WO2022006541A1

WO2022006541A1 - Methods for the treatment of adjustment disorder

Info

Publication number: WO2022006541A1
Application number: PCT/US2021/040343
Authority: WO
Inventors: Bernard RAVINA; Nicholas DEMARTINIS; Carlos LOYA
Original assignee: Praxis Precision Medicines, Inc.
Priority date: 2020-07-02
Filing date: 2021-07-02
Publication date: 2022-01-06

Abstract

The present disclosure relates to methods of treating adjustment disorder with Compound 1 or pharmaceutically acceptable salts thereof.

Description

METHODS FOR THE TREATMENT OF ADJUSTMENT DISORDER CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Application No. 63/047,643, filed July 2, 2020, and U.S. Application No. 63/069,464, filed August 24, 2020, which are hereby incorporated by reference in their entireties herein. FIELD OF THE DISCLOSURE [0002] The present disclosure relates to methods for the treatment of adjustment disorder using 3α-hydroxy-3β-methoxymethyl-21-(1′-imidazolyl)-5α-pregnan-20-one and salts thereof. BACKGROUND OF THE DISLOSURE [0003] 3α-Hydroxy-3β-methoxymethyl-21-(1′-imidazolyl)-5α-pregnan-20-one (Compound 1) is a synthetic neuroactive steroid. Its primary molecular target is the γ- aminobutyric acid type A (GABAA) receptor, where it acts as a positive allosteric modulator (PAM) of channel function. The structural formula of Compound 1 appears below.

[0004] Neuroactive steroid GABA_A PAMs have demonstrated clinical efficacy in anesthesia, epilepsy, post-partum depression, and major depression. SUMMARY OF THE DISCLOSURE [0005] The present disclosure provides methods of treating adjustment disorder (AD) by administering a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof. [0006] In some embodiments, the present disclosure provides a method of treating adjustment disorder in a patient in need thereof comprising orally administering a therapeutically effective amount of Compound 1:

or a pharmaceutically acceptable salt thereof to a patient in need thereof. [0007] In some embodiments, the adjustment disorder is adjustment disorder with depressed mood. [0008] In some embodiments, the adjustment disorder is adjustment disorder with anxiety. [0009] In some embodiments, the adjustment disorder is adjustment disorder with mixed anxiety and depressed mood. [0010] In some embodiments, about 5 mg to about 120 mg of Compound 1 or a pharmaceutically acceptable salt is administered per day. [0011] In some embodiments, about 15 mg to about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered per day. [0012] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered for about 1 weeks to about 4 weeks. [0013] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered for about 2 weeks. [0014] In some embodiments, after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least ten point decline in total Hamilton Depression Rating Scale (HAM-D) value compared to prior to the treatment. [0015] In some embodiments, after said administering for a period of at least 1 week, the patient experiences a reduction of adjustment disorder that is characterized by an at least two point decline in total Hamilton Rating Scale for anxiety (HAM-A) value compared to prior to the treatment. [0016] In some embodiments, after the administering, the patient experiences a reduction of adjustment disorder that is characterized by at least one point decline in Global Improvement Subscale (CGI-I) score compared to prior to the treatment. [0017] In some embodiments, after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 2 point reduction in the Hospital Anxiety and Depression Scale (HADS) total score compared to prior to the treatment. [0018] In some embodiments, after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 2 point reduction in the Adjustment Disorder – New Module 20 (ADNM-20) total score compared to prior to the treatment. [0019] In some embodiments, after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 1 point reduction in the Sheehan Disability Scale (SDS) total score compared to prior to the treatment. [0020] In some embodiments, the administering provides a mean steady state AUC0-24 of from about 600 ng ^h/mL to about 900 ng ^h. [0021] In some embodiments, the administering provides a mean steady state Cmax of from about 125 ng/mL to about 250 ng/mL. [0022] In some embodiments, the method comprises administering one or more anxiolytics. [0023] In some embodiments, the anxiolytic is one or more benzodiazepines. [0024] In some embodiments, the method comprises administering one or more antidepressants. [0025] In some embodiments, the method comprises administering etifoxine or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE DRAWINGS [0026] FIG.1 is a graphical representation of the mean Compound 1 plasma concentration versus time for 15.0 mg daily administration of Compound 1 (Cohort 1), 30.0 mg daily administration of Compound 1 (Cohort 2), and a 60.0 mg daily administration of Compound 1 (Cohort 3). [0027] FIG. 2 is a graphical representation of the mean Compound 1 steady state plasma concentration versus time for 15.0 mg daily administration of Compound 1 (Cohort 1), 30.0 mg daily administration of Compound 1 (Cohort 2), and a 60.0 mg daily administration of Compound 1 (Cohort 3). [0028] FIG. 3 shows the design of a study that evaluates Compound 1 for adjustment disorder. DEFINITIONS [0029] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example in a list of numerical values such as “about 49, about 50, about 55, …”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range. [0030] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure. [0031] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. [0032] The terms “administer,” “administering” or “administration” as used herein refer to either directly administering a compound or pharmaceutically acceptable salt or ester of the compound or a composition comprising the compound or pharmaceutically acceptable salt or ester of the compound to a patient. [0033] The term “adjustment disorder” is used in this disclosure to mean adjustment disorder as defined by a validated system for diagnosing mental disorders. In some embodiments, the term “adjustment disorder” is used to mean adjustment disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). In some embodiments, the term “adjustment disorder” is used to mean adjustment disorder as defined by code F43.2 of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). Similarly, the terms “adjustment disorder with depressed mood”, “adjustment disorder with anxiety”, and “adjustment disorder with mixed anxiety and depressed mood” are used in this disclosure to mean adjustment disorder with depressed mood, adjustment disorder with anxiety, and adjustment disorder with mixed anxiety and depressed mood, respectively, as defined in the DSM-5 or in the ICD-10. [0034] The term “carrier” as used herein encompasses carriers, excipients, and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ or portion of the body. [0035] The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. [0036] The terms “effective amount” and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound, or a salt, solvate or ester thereof, that, when administered to a patient, is capable of performing the intended result. For example, an effective amount of a salt of Compound 1 is that amount that is required to reduce at least one symptom of depression in a patient. The actual amount that comprises the “effective amount” or “therapeutically effective amount” will vary depending on a number of conditions including, but not limited to, the severity of the disorder, the size and health of the patient, and the route of administration. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical arts. [0037] The phrase “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0038] The term “salts” as used herein embraces pharmaceutically acceptable salts commonly used to form addition salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. The term “salts” also includes solvates of addition salts, such as hydrates, as well as polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from an inorganic acid or from an organic acid. [0039] The term “treating” as used herein with regard to a patient, refers to improving at least one symptom of the patient’s disorder. Treating can be curing, improving, or at least partially ameliorating a disorder. [0040] The term “therapeutic effect” as used herein refers to a desired or beneficial effect provided by the method and/or the composition. For example, the method for treating depression provides a therapeutic effect when the method reduces at least one symptom of depression in a patient. [0041] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C_1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C_1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C_1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C_1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C_1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C_2- 6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C₃), n-butyl (C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅), 3- pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n- hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10 alkyl (e.g., —CH3). In certain embodiments, the alkyl group is substituted C_1-10 alkyl. Common alkyl abbreviations include Me (—CH3), Et (—CH2CH3), iPr (—CH(CH3)2), nPr (—CH2CH2CH3), n-Bu (— CH₂CH₂CH₂CH₃), or i-Bu (—CH₂CH(CH₃)₂). [0042] As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group, respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” and “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein. [0043] “Alkylene” refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (—CH2—), ethylene (—CH2CH2—), propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), pentylene (— CH2CH2CH2CH2CH2—), hexylene (—CH2CH2CH2CH2CH2CH2—), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (—CH(CH3)—, (—C(CH3)2—), substituted ethylene (—CH(CH₃)CH₂—, —CH₂CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—), substituted propylene (—CH(CH3)CH2CH2—, —CH2CH(CH3)CH2—, —CH2CH2CH(CH3)— , —C(CH₃)₂CH₂CH₂—, —CH₂C(CH₃)₂CH₂—, —CH₂CH₂C(CH₃)₂—), and the like. [0044] “Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C_2-20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C_2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C_2- 9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C_2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C_2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is substituted C_2-10 alkenyl. [0045] “Alkenylene” refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (— CH═CH—) and propenylene (e.g., —CH═CHCH₂—, —CH₂—CH═CH—). Exemplary substituted alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted ethylene (—C(CH₃)═CH—, —CH═C(CH₃)—), substituted propylene (e.g., —C(CH3)═CHCH2—, —CH═C(CH3)CH2—, —CH═CHCH(CH3)—, — CH═CHC(CH₃)₂—, —CH(CH₃)—CH═CH—, —C(CH₃)₂—CH═CH—, —CH₂— C(CH3)═CH—, —CH2—CH═C(CH3)—), and the like. [0046] “Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2- ₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C_2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C_2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C_2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon- carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), and the like. Examples of C_2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C_2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C2-10 alkynyl. [0047] “Alkynylene” refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like. [0048] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1- ₁₀ alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC_1- 8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC_1-7 alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroC1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC_1-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC₁ alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC_11-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl. [0049] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC_2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC_2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC_2-10 alkenyl. [0050] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2- 8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC_2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC_2-6alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-5alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-4alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC_2-3alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC_2-6alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC_2-10 alkynyl. [0051] As used herein, “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” refer to a divalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular “alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein. [0052] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n: electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6- ₁₄ aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C_6-14 aryl. In certain embodiments, the aryl group is substituted C6-14 aryl. [0053] In certain embodiments, an aryl group substituted with one or more of groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino. [0054] Examples of representative substituted aryls include the following [

[0056] wherein one of R⁵⁶ and R⁵⁷ may be hydrogen and at least one of R⁵⁶ and R⁵⁷ is each independently selected from C₁-C₈ alkyl, C₁-C₈ haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹, NR⁵⁸SO₂R⁵⁹, COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO2NR⁵⁸R⁵⁹, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R⁵⁶ and R⁵⁷ may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R⁶⁰ and R⁶¹ are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, substituted C₆-C₁₀ aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl. [0057] Other representative aryl groups having a fused heterocyclyl group include the following: [

[0059] wherein each W is selected from C(R⁶⁶)2, NR⁶⁶, O, and S; and each Y is selected from carbonyl, NR⁶⁶, O and S; and R⁶⁶ is independently hydrogen, C₁-C₈ alkyl, C₃- C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl. [0060] “Fused aryl” refers to an aryl having two of its ring carbon in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring. [0061] “Aralkyl” is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group. [0062] “Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5- indolyl). [0063] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl. [0064] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. [0065] Examples of representative heteroaryls include the following: [

[0067] wherein each Y is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ is independently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆- C10 aryl, and 5-10 membered heteroaryl. [0068] “Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group. [0069] “Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C_3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C_5-10 carbocyclyl”). Exemplary C_3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C₆), and the like. Exemplary C_3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3- ₁₀ carbocyclyl groups include, without limitation, the aforementioned C₃-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C_3-10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10 carbocyclyl. In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C_3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C_5-10cycloalkyl”). Examples of C_5-6 cycloalkyl groups include cyclopentyl (C₅) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5- ₆ cycloalkyl groups as well as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C_3- 8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3- ₁₀ cycloalkyl. [0070] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl. [0071] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. [0072] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. [0073] Particular examples of heterocyclyl groups are shown in the following illustrative examples:

[0074]

