WO2023158668A1 - Neuroactive steroids for treatment of cns-related disorders - Google Patents

Neuroactive steroids for treatment of cns-related disorders Download PDF

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Publication number
WO2023158668A1
WO2023158668A1 PCT/US2023/013098 US2023013098W WO2023158668A1 WO 2023158668 A1 WO2023158668 A1 WO 2023158668A1 US 2023013098 W US2023013098 W US 2023013098W WO 2023158668 A1 WO2023158668 A1 WO 2023158668A1
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WIPO (PCT)
Prior art keywords
treatment
compound
antidepressant
subject
administered
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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PCT/US2023/013098
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English (en)
French (fr)
Inventor
Robert Alfonso LASSER
James Doherty
Jeffrey Martin JONAS
Stephen Jay KANES
Handan GUNDUZ-BRUCE
Amy E. BULLOCK
Timothy Y. MARIANO
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Sage Therapeutics Inc
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Sage Therapeutics Inc
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Application filed by Sage Therapeutics Inc filed Critical Sage Therapeutics Inc
Priority to EP23710570.5A priority Critical patent/EP4479032A1/en
Priority to CA3252357A priority patent/CA3252357A1/en
Priority to MX2024009974A priority patent/MX2024009974A/es
Priority to JP2024548386A priority patent/JP2025508406A/ja
Priority to AU2023220976A priority patent/AU2023220976A1/en
Priority to CN202380033285.6A priority patent/CN119072304A/zh
Priority to IL315023A priority patent/IL315023A/en
Priority to KR1020247030934A priority patent/KR20240148425A/ko
Priority to US18/839,147 priority patent/US20250295674A1/en
Publication of WO2023158668A1 publication Critical patent/WO2023158668A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to methods of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof with Compound (1) and an additional antidepressant.
  • MDD major depressive disorder
  • PPD postpartum depression
  • the World Health Organization has identified depression as a leading cause of disability worldwide, and as a major contributor to the overall global burden of disease (http://www.who.int/mediacentre/factsheets/fs369/en/). Globally, depression has been estimated to affect about 260 million people.
  • DMD-5 The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, American Psychiatric Association 2013) provides diagnostic criteria for major depressive disorder (MDD). These include at least 5 of 9 depressive symptoms (depressed mood and/or loss of interest or pleasure, and other changes affecting appetite or weight, sleep, psychomotor activity, energy level, feelings of guilt, concentration ability, and suicidality) during the same 2-week period that represents a change from previous functioning.
  • Antidepressants are a mainstay of pharmacological treatment for depressive disorders.
  • Selective serotonin uptake inhibitors SSRI
  • serotonin-norepinephrine reuptake inhibitors SNRI
  • tricyclic antidepressants SNRI
  • monoamine oxidase inhibitors MAOI
  • antidepressants While antidepressants are widely used, large scale studies have demonstrated their limited efficacy, including low remission rates and untreated symptoms.
  • these agents can take 4 to 8 weeks to demonstrate full clinical efficacy, and in the case of the most commonly prescribed classes — SSRIs and SNRIs — common side effects including weight gain, GI symptoms, and sexual dysfunction can prevent titration into an adequate therapeutic range.
  • An aspect of the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising:
  • Another aspect of the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising:
  • the subject is treatment-naive.
  • the subject has not received any antidepressant treatment within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 60 days prior to the start of the first treatment.
  • the first treatment administers the combination for about 14 days.
  • the second treatment administers the additional antidepressant for at least 28 days.
  • the second treatment administers the additional antidepressant for 28 days.
  • the second treatment administers the additional antidepressant for at least 28 days.
  • the additional antidepressant is administered at the same dose in the first and second treatment. In some embodiments, the additional antidepressant is administered at a different dose in the first and second treatment.
  • Compound (1) is not administered to the subject in the second treatment.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered in separate dosage forms. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered at the same time. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered at different times.
  • the additional antidepressant is administered at the same dose in the first treatment and the second treatment. In some embodiments, the additional antidepressant is administered at a different dose in the first treatment and the second treatment.
  • the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the first treatment.
  • the combination of Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant is re-administered to the subject in response to a recurrence of depression symptoms. In some embodiments, there is at least a 6 week interval between the last dose of the first treatment and the first dose of the readministration.
  • Another aspect of the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of Compound (1), or a pharmaceutically acceptable salt thereof,
  • Another aspect of the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a treatment-naive subject in need thereof, comprising co-initiation of administration of a combination comprising a therapeutically effective amount of Compound (1), or a pharmaceutically acceptable salt thereof,
  • MDD major depressive disorder
  • PPD postpartum depression
  • Compound (1) and a therapeutically effective amount of an additional antidepressant.
  • the subject has not received any antidepressant treatment within at least 30 days prior to the treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 30 days prior to the treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 60 days prior to the treatment.
  • the combination is administered for about 14 days.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant are administered in separate dosage forms. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant are administered at the same time. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant are administered at different times.
  • the treatment further comprises a second treatment comprising administering a therapeutically effective amount of an additional antidepressant.
  • the second treatment administers the additional antidepressant for at least 28 days.
  • Compound (1), or a pharmaceutically acceptable salt thereof, is not administered to the subject in the second treatment.
  • the additional antidepressant is administered at the same dose in the second treatment as in the combination. In some embodiments, the additional antidepressant is administered at a different dose in the second treatment compared to the dose administered in the combination. In some embodiments, the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the combination.
  • the subject has MDD. In some embodiments, the subject has MDD with elevated anxiety. In some embodiments, the subject is experiencing a major depressive episode. In some embodiments, the subject has elevated anxiety during a majority of days of a major depressive episode. In some embodiments, the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17, at least 18, at least 19, or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17, or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.
  • the subject has PPD. In some embodiments, the subject has PPD with elevated anxiety. In some embodiments, the subject is experiencing a major depressive episode with peripartum onset. In some embodiments, the subject has elevated anxiety during a majority of days of a major depressive episode with peripartum onset. In some embodiments, the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17, at least 18, at least 19, or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17, or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.
  • administering the combination reduces a gastrointestinal treatment-emergent adverse event.
  • the gastrointestinal treatment- emergent adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.
  • the gastrointestinal treatment-emergent adverse event comprises nausea and/or diarrhea.
  • the gastrointestinal treatment-emergent adverse event comprises nausea.
  • the gastrointestinal treatment-emergent adverse event comprises diarrhea.
  • the gastrointestinal treatment-emergent adverse event results from treatment with the additional antidepressant.
  • the combination of Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant is re-administered to the subject in response to a recurrence of depression symptoms.
  • Compound (1) is administered. In some embodiments, a pharmaceutically acceptable salt of Compound (1) is administered.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with about 40 mg to about 50 mg of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound: wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • MDD major depressive disorder
  • PPD postpartum depression
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety or postpartum depression (PPD) with elevated anxiety in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with about 40 mg to about 50 mg of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • MDD major depressive disorder
  • PPD postpartum depression
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety or postpartum depression (PPD) with elevated anxiety in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound:
  • Compound (1) wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • the subject is treatment-naive.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising: (i) providing a first treatment comprising administering a combination comprising a therapeutically effective amount of Compound (1): and a therapeutically effective amount of an additional antidepressant; and
  • the present disclosure is directed to a method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising
  • Compound (1) and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; followed by
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising
  • Compound (1) and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; followed by
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising
  • Compound (1) and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; followed by
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • the subject is experiencing a major depressive episode. In some embodiments, the subject has elevated anxiety during a majority of days of a major depressive episode. In some embodiments, the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 or at least 20 at baseline.
  • administering the combination reduces a gastrointestinal treatment-emergent adverse event.
  • providing the first treatment reduces a gastrointestinal treatment-emergent adverse event.
  • the gastrointestinal treatment-emergent adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.
  • the gastrointestinal treatment-emergent adverse event comprises nausea and/or diarrhea.
  • the gastrointestinal treatment-emergent adverse event results from treatment with the additional antidepressant.
  • the subject is treatment-naive. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 60 days prior to the start of the first treatment.
  • the first treatment administers the combination for about 14 days.
  • the second treatment administers the additional antidepressant for at least 28 days.
  • the additional antidepressant is administered at the same dose in the first and second treatment.
  • the additional antidepressant is administered at a different dose in the first and second treatment.
  • Compound (1), or the pharmaceutically acceptable salt of Compound (1) is not administered to the subject in the second treatment.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered in separate dosage forms. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered at the same time. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered at different times.
  • the additional antidepressant is administered at the same dose in (i) and (ii). In some embodiments, the additional antidepressant is administered at a different dose in (i) and (ii). In some embodiments, Compound (1), or the pharmaceutically acceptable salt of Compound (1), is not administered to the subject in (ii). In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in (i) are administered in separate dosage forms. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in (i) are administered at the same time.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in (i) are administered at different times.
  • the additional antidepressant administered in (ii) is the same as the additional antidepressant administered in (i).
  • the combination of Compound (1), or the pharmaceutically acceptable salt of Compound (1), and the additional antidepressant is re-administered to the subject in response to a recurrence of depression symptoms. In some embodiments, there is at least a 6 week interval between the last dose of the first treatment and the first dose of the readministration.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1): and a therapeutically effective amount of an additional antidepressant, wherein the subject is treatment-naive.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • the present disclosure is directed to a method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of Compound (1):
  • the present disclosure is directed to a method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering for about 14 days a combination comprising a therapeutically effective amount of Compound (1): and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; wherein the subject is treatment naive.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering for about 14 days a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1): and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; wherein the subject is treatment naive.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a combination comprising about 40 mg to about 50 mg of Compound (1):
  • Compound (1) and a therapeutically effective amount of an additional antidepressant.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a combination comprising a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound:
  • MDD major depressive disorder
  • Compound (1) and a therapeutically effective amount of an additional antidepressant.
  • the subject is experiencing a major depressive episode. In some embodiments, the subject has elevated anxiety during a majority of days of a major depressive episode. In some embodiments, the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 or at least 20 at baseline.
  • administering the combination reduces a gastrointestinal treatment-emergent adverse event.
  • providing the combination reduces a gastrointestinal treatment-emergent adverse event.
  • the gastrointestinal treatment-emergent adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.
  • the gastrointestinal treatment-emergent adverse event comprises nausea and/or diarrhea.
  • the gastrointestinal treatment- emergent adverse event results from treatment with the additional antidepressant.
  • the subject has not received any antidepressant treatment within at least 30 days prior to the start of treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 30 days prior to the start treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 60 days prior to the start treatment.
  • the treatment administers the combination for about 14 days.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the combination are administered in separate dosage forms.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the combination are administered at the same time.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the combination are administered at different times.
  • the treatment further comprises a second treatment comprising administering a therapeutically effective amount of an additional antidepressant.
  • the second treatment administers the additional antidepressant for at least 28 days.
  • the additional antidepressant is administered at the same dose in the second treatment as in the combination.
  • the additional antidepressant is administered at a different dose in the second treatment compared to the dose administered in the combination.
  • Compound (1), or the pharmaceutically acceptable salt of Compound (1) is not administered to the subject in the second treatment.
  • the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the combination.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with about 40 mg to about 50 mg of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound: wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising coadministering a therapeutically effective amount of an antidepressant with about 40 mg to about 50 mg of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising coadministering a therapeutically effective amount of an antidepressant with a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound: wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the subject is treatment-naive.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the subject is treatment-naive.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of Compound (1):
  • the present disclosure is directed to a method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising coadministering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • MDD major depressive disorder
  • Compound (1) wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising coadministering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • Compound (1) wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • the subject is experiencing a major depressive episode. In some embodiments, has elevated anxiety during a majority of days of a major depressive episode. In some embodiments, the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 or at least 20 at baseline.
  • the co-administration reduces a gastrointestinal treatment- emergent adverse event. In some embodiments, the co-administration reduces a gastrointestinal treatment-emergent adverse event. In some embodiments, the gastrointestinal treatment-emergent adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof. In some embodiments, the gastrointestinal treatment-emergent adverse event comprises nausea and/or diarrhea. In some embodiments, the gastrointestinal treatment- emergent adverse event results from treatment with the antidepressant.
  • the subject is treatment-naive. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of the co-administration. In some embodiments, the subject has not received treatment with the antidepressant within at least 30 days prior to the start of the co-administration. In some embodiments, the subject has not received treatment with the antidepressant within at least 60 days prior to the start of the co-administration.
  • the antidepressant continues to be administered for at least an additional 28 days after day 14 of the treatment.
  • Compound (1), or the pharmaceutically acceptable salt of Compound (1) is not administered after day 14 of the treatment.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the antidepressant in the co-administration are administered in separate dosage forms. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the antidepressant in the co-administration are administered at the same time. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the antidepressant in the co-administration are administered at different times. In some embodiments, the antidepressant is administered at the same dose from day 1 of treatment to about day 14 of treatment and after day 14 of treatment. In some embodiments, the antidepressant is administered at the same dose from day 1 of treatment to about day 14 of treatment and after day 14 of treatment.
  • the present disclosure provides method of treating major depressive disorder (MDD) in a treatment-naive subject in need thereof, comprising co-initiation of administration of a combination comprising a therapeutically effective amount of Compound
  • Compound (1) and a therapeutically effective amount of an antidepressant.
  • methods directed to treating MDD are also directed to treating postpartum depression (PPD).
  • PPD postpartum depression
  • FIG. 1 is a schematic study design of the clinical study of Example 1.
  • FIG. 2 shows patient disposition of the study of Example 2.
  • FIG. 3 is a bar chart showing change from baseline (CFB) in HAM-D total score at Day 3. Data are shown for the full analysis set using a mixed effects model for repeated measures. *p ⁇ 0.05.
  • FIG. 4 is a bar chart showing CFB in HAM-D total score over the blinded treatment period (14 days while on treatment; using equal weights for Days 3, 8, 12, and 15). Data are shown for the full analysis set using a mixed effects model for repeated measures. Change from baseline in HAMD-17 total score over the blinded treatment period was estimated using equal weights for the scheduled visits at Days 3, 8, 12, and 15. *p ⁇ 0.05.
  • FIG. 5 is a line plot showing change from baseline in HAM-D total score over time, least squares mean (LSM) ( ⁇ SE). Data are shown for the full analysis set using a mixed effects model for repeated measures. Day 3 is the primary endpoint; all other time points were no adjusted for multiplicity, and p-values are considered nominal. *p ⁇ 0.05. The dashed line signifies the end of the treatment period and the final assessment of the primary endpoint.
  • FIG. 6 is a forest plot of treatment differences in HAMD-17 total score at Day 3. Data are shown for the full analysis set.
  • FIG. 7A shows bar graphs of HAM-D Response (>50% reduction from baseline in HAMD-17) at various time points. Data are shown for the full analysis set. The endpoints were not adjusted for multiplicity and p values are considered nominal. *p ⁇ 0.05.
  • FIG. 7B shows bar graphs of HAM-D Remission (HAMD-17 ⁇ 7) at various time points. Data are shown for the full analysis set. The endpoints were not adjusted for multiplicity and p values are considered nominal. *p ⁇ 0.05.
  • FIG. 8 shows a line plot showing change from baseline in MADRS total score, LSM ( ⁇ SE). Data are shown for the full analysis set using a mixed effects model for repeated measures. These endpoints were not adjusted for multiplicity, and p-values are considered nominal. *p ⁇ 0.05.
  • FIG. 9 shows bar graphs of CGI-I response by study visit. Data are shown for the full analysis set. Response was defined as a CGI-I score of “very much improved” or “much improved.” These endpoints were not adjusted for multiplicity, and p-values are considered nominal. *p ⁇ 0.05.
  • FIG. 10A is a line plot showing change from baseline in HAM-D total score over time in patients with MDD with elevated anxiety. Data are shown for the full analysis set. *p ⁇ 0.05 for significant nominal differences, p-values were not adjusted for multiplicity.
  • the term “elevated anxiety” is used only in reference to or as a symptom of depression.
  • FIG. 10B shows a subgroup analysis of change from baseline in HAMD-17 total score in patients with MDD with elevated anxiety. Patients with MDD with elevated anxiety were defined as having baseline HAM-A total score >20. Data are shown for the full analysis set using a mixed effects model for repeated measures. The term “elevated anxiety” is used only in reference to or as a symptom of depression. These endpoints were not adjusted for multiplicity, and p-values are considered nominal. *p ⁇ 0.05.
  • FIG. 10C is a line plot showing change from baseline in HAM-D total score over time in patients with MDD without elevated anxiety. Data are shown for the full analysis set. p-values were not adjusted for multiplicity.
  • FIG. 11 is line plot showing change from baseline in HAM-A, LSM ( ⁇ SE), over time.
  • Compound (1) refers to the compound having the formula (or structure):
  • Compound (1) is also known as zuranolone, 3a-hydroxy-3P-methyl-21-(4- cyanopyrazol-l-yl)-5P-19-norpregnan-20-one, and by its IUPAC name:
  • Compound (1) is a neuroactive steroid that has been shown to be a positive allosteric modulator of GABAA receptors that target synaptic and extrasynaptic GAB AA receptors.
  • Compound (1) serves as a therapeutic agent to treat CNS related disorders, e.g., depression, postpartum depression and major depressive disorder and to treat neurological conditions, e.g., essential tremor, epilepsy, and Parkinson’s disease.
  • crystalline refers to a solid phase of a given chemical entity having well-defined 3 -dimensional structural order.
  • the atoms, ions, and/or molecules are arranged in a regular, periodic manner within a repeating 3 -dimensional lattice.
  • a crystalline material may comprise one or more discreet crystalline forms.
  • the terms "crystalline form”, “crystalline solid form,” “crystal form,” “solid form,” and related terms herein refer to crystalline modifications comprising a given substance (e.g., Compound (1)), including single-component crystal forms and multiplecomponent crystal forms, and including, but not limited to, polymorphs, solvates, hydrates, and salts.
  • substantially crystalline refers to forms that may be at least a particular weight percent crystalline. Particular weight percentages may include 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or any percentage between 70% and 100%. In certain embodiments, the particular weight percent of crystallinity is at least 90%. In certain other embodiments, the particular weight percent of crystallinity is at least 95%.
  • Compound (1) can be a substantially crystalline sample of any of the crystalline forms described herein (e.g., crystalline Forms A and C) and/or PCT Application Publication No. WO 2018/039378; the entire contents of the aforementioned application are incorporated herein by reference in its entirety.
