage. The particular weight percentage may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%. In some embodiments, Compound (1) may be a substantially pure sample of any of the crystalline forms 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.

[0071] As used herein, "XRPD" refers to X-ray powder diffraction. An XRPD pattern is an xy graph with 2Q (diffraction angle) plotted on the x-axis and intensity plotted on the y-axis. There are diffraction peaks that can be used to characterize crystalline materials. Diffraction peaks are usually represented and referenced by their position on the x-axis, rather than their intensity on the y-axis, because diffraction peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255- 257 (2003)). Thus, intensity is not usually used by those skilled in the art to characterize crystalline materials. As with any data measurement, XRPD data can have variability. In addition to variability in diffraction peak intensity, there can also be variability in the position of the diffraction peaks on the x-axis. However, this variability can usually be taken into account when reporting the position of the diffraction peaks for characterization purposes. Such variability in the position of the diffraction peaks along the x-axis can derive from several sources. One such source may be sample preparation. Samples of the same crystalline material prepared under different conditions may produce slightly different diffractograms. Factors such as particle size, moisture content, solvent content, temperature and orientation may all affect how a sample diffracts X-rays. Another source of variability is due to instrument parameters. Different X-ray powder diffractometers may operate using different parameters, resulting in slightly different diffraction patterns from the same crystalline material. Similarly, different software packages process XRPD data differently, which may also result in variability. These and other sources of variability are known to those skilled in the art. Due to such sources of variability, the value of each X-ray diffraction peak may be preceded by the term "about" or followed by an appropriate range (e.g., ±0.1°, ±0.2°, ±0.3°, ±0.4°, ±0.5°, etc.) that defines the experimental variability.

[0072] The term "characteristic peaks," when describing peaks in an XRPD pattern of a crystalline form of a given chemical entity (e.g., a crystalline form of Compound (1)), refers to a particular collection of diffraction peaks whose values, taken as a whole, span a range of 2θ values ​​(e.g., from 0° to 40°) that is characteristic of that particular crystalline form.

[0073] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government, or a corresponding agency in a country other than the United States, for use in animals, or more particularly in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias.

[0074] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharma- ceutically acceptable and that possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and inorganic or organic base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methyl ... or (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion, or is coordinated to an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, salts of non-toxic organic or inorganic acids, such as sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, if the compound contains a basic functional group, salts of hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmacologically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.

[0075] Chemical elements are identified according to the Periodic Table of the Elements (CAS version) on the inside cover of Handbook of Chemistry and Physics, 75th Edition, and specific functional groups are defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0076] When the use of the term "about" is present before a quantitative value, the present teachings also include the particular quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless specifically stated or implied.

[0077] As used herein, a "child" is a human under the age of 18. In some embodiments, the child is a human aged 0-18 years, or 0-5 years, or 0-4 years, or 0-3 years, or 0-2 years, or 0-18 months, or 0-12 months, or 0-6 months. In some embodiments, the child is a human aged 0-18 months. In some embodiments, the child is a human aged 0-12 months. In some embodiments, the child is a human aged 0-6 months.

[0078] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0079] As used herein, the term "dose equivalent" refers to a biologically equivalent dose.For example, in the case of a 50 mg dose of compound (1), the dose equivalent of a pharma- ceutically acceptable salt of compound (1) is the amount of pharma-ceutically acceptable salt (by weight) required to provide a biologically equivalent dose to a 50 mg dose of the free base of compound (1).

[0080] As used herein, the "effective amount" of a compound (or its pharmaceutically acceptable salt) refers to an amount sufficient to elicit a desired biological response, for example, to treat a CNS-related disorder, for example, depression, for example, postpartum depression (PPD), major depressive disorder (MDD), postpartum depression (PPD) with elevated anxiety or major depressive disorder (MDD) with elevated anxiety.As recognized by those skilled in the art, the effective amount of the compound of the present invention (or its pharmaceutically acceptable salt) can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health and condition of the subject.The effective amount includes therapeutic and prophylactic treatments.

[0081] As used herein, a "transient dosing regimen" is a dosing regimen in which a compound or a composition comprising a compound is administered to a subject for a limited 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 moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder. In some embodiments, the compound is formulated as individual dosage units, each unit comprising Compound (1) and one or more suitable pharmaceutical excipients. In some embodiments, the transient dosing regimen has a duration of multiple weeks, e.g., about 8 weeks. In contrast to chronic administration as defined herein, transient dosing of a compound is administered for a limited 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, the transient dosing is administered once a day for multiple weeks, e.g., about 2 weeks to about 6 weeks. In one embodiment, the episodic dosing has a duration of 2 weeks. In some embodiments, more than one episodic dosing regimen, but no more than three episodic dosing regimens, for example, two or more episodic regimens, are administered to a subject over a 12 month period.

[0082] As used herein, the term "modulation" refers to the inhibition or activation of GABA A receptor function. A "modulator" (e.g., a compound that modulates GABA A receptor function or its pharma- ceutically acceptable salt) can be, for example, an agonist, partial agonist, antagonist or partial antagonist of GABA A receptor.

[0083] "MDD with elevated anxiety" or "MDD with anxiety distress" are used interchangeably and refer to a subject with MDD who exhibits elevated anxiety as a symptom of their depression. In some embodiments, MDD with elevated anxiety is characterized by a HAM-D anxiety / somatization subscale score of at least 7 at baseline (e.g., before administration of Compound (1) or a pharma- ceutically acceptable salt thereof). In some embodiments, MDD with elevated anxiety is characterized by a HAM-A total score of at least 17 at baseline (e.g., before administration of Compound (1) or a pharma- ceutically acceptable salt thereof). In some embodiments, MDD with elevated anxiety is characterized by a HAM-A total score of at least 18 at baseline. In some embodiments, MDD with elevated anxiety is characterized by a HAM-A total score of at least 20 at baseline. "PPD with elevated anxiety" or "PPD with anxiety distress" are used interchangeably and refer to a subject with PPD who exhibits elevated anxiety as a symptom of their depression. In some embodiments, PPD with elevated anxiety is characterized by a HAM-D anxiety / somatization subscale score of at least 7 at baseline (e.g., before administration of Compound (1) or a pharma- ceutically acceptable salt thereof). In some embodiments, PPD with elevated anxiety is characterized by a HAM-A total score of at least 17 at baseline (e.g., before administration of Compound (1) or a pharma- ceutically acceptable salt thereof). In some embodiments, PPD with elevated anxiety is characterized by a HAM-A total score of at least 18 at baseline. In some embodiments, PPD with elevated anxiety is characterized by a HAM-A total score of at least 20 at baseline.

[0084] In other embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items and the somatic items. In some embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety, somatic anxiety, GI somatic symptoms, and / or general somatic symptoms. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D anxiety / somatization subscale score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D Anxiety / Somatization subscale score based primarily on items assessing the anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the anxiety symptoms of depression.

[0085] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound (or a pharma- ceutically acceptable salt thereof) is an amount sufficient to realize a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound (or a pharma- ceutically acceptable salt thereof) refers to the amount of a therapeutic agent, alone or in combination with other therapies, that realizes a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0086] In an alternative embodiment, the present disclosure contemplates administration of compound (1), or a pharma- ceutically acceptable salt or pharma- ceutically acceptable composition thereof, as a prophylaxis before a subject begins to suffer from a particular disease, disorder, or condition. As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with a disease, disorder, or condition, or to prevent its recurrence. A prophylactically effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that achieves a prophylactic benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0087] As used herein, "solid dosage form" means a pharmaceutical dose(s) in solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalation formulations and chewables.

[0088] A "subject" can also be a human female (e.g., a female of any age group) who is pregnant, about to give birth, or has given birth. The terms "human," "patient," and "subject" are used interchangeably herein.

[0089] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is afflicted with a particular disease, disorder, or condition, which actions reduce the severity of the disease, disorder, or condition (or any symptoms thereof) or delay or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate prophylactic actions taken before a subject begins to suffer from a particular disease, disorder, or condition.

[0090] As used herein, "treatment-naive" refers to a subject who has not been previously treated with additional antidepressants within the scope of the current depressive episode. "Treatment-naive" also refers to a subject who has not taken any antidepressant within at least 30 days before the start of treatment (e.g., day 1) or within at least 60 days before the start of treatment. In some embodiments, a treatment-naive subject has not taken any antidepressant within at least 30 days before the start of treatment. In some embodiments, a treatment-naive subject has not taken any antidepressant within at least 60 days before the start of treatment.

[0091] As used herein, the term "unit dosage form" is defined to refer to the form in which Compound (1) is administered to a subject. In some embodiments, the unit dosage form can be, for example, a pill, capsule, or 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).

[0092] In some embodiments, the unit dosage form comprises about 30 mg of Compound (1) and is in the form of a capsule. In some embodiments, the unit dosage form comprises about 50 mg of Compound (1) and is in the form of a capsule. In some embodiments, the unit dosage form comprises about 40 mg of Compound (1) and is in the form of a capsule. In some embodiments, the unit dosage form comprises about 45 mg of Compound (1) and is in the form of a capsule. In some embodiments, the unit dosage form comprises about 20 mg of Compound (1) and is in the form of a capsule. In some embodiments, the unit dosage form comprises about 10 mg of Compound (1) and is in the form of a capsule. In some embodiments, the unit dosage form comprises about 15 mg of Compound (1) and is in the form of a capsule. In some embodiments, the unit dosage form comprises about 25 mg of Compound (1) and is in the form of a capsule. In some embodiments, one or more capsules comprising about 30 mg or 45 mg of Compound (1) are administered to the subject once a day. In some embodiments, the three capsules together contain 30 mg of Compound (1). In some embodiments, the three capsules together contain 45 mg of Compound (1).

