RU2851101C2 - 19-nor c3,3-substituted c21-n-pyrazolyl steroid and methods of use thereof - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a method of treating postpartum depression comprising administering a therapeutically effective amount of Compound 1 to a subject once a day for two weeks, including in which the subject has a total score on a Hamilton depression scale (HAM-D) greater than or equal to 26 compared to a baseline; and in which the subject demonstrates a response consisting in a decrease of the HAM-D value from the initial level by more than or equal to 50%, and where the method does not cause significant changes in cognitive functions in the subject.

EFFECT: using the invention enables treating postpartum depression effectively.

15 cl, 9 dwg, 7 tbl, 4 ex

Description

Other applications related to this application

This application claims priority from U.S. Provisional Patent Application Nos. 62/684,155, filed June 12, 2018, 62/789,329, filed January 7, 2019, and 62/841,645, filed May 1, 2019, each of which is incorporated herein by reference in its entirety.

Field of technology to which the invention relates

The present invention relates to methods for treating depression, such as postpartum depression and major depressive disorder, by administering Compound 1 as described herein.

Introduction

GABA (gamma-aminobutyric acid) significantly influences overall brain excitability, as up to 40% of brain neurons use GABA as a neurotransmitter. GABA interacts with its recognition site on the GRC (GABA receptor complex) and facilitates the flow of chloride ions along the GRC's electrochemical gradient into the cell. An intracellular increase in chloride anion levels causes hyperpolarization of the transmembrane potential, making the neuron less responsive to excitatory signals (i.e., decreased neuronal excitability). In other words, the higher the chloride ion concentration in a neuron, the lower the brain's excitability (i.e., the level of arousal). GRC has been implicated in anxiety, seizure activity, and sedation. Thus, GABA and drugs that exert GABA-like effects (e.g., therapeutically used barbiturates and benzodiazepines (BDs) such as Valium®) exert their therapeutically beneficial effects by interacting with specific regulatory sites on the GRC.

Accumulating evidence has shown that the GRC contains a distinct site for neuroactive steroids (Lan, N.C. et al. Neuwchem. Res. 16: 347–356 (1991)). Neuroactive steroids can be formed endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one, metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was discovered in 1986 (Majewska, MD et al. Science 232: 1004-1007 (1986); Harrison, NL et al. J. Pharmacol. Exp. Ther. 241: 346-353 (1987)).

Compound 1, a neuroactive steroid described herein, has been shown to be a positive allosteric modulator of GABA _A receptors that targets synaptic and extrasynaptic GABA _A receptors. As a positive allosteric modulator of GABA _A receptors, Compound 1 serves as a therapeutic agent for the treatment of CNS-related disorders, such as depression, such as postpartum depression and major depressive disorder. Current treatments for CNS-related disorders typically require long-term, sometimes chronic, treatment, and patient compliance can be a significant challenge. Patients with CNS-related disorders would benefit significantly from a new treatment regimen that is effective, easy to administer, and/or requires fewer administrations and avoids or minimizes side effects.

Brief description of the invention

The present document provides methods for treating depression in a subject, wherein the method comprises administering to the subject a therapeutically 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 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 to a subject in need thereof once a day for several 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 to a subject in need thereof once a day for several weeks.

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

In some aspects, provided herein is an episodic dosing regimen for the treatment of depression comprising administering Compound 1 to a subject in need thereof. In some embodiments, the subject is administered about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound 1. In some embodiments, Compound 1 is administered to the subject once a day for several weeks. In some embodiments, the patient is administered about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound 1 once a day for several weeks. In a preferred embodiment, the episodic dosing regimen has a duration of about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen has a duration of about 2 weeks to about 4 weeks. In an even more preferred embodiment, the episodic dosing regimen has a duration of about 2 weeks. In an even more preferred embodiment, the episodic dosing regimen has a duration of 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 has a duration of about 2 weeks (or about 14 days), with the subject being administered about 30 mg of Compound 1 once daily for a period of 2 weeks (or about 14 days). If the subject does not tolerate administration of about 30 mg of Compound 1 once daily, the subject is administered about 20 mg of Compound 1 once daily.

In some embodiments, the subject exhibits a response to the episodic dosing regimen, wherein the response consists of a reduction in the HAM-D score from baseline by greater than or about 50%. In some embodiments, the response consists of a remission of depressive symptoms.