  • composition of a specific crystalline form e.g., a crystalline form of Compound (1)
  • a specific crystalline form e.g., a crystalline form of Compound (1)
  • Particular weight percentages may include 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any percentage between 70% and 100%.
  • Compound (1) can be a substantially pure sample of any of the crystalline forms described herein, (e.g., crystalline Forms A and C).
  • Compound (1) can be substantially pure Form A.
  • Compound (1) can be substantially pure Form C.
  • XRPD refers to X-ray powder diffraction.
  • An XRPD pattern is an x-y graph with 2Q (diffraction angle) plotted on the x-axis and intensity plotted on the y-axis.
  • 2Q diffiffraction angle
  • These are the diffraction peaks which may be used to characterize a crystalline material.
  • the diffraction peaks are usually represented and referred to by their position on the x-axis rather than the intensity of the diffraction peaks on the y-axis because diffraction peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255- 257 (2003)).
  • intensity is not typically used by those of skill in the art to characterize a crystalline material.
  • variability in XRPD data there may be variability in XRPD data.
  • variability in diffraction peak intensity there may also be variability in the position of the diffraction peaks on the x-axis. This variability can, however, typically be accounted for when reporting the positions of diffraction peaks for purposes of characterization.
  • Such variability in the position of diffraction peaks along the x-axis may be derived from several sources. One such source can be sample preparation. Samples of the same crystalline material prepared under different conditions may yield slightly different diffractograms.
  • Factors such as particle size, moisture content, solvent content, temperature, and orientation may all affect how a sample diffracts X-rays. Another source of variability comes from instrument parameters. Different X-ray powder diffractometers operate using different parameters and may lead to slightly different diffraction patterns from the same crystalline material. Likewise, different software packages process XRPD data differently and this may also lead to variability. These and other sources of variability are known to those of ordinary skill in the art.
  • each X-ray diffraction peak may be preceded with the term “about” or proceeded with an appropriate range defining the experimental variability (e.g., ⁇ 0.1°, ⁇ 0.2°, ⁇ 0.3°, ⁇ 0.4°, ⁇ 0.5°, etc.).
  • characteristic peaks when referring to the 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 collection of specific diffraction peaks whose values span a range of 29 values (e.g., 0° to 40°) that are, as a whole, unique to that specific crystalline form.
  • “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • 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 formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulf
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically 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.
  • the term "about”, when referring to a numerical value or range, allows for a degree of variability in the value or range, for example, within 10%, or within 5% of a stated value or of a stated limit of a range.
  • modulation refers to the inhibition or potentiation of GABAA receptor function.
  • a “modulator” e.g., a compound or pharmaceutically acceptable salt thereof that modulates GABAA receptor function
  • the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition (or any symptom thereof), or retards or slows the progression of the disease, disorder or condition ("therapeutic treatment"), and also contemplates a prophylactic action that occurs before a subject begins to suffer from the specified disease, disorder or condition.
  • therapeutic treatment a prophylactic action that occurs before a subject begins to suffer from the specified disease, disorder or condition.
  • treatment naive refers to a subject that has not been previously treated with the additional antidepressant within the current depressive episode.
  • Treatment naive also refers to a subject that has not taken any antidepressant within at least 30 days prior to the start of treatment (i.e., Day 1). In some embodiments, the subject has not taken any antidepressant within at least 60 days prior to the start of treatment (i.e., Day 1).
  • the Hamilton Rating Scale for Depression is a multiple-item questionnaire used to provide an indication of depression.
  • the original scale/version published by Max Hamilton in 1960 included 17 items for rating, with other versions available that include up to 29 items.
  • HAMD- 17 or “17-HAM-D” refers to the 17-item Hamilton Rating Scale for Depression.
  • HAM-D total score and “HAMD- 17 total score” are used interchangeably and refer to total score obtained using the 17-item Hamilton Rating Scale for Depression.
  • “HAM-D” followed by a subscale or single item score, such as HAM-D Anxiety/Somatization subscale refers to a subscale or single item score using the 17-item Hamilton Rating Scale for Depression.
  • MDD with elevated anxiety is used interchangeably and refer to subjects with MDD who present elevated anxiety as a symptom of their depression.
  • MDD with elevated anxiety is characterized by a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline.
  • MDD with elevated anxiety is characterized by a HAM-D Anxiety/Somatization subscale standardized or normalized score of at least 39 at baseline.
  • a HAM-D Anxiety/Somatization subscale standardized or normalized score of at least 39 is equivalent to a HAM-D Anxiety/Somatization subscale (raw) score of at least 7.
  • MDD with elevated anxiety is characterized by a HAM-A total score of at least 17 at baseline (i.e. prior to administration of Compound (1) or a pharmaceutically acceptable salt thereof).
  • MDD with elevated anxiety is characterized by a HAM-A total score of at least 18 at baseline.
  • MDD with elevated anxiety is characterized by a HAM-A total score of at least 20 at baseline.
  • MDD with elevated anxiety is defined in accordance with the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition, which is MDD with an anxious distress specifier.
  • “elevated anxiety” is characterized by a HAM-A score based on the HAM-A anxiety items and somatic items.
  • “elevated anxiety” is characterized by a HAM-A score based on the HAM-A anxiety items.
  • “elevated anxiety” is characterized by a HAM-D score based on the following HAM-D items: psychic anxiety, somatic anxiety, GI somatic symptoms, and/or general somatic symptoms.
  • “elevated anxiety” is characterized by a HAM-D score based on the following HAM-D item: psychic anxiety. In some embodiments, “elevated anxiety” is characterized by a HAM-D score based predominately on the items evaluating somatic symptoms of depression. In some embodiments, “elevated anxiety” is characterized by a HAM-D score based predominately on the items evaluating anxiety symptoms of depression. In some embodiments, “elevated anxiety” is characterized by a HAM-D Anxiety/Somatization subscale score based predominately on the items evaluating somatic symptoms of depression.
  • “elevated anxiety” is characterized by a HAM-D Anxiety/Somatization subscale score based predominately on the items evaluating anxiety symptoms of depression. In some embodiments, “elevated anxiety” is characterized by a MADRS score based predominately on the items evaluating the somatic symptoms of depression. In some embodiments, “elevated anxiety” is characterized by a MADRS score based predominately on the items evaluating the anxiety symptoms of depression.
  • PPD with elevated anxiety “PPD with anxious distress,” or “MDD with peripartum onset, with anxious distress” are used interchangeably and refer to subjects with PPD who present elevated anxiety as a symptom of their depression.
  • PPD with elevated anxiety is defined in accordance with the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) definition, which is MDD with peripartum onset specifier and with an anxious distress specifier.
  • DSM-5 American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders
  • DSM-5 Fifth Edition
  • PPD with elevated anxiety is characterized by HAM-D Anxiety/Somatization subscale score, HAM-A total score, and/or MADRS score as described herein.
  • an "effective amount" of a compound (or pharmaceutically acceptable salt thereof) refers to an amount sufficient to elicit the desired biological response, e.g, to treat sexual dysfunction, e.g, to treat treatment-induced sexual dysfunction.
  • the effective amount of a compound (or pharmaceutically acceptable salt thereof) of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • a “therapeutically effective amount” of a compound (or pharmaceutically acceptable salt thereof) is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition.
  • a therapeutically effective amount of a compound (or pharmaceutically acceptable salt thereof) means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
  • the present invention contemplates administration of the compounds of the present invention or a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof, as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition.
  • a prophylactically effective amount of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the 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.
  • a “subject” or “patient” is a human (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle- aged adult or senior adult)).
  • a pediatric subject e.g., infant, child, adolescent
  • adult subject e.g., young adult, middle- aged adult or senior adult
  • the term "dose equivalent” means a bioequivalent dose.
  • the dose equivalent of a pharmaceutically acceptable salt of Compound (1) for a 50 mg dose of Compound (1) is the amount of the pharmaceutically acceptable salt (by weight) needed to provide a bioequivalent dose to the 50 mg dose of the free base of Compound (1).
  • the term "unit dosage form” is defined to refer to the form in which Compound (1) is administered to the patient.
  • the unit dosage form can be, for example, a pill, capsule, or tablet.
  • the unit dosage form is a capsule.
  • the unit dosage form is a tablet.
  • solid dosage form means a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewables.
  • administer refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
  • co-admini strati on” or administration of “a combination” means administration of the selected therapeutic agents to a single patient, and includes treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
  • the agents are in a fixed dose combination.
  • the agents are not in a fixed dose.
  • the agents are administered concurrently.
  • the agents are administered sequentially.
  • the agents are not in a fixed dose and are administered at the same or different time.
  • the present disclosure is directed to methods of treating major depressive disorder (MDD) or postpartum depression.
  • MDD major depressive disorder
  • the diagnosis and severity of the MDD or PPD treated by the methods described herein can be characterized as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5 th Edition (DSM-5).
  • Depressive disorders include disruptive mood dysregulation disorder, major depressive disorder (including major depressive episode), 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 sad, empty, or irritable mood, accompanied by somatic and cognitive changes that significantly affect the individual’s capacity to function. What differs among them are issues of duration, timing, or presumed etiology.
  • Major depressive disorder represents the classic condition in this group of disorders. It is characterized by discrete episodes of at least 2 weeks’ duration (although most episodes last considerably longer) involving clear-cut changes in affect, cognition, and neurovegetative functions and inter-episode remissions. A discrete episode of major depressive disorder may be referred to as a “major depressive episode” or “depressive episode”.
  • Major depressive disorder is generally known in the art.
  • MDD is also known as depression or clinical depression and it is a mood disorder that causes a persistent feeling of sadness and loss of interest. MDD affects how a subject may feel, think, and behave, and can lead to a variety of emotional and physical problems.
  • MDD is defined and diagnosed according to the DSM-5, for example, MDD is diagnosed according to Criterion A, as described below.
  • Criterion A Five (or more) of the following symptoms have been present during the same 2-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.
  • Criteria B-E are additional descriptions of MDD and may be considered for describing or diagnosing MDD, but are not required.
  • Criterion B The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • Criterion C The episode is not attributable to the physiological effects of a substance or to another medical condition.
  • Criteria A-C represent a major depressive episode.
  • Criterion D The occurrence of the 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.
  • a major depressive episode is a period characterized by the symptoms of MDD as described above.
  • MDD is a clinical course that is characterized by one or more major depressive episodes (MDE) in a subject.
  • MDE major depressive episodes
  • MDD is diagnosed according to Criteria A-C, as described above. In some embodiments, MDD is diagnosed according to Criteria A-E, as described above.
  • the criterion symptoms for major depressive disorder must be present nearly every day to be considered present, with the exception of weight change and suicidal ideation.
  • Depressed mood must be present for most of the day, in addition to being present nearly every day.
  • insomnia or fatigue is the presenting complaint, and failure to probe for accompanying depressive symptoms will result in underdiagnosis.
  • Sadness may be denied at first but may be elicited through interview or inferred from facial expression and demeanor.
  • clinicians should determine whether the distress from that complaint is associated with specific depressive symptoms. Fatigue and sleep disturbance are present in a high proportion of cases; psychomotor disturbances are much less common but are indicative of greater overall severity, as is the presence of delusional or near-delusional guilt.
  • the essential feature of a major depressive episode is a period of at least 2 weeks during which there is either depressed mood or the loss of interest or pleasure in nearly 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 that includes changes in appetite or weight, sleep, and psychomotor activity; decreased energy; feelings of worthlessness or guilt; difficulty thinking, concentrating, or making decisions; or recurrent thoughts of death or suicidal ideation or suicide plans or attempts. To count toward a major depressive episode, a symptom must either be newly present or must have clearly worsened compared with the person’s pre-episode status.
  • the symptoms must persist for most of the day, nearly 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 to be normal but requires markedly increased effort.
  • Sleep disturbance may take the form of either difficulty sleeping or sleeping excessively (Criterion A4).
  • insomnia When insomnia is present, it typically takes the form of middle in-somnia (i.e., waking up during the night and then having difficulty returning to sleep) or terminal insomnia (i.e., waking too early and being unable to return to sleep).
  • Initial insomnia i.e., difficulty falling asleep
  • Individuals who present with over-sleeping may experience prolonged sleep episodes at night or increased daytime sleep. Sometimes the reason that the individual seeks treatment is for the disturbed sleep.
  • the MDD can have a specifier as defined by the DSM-5, for example “anxious distress” or “elevated anxiety.”
  • the “anxious distress” identifier for MDD indicates the presence of at least two of the following symptoms during the majority of days of a major depressive episode or persistent depressive disorder (dysthymia):
  • Severity is defined as:
  • Moderate-severe Four or five symptoms.
  • Severe Four or five symptoms and with motor agitation.
  • Anxious distress has been noted as a prominent feature of both bipolar and major depressive disorder in both primary care and specialty mental health settings. High levels of anxiety have been associated with higher suicide risk, longer duration of illness, and greater likelihood of treatment nonresponse.
  • TEAEs Gastrointestinal treatment-emergent adverse events
  • MDD major depressive disorder
  • escital opram and sertraline were the least tolerated antidepressants on the gastrointestinal tract, being associated with all the considered TEAEs (nausea/vomiting, diarrhoea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite and dry mouth) with the exception of constipation and increased appetite.
  • each of the methods described herein are also directed to treating postpartum depression (PPD).
  • PPD postpartum depression
  • Postpartum depression also called postnatal depression, is a type of mood disorder associated with childbirth. Postpartum depression (PPD) is generally known in the art.
  • PPD is identified as the most common psychiatric illness to occur in the puerperium (O’Hara MW, Wisner KL. Best Pract Res Clin Obstet Gynaecol. 2014;28(l):3-12); and it can occur during the third trimester or after giving birth. If untreated, PPD can have devastating consequences for the woman and her family.
  • PPD is characterized by significant functional impairment for the mother due to sadness and depressed mood, loss of interest in daily activities, changes in eating and sleeping habits, fatigue and decreased energy, 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 following childbirth in developed countries.
  • the diagnosis of the PPD treated by the methods described herein can be characterized as defined by the DSM-5.
  • the diagnosis of the PPD treated by the methods described herein can be characterized as defined by the ACOG.
  • the diagnosis of the PPD treated by the methods described herein can be characterized as defined by the ICD-10.
  • the diagnosis of the PPD and/or PPD with elevated anxiety treated by the methods described herein can be characterized as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5 th Edition (DSM-5), that is as a MDD with peripartum onset and/or MDD with peripartum onset, with anxious distress specifiers.
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5 th Edition
  • the MDD and anxious distress specifier as defined by the DSM-5 are described above.
  • Mood episodes can have their onset either during pregnancy or postpartum. Although the estimates differ according to the period of follow-up after delivery, between 3% and 6% of women will experience the onset of a major depressive episode during pregnancy or in the weeks or months following delivery. Fifty percent of “postpartum” major depressive episodes actually begin prior to delivery. Thus, these episodes are referred to collectively as peripartum episodes. Women with peripartum 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 for a post partum major depressive episode. Peripartum-onset mood episodes can present either with or without psychotic features.
  • Infanticide is most often associated with postpartum psychotic episodes that are characterized by command hallucinations to kill the infant or delusions that the infant is possessed, but psychotic symptoms can also occur in severe post partum mood episodes without such specific delusions or hallucinations.
  • An aspect of the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising:
  • Another aspect of the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising:
  • the subject is treatment-naive.
  • the subject has not received any antidepressant treatment within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 60 days prior to the start of the first treatment.
  • the first treatment administers the combination for about 14 days.
  • the second treatment administers the additional antidepressant for at least 28 days. In some embodiments, the second treatment administers the additional antidepressant for 28 days. In some embodiments, the second treatment administers the additional antidepressant for at least 28 days.
  • the additional antidepressant is administered at the same dose in the first and second treatment. In some embodiments, the additional antidepressant is administered at a different dose in the first and second treatment.
  • Compound (1) is not administered to the subject in the second treatment.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered in separate dosage forms. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered at the same time. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered at different times.
  • the additional antidepressant is administered at the same dose in the first treatment and the second treatment. In some embodiments, the additional antidepressant is administered at a different dose in the first treatment and the second treatment.
  • the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the first treatment.
  • the combination of Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant is re-administered to the subject in response to a recurrence of depression symptoms. In some embodiments, there is at least a 6 week interval between the last dose of the first treatment and the first dose of the readministration.
  • Another aspect of the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of Compound (1), or a pharmaceutically acceptable salt thereof, Compound (1) and a therapeutically effective amount of an additional antidepressant, wherein the subject is treatment-naive.
  • MDD major depressive disorder
  • PPD postpartum depression
  • Another aspect of the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a treatment-naive subject in need thereof, comprising co-initiation of administration of a combination comprising a therapeutically effective amount of Compound (1), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an additional antidepressant.
  • MDD major depressive disorder
  • PPD postpartum depression
  • the subject has not received any antidepressant treatment within at least 30 days prior to the treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 30 days prior to the treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 60 days prior to the treatment. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 30 days prior to the start of treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 60 days prior to the start of treatment.
  • the combination is administered for about 14 days.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant are administered in separate dosage forms. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant are administered at the same time. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant are administered at different times.
  • the treatment further comprises a second treatment comprising administering a therapeutically effective amount of an additional antidepressant.
  • the second treatment administers the additional antidepressant for at least 28 days.
  • Compound (1), or a pharmaceutically acceptable salt thereof, is not administered to the subject in the second treatment.
  • the additional antidepressant is administered at the same dose in the second treatment as in the combination. In some embodiments, the additional antidepressant is administered at a different dose in the second treatment compared to the dose administered in the combination. In some embodiments, the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the combination.
  • the subject has MDD. In some embodiments, the subject has MDD with elevated anxiety. In some embodiments, the subject is experiencing a major depressive episode. In some embodiments, the subject has elevated anxiety during a majority of days of a major depressive episode. In some embodiments, the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17, at least 18, at least 19, or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17, or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.
  • the subject has PPD. In some embodiments, the subject has PPD with elevated anxiety. In some embodiments, the subject is experiencing a major depressive episode with peripartum onset. In some embodiments, the subject has elevated anxiety during a majority of days of a major depressive episode with peripartum onset. In some embodiments, the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17, at least 18, at least 19, or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17, or at least 20 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.
  • administering the combination reduces a gastrointestinal treatment-emergent adverse event.