[0075] wherein each W is selected from CR⁶⁷, C(R⁶⁷)₂, NR⁶⁷, O, and S; and each Y is selected from NR⁶⁷, O, and S; and R⁶⁷ is independently hydrogen, C1-C8 alkyl, C3- C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, —S-alkyl, —S-aryl, —S(O)-alkyl, —S(O)-aryl, —S(O)₂-alkyl, and —S(O)2-aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives. [0076] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms. [0077] “Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. “Alkanoyl” is an acyl group wherein R²⁰ is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl (—C(═O)CH2Ph), — C(O)—C1-C8 alkyl, —C(O)—(CH2)t(C6-C10 aryl), —C(O)—(CH2)t(5-10 membered heteroaryl), —C(O)—(CH₂)_t(C₃-C₁₀cycloalkyl), and —C(O)—(CH₂)_t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R²¹ is C1-C8 alkyl, substituted with halo or hydroxy; or C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆- C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁- C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. [0078] “Acylamino” refers to a radical —NR²²C(O)R²³, where each instance of R²² and R23 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein, or R²² is an amino protecting group. Exemplary “acylamino” groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino. Particular exemplary “acylamino” groups are —NR²⁴C(O)—C1- C₈ alkyl, —NR²⁴C(O)—(CH₂)_t(C₆-C₁₀ aryl), —NR²⁴C(O)—(CH₂)_t(5-10 membered heteroaryl), —NR²⁴C(O)—(CH2)t(C3-C10 cycloalkyl), and —NR²⁴C(O)—(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, and each R²⁴ independently represents H or C1-C8 alkyl. In certain embodiments, R²⁵ is H, C1-C8 alkyl, substituted with halo or hydroxy; C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1- C₄ alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁- C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; and R²⁶ is H, C1-C8 alkyl, substituted with halo or hydroxy; C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl; provided at least one of R²⁵ and R²⁶ is other than H. [0079] “Acyloxy” refers to a radical —OC(O)R²⁷, where R²⁷ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. In certain embodiments, R²⁸ is C1- C₈ alkyl, substituted with halo or hydroxy; C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆- C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁- C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. [0080] “Alkoxy” refers to the group —OR²⁹ where R²⁹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms. [0081] In certain embodiments, R²⁹ is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-C10 aryl, aryloxy, carboxyl, cyano, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)2— and aryl-S(O)₂—. Exemplary ‘substituted alkoxy’ groups include, but are not limited to, —O— (CH2)t(C6-C10 aryl), —O—(CH2)t(5-10 membered heteroaryl), —O—(CH2)t(C3- C₁₀ cycloalkyl), and —O—(CH₂)_t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁- C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particular exemplary ‘substituted alkoxy’ groups are —OCF₃, —OCH₂CF₃, —OCH₂Ph, — OCH2-cyclopropyl, —OCH2CH2OH, and —OCH2CH2NMe2. [0082] “Amino” refers to the radical —NH₂. [0083] “Substituted amino” refers to an amino group of the formula —N(R³⁸)2 wherein R³⁸ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein at least one of R³⁸ is not a hydrogen. In certain embodiments, each R³⁸ is independently selected from hydrogen, C₁-C₈ alkyl, C₃- C8 alkenyl, C3-C8 alkynyl, C6-C10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-C10 cycloalkyl; or C1-C8 alkyl, substituted with halo or hydroxy; C3- C₈ alkenyl, substituted with halo or hydroxy; C₃-C₈ alkynyl, substituted with halo or hydroxy, or —(CH2)t(C6-C10 aryl), —(CH2)t(5-10 membered heteroaryl), —(CH2)t(C3-C10 cycloalkyl), or —(CH₂)_t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁- C4 haloalkoxy or hydroxy; or both R³⁸ groups are joined to form an alkylene group. [0084] Exemplary “substituted amino” groups include, but are not limited to, —NR³⁹—C₁- C8 alkyl, —NR³⁹—(CH2)t(C6-C10 aryl), —NR³⁹—(CH2)t(5-10 membered heteroaryl), — NR³⁹—(CH₂)_t(C₃-C₁₀ cycloalkyl), and —NR³⁹—(CH₂)_t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R³⁹ independently represents H or C₁-C₈ alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁- C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy or hydroxy. For the avoidance of doubt the term ‘substituted amino’ includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups. [0085] “Azido” refers to the radical —N3. [0086] “Carbamoyl” or “amido” refers to the radical —C(O)NH₂. [0087] “Substituted carbamoyl” or “substituted amido” refers to the radical — C(O)N(R⁶²)₂ wherein each R⁶² is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein at least one of R⁶² is not a hydrogen. In certain embodiments, R⁶² is selected from H, C1-C8 alkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or C₁-C₈ alkyl substituted with halo or hydroxy; or C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R⁶² is other than H. [0088] Exemplary “substituted carbamoyl” groups include, but are not limited to, —C(O) NR⁶⁴—C1-C8 alkyl, —C(O)NR⁶⁴—(CH2)t(C6-C10 aryl), —C(O)N⁶⁴—(CH2)t(5-10 membered heteroaryl), —C(O)NR⁶⁴—(CH₂)_t(C₃-C₁₀ cycloalkyl), and —C(O)NR⁶⁴—(CH₂)_t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, each R⁶⁴ independently represents H or C₁-C₈ alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁- C4 haloalkoxy or hydroxy. [0089] “Carboxy” refers to the radical —C(O)OH. [0090] “Cyano” refers to the radical —CN. [0091] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro. [0092] “Hydroxy” refers to the radical —OH. [0093] “Nitro” refers to the radical —NO2. [0094] “Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like. [0095] “Heterocyclylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like. [0096] “Cycloalkenyl” refers to substituted or unsubstituted carbocyclyl group having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like. [0097] “Fused cycloalkenyl” refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring. [0098] “Ethylene” refers to substituted or unsubstituted —(C—C)—. [0099] “Ethenyl” refers to substituted or unsubstituted —(C═C)—. [00100] “Ethynyl” refers to —(C≡C)—. [0100] “Nitrogen-containing heterocyclyl” group means a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2- pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Particular examples include azetidine, piperidone and piperazone. [0101] “Thioketo” refers to the group ═S. [0102] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. [0103] Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^aa, —ON(R^bb)₂, —N(R^bb)₂, —N(R^bb)₃ ⁺X⁻, — N(OR^cc)R^bb, —SH, −SR^aa, —SSR^cc, —C(═O)R^aa, —CO2H, —CHO, —C(OR^cc)2, —CO2R^aa, —OC(═O)R^aa, —OCO₂R^aa, —C(═O)N(R^bb)₂, —OC(═O)N(R^bb)₂, —NR^bbC(═O)R^aa, — NR^bbCO2R^aa, —NR^bbC(═)N(R^bb)2, —C(═NR^bb)R^aa, —C(═NR^bb)OR^aa, —OC(═NR^bb)R^aa, — OC(═NR^bb)OR^aa, —C(═NR^bb)N(R^bb)2, —OC(═NR^bb)N(R^bb)2, —NR^bbC(═NR^bb)N(R^bb)2, — C(═O)NR^bbSO₂R^aa, NR^bbSO₂R^aa, —SO₂N(R^bb)₂, —SO₂R^aa, —SO₂OR^aa, —OSO₂R^aa, — S(O)R^aa, e.g., —S(═O)R^aa, —OS(═O)R^aa, —Si(R^aa)3, —OSi(R^aa)3, —C(═S)N(R^bb)2, — C(═O)SR^aa, —C(═S)SR^aa, —SC(═S)SR^aa, —SC(═O)SR^aa, —OC(═O)SR^aa, —SC(═O)OR^aa, —SC(═O)R^aa, —P(═O)2R^aa, —OP(═O)2R^aa, —P(═O)(R^aa)2, —OP(═O)(R^aa)2, — OP(═O)(OR^cc)₂, —P(═O)₂N(R^bb)₂, —OP(═O)₂N(R^bb)₂, —P(═O)(NR^bb)₂, —OP(═O)(NR^bb)₂, —NR^bbP(═O)(OR^cc)2, —NR^bbP(═O)(NR^bb)2, —P(R^cc)2, —P(R^cc)3, —OP(R^cc)2, —OP(R^cc)3, —B(R^aa)₂, —B(OR^cc)₂, —BR^aa(OR^cc), C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2- 10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; [0104] or two geminal hydrogens on a carbon atom are replaced with the group ═O, ═S, ═NN(R^bb)2, ═NNR^bbC(═O)R^aa, ═NNR^bbC(═O)OR^aa, ═NNR^bbS(═O)2R^aa, ═NR^bb, or ═NOR^cc; [0105] each instance of R^aa is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; [0106] each instance of R^bb is, independently, selected from hydrogen, —OH, —OR^aa, — N(R^cc)2, —CN, —C(═O)R^aa, —C(═O)N(R^cc)2, —CO2R^aa, —SO2R^aa, —C(═NR^cc)OR^aa, — C(═NR^cc)N(R^cc)₂, —SO₂N(R^cc)₂, —SO₂R^cc, —SO₂OR^cc, —SOR^aa, —C(═S)N(R^cc)₂, — C(═O)SR^cc, —C(═S)SR^cc, —P(═O)2R^aa, —P(═O)(R^aa)2, —P(═O)2N(R^cc)2, —P(═O)(NR^cc)2, C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R^bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; [0107] each instance of R^cc is, independently, selected from hydrogen, C1-10 alkyl, C1- ₁₀ perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6- 14 aryl, and 5-14 membered heteroaryl, or two R^cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups; [0108] each instance of R^dd is, independently, selected from halogen, —CN, —NO₂, —N₃, —SO2H, —SO3H, —OH, —OR^ee, —ON(R^ff)2, —N(R^ff)2, —N(R^ff)3 ⁺X⁻, —N(OR^ee)R^ff, —SH, —SR^ee, —SSR^ee, —C(═O)R^ee, —CO₂H, —CO₂R^ee, —OC(═O)R^ee, —OCO₂R^ee, — C(═O)N(R^ff)2, —OC(═O)N(R^ff)2, —NR^ffC(═O)R^ee, —NR^ffCO2R^ee, —NR^ffC(═O)N(R^ff)2, — C(═NR^ff)OR^ee, —OC(═NR^ff)R^ee, —OC(═NR^ff)OR^ee, —C(═NR)N(R^ff)₂, — OC(═NR^ff)N(R^ff)2, —NR^ffC(═NR^ff)N(R^ff)2, —NR^ffSO2R^ee, —SO2N(R^ff)2, —SO2R^ee, — SO₂OR^ee, —OSO₂R^ee, —S(O)R^ee, e.g., —S(═O)R^ee, —Si(R^ee)₃, —OSi(R^ee)₃, —C(═S)N(R^ff)₂, —C(═O)SR^ee, —C(═S)SR^ee, —SC(═S)SR^ee, —P(═O)2R^ee, —P(═O)(R^ee)2, —OP(═O)(R^ee)2, —OP(═O)(OR^ee)₂, C_1-6 alkyl, C_1-6 perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, 3- 10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups, or two geminal R^dd substituents can be joined to form ═O or ═S; [0109] each instance of R^ee is, independently, selected from C_1-6 alkyl, C_1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups; [0110] each instance of R^ff is, independently, selected from hydrogen, C1-6 alkyl, C1- ₆ perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 carbocyclyl, 3-10 membered heterocyclyl, C_6- 10 aryl and 5-10 membered heteroaryl, or two R^ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gg groups; and [0111] each instance of R^gg is, independently, halogen, —CN, —NO2, —N3, —SO2H, — SO₃H, —OH, —OC_1-6 alkyl, —ON(C_1-6 alkyl)₂, —N(C_1-6 alkyl)₂, —N(C_1-6 alkyl)₃ ⁺X⁻, — NH(C1-6 alkyl)2 ⁺X⁻, —NH2(C1-6 alkyl)⁺X⁻, —NH3 ⁺X⁻, —N(OC1-6 alkyl)(C1-6 alkyl), — N(OH)(C_1-6 alkyl), —NH(OH), —SH, —SC_1-6 alkyl, —SS(C_1-6 alkyl), —C(═O)(C_1-6 alkyl), — CO2H, —CO2(C1-6 alkyl), —OC(═O)(C1-6 alkyl), —OCO2(C1-6 alkyl), —C(═O)NH2, — C(═O)N(C_1-6 alkyl)₂, —OC(═O)NH(C_1-6 alkyl), —NHC(═O)(C_1-6 alkyl), —N(C_1- 6 alkyl)C(═O)(C1-6 alkyl), —NHCO2(C1-6 alkyl), —NHC(═O)N(C1-6 alkyl)2, — NHC(═O)NH(C_1-6 alkyl), —NHC(═O)NH₂, —C(═NH)O(C_1-6 alkyl), —OC(═NH)(C_1- 6 alkyl), —OC(═NH)OC1-6 alkyl, —C(═NH)N(C1-6 alkyl)2, —C(═NH)NH(C1-6 alkyl), — C(═NH)NH2, —OC(═NH)N(C1-6 alkyl)2, —OC(NH)NH(C1-6 alkyl), —OC(NH)NH2, — NHC(NH)N(C_1-6 alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C_1-6 alkyl), —SO₂N(C_1-6 alkyl)₂, — SO2NH(C1-6 alkyl), —SO2NH2, —SO2C1-6 alkyl, —SO2OC1-6 alkyl, —OSO2C1-6 alkyl, — SOC_1-6 alkyl, —Si(C_1-6 alkyl)₃, —OSi(C_1-6 alkyl)₃—C(═S)N(C_1-6 alkyl)₂, C(═S)NH(C_1- 6 alkyl), C(═S)NH2, —C(═O)S(C1-6 alkyl), —C(═S)SC1-6 alkyl, —SC(═S)SC1-6 alkyl, — P(═O)₂(C_1-6 alkyl), —P(═O)(C_1-6 alkyl)₂, —OP(═O)(C_1-6 alkyl)₂, —OP(═O)(OC_1-6 alkyl)₂, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R^gg substituents can be joined to form ═O or ═S; wherein X⁻ is a counterion. [0112] A “counterion” or “anionic counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F⁻, C⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, SO4 ⁻² sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like). [0113] Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, —OH, —OR^aa, —N(R^cc)2, —CN, — C(═O)R^aa, —C(═O)N(R^cc)₂, —CO₂R^aa, —SO₂R^aa, —C(═NR^bb)R^aa, —C(═NR^cc)OR^aa, — C(═NR^cc)N(R^cc)2, —SO2N(R^cc)2, —SO2R^cc, —SO2OR^cc, —SOR^aa, —C(═S)N(R^cc)2, — C(═O)SR^cc, —C(═S)SR^cc, —P(═O)₂R^aa, —P(═O)(R^aa)₂, —P(═O)₂N(R^cc)₂, —P(═O)(NR^cc)₂, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^cc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^dd groups, and wherein R^aa, R^bb, R^cc and R^dd are as defined above. DETAILED DESCRIPTION OF THE DISCLOSURE [0114] Adjustment Disorder (abbreviated herein as “AD”) is a common psychiatric illness that causes disability and diminishes quality of life, depletes limited health care resources, increases morbidity and mortality, and increases the rates of substance abuse and suicide. Adjustment disorder is a common mental disorder in clinical practice, diagnosed in 5-20% of outpatient mental health patients and from 30-50% of psychiatric outpatient and inpatient medical consultation patients (Casey, P. (2014). Current Psychiatry Reports, 16(6), 1–8.; ; DSM-5). The six types of adjustment disorders include: adjustment disorder with depressed mood, adjustment disorder with anxiety, adjustment disorder with mixed anxiety and depressed mood, adjustment disorder with disturbance of conduct, adjustment disorder with mixed disturbance of emotions and conducts, and adjustment disorder unspecified. Symptoms of adjustment disorders include: feelings of hopelessness and sadness, crying, problems with concentration and memory, separation anxiety, depression, anxiety, worry and preoccupation with thoughts about the stressor, failure to adapt, avoidance, impulse disturbance, and behavioral issues. A key feature of the adjustment disorders highlighted below is that the symptoms cannot be due to another axis I disorder such as major depressive disorder or an anxiety disorder. [0115] The main features of AD are: (a) the symptoms arise in response to a stressful event or situation; (b) the onset of symptoms is within 3 months (DSM-5) or 1 month (ICD-10) of exposure to a stressor; (c) the symptoms are distressing and in excess of what would be expected by exposure to the stressor and/or there is significant impairment in social or occupational functioning; (d) the symptoms are not due to another axis I disorder (or bereavement in the DSM-5); (e) the symptoms resolve within six months once the stressor or its consequences are removed. [0116] Adjustment disorder has been reported to be almost three times as common as major depression in acutely ill medical in-patients and diagnosed in up to one third of cancer patients experiencing a recurrence. In children and adolescents, adjustment disorder has the risk of significant morbidity and frequently develops into major psychiatric illness. [0117] As compared to patients with major depressive disorder (MDD), in AD, suicidal behavior occurs earlier and the interval from suicidal communication to completion of suicide is shorter. One third of adolescents who die by suicide are diagnosed with AD, highlighting the need for an acute rapid acting treatments for AD. [0118] Moreover, AD patients have not been found to consistently respond to antidepressants; the slow onset of efficacy with current standard of care antidepressants and the frequent need for more than one antidepressant treatment trial to achieve remission of symptoms does not align well with the acute onset and course of illness in AD . This highlights the need for improved treatments for AD. Casey et al. World Psychiatry.2011 Feb; 10(1): 11– 18. Disturbances of the GABAergic system have been implicated in the development of the symptoms of AD. Stress has been demonstrated to have a number of interactions with GABA signaling that can mediate a number of symptoms associated with AD. Chronic stress results in disinhibition of CRF neurons that trigger the stress response (Liu et al. 2014; Gao et al. 2017; Sarkar et al.) In addition, GABA modulates fear responses and fear extinction after stress Jie et al.2018; Giachero et al.2013). Evidence of a reduction in GABA neurons in a key anxiety regulating nucleus of the amygdala has been observed in a rat strain (WKY) that demonstrates enhanced conditioned fear, a model of excessive anxiety in response to stressors (Jiao et al. 2011). Stress alters extrasynaptic GABAA receptors (Verkuyl et al. 2004) involved in regulation of symptoms common in AD; these receptors are a mechanistic target of Compound 1. Benzodiazepines, which are positive allosteric modulators (PAMs) of the GABAA receptor, have been used clinically to treat anxiety symptoms associated with AD, although there is limited controlled clinical trial data demonstrating efficacy. However, significant side effects (e.g., sedation), tolerance development, withdrawal symptoms upon cessation, and risk for abuse potential have raised concerns about long-term use of benzodiazepines for the treatment of AD. Therefore, there is a need for new treatment options for patients suffering from AD that are better suited to its clinical characteristics. [0119] Neuroactive steroids (NASs) are a family of compounds (synthetic and naturally occurring) that affect neurophysiological functions through allosteric modulation of GABA_A receptors. The endogenous NASs allopregnanolone and pregnanolone are GABAA PAMs that are dysregulated in mood disorders and show preclinical efficacy in animal models of anxiety and depression. NASs bind to a different binding site on the GABAA receptor than benzodiazepines or the endogenous agonist GABA (Hosie AM, Wilkins ME, Da Silva HMA, Smart TG. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature. 2006; 444(7118):486-489.). Benzodiazepines exclusively potentiate GABAA receptors that contain a gamma subunit, which are primarily localized at synapses. In contrast, NASs bind to alpha and beta subunits, which are present in a larger proportion of GABAA receptors, resulting broad activity at both synaptic and extrasynaptic sites. Stress has been demonstrated to alter endogenous NAS in a manner that may contribute to the symptomatology of AD. Chronic social isolation stress in rodents results in reduced NAS biosynthesis in hippocampus, amygdala and PFC (Agis-Balboa et al 2007), regions associated with the range of symptoms observed in in AD. Prolonged stress leads to reduced levels of allopregnanolone and changes in extracellular GABAA receptor subuits (Pisu et al 2013; Serra et al.2006; Pibiri et al.2008). Inhibition of NAS-synthesis during social isolation exacerbates deficits in fear extinction. (Pibiri et al. 2008); a phenomenon relevant to the development of persistent anxiety and other stress-reactive symptoms in AD. [0120] In one aspect, the present disclosure provides a method of treating AD comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof to a patient in need of such treatment. In some embodiments of the present disclosure, about 5 mg to about 120 mg of Compound I, for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg or about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered. [0121] In another aspect, the present disclosure provides a method of treating AD comprising administering an effective amount of a neuroactive steroid (NAS) or pharmaceutically acceptably salt thereof to a patient in need of such treatment. In some embodiments of the present disclosure, about 5 mg to about 120 mg of a neuroactive steroid, for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg or about 120 mg of a neuroactive steroid or a pharmaceutically acceptable salt thereof is administered. Compound 1 [0122] Compound 1 as employed in the present methods can form a part of a pharmaceutical composition by combining Compound 1, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier. Additionally, the compositions can include an additive selected from the group consisting of adjuvants, excipients, diluents, release- modifying agents and stabilizers. The composition can be an immediate release formulation, a delayed release formulation, a sustained release formulation or an extended release formulation. [0123] 3α-Hydroxy-3β-methoxymethyl-21-(1′-imidazolyl)-5α-pregnan-20-one (Compound 1) is a synthetic neuroactive steroid. The structural formula of Compound 1 appears below.