[0093] In some embodiments, administering compound (1) improves cognitive function. In some embodiments, cognitive function refers to a collection of mental tasks and functions, including but not limited to memory (e.g., semantic, temporal, procedural, priming or working); orientation; language; problem solving; visual recognition, construction and integration; planning; organization; 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, temporal, procedural, priming or working); orientation; language; problem solving; visual recognition, construction and integration; planning; organization; selective attention; inhibitory control, and the ability to mentally manipulate information. Measures of cognitive function include, for example, assessment instruments designed to measure (a) general intelligence, (b) non-verbal intelligence, (c) achievement, (d) attention / executive function, (e) memory and learning, (f) visual motor and motor function, and (g) language.

[0094] 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" refers to the positive change in the subject's ability to carry out symbolic operations, for example, to perceive, to remember, to create mental images, to have clarity of thought, to be aware, to reason, to think or to judge.Positive change can be measured using any of the above-mentioned tests on two or more occasions, for example, the first occasion for measuring baseline cognitive function, and the second occasion for measuring cognitive function after a certain period of time (may be treated).

[0095] II. Method of Treatment

[0096] Postpartum depression (PPD)

[0097] In one aspect, the present disclosure is directed to a method for treating postpartum depression (PPD) in a human female subject during the postpartum period. In some embodiments, the PPD is PPD associated with elevated anxiety.

[0098] Postpartum depression (PPD), also called depression after childbirth, is a type of mood disorder that accompanies childbirth. Postpartum depression (PPD) is commonly known in the art.

[0099] Postnatal depression (PND), also called postpartum depression (PPD), refers to a type of clinical depression that women suffer from after giving birth.Symptoms can include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety and irritability.In one embodiment, PND is treatment-resistant depression.In one embodiment, PND is treatment-refractory depression.

[0100] In one embodiment, the subject with PND also experiences depression or symptoms of depression during pregnancy.This depression can be referred to as perinatal depression.In an embodiment, the subject experiencing perinatal depression is at increased risk of experiencing PND.

[0101] PPD has been identified as the most common psychopathological illness occurring during the postpartum period (O'Hara MW, Wisner KL. Best Pract Res Clin Obstet Gynaecol. 2014;28(1):3-12); PPD can occur during the third trimester or after birth. If untreated, PPD can have devastating consequences for the woman and her family. In some embodiments, PPD is characterized by significant maternal functional impairment due to sadness and depressed mood, loss of interest in daily activities, changes in eating and sleeping habits, fatigue, and reduced motivation, inability to concentrate, and feelings of worthlessness, shame, or guilt. Postpartum depression also carries an increased risk for suicide, which is the leading cause of maternal death after childbirth in developed countries.

[0102] Professional health organizations vary in their definitions of PPD occurrence. For example, the American Psychiatric Association characterizes PPD as having an onset during pregnancy or within 4 weeks of delivery (DSM-5). The American College of Obstetricians and Gynecologists characterizes PPD as having an onset during pregnancy or within 12 months after delivery (ACOG, updated December 2021). The World Health Organization characterizes PPD as having an onset within 12 months after delivery (International Classification of Diseases 10 thedition (ICD-10). Thus, in some embodiments, a diagnosis of PPD treated by the methods described herein can be characterized as defined by DSM-5. In some embodiments, a diagnosis of PPD treated by the methods described herein can be characterized as defined by ACOG. In some embodiments, a diagnosis of PPD treated by the methods described herein can be characterized as defined by ICD-10.

[0103] In some embodiments, the diagnosis of PPD to be treated by the methods described herein is based on the Diagnostic and Statistical Manual of Mental Disorders, 5 th It can be characterized as MDD with perinatal onset, as defined by the DSM-5 Edition (DSM-5), i.e., as described below.

[0104] Depressive disorder

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

[0106] Major depressive disorder represents the classic presentation in this group of disorders. It is characterized by discrete episodes of at least 2 weeks duration (although most episodes last much longer) with distinct changes in affect, cognition and autonomic nervous system function and remissions between episodes. Discrete episodes of major depressive disorder may be called "major depressive episodes" or "depressive episodes".

[0107] Major Depressive Disorder (MDD)

[0108] In some embodiments, MDD, also known as major depressive disorder or clinical depression, is a mood disorder that causes persistent feelings of sadness and loss of interest.

[0109] In some embodiments, MDD is defined and diagnosed according to DSM-5, for example, MDD is diagnosed according to diagnostic criterion A, as described below.

[0110] Diagnostic Criteria A. Five (or more) of the following symptoms appear during the same two-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1. Depressed mood for most of the day, almost every day, as indicated by either subjective report (e.g., feeling sad, empty, hopeless) or observation made by others (e.g., appearing tearful) (Note: in children and adolescents, irritable mood is possible). 2. Markedly diminished interest or pleasure in all or almost all activities for most of the day, almost every day (as indicated by either subjective description or observation). 3. Significant weight loss or gain when not on a diet (e.g., more than a 5% change in body weight in one month) or decreased or increased appetite on most days (Note: in children, consider that this may not be expected weight gain). 4. Having insomnia or excessive sleep almost every day. 5. Psychomotor agitation or retardation (observable by others, not just a subjective feeling of restlessness or slowness) almost every day. 6. Feeling fatigued or inactive almost every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) almost every day (not just remorse or guilt about being ill). 8. Poor ability to think or concentrate, or indecisiveness almost every day (either subjectively described or observed by others). 9. Recurrent thoughts of death (not just the fear of death), recurrent suicidal thoughts without a specific plan, or a specific plan to attempt or commit suicide.

[0111] Diagnostic criteria B through E described below are further explanations of MDD and may be considered explanations or diagnoses of MDD, but are not required.

[0112] Diagnostic Criterion B. Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0113] Criterion C. The episode cannot be attributed to the physiological effects of a substance or to another medical condition.

[0114] Criteria A-C may represent a major depressive episode.

[0115] Diagnostic Criterion D. The occurrence of a major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder or other specified and unspecified schizophrenia spectrum and other psychotic disorders.

[0116] Diagnostic Criterion E. Never had a manic or hypomanic episode.

[0117] In some embodiments, a major depressive episode (MDE) is a period characterized by the symptoms described above.

[0118] In some embodiments, MDD is a clinical pathway characterized by one or more major depressive episodes (MDEs) in a subject.

[0119] In some embodiments, MDD is diagnosed according to diagnostic criteria A through C, as described above. In some embodiments, MDD is diagnosed according to diagnostic criteria A through E, as described above.

[0120] Diagnostic Features

[0121] The diagnostic criteria symptoms of major depressive disorder, except for weight change and suicidal ideation, must be present almost every day to be considered present. In addition to being present almost every day, depressed mood must be present for a large portion of the day. Often, insomnia or fatigue is the presenting complaint, leading to underdiagnosis if the patient fails to investigate the accompanying depressive symptoms. Sadness may be initially denied, but may be elicited by interview or inferred from facial expression and demeanor. For individuals who focus on somatic complaints, the clinician should determine whether the distress resulting from the complaint is related to a specific depressive symptom. Fatigue and sleep disturbance are present in a high percentage of cases. Psychomotor disorders are less common but are indicators of greater overall severity, as are delusional or delusional feelings of guilt.

[0122] The essential feature of a major depressive episode is a period of at least 2 weeks during which there is either a depressed mood or a loss of interest or pleasure in almost all activities (criterion A above). In children and adolescents, the mood may be irritable rather than sad. The individual must also experience at least four additional symptoms drawn from a list including: changes in appetite or weight, sleep and psychomotor activity; decreased motivation; feelings of worthlessness or guilt; difficulty thinking, concentrating or making decisions; or recurrent thoughts of death or suicidal ideation or suicide plans or suicide attempts. To count as a major depressive episode, the symptoms must be new or have clearly worsened compared with the person's pre-episode state. Symptoms must persist for most of the day, almost every day, for at least 2 consecutive weeks. The episode must be accompanied by clinically significant distress or impairment in social, occupational or other important areas of functioning. For some individuals with mild episodes, functioning may appear normal but requires significantly increased effort.

[0123] Sleep disturbances may take the form of either difficulty sleeping or excessive sleeping (criterion A4). When insomnia is present, it usually takes the form of intermediate insomnia (e.g., difficulty getting back to sleep after waking up in the middle of the night) or end-stage insomnia (e.g., waking up too early and not being able to get back to sleep). Early-stage insomnia (e.g., difficulty falling asleep) may also occur. Individuals who exhibit hypersomnia (excessive sleep) may experience longer episodes of sleep at night or increased daytime sleep. Sometimes, the reason an individual seeks treatment is because of a sleep disorder.

[0124] In the case of perinatal onset (DSM-5 designator of depressive disorder)

[0125] This designation can be applied to a recent major depressive episode if the full diagnostic criteria are currently not met for a major depressive episode, or if the onset of mood symptoms occurred during pregnancy or within 4 weeks after delivery.

[0126] Mood episodes may have an occurrence either during pregnancy or after birth. Depending on the duration of postpartum follow-up, estimates vary, but 3% to 6% of women experience an occurrence of a major depressive episode during pregnancy or in the weeks or months after birth. Fifty percent of "postpartum" major depressive episodes actually begin before birth. These episodes are therefore collectively referred to as perinatal episodes. Women with perinatal major depressive episodes often have severe anxiety and even panic attacks. Prospective studies have demonstrated that mood and anxiety symptoms during pregnancy, as well as the "baby blues," increase the risk of a postpartum major depressive episode. Mood episodes occurring perinatally may manifest with or without psychiatric features. Infanticide is most often associated with a postpartum psychiatric episode characterized by command hallucinations to kill the infant or delusions that the infant is possessed, although psychiatric symptoms may also occur in severe postpartum mood episodes without such specific delusions or hallucinations.

