19-nor c3,3-disubstituted c21-n-pyrazolyl steroid and methods of use thereof

Abstract

To provide 19-nor C3,3-disubstituted C21-N-pyrazolyl steroid and methods of use thereof.SOLUTION: Provided herein are methods of treating depression, such as postpartum depression or major depressive disorder, in a subject in need of treatment of the depression, the methods comprising administering to the subject an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. In further embodiments, Compound 1 is administered using an episodic dosing regimen. In some aspects, provided herein is an episodic dosing regimen comprising administering Compound 1 to a subject in need of administration of Compound 1. In some embodiments, about 10 mg, about 15 mg, about 20 mg, about 25 mg or about 30 mg of Compound 1 is administered to a subject in need thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority and the benefit of the provisional applications to U.S. Provisional Patent Application No. 62 / 684,155, filed Jun. 12, 2018; U.S. Provisional Patent Application No. 62 / 789,329, filed Jan. 7, 2019; and U.S. Provisional Patent Application No. 62 / 841,645, filed May 1, 2019, the entireties of each of which are incorporated herein by reference.

[0002] Field of the Invention The present invention generally relates to a method of treating depression such as postpartum depression and major depressive disorder by administering Compound 1 as described herein.

Background Art

[0003] Background Since up to 40% of the neurons in the brain utilize gamma - aminobutyric acid (GABA) as a neurotransmitter, GABA has a significant impact on the excitability of the entire brain. GABA promotes the flow of chloride ions into the cell downward the electrochemical gradient of the GRC (GABA receptor complex) by interacting with the recognition site on the GRC. This intracellular increase in the level of this anion causes hyperpolarization of the membrane potential across the membrane and reduces the sensitivity of the neuron to excitatory inputs (i.e., the excitability of the neuron is reduced). In other words, the higher the chloride ion concentration in the neuron, the lower the excitability (arousal level) of the brain. The GRC has been well - documented to be involved in the mediation of anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZ), e.g., Valium®) produce their therapeutically useful effects by interacting with specific regulatory sites on the GRC.

[0004] Accumulating evidence suggests that GRC contains distinct sites for neurosteroids (Lan, N.C. et al., Neuwchem.Res. 16:347-356 (1991)). Neurosteroids can occur endogenously. The most potent endogenous neurosteroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one (metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively). The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M.D. et al., Science 232:1004-1007 (1986); Harrison, N.L. et al., J Pharmacol.Exp.Ther. 241:346-353 (1987)). Compound 1, a neurosteroid described herein, is a GABA A synaptic receptor and GABA A extrasynaptic receptor targeting, GABA A is shown to be a positive allosteric modulator of the receptor. GABA A As a positive allosteric modulator of the GABA receptor, compound 1 serves as a therapeutic agent for treating CNS-related disorders, such as depression, such as postpartum depression and major depression. Current treatments for CNS-related disorders typically require long-term, sometimes chronic treatment, and patient medication compliance can be a major problem. Patients suffering from CNS-related disorders would benefit greatly from new treatment regimens that are effective, easy to administer, and / or require fewer doses, as well as avoid or minimize side effects.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Means for Solving the Problems

[0006] Abstract Methods for treating depression in a subject are provided herein, the methods comprising administering to the subject a therapeutically effective amount of Compound 1

Chemical

[0007] In some aspects, an episodic dosing regimen is provided herein that comprises administering Compound 1 to a subject in need thereof. In some embodiments, about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound 1 is administered to a subject in need thereof. In some embodiments, Compound 1 is administered once daily to a subject in need thereof over a plurality of weeks, for example, from about 2 weeks to about 6 weeks, for example, from about 2 weeks to about 4 weeks, for example, for about 2 weeks. In some embodiments, about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound 1 is administered once daily to a subject in need thereof over a plurality of weeks.

[0008] In preferred embodiments, Compound 1 is administered using an episodic dosing regimen that is carried out for from about 2 weeks to about 6 weeks. In more preferred embodiments, the episodic dosing regimen is carried out for from about 2 weeks to about 4 weeks. In even more preferred embodiments, the episodic dosing regimen is carried out for about 2 weeks (or about 14 days). In another embodiment, the episodic dosing regimen has a duration of 2 weeks, i.e., 14 days.

[0009] In some aspects, an episodic dosing regimen for treating depression is provided herein, the dosing regimen comprising administering Compound 1 to a subject in need thereof. In some embodiments, about 10 mg, about 15 mg, about 20 mg, about 25 mg or about 30 mg of Compound 1 is administered to the subject. In some embodiments, Compound 1 is administered once daily to the subject over a plurality of weeks. In some embodiments, about 10 mg, about 15 mg, about 20 mg, about 25 mg or about 30 mg of Compound 1 is administered once daily to the subject over a plurality of weeks. In preferred embodiments, the episodic dosing regimen is carried out for about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen is carried out for about 2 weeks to about 4 weeks. In an even more preferred embodiment, the episodic dosing regimen is carried out for about 2 weeks. In an even more preferred embodiment, the episodic dosing regimen is carried out for about 14 days. In another embodiment, the episodic dosing regimen has a duration of 2 weeks, i.e., 14 days. In an even more preferred embodiment, the episodic dosing regimen is carried out for about 2 weeks (or about 14 days), during which about 30 mg of Compound 1 is administered once daily to the subject. If the subject does not show tolerance to the once-daily administration of about 30 mg of Compound 1, about 20 mg of Compound 1 is administered once daily to the subject.

[0010] In some embodiments, the subject shows a response to the episodic dosing regimen, the response being indicated by a decrease of greater than or equal to about 50% in the HAM-D score from baseline. In some embodiments, the response is indicated by remission of depressive symptoms.

[0011] In some embodiments, the subject is evaluated for recurrence, i.e., the reappearance of depressive symptoms. In some embodiments, the method of treating the subject includes a plurality of episodic dosing regimens. In some embodiments, after completion of one episodic dosing regimen, the next episodic dosing regimen is administered with the reappearance of depressive symptoms. In some embodiments, the episodic dosing regimens are spaced at least 6 weeks apart. In some embodiments, the episodic dosing regimens are spaced 6 weeks apart. In some embodiments, the episodic dosing regimens are spaced 7 weeks apart. In some embodiments, the episodic dosing regimens are spaced 8 weeks apart.

[0012] In some aspects, an episodic dosing regimen for treating major depressive disorder, bipolar depression, anxiety or postpartum depression is provided herein, the dosing regimen including dosing of Compound 1 to a subject in need thereof. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder. In some embodiments, about 10 mg, about 15 mg, about 20 mg, about 25 mg or about 30 mg of Compound 1 is administered to the subject. In some embodiments, Compound 1 is administered once daily for a plurality of weeks, e.g., about 2 weeks to about 6 weeks, e.g., about 2 weeks to about 4 weeks, e.g., about 2 weeks, for treating major depressive disorder, bipolar depression, anxiety or postpartum depression. In some embodiments, about 10 mg, about 15 mg, about 20 mg, about 25 mg or about 30 mg of Compound 1 is administered once daily to the subject for a plurality of weeks for treating major depressive disorder, bipolar depression, anxiety or postpartum depression. In a preferred embodiment, the episodic dosing regimen is carried out for about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen is carried out for about 2 weeks to about 4 weeks. Even more preferably, the episodic dosing regimen is carried out for about 2 weeks, i.e., about 14 days. In another embodiment, the episodic dosing regimen has a duration of 2 weeks.

[0013] In some aspects, methods for treating depression in a subject in need thereof are provided herein, the methods comprising administering to the subject an episodic dosing regimen of Compound 1. In some aspects, methods for treating postpartum depression in a subject in need thereof are provided herein, the methods comprising administering to the subject a once-daily episodic dosing regimen of 30 mg of Compound 1 for two weeks (or about 14 days). If the subject does not tolerate once-daily dosing of 30 mg of Compound 1, the subject is dosed once-daily with 20 mg of Compound 1. In some embodiments, the subject is a human female diagnosed with severe postpartum depression. In some embodiments, the subject has experienced major depressive episodes over a period of about one year. In some embodiments, the subject is about 18 to about 75 years old. In some embodiments, the subject is about 18 to about 65 years old.

[0014] The episodic dosing regimen of the present invention provides the advantage that it is not a chronic dosing regimen, unlike current treatments for depression, such as major depressive disorder (MDD). Thus, according to the present invention, a pharmaceutically effective amount of Compound 1 is administered in response to each episode of symptom occurrence. This episodic dosing regimen has the advantage of avoiding many of the disadvantages of current depression treatments since it does not require chronic dosing.

[0015] In another aspect, methods for treating depression in a subject in need thereof are provided herein, the methods comprising (i) administering to the subject once-daily for about two weeks a therapeutically effective amount of a compound having the formula

Chemical formula

[0016] In some embodiments, Compound 1 is administered to a subject for two weeks, i.e., 14 days. In some embodiments, Compound 1 is readministered to a subject for two weeks, i.e., 14 days. In some embodiments, the interval between the administration of Compound 1 to the subject and the readministration of Compound 1 to the subject is from 2 to 4 weeks. In some embodiments, the interval is 4 weeks. In some embodiments, the interval is 5 weeks. In some embodiments, the interval is 6 weeks. In some embodiments, the interval between the administration of Compound 1 to the subject and the readministration of Compound 1 to the subject is 7 weeks. In some embodiments, the interval between the administration of Compound 1 to the subject and the readministration of Compound 1 to the subject is 8 weeks.

[0017] In some embodiments, the depression is major depressive disorder (MDD). In some embodiments, the MDD is moderate major depressive disorder. In some embodiments, the MDD is severe major depressive disorder. In some embodiments, the depression is bipolar depression. In some embodiments, the depression is postpartum depression. In some embodiments, the subject is diagnosed with depression. In some embodiments, the depression is major depressive disorder or bipolar depression. In some embodiments, the subject is a female diagnosed with severe postpartum depression. In some embodiments, the subject has experienced a major depressive episode over a period of about one year. In some embodiments, the subject is about 18 to about 75 years old. In some embodiments, the subject is about 18 to about 65 years old.

[0018] In some embodiments, a method of treating major depressive disorder, bipolar depression, anxiety, or postpartum depression by administering Compound 1 improves cognitive function. In other embodiments, the method improves the cognitive function of a subject after completion of an episodic dosing regimen. In some aspects, the method improves the cognitive function of a subject after completion of an episodic dosing regimen that has a duration of about 2 to about 8 weeks. In further aspects, the method improves the cognitive function of a subject after completion of an episodic dosing regimen that has a duration of about 2 to about 6 weeks. In other embodiments, the method improves the cognitive function of a subject after completion of an episodic dosing regimen that has a duration of about 2 to about 4 weeks. In further embodiments, the method improves the cognitive function of a subject after completion of an episodic dosing regimen that has a duration of about 2 weeks or 14 days. In other aspects, the method improves the cognitive function of a subject after completion of an episodic dosing regimen that has a duration of 2 weeks.

[0019] In some embodiments, about 10 mg of Compound 1 is administered to a subject. In some embodiments, about 20 mg of Compound 1 is administered to a subject. In some embodiments, about 30 mg of Compound 1 is administered to a subject. In some embodiments, about 40 mg of Compound 1 is administered to a subject. In some embodiments, about 10 mg of Compound 1 is administered once daily to a subject. In some embodiments, about 20 mg of Compound 1 is administered once daily to a subject. In some embodiments, about 30 mg of Compound 1 is administered once daily to a subject. In some embodiments, about 40 mg of Compound 1 is administered once daily to a subject. In some embodiments, the amount of Compound 1 administered to a subject is decreased when severe adverse effects occur. In some embodiments, Compound 1 is administered at night. In some embodiments, Compound 1 is administered with food. In some embodiments, Compound 1 is in capsule form. In some embodiments, the method further comprises administering a second therapeutic agent.