[0124] Compound 1 is a neuroactive steroid GABA-A positive allosteric modulator (PAM) with high potency similar to clinical stage neuroactive steroids (allopregnanolone, ganaxolone, SAGE-217, alphaxolone). [0125] The synthesis of Compound 1 is described in U.S. Publication Nos. 2004/034002 and 2009/0118248; crystalline polymorph of Compound 1 free base is described in U.S. Publication No. 2006/0074059; pharmaceutical compositions containing Compound 1 are described in U.S. Publication No.2009/0131383, which are hereby incorporated by reference in their entirety for all purposes. [0126] In some embodiments, the Compound 1 used in the formulations and methods of the present disclosure is a pharmaceutically acceptable salt of Compound 1. Salts of Compound 1 and polymorphs thereof are described in U.S. Patent No. 10,562,930, which is hereby incorporated by reference in its entirety. In some embodiments, the pharmaceutically acceptable salt of Compound 1 used in the formulations and methods of the present disclosure is selected from the group consisting of hydrobromide, citrate, malate, mesylate, phosphate, tartrate, hydrochloride, tosylate, glucuronate, ethanesulfonate, fumarate, sulfate, napthalene-2- sulfonate, ascorbate, oxalate, napthalene-1,5-disulfonate, malonate, aminosalicylate, benzenesulfonate, isethionate, gentistate, 1-hydroxy-2-napthoate, dichloroacetate, cyclamate, and ethane-1,2-disulfonate salts. In some embodiments, the salt of Compound 1 is Compound 1 Hydrobromide. In some embodiments, the salt of Compound 1 is Compound 1 Citrate. In some embodiments, the salt of Compound 1 is Compound 1 L-Malate. In some embodiments, the salt of Compound 1 is Compound 1 Mesylate. In some embodiments, the salt of Compound 1 is Compound 1 Phosphate. In some embodiments, the salt of Compound 1 is Compound 1 L(+)-Tartrate. In some embodiments, the salt of Compound 1 is Compound 1 Hydrochloride. In some embodiments, the salt of Compound 1 is Compound 1 Tosylate. In some embodiments, the salt of Compound 1 is Compound 1 Glucuronate. In some embodiments, the salt of Compound 1 is Compound 1 Ethanesulfonate. [0127] In some embodiments, the Compound 1 used in the formulations and methods of the present disclosure is a deuterated derivative of Compound 1. In some embodiments, Compound 1 used in the formulations and methods of the present disclosure is a deuterated derivative as described in International Publication No. 2020/131918, which is hereby incorporated by reference in its entirety for all purposes. Neuroactive Steroid (NAS) [0128] A NAS as employed in the present methods can form a part of a pharmaceutical composition by combining a NAS, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier. Additionally, the compositions can include an additive selected from the group consisting of adjuvants, excipients, diluents, release-modifying agents and stabilizers. The composition can be an immediate release formulation, a delayed release formulation, a sustained release formulation or an extended release formulation. [0129] NASs belong to a family of steroid-based compounds of both natural and synthetic origin, which impact central nervous system (CNS) function. NASs are classified as pregnane, androstane, and sulfated neurosteroids. Tuem et al. describes these classes of NASs and is incorporated by reference herein in its entirety: Tuem et al. Front Neurol.2017; 8: 442. In some embodiments, a NAS as employed in the present methods is a pregnane neurosteroid. In some embodiments, a NAS as employed in the present methods is an androstane neurosteroid. In some embodiments, a NAS as employed in the present methods is a sulfated neurosteroid. In some embodiments, the pregnane neurosteroid used in the present methods is selected from progesterone derivatives such as allopregnanolone (ALLO) (3α, 5α-tetrahydroprogesterone), epiallopregnanolone (3β, 5α-tetrahydroprogesterone), pregnanolone (3α, 5β- tetrahydroprogesterone), pregnenolone (PREG), dehydroepiandrosterone (DHEA), and allotetrahydrodeoxycorticosterone (THDOC). In some embodiments, the androstane neurosteroid used in the present methods is selected from androstanediol and etiocholanone. In some embodiments, the sulfated neurosteroid used in the present methods is selected from dehydroepiandrosterone sulfate (DHEAS), pregnenolone sulfate (PREGS), and vitamin D. [0130] NAS modulate many processes through allosteric modulation of various proteins. In some embodiments, the proteins are receptors. Non-limiting examples of proteins modulated by NASs include the GABA (γ-aminobutyric acid) receptor, a GABA-A receptor, the N- methyl-d-aspartic acid (NMDA) class of glutamate receptors, serotonin receptors, voltage- gated calcium channels, voltage-dependent anion channels, α-adrenoreceptors, X-receptors of the liver, transient receptor potential channels, microtubule-associated protein 2, neurotrophin nerve growth factor, and σ1 receptors. In some embodiments, the NAS employed in the present methods is an allosteric modulator of the GABA receptor. In some embodiments, the NAS employed in the present methods is an allosteric modulator of the GABA-A receptor. In some embodiments, the NAS employed in the present methods is an allosteric modulator of a member of the NMDA class of glutamate receptors. In some embodiments, the NAS employed in the present methods positively allosterically modulates one or more of the aforementioned receptors. In some embodiments, the NAS employed in the present methods negatively allosterically modulates one or more of the aforementioned receptors. Martinez-Botella describes the interaction of NASs with various proteins and is incorporated by reference herein in its entirety: Martinez-Botella et al. Annual Reports in Medicinal Chemistry. 2014; 49: 27- 42.In some embodiments, the NAS employed in the present method is disclosed in a patent document selected from the group consisting of International Publication No. 2013/036835; International Publication No. 2013/056181; International Publication No. 2013/112605; International Publication No. 2013/188792; International Publication No. 2014/031792; International Publication No. 2014/100228; International Publication No. 2014/160441; International Publication No. 2014/160480; International Publication No. 2014/169831; International Publication No. 2014/169832; International Publication No. 2014/169832; International Publication No. 2014/169833; International Publication No. 2014/169833; International Publication No. 2014/169836; International Publication No. 2015/010054; International Publication No. 2015/027227; International Publication No. 2015/195962; International Publication No. 2016/040322; International Publication No. 2016/057713; International Publication No. 2016/061527; International Publication No. 2016/061537; International Publication No. 2016/082789; International Publication No. 2016/123056; International Publication No. 2016/134301; International Publication No. 2016/164763; International Publication No. 2016/205721; International Publication No. 2017/007836; International Publication No. 2017/087864; International Publication No. 2017/156103; International Publication No. 2017/173358; International Publication No. 2018/013613; International Publication No. 2018/013615; International Publication No. 2019/051264; International Publication No. 2019/055764; International Publication No. 2019/075361; International Publication No. 2019/075362; International Publication No. 2019/113494; International Publication No. 2019/126741; International Publication No. 2019/126761; International Publication No. 2019/140272; International Publication No. 2019/241442; International Publication No. 2020/077255; International Publication No. 2020/082065; International Publication No. 2020/118060; International Publication No. 2020/132504; U.S. Patent No. 10,023,606; U.S. Patent No. 10,172,871; U.S. Patent No. 10,201,550; U.S. Patent No. 10,227,375; U.S. Patent No. 10,246,482; U.S. Patent No. 10,259,840; U.S. Patent No. 10,322,139; U.S. Patent No. 10,323,059; U.S. Patent No. 10,329,320; U.S. Patent No. 10,342,809; U.S. Patent No. 10,342,810; U.S. Patent No. 10,377,790; U.S. Patent No. 10,391,106; U.S. Patent No. 10,426,837; U.S. Patent No. 10,435,431; U.S. Patent No. 10,577,390; U.S. Patent No. 10,696,712; U.S. Patent No. 10,723,758; U.S. Patent No. 9,365,611; U.S. Patent No.9,512,165; U.S. Patent No. 9,630,986; U.S. Patent No. 9,676,812; U.S. Patent No. 9,725,481; U.S. Publication No. 2014/0057885; U.S. Publication No. 2014/0235600; U.S. Publication No.2015/0018327; U.S. Publication No.2015/0158903; U.S. Publication No. 2015/0175651; U.S. Publication No. 2015/0291654; U.S. Publication No. 2015/0315230; U.S. Publication No.2016/0022701; U.S. Publication No.2016/0031930; U.S. Publication No. 2016/0068563; U.S. Publication No. 2016/0083417; U.S. Publication No. 2016/0083418; U.S. Publication No.2016/0108080; U.S. Publication No.2016/0152658; U.S. Publication No. 2016/0229887; U.S. Publication No. 2017/0152282; U.S. Publication No. 2017/0190732; U.S. Publication No.2017/0232006; U.S. Publication No.2017/0233432; U.S. Publication No. 2017/0233433; U.S. Publication No. 2017/0240589; U.S. Publication No. 2017/0246191; U.S. Publication No.2017/0247406; U.S. Publication No.2017/0304321; U.S. Publication No. 2017/0305960; U.S. Publication No. 2017/0319695; U.S. Publication No. 2017/0342102; U.S. Publication No.2017/0342103; U.S. Publication No.2017/0348326; U.S. Publication No. 2017/0348327; U.S. Publication No. 2018/0037602; U.S. Publication No. 2018/0051052; U.S. Publication No.2018/0141971; U.S. Publication No.2018/0179247; U.S. Publication No. 2018/0200267; U.S. Publication No. 2018/0215779; U.S. Publication No. 2018/0237470; U.S. Publication No.2018/0311258; U.S. Publication No.2018/0311262; U.S. Publication No. 2018/0362573; U.S. Publication No. 2019/0008873; U.S. Publication No. 2019/0038639; U.S. Publication No.2019/0112331; U.S. Publication No.2019/0125764; U.S. Publication No. 2019/0127414; U.S. Publication No. 2019/0169226; U.S. Publication No. 2019/0177358; U.S. Publication No.2019/0211054; U.S. Publication No.2019/0233465; U.S. Publication No. 2019/0247402; U.S. Publication No. 2019/0248831; U.S. Publication No. 2019/0269699; U.S. Publication No.2019/0330259; U.S. Publication No.2019/0350944; U.S. Publication No. 2020/0016178; U.S. Publication No. 2020/0017542; U.S. Publication No. 2020/0024301; U.S. Publication No.2020/0024302; U.S. Publication No.2020/0048300; U.S. Publication No. 2020/0113916; U.S. Publication No. 2020/0113917; U.S. Publication No. 2020/0155576; U.S. Publication No.2020/0165291; U.S. Publication No.2020/0171049; U.S. Publication No.2020/0223884; U.S. Publication No.2020/0246459; [0131] In some embodiments, the NAS employed in the present method is disclosed in a patent document selected from: International Publication No. 2013/036835; International Publication No. 2013/056181; International Publication No. 2013/112605; International Publication No. 2013/188792; International Publication No. 2014/031792; International Publication No. 2014/100228; International Publication No. 2014/169831; International Publication No. 2014/169832; International Publication No. 2014/169832; International Publication No. 2014/169833; International Publication No. 2014/169833; International Publication No. 2014/169836; International Publication No. 2015/010054; International Publication No. 2015/027227; International Publication No. 2015/195962; International Publication No. 2016/040322; International Publication No. 2016/057713; International Publication No. 2016/061527; International Publication No. 2016/061537; International Publication No. 2016/082789; International Publication No. 2016/123056; International Publication No. 2016/134301; International Publication No. 2016/164763; International Publication No. 2016/205721; International Publication No. 2017/087864; International Publication No. 2017/156103; International Publication No. 2018/013613; International Publication No. 2018/013615; International Publication No. 2019/051264; International Publication No. 2019/055764; International Publication No. 2019/075361; International Publication No. 2019/075362; International Publication No. 2019/113494; International Publication No. 2019/126741; International Publication No. 2019/126761; International Publication No. 2019/140272; International Publication No. 2019/241442; International Publication No. 2020/077255; International Publication No. 2020/082065; International Publication No. 2020/118060; International Publication No. 2020/132504; U.S. Patent No. 10,023,606; U.S. Patent No. 10,172,871; U.S. Patent No. 10,246,482; U.S. Patent No. 10,322,139; U.S. Patent No. 10,323,059; U.S. Patent No. 10,329,320; U.S. Patent No. 10,342,809; U.S. Patent No. 10,342,810; U.S. Patent No. 10,377,790; U.S. Patent No. 10,391,106; U.S. Patent No. 10,426,837; U.S. Patent No. 10,435,431; U.S. Patent No. 10,577,390; U.S. Patent No.9,365,611; U.S. Patent No.9,512,165; U.S. Patent No.9,630,986; U.S. Patent No. 9,676,812; U.S. Patent No. 9,725,481; U.S. Publication No. 2014/0057885; U.S. Publication No.2014/0235600; U.S. Publication No.2015/0018327; U.S. Publication No. 2015/0158903; U.S. Publication No.2015/0175651; U.S. Publication No.2015/0291654; U.S. Publication No. 2015/0315230; U.S. Publication No. 2016/0068563; U.S. Publication No. 2016/0083417; U.S. Publication No.2016/0083418; U.S. Publication No.2016/0108080; U.S. Publication No. 2016/0152658; U.S. Publication No. 2016/0229887; U.S. Publication No. 2017/0152282; U.S. Publication No.2017/0190732; U.S. Publication No.2017/0232006; U.S. Publication No. 2017/0233432; U.S. Publication No. 2017/0233433; U.S. Publication No. 2017/0240589; U.S. Publication No.2017/0246191; U.S. Publication No.2017/0247406; U.S. Publication No. 2017/0304321; U.S. Publication No. 2017/0319695; U.S. Publication No. 2017/0342102; U.S. Publication No.2017/0342103; U.S. Publication No.2017/0348326; U.S. Publication No. 2017/0348327; U.S. Publication No. 2018/0037602; U.S. Publication No. 2018/0051052; U.S. Publication No.2018/0141971; U.S. Publication No.2018/0179247; U.S. Publication No. 2018/0215779; U.S. Publication No. 2018/0311258; U.S. Publication No. 2018/0311262; U.S. Publication No.2018/0362573; U.S. Publication No.2019/0008873; U.S. Publication No. 2019/0038639; U.S. Publication No. 2019/0112331; U.S. Publication No. 2019/0169226; U.S. Publication No.2019/0177358; U.S. Publication No.2019/0211054; U.S. Publication No. 2019/0233465; U.S. Publication No. 2019/0247402; U.S. Publication No. 2019/0248831; U.S. Publication No.2019/0269699; U.S. Publication No.2019/0350944; U.S. Publication No. 2020/0016178; U.S. Publication No. 2020/0017542; U.S. Publication No. 2020/0024301; U.S. Publication No.2020/0024302; U.S. Publication No.2020/0048300; U.S. Publication No. 2020/0113916; U.S. Publication No. 2020/0113917; U.S. Publication No. 2020/0155576; U.S. Publication No.2020/0165291; U.S. Publication No.2020/0171049; U.S. Publication No.2020/0223884; U.S. Publication No.2020/0246459; [0132] In some embodiments, the neuroactive steroid is a 19-nor C3,3-disubstituted C21- pyrazolyl steroid of Formula I, or a pharmaceutically acceptable salt thereof. The structural formula of Formula I appears below:

[0133] wherein: represents a single or double bond; R¹ is substituted or unsubstituted C-alkyl, substituted or unsubstituted C2-6alkenyl, Substituted or unsubstituted C- alkynyl, or Substituted or unsubstituted C_3-6 carbocyclyl; R² is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted C_3-6 carbocyclyl, or —OR^A2, wherein R^A2 is hydrogen or substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, or substituted or unsubstituted C_3-6 carbocyclyl; [0134] R^3a is hydrogen or —OR^A3, wherein R^A3 is hydrogen or substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl, and R^3b is hydrogen; or R^3a and R^3b are joined to form an oxo (═O) group; [0135] each instance of R^4a and R^4b is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or halogen, provided if the between C5 and C6 is a single bond, then the hydrogen at C5 and R^4a are each independently provided in the alpha or beta configuration, and R^4b is absent; each instance of R⁵, R⁶, and R⁷ is, independently, hydrogen, halogen, —NO2, — CN, —OR^GA, —N(R^GA)2, —C(═O)R^GA, —C(═O)OR^GA, —OC(═O)R^GA, —OC(═O)OR^GA, —C(═O)N(R^GA)₂, —N(R^GA)C(═O)R^GA, —OC(═O)N(R^GA)₂, —N(R^GA)C(═O)OR^GA, — N(R^GA)C(═O)N(R^GA)2, —SR^GA, —S(O)R^GA, e.g., —S(═O)R^GA, —S(═O)2R^GA, — S(═O)2OR^GA, —OS(═O)2R^GA, —S(═O)2N(R^GA)2, —N(R^GA)S(═O)2R^GA, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, or substituted or unsubstituted 3- to 6-membered heterocylyl; and each instance of R^GA is independently hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted C_3-6 carbocylyl, substituted or unsubstituted 3- to 6- membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, or two R^GA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocylyl or heteroaryl ring. [0136] A compound of Formula I as employed in the present methods can form a part of a pharmaceutical composition by combining the compound of Formula I, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier. Additionally, the compositions comprising a compound of Formula I can include an additive selected from the group consisting of adjuvants, excipients, diluents, release-modifying agents and stabilizers. The composition comprising a compound of Formula I can be an immediate release formulation, a delayed release formulation, a sustained release formulation or an extended release formulation. Compounds of Formula I are described in U.S. Patent No. 9,512,165, which is incorporated by reference in its entirety, herein. [0137] In some embodiments, represents a single or double bond; R¹ is substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3-6 carbocyclyl; R² is hydrogen, halogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocyclyl, or —OR^A2, wherein R^A2 is hydrogen or substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2- 6 alkenyl, substituted or unsubstituted C2-6 alkynyl, or substituted or unsubstituted C3- ₆ carbocyclyl; R^3a is hydrogen or —OR^A3, wherein R^A3 is hydrogen or substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C_2-6 alkynyl, or substituted or unsubstituted C_3-6 carbocyclyl, and R^3b is hydrogen; or R^3a and R^3b are joined to form an oxo (═O) group; each instance of R^4a and R^4b is independently hydrogen, substituted or unsubstituted C_1-6 alkyl, or halogen, provided if the between C5 and C6 is a single bond, then the hydrogen at C5 and R^4a are each independently provided in the alpha or beta configuration, and R^4b is absent; each instance of R⁵, R⁶, and R⁷ is, independently, hydrogen, halogen, —NO2, —CN, —OR^GA, —N(R^GA)2, —C(═O)R^GA, — C(═O)OR^GA, —OC(═O)R^GA, —OC(═O)OR^GA, —C(═O)N(R^GA)₂, —N(R^GA)C(═O)R^GA, — OC(═O)N(R^GA)2, —N(R^GA)C(═O)OR^GA, —N(R^GA)C(═O)N(R^GA)2, —SR^GA, —S(O)R^GA, e.g., —S(═O)R^GA, —S(═O)₂R^GA, —S(═O)₂OR^GA, —OS(═O)₂R^GA, —S(═O)₂N(R^GA)₂, — N(R^GA)S(═O)2R^GA, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2- ₆ alkenyl, substituted or unsubstituted C_2-6 alkynyl, substituted or unsubstituted C_3-6 carbocylyl, or substituted or unsubstituted 3- to 6-membered heterocylyl; and each instance of R^GA is independently hydrogen, substituted or unsubstituted C_1-6 alkyl, substituted or unsubstituted C_2- 6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-6 carbocylyl, substituted or unsubstituted 3- to 6-membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, or two R^GA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocylyl or heteroaryl ring. [0138] In some embodiments, the compound of Formula I is Compound 2. The structure of Compound 2 is below:

[0139] In some embodiments, the compound of Formula I is SAGE-324. In some embodiments, the neuroactive steroid is SAGE-324. Formulations [0140] The methods of the present disclosure can employ various formulations for administration to patients, e.g., humans in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions (e.g., intramuscular (IM), subcutaneous (SC) and intravenous (IV)), transdermal patches, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of Compound 1 or a pharmaceutically acceptable salt thereof. [0141] The methods of the present disclosure can employ various formulations for administration to patients, e.g., humans in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions (e.g., intramuscular (IM), subcutaneous (SC) and intravenous (IV)), transdermal patches, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of a compound of Formula I (e.g. Compound 2) or a pharmaceutically acceptable salt thereof. [0142] The methods of the present disclosure can employ various formulations for administration to patients, e.g., humans in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions (e.g., intramuscular (IM), subcutaneous (SC) and intravenous (IV)), transdermal patches, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of a neuroactive steroid or a pharmaceutically acceptable salt thereof. [0143] Oral pharmaceutical dosage forms can be either solid or liquid. The solid dosage forms can be tablets, capsules, granules, films (e.g., buccal films) and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets, which can be enteric-coated, sugar-coated or film-coated. Capsules can be hard or soft gelatin capsules, while granules and powders can be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art. In some embodiments, the present oral dosage forms may include orally disintegrating tablets. [0144] Pharmaceutically acceptable carriers utilized in tablets include binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. [0145] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. [0146] Aqueous solutions include, for example, elixirs and syrups. Emulsions can be either oil-in water or water-in-oil. Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups can be concentrated aqueous solutions of a sugar, for example, sucrose, and can contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions can use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substance used in effervescent granules, to be reconstituted into a liquid oral dosage form, can include organic acids and a source of carbon dioxide. Coloring and flavoring agents can be used in all of the above dosage forms. [0147] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a salt of Compound 1. In some embodiments, the salt of Compound 1 is Compound 1 Hydrobromide, Compound 1 Citrate, Compound 1 L-Malate, Compound 1 Mesylate, Compound 1 Phosphate, Compound 1 L(+)-Tartrate, Compound 1 Hydrochloride, Compound 1 Tosylate, Compound 1 Glucuronate, or Compound 1 Ethanesulfonate. Co-therapy [0148] While the compositions can be administered as the sole active pharmaceutical ingredient (i.e., Compound 1) or sole active anti-adjustment disorder ingredient in the methods described herein, in some embodiments they can also be used in combination with one or more ingredients which are known to be therapeutically effective against adjustment disorder and/or compliment the anti-adjustment disorder effect of the Compound 1 ingredient. [0149] In some embodiments, the present methods can employ Compound 1, or a pharmaceutically acceptable salt thereof, in conjunction with one or more anti-antidepressants. In some embodiments, the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, mirtazapine bupropion, lamotrigine and atypical antipsychotics. [0150] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in combination with an additional anti-depressant agent, e.g., co-formulated or administered separately. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, mirtazapine, bupropion, lamotrigine atypical antipsychotics, or combinations thereof. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in combination with electroconvulsive therapy (ECT). In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in combination with transcranial magnetic stimulation (TMS). [0151] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more selective serotonin reuptake inhibitors. In some embodiments, the one or more selective serotonin reuptake inhibitors is selected from the group consisting of fluoxetine, escitalopram, citalopram, sertraline, and paroxetine. [0152] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more serotonin norepinephrine reuptake inhibitors. In some embodiments, the one or more serotonin norepinephrine reuptake inhibitors is selected from the group consisting of venlafaxine and duloxetine. [0153] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more serotonin tricyclic antidepressants. In some embodiments, the one or more tricyclic antidepressants is selected from the group consisting of amitriptyline, imipramine, and nortriptyline. [0154] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more monoamine oxidase inhibitors. In some embodiments, the one or more monoamine oxidase inhibitors is selected from the group consisting of phenelzine and tranylcypromine. [0155] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more atypical antipsychotics. In some embodiments, the one or more atypical antipsychotics is selected from the group consisting of lurasidone, aripiprazole, risperidone, olanzapine, quetiapine, ziprasidone, clozapine, iloperidone, paliperidone, asenapine and olanzapine/fluoxetine. [0156] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is a non-benzodiazepine anxiolytic drug. In some embodiments, the non-benzodiazepine anxiolytic drug is etifoxine or a pharmaceutically acceptable salt thereof. In some embodiments, the non-benzodiazepine anxiolytic drug is an etifoxine derivative (such as deuterated etifoxine or an etifoxine pro-drug). [0157] In some embodiments, the present methods can employ Compound 1, or a pharmaceutically acceptable salt thereof, in conjunction with one or more anxiolytics. In some embodiments, the anxiolytic is one or more benzodiazepines. In some embodiments, the benzodiazepine is selected from the group consisting of midazolam, diazepam, chlordiazepoxide, alprazolam, and adinazolam. [0158] While the compositions can be administered as the sole active pharmaceutical ingredient (i.e., a compound of Formula I, like Compound 2) or sole active anti-adjustment disorder ingredient in the methods described herein, in some embodiments they can also be used in combination with one or more ingredients which are known to be therapeutically effective against adjustment disorder and/or compliment the anti-adjustment disorder effect of the Compound 1 ingredient. [0159] In some embodiments, the present methods can employ a compound of Formula I, such as Compound 2, or a pharmaceutically acceptable salt thereof, in conjunction with one or more anti-antidepressants. In some embodiments, the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, mirtazapine bupropion, lamotrigine and atypical antipsychotics. [0160] In some embodiments, a compound of Formula I, such as Compound 2 or a pharmaceutically acceptable salt thereof is administered in combination with an additional anti- depressant agent, e.g., co-formulated or administered separately. In some embodiments, a compound of Formula I, such as Compound 2, or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, mirtazapine, bupropion, lamotrigine atypical antipsychotics, or combinations thereof. In some embodiments, a compound of Formula I, such as Compound 2, or a pharmaceutically acceptable salt thereof is administered in combination with electroconvulsive therapy (ECT). In some embodiments, a compound of Formula I, such as Compound 2, or a pharmaceutically acceptable salt thereof is administered in combination with transcranial magnetic stimulation (TMS). [0161] In some embodiments, a compound of Formula I, such as Compound 2, or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more selective serotonin reuptake inhibitors. In some embodiments, the one or more selective serotonin reuptake inhibitors is selected from the group consisting of fluoxetine, escitalopram, citalopram, sertraline, and paroxetine. [0162] In some embodiments, a compound of Formula I, such as Compound 2, or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more serotonin norepinephrine reuptake inhibitors. In some embodiments, the one or more serotonin norepinephrine reuptake inhibitors is selected from the group consisting of venlafaxine and duloxetine. [0163] In some embodiments, a compound of Formula I, such as Compound 2, or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more serotonin tricyclic antidepressants. In some embodiments, the one or more tricyclic antidepressants is selected from the group consisting of amitriptyline, imipramine, and nortriptyline. [0164] In some embodiments, a compound of Formula I, such as Compound 2, or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more monoamine oxidase inhibitors. In some embodiments, the one or more monoamine oxidase inhibitors is selected from the group consisting of phenelzine and tranylcypromine. [0165] In some embodiments, a compound of Formula I, such as Compound 2, or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more atypical antipsychotics. In some embodiments, the one or more atypical antipsychotics is selected from the group consisting of lurasidone, aripiprazole, risperidone, olanzapine, quetiapine, ziprasidone, clozapine, iloperidone, paliperidone, asenapine and olanzapine/fluoxetine. [0166] In some embodiments, a compound of Formula I, such as Compound 2, or a pharmaceutically acceptable salt thereof is administered in conjunction with a non- benzodiazepine anxiolytic drug. In some embodiments, the non-benzodiazepine anxiolytic drug is etifoxine or a pharmaceutically acceptable salt thereof. In some embodiments, the non- benzodiazepine anxiolytic drug is an etifoxine derivative (such as deuterated etifoxine or an etifoxine pro-drug). [0167] In some embodiments, the present methods can employ a compound of Formula I, such as Compound 2, or a pharmaceutically acceptable salt thereof, in conjunction with one or more anxiolytics. In some embodiments, the anxiolytic is one or more benzodiazepines. In some embodiments, the benzodiazepine is selected from the group consisting of midazolam, diazepam, chlordiazepoxide, alprazolam, and adinazolam. [0168] While the compositions can be administered as the sole active pharmaceutical ingredient (i.e., NAS) or sole active anti-adjustment disorder ingredient in the methods described herein, in some embodiments they can also be used in combination with one or more ingredients which are known to be therapeutically effective against adjustment disorder and/or compliment the anti-adjustment disorder effect of the NAS. [0169] In some embodiments, the present methods can employ a NAS, as described herein, or a pharmaceutically acceptable salt thereof, in conjunction with one or more anti- antidepressants. In some embodiments, the antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, mirtazapine bupropion, lamotrigine and atypical antipsychotics. [0170] In some embodiments, a NAS, as described herein or a pharmaceutically acceptable salt thereof is administered in combination with an additional anti-depressant agent, e.g., co- formulated or administered separately. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, mirtazapine, bupropion, lamotrigine atypical antipsychotics, or combinations thereof. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in combination with electroconvulsive therapy (ECT). In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered in combination with transcranial magnetic stimulation (TMS). [0171] In some embodiments, a NAS, as described herein or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more selective serotonin reuptake inhibitors. In some embodiments, the one or more selective serotonin reuptake inhibitors is selected from the group consisting of fluoxetine, escitalopram, citalopram, sertraline, and paroxetine. [0172] In some embodiments, a NAS, as described herein or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more serotonin norepinephrine reuptake inhibitors. In some embodiments, the one or more serotonin norepinephrine reuptake inhibitors is selected from the group consisting of venlafaxine and duloxetine. [0173] In some embodiments, a NAS, as described herein or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more serotonin tricyclic antidepressants. In some embodiments, the one or more tricyclic antidepressants is selected from the group consisting of amitriptyline, imipramine, and nortriptyline. [0174] In some embodiments, a NAS, as described herein or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more monoamine oxidase inhibitors. In some embodiments, the one or more monoamine oxidase inhibitors is selected from the group consisting of phenelzine and tranylcypromine. [0175] In some embodiments, a NAS, as described herein or a pharmaceutically acceptable salt thereof is administered in conjunction with one or more atypical antipsychotics. In some embodiments, the one or more atypical antipsychotics is selected from the group consisting of lurasidone, aripiprazole, risperidone, olanzapine, quetiapine, ziprasidone, clozapine, iloperidone, paliperidone, asenapine and olanzapine/fluoxetine. [0176] In some embodiments, a NAS, as described herein or a pharmaceutically acceptable salt thereof is administered in conjunction with a non-benzodiazepine anxiolytic drug. In some embodiments, the non-benzodiazepine anxiolytic drug is etifoxine or a pharmaceutically acceptable salt thereof. In some embodiments, the non-benzodiazepine anxiolytic drug is an etifoxine derivative (such as deuterated etifoxine or an etifoxine pro-drug). [0177] In some embodiments, the present methods can employ a NAS, as described herein, or a pharmaceutically acceptable salt thereof, in conjunction with one or more anxiolytics. In some embodiments, the anxiolytic is one or more benzodiazepines. In some embodiments, the benzodiazepine is selected from the group consisting of midazolam, diazepam, chlordiazepoxide, alprazolam, and adinazolam. [0178] Reduction of AD or the symptoms thereof in patients with AD can be determined by various methods. In some embodiments, the effectiveness of a dosage regimen can be determined by evaluation via Hamilton Rating Scale for Anxiety (HAM-A). In some embodiments, the effectiveness of a dosage regimen can be determined by evaluation via Hamilton Depression Rating Scale (HAM-D). In some embodiments, the effectiveness of a dosage regimen can be determined by evaluation via the Adjustment Disorder New Module (ADNM). In some embodiments, the effectiveness of a dosage regimen can be determined by evaluation via the Clinical Global Impression Global Improvement Subscale (CGI-I). In some embodiments, the effectiveness of a dosage regimen can be determined by evaluation via the Hospital anxiety depression scale (HADS). In some embodiments, the effectiveness of a dosage regimen can be determined by evaluation via the Sheehan Disability Scale (SDS). In some embodiments, the effectiveness of a dosage regimen can be determined by evaluation via the Patient Global Impression – Improvement (PGI-I) scale. In some embodiments, the effectiveness of a dosage regimen can be determined by evaluation via HAM-A, HAM-D, CGI-I, ADNM, HADS, SDS, PGI-I, or any combination thereof. [0179] In some embodiments, the effectiveness of a dosage regimen can be determined by evaluation via HADS or ADNM as a primary efficacy endpoint in association with secondary efficacy endpoints such as the CGI-I, PGI-I, SDS, HAM-A, HAM-D, or any combination thereof. [0180] The Hospital Anxiety and Depression Scale (HADS) is used to detect the presence and severity of depression and anxiety. HADS consists of 14 items divided equally between anxiety depression. Each item is assigned a score from 0 to 3. A higher item score (e.g., a score closer to or 3) corresponds to more severe depression or anxiety, and a lower item score (e.g., a score closer to or 0) corresponds to less severe depression or anxiety. The sum of the seven anxiety is the HADS Anxiety subscale score, and the sum of the seven depression items is the HADS Depression subscale score. The sum of the HADS Anxiety subscale score and the HADS Depression subscale score is the HADS total score. The magnitude of the HADS Depression subscale score or HADS Anxiety subscale category are divided into the following categories: “normal,” “borderline,” or “clinical casedness.” A HADS Depression subscale score or HADS Anxiety subscale score of 0-7 is considered normal. A HADS Depression subscale score or HADS Anxiety subscale score of 8-10 is considered borderline. A HADS Depression subscale score or HADS Anxiety subscale score of 11 or over indicates clinical casedness, e.g., the presence of depression or anxiety, respectively. Therefore, a decrease in the HADS total score or one of the HADS subscale score (e.g. the HADS Depression subscale score or the HADS Anxiety subscale score) indicates improvement. Snaith, R.P. The Hospital Anxiety And Depression Scale. Health Qual Life Outcomes 1, 29 (2003). [0181] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50% decline in the HADS total score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HADS total score ranging from about 30% to about 100%, for example, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0182] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in HADS total score compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a two point decline in HADS total score compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a ten point decline in HADS total score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HADS total score ranging from about one point to about 42 points, for example, about one point, about two points, about three points, about four points, about five points, about six points, about seven points, about eight points, about nine points, about ten points, about eleven points, about twelve points, about thirteen points, about fourteen points, about fifteen points, about sixteen points, about seventeen points, about eighteen points, about nineteen points, about twenty points, about 21 points, about 22 points, about 23 points, about 24 points, about 25 points, about 26 points, about 27 points, about 28 points, about 29 points, about 30 points, about 31 points, about 32 points, about 33 points, about 34 points, about 35 points, about 36 points, about 37 points, about 38 points, about 39 points, about 40 points, about 41 points, and about 42 points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about two points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about three points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about four points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about five points. In some embodiments, the reduction of AD is characterized by a decline HADS total score of about six points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about seven points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about eight points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about nine points. In some embodiments, the reduction of AD is characterized by a decline HADS total score of about ten points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about eleven points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about twelve points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about thirteen points. In some embodiments, the reduction of AD is characterized by a decline HADS total score of about fourteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about fifteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about sixteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about seventeen points. In some embodiments, the reduction of AD is characterized by a decline HADS total score of about eighteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about nineteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about twenty points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 21 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 22 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 23 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 24 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 25 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 26 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 27 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 28 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 29 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 30 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 31 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 32 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 33 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 34 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 35 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 36 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 37 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 38 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 39 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 40 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 41 points. In some embodiments, the reduction of AD is characterized by a decline in HADS total score of about 42 points. [0183] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50% decline in the HADS Anxiety subscale score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score ranging from about 30% to about 100%, for example, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0184] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in HADS Anxiety subscale score compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a two point decline in HADS Anxiety subscale score compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a ten point decline in HADS Anxiety subscale score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score ranging from about one point to about twenty points, for example, about one point, about two points, about three points, about four points, about five points, about six points, about seven points, about eight points, about nine points, about ten points, about eleven points, about twelve points, about thirteen points, about fourteen points, about fifteen points, about sixteen points, about seventeen points, about eighteen points, about nineteen points, and about twenty points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about two points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about three points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about four points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about five points. In some embodiments, the reduction of AD is characterized by a decline HADS Anxiety subscale score of about six points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about seven points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about eight points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about nine points. In some embodiments, the reduction of AD is characterized by a decline HADS Anxiety subscale score of about ten points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about eleven points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about twelve points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about thirteen points. In some embodiments, the reduction of AD is characterized by a decline HADS Anxiety subscale score of about fourteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about fifteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about sixteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about seventeen points. In some embodiments, the reduction of AD is characterized by a decline HADS Anxiety subscale score of about eighteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about nineteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS Anxiety subscale score of about twenty points. [0185] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50% decline in the HADS Depression subscale score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score ranging from about 30% to about 100%, for example, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0186] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in HADS Depression subscale score compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a two point decline in HADS Depression subscale score compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a ten point decline in HADS Depression subscale score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score ranging from about one point to about twenty points, for example, about one point, about two points, about three points, about four points, about five points, about six points, about seven points, about eight points, about nine points, about ten points, about eleven points, about twelve points, about thirteen points, about fourteen points, about fifteen points, about sixteen points, about seventeen points, about eighteen points, about nineteen points, and about twenty points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about two points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about three points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about four points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about five points. In some embodiments, the reduction of AD is characterized by a decline HADS Depression subscale score of about six points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about seven points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about eight points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about nine points. In some embodiments, the reduction of AD is characterized by a decline HADS Depression subscale score of about ten points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about eleven points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about twelve points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about thirteen points. In some embodiments, the reduction of AD is characterized by a decline HADS Depression subscale score of about fourteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about fifteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about sixteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about seventeen points. In some embodiments, the reduction of AD is characterized by a decline HADS Depression subscale score of about eighteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about nineteen points. In some embodiments, the reduction of AD is characterized by a decline in HADS Depression subscale score of about twenty points. [0187] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one category change in HADS subscale severity classification compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a one category change HADS subscale severity classification compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a two category change HADS subscale severity classification compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by remission according to the HADS subscale score after said treatment (e.g., a HADS Anxiety subscale score or a HADS Depression subscale score of 7 or less). [0188] The Adjustment Disorder New Module 20 (ADNM-20) is a questionnaire used to assess the core symptoms and accessory symptoms of AD. The core symptoms of AD include preoccupations and failure to adapt, and the accessory symptoms of AD include avoidance, depressive mood, anxiety, and impulse disturbance. The ADNM-20 contains 20 items, which are rated 1 “never”, 2 “rarely, 3 “sometimes”, and 4 “often.” The ADNM-20 total score ranges from 1-80 and is the sum of each item score. The sum of items that assess core symptoms is called the ADNM-20 Core Symptoms subscale score. The ADNM-20 Core Symptoms subscale score ranges from 1-32. The sum of items that assess accessory symptoms is called the ADNM- 20 Accessory Symptoms subscale score. The ADNM-20 Accessory Symptoms subscale score ranges from 1-48. A decrease in the ADNM-20 total score, ADNM-20 Core Symptoms subscale score, or in the ADNM-20 Accessory Symptoms subscale score indicates improvement. Glaesmer et al. Psychiatry Res.2015;229(3):940-948. [0189] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50% decline in the ADNM-20 total score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score ranging from about 30% to about 100%, for example, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0190] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in ADNM-20 total score compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a two point decline in ADNM-20 total score compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a ten point decline in ADNM-20 total score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score ranging from about one point to about 80 points, for example, about one point, about two points, about three points, about four points, about five points, about six points, about seven points, about eight points, about nine points, about ten points, about eleven points, about twelve points, about thirteen points, about fourteen points, about fifteen points, about sixteen points, about seventeen points, about eighteen points, about nineteen points, about twenty points, about 21 points, about 22 points, about 23 points, about 24 points, about 25 points, about 26 points, about 27 points, about 28 points, about 29 points, about 30 points, about 31 points, about 32 points, about 33 points, about 34 points, about 35 points, about 36 points, about 37 points, about 38 points, about 39 points, about 40 points, about 41 points, about 42 points, about 43 points, about 44 points, about 45 points, about 46 points, about 47 points, about 48 points, about 49 points, about 50 points, about 51 points, about 52 points, about 53 points, about 54 points, about 55 points, about 56 points, about 57 points, about 58 points, about 59 points, about 60 points, about 61 points, about 62 points, about 63 points, about 64 points, about 65 points, about 66 points, about 67 points, about 68 points, about 69 points, about 70 points, about 71 points, about 72 points, about 73 points, about 74 points, about 