[0127] In some embodiments, a diagnosis of PPD with elevated anxiety treated by the methods described herein is based on the criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders, 5 th It can be characterized as MDD with perinatal onset and specifiers of anxiety distress, as defined by the DSM-5 Edition (DSM-5), i.e., as described below.

[0128] Elevated anxiety / anxiety distress (DSM-5 indicator of depressive disorder)

[0129] The DSM-5 defines the "anxiety distress" specifier as the presence of at least two of the following symptoms during most days of a major depressive episode (MDD) or persistent depressive disorder (dysthymia): 1. Feeling excited or nervous. 2. Feeling unusually restless. 3. Worrying makes it hard to concentrate. 4. You are afraid that something terrible might happen. 5. I feel like I'm losing control.

[0130] Severity is defined as follows: Mild: 2 symptoms. Moderate: 3 symptoms. Moderate to severe: 4 or 5 symptoms. Severe: Four or five symptoms with motor agitation.

[0131] Anxiety distress has been documented as a prominent feature of both bipolar disorder and major depressive disorder in both primary care and specialty mental health settings. High levels of anxiety have been associated with a higher suicide risk, longer duration of illness, and a higher likelihood of not responding to treatment.

[0132] In some embodiments, the PPD is MDD with perinatal onset. In some embodiments, the PPD with elevated anxiety is MDD with perinatal onset and anxiety distress.

[0133] Accordingly, one aspect of the present disclosure is a method of treating postpartum depression (PPD) in a human female subject during the postpartum period of said subject, comprising administering to said subject a therapeutically effective amount of Compound (1): [ka] administering The method is directed to a subject, wherein said subject is breastfeeding a child during said treatment period.

[0134] Another embodiment of the present disclosure is a method of treating postpartum depression (PPD) in a human female subject during the postpartum period of the subject, comprising administering to the subject during the treatment period a therapeutically effective amount of a pharma- ceutically acceptable salt of Compound (1): [ka] administering The method is directed to a subject, wherein said subject is breastfeeding a child during said treatment period.

[0135] Another embodiment of the present disclosure is a method of treating postpartum depression (PPD) associated with elevated anxiety in a human female subject during the postpartum period of the subject, comprising administering to the subject a therapeutically effective amount of Compound (1): [ka] administering The method is directed to a subject, wherein said subject is breastfeeding a child during said treatment period.

[0136] Another embodiment of the present disclosure is a method of treating postpartum depression (PPD) associated with elevated anxiety in a human female subject during the postpartum period of the subject, comprising administering to the subject during the treatment period a therapeutically effective amount of a pharma- ceutically acceptable salt of Compound (1): [ka] administering The method is directed to a subject, wherein said subject is breastfeeding a child during said treatment period.

[0137] In some embodiments, the subject breastfeeds the infant at least once per day. In another embodiment, the subject breastfeeds the infant at least twice per day. In another embodiment, the subject breastfeeds the infant at least three times per day. In another embodiment, the subject breastfeeds the infant at least 4, 5, 6, 7, 8, 9, 10, 11 or 12 times per day.

[0138] In some embodiments, the treatment period is about 2 weeks or about 14 days. In some embodiments, the treatment period is about 2 weeks. In some embodiments, the treatment period is about 14 days.

[0139] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about 14 days or about two weeks. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about 14 days. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about two weeks.

[0140] 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. In some embodiments, Compound (1) is administered at a dose of about 30 mg.

[0141] 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 daily at a dose of about 50 mg. In some embodiments, compound (1) is administered once daily at a dose of about 40 mg. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg.

[0142] In some embodiments, compound (1) is administered once a day at a dose of about 20 mg to about 55 mg for about two weeks or about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg to about 50 mg for about two weeks or about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 45 mg to about 55 mg for about two weeks or about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 50 mg for less than two weeks. In some embodiments, compound (1) is administered once a day at a dose of about 50 mg for about two weeks. In some embodiments, compound (1) is administered once a day at a dose of about 50 mg for about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg for less than two weeks. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg for about 2 weeks. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg for about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg for less than 2 weeks. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg for about 2 weeks. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg for about 14 days.

[0143] In other embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 15 mg to about 75 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 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 a dose equivalent of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 40 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 30 mg of the free base compound.

[0144] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 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 daily at a dose equivalent of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 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 daily at a dose equivalent 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 daily at a dose equivalent of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 40 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 30 mg of the free base compound.

[0145] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 20 mg to about 55 mg of the free base compound for about two weeks or about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 30 mg to about 50 mg of the free base compound for about two weeks or about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 45 mg to about 55 mg of the free base compound for about two weeks or about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound for about two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 50 mg of the free base compound for about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for about two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 30 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 30 mg of the free base compound for about two weeks. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 30 mg of the free base compound once daily for about 14 days.

[0146] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally.

[0147] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered chronically.

[0148] 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.

[0149] 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 a fat-containing meal. Examples of fat-containing meals 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 a fat-containing meal in the evening (e.g., within 1 hour of a fat-containing dinner or with a fat-containing snack).

[0150] 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 sleep. 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 sleep. 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 sleep. 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 sleep.

[0151] In some embodiments, compound (1) is in a crystalline form. In some embodiments, the crystalline form of compound (1) is any of the crystalline forms disclosed in PCT Publication No. WO2018 / 039378, the entire contents of which are incorporated herein by reference.

[0152] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.7 and 10.1 degrees 2θ (inclusive), between 11.6 and 12.0 degrees 2θ (inclusive), between 13.2 and 13.6 degrees 2θ (inclusive), between 14.2 and 14.6 degrees 2θ (inclusive), between 14.6 and 15.0 degrees 2θ (inclusive), between 16.8 and 17.2 degrees 2θ (inclusive), between 20.5 and 20.9 degrees 2θ (inclusive), between 21.3 and 21.7 degrees 2θ (inclusive), between 21.4 and 21.8 degrees 2θ (inclusive), and between 22.4 and 22.8 degrees 2θ (inclusive). In some embodiments, compound (1) is in a crystalline form having an XRPD pattern that includes peaks between 9.7 and 10.1 degrees 2θ (inclusive), between 14.6 and 15.0 degrees 2θ (inclusive), between 16.8 and 17.2 degrees 2θ (inclusive), between 20.5 and 20.9 degrees 2θ (inclusive), and between 21.3 and 21.7 degrees 2θ (inclusive).

[0153] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ (inclusive), between 10.6 and 11.0 degrees 2θ (inclusive), between 13.0 and 13.4 degrees 2θ (inclusive), between 14.7 and 15.1 degrees 2θ (inclusive), between 15.8 and 16.2 degrees 2θ (inclusive), between 18.1 and 18.5 degrees 2θ (inclusive), between 18.7 and 19.1 degrees 2θ (inclusive), between 20.9 and 21.3 degrees 2θ (inclusive), between 21.4 and 21.8 degrees 2θ (inclusive), and between 23.3 and 23.7 degrees 2θ (inclusive). In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ (inclusive), between 10.6 and 11.0 degrees 2θ (inclusive), between 13.0 and 13.4 degrees 2θ (inclusive), between 18.7 and 19.1 degrees 2θ (inclusive), and between 21.4 and 21.8 degrees 2θ (inclusive).

[0154] In some embodiments, the crystalline form of Compound (1) comprises a mixture of two or more crystalline forms.

[0155] 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 administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, the subject has not received any antidepressant treatment within at least 60 days prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0156] In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days or at least 60 days prior to the start of the treatment period.In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days prior to the start of the treatment period.In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 60 days prior to the start of the treatment period.

[0157] In some embodiments, the subject's breast milk is monitored to determine the relative infant dose (RID) of Compound (1) or a pharma- ceutically acceptable salt of Compound (1) in breast milk, and the daily dose of Compound (1) is adjusted to provide less than the maximum relative infant dose (RID). The RID estimates the infant's drug exposure through breast milk. The RID uses a known milk concentration and compares this concentration to either the infant therapeutic dose or, if the infant dose is not well established, the maternal dose adjusted for weight. Typically, breastfeeding is considered acceptable if the relative infant dose is <10%. Further considerations include the infant's gestational and postnatal age, the actual amount of milk ingested (less during the first 2 days of life and at weaning), the specific maternal drug properties, the infant's medical condition, and the medication the infant is receiving therapeutically.

[0158] In some embodiments, the maximum relative infant dose (RID) is at most about 0.5% of the daily dose administered to the subject.In some embodiments, the maximum relative infant dose (RID) is at most about 0.4% of the daily dose administered to the subject.In some embodiments, the maximum relative infant dose (RID) is at most about 0.357% of the daily dose administered to the subject.

[0159] In some embodiments, the child is monitored for abnormal behavior, hi some embodiments, the abnormal behavior is selected from the group consisting of agitation, irritability, lethargy, excessive sleepiness, poor appetite and poor weight gain.

[0160] In some embodiments, the daily dose administered to the subject is reduced by 10 mg if the relative infant dose exceeds the maximum relative infant dose (RID) or if the child exhibits abnormal behavior.In some embodiments, the daily dose administered to the subject is reduced by 10 mg if the relative infant dose exceeds the maximum relative infant dose (RID).In some embodiments, the daily dose administered to the subject is reduced by 10 mg if the child exhibits abnormal behavior.

[0161] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is re-administered to the subject after the completion of the initial treatment period, in response to the recurrence of depressive symptoms.In some embodiments, the last dose of the initial treatment period and the first dose of the re-administration are spaced apart by at least 6 weeks.In some embodiments, each of the initial treatment period and the re-administration is carried out for about 14 days, i.e., about 2 weeks.

[0162] In some embodiments, the method further comprises administration of a second therapeutic agent.