In some embodiments, the subject is assessed for relapse, i.e., the reappearance of depressive symptoms. In some embodiments, the method of treating the subject comprises multiple episodic dosing regimens. In some embodiments, after completion of the episodic dosing regimen, a subsequent episodic dosing regimen is administered if depressive symptoms reappear. In some embodiments, the episodic dosing regimens are separated by at least a 6-week interval. In some embodiments, the episodic dosing regimens are separated by a 6-week interval. In some embodiments, the episodic dosing regimens are separated by a 7-week interval. In some embodiments, the episodic dosing regimens are separated by an 8-week interval.

In some aspects, provided herein is an episodic dosing regimen for the treatment of major depressive disorder, bipolar depression, anxiety disorder, or postpartum depression, comprising dosing 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, the subject is administered about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound 1. In some embodiments, Compound 1 is administered once daily for several 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 for the treatment of major depressive disorder, bipolar depressive disorder, 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 to a subject once daily for several weeks to treat major depressive disorder, bipolar depression, anxiety, or postpartum depression. In a preferred embodiment, the episodic dosing regimen has a duration of about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen has a duration of about 2 weeks to about 4 weeks. In an even more preferred embodiment, the episodic dosing regimen has a duration of about 2 weeks or about 14 days. In other embodiments, the episodic dosing regimen has a duration of 2 weeks.

In some aspects, provided herein is a method of treating depression in a subject in need thereof, comprising administering Compound 1 to said subject in an episodic dosing regimen. In some aspects, provided herein is a method of treating postpartum depression in a subject in need thereof. Such a method comprises administering 30 mg of Compound 1 to said subject once a day in an episodic dosing regimen for 2 weeks (or about 14 days). If the subject does not tolerate administration of 30 mg of Compound 1 once a day, the subject is administered 20 mg of Compound 1 once a day. In some embodiments, the subject is a woman diagnosed with major postpartum depression. In some embodiments, the subject has been experiencing a major depressive episode for about a year. In some embodiments, the subject is between about 18 and about 75 years of age. In some embodiments, the subject is between about 18 and about 65 years of age.

The episodic dosing regimen of the present invention offers the advantage of not requiring a continuous 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 symptomatic episode. The advantage of such an episodic dosing regimen is that it does not require continuous dosing and thus avoids many of the drawbacks of current depression treatments.

In another aspect, the present document provides a method for treating depression in a subject in need thereof, the method comprising the following steps:

(i) administering to a subject once daily a therapeutically effective amount of a Compound having the formula:

over a period of about two weeks; and

(ii) re-administering to the subject once daily a therapeutically effective amount of Compound 1 for about two weeks upon occurrence of a relapse of depressive symptoms;

provided that there is an interval between the administration of Compound 1 to the subject and the re-administration of Compound 1 to the subject.

In some embodiments, Compound 1 is administered to the subject for 2 weeks, i.e., 14 days. In some embodiments, Compound 1 is re-administered to the subject for 2 weeks, i.e., 14 days. In some embodiments, the interval between administration of Compound 1 to the subject and re-administration of Compound 1 to the subject is 2-4 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 administration of Compound 1 to the subject and re-administration of Compound 1 to the subject is 7 weeks. In some embodiments, the interval between administration of Compound 1 to the subject and re-administration of Compound 1 to the subject is 8 weeks.

In some embodiments, the depression is major depressive disorder (MDD). In some embodiments, MDD is moderate major depressive disorder. In some embodiments, 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 woman diagnosed with severe postpartum depression. In some embodiments, the subject has been experiencing a major depressive episode for about one year. In some embodiments, the subject is between about 18 and about 75 years of age. In some embodiments, the subject is between about 18 and about 65 years of age.

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

In some embodiments, the subject is administered about 10 mg of Compound 1. In some embodiments, the subject is administered about 20 mg of Compound 1. In some embodiments, the subject is administered about 30 mg of Compound 1. In some embodiments, the subject is administered about 40 mg of Compound 1. In some embodiments, the subject is administered about 10 mg of Compound 1 once per day. In some embodiments, the subject is administered about 20 mg of Compound 1 once per day. In some embodiments, the subject is administered about 30 mg of Compound 1 once per day. In some embodiments, the subject is administered about 40 mg of Compound 1 once per day. In some embodiments, the amount of Compound 1 administered to the subject is reduced when a serious side effect occurs. In some embodiments, Compound 1 is administered in the evening. In some embodiments, Compound 1 is administered with food. In some embodiments, Compound 1 is in a capsule. In some embodiments, the method further comprises administering a second therapeutic agent.