  • the gastrointestinal treatment- emergent adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.
  • the gastrointestinal treatment-emergent adverse event comprises nausea and/or diarrhea.
  • the gastrointestinal treatment-emergent adverse event comprises nausea.
  • the gastrointestinal treatment-emergent adverse event comprises diarrhea.
  • the gastrointestinal treatment-emergent adverse event results from treatment with the additional antidepressant.
  • the combination of Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant is re-administered to the subject in response to a recurrence of depression symptoms.
  • Compound (1) is administered. In some embodiments, a pharmaceutically acceptable salt of Compound (1) is administered.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with about 40 mg to about 50 mg of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • MDD major depressive disorder
  • PPD postpartum depression
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) or postpartum depression (PPD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound: Compound (1), wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • MDD major depressive disorder
  • PPD postpartum depression
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety or postpartum depression (PPD) with elevated anxiety in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with about 40 mg to about 50 mg of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety or postpartum depression (PPD) with elevated anxiety in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound: wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • MDD major depressive disorder
  • PPD postpartum depression
  • the subject is treatment-naive.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) providing a first treatment comprising administering a combination comprising about 40 mg to about 50 mg of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising: (i) providing a first treatment comprising administering a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • the present disclosure is directed to a method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • Compound (1) (b) a therapeutically effective amount of an additional antidepressant, wherein the pharmaceutically acceptable salt of Compound (1) is administered once a day, and wherein the pharmaceutically acceptable salt of Compound (1) and the additional antidepressant in the first treatment are administered in separate dosage forms; and
  • the subject is experiencing a major depressive episode. In some embodiments, the subject has elevated anxiety during a majority of days of a major depressive episode. In some embodiments, the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 18 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.
  • the subject has a HAM-D total score of at least 24 and a HAM- A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 18 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 19 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM- A total score of at least 20 at baseline.
  • the subject has a HAM-D total score of at least 24 and a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline.
  • administering the combination reduces a gastrointestinal treatment-emergent adverse event.
  • providing the first treatment reduces a gastrointestinal treatment-emergent adverse event.
  • the gastrointestinal treatment-emergent adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.
  • the gastrointestinal treatment-emergent adverse event comprises nausea and/or diarrhea.
  • the gastrointestinal treatment-emergent adverse event results from treatment with the additional antidepressant.
  • the subject is treatment-naive. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 30 days prior to the start of the first treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 60 days prior to the start of the first treatment.
  • the first treatment administers the combination for about 14 days.
  • the second treatment administers the additional antidepressant for at least 28 days.
  • the additional antidepressant is administered at the same dose in the first and second treatment.
  • the additional antidepressant is administered at a different dose in the first and second treatment.
  • Compound (1), or the pharmaceutically acceptable salt of Compound (1) is not administered to the subject in the second treatment.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered in separate dosage forms. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered at the same time. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered at different times.
  • the additional antidepressant is administered at the same dose in (i) and (ii). In some embodiments, the additional antidepressant is administered at a different dose in (i) and (ii). In some embodiments, Compound (1), or the pharmaceutically acceptable salt of Compound (1), is not administered to the subject in (ii). In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in (i) are administered in separate dosage forms. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in (i) are administered at the same time.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in (i) are administered at different times.
  • the additional antidepressant administered in (ii) is the same as the additional antidepressant administered in (i).
  • the combination of Compound (1), or the pharmaceutically acceptable salt of Compound (1), and the additional antidepressant is re-administered to the subject in response to a recurrence of depression symptoms.
  • methods directed to treating MDD are also directed to treating postpartum depression (PPD).
  • PPD postpartum depression
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • the present disclosure is directed to a method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of Compound (1):
  • the present disclosure is directed to a method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1): and a therapeutically effective amount of an additional antidepressant wherein the subject is treatment-naive.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering for about 14 days a combination comprising a therapeutically effective amount of Compound (1):
  • Compound (1) and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; wherein the subject is treatment naive.
  • an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; wherein the subject is treatment naive.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering for about 14 days a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • Compound (1) and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; wherein the subject is treatment naive.
  • an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; wherein the subject is treatment naive.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a combination comprising about 40 mg to about 50 mg of Compound (1):
  • Compound (1) and a therapeutically effective amount of an additional antidepressant.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a combination comprising a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound:
  • MDD major depressive disorder
  • Compound (1) and a therapeutically effective amount of an additional antidepressant.
  • the subject is experiencing a major depressive episode. In some embodiments, the subject has elevated anxiety during a majority of days of a major depressive episode. In some embodiments, the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 18 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.
  • the subject has a HAM-D total score of at least 24 and a HAM- A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 18 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 19 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM- A total score of at least 20 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline.
  • administering the combination reduces a gastrointestinal treatment-emergent adverse event.
  • providing the combination reduces a gastrointestinal treatment-emergent adverse event.
  • the gastrointestinal treatment-emergent adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.
  • the gastrointestinal treatment-emergent adverse event comprises nausea and/or diarrhea.
  • the gastrointestinal treatment- emergent adverse event results from treatment with the additional antidepressant.
  • the subject has not received any antidepressant treatment within at least 30 days prior to the start of treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 30 days prior to the start treatment. In some embodiments, the subject has not received treatment with the additional antidepressant within at least 60 days prior to the start treatment.
  • the treatment administers the combination for about 14 days.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the combination are administered in separate dosage forms.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the combination are administered at the same time.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the combination are administered at different times.
  • the treatment further comprises a second treatment comprising administering a therapeutically effective amount of an additional antidepressant.
  • the second treatment administers the additional antidepressant for at least 28 days.
  • the additional antidepressant is administered at the same dose in the second treatment as in the combination.
  • the additional antidepressant is administered at a different dose in the second treatment compared to the dose administered in the combination.
  • Compound (1), or the pharmaceutically acceptable salt of Compound (1) is not administered to the subject in the second treatment.
  • the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the combination.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with about 40 mg to about 50 mg of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound: wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising coadministering a therapeutically effective amount of an antidepressant with about 40 mg to about 50 mg of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising coadministering a therapeutically effective amount of an antidepressant with a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound: wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the subject is treatment-naive.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the subject is treatment-naive.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of Compound (1):
  • the present disclosure is directed to a method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • MDD major depressive disorder
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising coadministering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of Compound (1):
  • Compound (1) wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • the present disclosure is directed to a method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising coadministering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • Compound (1) wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • the subject is experiencing a major depressive episode. In some embodiments, has elevated anxiety during a majority of days of a major depressive episode. In some embodiments, the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline. In some embodiments, the subject has a HAM-A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-A total score of at least 18 at baseline. In some embodiments, the subject has a HAM-A total score of at least 20 at baseline.
  • the subject has a HAM-D total score of at least 24 and a HAM- A total score of at least 17 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 18 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM-A total score of at least 19 at baseline. In some embodiments, the subject has a HAM-D total score of at least 24 and a HAM- A total score of at least 20 at baseline.
  • the subject has a HAM-D total score of at least 24 and a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline.
  • the co-administration reduces a gastrointestinal treatment- emergent adverse event.
  • the co-administration reduces a gastrointestinal treatment-emergent adverse event.
  • the gastrointestinal treatment-emergent adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.
  • the gastrointestinal treatment-emergent adverse event comprises nausea and/or diarrhea.
  • the gastrointestinal treatment- emergent adverse event results from treatment with the antidepressant.
  • the subject is treatment-naive. In some embodiments, the subject has not received any antidepressant treatment within at least 30 days prior to the start of the co-administration. In some embodiments, the subject has not received treatment with the antidepressant within at least 30 days prior to the start of the co-administration. In some embodiments, the subject has not received treatment with the antidepressant within at least 60 days prior to the start of the co-administration.
  • the antidepressant continues to be administered for at least an additional 28 days after day 14 of the treatment.
  • Compound (1), or the pharmaceutically acceptable salt of Compound (1) is not administered after day 14 of the treatment.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the antidepressant in the co-administration are administered in separate dosage forms.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the antidepressant in the co-administration are administered at the same time.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the antidepressant in the co-administration are administered at different times.
  • the antidepressant is administered at the same dose from day 1 of treatment to about day 14 of treatment and after day 14 of treatment. In some embodiments, the antidepressant is administered at the same dose from day 1 of treatment to about day 14 of treatment and after day 14 of treatment.
  • the present disclosure provides method of treating major depressive disorder (MDD) in a treatment-naive subject in need thereof, comprising co-initiation of administration of a combination comprising a therapeutically effective amount of Compound (1):
  • Compound (1) and a therapeutically effective amount of an antidepressant.
  • methods directed to treating MDD are also directed to treating postpartum depression (PPD).
  • PPD postpartum depression
  • the severity of disorders treated by the methods described herein can be characterized by methods known to one of skill in the art. These methods can include, but are not limited to, the following scales/assessments: Hamilton Depression Score (HAM-D), Hamilton Anxiety Score (HAM-A), Montgomery- Asb erg Depression Rating Scale (MADRS), Clinical Global Impression (CGI) scale, Clinical Global Impression- Improvement Scale (CGI-I), Clinical Global Impression-Severity of Illness (CGI-S), Clinical Global Impression- Change (CGI-C), Sheehan Disability Scale (SDS), 9-item Patient Health Questionnaire (PHQ-9), and Short Form 36 Health Survey version 2 (SF-36v2). Scoring for each of the aforementioned scales/assessments is based on each of the assessments measurements and their results can be reported as a total score, subscale score, and/or single item score.
  • HAM-D Hamilton Depression Score
  • HAM-A Hamilton Anxiety Score
  • MADRS Montgomery- Asb erg Depression Rating
  • Safety and tolerability of Compound (1) can be evaluated by methods known to one of skill in the art. These methods can include, but are not limited to, collecting and summarizing adverse events (AEs), clinical laboratory measures, vital signs, and 12 lead- electrocardiography. Emergent suicidal ideation and behaviors can be assessed using the Columbia-Suicide Severity Rating scale (C-SSRS). Sedation/sleepiness can be assessed using the Stanford Sleepiness Scale (SSS). The Physician Withdrawal Checklist-20 total score (PWC-20) can be used to monitor the presence of potential withdrawal symptoms following discontinuation of treatment with Compound (1).
  • C-SSRS Columbia-Suicide Severity Rating scale
  • SSS Stanford Sleepiness Scale
  • PWC-20 The Physician Withdrawal Checklist-20 total score (PWC-20) can be used to monitor the presence of potential withdrawal symptoms following discontinuation of treatment with Compound (1).
  • the method provides therapeutic effect.
  • the therapeutic effect is observed as measured by reduction in a HAM-D total score within about 42 ( ⁇ 3) days, about 35 ( ⁇ 3) days, about 28 ( ⁇ 3) days, about 21 ( ⁇ 1) days, about 18 ( ⁇ 1) days, about 15 ( ⁇ 1) days, about 12 ( ⁇ 1) days, about 8 ( ⁇ 1), about 3 ( ⁇ 1) days, or about 1 day.
  • the therapeutic effect is a decrease from baseline in HAM-D total score at the end of the first treatment period or combined administration of Compound (1) and the additional antidepressant, i.e., at the end of 14 days of administration of administration of Compound (1) and the additional antidepressant.
  • the therapeutic effect is a decrease from baseline in HAM-D total score at the end of the second treatment period.
  • the decrease from baseline in HAM-D total score is from severe (e.g., HAM-D total score of 24 or greater; or a score of 26 or greater) to symptom-free, i.e. remission of depression (e.g., HAM-D total score of 7 or lower).
  • the decrease from baseline in HAM-D total score is from severe (e.g., HAM-D total score of 24 or greater; or a total score of 26 or greater) to normal or mild depression (e.g., HAM-D total score of 7 or lower; or HAM-D total score of 18-13).
  • the HAM-D total score change from baseline (LS mean) at day 3 is at least about 8-10. In some embodiments, the HAM-D total score change from baseline (LS mean) at day 3 is at least about 8. In some embodiments, the HAM-D total score change from baseline (LS mean) at day 3 is at least about 9. In some embodiments, the HAM-D total score change from baseline (LS mean) for the treatment period (i.e., first treatment or combination or co-administration) is at least about 11. In some embodiments, the HAM-D total score change from baseline (LS mean) for the treatment period (i.e., first treatment or combination or co-administration) is at least about 11.5. In some embodiments, the HAM-D total score change from baseline (LS mean) for the treatment period (i.e., first treatment or combination or co-administration) is at least about 12.
  • the method provides therapeutic effect as measured by reduction in Montgomery- Asberg Depression Rating Scale (MADRS) total score within about 42 ( ⁇ 3) days, about 35 ( ⁇ 3) days, about 28 ( ⁇ 3) days, about 21 ( ⁇ 1) days, about 18 ( ⁇ 1) days, about 15 ( ⁇ 1) days, about 12 ( ⁇ 1) days, about 8 ( ⁇ 1), about 3 ( ⁇ 1) days, or about 1 day.
  • the Montgomery-Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire (regarding apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts) which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders.
  • the therapeutic effect is a decrease from baseline in MADRS total score at the end of the first treatment period or combined administration of Compound (1) and the additional antidepressant, i.e., at the end of 14 days of administration of administration of Compound (1) and the additional antidepressant.
  • the therapeutic effect is a decrease from baseline in MADRS total score at the end of the second treatment period.
  • the decrease from baseline in MADRS score is from severe (e.g., MADRS score of 30 or greater) to symptom-free (e.g., MADRS score of 20 or lower).
  • the MADRS total score change from baseline (LS mean) at day 8 is at least about 12-14.
  • the MADRS total score change from baseline (LS mean) at day 15 is at least about 16-18.
  • the method provides therapeutic effect as measured by reduction in Hamilton Anxiety Score (HAM- A) within about 42 ( ⁇ 3) days, about 35 ( ⁇ 3) days, about 28 ( ⁇ 3) days, about 21 ( ⁇ 1) days, about 18 ( ⁇ 1) days, about 15 ( ⁇ 1) days, about 12 ( ⁇ 1) days, about 8 ( ⁇ 1), about 3 ( ⁇ 1) days, or about 1 day.
  • HAM-A is scored where ⁇ 17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.
  • the therapeutic effect is a decrease from baseline in HAM-A score at the end of the first treatment period or combined administration of Compound (1) and the additional antidepressant, i.e., at the end of 14 days of administration of administration of Compound (1) and the additional antidepressant.
  • the therapeutic effect is a decrease from baseline in HAM-A score at the end of the second treatment period.
  • the decrease from baseline in HAM-A score is from severe (e.g., HAM- A score of 25 or greater) to symptom-free (e.g., HAM-A score of 17 or lower).
  • the decrease from baseline in HAM-A score is from severe (e.g., HAM-A score of 25 or greater) to mild (e.g., HAM-A score of 24 or lower).
  • the HAM-A total score change from baseline (LS mean) at day 3 is at least about 9.
  • the HAM-A total score change from baseline (LS mean) at day 8 is at least about 11.
  • the HAM-A total score change from baseline (LS mean) at day 15 is at least about 14.
  • the antidepressant in the first and second treatments, or combination, or co-admini strati on is a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), a serotonin modulator and stimulator (SMS), a serotonin antagonist and reuptake inhibitor (SARI), a norepinephrine reuptake inhibitor (NRI), a norepinephrine dopamine reuptake inhibitor (NDRI), a tricyclic antidepressant (TCA), a tetracyclic antidepressant (TeCA), a monoamine oxidase inhibitor (MAOI), an atypical antipsychotic, agomelatine, esketamine, tianeptine, ketamine, a- methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine
  • SSRI selective seroton
  • the antidepressant in the first and second treatments, or combination, or co-admini strati on is 4-Chlorokynurenine (AV-101), Apimostinel (NRX- 1074), Arketamine (PCN-101, HR-071603), Dextromethadone (REL-1017), MU-821, Rislenemdaz (CERC-301, MK-0657), TAK-653 (NBI- 1065845), OPC-64005, PDC-1421 (BLI-1005), Toludesvenlafaxinem, Hypidone (YL-0919), TGBA01AD (FKB01MD), Vortioxetinem, Lisdexamfetamine, Midomafetamine, Aramisulpride/esamisulpride (85: 15 ratio) (SEP-4199), Gepirone, Pramipexole, Psilocybin, Brilaroxazine, Cariprazine, Lumateperone,
  • the antidepressant in the first or second treatment, or combination, or co-admini strati on is an SSRI.
  • the SSRI is sertraline, escitalopram, citalopram, fluvoxamine, paroxetine, fluoxetine, indalpine, or zimelidine.
  • the SSRI is sertraline.
  • the SSRI is escitalopram.
  • the SSRI is citalopram.
  • the antidepressant in the first or second treatment, or combination, or co-admini strati on is an SNRI.
  • the SNRI is duloxetine, desvenlafaxine, levomilnacipran, milnacipran, or venlafaxine.
  • the SNRI is duloxetine.
  • the SNRI is desvenlafaxine.
  • the antidepressant in the first or second treatment, or combination, or co-admini strati on is an SMS.
  • the SMS is vilazodone or vortioxetine.
  • the antidepressant in the first or second treatment, or combination, or co-admini strati on is an SARI.
  • the SARI is nefazodone, trazodone, or etoperidone.
  • the antidepressant in the first or second treatment, or combination, or co-admini strati on is an NRI.
  • the NRI is reboxetine, teniloxazine, viloxazine, or atomoxetine.
  • the antidepressant in the first or second treatment, or combination, or co-admini strati on is a NDRI.
  • the NDRI is bupropion, amphetamine, methylphenidate, modafinil, amineptine, or nomifensine.
  • the antidepressant in the first or second treatment, or combination, or co-admini strati on is a TCA.
  • the TCA is amitriptyline, amitriptylinoxide, clomipramine, desipramine, diebnzepin, dimetacrine, dosluepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, notriptyline, noxiptiline, opipramol, pipofezine, protriptyline, trimipramine, butriptyline, demexiptiline, fluacizine, imipraminoxide, iprindole, metapramine, propizepine, quinupramine, tiazesim, or tofenacin.
  • the antidepressant in the first or second treatment, or combination, or co-admini strati on is a TeCA.
  • the TeCA is amoxapine, maprotiline, mianserin, mirtazapine, or setiptiline.
  • the antidepressant in the first or second treatment, or combination, or co-admini strati on is a MAOI.