[0163] In some embodiments, the subject is identified as having postpartum depression by a screening method (e.g., the Edinburgh Postnatal Depression Scale (EPDS), e.g., a score of 10 or higher on the EPDS, a score of 13 or higher on the EPDS). In some embodiments, the subject is identified as having postpartum depression by a screening instrument such as various forms of the Patient Health Questionnaire (PHQ), or the Hospital Anxiety and Depression Scale or the Geriatric Depression Scale.

[0164] In some embodiments, the subject has a medical illness, complicated grief, chronic sleep disturbance, loneliness or a history of depression, or has a poor health condition. In some embodiments, the subject has low self-esteem, parenting stress, prenatal anxiety, life stress, reduced social support, single / unpartnered relationship status, a history of depression, difficult infant temperament, previous postpartum depression, low socioeconomic status or unplanned pregnancy. In some embodiments, the subject has hyperemesis gravidarum (e.g., severe forms of morning sickness, e.g., preventing proper intake of food and fluids). In some embodiments, the subject has pregnancy complications (e.g., emergency caesarean section, preeclampsia, hospitalization during pregnancy, concerns about infantile distress and admission to special child care (NICU), where the child is admitted to NICU). In some embodiments, the subject has had an emotionally painful or stressful experience with pregnancy, childbirth, or early parenting (e.g., the subject has undergone infertility treatment, has had a previous miscarriage or other pregnancy loss, multiple births, special needs, colic or difficult child temperament, difficulty feeding). In some embodiments, the subject has a history of domestic violence, sexual abuse, or other abuse (e.g., abuse as a child or adult). In some embodiments, the subject has had a traumatic childhood (e.g., loss of a parent, difficult relationship with a parent). In some embodiments, the subject has had stress (e.g., loss of a loved one, unemployment, financial difficulties, divorce, relationship strain, relocation). In some embodiments, the subject lacks social support. In some embodiments, the subject has a perfectionist or controlling personality.

[0165] In some embodiments, the subject has given birth. In some embodiments, the subject has given birth at least 12 weeks prior to the start of treatment. In some embodiments, the subject is due to give birth. In some embodiments, the subject is due to give birth in 9, 8, 7, 6, 5, 4, 3, 2, or 1 months; 4, 3, 2, or 1 week; or 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the subject is in the third trimester of pregnancy. In some embodiments, the subject has an attribute, characteristic, or exposure that increases the likelihood of developing a disorder described herein, e.g., neuroactive steroid deficiency. In some embodiments, the subject has reached a full-term pregnancy (e.g., early (e.g., between 37 weeks and 38 weeks + 6 days); full term (e.g., between 39 weeks and 40 weeks + 6 days); late (e.g., between 41 weeks and 41 weeks + 6 days); or post-term (e.g., 42 weeks and beyond)), or has a preterm, full term, late, or post-term birth.

[0166] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Hamilton Depression Score (HAM-D)) within about 45, about 21, about 15, about 8, or about 3 days. In some embodiments, the therapeutic effect is a reduction in the HAM-D score from baseline at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days after the start of administration or transient dosing). In some embodiments, the reduction in the HAM-D score from baseline is from severe (e.g., a HAM-D score of 24 or higher, or a score of 26 or higher) to asymptomatic, e.g., remission of depression (e.g., a HAM-D score of 7 or lower). In some embodiments, the reduction from baseline in the HAM-D score ranges from severe (e.g., a HAM-D score of 24 or higher, or a score of 26 or higher) to normal or mild depression (e.g., a HAM-D score of 7 or less, or a HAM-D score of 18-13).

[0167] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Montgomery-Asberg Depression Rating Scale (MADRS)) within about 45, about 21, about 15, about 8, or about 3 days or less. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (relating to outward sadness, verbal sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, lethargy, inability to feel, pessimistic thoughts, and suicidal thoughts) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders. 0-6 indicates normal / absence of symptoms, 7-19 indicates mild depression, 20-34 indicates moderate depression, and >34 indicates severe depression. In some embodiments, the therapeutic effect is a decrease from baseline in MADRS score at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days, or fewer). In some embodiments, the decrease from baseline in MADRS score ranges from severe (e.g., MADRS score of 30 or higher) to asymptomatic (e.g., MADRS score of 20 or less). For example, the mean change from baseline in MADRS total score resulting from treatment with compound (1) is about -15, -20, -25, -30, while the mean change from baseline in MADRS total score resulting from treatment with placebo is about -15, -10, -5.

[0168] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Clinical Global Impression-Improvement scale (CGI)) within about 45, about 21, about 15, about 8, or about 3 days, or fewer. In some embodiments, the therapeutic effect is a CGI score of 2 or less.

[0169] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0170] In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher, 18 or higher, 19 or higher, or 20 or higher, or a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher, prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher. In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 18 or higher. In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 19 or higher. In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 20 or higher. In some embodiments, PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher.

[0171] In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 17 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 18 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 19 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 24 or greater and a HAM-A total score of 20 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 24 or greater and a HAM-D anxiety / somatization subscale score of 7 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0172] In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-A total score of 17 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-A total score of 18 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-A total score of 19 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-A total score of 20 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, PPD with elevated anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-D anxiety / somatization subscale score of 7 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0173] In other embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items and the somatic items. In some embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety, somatic anxiety, GI somatic symptoms, and / or general somatic symptoms. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D anxiety / somatization subscale score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D Anxiety / Somatization subscale score based primarily on items assessing the anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the anxiety symptoms of depression.

[0174] Major Depressive Disorder (MDD)

[0175] In another aspect, the present disclosure is directed to a method for treating major depressive disorder (MDD) in a human female subject during the postpartum period. In some embodiments, the MDD is MDD associated with elevated anxiety.

[0176] The diagnosis and severity of major depressive disorder treated by the methods described herein are determined according to the Diagnostic and Statistical Manual of Mental Disorders, 5 thIt can be characterized as defined by the DSM-5 Edition (DSM-5).

[0177] Depressive disorder

[0178] Depressive disorders include major mood dysregulation disorder, major depressive disorder (including major depressive episodes), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance / medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder. The common feature of all of these disorders is the presence of a sad, empty, or irritable mood accompanied by physical and cognitive changes that significantly affect an individual's ability to function. What differs between them is the matter of duration, timing, or presumed etiology.

[0179] Major depressive disorder represents the classic presentation in this group of disorders. It is characterized by discrete episodes of at least 2 weeks duration (although most episodes last much longer) with distinct changes in affect, cognition and autonomic nervous system function and remissions between episodes. Discrete episodes of major depressive disorder may be called "major depressive episodes" or "depressive episodes".

[0180] Major Depressive Disorder (MDD)

[0181] Major depressive disorder is generally known in the art.

[0182] In some embodiments, MDD, also known as depression or clinical depression, is a mood disorder that causes persistent feelings of sadness and loss of interest.MDD can affect how a subject feels, thinks, and acts, and can lead to a variety of emotional and physical problems.

[0183] In some embodiments, MDD is defined and diagnosed according to DSM-5, for example, MDD is diagnosed according to diagnostic criterion A, as described below.

[0184] Diagnostic Criteria A. Five (or more) of the following symptoms appear during the same two-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1. Depressed mood for most of the day, almost every day, as indicated by either subjective report (e.g., feeling sad, empty, hopeless) or observation made by others (e.g., appearing tearful) (Note: in children and adolescents, irritable mood is possible). 2. Markedly diminished interest or pleasure in all or almost all activities for most of the day, almost every day (as indicated by either subjective description or observation). 3. Significant weight loss or gain when not on a diet (e.g., more than a 5% change in body weight in one month) or decreased or increased appetite on most days (Note: in children, consider that this may not be expected weight gain). 4. Having insomnia or excessive sleep almost every day. 5. Psychomotor agitation or retardation (observable by others, not just a subjective feeling of restlessness or slowness) almost every day. 6. Feeling fatigued or inactive almost every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) almost every day (not just remorse or guilt about being ill). 8. Poor ability to think or concentrate, or indecisiveness almost every day (either subjectively described or observed by others). 9. Recurrent thoughts of death (not just fear of death), recurrent suicidal thoughts without a specific plan, or a specific plan to attempt or commit suicide.

[0185] Diagnostic criteria B through E described below are further explanations of MDD and may be considered explanations or diagnoses of MDD, but are not required.

[0186] Diagnostic Criterion B. Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

[0187] Criterion C. The episode cannot be attributed to the physiological effects of a substance or to another medical condition.

[0188] Criteria A-C may represent a major depressive episode.

[0189] Diagnostic Criterion D. The occurrence of a major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder or other specified and unspecified schizophrenia spectrum and other psychotic disorders.

[0190] Diagnostic Criterion E. Never had a manic or hypomanic episode.

[0191] In some embodiments, a major depressive episode (MDE) is a period characterized by the symptoms of MDD listed above.

[0192] In some embodiments, MDD is a clinical pathway characterized by one or more major depressive episodes (MDEs) in a subject.

[0193] In some embodiments, MDD is diagnosed according to diagnostic criteria A through C, as described above. In some embodiments, MDD is diagnosed according to diagnostic criteria A through E, as described above.

[0194] Diagnostic Features

[0195] The diagnostic criteria symptoms of major depressive disorder, except for weight change and suicidal ideation, must be present almost every day to be considered present. In addition to being present almost every day, depressed mood must be present for a large portion of the day. Often, insomnia or fatigue is the presenting complaint, leading to underdiagnosis if the patient fails to investigate the accompanying depressive symptoms. Sadness may be initially denied, but may be elicited by interview or inferred from facial expression and demeanor. For individuals who focus on somatic complaints, the clinician should determine whether the distress resulting from the complaint is related to a specific depressive symptom. Fatigue and sleep disturbance are present in a high percentage of cases. Psychomotor disorders are less common but are indicators of greater overall severity, as are delusional or delusional feelings of guilt.