[0020] In some aspects, a kit is provided herein that includes a pharmaceutical composition comprising Compound 1 and an instruction set for a method of treating depression using an episodic dosing regimen. In some embodiments, the pharmaceutical composition comprises about 10 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 15 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 20 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 25 mg of Compound 1. In some embodiments, the pharmaceutical composition comprises about 30 mg of Compound 1. In some embodiments, the episodic dosing regimen is carried out for about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen is carried out for about 2 weeks to about 4 weeks. In an even more preferred embodiment, the episodic dosing regimen is carried out for about 2 weeks. In a preferred embodiment, the episodic dosing regimen is carried out for 2 weeks. In some embodiments, the depression is major depressive disorder, bipolar depression, anxiety or postpartum depression. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder. In some embodiments, the episodic dosing regimen is carried out for about 2 weeks (or about 14 days) for the treatment of postpartum depression. In some embodiments, the instruction set is printed on a suitable material. In some embodiments, the individual dosage unit is a capsule or a tablet. In some embodiments, the individual dosage unit is a capsule. In some embodiments, the individual dosage unit is a size 1, 2, 3 or 4 capsule. In some embodiments, the capsule is size 1. In embodiments of the present invention, for example, the following items are provided. (Item 1) A method of treating depression in a subject in need thereof, the method comprising a therapeutically effective amount of a compound of the formula

Chemical formula

Chemical formula

[0021]

Figure 1

[0022]

Figure 2

[0023]

Figure 3

[0024]

Figure 4

[0025]

Figure 5

[0026]

Figure 6

[0027]

Figure 7

[0028]

Figure 8

[0029]

Figure 9

DETAILED DESCRIPTION OF THE INVENTION

[0030] DETAILED DESCRIPTION As generally described herein, the present invention provides compounds and compositions useful for the treatment of depression such as postpartum depression and major depressive disorder.

[0031] DEFINITIONS As used herein, the term "unit dosage form" is defined to refer to the form in which Compound 1 is administered to a subject. Specifically, the unit dosage form can be, for example, a pill, a capsule, or a tablet. Preferably, the unit dosage form is a capsule. A typical amount of Compound 1 in a unit dosage form useful in the present invention is from about 10 mg to about 100 mg, preferably from about 10 mg to about 50 mg (e.g., about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg).

[0032] In a preferred embodiment of the present invention, the unit dosage form contains about 30 mg of Compound 1 and is in the form of a capsule. In another preferred embodiment of the present invention, the unit dosage form contains about 45 mg of Compound 1 and is in the form of a capsule. In another preferred embodiment of the present invention, the unit dosage form contains about 20 mg of Compound 1 and is in the form of a capsule. In another preferred embodiment of the present invention, the unit dosage form contains about 10 mg of Compound 1 and is in the form of a capsule. In another preferred embodiment of the present invention, the unit dosage form contains about 15 mg of Compound 1 and is in the form of a capsule. In another preferred embodiment of the present invention, the unit dosage form contains about 25 mg of Compound 1 and is in the form of a capsule. Preferably, the capsule containing about 30 mg or 45 mg of Compound 1 is administered to the subject once a day. In some embodiments, three capsules are combined to contain 30 mg of Compound 1. In some embodiments, three capsules are combined to contain 45 mg of Compound 1.

[0033] As used herein, "solid dosage form" means a solid, e.g., a tablet, capsule, granule, powder, sachet, reconstitutable powder, dry powder inhaler, and chewable, for pharmaceutical dosages.

[0034] When the term "about" is used before a quantitative value, the present teachings include that particular quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a variation of ±10% from the nominal value, unless otherwise indicated or inferred.

[0035] The definitions of specific functional groups and chemical terms are described in detail below. Chemical elements are specified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Edition, inside front cover), and specific functional groups are generally defined as described therein. Further, the general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0036] "Pharmaceutically acceptable" means approved or approvable by a federal or state government regulatory agency, or the corresponding agency of a country other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals (more specifically, humans).

[0037] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic acid addition salts or organic acid addition salts and inorganic base addition salts or organic base addition salts. Specifically, such salts include (1) those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed when the acidic protons present in the parent compound are replaced by metal ions such as alkali metal ions, alkaline earth ions, or aluminum ions; or when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Examples of salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, salts of non-toxic organic acids or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion for an acidic functional group. Such cations are exemplified by sodium cation, potassium cation, calcium cation, magnesium cation, ammonium cation, tetraalkylammonium cation, etc.See, for example, Berge et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0038] A "subject" is a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or elderly adult)).

[0039] Diseases, disorders, and conditions are used interchangeably herein.

[0040] As used herein, unless otherwise specified, the terms "treat", "treating", and "treatment" are intended to mean an act (a "therapeutic treatment") that is performed while a subject is suffering from a particular disease, disorder or condition and that reduces the severity of, or delays or slows the progression of, the disease, disorder or condition, and also an act (a "preventive treatment") that is performed before a subject begins to suffer from a particular disease, disorder or condition.

[0041] Generally, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response, e.g., an amount sufficient to treat a CNS-related disorder, e.g., a disorder as described herein (e.g., tremor (e.g., essential tremor); depression (e.g., postpartum depression); or an anxiety disorder). As will be appreciated by those skilled in the art, the effective amount of the compounds of the invention may vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health status, and condition of the subject. The effective amount encompasses both therapeutic treatment and preventive treatment.

[0042] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with that disease, disorder or condition. A therapeutically effective amount of a compound means the amount of a therapeutic agent that provides a therapeutic benefit in the treatment of that disease, disorder or condition, either alone or in combination with other treatments. The term "therapeutically effective amount" can include an amount that improves the overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0043] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with that disease, disorder or condition, or to prevent its recurrence. A prophylactically effective amount of a compound means the amount of a therapeutic agent that provides a prophylactic benefit in the prevention of that disease, disorder or condition, either alone or in combination with other agents. The term "prophylactically effective amount" can include an amount that improves the overall prophylaxis, or enhances the prophylactic efficacy of another prophylactic agent.

[0044] As used herein, an "episodic dosing regimen" is a dosing regimen in which a compound or a composition comprising a compound is administered to a subject for a limited period of time in response to the diagnosis of a disorder or its symptoms, such as the diagnosis or symptoms of depression, major depressive disorder, bipolar depression, anxiety or postpartum depression. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder. In some embodiments, the compound is formulated as an individual dosage unit, each unit comprising Compound 1 and one or more suitable pharmaceutical excipients. In some embodiments, the episodic dosing regimen has a duration of multiple weeks, for example, about 8 weeks. In contrast to chronic dosing as defined herein, episodic dosing of a compound is carried out for a limited period of time, for example, about 2 weeks to about 8 weeks, in response to the diagnosis or recurrence of a disorder, such as depression, or its symptoms. In some embodiments, the episodic dosing is carried out once a day for multiple weeks, for example, about 2 weeks to about 6 weeks. In one embodiment, the episodic dosing has a duration of 2 weeks. In some embodiments, more than one episodic dosing regimen is administered to the subject, for example, two or more episodic regimens over the lifetime of the subject.

[0045] In some embodiments, administration of Compound 1 improves cognitive function. In some embodiments, cognitive function refers to a set of mental tasks and functions, including memory (e.g., semantic memory, episodic memory, procedural memory, priming memory, or working memory); orientation; language; problem solving; visual perception, construction, and integration; planning; organizational skills; selective attention; inhibitory control; and the ability to mentally manipulate information, but is not limited thereto. In one embodiment, cognitive function is one or more selected from the group consisting of memory (e.g., semantic memory, episodic memory, procedural memory, priming memory, or working memory); orientation; language; problem solving; visual perception, construction, and integration; planning; organizational skills; selective attention; inhibitory control; and the ability to mentally manipulate information. Measures of cognitive function include, for example, assessment tools designed to measure (a) general intelligence, (b) non-verbal intelligence, (c) achievement, (d) attention / executive function, (e) memory and learning, (f) visuomotor and motor function, and (g) language.

[0046] By using one or more of these established tests at two or more time points and comparing their results, any changes in cognitive function can be monitored, for example, over time or during treatment. The phrase "improves cognitive function" when referred to in this specification means a positive change in the subject's ability to perform symbolic operations, e.g., the ability to perceive, remember, form mental images, have clarity of thought, be aware, think logically, think, or judge. The positive change can be measured using any of the above tests at two or more opportunities, e.g., a first opportunity to measure baseline cognitive function and a second opportunity to measure cognitive function after a period (a period during which treatment may have occurred). Such assessment tools are well known in the art and include, for example, the assessment tools as described in Example 4 herein.

[0047] Pharmaceutical composition In one aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the invention (also referred to as the "active ingredient"), such as Compound 1, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0048] The pharmaceutical compositions provided herein can be administered by various routes, including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In a preferred embodiment, Compound 1 is administered orally to a subject.

[0049] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered is typically determined by a physician in light of the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0050] When used to prevent the occurrence of CNS disorders, the compounds provided herein can typically be administered to a subject at risk of developing the symptoms at the dosage levels described above, by and under the advice of a physician. Subjects at risk of developing certain symptoms generally include subjects having a family history of the symptoms or subjects identified by genetic testing or screening as being particularly susceptible to the development of the symptoms.

[0051] The pharmaceutical composition of the present invention can further be delivered using various dosing methods. For example, in certain embodiments, the pharmaceutical composition can be administered as a bolus, for example, for the purpose of raising the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the desired systemic level of the active ingredient throughout the body. For example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (e.g., by IV infusion) allows for a more rapid delivery, which rapidly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by IV infusion, to provide for the maintenance of a steady-state concentration of the active ingredient within the subject's body. Further, in still other embodiments, the pharmaceutical composition can first be administered as a bolus dose and then a continuous infusion can be carried out.

[0052] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, the compositions are provided in unit dosage forms that facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of the active material calculated to produce the desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight), and the remainder are various vehicles or excipients and processing aids useful for forming the desired dosage form.

[0053] The ingredients described above for compositions that can be administered orally, by injection, or locally are merely representative. Other materials as well as processing techniques, etc. are shown in Remington’s Pharmaceutical Sciences, 17th edition, 1985, Part 8, Mack Publishing Company, Easton, Pennsylvania (incorporated herein by reference).

[0054] The compounds of the present invention can be administered in sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0055] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharmaceutically acceptable salts are non-toxic acid addition salts, i.e., salts containing an anion that can be pharmacologically tolerated (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.).

[0056] Method of Use A method for treating postpartum depression, depression such as major depressive disorder, or anxiety such as generalized anxiety disorder in a subject is provided herein, the method comprising administering to the subject an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof.

[0057] Accordingly, in one aspect, provided herein is a method of treating depression such as postpartum depression or major depressive disorder, or anxiety such as generalized anxiety disorder, in a subject, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of Compound 1. In some embodiments, the subject is 18 years of age or older and 64 years of age or younger. In some embodiments, the subject is 18 years of age or older and 75 years of age or younger. In some embodiments, Compound 1 is administered with food. In some embodiments, the therapeutically effective amount of Compound 1 is 20 mg. In some embodiments, the therapeutically effective amount of Compound 1 is 10 mg. In some embodiments, the therapeutically effective amount of Compound 1 is 15 mg. In some embodiments, the therapeutically effective amount of Compound 1 is 25 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 30 mg. In some embodiments, the therapeutically effective amount of Compound 1 is about 45 mg. In some embodiments, Compound 1 is administered in one or more capsules. In some embodiments, the therapeutically effective amount is administered over three capsules. In some embodiments, the subject has no underlying condition. In some embodiments, the subject has an underlying condition.

[0058] In some aspects, provided herein is a method for treating a subject having depression or anxiety, the method comprising administering to the subject a pharmaceutical composition comprising Compound 1 using an episodic dosing regimen effective to treat depression in the subject. In some aspects, the dosing regimen has a duration of from about 2 weeks to about 8 weeks. In some other aspects, the dosing regimen has a duration of from about 2 weeks to about 6 weeks. In some other aspects, the dosing regimen has a duration of from about 2 weeks to about 4 weeks. In some other aspects, the dosing regimen has a duration of about 2 weeks. In some other aspects, the dosing regimen has a duration of about 2 weeks, i.e., about 14 days.