  • the MAOI is isocarboxazid, phenelzine, tranylcypromine, benmoxin, iproclozide, iproniazid, mebanazine, nialamide, octamoxin, pheniprazine, phenoxypropazine, pivhydrazine, safrazine, selegiline, caroxazone, metralindole, moclobemide, pirlindole, eprobemide, minaprine, toloxatone, or bifemelane.
  • the antidepressant in the first or second treatment, or combination, or co-admini strati on is an atypical antipsychotic.
  • the atypical antipsychotic is amisulpride, lumateperone, lurasidone, quetiapine, aripiprazole, brexpiprazole, lumateperone, lurasidone, olanzapine, quetiapine, or risperidone.
  • the antidepressant in the first or second treatment, or combination, or co-admini strati on is agomelatine, esketamine, tianeptine, ketamine, a- methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademetionine, hypericum perforatum, oxitriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine, or tranylcypromine and trifluoperazine.
  • the antidepressant in the first or second treatment, or combination, or co-admini strati on is administered per its labeled prescribing information.
  • the co-administration is co-initiation of administration of said Compound (1) or pharmaceutically acceptable salt; and said antidepressant.
  • the SSRI is sertraline and is administered at a dose of about 50 mg to about 200 mg, or about 50 mg to about 100 mg, or about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg.
  • the sertraline dose increases about 25 to about 50 mg per day of administration.
  • sertraline is administered at a dose of about 50 mg.
  • sertraline is administered at a dose of about 100 mg.
  • sertraline is administered at a dose of about 150 mg.
  • sertraline is administered at a dose of about 200 mg.
  • the SSRI is citalopram and is administered at a dose of about 10 mg to about 40 mg, or about 15 mg to about 30 mg, or about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.
  • citalopram is administered at a dose of about 20 mg.
  • citalopram is administered at a dose of about 30 mg.
  • citalopram is administered at a dose of about 40 mg.
  • the SSRI is escitalopram and is administered at a dose of about 10 mg to about 40 mg, or about 15 mg to about 30 mg, or about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.
  • escitalopram is administered at a dose of about 10 mg.
  • escitalopram is administered at a dose of about 15 mg.
  • escitalopram is administered at a dose of about 20 mg.
  • the SNRI is duloxetine and is administered at a dose of about 40 mg to about 120 mg, or about 60 mg to about 100 mg, or about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg.
  • duloxetine is administered at a dose of about 40 mg.
  • duloxetine is administered at a dose of about 60 mg.
  • the SNRI is desvenlafaxine and is administered at a dose of about 10 mg to about 100 mg, or about 20 mg to about 50 mg, or about 10 mg, about 20 mg, about 30 mg, about 40 mg, or about 50 mg. In some embodiments, desvenlafaxine is administered at a dose of about 50 mg.
  • Compound (1) is administered. In some embodiments, a pharmaceutically acceptable salt of Compound (1) is administered. In some embodiments, Compound (1) is present in a non-deuterated form. In some embodiments, Compound (1) is present in a deuterated form. In some embodiments, the deuterated forms of Compound (1) are those disclosed and described in PCT Application Publication No. WO 2019/113494 and in US Application No. 17/545,290; the entire contents of the aforementioned applications are incorporated herein by reference in their entireties.
  • Compound (1) is administered at a dose of about 10 mg to about 100 mg. In some embodiments, Compound (1) is administered at a dose of about 15 mg to about 75 mg. In some embodiments, Compound (1) is administered at a dose of about 20 mg to about 60 mg. In some embodiments, Compound (1) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg. In some embodiments, Compound (1) is administered at a dose of about 50 mg. In some embodiments, Compound (1) is administered at a dose of about 40 mg.
  • Compound (1) is administered at a dose of about 10 mg to about 100 mg once a day. In some embodiments, Compound (1) is administered at a dose of about 20 mg to about 60 mg once a day. In some embodiments, Compound (1) is administered at a dose of about 50 mg once a day. In some embodiments, Compound (1) is administered at a dose of about 40 mg once a day.
  • Compound (1) is administered at a dose of about 50 mg once a day for less than 2 weeks. In some embodiments, Compound (1) is administered at a dose of about 50 mg once a day for about 14 days. In some embodiments, Compound (1) is administered at a dose of about 40 mg once a day for less than 2 weeks. In some embodiments, Compound (1) is administered at a dose of about 40 mg once a day for about
  • the patient is administered Compound (1) at night. In some embodiments, the patient is administered Compound (1) no later than 1 hour before the patient sleeps. In some embodiments, the patient is administered Compound (1) no later than
  • Compound (1) is administered with food.
  • Compound (1) is administered with fat-containing food.
  • fatcontaining food include nuts, peanut butter, avocado, eggs, and cheese.
  • Compound (1) is administered at night with fat-containing food (e.g., within 1 hour of an evening meal which contains fat, or with a fat-containing snack).
  • Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal, sublingually, rectally, topically, as an inhalation, intranasaly, or transdermally. In some embodiments, Compound (1) is administered orally.
  • Compound (1) is administered in one or more capsules.
  • the therapeutically effective amount is administered across two capsules. In some embodiments, the therapeutically effective amount is administered across three capsules. In some embodiments, the therapeutically effective amount is administered across two capsules, wherein at least one capsule comprises about 20 mg of Compound (1). In some embodiments, the therapeutically effective amount is administered across two capsules, wherein at least one capsule comprises about 25 mg of Compound (1). In some embodiments, the therapeutically effective amount is administered across two capsules, wherein at least one capsule comprises about 30 mg of Compound (1). In some embodiments, the therapeutically effective amount is administered across two capsules, wherein each capsule comprises about 20 mg of Compound (1).
  • the therapeutically effective amount is administered across two capsules, wherein each capsule comprises about 25 mg of Compound (1). In some embodiments, the therapeutically effective amount is administered across two capsules, wherein one capsule comprises about 30 mg of Compound (1) and another capsule comprises about 20 mg of Compound (1).
  • the pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically 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 pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 50 mg of the free base compound. In some embodiments, the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 40 mg of the free base compound.
  • the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 10 mg to about 100 mg of the free base compound once a day. In some embodiments, the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 20 mg to about 60 mg of the free base compound once a day. In some embodiments, the pharmaceutically 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 once a day. In some embodiments, the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 50 mg of the free base compound once a day.
  • the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 40 mg of the free base compound once a day. [00303] In some embodiments, the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 50 mg of the free base compound once a day for less than 2 weeks. In some embodiments, the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 50 mg of the free base compound once a day for about 14 days. In some embodiments, the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 40 mg of the free base compound once a day for less than 2 weeks. In some embodiments, the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent of about 40 mg of the free base compound once a day for about 14 days.
  • the pharmaceutically acceptable salt of Compound (1) is administered at night. In some embodiments, the pharmaceutically acceptable salt of Compound (1) is administered no later than 1 hour before the subject sleeps. In some embodiments, the pharmaceutically acceptable salt of Compound (1) is administered no later than 15 minutes before the subject sleeps.
  • the pharmaceutically acceptable salt of Compound (1) is administered with food.
  • the pharmaceutically acceptable salt of Compound (1) is administered with fat-containing food.
  • fat-containing food examples include nuts, peanut butter, avocado, eggs, and cheese.
  • Compound (1) is administered at night with fat-containing food (e.g., within 1 hour of an evening meal which contains fat, or with a fat-containing snack).
  • the pharmaceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal, sublingually, rectally, topically, as an inhalation, intranasaly, or transdermally. In some embodiments, the pharmaceutically acceptable salt of Compound (1) is administered orally.
  • the pharmaceutically acceptable salt of Compound (1) is administered chronically.
  • the first treatment administers the combination of Compound (1), or pharmaceutically acceptable salt thereof, and the additional antidepressant for about 14 days.
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered in separate dosage forms. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered at the same time. In some embodiments, Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered at different times.
  • the second treatment administers the additional antidepressant for at least 28 days.
  • the additional antidepressant is administered at the same dose in the first and second treatment. In some embodiments, the additional antidepressant is administered at a different dose in the first and second treatment. [00312] In some embodiments, Compound (1), or the pharmaceutically acceptable salt of Compound (1), is not administered to the subject in the second treatment.
  • the combination of Compound (1), or the pharmaceutically acceptable salt of Compound (1), and the additional antidepressant is re-administered to the subject in response to a recurrence of depression symptoms.
  • the combination of Compound (1), or a pharmaceutically acceptable salt thereof, and an additional antidepressant can be administered in combination with another agent.
  • Administration in combination with another agent can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
  • the additional antidepressant in the second treatment, can be administered in combination with another agent.
  • Administration in combination with another agent can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.
  • Compound (1) is in a crystalline form.
  • the crystalline form Compound (1) is any crystalline form disclosed in PCT Application Publication No. WO 2018/039378; the entire contents of the aforementioned application are incorporated herein by reference in its entirety.
  • Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.7 to 10.1 degrees in 29, between and including 11.6 to 12.0 degrees in 29, between and including 13.2 to 13.6 degrees in 29, between and including 14.2 to 14.6 degrees in 29, between and including 14.6 to 15.0 degrees in 29, between and including 16.8 to 17.2 degrees in 29, between and including 20.5 to 20.9 degrees in 29, between and including 21.3 to 21.7 degrees in 29, between and including 21.4 to 21.8 degrees in 29, and between and including 22.4 to 22.8 degrees in 29.
  • Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.7 to 10.1 degrees in 29, between and including 14.6 to 15.0 degrees in 29, between and including 16.8 to 17.2 degrees in 29, between and including 20.5 to 20.9 degrees in 29, and between and including 21.3 to 21.7 degrees in 29.
  • Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.3 to 9.7 degrees in 29, between and including 10.6 to 11.0 degrees in 29, between and including 13.0 to 13.4 degrees in 29, between and including 14.7 to 15.1 degrees in 29, between and including 15.8 to 16.2 degrees in 29, between and including 18.1 to 18.5 degrees in 29, between and including 18.7 to 19.1 degrees in 29, between and including 20.9 to 21.3 degrees in 29, between and including 21.4 to 21.8 degrees in 29, and between and including 23.3 to 23.7 degrees in 29.
  • Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.3 to 9.7 degrees in 29, between and including 10.6 to 11.0 degrees in 29, between and including 13.0 to 13.4 degrees in 29, between and including 18.7 to 19.1 degrees in 29, and between and including 21.4 to 21.8 degrees in 29.
  • the crystalline form of Compound (1) comprises a mixture of two or more crystalline forms.
  • compositions of Compound (1) are any pharmaceutical composition disclosed in PCT Application Publication No. WO 2922/929363 A9; the entire contents of the aforementioned application are incorporated herein by reference in its entirety.
  • the pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.
  • the pharmaceutical composition is administered orally.
  • the pharmaceutical compositions of the present invention may be further delivered using a variety of dosing methods.
  • the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level.
  • the placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level.
  • the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject’s body.
  • the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form.
  • a minor component from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight
  • various vehicles or excipients and processing aids helpful for forming the desired dosing form are merely representative.
  • Other materials, as well as processing techniques and the like, are set forth in Part 8 of Remington ’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
  • compositions of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington ’s Pharmaceutical Sciences.
  • compositions suitable for administration to humans it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.
  • kits comprising a pharmaceutical composition comprising Compound (1), an additional antidepressant, and an instruction set describing a method for treating major depressive episode (MDD) or postpartum depression (PPD) as described herein.
  • MDD major depressive episode
  • PPD postpartum depression
  • the disclosure provides a kit comprising a pharmaceutical composition comprising about 40 mg to about 50 mg of Compound (1), an additional antidepressant, and an instruction set describing a method for treating major depressive episode (MDD) or postpartum depression (PPD), wherein the method provides (i) a first treatment comprising administering a combination of the pharmaceutical composition comprising Compound (1) and the additional antidepressant; and (ii) a second treatment comprising administering the additional antidepressant.
  • MDD major depressive episode
  • PPD postpartum depression
  • the disclosure provides a kit comprising a combination of a pharmaceutical composition comprising Compound (1) and an additional antidepressant, and an instruction set describing a method for using the combination for treating major depressive episode (MDD) or postpartum depression (PPD) in a treatment naive subject.
  • MDD major depressive episode
  • PPD postpartum depression
  • kits comprising a plurality of therapeutically efficacious dosages of Compound (1), a plurality of therapeutically efficacious dosages of an additional antidepressant, and an instruction set describing a method of administering the dosages for treating major depressive episode (MDD) or postpartum depression (PPD) in a treatment naive subject.
  • MDD major depressive episode
  • PPD postpartum depression
  • the method of administering the dosages is any one of the methods described herein.
  • the dosages of Compound (1) are individual dosage units of Compound (1).
  • an individual dosage unit comprises from about 20 mg to about 30 mg of Compound (1).
  • an individual dosage unit comprises about 20 mg of Compound (1).
  • an individual dosage unit comprises about 25 mg of Compound (1). In some embodiments, an individual dosage unit comprises about 30 mg of Compound (1). In some embodiments, the individual dosage unit of Compound (1) is a capsule or a tablet. In some embodiments, the individual dosage unit of Compound (1) is a capsule. In some embodiments, the individual dosage unit of Compound (1) is a capsule of size 1, 2, 3, or 4. In some embodiments, the capsule is size 1. In some embodiments, the capsule is a hard gelatin capsule.
  • the capsule in addition to the specified amount of Compound (1) (e.g., 20 mg, 25 mg or 30 mg), the capsule further comprises croscarmellose sodium, mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, and sodium stearyl fumarate.
  • the plurality of therapeutically efficacious dosages of Compound (1) comprises two capsules. In some embodiments, the plurality of therapeutically efficacious dosages of Compound (1) comprises three capsules.
  • the dosages of the additional antidepressant are individual dosage units of the additional antidepressant.
  • the additional antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine, and desvenlafaxine.
  • the individual dosage units of the additional antidepressant are packaged and labeled by a commercial manufacturer.
  • the additional antidepressant is sertraline.
  • the dosages of the additional antidepressant are individual dosage units of sertraline.
  • the individual dosage units of sertraline are tablets.
  • the individual dosage units of sertraline comprise about 25 mg, 50 mg, or 100 mg of sertraline.
  • the individual dosage units of sertraline are a container comprising a liquid concentrate wherein each mL of the concentrate is equivalent to 20 mg of sertraline.
  • the additional antidepressant is escitalopram.
  • the dosages of the additional antidepressant are individual dosage units of escitalopram.
  • the individual dosage units of escitalopram are tablets. In some embodiments, the individual dosage units of escitalopram comprise about 5 mg, 10 mg, or 20 mg of escitalopram. In some embodiments, the additional antidepressant is citalopram. In some embodiments, the the dosages of the additional antidepressant are individual dosage units of citalopram. In some embodiments, the individual dosage units of citalopram are tablets. In some embodiments, the individual dosage units of citalopram comprise about 10 mg, 20 mg, or 40 mg of citalopram. In some embodiments, the additional antidepressant is duloxetine. In some embodiments, the the dosages of the additional antidepressant are individual dosage units of duloxetine.
  • the individual dosage units of duloxetine are capsules. In some embodiments, the individual dosage units of duloxetine comprise about 20 mg, 30 mg, or 60 mg of duloxetine.
  • the additional antidepressant is desvenlafaxine. In some embodiments, the the dosages of the additional antidepressant are individual dosage units of desvenlafaxine. In some embodiments, the individual dosage units of desvenlafaxine are tablets. In some embodiments, the individual dosage units of desvenlafaxine comprise about 25 mg, 50 mg, or 100 mg of desvenlafaxine.
  • the instruction set is printed on a suitable material.
  • Embodiments of the present subject matter disclosed herein may be beneficial alone or in combination with one or more other embodiments. Without limiting the foregoing description, certain non-limiting embodiments of the disclosure, numbered 1-258 are provided below. As will be apparent to those of skill in the art upon reading this disclosure, each of the individually numbered embodiments may be used or combined with any of the preceding or following individually numbered embodiments. This is intended to provide support for all such combinations of embodiments and is not limited to combinations of embodiments explicitly provided below.
  • Embodiment 1 A method of treating maj or depressive disorder (MDD) in a subject in need thereof, comprising:
  • Embodiment 2 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • Embodiment 3 A method of treating maj or depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising:
  • Embodiment 4 A method of treating maj or depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising:
  • Embodiment 5 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • Embodiment 6 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • Embodiment 7 A method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising:
  • Embodiment 8 A method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising:
  • Embodiment 9 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising
  • Compound (1) and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; followed by
  • Embodiment 10 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising
  • Compound (1) and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; followed by
  • Embodiment 11 A method of treating maj or depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising
  • Compound (1) and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; followed by
  • Embodiment 12 A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising
  • Compound (1) and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; followed by
  • Embodiment 13 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • Embodiment 14 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising:
  • Embodiment 15 The method of any one of Embodiments 1, 2, 9, or 10, wherein the subject is experiencing a major depressive episode.
  • Embodiment 16 The method of Embodiment 15, wherein the subject has elevated anxiety during a majority of days of a major depressive episode.
  • Embodiment 17 The method of any one of Embodiments 3, 4, 11, or 12, wherein the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline.
  • Embodiment 18 The method of any one of Embodiments 3, 4, 11, or 12, wherein the subject has a ELAM-A total score of at least 17 or at least 20 at baseline.
  • Embodiment 19 The method of any one of Embodiments 1-6 or 9-12, wherein administering the combination reduces a gastrointestinal treatment-emergent adverse event.
  • Embodiment 20 The method of Embodiment 13 or 14, wherein providing the first treatment reduces a gastrointestinal treatment-emergent adverse event.
  • Embodiment 21 The method of any one of Embodiments 7, 8, 19 or 20, wherein the gastrointestinal treatment-emergent adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.
  • Embodiment 22 The method of Embodiment 21, wherein the gastrointestinal treatment-emergent adverse event comprises nausea and/or diarrhea.
  • Embodiment 23 The method of any one of Embodiments 7, 8, or 19-22, wherein the gastrointestinal treatment-emergent adverse event results from treatment with the additional antidepressant.
  • Embodiment 24 The method of any one of Embodiments 1-4 or 7-23, wherein the subject is treatment-naive.
  • Embodiment 25 The method of any one of Embodiments 1-4 or 7-23, wherein the subject has not received any antidepressant treatment within at least 30 days prior to the start of the first treatment.