[0196] The essential feature of a major depressive episode is a period of at least 2 weeks during which there is either a depressed mood or a loss of interest or pleasure in almost all activities (criterion A above). In children and adolescents, the mood may be irritable rather than sad. The individual must also experience at least four additional symptoms drawn from a list including: changes in appetite or weight, sleep and psychomotor activity; decreased motivation; feelings of worthlessness or guilt; difficulty thinking, concentrating or making decisions; or recurrent thoughts of death or suicidal ideation or suicide plans or suicide attempts. To count as a major depressive episode, the symptoms must be new or have clearly worsened compared with the person's pre-episode state. Symptoms must persist for most of the day, almost every day, for at least 2 consecutive weeks. The episode must be accompanied by clinically significant distress or impairment in social, occupational or other important areas of functioning. For some individuals with mild episodes, functioning may appear normal but requires significantly increased effort.

[0197] Sleep disturbances may take the form of either difficulty sleeping or excessive sleeping (criterion A4). When insomnia is present, it usually takes the form of intermediate insomnia (e.g., difficulty getting back to sleep after waking up in the middle of the night) or end-stage insomnia (e.g., waking up too early and not being able to get back to sleep). Early-stage insomnia (e.g., difficulty falling asleep) may also occur. Individuals who exhibit hypersomnia (excessive sleep) may experience longer episodes of sleep at night or increased daytime sleep. Sometimes, the reason an individual seeks treatment is because of a sleep disorder.

[0198] Major depressive disorder with elevated anxiety / anxiety distress

[0199] The DSM-5-defined identifier "anxiety distress" for MDD indicates the presence of at least two of the following symptoms during most days of a major depressive episode or persistent depressive disorder (dysthymia): 1. Feeling excited or nervous. 2. Feeling unusually restless. 3. Worrying makes it hard to concentrate. 4. You are afraid that something terrible might happen. 5. I feel like I'm losing control.

[0200] Severity is defined as follows: Mild: 2 symptoms. Moderate: 3 symptoms. Moderate to severe: 4 or 5 symptoms. Severe: Four or five symptoms with motor agitation.

[0201] Anxiety distress has been documented as a prominent feature of both bipolar disorder and major depressive disorder in both primary care and specialty mental health settings. High levels of anxiety have been associated with a higher suicide risk, longer duration of illness, and a higher likelihood of not responding to treatment.

[0202] Accordingly, one aspect of the disclosure is a method of treating major depressive disorder (MDD) in a human female subject, comprising administering to the subject a therapeutically effective amount of Compound (1): [ka] administering The method is directed to a subject, wherein said subject is breastfeeding a child during said treatment period.

[0203] Another embodiment of the present disclosure is a method of treating major depressive disorder (MDD) in a human female subject, comprising administering to the subject a therapeutically effective amount of a pharma- ceutically acceptable salt of Compound (1): [ka] administering wherein said subject is breastfeeding a child during said treatment period.

[0204] Another aspect of the disclosure is a method of treating major depressive disorder (MDD) with elevated anxiety in a human female subject, comprising administering to the subject a therapeutically effective amount of Compound (1): [ka] administering wherein said subject is breastfeeding a child during said treatment period.

[0205] Another embodiment of the present disclosure is a method of treating major depressive disorder (MDD) with elevated anxiety in a human female subject, comprising administering to the subject a therapeutically effective amount of a pharma- ceutically acceptable salt of Compound (1): [ka] administering wherein said subject is breastfeeding a child during said treatment period.

[0206] In some embodiments, the subject breastfeeds the infant at least once per day. In another embodiment, the subject breastfeeds the infant at least twice per day. In another embodiment, the subject breastfeeds the infant at least three times per day. In another embodiment, the subject breastfeeds the infant at least 4, 5, 6, 7, 8, 9, 10, 11 or 12 times per day.

[0207] In some embodiments, the treatment period is about 2 weeks or about 14 days. In some embodiments, the treatment period is about 2 weeks. In some embodiments, the treatment period is about 14 days.

[0208] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about 14 days or about two weeks. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about 14 days. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered once a day for about two weeks.

[0209] 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. In some embodiments, Compound (1) is administered at a dose of about 30 mg.

[0210] 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 daily at a dose of about 50 mg. In some embodiments, compound (1) is administered once daily at a dose of about 40 mg. In some embodiments, compound (1) is administered once daily at a dose of about 30 mg.

[0211] In some embodiments, compound (1) is administered once a day at a dose of about 20 mg to about 55 mg for about two weeks or about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg to about 50 mg for about two weeks or about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 45 mg to about 55 mg for about two weeks or about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 50 mg for less than two weeks. In some embodiments, compound (1) is administered once a day at a dose of about 50 mg for about two weeks. In some embodiments, compound (1) is administered once a day at a dose of about 50 mg for about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg for less than two weeks. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg for about 2 weeks. In some embodiments, compound (1) is administered once a day at a dose of about 40 mg for about 14 days. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg for less than 2 weeks. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg for about 2 weeks. In some embodiments, compound (1) is administered once a day at a dose of about 30 mg for about 14 days.

[0212] In other embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 15 mg to about 75 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 30 mg to about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 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 a dose equivalent of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 40 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 30 mg of the free base compound.

[0213] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 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 daily at a dose equivalent of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 20 mg to about 55 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 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 daily at a dose equivalent 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 daily at a dose equivalent of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 40 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 30 mg of the free base compound.

[0214] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 20 mg to about 55 mg of the free base compound for about two weeks or about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 30 mg to about 50 mg of the free base compound for about two weeks or about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 45 mg to about 55 mg of the free base compound for about two weeks or about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once daily at a dose equivalent of about 50 mg of the free base compound for about two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 50 mg of the free base compound for about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for about two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 40 mg of the free base compound for about 14 days. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 30 mg of the free base compound for less than two weeks. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) is administered once a day at a dose equivalent to about 30 mg of the free base compound for about two weeks. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 30 mg of the free base compound once daily for about 14 days.

[0215] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally.

[0216] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered chronically.

[0217] 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.

[0218] 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 a fat-containing meal. Examples of fat-containing meals 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 a fat-containing meal in the evening (e.g., within 1 hour of a fat-containing dinner or with a fat-containing snack).

[0219] 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 sleep. 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 sleep. 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 sleep. 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 sleep.

[0220] In some embodiments, compound (1) is in a crystalline form. In some embodiments, the crystalline form of compound (1) is any of the crystalline forms disclosed in PCT Publication No. WO2018 / 039378, the entire contents of which are incorporated herein by reference.

[0221] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.7 and 10.1 degrees 2θ (inclusive), between 11.6 and 12.0 degrees 2θ (inclusive), between 13.2 and 13.6 degrees 2θ (inclusive), between 14.2 and 14.6 degrees 2θ (inclusive), between 14.6 and 15.0 degrees 2θ (inclusive), between 16.8 and 17.2 degrees 2θ (inclusive), between 20.5 and 20.9 degrees 2θ (inclusive), between 21.3 and 21.7 degrees 2θ (inclusive), between 21.4 and 21.8 degrees 2θ (inclusive), and between 22.4 and 22.8 degrees 2θ (inclusive). In some embodiments, compound (1) is in a crystalline form having an XRPD pattern that includes peaks between 9.7 and 10.1 degrees 2θ (inclusive), between 14.6 and 15.0 degrees 2θ (inclusive), between 16.8 and 17.2 degrees 2θ (inclusive), between 20.5 and 20.9 degrees 2θ (inclusive), and between 21.3 and 21.7 degrees 2θ (inclusive).

[0222] In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ (inclusive), between 10.6 and 11.0 degrees 2θ (inclusive), between 13.0 and 13.4 degrees 2θ (inclusive), between 14.7 and 15.1 degrees 2θ (inclusive), between 15.8 and 16.2 degrees 2θ (inclusive), between 18.1 and 18.5 degrees 2θ (inclusive), between 18.7 and 19.1 degrees 2θ (inclusive), between 20.9 and 21.3 degrees 2θ (inclusive), between 21.4 and 21.8 degrees 2θ (inclusive), and between 23.3 and 23.7 degrees 2θ (inclusive). In some embodiments, compound (1) is in a crystalline form having an XRPD pattern including peaks between 9.3 and 9.7 degrees 2θ (inclusive), between 10.6 and 11.0 degrees 2θ (inclusive), between 13.0 and 13.4 degrees 2θ (inclusive), between 18.7 and 19.1 degrees 2θ (inclusive), and between 21.4 and 21.8 degrees 2θ (inclusive).

[0223] In some embodiments, the crystalline form of Compound (1) comprises a mixture of two or more crystalline forms.

[0224] 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 administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, the subject has not received any antidepressant treatment within at least 60 days prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0225] In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days or at least 60 days prior to the start of the treatment period.In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 60 days prior to the start of the treatment period.In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days prior to the start of the treatment period.

[0226] In some embodiments, the subject's breast milk is monitored to determine the relative infant dose (RID) of Compound (1) or a pharma- ceutically acceptable salt of Compound (1) in breast milk, and the daily dose of Compound (1) is adjusted to provide less than the maximum relative infant dose (RID). The RID estimates the infant's drug exposure through breast milk. The RID uses a known milk concentration and compares this concentration to either the infant therapeutic dose or, if the infant dose is not well established, the maternal dose adjusted for weight. Typically, breastfeeding is considered acceptable if the relative infant dose is <10%. Further considerations include the infant's gestational and postnatal age, the actual amount of milk ingested (less during the first 2 days of life and at weaning), the specific maternal drug properties, the infant's medical condition, and the medication the infant is receiving therapeutically.

[0227] In some embodiments, the maximum relative infant dose (RID) is at most about 0.5% of the daily dose administered to the subject.In some embodiments, the maximum relative infant dose (RID) is at most about 0.4% of the daily dose administered to the subject.In some embodiments, the maximum relative infant dose (RID) is at most about 0.357% of the daily dose administered to the subject.