[0059] In some embodiments, about 10 mg of Compound 1 is administered once daily to a subject over multiple weeks. In some embodiments, about 15 mg of Compound 1 is administered once daily to a subject over multiple weeks. In some embodiments, about 20 mg of Compound 1 is administered once daily to a subject over multiple weeks. In some embodiments, about 25 mg of Compound 1 is administered once daily to a subject over multiple weeks. In some embodiments, 30 mg of Compound 1 is administered once daily to a subject. In some embodiments, 30 mg of Compound 1 is administered once daily to a subject, and if the subject does not show tolerance to 30 mg of Compound 1, then 20 mg of Compound 1 is administered once daily to the subject. In some embodiments, 30 mg of Compound 1 is administered once daily to a subject for about two weeks. In some embodiments, 30 mg of Compound 1 is administered once daily to a subject for about two weeks (or about 14 days), and if the subject does not show tolerance to 30 mg of Compound 1, then 20 mg of Compound 1 is administered once daily to the subject for about two weeks (or about 14 days). In some embodiments, 30 mg of Compound 1 is administered once daily to a subject for two weeks, and if the subject does not show tolerance to 30 mg of Compound 1, then 20 mg of Compound 1 is administered once daily to the subject for two weeks. In some embodiments, 30 mg of Compound 1 is administered once daily to a subject for at least two weeks (or about 14 days). In some embodiments, 30 mg of Compound 1 is administered once daily to a subject for two weeks (or about 14 days), and if the subject does not show tolerance to 30 mg of Compound 1, then 20 mg of Compound 1 is administered once daily to the subject for at least two weeks (or about 14 days). In some embodiments, 30 mg of Compound 1 is administered once daily to a subject for two weeks.

[0060] In some aspects, the method includes an episodic dosing regimen, and the method includes administering Compound 1 to a subject concurrently with an episode of a disorder being treated, such as an episode of a major depressive disorder, bipolar depression, anxiety (including generalized anxiety disorder) or postpartum depression, a major depressive disorder, bipolar depression, anxiety or postpartum depression. In some embodiments, the major depressive disorder is a moderate major depressive disorder. In some embodiments, the major depressive disorder is a severe major depressive disorder. In some embodiments, the major depressive disorder is a moderate major depressive disorder. In some embodiments, the major depressive disorder is a severe major depressive disorder. In some embodiments, the anxiety is generalized anxiety disorder.

[0061] In some embodiments, the subject shows a response to the episodic dosing regimen, and the response is indicated by a decrease of greater than or equal to about 50% in the HAM-D score from baseline.

[0062] In some embodiments, the subject is evaluated for recurrence of depressive symptoms. In some embodiments, the treatment method includes a plurality of episodic dosing regimens. In some embodiments, the episodic dosing regimens are spaced at least 6 weeks apart. In some embodiments, the episodic dosing regimens are spaced 6 weeks apart. In some embodiments, the episodic dosing regimens are spaced 7 weeks apart. In some embodiments, the episodic dosing regimens are spaced 8 weeks apart.

[0063] In some aspects, a method of treating postpartum depression in a subject in need thereof is provided herein, the method including administering to the subject an episodic dosing regimen of 30 mg of Compound 1 once daily for about 2 weeks (or about 14 days), and if the subject does not show tolerance to the administration of 30 mg of Compound 1 once daily, the subject is administered 20 mg of Compound 1 once daily.

[0064] In some embodiments, the method provides a treatment effect (e.g., as measured by a decrease in the Hamilton Depression Score (HAM-D)) within about 45, about 21, about 15, about 8, or about 3 days. In some embodiments, the treatment effect is a decrease in the HAM-D score from baseline at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days after initiation of dosing or episodic dosing). In some embodiments, the decrease in the HAM-D score from baseline is a decrease from severe (e.g., a HAM-D score of 24 or greater; or a score of 26 or greater) to symptom-free, i.e., remission of depression (e.g., a HAM-D score of 7 or less). In some embodiments, the decrease in the HAM-D score from baseline is a decrease from severe (e.g., a HAM-D score of 24 or greater; or a score of 26 or greater) to normal or mild depression (e.g., a HAM-D score of 7 or less; or a HAM-D score of 18 - 13).

[0065] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Montgomery-Åsberg Depression Rating Scale (MADRS)) within about 45, about 21, about 15, about 8, or about 3 days or less. The Montgomery-Åsberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (relating to outward sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, lassitude, inability to feel emotions, pessimistic thoughts, and suicidal thoughts) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders. 0-6 indicates normal / no symptoms; 7-19 indicates mild depression; 20-34 indicates moderate depression; >34 indicates severe depression. In some embodiments, the therapeutic effect is a decrease in the MADRS score from baseline at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days or less). In some embodiments, the decrease in the MADRS score from baseline is a decrease from severe (e.g., a MADRS score of 30 or more) to no symptoms (e.g., a MADRS score of 20 or less). For example, the average change in the total MADRS score from baseline by treatment with the compounds described herein is about -15, -20, -25, -30, and the average change in the total MADRS score from baseline by treatment with placebo is about -15, -10, -5.

[0066] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Clinical Global Impression - Improvement (CGI)) within about 45, about 21, about 15, about 8, or about 3 days or less. In some embodiments, the therapeutic effect is a CGI score of 2 or less.

[0067] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Hamilton Anxiety Score (HAM-A)) within about 45, about 21, about 15, about 8, or about 3 days. The HAM-A is scored such that <17 indicates mild severity, 18 - 24 indicates mild to moderate severity, and 25 - 30 indicates moderate to severe severity. In some embodiments, the therapeutic effect is a decrease in the HAM-A score from baseline at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days after starting administration or episodic dosing). In some embodiments, the decrease in the HAM-A score from baseline is a decrease from severe (e.g., a HAM-A score of 25 or greater) to symptom-free (e.g., a HAM-A score of 17 or less). In some embodiments, the decrease in the HAM-A score from baseline is a decrease from severe (e.g., a HAM-A score of 25 or greater) to mild (e.g., a HAM-A score of 24 or less).

[0068] In some embodiments, the instructions set describes a method that includes an episodic dosing regimen that is carried out for about 2 weeks to about 6 weeks. In some embodiments, the instructions set describes a method that includes an episodic dosing regimen that is carried out for about 2 weeks to about 4 weeks. In some embodiments, the instructions set describes a method that includes an episodic dosing regimen that is carried out for about 2 weeks, i.e., about 14 days. In some embodiments, the instructions set describes a method that includes an episodic dosing regimen that is carried out for 2 weeks.

[0069] In one embodiment, the instructions set is a printed instructions set.

[0070] In further embodiments, the Instructions set describes a method comprising an episodic dosing regimen, the method comprising administering Compound 1 to a subject concurrently with an episode of the disorder being treated. In some aspects, the Instructions set describes a method comprising an episodic dosing regimen, the method comprising administering Compound 1 to a subject concurrently with an episode of the disorder being treated, such as an episode of depression. In some aspects, the Instructions set describes a method comprising an episodic dosing regimen, the method comprising administering Compound 1 to a subject concurrently with an episode of the disorder being treated, such as an episode of depression. In some aspects, the Instructions set describes a method comprising an episodic dosing regimen, the method comprising administering Compound 1 to a subject concurrently with an episode of the disorder being treated, such as an episode of major depressive disorder, bipolar depression, anxiety or postpartum depression. In some embodiments, the major depressive disorder is a moderate major depressive disorder. In some embodiments, the major depressive disorder is a severe major depressive disorder.

[0071] In one aspect, a method of treating depression in a subject in need thereof is provided herein, the method comprising (i) administering to the subject, once daily for about two weeks, a therapeutically effective amount of a compound having the formula [Chemical formula] ; and (ii) re-administering to the subject, once daily for about two weeks, a therapeutically effective amount of Compound 1 in response to recurrence of depressive symptoms with the proviso that there is an interval of at least six weeks between the administration of Compound 1 to the subject and the re-administration of Compound 1 to the subject.

[0072] The six-week interval described above is understood to be the duration between the final dose of the administration of Compound 1 to the subject and the first dose of the re-administration of Compound 1 to the subject.

[0073] In some embodiments, Compound 1 is administered to a subject for two weeks. In some embodiments, Compound 1 is readministered to a subject for two weeks. In some embodiments, the interval between the administration of Compound 1 to the subject and the readministration of Compound 1 to the subject is six weeks. In some embodiments, the interval between the administration of Compound 1 to the subject and the readministration of Compound 1 to the subject is seven weeks. In some embodiments, the interval between the administration of Compound 1 to the subject and the readministration of Compound 1 to the subject is eight weeks.

[0074] In some embodiments, the depression is major depressive disorder (MDD). In some embodiments, the MDD is moderate major depressive disorder. In some embodiments, the MDD is severe major depressive disorder. In some embodiments, the depression is bipolar depression. In some embodiments, the depression is postpartum depression. In some embodiments, the subject is diagnosed with depression. In some embodiments, the depression is major depressive disorder or bipolar depression. In some embodiments, the subject is a female diagnosed with severe postpartum depression. In some embodiments, the subject has experienced a major depressive episode over a period of about one year. In some embodiments, the subject is about 18 to about 75 years old. In some embodiments, the subject is about 18 to about 65 years old.

[0075] In some embodiments, a subject is administered about 10 mg of Compound 1. In some embodiments, a subject is administered about 20 mg of Compound 1. In some embodiments, a subject is administered about 30 mg of Compound 1. In some embodiments, a subject is administered about 40 mg of Compound 1. In some embodiments, a subject is administered about 10 mg of Compound 1 once daily. In some embodiments, a subject is administered about 20 mg of Compound 1 once daily. In some embodiments, a subject is administered about 30 mg of Compound 1 once daily. In some embodiments, a subject is administered about 40 mg of Compound 1 once daily. In some embodiments, the amount of Compound 1 administered to the subject is decreased when severe adverse effects occur. In some embodiments, Compound 1 is administered at night. In some embodiments, Compound 1 is administered with food. In some embodiments, Compound 1 is in capsule form. In some embodiments, the method further comprises administration of a second therapeutic agent.

[0076] In one aspect, a method of treating a major depressive disorder in a subject in need of treatment for a major depressive disorder is provided herein, the method comprising (i) a first administration of a therapeutically effective amount of a compound of formula (I) once daily for 14 days to the subject:

Chemical formula

[0077] In one aspect, a method of treating postpartum depression in a subject in need of treatment for a major depressive disorder is provided herein, the method comprising (i) a first administration of a therapeutically effective amount of a compound of formula (I) once daily for 14 days to the subject: [Chem.] and (ii) a second administration of a therapeutically effective amount of Compound 1 to the subject once a day in response to recurrence of symptoms of major depressive disorder including, provided that there is an interval of at least 6 weeks between the final dose of the first administration of Compound 1 to the subject and the first dose of the second administration of Compound 1 to the subject.

[0078] In one aspect, a method of treating generalized anxiety disorder in a subject in need of treatment for major depressive disorder is provided herein, the method comprising (i) a first administration of a therapeutically effective amount of a compound of formula (I) to the subject once a day for 14 days: [Chem.] and (ii) a second administration of a therapeutically effective amount of Compound 1 to the subject once a day in response to recurrence of symptoms of major depressive disorder including, provided that there is an interval of at least 6 weeks between the final dose of the first administration of Compound 1 to the subject and the first dose of the second administration of Compound 1 to the subject.