75 points, about 76 points, about 77 points, about 78 points, about 79 points, or about 80 points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about two points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about three points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about four points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about five points. In some embodiments, the reduction of AD is characterized by a decline ADNM-20 total score of about six points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about seven points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about eight points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about nine points. In some embodiments, the reduction of AD is characterized by a decline ADNM-20 total score of about ten points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about eleven points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about twelve points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about thirteen points. In some embodiments, the reduction of AD is characterized by a decline ADNM-20 total score of about fourteen points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about fifteen points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about sixteen points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about seventeen points. In some embodiments, the reduction of AD is characterized by a decline ADNM-20 total score of about eighteen points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about nineteen points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about twenty points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 21 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 22 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 23 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 24 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 25 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 26 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 27 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 28 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 29 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 30 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 31 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 32 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 33 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 34 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 35 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 36 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 37 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 38 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 39 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 40 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 41 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 42 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 43 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 44 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 45 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 46 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 47 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 48 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 49 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 50 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 51 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 52 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 53 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 54 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 55 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 56 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 57 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 58 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 59 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 60 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 61 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 62 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 63 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 64 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 65 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 66 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 67 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 68 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 69 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 70 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 71 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 72 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 73 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 74 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 75 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 76 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 77 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 78 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 79 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 total score of about 80 points. [0191] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50% decline in the ADNM-20 Core Symptoms subscale score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score ranging from about 30% to about 100%, for example, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0192] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in ADNM-20 Core Symptoms subscale score compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a two point decline in ADNM-20 Core Symptoms subscale score compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a ten point decline in ADNM-20 Core Symptoms subscale score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score ranging from about one point to about 32 points, for example, about one point, about two points, about three points, about four points, about five points, about six points, about seven points, about eight points, about nine points, about ten points, about eleven points, about twelve points, about thirteen points, about fourteen points, about fifteen points, about sixteen points, about seventeen points, about eighteen points, about nineteen points, about twenty points, about 21 points, about 22 points, about 23 points, about 24 points, about 25 points, about 26 points, about 27 points, about 28 points, about 29 points, about 30 points, about 31 points, or about 32 points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about two points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about three points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about four points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about five points. In some embodiments, the reduction of AD is characterized by a decline ADNM-20 Core Symptoms subscale score of about six points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about seven points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about eight points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about nine points. In some embodiments, the reduction of AD is characterized by a decline ADNM-20 Core Symptoms subscale score of about ten points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about eleven points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about twelve points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about thirteen points. In some embodiments, the reduction of AD is characterized by a decline ADNM-20 Core Symptoms subscale score of about fourteen points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about fifteen points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about sixteen points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about seventeen points. In some embodiments, the reduction of AD is characterized by a decline ADNM-20 Core Symptoms subscale score of about eighteen points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about nineteen points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about twenty points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about 21 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about 22 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about 23 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about 24 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about 25 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about 26 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about 27 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about 28 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about 29 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about 30 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about 31 points. In some embodiments, the reduction of AD is characterized by a decline in ADNM-20 Core Symptoms subscale score of about 32 points. [0193] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50% decline in the Accessory Symptoms subscale score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score ranging from about 30% to about 100%, for example, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0194] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in Accessory Symptoms subscale score compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a two point decline in Accessory Symptoms subscale score compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a ten point decline in Accessory Symptoms subscale score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score ranging from about one point to about 42 points, for example, about one point, about two points, about three points, about four points, about five points, about six points, about seven points, about eight points, about nine points, about ten points, about eleven points, about twelve points, about thirteen points, about fourteen points, about fifteen points, about sixteen points, about seventeen points, about eighteen points, about nineteen points, about twenty points, about 21 points, about 22 points, about 23 points, about 24 points, about 25 points, about 26 points, about 27 points, about 28 points, about 29 points, about 30 points, about 31 points, about 32 points, about 33 points, about 34 points, about 35 points, about 36 points, about 37 points, about 38 points, about 39 points, about 40 points, about 41 points, or about 42 points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about two points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about three points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about four points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about five points. In some embodiments, the reduction of AD is characterized by a decline Accessory Symptoms subscale score of about six points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about seven points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about eight points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about nine points. In some embodiments, the reduction of AD is characterized by a decline Accessory Symptoms subscale score of about ten points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about eleven points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about twelve points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about thirteen points. In some embodiments, the reduction of AD is characterized by a decline Accessory Symptoms subscale score of about fourteen points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about fifteen points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about sixteen points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about seventeen points. In some embodiments, the reduction of AD is characterized by a decline Accessory Symptoms subscale score of about eighteen points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about nineteen points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about twenty points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 21 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 22 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 23 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 24 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 25 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 26 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 27 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 28 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 29 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 30 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 31 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 32 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 33 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 34 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 35 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 36 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 37 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 38 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 39 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 40 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 41 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 42 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 43 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 44 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 45 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 46 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 47 points. In some embodiments, the reduction of AD is characterized by a decline in Accessory Symptoms subscale score of about 48 points. [0195] The HAM-D is a depression rating scale consisting of 17 items, eight items are scored on a 5-point scale (ranging from 0 to 4), and 9 items are scores on a 3-point scale (ranging from 0 to 2). The total score of the 17 items ranges from 0 to 50 with higher scores indicating greater depression. The total score the 17 items is used to categorize the severity of depression: normal (total score between 0 and 7), mild depression (total score between 8 and 13), moderate depression (total score between 14-18), severe depression (total score between 19-22). Therefore, a decrease in the total score or on individual item scores indicates improvement Hamilton, M. A Rating Scale for Depression, Journal of Neurology, Neurosurgery, and Psychiatry. (1960) 23, pages 56-62. [0196] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 30% decline in total Hamilton Depression Rating Scale (HAM-D) value compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50 % decline in total Hamilton Depression Rating Scale (HAM-D) value compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value ranging from about 30% to about 100%, for example, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0197] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in HAM-D value compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a ten point decline in HAM-D value compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value ranging from about one point to about twenty points, for example, about one point, about two points, about three points, about four points, about five points, about six points, about seven points, about eight points, about nine points, about ten points, about eleven points, about twelve points, about thirteen points, about fourteen points, about fifteen points, about sixteen points, about seventeen points, about eighteen points, about nineteen points, and about twenty points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about two points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about three points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about four points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about five points. In some embodiments, the reduction of AD is characterized by a decline HAM-D value of about six points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about seven points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about eight points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about nine points. In some embodiments, the reduction of AD is characterized by a decline HAM-D value of about ten points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about eleven points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about twelve points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about thirteen points. In some embodiments, the reduction of AD is characterized by a decline HAM- D value of about fourteen points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about fifteen points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about sixteen points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about seventeen points. In some embodiments, the reduction of AD is characterized by a decline HAM-D value of about eighteen points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about nineteen points. In some embodiments, the reduction of AD is characterized by a decline in HAM-D value of about twenty points. [0198] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one category change in HAM-D severity classification compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a one category change HAM-D severity classification compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a two category change HAM-D severity classification compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a three category change HAM-D severity classification compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by remission according to HAM-D value after said treatment (i.e., total HAM-D value of 7 or less). [0199] The Hamilton Rating Scale for Anxiety (HAM-A) is an anxiety rating scale consisting of 14 items that assess anxious mood, tension, fear, insomnia, intellectual (cognitive) functioning, depressed mood, behavior at interview, somatic (sensory), cardiovascular, respiratory, gastrointestinal, genitourinary, autonomic, and somatic (muscular) symptom (Hamilton, M. The Assessment of Anxiety States by Rating, Br J Med Psychol. (1959); 32 (1), pages 50-5). Each symptom is rated from 0 (absent) to 4 (maximum severity) scale. The total score is used to categorize the severity of anxiety: mild severity (total score less than 17), mild to moderate severity (total score between 18-24), and moderate to severe (total score between 25–30). Total scores range from 0 to 56 with higher scores indicating greater severity. [0200] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 30% decline in total HAM-A value compared to prior to the treatment. In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50% decline in total HAM-A value compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HAM-A value ranging from about 10% to about 100%, for example, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0201] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in HAM-A value compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in HAM-A value ranging from about one point to about five points, for example, about one point, about two points, about three points, about four points, and about five points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline HAM-A value of about two points. In some embodiments, the reduction of AD is characterized by a decline in HAM-A value of about three points. In some embodiments, the reduction of AD is characterized by a decline in HAM-A value of about four points. In some embodiments, the reduction of AD is characterized by a decline in HAM-A value of about five points. [0202] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one category change in HAM-A severity classification compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a one category change HAM-A severity classification compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a two category change HAM-A severity classification compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a three category change HAM-A severity classification compared to prior to the treatment. [0203] The Clinical Global Impression (CGI) (Guy 1976 (Guy W (1976), ECDEU Assessment Manual for Psychopharmacology, Revised. Rockville, MD: US Department of Health, Education and Welfare) consists of three subscales: the CGI-Severity (CGI-S), the CGI-Improvement (CGI-I) and Efficacy Index. The CGI-S assesses the clinician’s impression of the patient’s current mental illness. A treating clinician categorizes the severity of the patient’s current mental illness on a 7-point scale: 1 (normal, not at all ill), 2 (borderline mentally ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill), and 7 (among the most extremely ill patients). The CGI-I assesses the participant’s improvement (or worsening) from baseline. A treating clinician categorizes the patient’s condition relative to Baseline (e.g., prior to administering an antidepressant) on a 7-point scale: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), and 7 (very much worse). [0204] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in CGI-S value compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a one point decline in CGI-S value compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a two point decline in CGI-S value compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a three point decline in CGI-S value compared to prior to the treatment. [0205] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterizeed by at least a one point decline in CGI-I value compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a one point decline in CGI-I value compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a two point decline in CGI-I value compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a three point decline in CGI-I value compared to prior to the treatment. [0206] The Patient Global Impression-Improvement (PGI-I) scale is a global self- assessment used to rate the response of a subject’s condition (e.g. AD) to therapy or intervention (e.g. to administration of Compound 1). It consists of one question that asks the subject to rate their current condition compared to how it was prior to beginning treatment on a scale of 1 (very much better) to 7 (very much worse). [0207] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50% decline in the PGI-I compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in the PGI-I ranging from about 30% to about 100%, for example, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0208] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in the PGI-I compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in the PGI-I ranging from about one point to about seven points, for example, about one point, about two points, about three points, about four points, about five points, about six points, or about seven points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in PGI-I of about one point. In some embodiments, the reduction of AD is characterized by a decline in PGI-I of about two points. In some embodiments, the reduction of AD is characterized by a decline in PGI-I of about three points. In some embodiments, the reduction of AD is characterized by a decline in PGI-I of about four points. In some embodiments, the reduction of AD is characterized by a decline in PGI-I of about five points. In some embodiments, the reduction of AD is characterized by a decline in PGI-I of about six points. In some embodiments, the reduction of AD is characterized by a decline in PGI-I of about seven points. [0209] The Sheehan Disability Scale (SDS) is a self‐report questionnaire measuring functional impairment in the domains of work, social, and family life. Each domain is assigned a SDS domain score on a scale from 0 “unimpaired” to 10 “highly impaired”. A SDS domain score of ≥ 5 on any functional domain is associated with significant functional impairment. The sum of the work, social, and family life SDS domain scores is the global SDS score, which ranges from 0 to 30, where “0” is unimpaired and “30” is impaired. Leon, A. C. et al. (1997). The International Journal of Psychiatry in Medicine, 27(2), 93–105. [0210] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50% decline in the global SDS score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in the global SDS score ranging from about 30% to about 100%, for example, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0211] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in the global SDS score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in the global SDS score ranging from about one point to about thirty points, for example, about one point, about two points, about three points, about four points, about five points, about six points, about seven points, about eight points, about nine points, about ten points, about 11 points, about 12 points, about 13 points, about 14 points, about 15 points, about 16 points, about 17 points, about 18 points, about 19 points, about 20 points, about 21 points, about 22 points, about 23 points, about 24 points, about 25 points, about 26 points, about 27 points, about 28 points, about 29 points, or about 30 points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about one point. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about two points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about three points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about four points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about five points. In some embodiments, the reduction of AD is characterized by a decline global SDS score of about six points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about seven points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about eight points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about nine points. In some embodiments, the reduction of AD is characterized by a decline global SDS score of about ten points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about eleven points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about twelve points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about thirteen points. In some embodiments, the reduction of AD is characterized by a decline global SDS score of about fourteen points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about fifteen points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about sixteen points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about seventeen points. In some embodiments, the reduction of AD is characterized by a decline global SDS score of about eighteen points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about nineteen points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about twenty points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about 21 points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about 22 points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about 23 points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about 24 points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about 25 points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about 26 points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about 27 points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about 28 points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about 29 points. In some embodiments, the reduction of AD is characterized by a decline in global SDS score of about 30 points [0212] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50% decline in the work SDS domain score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in the work SDS domain score ranging from about 30% to about 100%, for example, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0213] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in the work SDS domain score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in the work SDS domain score ranging from about one point to about twenty points, for example, about one point, about two points, about three points, about four points, about five points, about six points, about seven points, about eight points, about nine points, or about ten points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in work SDS domain score of about one point. In some embodiments, the reduction of AD is characterized by a decline in work SDS domain score of about two points. In some embodiments, the reduction of AD is characterized by a decline in work SDS domain score of about three points. In some embodiments, the reduction of AD is characterized by a decline in work SDS domain score of about four points. In some embodiments, the reduction of AD is characterized by a decline in work SDS domain score of about five points. In some embodiments, the reduction of AD is characterized by a decline work SDS domain score of about six points. In some embodiments, the reduction of AD is characterized by a decline in work SDS domain score of about seven points. In some embodiments, the reduction of AD is characterized by a decline in work SDS domain score of about eight points. In some embodiments, the reduction of AD is characterized by a decline in work SDS domain score of about nine points. In some embodiments, the reduction of AD is characterized by a decline work SDS domain score of about ten points. [0214] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50% decline in the social SDS domain score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in the social SDS domain score ranging from about 30% to about 100%, for example, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0215] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in the social SDS domain score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in the social SDS domain score ranging from about one point to about twenty points, for example, about one point, about two points, about three points, about four points, about five points, about six points, about seven points, about eight points, about nine points, or about ten points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in social SDS domain score of about one point. In some embodiments, the reduction of AD is characterized by a decline in social SDS domain score of about two points. In some embodiments, the reduction of AD is characterized by a decline in social SDS domain score of about three points. In some embodiments, the reduction of AD is characterized by a decline in social SDS domain score of about four points. In some embodiments, the reduction of AD is characterized by a decline in social SDS domain score of about five points. In some embodiments, the reduction of AD is characterized by a decline social SDS domain score of