[0228] In some embodiments, the child is monitored for abnormal behavior, hi some embodiments, the abnormal behavior is selected from the group consisting of agitation, irritability, lethargy, excessive sleepiness, poor appetite and poor weight gain.

[0229] In some embodiments, the daily dose administered to the subject is reduced by 10 mg if the relative infant dose exceeds the maximum relative infant dose (RID) or if the child exhibits abnormal behavior.In some embodiments, the daily dose administered to the subject is reduced by 10 mg if the relative infant dose exceeds the maximum relative infant dose (RID).In some embodiments, the daily dose administered to the subject is reduced by 10 mg if the child exhibits abnormal behavior.

[0230] In some embodiments, the method further comprises administration of a second therapeutic agent.

[0231] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is re-administered to the subject after the completion of the initial treatment period, in response to the recurrence of depressive symptoms.In some embodiments, the last dose of the initial treatment period and the first dose of the re-administration are spaced apart by at least 6 weeks.In some embodiments, each of the initial treatment period and the re-administration is carried out for about 14 days, i.e., about 2 weeks.

[0232] In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher, 18 or higher, 19 or higher, or 20 or higher. In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher, or a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher before administration of compound (1) or a pharma- ceutically acceptable salt of compound (1). In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher. In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 18 or higher. In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 19 or higher. In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 20 or higher. In some embodiments, MDD with elevated anxiety is characterized by a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher.

[0233] In some embodiments, the MDD with elevated anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 17 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, the MDD with elevated anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 18 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, the MDD with elevated anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 19 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, the MDD with elevated anxiety is characterized by a HAM-D total score of 24 or greater and a HAM-A total score of 20 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, the MDD with elevated anxiety is characterized by a HAM-D total score of 24 or greater and a HAM-D anxiety / somatization subscale score of 7 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0234] In some embodiments, the MDD with elevated anxiety is characterized by a HAM-D total score of 20 or higher, a MADRS total score of 28 or higher, and a HAM-A total score of 17 or higher (e.g., 18 or higher, 19 or higher, or 20 or higher) prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, the MDD with elevated anxiety is characterized by a HAM-D total score of 20 or higher, a MADRS total score of 28 or higher, and a HAM-D anxiety / somatization subscale score of 7 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0235] In other embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items and the somatic items. In some embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety, somatic anxiety, GI somatic symptoms, and / or general somatic symptoms. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D anxiety / somatization subscale score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D Anxiety / Somatization subscale score based primarily on items assessing the anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the anxiety symptoms of depression.

[0236] Another aspect of the present disclosure is a method of treating postpartum depression (PPD) in a human female subject during the postpartum period, comprising: a) administering to the subject about 30 mg to about 50 mg of Compound (1) for the treatment period: [ka] once daily for about 14 days. said subject nursing a child during said treatment period; b) comparing the relative infant dose of compound (1) in the subject's breast milk to a predetermined maximum relative infant dose; and c) reducing the daily dose administered to the subject if the relative infant dose of compound (1) in the subject's breast milk exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior. The present invention provides a method comprising:

[0237] Another aspect of the present disclosure is a method of treating postpartum depression (PPD) in a human female subject during the postpartum period, comprising: a) administering to the subject, for the treatment period, a dose equivalent to about 30 mg to about 50 mg of the free base compound of a pharma- ceutically acceptable salt of Compound (1): [ka] once daily for about 14 days, said subject nursing a child during said treatment period; b) comparing said relative infant dose of compound (1) in said subject's breast milk to a predetermined maximum relative infant dose; and c) reducing the daily dose administered to the subject if the relative infant dose of compound (1) in the subject's breast milk exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior. The present invention provides a method comprising:

[0238] Another aspect of the disclosure is a method of treating major depressive disorder (MDD) in a human female subject, comprising: a) administering to the subject about 30 mg to about 50 mg of Compound (1) for the treatment period: [ka] once daily for about 14 days. said subject nursing a child during said treatment period; b) comparing the relative infant dose of compound (1) in the subject's breast milk to a predetermined maximum relative infant dose; and c) reducing the daily dose administered to the subject if the relative infant dose of compound (1) in the subject's breast milk exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior. The present invention provides a method comprising:

[0239] Another aspect of the disclosure is a method of treating major depressive disorder (MDD) in a human female, comprising: a) administering to a subject, for the treatment period, a dose equivalent to about 30 mg to about 50 mg of the free base compound of a pharma- ceutically acceptable salt of Compound (1): [ka] once daily for about 14 days, said subject nursing a child during said treatment period; b) comparing the relative infant dose of compound (1) in the subject's breast milk to a predetermined maximum relative infant dose; and c) reducing the daily dose administered to the subject if the relative infant dose of compound (1) in the subject's breast milk exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior. The present invention provides a method comprising:

[0240] Another aspect of the present disclosure is a method of treating postpartum depression (PPD) in a human female subject during the postpartum period, comprising: a) administering to the subject about 30 mg to about 50 mg of Compound (1) for the treatment period: [ka] once daily for about 14 days. said subject nursing a child during said treatment period; b) collecting and testing a sample of said subject's breast milk to determine the relative infant dose of Compound (1) in said breast milk; c) comparing the relative infant dose determined in step b) with a predetermined maximum relative infant dose; d) monitoring the child for abnormal behavior; e) reducing the daily dose administered to the subject if the relative infant dose determined in step b) exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior; and f) repeating steps a) through e) daily for the duration of said treatment period. The present invention provides a method comprising:

[0241] Another aspect of the present disclosure is a method of treating postpartum depression (PPD) in a human female subject during the postpartum period, comprising: a) administering to the subject, for the treatment period, a dose equivalent to about 30 mg to about 50 mg of the free base compound of a pharma- ceutically acceptable salt of Compound (1): [ka] once daily for about 14 days, said subject nursing a child during said treatment period; b) collecting and testing a sample of said subject's breast milk to determine the relative infant dose of said pharmacologic acceptable salt of Compound (1) in said breast milk; c) comparing the relative infant dose determined in step b) with a predetermined maximum relative infant dose; d) monitoring the child for abnormal behavior; e) reducing the daily dose administered to the subject if the relative infant dose determined in step b) exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior; and f) repeating steps a) through e) daily for the duration of said treatment period. The present invention provides a method comprising:

[0242] Another aspect of the disclosure is a method of treating major depressive disorder (MDD) in a human female subject, comprising: a) administering to the subject about 30 mg to about 50 mg of Compound (1) for the treatment period: [ka] once daily for about 14 days. said subject nursing a child during said treatment period; b) collecting and testing a sample of said subject's breast milk to determine the relative infant dose of Compound (1) in said breast milk; c) comparing the relative infant dose determined in step b) with a predetermined maximum relative infant dose; d) monitoring the child for abnormal behavior; e) reducing the daily dose administered to the subject if the relative infant dose determined in step b) exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior; and f) repeating steps a) through e) daily for the duration of said treatment period. The present invention provides a method comprising:

[0243] Another aspect of the disclosure is a method of treating major depressive disorder (MDD) in a human female subject, comprising: a) administering to a subject, for the treatment period, a dose equivalent to about 30 mg to about 50 mg of the free base compound of a pharma- ceutically acceptable salt of Compound (1): [ka] once daily for about 14 days, said subject nursing a child during said treatment period; b) collecting and testing a sample of said subject's breast milk to determine the relative infant dose of said pharmacologic acceptable salt of Compound (1) in said breast milk; c) comparing the relative infant dose determined in step b) with a predetermined maximum relative infant dose; d) monitoring the child for abnormal behavior; e) reducing the daily dose administered to the subject if the relative infant dose determined in step b) exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior; and f) repeating steps a) through e) daily for the duration of said treatment period. The present invention provides a method comprising:

[0244] In some embodiments, the PPD is PPD with elevated anxiety, hi some embodiments, the MDD is MDD with elevated anxiety.

[0245] In some embodiments, the MDD with elevated anxiety or PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher, 18 or higher, 19 or higher, or 20 or higher prior to administration of compound (1) or a pharma- ceutically acceptable salt of compound (1), or a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher. In some embodiments, the MDD with elevated anxiety or PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 17 or higher prior to administration of compound (1) or a pharma- ceutically acceptable salt of compound (1). In some embodiments, the MDD with elevated anxiety or PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 18 or higher prior to administration of compound (1) or a pharma- ceutically acceptable salt of compound (1). In some embodiments, MDD with elevated anxiety or PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 19 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, MDD with elevated anxiety or PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Anxiety (HAM-A) total score of 20 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, MDD with elevated anxiety or PPD with elevated anxiety is characterized by a Hamilton Rating Scale for Depression (HAM-D) Anxiety / Somatization subscale score of 7 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0246] In some embodiments, MDD with elevated anxiety or PPD with elevated anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 17 or higher before administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, MDD with elevated anxiety or PPD with elevated anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 18 or higher before administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, MDD with elevated anxiety or PPD with elevated anxiety is characterized by a HAM-D total score of 24 or higher and a HAM-A total score of 19 or higher before administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, the MDD with elevated anxiety or PPD with elevated anxiety is characterized by a HAM-D total score of 24 or greater and a HAM-A total score of 20 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0247] In some embodiments, the MDD with elevated anxiety or PPD with elevated anxiety is characterized by a HAM-D total score of 24 or greater and a HAM-D anxiety / somatization subscale score of 7 or greater prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0248] In some embodiments, MDD with elevated anxiety or PPD with elevated anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-A total score of 17 or higher (e.g., 18 or higher, 19 or higher, or 20 or higher) prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, MDD with elevated anxiety or PPD with elevated anxiety is characterized by a HAM-D total score of 26 or higher and a HAM-D anxiety / somatization subscale score of 7 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0249] In some embodiments, MDD with elevated anxiety or PPD with elevated anxiety is characterized by a HAM-D total score of 20 or higher, a MADRS total score of 28 or higher, and a HAM-A total score of 17 or higher (e.g., 18 or higher, 19 or higher, or 20 or higher) prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, MDD with elevated anxiety or PPD with elevated anxiety is characterized by a HAM-D total score of 20 or higher, a MADRS total score of 28 or higher, and a HAM-D anxiety / somatization subscale score of 7 or higher prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0250] In other embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items and the somatic items. In some embodiments, "elevated anxiety" is characterized by a HAM-A score based on the HAM-A anxiety items. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety, somatic anxiety, GI somatic symptoms, and general somatic symptoms. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based on the following HAM-D items: mental anxiety. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D score based primarily on items assessing anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D anxiety / somatization subscale score based primarily on items assessing somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a HAM-D Anxiety / Somatization subscale score based primarily on items assessing the anxiety symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the somatic symptoms of depression. In some embodiments, "elevated anxiety" is characterized by a MADRS score based primarily on items assessing the anxiety symptoms of depression.