[0079] In one aspect, a method of treating bipolar depression in a subject in need of treatment for major depressive disorder is provided herein, the method comprising (i) a first administration of a therapeutically effective amount of a compound of formula (I) to the subject once a day for 14 days: [Chem.] and (ii) a second administration of a therapeutically effective amount of Compound 1 to the subject once a day in response to recurrence of symptoms of major depressive disorder including, provided that there is an interval of at least 6 weeks between the final dose of the first administration of Compound 1 to the subject and the first dose of the second administration of Compound 1 to the subject. In some aspects, provided herein is a kit comprising an instruction set describing a method for treating major depressive disorder, bipolar depression, anxiety or postpartum depression by administering Compound 1, the method comprising an episodic dosing regimen. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder. In some embodiments, about 10 mg, about 15 mg, about 20 mg, about 25 mg or about 30 mg of Compound 1 is administered to the subject. In some embodiments, Compound 1 is administered once daily to the subject over a plurality of weeks, such as from about 2 weeks to about 6 weeks, such as from about 2 weeks to about 4 weeks, such as about 2 weeks. In some embodiments, about 10 mg, about 15 mg, about 20 mg, about 25 mg or about 30 mg of Compound 1 is administered once daily to the subject over a plurality of weeks. In a preferred embodiment, the episodic dosing regimen is carried out for about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen is carried out for about 2 weeks to about 4 weeks. In an even more preferred embodiment, the episodic dosing regimen is carried out for about 2 weeks, i.e., about 14 days. In another embodiment, the episodic dosing regimen is carried out for 2 weeks.

[0080] Also provided herein is a method of treating anxiety in a subject, the method comprising administering to the subject an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. Thus, in one aspect, provided herein is a method of treating anxiety in a subject, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of Compound 1. In some embodiments, the subject is 18 years of age or older and 64 years of age or younger. In some embodiments, the compound is administered with food. In some embodiments, the therapeutically effective amount is 20 mg. In some embodiments, the therapeutically effective amount is 10 mg. In some embodiments, the therapeutically effective amount is 15 mg. In some embodiments, the therapeutically effective amount is 25 mg. In some embodiments, the therapeutically effective amount is about 30 mg. In some embodiments, the therapeutically effective amount is about 45 mg. In some embodiments, Compound 1 is administered in one or more capsules. In some embodiments, the therapeutically effective amount is administered over three capsules.

[0081] In some embodiments, the anxiety is generalized anxiety disorder. Generalized anxiety disorder (GAD) is characterized by persistent and excessive worry about a variety of matters. People with GAD may anticipate disasters or worry excessively about money, health, family, work, or other problems. Individuals with GAD believe it is difficult to control their worry. Those individuals may worry more than seems warranted about actual events or anticipate the worst even when there is no obvious reason for concern.

[0082] In other embodiments, the anxiety is obsessive-compulsive disorder (OCD); panic disorder, post-traumatic stress disorder (PTSD) or social anxiety disorder. Obsessive-compulsive disorder, OCD, is an anxiety disorder characterized by repetitive, unwanted thoughts (obsessions) and / or repetitive behaviors (compulsions). People often perform repetitive behaviors such as washing their hands, counting, checking, or cleaning in the expectation of preventing or getting rid of the obsessive thoughts. However, performing these so-called "rituals" only provides temporary relief and the anxiety increases significantly if they are not performed. Panic disorder is also an anxiety disorder characterized by repeated episodes of intense fear, unexpected, and accompanied by physical symptoms that may include chest pain, palpitations, shortness of breath, dizziness or abdominal distress. Post-traumatic stress disorder, PTSD, is an anxiety disorder that can develop after exposure to a terrifying event or ordeal in which serious physical harm occurred or was threatened. Examples of traumatic events that can trigger PTSD include violent personal attacks, natural disasters or human-caused disasters, accidents or military combat. Social phobia or social anxiety disorder is an anxiety disorder characterized by overwhelming anxiety and excessive self-consciousness in everyday social situations. Social phobia may be limited to one type of situation, such as fear of speaking in formal or informal situations, or fear of eating or drinking in front of others. In its most severe form, it can be very extensive, with symptoms experienced almost constantly when other people are around.

[0083] Methods for treating major depressive disorder, bipolar depression, anxiety or postpartum depression using an episodic dosing regimen are provided herein, the method comprising the step of dosing a subject in need thereof with Compound 1. In some embodiments, the method results in no change in the cognitive function of the subject after completion of the episodic dosing regimen. In some embodiments, the method does not result in cognitive impairment or a change in cognitive function. In some embodiments, the method improves the cognitive function of the subject after completion of the episodic dosing regimen, the episodic dosing regimen having a duration of about 2 to about 8 weeks. In a further aspect, the method improves the cognitive function of the subject after completion of the episodic dosing regimen, the episodic dosing regimen having a duration of about 2 to about 6 weeks. In other embodiments, the method improves the cognitive function of the subject after completion of the episodic dosing regimen, the episodic dosing regimen having a duration of about 2 to about 4 weeks. In a further embodiment, the method improves the cognitive function of the subject after completion of the episodic dosing regimen, the episodic dosing regimen having a duration of about 2 weeks or 14 days. In another aspect, the method improves the cognitive function of the subject after completion of the episodic dosing regimen, the episodic dosing regimen having a duration of 2 weeks.

[0084] Methods for treating major depressive disorder, bipolar depression, anxiety or postpartum depression using an episodic dosing regimen are provided herein, the method comprising the step of dosing a subject in need thereof with Compound 1. In some embodiments, the method does not result in a change in the cognitive function of the subject after completion of the episodic dosing regimen. In some embodiments, the method does not result in cognitive impairment or a change in cognitive function.

[0085] In some other aspects, kits are described herein comprising a plurality of individual dosage units of a pharmaceutical composition comprising Compound 1 and an instruction set as described herein. In some embodiments, the instruction set describes a method for administering the pharmaceutical composition to a patient, the method comprising an episodic dosing regimen. In another embodiment, the invention 1. A plurality of individual dosage units of a pharmaceutical composition comprising Compound 1; and 2. A set of instructions for administering said dosage units to a patient in need thereof using an episodic dosing regimen comprising a kit.

[0086] In some embodiments, the set of instructions is printed on a suitable material such as paper. In some embodiments, the dosage unit is a capsule. In some embodiments, the unit dose or dosage unit includes pre-filled, pre-measured ampoules or syringes of a liquid composition, or in the case of a solid composition, pills, tablets, capsules, etc. In some embodiments, the dosage unit is a size 1 capsule. In other embodiments, the capsule is size 000, 00, 0, 1, 2, 3 or 4 as understood in the art.

Examples

[0087] Example 1: Compound 1 and Postpartum Depression Compound 1 was investigated for use in subjects with depression. Female subjects (18 - 65 years old) diagnosed with severe postpartum depression (PDD) having a HAM-D total score greater than or equal to 26 at screening and on day 1 were used in the study. The subjects were dosed once daily with a capsule containing 30 mg of Compound 1. If the subject did not show tolerance to the 30 mg dose, the dose could be adjusted to a capsule containing 20 mg of Compound 1. Subjects not dosed with Compound 1 were dosed with placebo. Overall, 78 subjects were treated with 30 mg of Compound 1 and 73 subjects were treated with placebo.

[0088] Statistics Assuming a two-sided test at the α level of 0.05, a sample size of approximately 65 evaluable subjects per treatment group provided 90% power to detect an approximately 4-point placebo-adjusted treatment difference in the change from baseline in the HAM-D total score on day 15, assuming a 7-point standard deviation (SD). The change in the HAM-D total score from baseline was analyzed using a mixed effects model for repeated measures (MMRM). This model included the change from baseline at each visit as the dependent variable. The primary comparison was the (least squares [LSMEAN] difference) between the compound 1 capsule and placebo at the 15-day time point.

[0089] For model-based point estimates (i.e., LSMEAN, 95% confidence interval, and p-value), the within-subject error was modeled using an unstructured covariance structure. If there were convergence problems with the unstructured covariance model, the Toeplitz, compound symmetry, or Autoregressive(1) (AR[1]) covariance structure was used in this order until convergence was achieved. If the model still did not converge to the AR(1) structure, the results were not reported. When the covariance structure was not UN, a sandwich estimator for the variance-covariance matrix was derived using the EMPIRICAL option in the PROC MIXED statement in SAS.

[0090] Similarly, MMRM was used for the analysis of the following variables: changes in the MADRS total score and HAM-A total score from baseline, as well as selected individual items and subscale scores. For each model, the comparison of interest was the comparison between the compound 1 capsule and the corresponding placebo at the 15-day time point. Model-based point estimates (i.e., LS means), 95% confidence intervals, and p-values were reported.

[0091] Results The results demonstrated that the primary endpoint was met. The mean decrease in the total HAM-D score from baseline was -18.0 (8.36) from a baseline mean of 28.4 (2.09) in subjects treated with compound 1 (30 mg) on day 15, and -13.6 (8.31) from a baseline mean of 28.8 (2.32) in subjects treated with placebo. The model-based difference between treatment groups on day 15 and the corresponding 95% confidence internal (CI) was -4.2 (-6.9, -1.5) in support of compound 1, with a p-value = 0.0029. Figure 1 shows the LS mean change in the total score of the Hamilton Depression Rating Scale (HAM-D) from baseline over time for each treatment group. Figure 2 shows a forest plot of the subgroup analysis for the primary endpoint on day 15. Figure 3 shows a bar graph of Hamilton Depression Rating Scale (HAM-D) remission by time point and treatment group. Figure 4 shows a bar graph of Hamilton Depression Rating Scale (HAM-D) remission by time point and treatment group.

[0092] The response rate and remission rate of HAM-D were significantly higher in subjects treated with compound 1 than in those treated with placebo: Response: 53 / 74 (71.6%) in subjects treated with compound 1 (30 mg) vs 35 / 73 (47.9%) in subjects treated with placebo. The model-based odds ratio and corresponding (95% CI) were 2.63 (1.34, 5.16), with a p-value = 0.0050. Remission: 33 / 74 (44.6%) in subjects treated with compound 1 (30 mg) vs 17 / 73 (23.3%) in subjects treated with placebo. The model-based odds ratio and corresponding (95% CI) were 2.50 (1.22, 5.11), with a p-value = 0.0122.

[0093] Change in the total MADRS score from baseline at day 15 and all other time points: The mean decrease in the MADRS total score from baseline was -22.0 (11.64) from a baseline of 34.9 (4.41) in subjects treated with Compound 1 (30 mg) on Day 15 and -17.7 (11.72) from a baseline of 36.3 (4.68) in subjects treated with placebo. The difference between the model-based treatment groups and the corresponding 95% confidence interval (CI) was -4.6 (-8.3, -0.8) in support of Compound 1, with a p-value = 0.0182. The results of this study are shown in Figure 5.

[0094] Change in the HAM-A total score from baseline at Day 15 and all other time points: The mean decrease in the HAMA total score from baseline was -16.5 (9.51) from a baseline mean of 26.1 (5.88) in subjects treated with Compound 1 (30 mg) on Day 15 and -12.9 (8.57) from a baseline of 27.2 (5.45) in subjects treated with placebo. The difference between the model-based treatment groups and the corresponding 95% confidence interval (CI) was -3.90 (-6.7, -1.1) in support of Compound 1, with a p-value = 0.0063. The results of this study are shown in Figure 6.

[0095] CGI-I response at Day 15: 53 / 74 (71.6%) in subjects treated with Compound 1 (30 mg) versus 38 / 73 (52.1%) in subjects treated with placebo. The model-based odds ratio and corresponding (95% CI) was 2.15 (1.09, 4.27) in support of Compound 1, with a p-value = 0.0280. The results of the study described herein are shown in Figure 7.

[0096] The above study demonstrated that Compound 1 (exemplary episodic dosing regimen) administered once daily at 30 mg for 15 days was effective in the treatment of postpartum depression compared to placebo.