  • Embodiment 26 The method of any one of Embodiments 1-4 or 7-23, wherein the subject has not received treatment with the additional antidepressant within at least 30 days prior to the start of the first treatment.
  • Embodiment 27 The method of any one of Embodiments 1-4 or 7-23, wherein the subject has not received treatment with the additional antidepressant within at least 60 days prior to the start of the first treatment.
  • Embodiment 28 The method of any one of Embodiments 1-8, wherein the first treatment administers the combination for about 14 days.
  • Embodiment 29 The method of any one of Embodiments 1-8, wherein the second treatment administers the additional antidepressant for at least 28 days.
  • Embodiment 30 The method of any one of Embodiments 1-8, wherein the additional antidepressant is administered at the same dose in the first and second treatment.
  • Embodiment 31 The method of any one of Embodiments 1-8, wherein the additional antidepressant is administered at a different dose in the first and second treatment.
  • Embodiment 32 The method of any one of Embodiments 1-8, wherein
  • Compound (1) or the pharmaceutically acceptable salt of Compound (1), is not administered to the subject in the second treatment.
  • Embodiment 33 The method of any one of Embodiments 1-8, wherein
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered in separate dosage forms.
  • Embodiment 34 The method of Embodiment 33, wherein Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered at the same time.
  • Embodiment 35 The method of Embodiment 33, wherein Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the first treatment are administered at different times.
  • Embodiment 36 The method of any one of Embodiments 9-14, wherein the additional antidepressant is administered at the same dose in (i) and (ii).
  • Embodiment 37 The method of any one of Embodiments 9-14, wherein the additional antidepressant is administered at a different dose in (i) and (ii).
  • Embodiment 38 The method of any one of Embodiments 9-14, wherein
  • Compound (1) or the pharmaceutically acceptable salt of Compound (1), is not administered to the subject in (ii).
  • Embodiment 39 The method of any one of Embodiments 9-14, wherein
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in (i) are administered in separate dosage forms.
  • Embodiment 40 The method of Embodiment 39, wherein Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in (i) are administered at the same time.
  • Embodiment 41 The method of Embodiment 39, wherein Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in (i) are administered at different times.
  • Embodiment 42 The method of any one of Embodiments 1-41, wherein the additional antidepressant administered in (ii) is the same as the additional antidepressant administered in (i).
  • Embodiment 43 The method of any one of Embodiments 1-12, wherein Compound (1), or a pharmaceutically acceptable salt thereof, is administered once a day.
  • Embodiment 44 The method of any one of Embodiments 5, 7, 9, or 11, wherein Compound (1) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg.
  • Embodiment 45 The method of Embodiment 1, 3, or 44, wherein Compound (1) is administered at a dose of about 50 mg.
  • Embodiment 46 The method of Embodiment 1, 3, or 44, wherein Compound (1) is administered at a dose of about 40 mg.
  • Embodiment 47 The method of Embodiment 45, wherein Compound (1) is administered at a dose of about 50 mg once a day.
  • Embodiment 48 The method of Embodiment 46, wherein Compound (1) is administered at a dose of about 40 mg once a day.
  • Embodiment 49 The method of any one of Embodiments 6, 8, 10, 12, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of the free base compound.
  • Embodiment 50 The method of Embodiment 2, 4, or 49, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 50 mg of the free base compound.
  • Embodiment 51 The method of Embodiment 2, 4, or 49, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 40 mg of the free base compound.
  • Embodiment 52 The method of Embodiment 50, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 50 mg of the free base compound once a day.
  • Embodiment 53 The method of Embodiment 51, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 40 mg of the free base compound once a day.
  • Embodiment 54 The method of any one of Embodiments 1-53, wherein Compound (1) or the pharmaceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal, sublingually, rectally, topically, as an inhalation, intranasaly, or transdermally.
  • Embodiment 55 The method of Embodiment 54, wherein Compound (1), or the pharmaceutically acceptable salt of Compound (1), is administered orally.
  • Embodiment 56 The method of any one of Embodiments 1-55, wherein Compound (1), or the pharmaceutically acceptable salt of Compound (1), is administered with food.
  • Embodiment 57 The method of any one of Embodiments 1-56, wherein Compound (1), or the pharmaceutically acceptable salt of Compound (1), is administered once a day at night.
  • Embodiment 58 The method of any one of Embodiments 1-57, wherein the combination of Compound (1), or the pharmaceutically acceptable salt of Compound (1), and the additional antidepressant is re-administered to the subject in response to a recurrence of depression symptoms.
  • Embodiment 59 The method of Embodiment 58, wherein there is at least a 6 week interval between the last dose of the first treatment and the first dose of the readministration.
  • Embodiment 60 The method of any one of Embodiments 1, 3, 5, 7, 9, 11 or 13, wherein Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.7 to 10.1 degrees in 29, between and including 11.6 to 12.0 degrees in 29, between and including 13.2 to 13.6 degrees in 29, between and including 14.2 to 14.6 degrees in 29, between and including 14.6 to 15.0 degrees in 29, between and including 16.8 to 17.2 degrees in 29, between and including 20.5 to 20.9 degrees in 29, between and including 21.3 to 21.7 degrees in 29, between and including 21.4 to 21.8 degrees in 29, and between and including 22.4 to 22.8 degrees in 29.
  • Embodiment 61 The method of any one of Embodiments 1, 3, 5, 7, 9, 11 or 13, wherein Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.3 to 9.7 degrees in 29, between and including 10.6 to 11.0 degrees in 29, between and including 13.0 to 13.4 degrees in 29, between and including 14.7 to 15.1 degrees in 29, between and including 15.8 to 16.2 degrees in 29, between and including 18.1 to 18.5 degrees in 29, between and including 18.7 to 19.1 degrees in 29, between and including 20.9 to 21.3 degrees in 29, between and including 21.4 to 21.8 degrees in 29, and between and including 23.3 to 23.7 degrees in 29.
  • Embodiment 62 Embodiment 62.
  • Embodiment 63 The method of any one of Embodiments 1, 3, 5, 7, 9, 11 or 13, wherein Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.3 to 9.7 degrees in 29, between and including 19.6 to 11.9 degrees in 29, between and including 13.9 to 13.4 degrees in 29, between and including 18.7 to 19.1 degrees in 29, and between and including 21.4 to 21.8 degrees in 29.
  • Embodiment 64 The method of any one of Embodiments 1-63, wherein the additional antidepressant in (i) and (ii) is a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), a serotonin modulator and stimulator (SMS), a serotonin antagonist and reuptake inhibitor (SARI), a norepinephrine reuptake inhibitor (NRI), a norepinephrine dopamine reuptake inhibitor (NDRI), a tricyclic antidepressant (TCA), a tetracyclic antidepressant (TeCA), a monoamine oxidase inhibitor (MAOI), an atypical antipsychotic, agomelatine, esketamine, tianeptine, ketamine, a- methyltryptamine, etryptamine, ethyltryptamine, indeloxa
  • SSRI
  • Embodiment 65 The method of Embodiment 64, wherein the additional antidepressant in (i) or (ii) is an SSRI.
  • Embodiment 66 The method of Embodiment 65, wherein the SSRI is sertraline, escitalopram, citalopram, fluvoxamine, paroxetine, fluoxetine, indalpine, or zimelidine.
  • Embodiment 67 The method of Embodiment 66, wherein the SSRI is sertraline.
  • Embodiment 68 The method of Embodiment 66, wherein the SSRI is escitalopram.
  • Embodiment 69 The method of Embodiment 66, wherein the SSRI is citalopram.
  • Embodiment 70 The method of Embodiment 64, wherein the additional antidepressant in (i) or (ii) is an SNRI.
  • Embodiment 71 The method of Embodiment 70, wherein the SNRI is duloxetine, desvenlafaxine, levomilnacipran, milnacipran, or venlafaxine
  • Embodiment 72 The method of Embodiment 71, wherein the SNRI is duloxetine.
  • Embodiment 73 The method of Embodiment 71, wherein the SNRI is desvenlafaxine.
  • Embodiment 74 The method of Embodiment 64, wherein the additional antidepressant in (i) or (ii) is an SMS.
  • Embodiment 75 The method of Embodiment 74, wherein the SMS is vilazodone or vortioxetine.
  • Embodiment 76 The method of Embodiment 64, wherein the additional antidepressant in (i) or (ii) is an SARI.
  • Embodiment 77 The method of Embodiment 76, wherein the SARI is nefazodone, trazodone, or etoperidone.
  • Embodiment 78 The method of Embodiment 64, wherein the additional antidepressant in (i) or (ii) is an NRI.
  • Embodiment 79 The method of Embodiment 78, wherein the NRI is reboxetine, teniloxazine, viloxazine, or atomoxetine.
  • Embodiment 80 The method of Embodiment 64, wherein the additional antidepressant in (i) or (ii) is a NDRI.
  • Embodiment 81 The method of Embodiment 80, wherein the NDRI is bupropion, amphetamine, methylphenidate, modafinil, amineptine, or nomifensine.
  • Embodiment 82 The method of Embodiment 64, wherein the additional antidepressant in (i) or (ii) is a TCA.
  • Embodiment 83 The method of Embodiment 82, wherein the TCA is amitriptyline, amitriptylinoxide, clomipramine, desipramine, diebnzepin, dimetacrine, dosluepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, notriptyline, noxiptiline, opipramol, pipofezine, protriptyline, trimipramine, butriptyline, demexiptiline, fluacizine, imipraminoxide, iprindole, metapramine, propizepine, quinupramine, tiazesim, or tofenacin.
  • TCA is amitriptyline, amitriptylinoxide, clomipramine, desipramine, diebnzepin, dimetacrine, dosluepin, doxepin,
  • Embodiment 84 The method of Embodiment 64, wherein the additional antidepressant in (i) or (ii) is a TeCA.
  • Embodiment 85 The method of Embodiment 84, wherein the TeCA is amoxapine, maprotiline, mianserin, mirtazapine, or setiptiline.
  • Embodiment 86 The method of Embodiment 64, wherein the additional antidepressant in (i) or (ii) is a MAOI.
  • Embodiment 87 The method of Embodiment 86, wherein the MAOI is isocarboxazid, phenelzine, tranylcypromine, benmoxin, iproclozide, iproniazid, mebanazine, nialamide, octamoxin, pheniprazine, phenoxypropazine, pivhydrazine, safrazine, selegiline, caroxazone, metralindole, moclobemide, pirlindole, eprobemide, minaprine, toloxatone, or bifemelane.
  • Embodiment 88 The method of Embodiment 64, wherein the additional antidepressant in (i) or (ii) is an atypical antipsychotic.
  • Embodiment 89 The method of Embodiment 88, wherein the atypical antipsychotic is amisulpride, lumateperone, lurasidone, quetiapine, aripiprazole, brexpiprazole, lumateperone, lurasidone, olanzapine, quetiapine, or risperidone.
  • the atypical antipsychotic is amisulpride, lumateperone, lurasidone, quetiapine, aripiprazole, brexpiprazole, lumateperone, lurasidone, olanzapine, quetiapine, or risperidone.
  • Embodiment 90 The method of Embodiment 64, wherein the additional antidepressant in the (i) or (ii) is agomelatine, esketamine, tianeptine, ketamine, a- methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademetionine, hypericum perforatum, oxitriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine, or tranylcypromine and trifluoperazine.
  • the additional antidepressant in the (i) or (ii) is agomelatine,
  • Embodiment 91 The method of any one of Embodiments 1-63, wherein the additional antidepressant in (i) or (ii) is 4-Chlorokynurenine (AV-101), Apimostinel (NRX- 1074), Arketamine (PCN-101, HR-071603), Dextromethadone (REL-1017), MU-821, Rislenemdaz (CERC-301, MK-0657), TAK-653 (NBI- 1065845), OPC-64005, PDC-1421 (BLI-1005), Toludesvenlafaxinem, Hypidone (YL-0919), TGBA01AD (FKB01MD), Vortioxetinem, Lisdexamfetamine, Midomafetamine, Aramisulpride/esamisulpride (85:15 ratio) (SEP-4199), Gepirone, Pramipexole, Psilocybin, Brilaroxazine, Caripraz
  • Embodiment 93 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of Compound (1): and a therapeutically effective amount of an additional antidepressant, wherein the subject is treatment-naive.
  • MDD major depressive disorder
  • Embodiment 94 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • Embodiment 95 A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of Compound (1): and a therapeutically effective amount of an additional antidepressant, wherein the subject is treatment-naive.
  • MDD major depressive disorder
  • Embodiment 96 A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1): and a therapeutically effective amount of an additional antidepressant, wherein the subject is treatment-naive.
  • MDD major depressive disorder
  • Embodiment 97 A method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of Compound (1): and a therapeutically effective amount of an additional antidepressant wherein the subject is treatment-naive.
  • Embodiment 98 A method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising administering a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • Embodiment 99 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering for about 14 days a combination comprising a therapeutically effective amount of Compound (1):
  • Compound (1) and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; wherein the subject is treatment naive.
  • an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; wherein the subject is treatment naive.
  • Embodiment 100 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering for about 14 days a combination comprising a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • Compound (1) and a therapeutically effective amount of an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; wherein the subject is treatment naive.
  • an additional antidepressant selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine; wherein the subject is treatment naive.
  • Embodiment 101 A method of treating maj or depressive disorder (MDD) in a subject in need thereof, comprising administering a combination comprising about 40 mg to about 50 mg of Compound (1):
  • Compound (1) and a therapeutically effective amount of an additional antidepressant.
  • Embodiment 102 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising administering a combination comprising a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound:
  • Compound (1) and a therapeutically effective amount of an additional antidepressant.
  • Embodiment 103 The method of any one of Embodiments 93, 94, or 99-102, wherein the subject is experiencing a major depressive episode.
  • Embodiment 104 The method of Embodiment 103, wherein the subject has elevated anxiety during a majority of days of a major depressive episode.
  • Embodiment 105 The method of any one of Embodiments 95, 96, or 104, wherein the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline.
  • Embodiment 106 The method of any one of Embodiments 95, 96, or 104, wherein the subject has a ELAM-A total score of at least 17 or at least 20 at baseline.
  • Embodiment 107 The method of any one of Embodiments 93-96 or 99-102, wherein administering the combination reduces a gastrointestinal treatment-emergent adverse event.
  • Embodiment 108 The method of Embodiment 97 or 98, wherein providing the combination reduces a gastrointestinal treatment-emergent adverse event.
  • Embodiment 109 The method of any one of Embodiments 97, 98, 107, or 108, wherein the gastrointestinal treatment-emergent adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.
  • Embodiment 110 The method of Embodiment 109, wherein the gastrointestinal treatment-emergent adverse event comprises nausea and/or diarrhea.
  • Embodiment 111 The method of any one of Embodiments 97, 98, or 107-110, wherein the gastrointestinal treatment-emergent adverse event results from treatment with the additional antidepressant.
  • Embodiment 112 The method of any one of Embodiments 93-111, wherein the subject has not received any antidepressant treatment within at least 30 days prior to the start of treatment.
  • Embodiment 113 The method of any one of Embodiments 93-111, wherein the subject has not received treatment with the additional antidepressant within at least 30 days prior to the start treatment.
  • Embodiment 114 The method of any one of Embodiments 93-111, wherein the subject has not received treatment with the additional antidepressant within at least 60 days prior to the start treatment.
  • Embodiment 115 The method of any one of Embodiments 93-98 or 101-102, wherein the treatment administers the combination for about 14 days.
  • Embodiment 116 The method of any one of Embodiments 93-102, wherein
  • Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the combination are administered in separate dosage forms.
  • Embodiment 117 The method of Embodiment 116, wherein Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the combination are administered at the same time.
  • Embodiment 118 The method of Embodiment 116, wherein Compound (1), or a pharmaceutically acceptable salt thereof, and the additional antidepressant in the combination are administered at different times.
  • Embodiment 119 The method of any one of Embodiments 93-118, wherein the treatment further comprises a second treatment comprising administering a therapeutically effective amount of an additional antidepressant.
  • Embodiment 120 The method of Embodiment 119, wherein the second treatment administers the additional antidepressant for at least 28 days.
  • Embodiment 121 The method of Embodiment 119, wherein the additional antidepressant is administered at the same dose in the second treatment as in the combination.
  • Embodiment 122 The method of Embodiment 119, wherein the additional antidepressant is administered at a different dose in the second treatment compared to the dose administered in the combination.
  • Embodiment 123 The method of Embodiment 119, wherein Compound (1), or the pharmaceutically acceptable salt of Compound (1), is not administered to the subject in the second treatment.
  • Embodiment 124 The method of any one of Embodiments 119-123, wherein the additional antidepressant administered in the second treatment is the same as the additional antidepressant administered in the combination.
  • Embodiment 125 The method of any one of Embodiments 93-102, wherein Compound (1), or a pharmaceutically acceptable salt thereof, is administered once a day.
  • Embodiment 126 The method of any one of Embodiments 93, 95, 97, or 99, wherein Compound (1) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg.
  • Embodiment 127 The method of Embodiment 101 or 126, wherein Compound (1) is administered at a dose of about 50 mg.
  • Embodiment 128 The method of Embodiment 101 or 126, wherein Compound (1) is administered at a dose of about 40 mg.
  • Embodiment 129 The method of Embodiment 127, wherein Compound (1) is administered at a dose of about 50 mg once a day.
  • Embodiment 130 The method of Embodiment 128, wherein Compound (1) is administered at a dose of about 40 mg once a day.
  • Embodiment 131 The method of any one of Embodiments 94, 96, 98, or 100, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg of the free base compound.
  • Embodiment 132 The method of Embodiment 102 or 131, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 50 mg of the free base compound.
  • Embodiment 133 The method of Embodiment 102 or 131, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 40 mg of the free base compound.
  • Embodiment 134 The method of Embodiment 132, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 50 mg of the free base compound once a day.
  • Embodiment 135. The method of Embodiment 133, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 40 mg of the free base compound once a day.
  • Embodiment 136 The method of any one of Embodiments 93-135, wherein Compound (1), or the pharmaceutically acceptable salt of Compound (1), is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal, sublingually, rectally, topically, as an inhalation, intranasaly, or transdermally.
  • Embodiment 137 The method of Embodiment 136, wherein Compound (1), or the pharmaceutically acceptable salt of Compound (1), is administered orally.
  • Embodiment 138 The method of any one of Embodiments 93-137, wherein Compound (1), or the pharmaceutically acceptable salt of Compound (1), is administered with food.