[0251] 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, or a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 40 mg of the free base compound. In some embodiments, compound (1) is administered in a dose of about 30 mg, or a pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 30 mg of the free base compound.

[0252] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally. In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered orally.

[0253] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is administered chronically.

[0254] 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.

[0255] 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 a fat-containing meal. Examples of fat-containing meals 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 a fat-containing meal in the evening (e.g., within 1 hour of a fat-containing dinner or with a fat-containing snack).

[0256] 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 sleep. 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 sleep. 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 sleep. 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 sleep.

[0257] 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 administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1). In some embodiments, the subject has not received any antidepressant treatment within at least 60 days prior to administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (1).

[0258] In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days or at least 60 days prior to the start of the treatment period.In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 60 days prior to the start of the treatment period.In some embodiments, the subject has been taking a stable dose of an additional antidepressant for at least 30 days prior to the start of the treatment period.

[0259] In some embodiments, the method further comprises administration of a second therapeutic agent.

[0260] In some embodiments, Compound (1) or a pharma- ceutically acceptable salt of Compound (1) is re-administered to the subject after the completion of the initial treatment period, in response to the recurrence of depressive symptoms.In some embodiments, the last dose of the initial treatment period and the first dose of the re-administration are spaced apart by at least 6 weeks.In some embodiments, each of the initial treatment period and the re-administration is carried out for about 14 days, i.e., about 2 weeks.

[0261] In some embodiments, the maximum relative infant dose (RID) is at most about 0.5% of the daily dose administered to the subject.In some embodiments, the maximum relative infant dose (RID) is at most about 0.4% of the daily dose administered to the subject.In some embodiments, the maximum relative infant dose (RID) is at most about 0.357% of the daily dose administered to the subject.

[0262] In some embodiments, the abnormal behavior is selected from the group consisting of agitation, irritability, lethargy, excessive sleepiness, loss of appetite and poor weight gain.

[0263] III. Pharmaceutical Compositions

[0264] Another aspect of the present disclosure provides a pharmaceutical composition comprising Compound (1) (also referred to as "active ingredient") and a pharma- ceutically acceptable excipient for use in the methods described herein. In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharma- ceutically acceptable salt of the active ingredient and a pharma- ceutically acceptable excipient for use in the methods described herein. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient, or a pharma- ceutically acceptable salt of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient, or a pharma- ceutically acceptable salt of the active ingredient. In some embodiments, the pharmaceutical composition of Compound (1) is any of the pharmaceutical compositions disclosed in PCT Publication No. WO2022 / 020363A9, the entire contents of which are incorporated herein by reference in their entirety.

[0265] The pharmaceutical compositions provided herein can be administered by various routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM) and intranasal. In some embodiments, the pharmaceutical composition is administered orally.

[0266] The pharmaceutical composition of the present disclosure may further be delivered using various dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, for example, to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic level of the active ingredient desired throughout the body, for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., by IV drip) allows for a much faster delivery that quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example, by IV drip, to achieve the maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still other embodiments, the pharmaceutical composition may be administered first as a bolus dose and then as a continuous infusion.

[0267] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, compositions are supplied in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in combination with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules, and the like, for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that help form the desired dosage form.

[0268] The above components of the orally administrable, injectable or topically administrable compositions are merely representative. Other materials, processing techniques, and the like are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0269] The compositions of the present disclosure can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0270] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to all kinds of animals.It is well understood that modifying pharmaceutical compositions suitable for administration to humans to make the composition suitable for administration to various animals is possible, and a skilled veterinary pharmacologist can use routine experimentation to design and / or carry out such modifications.General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.

[0271] The present disclosure also relates to pharma- ceutically acceptable acid addition salts of compound (1). Acids that can be used to prepare pharma- ceutically acceptable salts are those that form non-toxic acid addition salts, such as salts containing pharmacologically acceptable anions, such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, hydrogen sulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0272] Another aspect of the disclosure includes a method of treating postpartum depression in a human female subject during the postpartum period, comprising administering to the subject a therapeutically effective amount of Compound (1) during the treatment period, wherein the subject is breastfeeding an infant during the treatment period.

[0273] In an embodiment of this aspect, the treatment period is about 14 days. In some embodiments, the therapeutically effective amount is administered once a day. In some embodiments, the subject is breastfeeding the infant at least three times a day.

[0274] In some embodiments, the therapeutically effective amount is about 10 mg to about 55 mg of Compound (1) per day. In some embodiments, the therapeutically effective amount is about 20 mg to about 55 mg of Compound (1) per day. In some embodiments, the therapeutically effective amount is about 30 mg of Compound (1) per day. In some embodiments, the therapeutically effective amount is about 50 mg of Compound (1) per day.

[0275] In some embodiments, monitor the subject's breast milk to determine the relative infant dose (RID) of compound (1) in breast milk, and adjust the daily dose of compound (1) to provide less than the maximum RID. In some embodiments, the maximum RID is at most about 0.5% of the daily dose administered to the subject. In some embodiments, the maximum RID is at most about 0.4% of the daily dose administered to the subject. In some embodiments, the maximum RID is at most about 0.357% of the daily dose administered to the subject.

[0276] In some embodiments, the infant is monitored for abnormal behavior, hi some embodiments, the abnormal behavior is selected from the group consisting of agitation, irritability, lethargy, excessive sleepiness, poor appetite and poor weight gain.

[0277] In some embodiments, the daily dose administered to a subject is reduced by 10 mg if the RID exceeds the maximum RID or if the infant exhibits abnormal behavior.

[0278] Another aspect of the present disclosure is a method of treating postpartum depression in a human female subject during the postpartum period, comprising: a) administering to a subject during a treatment period Compound (1): [ka] administering a daily dose of 30 mg or 50 mg of said compound, wherein the subject is breastfeeding the infant during the treatment period; b) collecting and testing breast milk samples to determine the relative infant dose (RID) of compound (1) in the breast milk; c) comparing the RID determined in step b) with a predetermined maximum RID; d) monitoring the infant for abnormal behavior; e) reducing the daily dose administered to the subject if the RID determined in step b) exceeds a predetermined maximum RID or if the infant exhibits abnormal behavior; and f) repeating steps a) through e) daily for the duration of the treatment period. The present invention includes a method comprising the steps of:

[0279] In an embodiment of this aspect, the daily dose is 50 mg. In some embodiments, the daily dose is 30 mg.

[0280] In some embodiments, the predetermined maximum RID is at least about 0.5% of the daily dose administered to the subject. In some embodiments, the maximum RID is at least about 0.4% of the daily dose administered to the subject. In some embodiments, the maximum RID is at least about 0.357% of the daily dose administered to the subject.

[0281] In some embodiments, the abnormal behavior associated with the infant is selected from the group consisting of agitation, irritability, lethargy, excessive sleepiness, poor appetite and poor weight gain. EXAMPLES

[0282] Example 1 An open-label study to assess the concentrations of compound (1) in breast milk from healthy lactating women

[0283] the purpose

[0284] Compound (1) is an investigational synthetic oral neuroactive steroid under investigation as a once-daily treatment for major depressive disorder and postpartum depression. This open-label study evaluated the scope of Compound (1) in breast milk, breast milk volume, pharmacokinetics (PK), plasma protein binding, safety and tolerability in healthy lactating participants.

[0285] method

[0286] Healthy volunteers (N=15), aged 18-45 years, actively breastfeeding, pumping or breastfeeding ≥3 times per day, ≥12 weeks postpartum, self-administered 30 mg of compound (1) once daily with food for 5 days. Breast milk was collected from days -3 to 12. Blood samples for PK and plasma protein binding analysis were collected pre-dose (day 1), days 5-6, and during follow-up (days 7, 9, and 12). Population PK modeling was used to explore the relationship between plasma and breast milk concentrations.

[0287] result

[0288] Fifteen participants received ≥1 dose of Compound (1), and 14 (93.3%) completed the study. Participant PK profiles were similar to other clinical studies with Compound (1). In plasma, Compound (1) was highly protein bound, with free fractions ≤0.52% across participants. Compared to the maternal dose, Compound (1) was present in breast milk at low levels, with an estimated mean relative infant dose (RID) of 0.357% on day 5 and a daily infant dose of 0.00125 mg / kg / day. Milk volume collected was reduced by 8.3% from baseline. Interparticipant variability was observed.

[0289] Compound (1) concentrations were described with a constant partition coefficient of 0.501 between milk and plasma. The intersubject variability in partitioning was 23%. Plasma concentrations of Compound (1) had no apparent relationship to time or milk volume collected.