[0097] Example 2: Open-Label, 1-Year, Phase 3 Trial of the Safety, Tolerability, and Need for Retreatment with Compound 1 in Adult Subjects with Major Depressive Disorder (MDD) List of Abbreviations ADT Antidepressant Therapy AE Adverse Event CGI-I Clinical Global Impression - Improvement CGI-S Clinical Global Impression - Severity CS Clinically Significant C-SSRS Columbia Suicide Severity Rating Scale CYP Cytochrome P450 DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th Edition ECG Electrocardiogram eCRF Electronic Case Report Form EOT End of Treatment ET Early Termination FSH Follicle-Stimulating Hormone GABA Gamma-Aminobutyric Acid HAM-D Hamilton Depression Rating Scale HCV Hepatitis C Virus HIV Human Immunodeficiency Virus ICF Informed Consent Form IRB Institutional Review Board IRT Interactive Response Technology ISI Insomnia Severity Index MADRS Montgomery-Asberg Depression Rating Scale MDD Major Depressive Disorder MDE Major Depressive Episode NCS Not Clinically Significant PHQ-9 9-Item Patient Health Questionnaire PK Pharmacokinetics PSQ Patient Status Questionnaire QTcF QT Corrected According to Fridericia's Formula SAE Serious Adverse Event SAP Statistical Analysis Plan SCID-5-CT Structured Clinical Interview for DSM-5 Clinical Trial Version SD Standard Deviation SDS Severe Impairment Scale SUSAR Suspected Unexpected Serious Adverse Reaction TEAE Treatment-Emergent Adverse Event WHO World Health Organization

[0098] Overall Study Design Compound 1 was investigated in an open-label, long-term longitudinal study in adult subjects with MDD who were currently experiencing a major depressive episode (MDE). See Figure 8 for a schematic diagram of the study design.

[0099] The diagnosis of MDD was made according to the Structured Clinical Interview for DSM-5 Clinical Trials Version (SCID-5-CT) performed by qualified healthcare professionals. At the time of the screening visit, the subjects were evaluated in preliminary screening procedures such as the completion of the MADRS and CGI-S to determine eligibility.

[0100] The primary objective of this study was as follows: To determine the safety and tolerability of initial treatment and retreatment with Compound 1 in adults with MDD who were currently experiencing a major depressive episode (MDE) over a one-year period.

[0101] The secondary objectives of this study were as follows: To evaluate the need for retreatment with Compound 1 after initial treatment in adults with MDD who were currently experiencing MDE over a one-year period, and to evaluate the response to initial treatment with Compound 1 and the response to retreatment after the first two-week treatment period (exemplary episodic dosing regimen) in adults with MDD who were currently experiencing MDE over a one-year period.

[0102] The exploratory objectives of this trial were as follows: to develop a digital phenotype of adults with MDD who are currently experiencing an MDE and to evaluate potential correlations with clinical endpoints; to evaluate the effect of Compound 1 on sleep; and to evaluate patient-reported outcome measures as they relate to the impact of depression on the subject's life, the severity of depression, functionality, the subject's expectations regarding symptoms, and the subject's satisfaction with Compound 1.

[0103] The primary endpoints of this trial were as follows: the number and severity of AEs / SAEs; changes in clinical laboratory measures, vital signs, and electrocardiograms (ECGs) from baseline; and the safety and tolerability of initial treatment with Compound 1 and retreatment with Compound 1 as evaluated by scales including suicidal ideation and suicidal behavior (using the Columbia Suicide Severity Rating Scale (C-SSRS)).

[0104] The secondary endpoints of this trial were as follows: the need for retreatment with Compound 1 as evaluated by time to first retreatment (Kaplan-Meier curve); the number of subjects who achieved the criteria for retreatment; and the number of cycles of retreatment for each subject. Response to initial treatment and / or retreatment as evaluated by change in the 17-item HAM-D total score from baseline at the end of each 14-day treatment (initial treatment and / or retreatment) period; HAM-D response defined as a ≥50% decrease in the HAM-D score from baseline at the end of each 14-day treatment (initial treatment and / or retreatment) period; HAM-D remission defined as a HAM-D total score of ≤7 at the end of each 14-day treatment (initial treatment and / or retreatment) period; CGI-I response defined as "much improved" or "very much improved" at the end of each 14-day treatment (initial treatment and / or retreatment) period (also referred to as an exemplary episodic dosing regimen); and change in the Clinical Global Impression-Severity (CGI-S) score from baseline at the end of each 14-day treatment (initial treatment and / or retreatment) period.

[0105] The exploratory endpoints of this trial were as follows: digital phenotypes developed by passive collection of basic behavioral data (e.g., GPS, text / phone use, movement activity / sleep patterns) in subjects who consented to the use of a mobile phone-compatible software application; the effect of Compound 1 on sleep, as evaluated by the Insomnia Severity Index (ISI); the time to the first use of a new ADT (Kaplan-Meier curve) and the number of new ADTs used; depressive symptoms reported by patients, as evaluated by the 9-item Patient Health Questionnaire (PHQ-9); functionality reported by patients, as evaluated by the Sheehan Disability Scale (SDS); and the impact of depression reported by patients, as well as the expectations and satisfaction by patients, as evaluated by the Patient Status Questionnaire (PSQ).

[0106] The subject participation period was approximately 56 weeks: a screening period (28 days), an initial treatment period (14 days, or an exemplary episodic dosing regimen), a follow-up period (14 days), and an observation period (48 weeks). During the 48-week observation period, an additional 14-day retreatment period (or episodic dosing regimen) with Compound 1 may have been conducted.

[0107] All subjects were administered a single daily oral dose of Compound 1 from Day 1 to Day 14 of the first treatment cycle. Compound 1 was administered during the subsequent 14-day treatment period (readministration or additional episodic dosing regimen) following the recurrence, relapse, or reappearance of depressive symptoms.

[0108] Subjects who achieved efficacy with Compound 1 were followed for 48 weeks Starting on Day 1, eligible subjects self-administered 30 mg of Compound 1 once daily, orally, at night, for 14 days. Fourteen (±1) days after the completion of the 14-day treatment period, a follow-up visit was conducted.

[0109] If the subject did not show a response defined as a ≥ 50% decrease in the HAM-D score from baseline to Compound 1 by the 15th day of initial treatment, the subject terminated the trial at the end of the 14-day follow-up period.

[0110] After the initial treatment period, naturalistic follow-up of the subjects was conducted for 48 weeks. The subjects returned to the facility every 8 weeks during the 48-week observation period for clinical evaluation (starting after the first follow-up period).

[0111] Treatment cycle of Compound 1 Each 14-day treatment period of Compound 1 and the corresponding 14-day follow-up period were considered one cycle (28 days). The initial treatment was Cycle 1, and retreatments were numbered sequentially. Each cycle started on Day 1 (e.g., the first day of the first retreatment period was Day 1 of Cycle 2). A maximum of 5 treatment cycles were allowed; no new retreatment cycles were started after Week 48. Subjects who started a new treatment cycle of Compound 1 between Week 45 and Week 48 were followed until the end of the treatment cycle (Day 28, end of the follow-up period of the treatment cycle).

[0112] The need for retreatment was evaluated remotely every 14 days based on the results of the PHQ-9 reported by the subjects during the 48-week observation period; if the PHQ-9 score was ≥ 10, the subject returned to the facility to receive an evaluation by HAM-D performed by a clinician. For subjects with a PHQ-9 score ≥ 10 and a HAM-D score ≥ 20 evaluated approximately one week from the PHQ-9 score, a new cycle of Compound 1 was started.

[0113] A period or interval of at least 8 weeks (56 days) was required between treatment cycles of Compound 1. This is based on the 8-week period to establish "full remission" of a depressive episode (American Psychiatric Association 2013) and is consistent with the treatment period that may be required for any available antidepressant drug (ADT) to show maximum efficacy.

[0114] Since this was the first study to examine long-term retreatment with Compound 1, the potential for withdrawal-related events, including seizures, was monitored based on the known withdrawal symptoms with other GABAergic agents and the nonclinical findings of the 9-month study of Compound 1 in dogs (Investigational Medicinal Product Brochure).

[0115] Packaging and Labeling of the Investigational Medicinal Product Compound 1 was provided to the clinical pharmacist and / or designated site staff responsible for the preparation of the investigational medicinal product as a properly labeled subject-specific kit containing sealed unit doses. Each unit dose consisted of 1 capsule.

[0116] Administration of the Investigational Medicinal Product Compound 1 was administered orally once daily at night with food. Practical options included taking Compound 1 within 1 hour of dinner or taking Compound 1 late at night with a solid meal. If a subject missed a dose, the subject skipped that dose (i.e., should not take that dose in the morning) and took the next scheduled dose the following night.

[0117] Since this was the first study to examine long-term retreatment with Compound 1, the potential for withdrawal-related events, including seizures, was monitored based on the known withdrawal symptoms with other GABAergic agents and the nonclinical findings of the 9-month study of Compound 1 in dogs (Investigational Medicinal Product Brochure), which included discontinuation or dose reduction of the investigational medicinal product.

[0118] At any time, if a subject showed suicidal tendencies, the subject returned to the site as soon as possible for evaluation by the study physician.

[0119] The evaluations for the screening period, treatment period, and follow-up period are summarized in Table 1; the evaluations for the observation period and any unscheduled visits are summarized in Table 2.

Table 1-1

Table 1-2

[0120]

Table 2

[0121] Justification of the dose The dose level of 30 mg per day in this trial was an effective dose level in subjects with MDD and was a dose level with good tolerance in the Phase 2 trial. A dose adjustment to 20 mg of Compound 1 was permitted; Compound 1 at 20 mg was expected to have good tolerance as it was lower than the maximum tolerated dose level. Sedation / somnolence was observed in previous clinical trials administered in the morning, and in this trial, Compound 1 was administered at night due to the improved tolerance when administered at night.

[0122] According to the DSM-5, a period of 8 weeks is required to establish a “full remission” of a depressive episode (American Psychiatric Association 2013). Furthermore, available antidepressant therapy (ADT) is often conducted for up to 8 weeks to achieve maximum effectiveness. Therefore, a minimum period of 8 weeks (56 days) was required between the end of the 14-day treatment period and the start of a new Compound 1 treatment cycle.

[0123] Dose adjustment criteria At any time point, if a subject showed no tolerance to 30 mg of Compound 1 as evaluated by the occurrence of a serious AE determined by the investigator to be related to the investigational drug, the dose was reduced to 20 mg as soon as possible and that dose was continued for the remaining treatment period. Dose adjustments related to moderate AEs were determined by the investigator. If the investigator considered a dose adjustment from 30 mg to 20 mg necessary, the subject returned to the facility to have the adjusted dose dispensed. Regardless of whether the subject required a dose adjustment during the previous treatment period, any retreatment period started at a dose of 30 mg. Subjects who showed no tolerance to the 20 mg dose at any point discontinued the investigational drug and the subject ended the trial at the completion of the subsequent 14-day follow-up period.

[0124] Subject inclusion criteria Eligible subjects met all of the following criteria: 1. Subjects who signed the ICF before any study-specific procedures were performed. 2. Subjects who are male or female, aged 18 to 75 years (inclusive). 3. Subjects who are in good physical health and have no clinically significant findings in physical examination, 12-lead ECG, or clinical laboratory tests when measured by the responsible investigator. 4. Subjects who have consented to comply with the requirements of the study. 5. Subjects who have received a diagnosis of MDD, where the MDD is diagnosed by SCID-5-CT and the symptoms have been present for at least 4 weeks. 6. Subjects who have a MADRS total score of ≥28 at screening and on Day 1 (before dosing). 7. Subjects who are taking antidepressants used to treat major depressive disorder and have taken these drugs at the same dose for at least 60 days prior to Day 1. 8. Female subjects who are not postmenopausal (defined as 12 months of amenorrhea without other medical causes, confirmed by follicle-stimulating hormone [FSH] >40 mIU / mL), have not been surgically rendered infertile (hysterectomy or bilateral oophorectomy), or, if involved in a sexual relationship with a risk of pregnancy, have consented to use one of the following contraceptive methods during the study and for 30 days after the last dose of the study drug: combined (estrogen- and progestogen-containing) oral, vaginal, or transdermal hormonal contraception related to ovulation inhibition; hormonal contraception with oral, injectable, or implantable progestogen only related to ovulation inhibition; intrauterine contraceptive device; intrauterine hormone-releasing system; bilateral tubal ligation / occlusion; vasectomized partner; abstinence (no sexual intercourse). 9. Male subjects who, if involved in a sexual relationship with a risk of pregnancy, have consented to use an effective and acceptable contraceptive method during the study period and for 5 days after receiving the last dose of the study drug. When the female partner may be at risk of pregnancy, effective and acceptable contraceptive methods for the male include abstinence, vasectomy, or a condom with spermicide used with a highly effective female contraceptive method (see Incorporation Criteria #8 for acceptable contraceptive methods). 10. Male subjects who intended to refrain from sperm donation during the test period and for 5 days after receiving the last dose of the test drug. 11. Subjects who agreed to refrain from drug abuse and alcohol during the test period.