  • Embodiment 139 The method of any one of Embodiments 93-138, wherein Compound (1), or the pharmaceutically acceptable salt of Compound (1), is administered once a day at night.
  • Embodiment 140 The method of any one of Embodiments 93-139, wherein the combination of Compound (1), or the pharmaceutically acceptable salt of Compound (1), and the additional antidepressant is re-administered to the subject in response to a recurrence of depression symptoms.
  • Embodiment 141 The method of Embodiment 140, wherein there is at least a 6 week interval between the last dose of the first treatment and the first dose of the readministration.
  • Embodiment 142 The method of any one of Embodiments 93, 95, 97, 99, or 101, wherein Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.7 to 10.1 degrees in 29, between and including 11.6 to 12.0 degrees in 29, between and including 13.2 to 13.6 degrees in 29, between and including 14.2 to 14.6 degrees in 29, between and including 14.6 to 15.0 degrees in 29, between and including 16.8 to 17.2 degrees in 29, between and including 20.5 to 20.9 degrees in 29, between and including 21.3 to 21.7 degrees in 29, between and including 21.4 to 21.8 degrees in 29, and between and including 22.4 to 22.8 degrees in 29.
  • Embodiment 143 Embodiment 143.
  • Embodiment 144 The method of any one of Embodiments 93, 95, 97, 99, or 101, wherein Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.7 to 10.1 degrees in 29, between and including 14.6 to 15.0 degrees in 29, between and including 16.8 to 17.2 degrees in 29, between and including 20.5 to 20.9 degrees in 29, and between and including 21.3 to 21.7 degrees in 29.
  • Embodiment 145 The method of any one of Embodiments 93, 95, 97, 99, or 101, wherein Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.3 to 9.7 degrees in 29, between and including 10.6 to 11.0 degrees in 29, between and including 13.0 to 13.4 degrees in 29, between and including 18.7 to 19.1 degrees in 29, and between and including 21.4 to 21.8 degrees in 29.
  • Embodiment 146 The method of any one of Embodiments 93-145, wherein the additional antidepressant in the combination and the second treatment is a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), a serotonin modulator and stimulator (SMS), a serotonin antagonist and reuptake inhibitor (SARI), a norepinephrine reuptake inhibitor (NRI), a norepinephrine dopamine reuptake inhibitor (NDRI), a tricyclic antidepressant (TCA), a tetracyclic antidepressant (TeCA), a monoamine oxidase inhibitor (MAOI), an atypical antipsychotic, agomelatine, esketamine, tianeptine, ketamine, a-methyltryptamine, etryptamine, ethyltryptamine, indeloxa
  • SSRI
  • Embodiment 147 The method of Embodiment 146, wherein the additional antidepressant in the combination and the second treatment is an SSRI.
  • Embodiment 148 The method of Embodiment 147, wherein the SSRI is sertraline, escitalopram, citalopram, fluvoxamine, paroxetine, fluoxetine, indalpine, or zimelidine.
  • Embodiment 149 The method of Embodiment 148, wherein the SSRI is sertraline.
  • Embodiment 150 The method of Embodiment 148, wherein the SSRI is escitalopram.
  • Embodiment 151 The method of Embodiment 148, wherein the SSRI is citalopram.
  • Embodiment 152 The method of Embodiment 146, wherein the additional antidepressant in the combination and the second treatment is an SNRI.
  • Embodiment 153 The method of Embodiment 152, wherein the SNRI is duloxetine, desvenlafaxine, levomilnacipran, milnacipran, or venlafaxine
  • Embodiment 154 The method of Embodiment 153, wherein the SNRI is duloxetine.
  • Embodiment 155 The method of Embodiment 153, wherein the SNRI is desvenlafaxine.
  • Embodiment 156 The method of Embodiment 146, wherein the additional antidepressant in the combination and the second treatment is an SMS.
  • Embodiment 157 The method of Embodiment 156, wherein the SMS is vilazodone or vortioxetine.
  • Embodiment 158 The method of Embodiment 146, wherein the additional antidepressant in the combination and the second treatment is an SARI.
  • Embodiment 159 The method of Embodiment 158, wherein the SARI is nefazodone, trazodone, or etoperidone.
  • Embodiment 160 The method of Embodiment 146, wherein the additional antidepressant in the combination and the second treatment is an NRI.
  • Embodiment 161 The method of Embodiment 160, wherein the NRI is reboxetine, teniloxazine, viloxazine, or atomoxetine.
  • Embodiment 162 The method of Embodiment 146, wherein the additional antidepressant in the combination and the second treatment is a NDRI.
  • Embodiment 163 The method of Embodiment 162, wherein the NDRI is bupropion, amphetamine, methylphenidate, modafinil, amineptine, or nomifensine.
  • Embodiment 164 The method of Embodiment 146, wherein the additional antidepressant in the combination and the second treatment is a TCA.
  • Embodiment 165 The method of Embodiment 164, wherein the TCA is amitriptyline, amitriptylinoxide, clomipramine, desipramine, diebnzepin, dimetacrine, dosluepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, notriptyline, noxiptiline, opipramol, pipofezine, protriptyline, trimipramine, butriptyline, demexiptiline, fluacizine, imipraminoxide, iprindole, metapramine, propizepine, quinupramine, tiazesim, or tofenacin.
  • TCA is amitriptyline, amitriptylinoxide, clomipramine, desipramine, diebnzepin, dimetacrine, dosluepin, doxepin,
  • Embodiment 166 The method of Embodiment 146, wherein the additional antidepressant in the combination and the second treatment is a TeCA.
  • Embodiment 167 The method of Embodiment 166, wherein the TeCA is amoxapine, maprotiline, mianserin, mirtazapine, or setiptiline.
  • Embodiment 168 The method of Embodiment 146, wherein the additional antidepressant in the combination and the second treatment is a MAOI.
  • Embodiment 169 The method of Embodiment 168, wherein the MAOI is isocarboxazid, phenelzine, tranylcypromine, benmoxin, iproclozide, iproniazid, mebanazine, nialamide, octamoxin, pheniprazine, phenoxypropazine, pivhydrazine, safrazine, selegiline, caroxazone, metralindole, moclobemide, pirlindole, eprobemide, minaprine, toloxatone, or bifemelane.
  • the MAOI is isocarboxazid, phenelzine, tranylcypromine, benmoxin, iproclozide, iproniazid, mebanazine, nialamide, octamoxin, pheniprazine, phenoxypropazine, pivhydra
  • Embodiment 170 The method of Embodiment 146, wherein the additional antidepressant in the combination and the second treatment is an atypical antipsychotic.
  • Embodiment 171 The method of Embodiment 170, wherein the atypical antipsychotic is amisulpride, lumateperone, lurasidone, quetiapine, aripiprazole, brexpiprazole, lumateperone, lurasidone, olanzapine, quetiapine, or risperidone.
  • the atypical antipsychotic is amisulpride, lumateperone, lurasidone, quetiapine, aripiprazole, brexpiprazole, lumateperone, lurasidone, olanzapine, quetiapine, or risperidone.
  • Embodiment 172 The method of Embodiment 146, wherein the additional antidepressant in the combination and the second treatment is agomelatine, esketamine, tianeptine, ketamine, a-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademetionine, hypericum perforatum, oxitriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine, or tranylcypromine and trifluoperazine.
  • the additional antidepressant in the combination and the second treatment is agomelatine, esketamine
  • Embodiment 173 The method of any one of Embodiments 93-145, wherein the additional antidepressant in the combination and the second treatment is 4-Chlorokynurenine (AV-101), Apimostinel (NRX-1074), Arketamine (PCN-101, HR-071603), Dextromethadone (REL-1017), MU-821, Rislenemdaz (CERC-301, MK-0657), TAK-653 (NBI- 1065845), OPC-64005, PDC-1421 (BLI-1005), Toludesvenlafaxinem, Hypidone (YL-0919), TGBA01AD (FKB01MD), Vortioxetinem, Lisdexamfetamine, Midomafetamine, Aramisulpride/esamisulpride (85: 15 ratio) (SEP-4199), Gepirone, Pramipexole, Psilocybin, Brilaroxazine, Cariprazine,
  • Embodiment 174 The method of any one of Embodiments 93-173, wherein the additional antidepressant is administered per its labeled prescribing information.
  • Embodiment 175. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with about 40 mg to about 50 mg of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • Embodiment 176. A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound:
  • Embodiment 177 A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with about 40 mg to about 50 mg of Compound (1):
  • Embodiment 178 A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a pharmaceutically acceptable salt of Compound (1) at a dose equivalent to about 40 mg to about 50 mg of the free base compound: wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • MDD major depressive disorder
  • Embodiment 179 Embodiment 179.
  • MDD major depressive disorder
  • Embodiment 180 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • Compound (1) wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the subject is treatment-naive.
  • Embodiment 18 A method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising coadministering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of Compound (1):
  • Embodiment 182 A method of reducing a gastrointestinal treatment-emergent adverse event of an antidepressant treatment in a subject in need thereof, comprising coadministering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment.
  • Embodiment 183 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of Compound (1):
  • MDD major depressive disorder
  • Compound (1) wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • Embodiment 184 A method of treating major depressive disorder (MDD) in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • MDD major depressive disorder
  • Embodiment 185 A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of Compound (1): wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • MDD major depressive disorder
  • Compound (1) wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • Embodiment 186 A method of treating major depressive disorder (MDD) with elevated anxiety in a subject in need thereof, comprising co-administering a therapeutically effective amount of an antidepressant with a therapeutically effective amount of a pharmaceutically acceptable salt of Compound (1):
  • Compound (1) wherein the co-administration occurs from about day 1 of treatment to about day 14 of treatment, wherein the antidepressant continues to be administered after day 14 of treatment, wherein the antidepressant is selected from the group consisting of sertraline, escitalopram, citalopram, duloxetine and desvenlafaxine.
  • Embodiment 187 The method of any one of Embodiments 175-176, 179-180, or 183-184, wherein the subject is experiencing a major depressive episode.
  • Embodiment 188 The method of Embodiment 187, wherein the subject has elevated anxiety during a majority of days of a major depressive episode.
  • Embodiment 189 The method of any one of Embodiments 177-178, 185-186, or 188, wherein the subject has a HAM-D Anxiety/Somatization subscale score of at least 7 at baseline.
  • Embodiment 190 The method of any one of Embodiments 177-178, 185-186, or 188, wherein the subject has a ELAM-A total score of at least 17 or at least 20 at baseline.
  • Embodiment 19 The method of any one of Embodiments 175-180 or 183-186, wherein the co-administration reduces a gastrointestinal treatment-emergent adverse event.
  • Embodiment 192 The method of Embodiment 181 or 182, wherein providing the co-administration reduces a gastrointestinal treatment-emergent adverse event.
  • Embodiment 193 The method of any one of Embodiments 181, 182, 191, or 192, wherein the gastrointestinal treatment-emergent adverse event comprises nausea, vomiting, diarrhea, constipation, abdominal pain, dyspepsia, anorexia, increased appetite, or dry mouth, or any combination thereof.
  • Embodiment 194 The method of Embodiment 193, wherein the gastrointestinal treatment-emergent adverse event comprises nausea and/or diarrhea.
  • Embodiment 195 The method of any one of Embodiments 181, 182, or 192-194, wherein the gastrointestinal treatment-emergent adverse event results from treatment with the antidepressant.
  • Embodiment 196 The method of any one of Embodiments 175-178 or 181-195, wherein the subject is treatment-naive.
  • Embodiment 197 The method of any one of Embodiments 175-178 or 181-195, wherein the subject has not received any antidepressant treatment within at least 30 days prior to the start of the co-administration.
  • Embodiment 198 The method of any one of Embodiments 175-178 or 181-195, wherein the subject has not received treatment with the antidepressant within at least 30 days prior to the start of the co-administration.
  • Embodiment 199 The method of any one of Embodiments 175-178 or 181-195, wherein the subject has not received treatment with the antidepressant within at least 60 days prior to the start of the co-administration.
  • Embodiment 200 The method of any one of Embodiments 175-199, wherein the antidepressant continues to be administered for at least an additional 28 days after day 14 of the treatment.
  • Embodiment 201 The method of any one of Embodiments 175-199, wherein Compound (1), or the pharmaceutically acceptable salt of Compound (1), is not administered after day 14 of the treatment.
  • Embodiment 202 The method of any one of Embodiments 175-201, wherein Compound (1), or a pharmaceutically acceptable salt thereof, and the antidepressant in the co-administration are administered in separate dosage forms.
  • Embodiment 203 The method of Embodiment 203, wherein Compound (1), or a pharmaceutically acceptable salt thereof, and the antidepressant in the co-administration are administered at the same time.
  • Embodiment 204 The method of Embodiment 203, wherein Compound (1), or a pharmaceutically acceptable salt thereof, and the antidepressant in the co-administration are administered at different times.
  • Embodiment 205 The method of any one of Embodiments 175-204, wherein the antidepressant is administered at the same dose from day 1 of treatment to about day 14 of treatment and after day 14 of treatment.
  • Embodiment 206 The method of any one of Embodiments 175-204, wherein the antidepressant is administered at the same dose from day 1 of treatment to about day 14 of treatment and after day 14 of treatment.
  • Embodiment 207 The method of any one of Embodiments 175-206, wherein Compound (1), or a pharmaceutically acceptable salt thereof, is administered once a day.
  • Embodiment 208 The method of any one of Embodiments 179, 181, 183, and
  • Compound (1) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, or about 50 mg.
  • Embodiment 209 The method of Embodiment 175, 177, or 208, wherein
  • Compound (1) is administered at a dose of about 50 mg.
  • Embodiment 210 The method of Embodiment 175, 177, or 208, wherein
  • Compound (1) is administered at a dose of about 40 mg.
  • Embodiment 211 The method of Embodiment 209, wherein Compound (1) is administered at a dose of about 50 mg once a day.
  • Embodiment 212 The method of Embodiment 210, wherein Compound (1) is administered at a dose of about 40 mg once a day.
  • Embodiment 21 The method of any one of Embodiments 180, 182, 184, and
  • Embodiment 214 The method of Embodiment 176, 178, or 213, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 50 mg of the free base compound.
  • Embodiment 215. The method of Embodiment 176, 178, or 213, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 40 mg of the free base compound.
  • Embodiment 216 The method of Embodiment 214, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 50 mg of the free base compound once a day.
  • Embodiment 217 The method of Embodiment 215, wherein the pharmaceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 40 mg of the free base compound once a day.
  • Embodiment 218 The method of any one of Embodiments 175-217, wherein Compound (1) or the pharmaceutically acceptable salt of Compound (1) is administered orally, parenterally, intradermally, intrathecally, intramuscularly, subcutaneously, vaginally, as a buccal, sublingually, rectally, topically, as an inhalation, intranasaly, or transdermally.
  • Embodiment 219. The method of Embodiment 218, wherein Compound (1), or the pharmaceutically acceptable salt of Compound (1), is administered orally.
  • Embodiment 220 The method of any one of Embodiments 175-219, wherein Compound (1), or the pharmaceutically acceptable salt of Compound (1), is administered with food.
  • Embodiment 22 The method of any one of Embodiments 175-220, wherein Compound (1), or the pharmaceutically acceptable salt of Compound (1), is administered once a day at night.
  • Embodiment 222 The method of any one of Embodiments 175-222, wherein the co-admini strati on of Compound (1), or the pharmaceutically acceptable salt of Compound (1), and the antidepressant is re-administered to the subject in response to a recurrence of depression symptoms.
  • Embodiment 223. The method of Embodiment 222, wherein there is at least a 6 week interval between the last dose of the first treatment and the first dose of the readministration.
  • Embodiment 224 The method of any one of Embodiments 175, 177, 179, 181, 183, or 185, wherein Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.7 to 10.1 degrees in 29, between and including 11.6 to 12.0 degrees in 29, between and including 13.2 to 13.6 degrees in 29, between and including 14.2 to 14.6 degrees in 29, between and including 14.6 to 15.0 degrees in 29, between and including 16.8 to 17.2 degrees in 29, between and including 20.5 to 20.9 degrees in 29, between and including 21.3 to 21.7 degrees in 29, between and including 21.4 to 21.8 degrees in 29, and between and including 22.4 to 22.8 degrees in 29.
  • Embodiment 225 The method of any one of Embodiments 175, 177, 179, 181, 183, or 185, wherein Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.3 to 9.7 degrees in 29, between and including 10.6 to 11.0 degrees in 29, between and including 13.0 to 13.4 degrees in 29, between and including 14.7 to 15.1 degrees in 29, between and including 15.8 to 16.2 degrees in 29, between and including 18.1 to 18.5 degrees in 29, between and including 18.7 to 19.1 degrees in 29, between and including 20.9 to 21.3 degrees in 29, between and including 21.4 to 21.8 degrees in 29, and between and including 23.3 to 23.7 degrees in 29.
  • Embodiment 226 Embodiment 226.
  • Embodiment 227 The method of any one of Embodiments 175, 177, 179, 181, 183, or 185, wherein Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.7 to 10.1 degrees in 29, between and including 14.6 to 15.0 degrees in 29, between and including 16.8 to 17.2 degrees in 29, between and including 20.5 to 20.9 degrees in 29, and between and including 21.3 to 21.7 degrees in 29.
  • Embodiment 228 The method of any one of Embodiments 175, 177, 179, 181, 183, or 185, wherein Compound (1) is in a crystalline form having an XRPD pattern comprising peaks between and including 9.3 to 9.7 degrees in 29, between and including 10.6 to 11.0 degrees in 29, between and including 13.0 to 13.4 degrees in 29, between and including 18.7 to 19.1 degrees in 29, and between and including 21.4 to 21.8 degrees in 29. [00567] Embodiment 228.
  • the antidepressant is a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), a serotonin modulator and stimulator (SMS), a serotonin antagonist and reuptake inhibitor (SARI), a norepinephrine reuptake inhibitor (NRI), a norepinephrine dopamine reuptake inhibitor (NDRI), a tricyclic antidepressant (TCA), a tetracyclic antidepressant (TeCA), a monoamine oxidase inhibitor (MAOI), an atypical antipsychotic, agomelatine, esketamine, tianeptine, ketamine, a-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivaga
  • Embodiment 229. The method of Embodiment 228, wherein the antidepressant is an SSRI.