[0290] No deaths, serious adverse events, moderate or severe treatment-emergent adverse events (TEAEs), or TEAEs leading to discontinuation or study withdrawal were reported.

[0291] conclusion

[0292] Compound (1) was well tolerated when administered at 30 mg to healthy breast-feeding participants for 5 days. Negligible amounts were transferred to breast milk, resulting in a RID of 0.357%. Minimal concentrations were detected in breast milk (approximately half of the plasma concentration) and intersubject variability of distribution was low. Breast-feeding while taking Compound (1) may be considered appropriate if the benefits outweigh the risks to mother and baby. Equivalents and Scope

[0293] In the claims, articles such as "a," "an," and "the" can mean one or more than one, unless stated to the contrary or otherwise clear from the context. A claim or description containing "or" between one or more members of a group is considered satisfied if one, more than one, or all of the members of the group are present in, used in, or otherwise relevant to a given product or process, unless stated to the contrary or otherwise clear from the context. The invention includes embodiments in which exactly one member of a 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 of the members of a group are present in, used in, or otherwise relevant to a given product or process.

[0294] Moreover, the present invention embraces 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 lists, e.g., in Markush group format, each subgroup of 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 said to include 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 specifically described in precise terms herein. 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 presented, the endpoints are included. Further, unless otherwise indicated or 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 ranges set forth in various embodiments of the invention, down to one tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0295] 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 of the incorporated references and this specification, this specification shall control. Furthermore, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Since such embodiments are deemed known to those of skill in the art, they may be excluded even if the exclusion is not expressly described herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether related to the existence of prior art or not. Other embodiments

[0296] 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 present embodiments described herein is not intended to be limited to the above description, but rather is as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description can be made without departing from the spirit or scope of the invention, as defined in the following claims.

Claims

1. A composition for use in a method for treating depression in a human female subject for a treatment period, said composition comprising compound (1): 【Chemistry 35】 or a pharma- ceutically acceptable salt of compound (1), The subject is breastfeeding a child during the treatment period.

2. A composition for use in a method for treating depression accompanied by elevated anxiety in a human female subject during a treatment period, said composition comprising compound (1): 【Chemical 37】 or a pharma- ceutically acceptable salt of compound (1), The subject is breastfeeding a child during the treatment period.

3. 3. The composition of claim 1 or claim 2, wherein the subject is breastfeeding the child at least three times per day.

4. 3. The composition of claim 1 or claim 2, wherein the treatment period is about 2 weeks or about 14 days.

5. 3. The composition of claim 1 or claim 2, wherein compound (1) or the pharma- ceutically acceptable salt of compound (1) is administered once a day for about 14 days.

6. The composition according to claim 1 or claim 2, 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 50 mg of the free base compound.

7. Compound (1) is (A) peaks between 9.7 and 10.1 degrees 2θ [endpoints included], between 11.6 and 12.0 degrees 2θ [endpoints included], between 13.2 and 13.6 degrees 2θ [endpoints included], between 14.2 and 14.6 degrees 2θ [endpoints included], between 14.6 and 15.0 degrees 2θ [endpoints included], between 16.8 and 17.2 degrees 2θ [endpoints included], between 20.5 and 20.9 degrees 2θ [endpoints included], between 21.3 and 21.7 degrees 2θ [endpoints included], between 21.4 and 21.8 degrees 2θ [endpoints included], and between 22.4 and 22.8 degrees 2θ [endpoints included]; (B) peaks between 9.3 and 9.7 degrees 2θ [endpoints included], between 10.6 and 11.0 degrees 2θ [endpoints included], between 13.0 and 13.4 degrees 2θ [endpoints included], between 14.7 and 15.1 degrees 2θ [endpoints included], between 15.8 and 16.2 degrees 2θ [endpoints included], between 18.1 and 18.5 degrees 2θ [endpoints included], between 18.7 and 19.1 degrees 2θ [endpoints included], between 20.9 and 21.3 degrees 2θ [endpoints included], between 21.4 and 21.8 degrees 2θ [endpoints included], and between 23.3 and 23.7 degrees 2θ [endpoints included]; (C) peaks between 9.7 and 10.1 degrees 2θ [endpoints included], between 14.6 and 15.0 degrees 2θ [endpoints included], between 16.8 and 17.2 degrees 2θ [endpoints included], between 20.5 and 20.9 degrees 2θ [endpoints included], and between 21.3 and 21.7 degrees 2θ [endpoints included]; or (D) peaks between 9.3 and 9.7 degrees 2θ [endpoints included], between 10.6 and 11.0 degrees 2θ [endpoints included], between 13.0 and 13.4 degrees 2θ [endpoints included], between 18.7 and 19.1 degrees 2θ [endpoints included], and between 21.4 and 21.8 degrees 2θ [endpoints included] 3. The composition of claim 1 or claim 2, in a crystalline form having an XRPD pattern comprising:

8. The subject's breast milk is monitored to determine the relative infant dose of Compound (1) or the pharma- ceutically acceptable salt of Compound (1) in the breast milk, and the daily dose of Compound (1) is adjusted to provide less than a maximum relative infant dose; if necessary, the maximum relative infant dose is at most about 0.5%, at most about 0.4%, or at most about 0.357% of the daily dose administered to the subject. The composition of claim 1 or claim 2.

9. 3. The composition of claim 1 or claim 2, wherein the child is monitored for abnormal behavior; optionally, the abnormal behavior is selected from the group consisting of agitation, irritability, lethargy, excessive sleepiness, poor appetite and poor weight gain; and optionally, if the relative infant dose exceeds the maximum relative infant dose or if the child exhibits abnormal behavior, the daily dose administered to the subject is reduced by 10 mg.

10. 1. A composition for use in a method for treating depression in a human female subject, the composition comprising: Compound (1): 【Chemistry 43】 or a pharma- ceutically acceptable salt of compound (1), said method comprising: a) administering to said subject about 30 mg to about 50 mg of compound (1), or a pharma- ceutically acceptable salt of compound (1) at a dose equivalent to about 30 mg to about 50 mg of the free base, once daily for about 14 days during the treatment period; said subject breastfeeding a child during said treatment period; b) comparing the relative infant dose of Compound (1) or said pharmaceutically acceptable salt of Compound (1) in said subject's breast milk to a predetermined maximum relative infant dose; c) reducing the daily dose administered to the subject if the relative infant dose of Compound (1) or the pharma- ceutically acceptable salt of Compound (1) in the subject's breast milk exceeds the pre-determined maximum relative infant dose or if the child exhibits abnormal behavior. A composition comprising:

11. 1. A composition for use in a method for treating depression in a human female subject, the composition comprising: Compound (1): 【Chemistry 47】 or a pharma- ceutically acceptable salt of compound (1), said method comprising: a) administering to said subject about 30 mg to about 50 mg of Compound (1), or a pharma- ceutically acceptable salt of Compound (1) at a dose equivalent to about 30 mg to about 50 mg of the free base, once daily for about 14 days during a treatment period, wherein said subject is nursing a child during said treatment period; b) collecting and testing a sample of said subject's breast milk to determine the relative infant dose of Compound (1) or said pharma- ceutically acceptable salt of Compound (1) in said breast milk; c) comparing the relative infant dose determined in step b) with a predetermined maximum relative infant dose; d) monitoring the child for abnormal behavior; e) reducing the daily dose administered to the subject if the relative infant dose determined in step b) exceeds the predetermined maximum relative infant dose or if the child exhibits abnormal behavior; and f) repeating steps a) through e) daily for the duration of said treatment period. A composition comprising:

12. The composition according to any one of claims 1, 2, 10 and 11, wherein 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.

13. The composition according to any one of claims 1, 2, 10 and 11, wherein 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.

14. The composition according to any one of claims 1, 2, 10 and 11, wherein compound (1) is administered in a dose of about 30 mg, or the pharma- ceutically acceptable salt of compound (1) is administered in a dose equivalent to about 30 mg of the free base compound.

15. Compound (1) or the pharma- ceutically acceptable salt of compound (1) is (A) orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, intravaginally, as a buccal tablet, sublingually, rectally, topically, as an inhalant, intranasally, or transdermally; (B) orally; (C) with food; and / or (D) At night, once a day The composition according to any one of claims 1, 2, 10 and 11, characterized in that it is administered.

16. The composition of any one of claims 1, 2, 10 and 11, wherein the subject is treatment naive.

17. 12. The composition of any one of claims 1, 2, 10 and 11, wherein the subject has been taking a stable dose of an additional antidepressant for at least 30 days or at least 60 days prior to the start of the treatment period.

18. Compound (1) or the pharma- ceutically acceptable salt of compound (1) is re-administered to the subject upon recurrence of depressive symptoms after completion of an initial treatment period; 12. The composition of any one of claims 1, 2, 10 and 11, optionally characterized in that there is an interval of at least 6 weeks between the last dose of the initial treatment period and the first dose of the re-administration.

19. (A) the predetermined maximum relative infant dose is at least about 0.5%, at least about 0.4%, or at least about 0.357% of the daily dose administered to the subject; or (B) the abnormal behavior of the infant is selected from the group consisting of agitation, irritability, lethargy, excessive sleepiness, loss of appetite and poor weight gain.

20. A composition described in any one of claims 1, 10 and 11, wherein the depression is postpartum depression (PPD).

21. The composition described in claim 20, wherein the PPD is PPD accompanied by elevated anxiety.

22. The composition described in claim 2, wherein the depression is postpartum depression (PPD).

23. The composition described in any one of claims 1, 10 and 11, wherein the depression is major depressive disorder (MDD).

24. The composition described in claim 23, wherein the MDD is MDD accompanied by elevated anxiety.

25. The composition described in claim 2, wherein the depression is major depressive disorder (MDD).

Images