[0125] Exclusion Criteria for Subjects Subjects who met any of the following criteria were not eligible to participate in this study: 1. Subjects who had attempted suicide during the current episode of MDD. 2. Subjects with a recent history or clinically significant manifestation of active metabolic disorders, liver disorders, kidney disorders, blood disorders, lung disorders, cardiovascular disorders, gastrointestinal disorders, musculoskeletal disorders, skin disorders, urogenital disorders, neurological disorders or eye disorders, ear disorders, nasal disorders and throat disorders or any other acute or chronic conditions (in the opinion of the investigator, those that may limit the subject's ability to complete or participate in this clinical trial). 3. Subjects who had treatment-resistant depression defined as persistent depressive symptoms despite treatment with at least 4 weeks of adequate doses of two different classes of antidepressants (excluding antipsychotics) within the current major depressive episode. The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire was used for this purpose. 4. Subjects who had received vagus nerve stimulation, electroconvulsive therapy, or had taken ketamine within the current major depressive episode. 5. Subjects who had taken benzodiazepines, barbiturates or GABAA modulators (e.g., eszopiclone, zopiclone, zaleplon and zolpidem) on Day - 28, or had used these drugs daily or almost daily (≥4 times per week) for more than 1 year. 6. Subjects who had taken non - GABA hypnotics (e.g., melatonin, Benadryl [antihistamine], trazodone, low - dose quetiapine, mirtazapine, etc.) and / or atypical antipsychotics (e.g., aripiprazole, quetiapine) on Day - 14. 7. Subjects with known allergies to Compound 1, allopregnanolone or related compounds. 8. Subjects who had a positive pregnancy test on the day of screening or on the first day before the start of administration of the investigational drug in any treatment cycle. 9. Subjects who were breastfeeding at the time of screening or on the first day (before administration of the investigational drug) and who did not consent to temporarily discontinue breastfeeding their child from immediately before administration of the investigational drug on the first day until 7 days after the last dose of the investigational drug in each treatment cycle. 10. Subjects in whom hepatitis B surface antigen, anti-hepatitis C virus (HCV), and positive HCV viral load, or human immunodeficiency virus (HIV) antibodies were detectable at the time of screening. 11. Subjects who had a clinically significant abnormal 12-lead ECG at the time of screening or at the baseline visit. Note: An average QT interval (QTcF) calculated using the Fridericia method of >450 msec for males or >470 msec for females was used as the basis for exclusion from the study. 12. Subjects who had active psychosis according to the assessment of the study physician. 13. Subjects with a history of seizures. 14. Subjects with a history of bipolar disorder, schizophrenia, and / or schizoaffective disorder. 15. Subjects who had a history of mild, moderate, or severe substance use disorder (including benzodiazepines) diagnosed using DSM-5 criteria during the 12 months prior to screening. 16. Subjects who had ingested chronic or episodic psychostimulants (e.g., methylphenidate, amphetamine) or opioids on day - 28. 17. Subjects who had been exposed to another investigational drug or investigational device within 30 days prior to screening. 18. Subjects who had previously participated in a clinical trial of compound 1 or brexanolone. 19. Use of any known potent inhibitor of cytochrome P450 (CYP) 3A4 within 28 days or within 5 half-lives (whichever is longer) before the first dose of the test article in any compound 1 treatment cycle, or consumption of grapefruit juice, grapefruit or pomelo or products containing these within 14 days before the first dose of the test article in any compound 1 treatment cycle. 20. Use of the following potent CYP3A4 inducers within 28 days before the first dose of the test article in any compound 1 treatment cycle: rifampin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John's wort. 21. Subjects with a positive drug screening and / or alcohol screening on the day of screening or on day 1 before dosing in the initial treatment cycle. 22. Subjects who had a planned elective surgery during the initial treatment period and during the follow-up period. 23. Subjects diagnosed with and / or treated for any type of cancer (excluding basal cell carcinoma and in situ melanoma) within the past 1 year before screening. 24. Subjects with a history of sleep apnea. 25. Subjects who have had gastric bypass surgery, have a sleeve gastrectomy or lap band, or have had any related procedure that impedes gastrointestinal passage.

[0126] Withdrawal criteria for subjects Subjects could withdraw from the test article or terminate the study for any reason at any time. The investigator could withdraw the subject from the test article or the study for any of the following reasons: the subject was not willing or unable to comply with the protocol; the subject experienced intolerable AEs; other medical or safety reasons at the discretion of the investigator and / or medical monitor.

[0127] If the subject withdrew from the investigational drug or terminated the trial for any reason, the investigator immediately notified the sponsor and / or the medical monitor. The reason was recorded in the subject's electronic case report form (eCRF).

[0128] If the subject did not comply with the medication throughout, the investigator discussed with the sponsor the possibility of withdrawing the subject from the trial. Reasons for lack of intention or inability to comply with the protocol (missed visits, interference with the investigational drug administration schedule, unauthorized medications, etc.) were recorded in the subject's eCRF.

[0129] Subjects whose trials were terminated due to an AE, regardless of the causality determined by the investigator, were followed until the event resolved, until stable, or until the event determined by the investigator was no longer clinically significant.

[0130] Subjects who discontinued the investigational drug early during the treatment period returned to the facility for the end-of-treatment (EOT) visit as soon as possible, preferably on the day after discontinuing treatment. Telephone follow-up and remote assessments were conducted 14 days after the last dose of treatment. Thereafter, the subjects continued the planned observation period (Table 2).

[0131] If the subject decided to terminate the trial at any point during the follow-up or observation period, the subject contacted the facility and completed a remote assessment as an early termination (ET) visit. If the subject discontinued the investigational drug and terminated the trial on the same day during the treatment period, the ET visit was on the same day as the EOT visit; in this case, all events scheduled for the EOT visit were conducted.

[0132] After attempts to contact the subject failed, the subject was considered lost to follow-up.

[0133] Withdrawal criteria for each subject This study was the first to examine the long-term retreatment with Compound 1. Based on the known withdrawal symptoms with other GABAergic agents and the non-clinical findings of the 9-month study of Compound 1 in dogs (Investigational Medicinal Product Brochure), there was a potential for withdrawal-related events including seizures. To support the safety of the subjects, the following guidelines for discontinuation or dose reduction of the investigational medicinal product were presented: (1) Any subject who reported the confirmation or suspicion of a seizure at any time was withdrawn from treatment and was not eligible to receive another treatment cycle, but was followed up in this study; (2) After the first treatment period, the study physicians monitored the course of CNS-based signs and symptoms suggestive of seizures not explained by co-existing mental or medical conditions. Reported examples of serious or critical events that may reflect future risk and / or high risk for seizures included transient confusion, tremors, involuntary myoclonic contractions or spasms of the arms or legs, or perceptual abnormalities. If such symptoms occurred, the study physicians consulted with the Sage Medical Monitor and considered reducing the dose of the investigational medicinal product by up to 20 mg, stopping the treatment to evaluate the effect on those symptoms (e.g., resolution, improvement, etc.), or withdrawing the subject from the treatment. Subjects withdrawn from treatment remained in the study and continued the protocol-required evaluations until the end of the study.

[0134] Since this study was an open-label study, any serious or critical events, including the assessment of the benefit / risk profile of Compound 1 in the context of this study, were continuously evaluated. As a result, the sponsor amended or terminated the study.

[0135] Previous Therapeutic and Concomitant Medications and / or Supplements The start and end dates, route, dose / unit, frequency, and indication of all medications and / or supplements taken within 30 days prior to screening and throughout the study period were recorded. In addition, antidepressant treatments received in the 3 years prior to screening were recorded.

[0136] Any medications and / or supplements determined to be necessary for the well-being of the subject were given at the discretion of the investigator at any point during the trial.

[0137] If the subject intended to continue a stable dose throughout the initial treatment period and follow-up period (up to day 28 of cycle 1), antidepressants that had been taken at the same dose for at least 60 days prior to day 1 were permitted.

[0138] For psychotropic medications permitted for co-administration during each period of the trial, see Table 3.

[0139] Drug use for depressive symptoms that worsen after the compound 1 treatment cycle For subjects who achieved remission or response on day 15 (78.6%), 6.1% had a HAM-D of ≥22 on day 42; another 18.2% had a HAM-D score of 16 - 21 on day 42. This suggests that most subjects who are at risk of experiencing a new MDE can have this experience after reaching the minimum required period (8 weeks or 56 days) before a new compound 1 treatment cycle. Thus, most subjects were eligible for the compound 1 treatment cycle when needed (i.e., a PHQ-9 of ≥10 and a HAM-D of ≥20 were confirmed over a 2-week period); a 2-week period was required to establish a new MDE (DSM-5).

[0140] For subjects who developed depressive symptoms after day 28 and were no longer eligible for a new compound 1 treatment cycle, there were two intervention options: rescue medication (limited to a maximum of 4 days per week) and / or introduction of a new ADT or an increase in the dose of the current ADT (Table 3). To maintain clinical equivalence across all ADT use (i.e., new compound 1, new ADT, or an increase in the dose of the current ADT), a requirement was needed that ≥10 PHQ-9 and ≥20 HAM-D be confirmed over 2 weeks in all ADT use conditions. For subjects receiving stable ADT who developed depressive symptoms (PHQ-9 ≥10), if the HAM-D score was <20, it was recommended to use rescue medication only; if the HAM-D score was ≥20, the current dose was increased or a new ADT was introduced. Additionally, clinicians considered the individual subject's initial experience with compound 1 when starting any new ADT. This is because that initial experience could substantially reduce the likelihood that the subject could become eligible for a new compound 1 treatment cycle (i.e., the HAM-D could become <20) if time permitted. There were no PHQ-9 or HAM-D score requirements for rescue medication use.

[0141] Rescue medications permitted for symptom management included benzodiazepines, GABA modulators for insomnia (e.g., eszopiclone, zopiclone, zaleplon, and zolpidem), and non-GABA treatments for insomnia; the use of such treatments should be limited to a maximum of 4 days per week.

[0142] If a subject continued to show a HAM-D of ≥20 after rescue medication and / or introduction of a new ADT or an increase in the dose of the current ADT, a new compound 1 treatment cycle could be started on day 70 or later. After completion of the new compound 1 cycle, continued use of any intervention used during the previous observation period was at the discretion of the investigator.

[0143] The use of any benzodiazepine and / or GABA-modulating agent during the observation period was discontinued 7 days prior to any new compound 1 treatment cycle. The use of short-acting non-GABA-modulating agents was discontinued 1 day prior to any new compound 1 treatment cycle.

[0144] Female subjects were permitted to use agents intended for contraception.

Table 3

[0145] Example 3: Phase 3 randomized double-blind placebo-controlled trial on the efficacy and safety of compound 1 using a fixed repeated treatment regimen for relapse prevention in adults with major depressive disorder (MDD) This trial was a randomized double-blind placebo-controlled trial after the open-label period. This trial evaluated the effect of monotherapy with Compound 1 in a fixed repetitive treatment regimen for relapse prevention in adults with MDD (Montgomery-Åsberg Depression Rating Scale [MADRS] ≥ 32, Hamilton Depression Rating Scale [HAM-D] ≥ 22) who were not currently taking antidepressants, compared with placebo. Refer to Figure 9 for a schematic diagram of the study design.