In some aspects, provided herein is a kit comprising a pharmaceutical composition comprising Compound 1 and a list of instructions describing a method for using an episodic dosing regimen to treat depression. 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 further comprises about 30 mg of Compound 1. In some embodiments, the episodic dosing regimen is from about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen is from about 2 weeks to about 4 weeks. In an even more preferred embodiment, the episodic dosing regimen is about 2 weeks. In a preferred embodiment, the episodic dosing regimen is 2 weeks. In some embodiments, the depression is major depressive disorder, bipolar depression, anxiety disorder, 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, for the treatment of postpartum depression, the episodic dosing regimen is about 2 weeks (or about 14 days). In some embodiments, the instructions are printed on a suitable material. In some embodiments, the individual dosage units are capsules or tablets. 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.

Brief description of the drawings

FIGURE 1 shows the mean change from baseline in the Hamilton Rating Scale for Depression (HAM-D) total score over time by treatment group.

FIGURE 2 shows the forest plot of the subgroup analysis for the primary endpoint at day 15.

FIG. 3 shows the histogram of Hamilton Depression Rating Scale (HAM-D) remission by time point and treatment group.

FIG. 4 shows the histogram of Hamilton Depression Rating Scale (HAM-D) remission by time point and treatment group.

FIG. 5 shows the change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score over time by treatment group.

FIGURE 6 shows the change from baseline in the Hamilton Anxiety Rating Scale (HAM-A) total score over time by treatment group.

FIG. 7 shows a histogram of improvement in Clinical Global Impression (CGI) scores by time point and treatment group.

FIG. 8 shows a typical study design for the treatment of MDD with Compound 1.

FIG. 9 shows a typical study design for the treatment of MDD with Compound 1.

Detailed description of the invention

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.

Definitions

The term "unit dosage form" as used herein is used to denote the form in which Compound 1 is administered to a subject. In particular, the unit dosage form can be, for example, a pill, capsule, or tablet. Preferably, the unit dosage form is a capsule. A typical amount of Compound 1 in a unit dosage form used in the invention is from about 10 mg to about 100 mg, preferably from about 10 mg to about 50 mg (e.g., about 10, about 15, about 20, about 25 mg, or about 30 mg).

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

As used herein, the term "solid dosage form" means a pharmaceutical dose(s) provided in a solid form, such as a tablet, capsule, granule, powder, sachet, reconstitutable powder, dry powder inhaler, and chewable tablet.

When the term "about" is used before a quantitative value, the concepts presented herein also include the specific quantitative value itself, unless otherwise specifically stated. The term "about" as used herein refers to a deviation of ±10% from the nominal value, unless otherwise stated or implied.

Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics , ^75th Ed., inside cover, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Thomas Sorrell, Organic Chemistry , University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry , ^5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations , VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis , ^3rd Edition, Cambridge University Press, Cambridge, 1987.

"Pharmaceutically acceptable" means approved or submitted for approval by a regulatory agency of the federal or state government, or by a relevant agency in countries other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such non-toxic salts can be addition salts with inorganic or organic acids and addition salts with bases. In particular, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid. acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic 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, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or coordinated to an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of the acidic functional group. Examples of such cations are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like. See, e.g., Berge et al. J. Pharm. Sci. (1977) 66(1):1–79.

A "subject" is a human being (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, a child, an adolescent) or an adult subject (e.g., a young or middle-aged adult or an elderly person).

The terms "disease," "disorder," and "condition" are used here interchangeably.

In the context of the present description, unless otherwise specified, the terms "treat," "treatment," and "treatment" mean an action that occurs while a subject is suffering from the specified disease, disorder, or condition and that reduces the severity of the disease, disorder, or condition, or halts or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), and which also includes an action that occurs before the subject begins to suffer from the specified disease, disorder, or condition ("prophylactic treatment").