  • Embodiment 230 The method of Embodiment 229, wherein the SSRI is sertraline, escitalopram, citalopram, fluvoxamine, paroxetine, fluoxetine, indalpine, or zimelidine.
  • Embodiment 23 The method of Embodiment 230, wherein the SSRI is sertraline.
  • Embodiment 232 The method of Embodiment 230, wherein the SSRI is escitalopram.
  • Embodiment 233 The method of Embodiment 230, wherein the SSRI is citalopram.
  • Embodiment 234. The method of Embodiment 228, wherein the antidepressant is an SNRI.
  • Embodiment 235 The method of Embodiment 234, wherein the SNRI is duloxetine, desvenlafaxine, levomilnacipran, milnacipran, or venlafaxine
  • Embodiment 236 The method of Embodiment 235, wherein the SNRI is duloxetine.
  • Embodiment 237 The method of Embodiment 235, wherein the SNRI is desvenlafaxine.
  • Embodiment 238 The method of Embodiment 228, wherein the antidepressant is an SMS.
  • Embodiment 239. The method of Embodiment 238, wherein the SMS is vilazodone or vortioxetine.
  • Embodiment 240 The method of Embodiment 228, wherein the antidepressant is an SARI.
  • Embodiment 241 The method of Embodiment 240, wherein the SARI is nefazodone, trazodone, or etoperidone.
  • Embodiment 242 The method of Embodiment 228, wherein the antidepressant is an NR. I.
  • Embodiment 243 The method of Embodiment 242, wherein the NRI is reboxetine, teniloxazine, viloxazine, or atomoxetine.
  • Embodiment 244 The method of Embodiment 228, wherein the antidepressant is a NDRI.
  • Embodiment 245. The method of Embodiment 244, wherein the NDRI is bupropion, amphetamine, methylphenidate, modafinil, amineptine, or nomifensine.
  • Embodiment 246 The method of Embodiment 228, wherein the antidepressant is a TCA.
  • Embodiment 247 The method of Embodiment 246, wherein the TCA is amitriptyline, amitriptylinoxide, clomipramine, desipramine, diebnzepin, dimetacrine, dosluepin, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, notriptyline, noxiptiline, opipramol, pipofezine, protriptyline, trimipramine, butriptyline, demexiptiline, fluacizine, imipraminoxide, iprindole, metapramine, propizepine, quinupramine, tiazesim, or tofenacin.
  • Embodiment 248 The method of Embodiment 228, wherein the antidepressant is a TeCA.
  • Embodiment 249. The method of Embodiment 248, wherein the TeCA is amoxapine, maprotiline, mianserin, mirtazapine, or setiptiline.
  • Embodiment 250 The method of Embodiment 228, wherein the antidepressant is a MAOI.
  • Embodiment 251 The method of Embodiment 250, wherein the MAOI is isocarboxazid, phenelzine, tranylcypromine, benmoxin, iproclozide, iproniazid, mebanazine, nialamide, octamoxin, pheniprazine, phenoxypropazine, pivhydrazine, safrazine, selegiline, caroxazone, metralindole, moclobemide, pirlindole, eprobemide, minaprine, toloxatone, or bifemelane.
  • Embodiment 252 The method of Embodiment 228, wherein the antidepressant is an atypical antipsychotic.
  • Embodiment 253 The method of Embodiment 252, wherein the atypical antipsychotic is amisulpride, lumateperone, lurasidone, quetiapine, aripiprazole, brexpiprazole, lumateperone, lurasidone, olanzapine, quetiapine, or risperidone.
  • the atypical antipsychotic is amisulpride, lumateperone, lurasidone, quetiapine, aripiprazole, brexpiprazole, lumateperone, lurasidone, olanzapine, quetiapine, or risperidone.
  • Embodiment 254 The method of Embodiment 228, wherein the antidepressant is agomelatine, esketamine, tianeptine, ketamine, a-methyltryptamine, etryptamine, ethyltryptamine, indeloxazine, medifoxamine, oxaflozane, pivagabine, ademetionine, hypericum perforatum, oxitriptan, tryptophan, trifluoperazine, buspirone, lithium, thyroxine, triiodothyronine, amitriptyline and chlordiazepoxide, amitriptyline and perphenazine, flupentixol and melitracen, olanzapine and fluoxetine, or tranylcypromine and trifluoperazine.
  • the antidepressant is agomelatine, esketamine, tianeptine, ketamine, a-methyltrypt
  • Embodiment 255 The method of any one of Embodiments 175-227, wherein the antidepressant is 4-Chlorokynurenine (AV-101), Apimostinel (NRX-1074), Arketamine (PCN-101, HR-071603), Dextromethadone (REL-1017), MU-821, Rislenemdaz (CERC-301, MK-0657), TAK-653 (NBI-1065845), OPC-64005, PDC-1421 (BLI-1005), Toludesvenlafaxinem, Hypidone (YL-0919), TGBA01AD (FKB01MD), Vortioxetinem, Lisdexamfetamine, Midomafetamine, Aramisulpride/esamisulpride (85:15 ratio) (SEP-4199), Gepirone, Pramipexole, Psilocybin, Brilaroxazine, Cariprazine, Lumateperone, Lurasidon
  • Embodiment 256 The method of any one of Embodiments 175-255 wherein the antidepressant is administered per its labeled prescribing information.
  • Embodiment 257 The method of any one of Embodiments 13, 14, and 175-255, wherein the co-administration is co-initiation of administration of said Compound (1) or pharmaceutically acceptable salt; and said antidepressant.
  • Embodiment 258 A method of treating major depressive disorder (MDD) in a treatment-naive subject in need thereof, comprising co-initiation of administration of a combination comprising a therapeutically effective amount of Compound (1): and a therapeutically effective amount of an antidepressant.
  • MDD major depressive disorder
  • Example 1 Study Protocol for A Phase 3, Randomized, Double-Blind Study Comparing the Efficacy and Safety of Compound (1) plus an Antidepressant Versus Placebo plus an Antidepressant in Adults with Major Depressive Disorder (CORAL).
  • CORAL Major Depressive Disorder
  • MDD Major depressive disorder
  • QoL quality of life
  • Standard-of-care (SOC) antidepressant therapies such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), are efficacious but generally take weeks or months to improve depressive symptoms, which may lead to an increased risk of suicide and treatment discontinuation.
  • SOC selective serotonin reuptake inhibitors
  • SNRIs serotonin norepinephrine reuptake inhibitors
  • GABA y-aminobutyric acid
  • Compound (1) is a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors, and an NAS in clinical development (as a monotherapy or adjunct therapy) as an oral, once-daily, 14-day treatment course for adults with MDD and PPD in the LANDSCAPE and NEST clinical development programs, respectively.
  • the ongoing SHORELINE study (NCT03864614) was designed to assess the safety and tolerability of a 14-day treatment course of Compound (1) 30 or 50 mg, as well as the need for up to 5 total treatment courses in 1 year or less.
  • the primary endpoint was indicated by a change from baseline in 17-item Hamilton Rating Scale for Depression (HAM-D) total score at day 3.
  • the key secondary endpoint was change from baseline (CFB) in HAM-D total score over the blinded treatment period (using equal weights for the scheduled visits - Day 3, Day 8, Day 12, Day 15).
  • Other secondary endpoints included change from baseline in HAM-D total score at Day 15 and Day 42, change from baseline in HAM-D total score around end of blinded treatment (using equal weights for the scheduled visits -Day 12, Day 15, Day 18), HAM-D response at Day 15 and Day 42, HAM-D remission at Day 15 and Day 42, change from baseline in Clinical Global Impression - Severity (CGI-S) at Day 15, CGI-I response, defined as “much improved” or “very much improved”, at Day 3 and Day 15, change from baseline in MADRS total score at Day 15, MADRS response (>50% reduction from baseline in MADRS total score) at Day 15, MADRS remission (MADRS total score ⁇ 10) at Day 15, change from baseline in HAM-A total score at Day 15, time to first HAM-D response
  • Other endpoints included a change from baseline to day 15 in PRO measures of health-related quality of life as assessed by responses to SF-36v2, a change from baseline to day 15 in PRO measures as they related to functionality as assessed by the Sheehan Disability Scale (SDS), changes from baseline in clinical laboratory measures, vital signs, and electrocardiograms (ECGs), suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale (C-SSRS), potential withdrawal symptoms using the 20-item Physician Withdrawal Checklist (PWC-20), and pharmacokinetic (PK) parameters (e.g., clearance) and exposure estimates (e.g., area under the curve over a dosing interval, maximum plasma concentration) as assessed via population PK methods.
  • SDS Sheehan Disability Scale
  • ECGs electrocardiograms
  • C-SSRS Columbia Suicide Severity Rating Scale
  • PWC-20 20-item Physician Withdrawal Checklist
  • PK pharmacokinetic
  • the study consisted of a screening period of up to 28 days, a 14-day double-blind treatment period, and a 28-day ADT continuation period.
  • the screening period began with the signing of the informed consent form (ICF) at the screening visit.
  • ICF informed consent form
  • Preliminary screening procedures to determine eligibility included completion of the MGH-ATRQ and HAM-D.
  • Participants were randomized to receive blinded Compound (1) 50 mg or placebo for administration each evening from Days 1 through 14.
  • a selective serotonin reuptake inhibitor sertraline, escitalopram, citalopram
  • SNRI serotonin-norepinephrine reuptake inhibitor
  • the ADT was administered per labeled prescribing information.
  • the investigator assigned 1 of the 5 ADTs based on clinical standard of care; the participant must not have had been previously treated with the assigned ADT within the current depressive episode and must not have had taken any ADT within 30 days prior to Day 1 (or taken fluoxetine within 60 days prior to Day 1).
  • Randomization was stratified by ADT class (SSRI or SNRI).
  • ADT was continued each evening for the remainder of the study (ADT Continuation Period). During this period (Weeks 3 to 6) ADT dosing could have been modified based on individual response, at the discretion of the investigator and per the labeled prescribing information.
  • IP blinded investigational product
  • fat-containing food e.g., within 1 hour of an evening meal which contains fat, or with a fat-containing snack
  • the ADT and Compound (l)/placebo were administered at the same time during the treatment period; participants that were assigned duloxetine also administered ADT in the morning (for twice- daily dosing) as part of a divided dose for the first 7 days. Participants returned to the study center as outlined in the schedule of assessments (Table 1).
  • Participant was a male or female between 18 and 64 years of age, inclusive;
  • Participant had a diagnosis of MDD as diagnosed by SCID-5-CT, with symptoms that were present for at least a 4-week period; Participant had a HAMD-17 total score of >24 at screening and day 1 (prior to dosing);
  • Participants were willing, able, and eligible to take at least 1 of the 5 ADTs specified in the protocol (an eligible ADT was an ADT that had not been taken during the current depressive episode and for which the participant had no contraindications; further, a participant was not eligible for citalopram if escitalopram had been taken during the current depressive episode, and vice versa).
  • Participant had onset of the current depressive episode during pregnancy or 4 weeks postpartum, or the participant had presented for screening during the 6-month postpartum period;
  • Participant had a recent history or active clinically significant manifestations of metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological, urogenital, neurological, or eyes, ears, nose, and throat disorders, or any other acute or chronic condition that, in the investigator's opinion, would have limited the participant's ability to complete or participate in this clinical study; a BMI ⁇ 18 or >45 kg/m2 was exclusionary; a BMI of 40 to 44.9 kg/m2, inclusive, at screening was subject to a broader evaluation of medical comorbidities as described above;
  • Participant had treatment-resistant depression, defined as persistent depressive symptoms despite treatment with adequate doses of antidepressants within the current major depressive episode (excluding antipsychotics) from 2 different classes for at least 4 weeks of treatment.
  • MGH ATRQ Massachusetts General Hospital Antidepressant Treatment Response Questionnaire
  • Participant had vagus nerve stimulation, electroconvulsive therapy, or had taken ketamine within the current major depressive episode;
  • CBT-I Cognitive Behavioral Therapy for Insomnia
  • Participant had taken antidepressants within 30 days prior to day 1, and/or had taken fluoxetine within 60 days prior to day 1;
  • Participant had a medical history of bipolar disorder, schizophrenia, and/or schizoaffective disorder; • Participant had a history of mild, moderate, or severe substance use disorder (including benzodiazepines) diagnosed using DSM-5 criteria in the 12 months prior to screening or participant had a history of mild or moderate substance use disorder not in sustained remission for at least 6 months prior to screening;
  • Participant had used any strong CYP3 A inducer, such as rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, or St John’s Wort, within 28 days prior to day 1;
  • Participant had a positive drug and/or alcohol screen at screening or on day 1 prior to dosing;
  • Participant was taking benzodiazepines, barbiturates, or y-aminobutyric acid type A (GABAA) modulators (e.g., eszopiclone, zopiclone, zaleplon, and zolpidem) within 28 days prior to day 1, or had been using these agents daily or near-daily (>4 times per week) for more than 1 year. Participant was taking any benzodiazepine or GABA modulator with a half-life of >48 hours (e.g., diazepam) from 60 days prior to day 1;
  • GABAA y-aminobutyric acid type A
  • Participant was taking non-GABA anti -insomnia medications (e.g., prescribed therapeutics specifically for insomnia and/or over the counter sleep aids), or first generation or second generation (typical/atypical) antipsychotics within 14 days prior to day 1. Nonsedating antihistamines were permitted;
  • Participant had been diagnosed with and/or treated for any type of cancer (excluding basal cell carcinoma and melanoma in situ) within the past year prior to screening;
  • Participant had gastric bypass surgery, had a gastric sleeve or lap band, or had any related procedures that interfered with gastrointestinal transit;
  • Participant was taking psychostimulants (e.g., methylphenidate, amphetamine) or opioids, regularly or as needed, within 28 days prior to day 1;
  • psychostimulants e.g., methylphenidate, amphetamine
  • opioids regularly or as needed, within 28 days prior to day 1;
  • Participant was a dependent of the sponsor, investigator, investigator’s deputy, or study site staff; Participant expected to perform night shift work during the 14-day treatment period; or
  • Compound (1) was available as hard gelatin capsules for oral administration; multiple capsules (in 30-mg or 20-mg dose strengths) were provided to total a 50-mg dose, with option to reduce to 40 mg based on tolerability.
  • Sertraline, escitalopram, citalopram, duloxetine, or desvenlafaxine were administered as per labeled prescribing information.
  • sertraline be administered as per labeled prescribing information, starting with 50 mg each evening during Week 1 and it was recommended that the dose be increased to 100 mg each evening during Week 2.
  • duloxetine be administered per labeled prescribing information, starting with 40 or 60 mg/day (divided as 20 or 30 mg, respectively, twice daily for the first 7 days).
  • Compound (1) was administered as a 14-day regimen of an evening dose of 50 mg with reduction to 40 mg as needed based on tolerability.
  • the 50-mg dose of Compound (1) was expected to exhibit a favorable benefit-risk profile in the context of results from previous Compound (1) studies utilizing a 30-mg dose, identified as a minimally effective dose.
  • Compound (1) was expected to maintain an acceptable tolerability profile, based on a current safety database of over 2000 participants exposed across different doses/concentrations.
  • Sertraline is a commercially available SSRI indicated for the treatment of MDD and other psychiatric disorders.
  • Dosage and administration of sertraline as described in the approved US Prescribing Information recommends a starting dose of 50 mg per day in patients with MDD, with an incremental weekly increase in dose of 25-50 mg per day, if there was an inadequate response to the starting dose, to a maximum dose of 200 mg per day.
  • a starting dose of 50 mg per day was recommended for 7 days, with a subsequent increase to 100 mg per day.
  • Citalopram and escitalopram are commercially available SSRIs that are both indicated for acute and maintenance treatment of MDD. Escitalopram is also indicated for treatment of generalized anxiety disorder.
  • the starting dosage for MDD in the US PI for citalopram is 20 mg/day and for escitalopram is 10 mg/day, with maxima of 40 mg/day and 20 mg/day, respectively.
  • a starting dose of 20 mg/day was recommended for citalopram and of 10 mg/day was recommended for escitalopram for the first 14 days; subsequent dose increases could be considered, except for participants >60 years old taking citalopram.
  • Duloxetine is a commercially available SNRI indicated for the treatment of MDD, generalized anxiety disorder, and pain disorders.
  • the starting dosage for MDD in the US PI is 40 to 60 mg/day.
  • the maximum dosage is 120 mg/day, although there is no evidence that dosages greater than 60 mg/day confer any additional benefits.
  • a starting dose of 40 or 60 mg/day was recommended (divided as 20 or 30 mg, respectively, twice daily for the first 7 days).
  • Desvenlafaxine is a commercially available SNRI indicated for the treatment of MDD.
  • the recommended dosage in the US PI is 50 mg/day. In this study, a dose of 50 mg/day was recommended. There has been no evidence that doses greater than 50 mg/day confer any additional benefit.
  • Participants were assigned to blinded IP (Compound (1) or placebo) in accordance with the randomization schedule on Day 1.
  • the investigator assigned 1 of the 5 ADTs based on clinical standard of care.
  • the assigned ADT for a participant could not have been taken previously by the participant during the current depressive episode. Further, citalopram could not be assigned if escital opram had been taken during the current depressive episode, and vice versa.
  • Randomization was stratified by antidepressant class (SSRI or SNRI).
  • First generation (typical) antipsychotics e.g., haloperidol, perphenazine
  • second generation antipsychotics e.g., aripiprazole, quetiapine
  • Use of any non-GABA anti-insomnia medications e.g., prescribed therapeutics specifically for insomnia and/or over the counter sleep aids
  • Nonsedating antihistamines were permitted;
  • CYP3 A inducer such as rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, or St John’s Wort from Day -28 through the treatment period; or
  • Randomization and Blinding [00667] Participants were randomized in a 1 : 1 ratio to receive Compound (1) or matched placebo. Participants, site staff, and the sponsor were blinded to treatment allocation. All participants also received an open-label ADT. Randomization was performed centrally via an interactive response technology (IRT) system. Randomization schedules were generated by an independent statistician. The allocation to blinded treatment (Compound (1) or placebo) were based on the randomization schedule. The randomization schedules were kept strictly confidential, accessible only to authorized personnel until the time of unblinding. The blinding of the study was broken after the database had been locked.
  • IRT interactive response technology
  • Compound (1) was available as hard gelatin capsules containing a white to off-white powder.