about six points. In some embodiments, the reduction of AD is characterized by a decline in social SDS domain score of about seven points. In some embodiments, the reduction of AD is characterized by a decline in social SDS domain score of about eight points. In some embodiments, the reduction of AD is characterized by a decline in social SDS domain score of about nine points. In some embodiments, the reduction of AD is characterized by a decline social SDS domain score of about ten points. [0216] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least about a 50% decline in the family life SDS domain score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in the family life SDS domain score ranging from about 30% to about 100%, for example, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, and about 100%, compared to prior to the treatment. [0217] In some embodiments, after the treatment the patient experiences a substantial reduction of AD that is characterized by at least a one point decline in the family life SDS domain score compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in the family life SDS domain score ranging from about one point to about twenty points, for example, about one point, about two points, about three points, about four points, about five points, about six points, about seven points, about eight points, about nine points, or about ten points compared to prior to the treatment. In some embodiments, the reduction of AD is characterized by a decline in family life SDS domain score of about one point. In some embodiments, the reduction of AD is characterized by a decline in family life SDS domain score of about two points. In some embodiments, the reduction of AD is characterized by a decline in family life SDS domain score of about three points. In some embodiments, the reduction of AD is characterized by a decline in family life SDS domain score of about four points. In some embodiments, the reduction of AD is characterized by a decline in family life SDS domain score of about five points. In some embodiments, the reduction of AD is characterized by a decline family life SDS domain score of about six points. In some embodiments, the reduction of AD is characterized by a decline in family life SDS domain score of about seven points. In some embodiments, the reduction of AD is characterized by a decline in family life SDS domain score of about eight points. In some embodiments, the reduction of AD is characterized by a decline in family life SDS domain score of about nine points. In some embodiments, the reduction of AD is characterized by a decline family life SDS domain score of about ten points. Dosing [0218] The present disclosure provides methods for treating AD by administering an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof. An effective amount is an amount sufficient to eliminate or significantly reduce AD symptoms or to alleviate those symptoms (e.g., reduce the symptoms, such as depressed mood or anxiety, compared to the symptoms present prior to treatment). In some embodiments, any of the methods disclosed herein for administering Compound 1 can be applied to other neuroactive steroids described herein, including compounds of Formula I, e.g., Compound 2. [0219] In some embodiments of the present disclosure, administering Compound 1 or a pharmaceutically acceptable salt thereof provides statistically significant therapeutic effect. In one embodiment, the statistically significant therapeutic effect is determined based on one or more standards or criteria provided by one or more regulatory agencies in the United States, e.g., FDA or other countries (such as Australia). In some embodiments, the statistically significant therapeutic effect is determined based on results obtained from regulatory agency approved clinical trial set up and/or procedure. [0220] In some embodiments, the statistically significant therapeutic effect is determined based on a patient population of at least 20, 50, 60, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 or 2000. In some embodiments, the statistically significant therapeutic effect is determined based on data obtained from randomized and double-blinded clinical trial set up. In some embodiments, the statistically significant therapeutic effect is determined based on data with a p value of less than or equal to about 0.05, 0.04, 0.03, 0.02 or 0.01. In some embodiments, the statistically significant therapeutic effect is determined based on data with a confidence interval greater than or equal to 95%, 96%, 97%, 98% or 99%. [0221] In some embodiments, the statistically significant therapeutic effect is determined by a randomized double-blind clinical trial of patients treated with Compound 1 or a pharmaceutically acceptable salt thereof and optionally in combination with standard care. In some embodiments, the statistically significant therapeutic effect is determined by a randomized clinical trial and using Hospital Anxiety Depression Scale (HADS) and/or Adjustment Disorder New Module (ADNM) as primary efficacy parameters and optionally in combination with any other commonly accepted criteria for AD assessment including those described herein. [0222] In general, statistical analysis can include any suitable method permitted by a regulatory agency, e.g., FDA in the US or Europe or any other country. In some embodiments, statistical analysis includes non-stratified analysis, log-rank analysis, e.g., from Kaplan-Meier, Jacobson-Truax, Gulliken-Lord-Novick, Edwards-Nunnally, Hageman-Arrindel and Hierarchical Linear Modeling (HLM) and Cox regression analysis. [0223] According to the present disclosure, Compound 1 is administered on a once or twice a day basis to provide effective relief of the symptoms of AD. [0224] In some embodiments, the total daily dose of Compound 1 is from about 5 mg to about 120 mg, including about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, and about 120 mg, including all ranges there between. In some embodiments, the total daily dose of Compound 1 is from about 15 mg to about 60 mg. In some embodiments, the total daily dose of Compound 1 is from about 15 mg to about 80 mg. In some embodiments, the total daily dose of Compound 1 is from about 15 mg to about 100 mg. In some embodiments, the total daily dose of Compound 1 is from about 45 mg to about 60 mg. In some embodiments, the total daily dose of Compound 1 is from about 45 mg to about 80 mg. [0225] In some embodiments, the total daily dose of Compound 2 is from about 5 mg to about 120 mg, including about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, and about 120 mg, including all ranges there between. In some embodiments, the total daily dose of Compound 2 is from about 15 mg to about 60 mg. In some embodiments, the total daily dose of Compound 2 is from about 15 mg to about 80 mg. In some embodiments, the total daily dose of Compound 2 is from about 15 mg to about 100 mg. In some embodiments, the total daily dose of Compound 2 is from about 45 mg to about 60 mg. In some embodiments, the total daily dose of Compound 2 is from about 45 mg to about 80 mg. In some embodiments, the total daily dose of Compound 2 is about 30 mg. [0226] In the embodiments described herein, reference is made to the dose of Compound 1 for the treatment of AD (which includes adjustment disorder with depressed mood, adjustment disorder with anxiety, adjustment disorder with mixed anxiety and depressed mood, adjustment disorder with disturbance of conduct, adjustment disorder with mixed disturbance of emotions and conducts, and adjustment disorder unspecified). [0227] In some embodiments, the total daily dose of Compound 1 is at least about 5 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 10 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 15 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 20 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 25 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 30 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 35 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 40 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 45 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 50 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 55 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 60 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 65 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 70 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 75 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 80 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 85 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 90 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 95 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 100 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 105 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 110 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 115 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is at least about 120 mg a day for the treatment of AD. [0228] In some embodiments, the total daily dose of Compound 1 is about 5 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 10 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 15 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 20 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 25 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 30 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 35 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 40 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 45 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 50 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 55 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 60 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 65 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 70 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 75 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 80 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 85 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 90 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 95 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 100 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 105 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 110 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 115 mg a day for the treatment of AD. In some embodiments, the total daily dose of Compound 1 is about 120 mg a day for the treatment of AD. [0229] In some embodiments, about 5 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 5 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 10 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 10 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 15 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 15 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 20 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 20 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 25 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 25 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 30 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 30 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 30 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 30 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 35 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 35 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 40 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 40 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 45 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 45 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 50 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 50 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 55 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 55 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 60 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 60 mg of Compound 1 twice a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 65 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 70 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 75 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 80 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 85 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 90 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 95 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 100 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 105 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 110 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 115 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. In some embodiments, about 120 mg of Compound 1 once a day is selected to provide a substantial reduction in AD or the symptoms thereof. [0230] In some embodiments, the dosing frequency and dose amount per administration of Compound 1 are selected to provide therapeutic effects for the treatment of AD. In some embodiments, the AD is selected from adjustment disorder with depressed mood, adjustment disorder with anxiety, adjustment disorder with mixed anxiety and depressed mood, adjustment disorder with disturbance of conduct, adjustment disorder with mixed disturbance of emotions and conducts, and adjustment disorder unspecified. In some embodiments, the AD is selected from adjustment disorder, adjustment disorder with depressed mood, adjustment disorder with anxiety, or adjustment disorder with mixed anxiety and depressed mood. In some embodiments, the AD is adjustment disorder with depressed mood. In some embodiments, the adjustment disorder is adjustment disorder with anxiety. In some embodiments, the adjustment disorder is adjustment disorder with mixed anxiety and depressed mood. [0231] In some embodiments, the dosing frequency and dose amount per administration of Compound 1 are selected to provide therapeutic effects for the treatment of AD that is refractory to other treatments. [0232] In some embodiments, the dosing frequency and dose amount per administration of Compound 1 are selected to provide therapeutic effects for the treatment of AD that is partially responsive to other AD therapies. In some embodiments, the dosing frequency and dose amount per administration of Compound 1 are selected to provide an adjunctive treatment for AD. In some embodiments, the dosing frequency and dose amount per administration of Compound 1 are selected to provide therapeutic effects for the treatment of AD that is partially responsive to treatment with SSRIs. According to some embodiments of the present disclosure, the dosing frequency and dose amount per administration of Compound 1 are selected to provide therapeutic effects for the treatment of adjustment disorder that is not responsive to treatment with SSRIs. [0233] In some embodiments, the dosing frequency and dose amount per administration of Compound 1 are selected to provide therapeutic effects for the treatment of AD that is partially responsive to other anti-adjustment disorder therapies. In some embodiments, the AD patient that is partially responsive to other antidepressant therapies is an adult patient meeting DSM-5 criteria for AD who had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had demonstrated an inadequate response to 8 weeks of prospective antidepressant therapy. [0234] In some embodiments, the dosing frequency and dose amount per administration of Compound 1 are selected to prevent the recurrence of AD. In some embodiments, the dosing frequency and dose amount per administration of Compound 1 are selected to maintain remission of AD. [0235] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week, for example, about a week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks,about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks and up to 12 weeks. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for less than 3 months. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for about 1 week to about 4 weeks. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for about 1 week. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for about 2 weeks. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for about 3 weeks. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for about 4 weeks. [0236] In some embodiments, at least about 5 mg or about 5 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week. In some embodiments, at least about 10 mg or about 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week. In some embodiments, at least about 15 mg or about 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week. In some embodiments, at least about 20 mg or about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week. In some embodiments, at least about 25 mg or about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week. In some embodiments, at least about 30 mg or about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week. In some embodiments, at least about 35 mg or about 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week. In some embodiments, at least about 40 mg or about 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week. In some embodiments, at least about 45 mg or about 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week. In some embodiments, at least about 50 mg or about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week. In some embodiments, at least about 55 mg or about 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week. In some embodiments, at least about 60 mg or about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day or twice a day basis for at least a week. In some embodiments, at least about 65 mg or about 65 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day basis for at least a week. In some embodiments, at least about 70 mg or about 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day basis for at least a week. In some embodiments, at least about 75 mg or about 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day basis for at least a week. In some embodiments, at least about 80 mg or about 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day basis for at least a week. In some embodiments, at least about 85 mg or about 85 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day basis for at least a week. In some embodiments, at least about 90 mg or about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day basis for at least a week. In some embodiments, at least about 95 mg or about 95 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day basis for at least a week. In some embodiments, at least about 100 mg or about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day basis for at least a week. In some embodiments, at least about 105 mg or about 105 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day basis for at least a week. In some embodiments, at least about 110 mg or about .110 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day basis for at least a week. In some embodiments, at least about 115 mg or about 115 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day basis for at least a week. In some embodiments, at least about 120 mg or about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered on a once a day basis for at least a week. [0237] In some embodiments, the substantial reduction in AD or the symptoms thereof provided by the methods of the present disclosure requires treatment for a specified time interval (e.g., at least one week) before the patient experiences substantial reduction of AD or the symptoms thereof (i.e., there is an induction period before the patient experiences a substantial reduction in depression). In some embodiments, after treatment for at least one day, at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks or at least eight weeks, the patient experiences a substantial reduction of AD or the symptoms thereof compared to prior to the treatment. In some embodiments, after treatment for at least one week the patient experiences a substantial reduction of AD or the symptoms thereof compared to prior to the treatment. According to this embodiment, the substantial reduction in depression may be expressed using any of the methods described herein (for example, decline in total Hamilton Depression Rating Scale (HAM-D) value compared to prior to the treatment, a decline in total Hamilton Rating Scale for Anxiety (HAM-A) value compared to prior to the treatment, a decline in the Global Improvement Subscale (CGI-I) compared to prior to treatment, a reduction in the Hospital Anxiety and Depression Scale (HADS) total score compared to prior to treatment, a reduction in the Adjustment Disorder –New Module 20 (ADNM-20) total score compared to prior to the treatment, etc.). [0238] In some embodiments, the method of treating AD further includes a step of titrating the dose of Compound 1 until a second daily dose is achieved in the patient. In some embodiments, the titration is conducted for at least about one week until a second daily dose is achieved in the patient. In one embodiment, the titration is conducted for about 2 weeks until a second daily dose is achieved in the patient. In some embodiments, the titration is conducted for about 7 days to about 14 days until a second daily dose is achieved in the patient. In some embodiments, the titration is conducted for about 12 days to about 14 days until a second daily dose is achieved in the patient. In some embodiments, during the titration step, a constant daily dose of Compound 1 is provided. In further embodiments, the constant daily dose of Compound 1 is provided for at least two weeks. [0239] The daily dose can be titrated in one or more steps. The daily dosage can be titrated by increasing a single daily dosage, or each dose of a twice-daily dosing regimen. The amount a dosage is stepped, where there are multiple titration steps, can be the same, or can be different. [0240] In some embodiments, the titration is initiated with from about 15 mg to about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof, including about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg and about 100 mg including all ranges there between once or twice daily. In some embodiments, the titration is initiated with about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg and about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof once or twice daily. In some embodiments, doses can be adjusted in 5-30 mg increments every 1 to 4 days. In some embodiments, doses can be adjusted in 5-30 mg increments every week. In some embodiments, the titration is conducted for at least about one week, or about 2 weeks prior to the second daily dose. [0241] In some embodiments, ascending doses of Compound 1 are administered during the titration until a maintenance dose is achieved in the patient. In some embodiments, ascending doses of the Compound 1 are administered during the titration until an effective amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg or about 120 mg is achieved in the patient. [0242] In some embodiments, patients are initially administered about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg of Compound 1 or a pharmaceutically acceptable salt once or twice a day and are titrated to a maintenance 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, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg or about 120 mg once or twice a day. In some embodiments, patients are initially administered from about 15 mg to about 100 mg of Compound 1 or a pharmaceutically acceptable salt, including about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg and about 100 mg, including all ranges there between once or twice a day and are titrated to a maintenance dose of from about 20 mg to about 120 mg, including about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg or about 120 mg including all ranges therebetween, once or twice a day. [0243] In some embodiments, the present disclosure provides a method of treating AD that includes the steps of: (a) administering a first daily dose of Compound 1 for at least one week and (b) administering a second daily dose for at least one week. In some embodiments, the first daily dose is greater than the second daily dose. In some embodiments, the first daily dose is less than the second daily dose. In some embodiments, the first daily dose is administered for two weeks and the second daily dose is administered is administered for at least one week. [0244] In some embodiments, the present disclosure provides a method of treating AD that includes the steps of: (a) administering a loading dose of Compound 1 and (b) administering a second daily dose of Compound 1; wherein the second daily dose is less than the loading dose. [0245] In some embodiments, the loading dose is administered for about 1 day to about 14 days, including about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days and about 14 days, including all ranges therebetween. In some embodiments, the loading dose is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days or about 14 days. [0246] In some embodiments, the methods comprise a loading dose of from about 30 mg to about 120 mg, including about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, and about 120 mg including all ranges therebetween. In some embodiments, the methods comprise a loading dose of about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 mg, [0247] In some embodiments, the second daily dose is administered for from about 1 week to about 3 months, including about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 week and about 12 weeks. In some embodiments, the second daily dose is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 week and about 12 weeks . [0248] In some embodiments, the methods comprise a second daily dose of from about 30 mg to about 120 mg, including about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, and about 120 mg including all ranges therebetween, once or twice a day. In some embodiments, the methods comprise a second daily dose of from about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, or about 120 mg, once or twice a day. [0249] In some embodiments, the loading dose administration methods further comprise a cessation period after administration of the loading dose and prior to administration of the second daily dose. [0250] In some embodiments, the cessation period is about one day, about two days, about three days, about four days, about five days, about six days, or about seven days. In some embodiments, the cessation period is from about one day to about seven days, including about one day, about two days, about three days, about four days, about five days, about six days, and about seven days, including all ranges there between. [0251] In some embodiments, the cessation period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks. In some embodiments, the cessation period is from about one week to about eight weeks, including about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, and about eight weeks including all ranges there between. [0252] In some embodiments, the methods of the present disclosure comprise continuous administration of Compound 1 or a pharmaceutically acceptable salt thereof for a specified interval (for example, one week) followed by a cessation period wherein the patient is not administered Compound 1. In some embodiments, the methods of the present disclosure comprise continuous administration of Compound 1 or a pharmaceutically acceptable salt thereof for from about one week to about eight weeks, including about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, and about eight weeks including all ranges there between. In some embodiments, the methods of the present disclosure comprise continuous administration of Compound 1 or a pharmaceutically acceptable salt thereof for about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks. [0253] In some embodiments, the methods of the present disclosure comprise continuous administration of Compound 1 or a pharmaceutically acceptable salt thereof for from about one week to about 12 weeks, including about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about ten weeks, about 11 weeks, or about 12 weeks , including all ranges there between. In some embodiments, the methods of the present disclosure comprise continuous administration of Compound 1 or a pharmaceutically acceptable salt thereof for about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about ten weeks, about 11 weeks, or about 12 weeks. [0254] In some embodiments, the methods of the present disclosure comprise intermittent administration of Compound 1 or a pharmaceutically acceptable salt thereof. As used herein, intermittent administration means cycling a patient in need thereof on and off treatment with Compound 1 or a pharmaceutically acceptable salt thereof for specified time intervals. [0255] In some embodiments, intermittent administration comprises: (a) administering Compound 1 for a first administration period; (b) after the first administration period (a), not administering Compound 1 for a cessation period; (c) after the cessation period (b), administering Compound 1 for a second administration period. [0256] In some embodiments, the intermittent administration further comprises one or more additional cessation periods (for example, a second cessation period) and/or administration periods (for example, a third administration period). In such embodiments, the present disclosure contemplates embodiments wherein the additional cessation and/or administration periods have the durations described herein for the first administration period and the cessation period. [0257] In some embodiments, two or more of the periods (a), (b) and (c) are the same (for example, the first administration period, cessation period and second administration period are each one week). In some embodiments, the periods (a) and (b) (for example, one week) are the same and the period (c) is different (for example, two weeks). In some embodiments, the periods (a) and (c) are the same and the period (b) is different. In some embodiments, the periods (b) and (c) are the same and the period (a) is different. In some embodiments, the periods (a), (b) and (c) are the different (for example, the first administration period is one week, the cessation period is two weeks and the second administration period is three weeks). [0258] In some embodiments, the first administration period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks. In some embodiments, the first administration period is from about one week to about eight weeks, including about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, and about eight weeks including all ranges there between. [0259] In some embodiments, the cessation period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks. In some embodiments, the cessation period is from about one week to about eight weeks, including about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, and about eight weeks including all ranges there between. [0260] In some embodiments, the second administration period is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks. In some embodiments, the second administration period is from about one week to about eight weeks, including about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, or about eight weeks including all ranges there between. [0261] In some embodiments, the first administration period, cessation period and second administration period are one week. In some embodiments, the first administration period, cessation period and second administration period are two weeks. In some embodiments, the first administration period, cessation period and second administration period are three weeks. In some embodiments, the first administration period, cessation period and second administration period are four weeks. In some embodiments, the first administration period, cessation period and second administration period are five weeks. In some embodiments, the first administration period, cessation period and second administration period are six weeks. In some embodiments, the first administration period, cessation period and second administration period are seven weeks. In some embodiments, the first administration period, cessation period and second administration period are eight weeks. [0262] In some embodiments, the first administration period is about one week; the cessation period is about three weeks; and the second administration period is about one week. [0263] In some embodiments, the first administration period is about two weeks; the first cessation period is about two weeks; the second administration period is about one week; the second cessation period is about one week and the third administration period is about one week. [0264] In some embodiments, the intermittent administration period (including the administration and cessation periods) is about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about ten weeks, about 11 weeks, or about 12 weeks, including all ranges there between. [0265] In some embodiments of the present disclosure, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient with food. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient about 5 minutes, about 10 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours or about 8 hours after food is ingested. [0266] In some embodiments, the food ingested is a high fat and high calorie food. In some embodiments, the caloric content of the high fat and high calorie food is at least about 700 kilocalories (kcal), and at least about 40 percent of the caloric content of the food is from fat. For example, the fat can contribute to about 50 percent of the caloric content of the food of high fat and high calorie. In some embodiments, the caloric content of the high fat and high calorie food is about 900 kilocalories. [0267] In some embodiments, the food ingested is a medium fat and medium calorie food. In some embodiments, the caloric content of the medium fat and medium calorie food is about 300 kcal to about 700 kcal, and between about 20 percent to about 40 percent of the caloric content of the food is from fat. In some embodiments, the caloric content of the medium fat and medium calorie food is about 400 kcal. [0268] In some embodiments, the food ingested is a low fat and low calorie food. In some embodiments, the caloric content of the low fat and low calorie food is between about 100 kcal to about 300 kcal, and the fat content is approximately 3 grams or less, or about 20 percent or less of the caloric content of the food are from fat. In some embodiments, the caloric content of the food of low fat and low calorie is about 100 kilocalories. [0269] In some embodiments of the present disclosure, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient after a fasting period. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient after a fasting period of about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours. [0270] In some embodiments of the present disclosure, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient without regard to meals. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient at bedtime. [0271] In some embodiments, the methods of the present disclosure comprise controlling the gastrointestinal pH of the patient prior to, concurrently with or after administration of Compound 1. In some embodiments, the gastrointestinal pH of the patient is controlled prior to administration of Compound 1. In some embodiments, the gastrointestinal pH of the patient is controlled after administration of Compound 1. [0272] In some embodiments, the pH is controlled by administering a drug, food or liquid to a patient that decreases gastrointestinal pH prior to, concurrently with or after administration of Compound 1. In some embodiments, the liquid is an acidic beverage (such as a carbonated beverage). [0273] In some embodiments, the pH is controlled by the patient avoiding a drug, food or beverage that increases gastrointestinal pH prior to, concurrently with or after administration of Compound 1. In some embodiments, the drug that increases gastrointestinal pH is a proton pump inhibitor or an orally-administered antacid. [0274] In some embodiments, the initial daily dosing frequency and dose amount per administration of Compound 1 are selected to provide therapeutic effects for the acute treatment of AD and the increased daily dosing frequency and dose amount per administration of Compound 1 are selected to maintain remission of AD. [0275] In some embodiments, the initial daily dosing frequency and dose amount per administration of Compound 1 are selected to provide therapeutic effects for the acute treatment of AD and the maintenance the daily dosing frequency and dose amount per administration of Compound 1 are selected to prevent recurrence of AD. [0276] In some embodiments, the initial daily dose is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg or about 120 mg and the maintenance daily dose is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, or about 115 mg provided the initial daily dose is greater than the maintenance daily dose. [0277] According to some embodiments of the present disclosure, the methods of the present disclosure provide therapeutically effective blood plasma levels of Compound 1 for treating AD. Blood plasma levels of Compound 1 may be expressed using pharmacokinetic parameters that are known to those skilled in the art, such as steady state plasma levels, AUC, Cmax and Cmin. Throughout the present disclosure pharmacokinetic parameters are described in terms of providing a steady state plasma level of a particular PK parameter (such as steady state plasma Cmax, steady state AUC, etc.). However, the present disclosure contemplates embodiments where the steady state PK parameters that are expressed herein are average values from a patient population (such as a mean value). Thus, the following description of pharmacokinetic parameters describes mean steady state PK parameter values as well values from an individual patient. [0278] In some embodiments, the present methods provide steady state plasma levels of Compound 1 that correlate to one or more statistically significant therapeutic effects. In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 provided by the methods of the present disclosure range from about 1 ng/mL to about 200 ng/mL, including about 1 ng/ml, about 5 ng/mL, about 10 ng/mL, about 15 ng/mL, about 20 ng/mL, about 25 ng/mL, about 30 ng/mL, about 35 ng/mL, about 40 ng/mL, about 45 ng/mL, about 50 ng/mL, about 55 ng/mL, about 60 ng/mL, about 65 ng/mL, about 70 ng/mL, about 75 ng/mL about 80 ng/mL, about 85 ng/mL, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, about 110 ng/mL, about 115 ng/mL, about 120 ng/mL, about 125 ng/mL, about 130 ng/mL, about 135 ng/mL, about 140 ng/mL, about 145 ng/mL, about 150 ng/mL, about 155 ng/mL, about 160 ng/mL, about 165 ng/mL, about 170 ng/mL, about 175 ng/mL about 180 ng/mL, about 185 ng/mL, about 190 ng/mL, about 195 ng/mL, and 200 ng/ml, including all ranges there between. In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 provided by the methods of the present disclosure range from about 50 ng/ml to 200 ng/ml. [0279] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 15 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0280] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 20 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0281] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 25 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0282] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 30 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0283] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 35 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0284] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 40 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0285] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 45 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0286] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 50 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0287] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 55 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0288] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 60 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0289] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 65 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 65 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0290] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 70 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0291] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 75 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0292] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 80 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0293] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 85 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 85 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0294] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 90 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0295] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 95 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 95 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0296] In some embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 100 mg. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma levels of Compound 1 is provided by administering about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0297] In some embodiments, the present methods provide mean steady state AUC 0-24h (expressed in terms of ng*hr/mL) levels of Compound 1 that correlate to one or more statistically significant therapeutic effects. In some embodiments, the therapeutically effective mean steady state AUC 0-24h levels of Compound 1 provided by the methods of the present disclosure range from about 50 ng*hr/mL to about 2300 ng*hr/mL, including about 50 ng*hr/mL, 100 ng*hr/mL, 150 ng*hr/mL, 200 ng*hr/mL, 250 ng*hr/mL, 300 ng*hr/mL, about 400 ng*hr/mL, about 500 ng*hr/mL, about 600 ng*hr/mL, about 700 ng*hr/mL, about 800 ng*hr/mL, about 900 ng*hr/mL, about 1000 ng*hr/mL, about 1100 ng*hr/mL, about 1200 ng*hr/mL, about 1300 ng*hr/mL, about 1400 ng*hr/mL, about 1500 ng*hr/mL, about 1600 ng*hr/mL, about 1700 ng*hr/mL, about 1800 ng*hr/mL, about 1900 ng*hr/mL, about 2000 ng*hr/mL, about 2100 ng*hr/mL, about 2200 ng*hr/mL and about 2300 ng*hr/mL, including all ranges there between. In some embodiments, the therapeutically effective mean steady state AUC _0-24h levels of Compound 1 provided by the methods of the present disclosure range from about 500 ng*hr/mL to about 1000 ng*hr/mL, including about 550 ng*hr/mL, about 600 ng*hr/mL, about 650 ng*hr/mL, about 700 ng*hr/mL, about 750 ng*hr/mL, about 800 ng*hr/mL, about 850 ng*hr/mL and about 900 ng*hr/mL, including all ranges there between. In some embodiments, the therapeutically effective mean steady state AUC _0-24h levels of Compound 1 provided by the methods of the present disclosure range from about 600 ng*hr/mL to about 900 ng*hr/mL. [0298] In some embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 15 mg. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0299] In some embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 20 mg. In further embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering about 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0300] In some embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 25 mg. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0301] In some embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 30 mg. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0302] In some embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 35 mg. In further embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering about 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0303] In some embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 40 mg. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0304] In some embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 45 mg. In further embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering about 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0305] In some embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 50 mg. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0306] In some embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 55 mg. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0307] In some embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 60 mg. In further embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0308] In some embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 65 mg. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 65 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0309] In some embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 70 mg. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0310] In some embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 75 mg. In further embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering about 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0311] In some embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 80 mg. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering about 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0312] In some embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 85 mg. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 85 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0313] In some embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 90 mg. In further embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering about 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0314] In some embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 95 mg. In further embodiments, the mean steady state AUC 0-24h levels of Compound 1 is provided by administering about 95 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0315] In some embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof of about 100 mg. In further embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the mean steady state AUC _0-24h levels of Compound 1 is provided by administering about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0316] In some embodiments, the present methods provide steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 that correlate to one or more statistically significant therapeutic effects. In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 provided by the methods of the present disclosure range from about 5 ng/mL to about 500 ng/mL, including about 5 ng/mL, 10 ng/mL, 20 ng/mL, 30 ng/mL, 40 ng/mL, 50 ng/mL, 60 ng/mL, about 70 ng/mL, about 80 ng/mL, about 90 ng/mL, about 100 ng/mL, about 110 ng/mL, about 120 ng/mL, about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 ng/mL about 180 ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 ng/mL, about 250 ng/mL, about 260 ng/mL, about 270 ng/mL about 280 ng/mL, about 290 ng/mL, about 300 ng/mL, about 310 ng/mL, about 320 ng/mL, about 330 ng/mL, about 340 ng/mL, about 350 ng/mL, about 360 ng/mL, about 370 ng/mL about 380 ng/mL, about 390 ng/mL, about 400 ng/mL, about 410 ng/mL, about 420 ng/mL, about 430 ng/mL, about 440 ng/mL, about 150 ng/mL, about 460 ng/mL, about 470 ng/mL about 480 ng/mL, about 490 ng/mL, about 500 ng/mL, about 510 ng/mL about 520 ng/mL, about 530 ng/mL, about 540 ng/mL, about 550 ng/mL, about 560 ng/mL, about 570 ng/mL about 580 ng/mL, about 590 ng/mL and about 600 ng/mL, including all ranges there between. In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 provided by the methods of the present disclosure are from about 100 ng/mL to about 275 ng/mL, including about 110 ng/mL, about 120 ng/mL, about 130 ng/mL, about 140 ng/mL, about 150 ng/mL, about 160 ng/mL, about 170 ng/mL about 180 ng/mL, about 190 ng/mL, about 200 ng/mL, about 210 ng/mL, about 220 ng/mL, about 230 ng/mL, about 240 ng/mL, about 250 ng/mL, about 260 ng/mL, about 270 ng/mL, including all ranges there between. In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 provided by the methods of the present disclosure are from about 125 ng/mL to about 250 ng/mL. [0317] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 15 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0318] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 20 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 10 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state Cmax plasma levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0319] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 25 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0320] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 30 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 15 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state Cmax plasma levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0321] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 35 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0322] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 40 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state Cmax plasma levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0323] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 45 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0324] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 50 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state Cmax plasma levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0325] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 55 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0326] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 60 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 30 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0327] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 65 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 65 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0328] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 70 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0329] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 75 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0330] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 80 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0331] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 85 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 85 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0332] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 90 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0333] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 95 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 95 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0334] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 100 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0335] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 105 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 105 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0336] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 110 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 110 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0337] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 115 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 115 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0338] In some embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering a daily dose of Compound 1 or a pharmaceutically acceptable salt thereof is about 120 mg. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof twice a day. In further embodiments, the therapeutically effective steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 is provided by administering about 120 mg of Compound 1 or a pharmaceutically acceptable salt thereof once a day. [0339] In some embodiments, the present methods provide steady state plasma Cmax levels (or mean steady state plasma Cmax levels) of Compound 1 that do not exceed 500 ng/mL. In some embodiments, the therapeutically effective steady state plasma Cmax levels of Compound 1 provided by the methods of the present disclosure do not exceed about 500 ng/mL, including less than about 500 ng/mL, less than about 475 ng/mL, less than about 450 ng/mL, than about 425 ng/mL, less than about 400 ng/mL, less than about 375 ng/mL, than about 350 ng/mL, less than about 325 ng/mL, and less than about 300 ng/mL. EXAMPLES [0340] The present disclosure is further illustrated by reference to the following Examples. However, it is noted that these Examples, like the embodiments described above, are illustrative and are not to be construed as restricting the scope of the disclosure in any way. Example 1: [0341] Healthy subjects aged 18 to 55 years were treated with an oral suspension of Compound 1 to study the safety, tolerability, pharmacokinetics and pharmacodynamics of Compound 1 in healthy subjects. From the results of the study, oral Compound 1 will be assessed for its potential to reduce the symptoms of AD in a dose-dependent manner. [0342] Study Design [0343] The study was a randomized, double-blind, placebo-controlled multiple escalating dose study comprised of 3 cohorts that each received an oral suspension. Each cohort consisted of two groups: one group treated with Compound 1 and another treated with placebo. In each cohort, the ratio of Compound 1-treated subjects to placebo-treated subjects was 3:1. [0344] The Compound 1-treated subjects of Cohort 1 were treated with 15.0 mg of Compound 1 once per day (QD). The Compound 1-treated subjects of Cohort 2 were treated with 30.0 mg of Compound 1 QD. The Compound 1-treated subjects of Cohort 3 were treated with 60.0 mg of Compound 1 QD. [0345] A Food Effect Cohort (Cohort 4) was conducted to assess the effect of food on the PK profile of a single dose of Compound 1 when administered to healthy subjects. The subjects of Cohort 4 were treated with 30 mg of Compound 1 QD. [0346] Dosing: [0347] Patients in each cohort were treated with Compound 1 for 14 consecutive days, unless dosing was halted by the Safety Review Committee (SRC). The dosing of subjects in each of the cohorts was staggered with the decision to dose escalate based on SRC review of a minimum of 14 days of observation of safety and tolerability data and review of the available plasma PK data from the preceding cohort(s). Thus, dose escalation was predicated on tolerability of the prior cohorts. [0348] Compound 1 was administered under fasted conditions (no food or drink, except water, for at least 10 hours prior to dosing). Immediately after administration of Compound 1, the subject was be administered 240 mL water. No additional fluid intake was allowed until 1 hour after Compound 1 administration. [0349] Cohort 1 subjects received a single 15.0 mg dose of a Compound 1 suspension on the morning of Days 1-14. Cohort 2 subjects received a single 30.0 mg dose of a Compound 1 suspension on the morning of Days 1-14. Cohort 3 subjects received a single 60.0 mg dose of a Compound 1 suspension on the morning of Days 1-14. For all cohorts, the last treatment was administered on the morning of Day 14. [0350] Cohort 4 subjects received a single 30 mg dose of a Compound 1 suspension on Days 1 and 5. The Day 1 dose was administered after a minimum of 10 hour fasting. No additional fluid intake was allowed until 1 hour after drug administration. A standard meal was given at least 4 hours post-dose. The Day 5 dose was administered following a high-fat, high calorie meal. Participants remained at the clinical site for a total of 8 days to complete PK sampling after the second dose. [0351] Blood and urine were obtained during each treatment period at designated times for PK and other analyses (see below). Standard safety assessments were measured during each treatment period. [0352] Pharmacokinetic (PK) Assessments [0353] PK parameters (e.g., Cmax, Tmax, T1/2, AUC, etc.) for healthy patients in each cohort was compared to assess the suitability of Compound 1 suspension for the treatment of AD. Data were obtained from the blood plasma samples collected from each cohort according to the schedule provided. [0354] Plasma samples were analyzed to determine Compound 1 concentrations using a validated assay method. Pharmacokinetic variables (including but not limited to C_max, T_max and AUC(0-last)) were calculated using non-compartmental analysis. PK parameters for Compound 1 were derived from the plasma concentration data using non-compartmental analysis with Phoenix™ WinNonlin® v 8.0 (Pharsight Corporation, USA). [0355] Protocol: [0356] Blood (Cohorts 1-3): For each cohort, blood samples were collected on Days 1, 2, 3, 4, 5, 6 and 14 at the following time points: Day 1 at pre-dose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 h post-dose; Day 2 at pre-dose (24 h), Day 3 at pre-dose (48 h), Day 4 at pre-dose (72 h), Day 5 at pre-dose (96 h), Day 6 at pre-dose (120 h); Day 14 at pre- dose 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours. Trough level blood samples were collected on Days 2, 3, 4, 5, 6 and 14, prior to the morning dose administrations. [0357] The following PK parameters were calculated based on the plasma concentrations of Compound 1: maximum observed concentration (Cmax) on Day 1 and at steady state on Day 15 (Cmax,SS), Time of Cmax (Tmax) and Cmax,SS (Tmax,SS), area under the concentration-time curve through the dosing interval on Day 1 and 15 (AUCtau and AUCSS), total clearance at steady state, measured on Day 15 (CLSS), and volume of distribution at steady state, measured on Day 15 (VSS). [0358] Urine (Cohorts 1-3): Urine was collected/pooled at the following collection windows: Day -1 (6 hours) and at Day 14: (0 to 6 hours), (6 to 12 hours), (12 to 24 hours), and (24-48 hours). Urine samples were analyzed to determine Compound 1 concentrations using a validated assay method. Pooling of urine across patients may be allowed if volumes are not sufficient to allow individual determination. [0359] The following PK parameters were calculated based on the urine concentrations of Compound 1: absolute and cumulative amount of Compound 1 excreted in urine and renal clearance (CLR). [0360] Blood (Cohort 4): Serial blood samples were collected relative to the dosing Compound 1 at the following time points on both Day 1 and Day 5: Pre-dose (0 hours), 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 12.00, 16.00, 24.00, 36.00, 48.00 and 72.00 hours post-dose (±2 min). Urine (Cohort 4): No urine analysis was conducted in Cohort 4. [0361] Pharmacodynamic Assessment [0362] Pharmacodynamic (PD) effects of first dose and steady state Compound 1 concentrations on wake electroencephalograms (EEGs) was studied. Standard 16 channel continuous EEGs were obtained at the following time points: Day-1, Day 1 (1 h after dosing), and Day 14 (1 h after dosing). [0363] Safety Assessments/monitoring [0364] Adverse events (AEs) were monitored throughout the duration of the study. [0365] To monitor for possible adverse events, vital signs, hematology and clinical chemistry laboratory parameters, ECG readings, neurological examination findings, and EEG parameters and abnormal findings were recorded at each visit. [0366] Statistical Analysis [0367] Descriptive statistics were calculated for plasma and urine PK parameter and concentration data, and summarized by study day and time point. Arithmetic means, coefficient of variation (CV), standard deviation, median, minimum, and maximum values, and number of observations were calculated for all PK parameters and trough concentration data. Except for Tmax, the geometric mean, geometric standard deviation, and geometric CV were provided for all PK parameter and concentration data. [0368] Cohorts 1-3 Results: [0369] The following pharmacokinetic parameters were determined for each cohort: maximum plasma concentration (C_max, observed, Day 1 only); time to reach the maximum plasma concentration (Tmax, observed, Day 1 only); and area under the plasma concentration- time curve from time 0 to 24 h post dose (AUC_0-tau). [0370] The following steady state pharmacokinetic (Day 14) parameters were determined: t_1/2: elimination half-life associated with the terminal slope (λz) of the semi-logarithmic drug concentration-time curve, calculated as 0.693/ λz; Cmax,ss: maximum plasma concentration (observed); T_max,ss: time to reach the maximum plasma concentration (observed); AUC_ss: area under the plasma concentration-time curve from 0 to 24 h post dose; AUCinf : area under the plasma concentration-time curve from 0 to infinite time; C_avg: average concentration over dosing interval; CLss/F: steady state clearance; and Vz/F: volume of distribution of terminal phase. [0371] Table 1 shows a summary of the observed PK parameters Day 1. [0372] Table 1: Summary of Parameters for Compound 1 (calculated from Day 1 data for Cohorts 1-3)