In general, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response, such as in the treatment of a CNS disorder, such as a disorder described herein (e.g., tremor (e.g., essential tremor), depression (e.g., postpartum depression), or anxiety disorder). Those skilled in the art will appreciate that an effective amount of a compound of the present invention may vary depending on factors such as the achievement of the desired biological effect (endpoint), the pharmacokinetics of the compound, the characteristics of the disease being treated, the route of administration, and the age, weight, general health, and condition of the subject. The term "effective amount" applies to both therapeutic and prophylactic treatment.

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

In this context, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, and to prevent the recurrence thereof. A prophylactically effective amount of a compound means the amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic effect in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

As used herein, the term "episodic dosing regimen/episodic dosing regimen" is a dosing regimen in which a compound or a composition comprising the compound is administered to a subject over a finite period of time in response to a diagnosed disorder or symptom thereof, for example, in the case where symptoms of depression, episodes of major depressive disorder, symptoms of bipolar depression, anxiety disorder, or postpartum depression are diagnosed or observed. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder. In some embodiments, the compound is formulated as individual dosage units, wherein each unit comprises Compound 1 and one or more suitable pharmaceutical excipients. In some embodiments, the episodic dosing regimen has a duration of several weeks, for example, about 8 weeks. In contrast to chronic administration, as defined herein, episodic administration of a compound is administered for a limited period of time, such as from about 2 weeks to about 8 weeks, upon diagnosis or relapse of a disorder, such as depression or a symptom thereof. In some embodiments, episodic dosing is administered once daily for several weeks, such as from about 2 weeks to about 6 weeks. In one embodiment, episodic dosing lasts for two weeks. In some embodiments, the subject is administered more than one episodic dosing regimen, such as two or more episodic dosing regimens throughout the subject's life.

In some embodiments, administration of Compound 1 improves cognitive function. In some embodiments, cognitive function is defined by a set of mental tasks and functions including, but not limited to: memory (e.g., semantic, episodic, procedural, primary, or working); orientation ability; language proficiency; problem solving; visual perception, holistic imagery, and integration; planning ability; organizational skills; selective attention; self-control; and the ability to mentally manipulate information. In one embodiment, cognitive function is one or more functions selected from the group consisting of memory (e.g., semantic, episodic, procedural, primary, or working); orientation ability; language proficiency; problem solving; visual perception, holistic imagery, and integration; planning; organizational skills; selective attention; self-control; and the ability to mentally manipulate information. To measure functioning at the cognitive level, assessment instruments are used that are designed to measure, for example: (a) general intelligence, (b) nonverbal intelligence, (c) achievement, (d) attention/executive functioning, (e) memory and learning, (f) visual perception and motor function, and (g) language proficiency.

Any change in cognitive function, for example, over time or as a result of treatment, can be monitored using one or more of these established tests at two or more time points by comparing the results. The phrase "improves cognitive function," as used herein, means a positive change in a subject's ability to perform a symbolic operation, such as perceiving, remembering, creating a mental image, exhibiting clarity of thought, awareness, reasoning, thinking, or judging. A positive change can be measured using any of the aforementioned tests at two or more times, for example, a first time to measure baseline cognitive function and a second time to measure cognitive function after a specified period of time (during which treatment may have been administered). Such assessment instruments are well known in the art and include, for example, those assessment instruments described in Example 4 of this document.

Pharmaceutical compositions

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

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

Generally, the compounds described herein are administered in an effective amount. The amount of compound administered is typically determined by the physician based on the relevant circumstances, including the disease being treated, the chosen route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

To prevent a primary CNS disorder, the compounds described herein should be administered to a subject at risk for developing the disorder, generally under the advice and supervision of a physician, in accordance with the dosage levels described above. Subjects at risk for developing a particular disorder/condition typically include those with a family history of the disorder or those identified through genetic testing or screening as being particularly susceptible to developing the disorder.

The pharmaceutical compositions of the present invention can be further delivered using various dosing methods. For example, in some embodiments, the pharmaceutical composition can be administered by bolus administration, for example, to increase the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the desired systemic levels 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 intravenously (e.g., via an IV drip) provides much more rapid delivery, rapidly raising 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 drip, to ensure a constant concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, the pharmaceutical composition can be administered as a bolus dose followed by a continuous infusion.

Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders. However, the compositions are more often presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for humans and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled ampoules or syringes with a specific amount of material for liquid compositions, or pills, tablets, capsules, and the like for solid compositions. In such compositions, the compound is typically a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), and the majority of the composition represents various carriers or excipients and processing aids useful in forming the desired dosage form.

The above-described components for orally, injectably, or topically administered compositions are generally conventional and typical. Other materials, as well as processing methods, etc., are set forth in Section 8 of Remington's Pharmaceutical Sciences , ^17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

The compounds of the present invention can also be administered in sustained-release forms or via delayed-release drug delivery systems. A description of typical delayed-release materials can be found in Remington's Pharmaceutical Sciences.

The present invention also includes pharmaceutically acceptable acid addition salts of the compound of the present invention. An acid that can be used to prepare a pharmaceutically acceptable salt is an acid that forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate, and the like.

Methods of use

Described herein are methods for treating depression, such as postpartum depression or major depressive disorder, or an anxiety disorder, such as generalized anxiety disorder, in a subject, wherein the method comprises 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 depression, such as postpartum depression or major depressive disorder, or an anxiety disorder, such as generalized anxiety disorder, in a subject, the method comprising administering to the subject an 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 between 18 and 64 years of age, inclusive. In some embodiments, the subject is between 18 and 75 years of age, inclusive. 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 in three capsules. In some embodiments, the subject does not have an underlying disease. In some embodiments, the subject has an underlying disease.

In some aspects, the present document provides methods for treating a subject with depression or anxiety disorder, said method comprising administering to said subject a pharmaceutical composition comprising Compound 1 using an episodic dosing regimen effective to treat depression in said subject. In some aspects, the dosing regimen is from about 2 weeks to about 8 weeks. In some other aspects, the dosing regimen is from about 2 weeks to about 6 weeks. In some other aspects, the dosing regimen is from about 2 weeks to about 4 weeks. In some other aspects, the dosing regimen is about 2 weeks. In some other aspects, the dosing regimen is about 2 weeks or about 14 days.

In some embodiments, about 10 mg of Compound 1 is administered to the subject once a day for several weeks. In some embodiments, about 15 mg of Compound 1 is administered to the subject once a day for several weeks. In some embodiments, about 20 mg of Compound 1 is administered to the subject once a day for several weeks. In some embodiments, about 25 mg of Compound 1 is administered to the subject once a day for several weeks. In some embodiments, 30 mg of Compound 1 is administered to the subject once a day. In some embodiments, 30 mg of Compound 1 is administered to the subject once a day, and if the subject does not tolerate 30 mg of Compound 1, then the subject is administered 20 mg of Compound 1 once a day. In some embodiments, 30 mg of Compound 1 is administered to the subject once a day for about two weeks. In some embodiments, 30 mg of Compound 1 is administered to the subject once a day for about two weeks (or about 14 days), and if the subject does not tolerate 30 mg of Compound 1, then the subject is administered 20 mg of Compound 1 once a day for about two weeks (or about 14 days). In some embodiments, 30 mg of Compound 1 is administered to the subject once a day for two weeks, and if the subject does not tolerate 30 mg of Compound 1, then the subject is administered 20 mg of Compound 1 once a day for two weeks. In some embodiments, 30 mg of Compound 1 is administered to the subject once a day for at least two weeks (or about 14 days). In some embodiments, 30 mg of Compound 1 is administered to the subject once daily for two weeks (or about 14 days), and if the subject does not tolerate 30 mg of Compound 1, then the subject is administered 20 mg of Compound 1 once daily for at least two weeks (or about 14 days). In some embodiments, 30 mg of Compound 1 is administered to the subject once daily for two weeks.

In some aspects, the method comprises an episodic dosing regimen, wherein the method comprises administering Compound 1 to the subject concurrently with the onset/course of an episode of the disorder to be treated, such as an episode of major depressive disorder, bipolar depression, anxiety disorder, including generalized anxiety disorder, 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 major depressive disorder is severe major depressive disorder. In some embodiments, the anxiety disorder is generalized anxiety disorder.

In some embodiments, the subject demonstrates a response to the episodic dosing regimen, wherein the response is determined by a reduction in the HAM-D score of about 50% or more from baseline.

In some embodiments, the subject is assessed for the potential for recurrence of depressive symptoms. In some embodiments, the treatment method comprises multiple episodic dosing regimens. In some embodiments, the episodic dosing regimens are separated by at least a 6-week interval. 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.