  • active Compound (1) capsules contained croscarmellose sodium, mannitol, silicified microcrystalline cellulose, colloidal silicon dioxide, and sodium stearyl fumarate as excipients. Capsules were available in 20-mg and 30-mg dose strengths.
  • Compound (1) and placebo was provided to the clinic pharmacist and/or designated site staff responsible for dispensing the blinded IP in appropriately labeled, participantspecific kits containing sealed unit doses. Each unit dose for 40-mg and 50-mg dose levels consisted of 2 capsules. Additional information regarding the packaging and labeling was provided in the pharmacy manual.
  • a participant misses a dose of blinded IP or open-label IP the participant should have skip that dose (e.g., they should not take the dose in the morning) and take the next scheduled dose the next evening.
  • the primary outcome measure was the change from baseline in 17-item HAM-D total score at Day 3. Every effort was made for the same rater to perform all HAM-D assessments for an individual participant. An assessment timeframe of past 7 days (1 week) was used at screening, and ‘Since Last Visit’ was used for all other visits.
  • the 17-item HAM-D was used to rate the severity of depression in participants who were already diagnosed as depressed.
  • the 17-item HAM-D comprises individual ratings related to the following symptoms: depressed mood (sadness, hopeless, helpless, worthless), feelings of guilt, suicide, insomnia (early, middle, late), work and activities, retardation (slowness of thought and speech; impaired ability to concentrate; decreased motor activity), agitation, anxiety (psychic and somatic), somatic symptoms (gastrointestinal and general), genital symptoms, hypochondriasis, loss of weight, and insight.
  • the HAM-D total score was calculated as the sum of the 17 individual item scores.
  • Hamilton Rating Scale for Depression subscale scores were calculated as the sum of the items comprising each subscale. Hamilton Rating Scale for Depression response was defined as having a 50% or greater reduction from baseline in HAM-D total score. Hamilton Rating Scale for Depression remission was defined as having a HAM-D total score of ⁇ 7.
  • the MADRS is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in participants with mood disorders. It was designed as an adjunct to the HAM-D that is more sensitive to the changes brought on by antidepressants and other forms of treatment than the Hamilton Scale. Higher MADRS scores indicate more severe depression, and each item yields a score of 0 to 6. The overall score ranges from 0 to 60. The MADRS total score was calculated as the sum of the 10 individual item scores.
  • the 14-item HAM-A will be used to rate the severity of symptoms of anxiety.
  • Each of the 14 items is defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Scoring for HAM-A is calculated by assigning scores of 0 (not present) to 4 (very severe), with a total score range of 0 to 56, where ⁇ 17 indicates mild severity, 18 to 24, mild to moderate severity, and 25 to 30, moderate to severe severity. The HAM-A total score was calculated as the sum of the 14 individual item scores.
  • the CGI is a validated measure often utilized in clinical studies to allow clinicians to integrate several sources of information into a single rating of the participant’s condition. Please see, e.g., Joan Busner and Steven D. Targum, “The Clinical Global Impressons Scale”, Psychiatry (Edgmont). 2007 Jul; 4(7): 28-37.
  • the CGI has two components - the CGI-Severity (SGI-S), which rates illness severity, and the CGI-Improvement (CGI-I), which rates change from the initiation (baseline) of treatment.
  • the CGI-I employs a 7-point Likert scale to measure the overall improvement in the participant’s condition posttreatment.
  • the CGI-I is only rated at posttreatment assessments. By definition, all CGI-I assessments were evaluated against baseline conditions. CGI-I response was defined as having a CGI-I score of “very much improved” or “much improved.”
  • the Medical Outcomes Study SF-36v2 is a 36-item measure of health status that has undergone validation in many different disease states.
  • the SF-36v2 covers 8 health dimensions including 4 physical health status domains (physical functioning, role participation with physical health problems [role-physical], bodily pain, and general health) and 4 mental health status domains (vitality, social functioning, role participation with emotional health problems [role- emotional], and mental health).
  • 2 summary scores, physical component summary and mental component summary are produced by taking a weighted linear combination of the 8 individual domains.
  • the SF-36v2 is available with two recall periods: the standard recall period is 4 weeks and the acute recall period is 1 week. This study used the acute version, which asked patients to respond to questions as they pertain to the past week. Higher SF-36v2 scores indicate a better state of health.
  • the PHQ-9 total score will be calculated as the sum of the 9 individual item scores.
  • the SDS is a participant-rated assessment that measures the extent to which work/school, social life, and home life or family responsibilities were impaired by symptoms of psychiatric illness.
  • the SDS total score ranges from a minimum of 0 to a maximum of 30. For the SDS total score, lower scores indicate a better outcome and higher scores indicate a worse outcome. A negative change from baseline value (decrease in score) is considered a better outcome, and a positive change from baseline value (increase in score) is considered a worse outcome.
  • the SDS contains 3 items; the total score is computed as the sum of the scores for the 3 items.
  • Pharmacokinetic parameters e.g., clearance
  • exposure estimates e.g., area under the curve over a dosing interval, maximum plasma concentration
  • Plasma samples for PK analysis will be collected according to the sampling schedule.
  • the investigator or designee will arrange to have the plasma samples transported as directed for bioanalysis.
  • An additional PK sample could have been collected at any time if clinically indicated and at the discretion of the investigator (e.g., for unusual or severe AEs). In the event of a dose adjustment, an unscheduled PK sample should have been collected, if possible, just prior to the dose adjustment.
  • Each sample was marked with unique identifiers with at least the study number, participant number, and visit day. The date and actual time that the blood sample was taken was recorded on the case report form.
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • Suicidality was monitored during the study using the C-SSRS.
  • This scale consists of a baseline evaluation that assesses the lifetime experience of the participant with suicidal ideation and behavior, and a postbaseline evaluation that focuses on suicidality since the last study visit.
  • the C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most severe).
  • the “Baseline/Screening” C-SSRS form was completed at screening (lifetime history and past 24 months).
  • the “Since Last Visit” C-SSRS form was completed at all subsequent time points, as outlined in Table 1.
  • the Penn Physician Withdrawal Checklist (PWC) consists of 35 items developed to measure benzodiazepine and benzodiazepine-like discontinuation symptoms.
  • the PWC-20 is a shorter version of the PWC based on the 20 items that provided the best differentiation from placebo in previous trials.
  • the PWC-20 is made up of a list of 20 symptoms (e.g., loss of appetite, nausea- vomiting, diarrhea, anxiety-nervousness, irritability, etc.) that are rated on a scale of 0 (not present) to 3 (severe).
  • the PWC-20 was used to monitor for the presence of potential withdrawal symptoms following discontinuation of Compound (1).
  • An AE was any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.
  • An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product whether or not related to the medicinal (investigational) product.
  • an AE could include an undesirable medical condition occurring at any time, including baseline or washout periods, even if no study treatment has been administered.
  • a TEAE was defined as an AE with onset after the start of IP, or any worsening of a pre-existing medical condition/AE with onset after the start of IP and throughout the study.
  • IP included any Sage IP, a comparator, or a placebo administered in a clinical study.
  • An SAE was any untoward medical occurrence that at any dose:
  • An SAE could also be any other medically important event that, in the opinion of the investigator may have jeopardized the participant or may have required medical intervention to prevent 1 of the outcomes listed above (examples of such events included allergic bronchospasm requiring intensive treatment in an emergency room or convulsions occurring at home that do not require an inpatient hospitalization).
  • the AE term should have been reported in standard medical terminology when possible.
  • Severe symptom(s) cause severe discomfort; symptoms cause incapacitation or significant impact on participant’s daily life; severity may cause cessation of treatment with IP; treatment for symptom(s) may be given and/or participant hospitalized.
  • Overdoses regardless of presence of associated clinical manifestation(s) (e.g., headache, abnormal laboratory value) was considered an AE and recorded as such on the eCRF. Any clinical manifestation(s) of overdose must also have been recorded as an AE on the eCRF. In addition, all overdoses must have been recorded on an overdose form and sent to Sage or designee within 24 hours of the site becoming aware of the overdose.
  • clinical manifestation(s) e.g., headache, abnormal laboratory value
  • AE adverse event
  • CGI-I Clinical Global Impression - Improvement
  • CGI-S Clinical Global Impression - Severity
  • C-SSRS Columbia Suicide Severity Rating Scale
  • D day
  • EOT end of treatment
  • ET early termination
  • ECG electrocardiogram
  • FSH follicle stimulating hormone
  • HAM-A Hamilton Anxiety Rating Scale
  • HAM-D Hamilton Rating Scale for Depression, 17-item
  • HIV human immunodeficiency virus
  • IP investigational product
  • MADRS Montgomery- sberg Depression Rating Scale
  • MGH ATRQ Massachusetts General Hospital Antidepressant Treatment Response Questionnaire
  • PHQ-9 9-item Patient Health Questionnaire
  • PWC- 20 20-item Physician Withdrawal Checklist
  • O Optional
  • PK pharmacokinetic
  • SCID-5-CT Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition Clinical Trials Version
  • SDS Sheehan Disability Scale
  • SF-36v2 36-
  • a Participants who discontinue treatment early should return to the site for an end of treatment (EOT) visit as soon as possible, preferably the day after treatment is discontinued. If necessary, the EOT and ET visits can be on the same day if a participant discontinues IP and terminates the study on the same day during a clinic visit; in this case, all EOT visit assessments should be conducted.
  • Participants will be asked to authorize that their unique participant identifiers be entered into a registry (www.subjectregistry.com) with the intent of identifying participants who may meet exclusion criteria for participation in another clinical study.
  • a serum FSH test will be conducted at screening for female participants that are not surgically sterile to confirm whether a female participant with >12 months of spontaneous amenorrhea meets the protocol-defined criteria for being postmenopausal.
  • Participants will be trained on use of software applications and devices necessary for the conduct of the study by site personnel.
  • a full physical examination will be conducted at screening and abbreviated physical examinations will be conducted thereafter.
  • a full physical examination includes assessment of body systems (e.g., head, eye, ear, nose, and throat; heart; lungs; abdomen; and extremities).
  • An abbreviated physical examination includes a brief medical history followed by targeted physical examination
  • Safety laboratory tests will include hematology, serum chemistry, coagulation, and urinalysis.
  • j An optional genetic sample for exploratory biomarker testing, where consent is given.
  • k When vital signs are scheduled at the same time as blood draws, vital signs will be obtained first. Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (supine and standing). Heart rate and blood pressure to be collected in supine position at all scheduled time points after the participant has been resting for 5 minutes and then after approximately 3 minutes in the standing position. Vital signs may be repeated at the discretion of the investigator as clinically indicated. 1 Triplicate ECGs will be collected. When ECGs and PK sample collection occur on the same day, the 12-lead ECGs will be performed before PK sample collection.
  • the “Baseline/Screening” C-SSRS form will be completed at Screening.
  • the “Since Last Visit” C-SSRS form will be completed at all subsequent time points.
  • the HAM-D is to be completed as early during the visit as possible.
  • the assessment timeframe for HAM-D scales will refer to the past 7 days (1 week) at Screening and “Since Last Visit” for all other visits.
  • the assessment timeframe for HAM-A scales will refer to the past 7 days (1 week) at all visits.
  • p Blood samples for PK analysis will be collected anytime during the clinic visit. In the event of a dose adjustment, an unscheduled PK sample should be collected, if possible, just prior to the dose adjustment. The date and time of sample collection and date and time of the last dose administration must be recorded. When ECGs and PK sample collection occur on the same day, the 12-lead ECGs will be performed before PK sample collection.
  • IP administration will be monitored via a medication adherence monitoring platform used on smartphones to confirm IP ingestion. IP adherence will not be captured after participants discontinue IP.
  • r ADT will be administered as per labeled prescribing information s AEs will be collected starting at the time of informed consent and throughout the duration of the participant’s participation in the study.
  • Example 2 Results for the Study of Example 1.
  • Example 1 This was a randomized, double-blind, parallel-group, active/placebo -controlled phase 3 study (NCT04476030) in participants with major depressive disorder (MDD), described in Example 1.
  • SOC standard-of-care
  • Compound (1) was taken for 14 days only, but ADT was continued until the end of the study (42 days).
  • FIG. l is a schematic of the clinical study design.
  • the study period consisted of a screening period of up to 28 days, followed by a double-blind treatment course of 14 days (treatment period), and then a 28-day, open-label follow-up period with continued SOC ADT treatment.
  • the study met its objectives, demonstrating a rapid and statistically significant reduction in depressive symptoms at Day 3 and over the 2-week treatment period, achieving the primary and key secondary endpoints. This significance was demonstrated at the first measured time point, Day 3, with Compound (1) 50 mg co-initiated with an open-label standard of care antidepressant (ADT) as assessed by change from baseline in the 17-item Hamilton Rating Scale for Depression (HAMD-17).
  • ADT open-label standard of care antidepressant
  • Compound (1) was generally-well tolerated and no new safety signals attributable to Compound (1) were identified. In meeting its pre-defined objectives, the study supports the potential of Compound (1), when co-initiated with standard of care, to accelerate the benefit of depression treatment compared to treatment with ADTs alone.
  • a total of 440 participants were randomized in 1 : 1 proportion to Compound (1) + ADT and placebo + ADT treatment groups.
  • a total of 430 participants received at least one dose of blinded treatment (Safety Set) - 212 in Compound (1) + ADT and 218 in placebo + ADT.
  • the safety set included all patients who received blinded study drug.
  • the full analysis set included all randomized patients in the safety set with a valid baseline and >1 postbaseline total score on at least one of the efficacy assessments (HAMD-17, Hamilton Rating Scale for Anxiety [HAM-A], Montgomery-Asberg Depression Rating Scale, or the 9- item Patient Health Questionnaire) or those with a valid baseline and >1 postbaseline value on the Clinical Global Impressions-Improvement score and/or Clinical Global Impressions- Severity score.
  • a sample size of 382 evaluable patients was determined to provide 90% power to detect a statistically significant difference in the primary endpoint using a two-sided alpha level of 0.05, assuming the true difference is 3 points and a standard deviation (SD) of 9 points.
  • Evaluable patients were those who were randomized and received blinded study drug and had a valid baseline and >1 postbaseline HAMD-17 assessment.
  • HAMD-17 response, HAMD-17 remission, and CGI-I response were analyzed using generalized estimating equation methods.
  • the Kaplan-Meier method was employed to estimate time to first HAMD-17 response, with the number and percentage of patients who had a response or who were censored included in the analysis.
  • the Kaplan-Meier method was employed to estimate the time to first HAMD-17 remission.
  • Table 2 shows the patient disposition of the study.
  • HAMD-17 total score at baseline was 26.8 (2.5) in patients who received Compound (1)+ADT and 26.6 (2.6) in patients who received placebo+ADT. Approximately half of patients who received Compound (1)+ADT and placebo+ADT (49.5% and 53.2%, respectively) had MDD with elevated anxiety at baseline (defined as HAM-A total score >20).
  • escitalopram 77/218; 35.3%
  • sertraline 53/218; 24.3%
  • desvenlafaxine 32/218; 14.7%
  • duloxetine 27/218; 12.4%
  • citalopram 29/218; 13.3%
  • Table 3 Demographics and Baseline Characteristics - Safety Set start date of the first depressive episode. b Includes current episode.
  • ADT antidepressant therapy BMI body mass index, CGI-S Clinical Global Impression-Severity, HAM-A Hamilton Rating Scale for Anxiety, HAMD-17 17-item Hamilton Rating Scale for Depression, MADRS Montgomery-Asberg Depression Rating Scale, MDD major depressive disorder, SD standard deviation.
  • the key secondary endpoint was the least-squares (LS) mean (SE) change from baseline in the HAM- D total score for the contrast over the treatment period for the scheduled visits Day 3, Day 8, Day 12, and Day 15, calculated using equal weights (Table 5.2).
  • Table 5.1 Change from Baseline in HAM-D Total Score over the Blinded Treatment Period at Days 3, 8, 12, and 15.
  • Table 5.2 Change from Baseline in HAM-D Total Score at Days 3, 8, 12, and 15 (Applied for the Key Secondary Endpoint).
  • HAMD-17 response defined as >50% reduction from baseline in HAMD-17 total score, at Days 15 and 42; time to first HAMD-17 response; HAMD-17 remission, defined as HAMD-17 total score ⁇ 7, at Days 15 and 42; CFB in Montgomery - Asberg Depression Rating Scale (MADRS) total score at Day 15; MADRS response, defined as >50% reduction from baseline in MADRS total score, at Day 15; MADRS remission, defined as MADRS total score ⁇ 10, at Day 15; Clinical Global Impressions-Improvement (CGI-I) response of “very much improved” or “much improved” from baseline at Days 3 and 15; CFB in Clinical Global Impressions-S
  • CGI-S was assessed at Days 1, 3, 8, 12, 15, 21, 28, 35, and 42.
  • MADRS and HAM- A were assessed at Days 1, 8, 15, 28, and 42.
  • CGI-I was evaluated at Days 3, 8, 12, 15, 21, 28, 35, and 42.
  • PHQ-9 was evaluated at Days 1, 3, 8, 15, 28, and 42.
  • the CFB in MADRS total score is shown in FIG. 8.
  • HAMD-17 response was defined as CFB (improvement) in HAMD-17 total score >50%.
  • HAMD-17 remission was defined as HAMD-17 total score ⁇ 7.
  • CGI-I response was defined as “much” or “very much” improved.
  • ADT antidepressant therapy CFB change from baseline, CGI-S Clinical Global Impressions- Severity, CI confidence interval, HAM-A Hamilton Rating Scale for Anxiety, HAMD-17 17-item Hamilton Rating Scale for Depression, LS least squares, MADRS Montgomery-Asberg Depression Rating Scale, OR odds ratio, PHQ-9 9-item Patient Health Questionnaire, SE standard error
  • FIGS. 10A and 10B show the change from baseline in HAMD-17 total score over time for patients with MDD with elevated anxiety.
  • Patients with MDD with elevated anxiety at baseline who received Compound (1)+ADT demonstrated nominally significant improvements in depressive symptoms at Day 3, as measured by the LS mean CFB in HAMD-17 total score(LS mean [SE], -9.3 [0.57] vs-6.0 [0.55]; p ⁇ 0.0001).

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CN117442618A (zh) * 2023-10-23 2024-01-26 国科大杭州高等研究院 化合物ly2940094在制备治疗中枢神经系统脱髓鞘疾病药物中的应用

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