[0373] Table 2 shows a summary of the observed PK parameters Day 14 for Cohorts 1-3.

PRAP-012/02WO 334726- [0374] T^rea Co Co Co

Geo Mean 12.164 0.944 320.410 2253.016 30.398 533.456 1973.814 82.242 CV% Geo Mean 11.36 23.83 54.42 35.80 36.78 42.61 36.78 36.78 106 253094544 v1

[0375] Conclusions: Compound 1 underwent rapid absorption with an approximate proportional increase in Cmax and AUC parameters at steady state. Where steady state data was available mean t_1/2 was varied between 12.23 and 14.77 h and steady state clearance was determined at approximately 31 L/h. [0376] Rapid absorption was observed with a Tmax occurring within the first 2 h of dosing (Tables 1-2). An accumulation factor of the dosing interval (ratio of AUCDay14/AUCDay1) of approximately 1.25 for Cohort 1 and Cohort 2 (Tables 1 and 2). For Cohort 3, the accumulation factor was 0.89 (Tables 1 and 2). The mean plasma concentration (ng/mL) for the first 24 hours after the initial dose is illustrated in FIG. 1. The mean plasma concentration (ng/mL) for the 24 hours after the last dose is illustrated in FIG.2. [0377] Mean t_1/2 for Cohort 1, Cohort 2 and Cohort 3 was 14.77 ± 2.26 h, 12.70 ± 1.23 h and 12.23 ± 1.32 h, respectively. Steady state clearance was approximately 31 L/h for the three cohorts at Day 14 and mean Vz/F was 655, 570 and 574 L for Cohorts 1, 2 and 3, respectively. A proportional increase in Cavg, AUCss and AUCinf was observed between Cohorts 1 and 3 (Tables 1 and 2). [0378] In Cohorts 1-3s, there were no Serious Adverse Events and no clinically relevant vital sign, ECG, or lab abnormalities. Additionally, several subjects experienced elevated mood at doses of 30 mg and 60 mg [0379] Cohort 4 Results: [0380] Table 3 shows a summary of the observed PK parameters Days 1 (fasted) and 5 (fed).

For Tmax, Median (Minimum, Maximum) values are displayed. [0381] Conclusions: [0382] Subjects displaying high concentrations following fasted conditions also tended to show higher concentrations (relative to others within the treatment group) following fed conditions. Similarly, subjects with low Compound 1 concentrations following fasted conditions tended to have low Compound 1 concentrations following fed conditions. The t1/2 was similar for both fasted and fed conditions (Table 3). [00101] There was evidence of a food effect for Compound 1 when administered as a single 30 mg dose. Approximately 15 to 20% greater overall exposure as measured by AUC0-last and AUCinf was observed following fed conditions. In addition, Cmax was 1.5 to 1.6 times higher under fasting conditions with a tendency for a shorter Tmax compared to fed conditions. Example 2: [0383] Healthy subjects aged 18 to 55 years were treated with an oral suspension of Compound 1 to study the safety, tolerability, pharmacokinetics and pharmacodynamics of Compound 1 in healthy subjects. Dose and dose frequencies were evaluated in order to select a regimen that is suitable for subjects with AD. From the results of the study, oral Compound 1 will be assessed for its potential to reduce the symptoms of AD in a dose-dependent manner. [0384] Study Design [0385] The study is a randomized, parallel, placebo-controlled group study comprised of two arms: one group is treated with Compound 1 and another is treated with placebo. The treatment population comprises an adjustment disorder population enriched for mixed anxiety, depression, and acute stress symptoms. Non-limiting endpoints that are evaluated include: HADS, ADNM, CGI, PGI-I, and Sheehan Disability Scale. Patients are assessed at days 1, 8, 15, 21, and 28. Fig.3 shows an exemplary study design. INCORPORATION BY REFERENCE [0386] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

CLAIMS What is claimed is: 1. A method of treating adjustment disorder in a patient in need thereof comprising orally administering a therapeutically effective amount of Compound 1:

or a pharmaceutically acceptable salt thereof to a patient in need thereof to treat adjustment disorder.

2. The method of claim 1, wherein the adjustment disorder is adjustment disorder with depressed mood.

3. The method of claim 1, wherein the adjustment disorder is adjustment disorder with anxiety.

4. The method of claim 1, wherein the adjustment disorder is adjustment disorder with mixed anxiety and depressed mood.

5. The method of any one of claims 1-4, wherein about 5 mg to about 120 mg of Compound 1 or a pharmaceutically acceptable salt is administered per day.

6. The method of any one of claims 1-5, wherein about 15 mg to about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered per day.

7. The method of any one of claims 1-5, wherein about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

8. The method of any one of claims 1-5, wherein about 20 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day.

9. The method of any one of claims 1-5, wherein about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

10. The method of any one of claims 1-5, wherein about 25 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day.

11. The method of any one of claims 1-5, wherein about 35 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

12. The method of any one of claims 1-5, wherein about 40 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

13. The method of any one of claims 1-5, wherein about 45 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

14. The method of any one of claims 1-5, wherein about 50 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

15. The method of any one of claims 1-5, wherein about 55 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

16. The method of any one of claims 1-5, wherein about 60 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

17. The method of any one of claims 1-5, wherein about 65 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

18. The method of any one of claims 1-5, wherein about 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

19. The method of any one of claims 1-5, wherein about 75 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

20. The method of any one of claims 1-5, wherein about 80 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

21. The method of any one of claims 1-5, wherein about 85 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

22. The method of any one of claims 1-5, wherein about 90 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

23. The method of any one of claims 1-5, wherein about 95 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

24. The method of any one of claims 1-5, wherein about 100 mg of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day.

25. The method of any one of claims 1-24, wherein said administering is for about 1 weeks to about 4 weeks.

26. The method of any one of claims 1-24, wherein said administering is for about 1 week.

27. The method of any one of claims 1-24, wherein said administering is for about 2 weeks.

28. The method of any one of claims 1-24, wherein said administering is for about 3 weeks.

29. The method of any one of claims 1-24, wherein said administering is for about 4 weeks.

30. The method of any one of claims 1-29, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least ten point decline in total Hamilton Depression Rating Scale (HAM-D) value compared to prior to the treatment.

31. The method of claim 30, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least 50% reduction in HAM-D value compared to prior to the treatment.

32. The method of claim 30, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least one category change in HAM-D severity classification compared to prior to the treatment.

33. The method of any one of claims 1-32, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of adjustment disorder that is characterized by an at least two point decline in total Hamilton Rating Scale for anxiety (HAM-A) value compared to prior to the treatment.

34. The method of claim 33, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of adjustment disorder that is characterized by an at least 50% reduction in HAM-A value compared to prior to the treatment.

35. The method of claim 33, wherein after said administering for a period of at least 1 week, the patient experiences a reduction of adjustment disorder that is characterized by an at least one category change in HAM-A severity classification compared to prior to the treatment.

36. The method of any one of claims 1-35, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by at least one point decline in Global Improvement Subscale (CGI-I) score compared to prior to the treatment.

37. The method of any one of claims 1-36, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 2 point reduction in the Hospital Anxiety and Depression Scale (HADS) total score compared to prior to the treatment.

38. The method of claim 37, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least 50% reduction in HADS total score compared to prior to the treatment.

39. The method of any one of claims 1-38, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 1 point reduction in the HADS Anxiety subscale score compared to prior to the treatment.

40. The method of any one of claims 1-39, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 1 point reduction in the HADS Depression subscale score compared to prior to the treatment.

41. The method of any one of claims 1-40, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 2 point reduction in the Adjustment Disorder – New Module 20 (ADNM-20) total score compared to prior to the treatment.

42. The method of claim 41, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least 50% reduction in ADNM-20 total score compared to prior to the treatment.

43. The method of any one of claims 1-42, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 1 point reduction in the ADNM-20 Core Symptoms subscale score compared to prior to the treatment.

44. The method of any one of claims 1-43, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 1 point reduction in the ADNM-20 Accessory Symptoms subscale score compared to prior to the treatment.

45. The method of any one of claims 1-44, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 1 point reduction in the Sheehan Disability Scale (SDS) total score compared to prior to the treatment.

46. The method of claim 45, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least 50% reduction in SDS total score.

47. The method of any one of claims 1-46, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 1 point reduction in the SDS Work Domain score compared to prior to the treatment.

48. The method of any one of claims 1-47, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 1 point reduction in the SDS Social Domain score compared to prior to the treatment.

49. The method of any one of claims 1-48, wherein after the administering, the patient experiences a reduction of adjustment disorder that is characterized by an at least a 1 point reduction in the SDS Family Life Domain score compared to prior to the treatment.

50. The method of any one of claims 1-49, wherein the administering provides a mean steady state AUC_0-24 of from about 600 ng ^h/mL to about 900 ng ^h.

51. The method of any one of claims 1-50, wherein the administering provides a mean steady state Cmax of from about 125 ng/mL to about 250 ng/mL.

52. The method of any one of claims 1-51, further comprising administering one or more anxiolytics.

53. The method of claim 52, wherein the anxiolytic is one or more benzodiazepines.

54. The method of claim 53, wherein the benzodiazepine is selected from the group consisting of midazolam, diazepam, chlordiazepoxide, alprazolam and adinazolam.

55. The method of any one of claims 1-54, further comprising administering one or more antidepressants.

56. The method of claim 55, wherein the additional antidepressant is selected from the group consisting of selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, mirtazapine bupropion, lamotrigine and atypical antipsychotics.

57. The method of claim 56, wherein the selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, escitalopram, citalopram, sertraline, and paroxetine.

58. The method of claim 56, wherein the serotonin norepinephrine reuptake inhibitor is selected from the group consisting of venlafaxine and duloxetine.

59. The method of claim 56, wherein the serotonin tricyclic antidepressant is selected from the group consisting of amitriptyline, imipramine, and nortriptyline.

60. The method of claim 56, wherein the monoamine oxidase inhibitor is selected from the group consisting of phenelzine and tranylcypromine.

61. The method of claim 56, wherein the atypical antipsychotic is selected from the group consisting of lurasidone, aripiprazole, risperidone, olanzapine, quetiapine, ziprasidone, clozapine, iloperidone, paliperidone, asenapine, and olanzapine/fluoxetine.

62. The method of any one of claims 1-61, further comprising administering etifoxine or a pharmaceutically acceptable salt thereof.

63. The method of any one of claims 1-62, further comprising administering an etifoxine derivatives (such as deuterated etifoxine, etifoxine pro-drugs).