[0146] The planned duration for subjects to participate was up to 52 weeks, including a screening period (up to 4 weeks), an open-label (OL) period (8 weeks), and a double-blind (DB) period (40 weeks).

[0147] The screening period (Table 4) started with the signature of the informed consent form (ICF); the signature of the ICF was done before any screening activities began. The diagnosis of MDD was made according to the Structured Clinical Interview for DSM-5 Clinical Trials Version (SCID-5-CT) by a qualified healthcare professional. Subjects underwent preliminary screening procedures (including completion of the MADRS and CGI-S) at the time of the screening visit and were determined to be eligible.

[0148] Starting on Day 1 of the OL period, eligible subjects self-administered a single dose of the study drug once daily at night with food on an outpatient basis for 14 consecutive days. The actual options included taking Compound 1 within 1 hour of dinner or taking Compound 1 late at night with a solid meal. Subjects returned to the study center during the OL treatment and follow-up periods as outlined in Table 5.

[0149] Subjects who completed the OL period (up to day 56) without significant tolerance problems as judged by the treating physician and showed HAM-D response defined as a ≥50% decrease in the total HAM-D score from baseline at visits 4, 6, 7, and 8 (see Table 5) were eligible for the DB period. One deviation of <50% decrease in the total HAM-D score from baseline at visit 6, 7, or 8 was allowed for eligibility for the DB period.

[0150] Starting from day 1 of the DB period, eligible subjects were randomized in a 1:1 ratio to receive 30 mg of Compound 1 or the corresponding placebo. The 40-week DB period consisted of five 14-day treatment periods, each separated by a 6-week follow-up period; the end of each follow-up period coincided with the first visit of the next treatment period. During the 14-day treatment period, subjects self-administered a single dose of the test drug once daily, at night, with food, on an outpatient basis. Subjects returned to the test center during the DB treatment period and during the follow-up period as outlined in Table 5.

[0151] During the follow-up period of the DB period, depressive symptoms were monitored every 7 days by the remote PHQ-9; if the PHQ-9 score was ≥10, the subject returned to the facility as soon as possible for evaluation by the treating physician using the HAM-D (Table 6). If the HAM-D was ≥18 at this visit, the subject returned to the facility 7 - 14 days later for re-evaluation using the HAM-D (Table 6); if the HAM-D remained ≥18, the subject was considered to have relapsed. Subjects were considered to have relapsed if there was an exacerbation of depression requiring hospitalization, a risk of suicide determined by the treating physician, and / or any other clinically relevant event not requiring hospitalization. During the DB period, subjects determined by the treating physician to have relapsed terminated the study at the completion of the early termination (ET) visit; if a subject was determined to have relapsed during the treatment period, that subject made an end-of-treatment (EOT) visit as soon as possible and an ET visit 7 days after the EOT visit. The final determination of relapse was made by the Independent It was conducted by the Relapse Adjudication Committee (IRAC).

[0152] At any time during the trial, if a subject showed intolerance to 30 mg of Compound 1 as evaluated by the occurrence of a serious AE determined by the investigator to be related to the investigational drug, the dose was reduced to 20 mg and the remaining treatment period continued at that dose. Dose adjustments related to moderate AEs were at the discretion of the investigator. Regardless of whether the subject required dose adjustment during the previous treatment period, subsequent treatment periods started at a dose of 30 mg. Subjects who were unable to show tolerance to a dose of 20 mg at any point terminated the trial as soon as possible upon completion of the EOT visit and had an ET visit 7 days later.

[0153] The primary objective of this trial was to evaluate the efficacy of Compound 1 using a fixed repeat treatment regimen in the prevention of relapse in subjects with major depressive disorder (MDD) who responded to OL treatment with Compound 1.

[0154] The secondary objective of this trial was to evaluate the long-term safety and tolerability of a fixed repeat treatment regimen of Compound 1 for up to 1 year.

[0155] Other objectives of this trial were to compare the efficacy of Compound 1 using a fixed repeat treatment regimen to placebo on work loss and activity loss and health-related quality of life in subjects with MDD, and to evaluate the pharmacokinetics (PK) of Compound 1 using a population PK approach.

[0156] The primary endpoint of this trial was the time (in days) to the first relapse during the DB period; [date] from the first dose of the investigational drug in the DB period to relapse during the DB period.

[0157] The secondary endpoints of this trial were as follows: percentage of subjects who relapsed during the DB period, change in the total score of the 17-item HAM-D from baseline at the end of each 14-day treatment period during the DB period, HAM-D response at the end of each 14-day treatment period during the DB period, defined as a ≥50% decrease in the HAM-D score from baseline, HAM-D remission at the end of each 14-day treatment period during the DB period, defined as a total HAM-D score of ≤7, CGI-I response at the end of each 14-day treatment period during the DB period, defined as "much improved" or "very much improved", change in the Clinical Global Impression-Severity (CGI-S) score from baseline at the end of each 14-day treatment period during the DB period, change in the score of the 9-item Patient Health Questionnaire (PHQ-9) from baseline at the end of each 14-day treatment period during the DB period, time (days; from the first dose of the study drug during the DB period to relapse during the DB period [date]) to the first relapse during the DB period for subjects who achieved HAM-D remission during the OL period, and the incidence and severity of treatment-emergent adverse events (TEAE).

[0158] The other endpoints of this trial were as follows: changes in clinical laboratory measures, vital signs, and electrocardiogram (ECG) from baseline; changes in suicidal ideation and suicidal behavior from baseline (using the Columbia-Suicide Severity Rating Scale (C-SSRS)); assessment of withdrawal symptoms as measured by a physician's withdrawal checklist.

[0159] (PWC-20); PRO measures of work loss and activity loss, as assessed by changes from baseline in the Work Productivity and Activity Impairment Questionnaire (WPAI), Specific Health Problem V2.0 (absenteeism, presenteeism, total work loss, and total activity loss); PRO measures of health-related quality of life, as assessed by changes from baseline in the 5-item 5-level questionnaire (EQ-5D-5L) developed by the EuroQol Group; PK parameters (e.g., clearance) and exposure estimates (e.g., area under the curve over the dosing interval, maximum plasma concentration), as evaluated by population PK methods.

[0160] Inclusion Criteria Eligible subjects met all of the following criteria: 1. Subjects who signed the ICF before any test-specific procedures were performed. 2. Subjects who were male or female, aged 18 to 65 years (inclusive). 3. Subjects in good physical health, with no clinically significant findings on physical examination, 12-lead ECG, or clinical laboratory tests as measured by the study physician. 4. Subjects who agreed to comply with the study requirements. 5. Subjects who had received a diagnosis of MDD, where the MDD was diagnosed by SCID-5-CT and the symptoms had been present for at least 4 weeks. 6. Subjects who had had at least one prior major depressive episode (MDE) in the 5 years prior to screening (excluding the current episode). 7. Subjects who had a MADRS total score of ≥32 and a HAM-D total score of ≥22 at screening and on Day 1 of the open-label period (before dosing). 8. Subjects who intended to delay the initiation of any antidepressant, anxiolytic, hypnotic, psychostimulant, or prescription opioid regimen until after study completion. 9. Subjects who had received psychotherapy and had to have received treatment on a regular schedule for at least 60 days prior to Day 1. 10. Women who were not postmenopausal (defined as 12 months of amenorrhea without other medical cause, confirmed by follicle-stimulating hormone [FSH] >40 mIU / mL), not surgically sterile (hysterectomy or bilateral oophorectomy), or, if involved in a sexual relationship with a risk of pregnancy, agreed to use one of the following highly effective contraceptive methods during the study and for 30 days after the last dose of study drug: · Combined (estrogen- and progestogen-containing) oral, vaginal, or transdermal hormonal contraception related to ovulation inhibition; · Oral, injectable, or implantable progestogen-only hormonal contraception related to ovulation inhibition; · Intrauterine contraceptive device; · Intrauterine hormone-releasing system; · Bilateral tubal ligation / occlusion; · Partner who has had a vasectomy; 11. Male subjects who, when involved in sexual relations with a risk of pregnancy, agreed to use an effective and acceptable contraceptive method during the study period and for 5 days after receiving the last dose of the investigational drug. If the female partner is at risk of pregnancy, effective and acceptable contraceptive methods for the male include vasectomy or a condom with spermicide used in conjunction with a highly effective female contraceptive method (see Incorporation Criteria #10 for acceptable contraceptive methods). 12. Male subjects who intended to refrain from sperm donation during the study period and for 5 days after receiving the last dose of the investigational drug. 13. Subjects who agreed to abstain from drug abuse and alcohol during the study period.

[0161] Exclusion Criteria Subjects who met any of the following criteria were not eligible to participate in this study: 1. Subjects who attempted suicide during the current episode of MDD. 2. Subjects with a recent history or clinically significant manifestation of active metabolic disorders, liver disorders, kidney disorders, blood disorders, lung disorders, cardiovascular disorders, gastrointestinal disorders, musculoskeletal disorders, skin disorders, urogenital disorders, neurological disorders or eye disorders, ear disorders, nasal disorders and throat disorders or any other acute or chronic condition (in the opinion of the study physician, which may limit the subject's ability to complete or participate in this clinical trial). 3. Excluded were body mass index (BMI) of ≤18 or ≥50 kg / m2 at screening; a BMI of 40 - 49 kg / m2 (inclusive) at screening was subject to a more extensive evaluation for medical comorbidities (e.g., sleep apnea, COPD), concomitant medications, and previous tolerance to sedatives. 4. Subjects who had treatment-resistant depression defined as persistent depressive symptoms despite receiving treatment with adequate doses of two different classes of antidepressants (excluding antipsychotics) for at least 4 weeks during the current major depressive episode. The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire was used for this purpose. 5. Subjects who had received vagus nerve stimulation, electroconvulsive therapy, or had taken ketamine during the current major depressive episode. 6. Subjects who had taken antidepressants within 60 days prior to Day 1. 7. Subjects who had taken benzodiazepines, barbiturates, or GABAA modulators (e.g., eszopiclone, zopiclone, zaleplon, and zolpidem) on Day - 28, or who had used these agents daily or almost daily (≥4 times per week) for over 1 year on Day - 28. 8. Subjects who had taken any benzodiazepine or GABA modulator (e.g., diazepam) with a half - life of ≥48 hours starting 60 days prior to Day 1. 9. Subjects who had taken non - GABA hypnotics (e.g., melatonin, Benadryl [antihistamine], trazodone) or first - or second - generation (typical / atypical) antipsychotics on Day - 14. 10. Subjects who had taken psychostimulants (e.g., methylphenidate, amphetamine) or opioids regularly or as needed on Day - 28. 11. Subjects who had known allergies to Compound 1, allopregnanolone, or related compounds. 12. Subjects who had a positive pregnancy test on Day 1 prior to dosing. 13. Subjects who were breastfeeding at the time of screening or on Day 1 (prior to administration of the test article) and who did not consent to temporarily discontinue breastfeeding their child from immediately prior to administration of the test article on Day 1 until 7 days after the last dose of the test article in each treatment period. 14. Subjects who had detectable hepatitis B surface antigen, anti - hepatitis C virus (HCV), and positive HCV viral load, or human immunodeficiency virus (HIV) antibodies at the time of screening. 15. Subjects who had a clinically significant abnormal 12-lead ECG at screening or at the baseline visit. Note: Subjects with a mean QT interval (QTcF) calculated using the Fridericia method of > 450 msec for men or > 470 msec for women were excluded from the study. 16. Subjects who had active psychosis as evaluated by the study physician. 17. Subjects with a history of seizures. 18. Subjects with a history of bipolar disorder, schizophrenia, and / or schizoaffective disorder. 19. Subjects with a history of mild, moderate, or severe substance use disorder (including benzodiazepines) diagnosed using DSM-5 criteria within the 12 months prior to screening. 20. Subjects who had been exposed to another investigational drug or device within 30 days prior to screening. 21. Subjects who had previously participated in a clinical trial of Compound 1 or brexanolone. 22. Subjects who had used any known strong inhibitor of cytochrome P450 (CYP) 3A4 within 28 days or 5 half-lives (whichever is longer) prior to the first dose of the investigational drug, or who planned to use these during any treatment period, or who had consumed grapefruit juice, grapefruit, or pomelo or products containing these within 14 days prior to the first dose of the investigational drug during any treatment period, or who planned to consume these products during any treatment period. 23. Use of the following strong CYP3A inducers within 28 days prior to the first dose of the investigational drug during any Compound 1 treatment period: rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, and St. John's wort. 24. Subjects who had a positive drug screening and / or alcohol screening at screening or on Day 1 prior to dosing during the open-label period. 25. Subjects who plan to undergo standby surgery or a procedure requiring general anesthesia at any time from screening through the study period. Procedures requiring conscious sedation and outpatient procedures performed under local anesthesia may be planned under the following guidelines: · Procedures requiring conscious sedation (e.g., colonoscopy) that are not later than 7 days prior to the start of the first dose and not earlier than 7 days after the last dose of each treatment period, from screening through the study period. · Outpatient standby procedures performed under local anesthesia are permitted at any time during the study. 26. Subjects diagnosed with and / or treated for any type of cancer (excluding basal cell carcinoma and in situ melanoma) within the past year prior to screening. 27. Subjects who have had gastric bypass surgery, have a sleeve gastrectomy or lap band, or have had any related procedure that impedes gastrointestinal passage. 28. Subjects who regularly worked night shifts or were expected to work night shifts during any 14-day treatment period (occasional night shifts during the follow-up period are permitted).

[0162] Dosage and Administration Compound 1 was available as a hard gelatin capsule containing a white to off-white powder. In addition to the active ingredient of Compound 1, Compound 1 capsules contained croscarmellose sodium, mannitol, siliconized microcrystalline cellulose (SMCC), colloidal silicon dioxide, and sodium stearyl fumarate as excipients. Colloidal silicon dioxide was either a component of SMCC or an independent excipient in the formulation. Compound 1 capsules were administered orally as 30 mg or 20 mg doses.

[0163] Reference Treatment, Dosage, and Administration: In the DB period, placebo was provided at night with food as a hard gelatin capsule for oral administration.

[0164] Treatment Period: All subjects were administered a daily dose of Compound 1 from Day 1 to Day 14 of the OL period. Subjects who showed a HAM-D response to Compound 1 during the OL period were randomized to receive a daily dose of Compound 1 or placebo for 14-day treatment periods separated by 6-week follow-up periods over 40 weeks (a total of six 14-day treatment periods during the 52-week study) of the DB period.

Table 4

[0165]

Table 5-1

Table 5-2

[0166]

Table 6

[0167] Example 4 Agnosia can occur in individuals with depression and anxiety, such as major depressive disorder (MDD). Subjects administered Compound 1 are evaluated using a cognitive test battery or, if there is a change in cognition, the Cogstate test for that.

[0168] The Cogstate test can be designed to measure specific cognitive domains and can be grouped to form a customized battery based on the unique requirements of the study design and population. Examples of the Cogstate test are as follows:

[0169] The Behavioral Pattern Separation Object test measures recognition memory using photographs of objects. A series of photographs of common objects are presented to the participant, and the participant must determine whether each object is used indoors or outdoors. Then a photograph of an object is presented to the participant, and the participant must recall whether the object is the same as, similar to, or different from the photographs already shown.

[0170] The Continuous Paired Associate Learning test measures visual memory using a paired-associate learning paradigm. In this test, participants must learn and remember pictures hidden under various locations on the screen. In the first stage of this test, the instructions on the pretest screen ask, "Which location do these pictures belong to?" A picture is presented in the center of the screen. Participants must tap on the location around the picture and remember that location. In the second stage of this test, the same picture is presented in the center of the screen, however, the locations around each picture are hidden. Participants must tap on the location around the picture where it previously appeared.

[0171] The Detection test measures processing speed using a simple reaction time paradigm. The instructions on the screen ask, "Did the card turn over?" A playing card is presented face-down in the center of the screen. The card turns over to face-up. As soon as the card turns over, participants must press "Yes". Participants are encouraged to work as quickly and accurately as possible.

[0172] The Face Name Associative Memory Exam measures associative memory using pictures of real faces. Participants are presented with a series of face pictures and names, pairing each face with its corresponding name. Participants must remember the face-name pairs.

[0173] The Go-No Go test is a measure of response inhibition and uses a well-validated recognition reaction time paradigm with playing card stimuli. In this test, all playing cards are red or black jokers. The subject is asked whether the card displayed in the center of the screen is black. The subject must press the Yes key when the joker card is black and withhold response (i.e., must not respond) when it is red.

[0174] The Groton Maze Learning test measures executive function using a maze learning paradigm. A 10×10 grid of tiles is presented to the participant on the screen. Hidden between these tiles is a 28-step path. The blue tile indicates the start, and the tile with a red circle drawn on it indicates the end. The participant must move one step at a time from the start to the end by touching the tile adjacent to their current location. If they move correctly, a green checkmark appears, and if they move incorrectly, a red X appears. Once completed, the participant must return to the starting location to repeat the test and try not to remember the path they just completed.

[0175] The Identification test measures attention using a choice reaction time paradigm. The instruction on the screen asks, "Is the card red?" A playing card is presented face-down in the center of the screen. The card is flipped over to face-up. As soon as the card is flipped, the participant must determine whether the card is red or not. If the card is red, the participant must press "Yes", and if it is not red, the participant must press "No". The participant is encouraged to work as quickly and accurately as possible.

[0176] The International Shopping List test measures language learning using a word list learning paradigm. The participant is read a list of items to purchase and must remember and recall as many items from that list as possible.

[0177] The One Back test measures working memory using the n-back paradigm. Instructions on the screen ask, "Was the previous card the same?" A playing card is presented face-up in the center of the screen. The participant must determine whether the card is the same as the previous card. If the card is the same, the participant must press "Yes", and if it is not the same, the participant must press "No". The participant is encouraged to work as quickly and accurately as possible.

[0178] The One Card Learning test measures visual memory using the pattern separation paradigm. Instructions on the screen ask, "Have you seen this card before in this test?" A playing card is presented face-up in the center of the screen, and the participant must determine whether they have seen the card before in this test. The participant is encouraged to work as quickly and accurately as possible.

[0179] The Set-Shifting test measures executive function using the set shifting paradigm. The instruction on the screen asks, "Is this the target card?" A playing card is presented face-up in the center of the screen, along with the word "number" or "color" on it. If the word is "color", the participant must guess whether the target card is black or red. If the word is "number", the participant must guess whether the current number displayed on the card is correct. At the beginning of this test, the participant only needs to simply guess whether the current card is the target card. If the participant thinks the card is the target card, the participant must press "Yes". If the participant thinks the card is not the target card, the participant must press "No". When the participant makes a guess, feedback is provided and the next card is not displayed until the correct response is made. After the participant experiences a set of cards, the hidden rule changes (e.g., from one color to another [intradimensional shift] or from color to number [extradimensional shift]). These set shifts occur without the participant being informed, and in order to proceed with this test, the participant must learn the new target rule. The participant is encouraged to work as quickly and accurately as possible.

[0180] The Social-Emotional Cognition test measures emotion recognition using the odd-one-out paradigm. The instruction on the screen requests, "Tap the odd one out." Four pictures are presented on the screen. One of these pictures is different from the others, and the participant must determine which picture is different and tap on it. The participant is encouraged to work as quickly and accurately as possible.

[0181] The Two Back test measures working memory using the n-back paradigm. Instructions on the screen ask, "Is that card the same as the one shown two cards ago?" A playing card is presented face up in the center of the screen. The participant must determine whether that card is the same as the card shown two cards ago. If the card is the same, the participant must press "Yes", and if it is not the same, the participant must press "No". The participant is encouraged to work as quickly and accurately as possible.

[0182] To evaluate cognitive decline, agnosia, or cognitive improvement in subjects administered Compound 1, cognition can be evaluated using a test battery (e.g., the battery shown in Table 7). [Table 7]

[0183] Subjects can be evaluated using the Cogstate test battery before, during, and after administration of Compound 1. References cited in Table 7: 1. Davis MT, DellaGioia N, Matuskey D, et al. Preliminary evidence concerning the pattern and magnitude of cognitive dysfunction in major depressive disorder using cogstate measures. J Affect Disord. 2017;218. doi:10.1016 / j.jad.2017.04.064 2. Holmes SE, Scheinost D, Finnema SJ, et al. Lower synaptic density is associated with depression severity and network alterations. Nat Commun. 2019;10(1):1529. doi:10.1038 / s41467-019-09562-7 3. Olver JS, Ignatiadis S, Maruff P, Burrows GD, Norman TR. Quetiapine augmentation in depressed patients with partial response to antidepressants. Hum Psychopharmacol. 2008;23(8):653-660. doi:10.1002 / hup.970 4. Galvez V, Li A, Huggins C, et al. Repeated intranasal ketamine for treatment- resistant depression - the way to go? Results from a pilot randomised controlled trial. 2018. doi:10.1177 / 0269881118760660 5. Hashimoto K, Yoshida T, Ishikawa M, et al. Increased serum levels of serine enantiomers in patients with depression. Acta Neuropsychiatr. 2015;(November):1-6. doi:10.1017 / neu.2015.59 6. Yoshida T, Ishikawa M, Niitsu T, et al. Decreased serum levels of mature brain-derived neurotrophic factor (BDNF), but not its precursor proBDNF, in patients with major depressive disorder. PLoS One. 2012;7(8):e42676. doi:10.1371 / journal.pone.0042676

[0184] Equivalents and ranges In the claims, the articles (e.g., "a", "an", and "the") can mean one or more than one unless the contrary is indicated or is otherwise apparent from the context. Unless the contrary is indicated or is otherwise apparent from the context, a claim or description that includes "or" between one or more members of a group is considered to satisfy that one, more than one, or all of the group members are present in, are used in, or are otherwise related to a given product or process. The present invention includes embodiments in which exactly one member of the group is present in, is used in, or is otherwise related to a given product or process. The present invention includes embodiments in which more than one or all of the group members are present in, are used in, or are otherwise related to a given product or process.

[0185] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the recited claims are introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends on the same base claim. If an element is presented as a list, for example, in the form of a Markush group, each subgroup of that element is also disclosed, and any element can be removed from that group. Generally, when the present invention or an aspect of the present invention is referred to as including a particular element and / or feature, a particular embodiment of the present invention or an aspect thereof should be understood to consist of or consist essentially of such element and / or feature. For simplicity purposes, those embodiments are not explicitly shown herein in such words. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow for the inclusion of additional elements or steps. When a range is given, the endpoints are included. Further, unless otherwise indicated or otherwise clear from the context and the understanding of one of ordinary skill in the art, values expressed as a range can assume any specific value or sub-range within the range stated in various embodiments of the present invention down to one tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0186] This application refers to various issued patents, published patent applications, academic papers, and other publications (all of which are incorporated herein by reference). If there is a conflict between any of the incorporated references and this specification, this specification shall govern. Further, any particular embodiment of the present invention that falls within the prior art can be explicitly excluded from any one or more of the claims. Since such embodiments are considered to be known to one of ordinary skill in the art, they can be excluded even if such exclusion is not explicitly shown herein. Any particular embodiment of the present invention can be excluded from any claim for any reason, regardless of whether it relates to the existence of the prior art.

[0187] One of ordinary skill in the art will recognize, or be able to ascertain, many equivalents to the specific embodiments described herein using nothing more than routine experimentation. The scope of the embodiments described herein is not intended to be limited to the above description, as it is as shown in the appended claims. One of ordinary skill in the art will recognize that various changes and modifications can be made to this description without departing from the spirit or scope of the invention as defined in the following claims.

Claims

【Claim 1】 The invention described in the specification of this application.

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