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

In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Hamilton Depression Rating Scale (HAM-D)) for about 45, about 21, about 15, about 8, or about 3 days. In some embodiments, the therapeutic effect is a reduction from baseline in the HAM-D score at the end of the treatment period (e.g., about 45, about 21, about 15, about 8, or about 3 days after the start of administration or episodic dosing). In some embodiments, the reduction in the HAM-D score from baseline is from severe (e.g., from a HAM-D score of 24 or higher; or a HAM-D score of 26 or higher) to an asymptomatic level, i.e., a remission of depression is observed (e.g., to a HAM-D score of 7 or lower). In some embodiments, the decrease in HAM-D score from baseline ranges from severe (e.g., a HAM-D score of 24 or 26 or higher) to normal or mild depression (e.g., to a HAM-D score of 7 or lower; or to a HAM-D score of 18-13).

In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS)) for about 45, about 21, about 15, about 8, or about 3 days or less. The Montgomery-Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire (regarding the manifestation of overt sadness, sadness, inner tension, insufficient sleep, decreased appetite, problems with concentration, fatigue, inability to feel, pessimistic and suicidal thoughts) that is used in psychiatry 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; and >34 indicates severe depression. In some embodiments, the therapeutic effect is a decrease in the MADRS score compared to baseline at the end of the treatment period (e.g., after about 45, about 21, about 15, about 8, or about 3 days or less). In some embodiments of the present invention, the decrease in the MADRS score compared to baseline is from a severe (e.g., a MADRS score of 30 or greater) to an asymptomatic (e.g., a MADRS score of 20 or less) level. For example, the average change in the MADRS total score from baseline after treatment with a compound described herein is about -15, -20, -25, -30, while the average change in the MADRS total score compared to baseline after treatment with placebo is about -15, -10, -5.

In some embodiments, the method provides a therapeutic effect (e.g., measured by a reduction in Clinical Global Impression (CGI) scores) for 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.

In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Hamilton Anxiety Measure (HAM-A)) for about 45, about 21, about 15, about 8, or about 3 days. On the HAM-A scale, a score of <17 indicates mild severity, 18-24 points indicate mild to moderate severity, and 25-30 points indicate moderate to severe severity. In some embodiments, the therapeutic effect is a decrease from baseline in the HAM-A score at the end of the treatment period (e.g., a period of about 45, about 21, about 15, about 8, or about 3 days after the start of administration or the start of episodic dosing). In some embodiments, the decrease in the HAM-A score from baseline is from severe (e.g., a HAM-A score of 25 or higher) to asymptomatic (e.g., a HAM-A score of 17 or lower). In some embodiments of the present invention, the decrease in HAM-A score compared to baseline is from severe (e.g., HAM-A score of 25 or greater) to moderate (e.g., HAM-A score of 24 or less).

In some embodiments, the list of instructions describes a method comprising an episodic dosing regimen, wherein the episodic dosing regimen is from about 2 weeks to about 6 weeks. In some embodiments, the list of instructions describes a method comprising an episodic dosing regimen, wherein the episodic dosing regimen is from about 2 weeks to about 4 weeks. In some embodiments, the list of instructions describes a method comprising an episodic dosing regimen, wherein the episodic dosing regimen continues for about 2 weeks or about 14 days. In some embodiments, the list of instructions describes a method comprising an episodic dosing regimen, wherein the episodic dosing regimen continues for 2 weeks.

In one embodiment, the list of instructions is printed.

In additional embodiments, the list of instructions describes a method comprising an episodic dosing regimen, wherein the method comprises administering Compound 1 to a subject concurrently with an episode of a disease to be treated. In some aspects, the list of instructions describes a method comprising an episodic dosing regimen, wherein the method comprises administering Compound 1 to a subject concurrently with an episode of a disease to be treated, for example, an episode of depression. In some aspects, the list of instructions describes a method comprising an episodic dosing regimen, wherein the method comprises administering Compound 1 to a subject concurrently with an episode of a disease to be treated, for example, an episode of depression. In some aspects, the list of instructions describes a method comprising an episodic dosing regimen, wherein the method comprises administering Compound 1 to a subject concurrently with an episode of a disease to be treated, for example, an episode of major depressive disorder, bipolar depression, anxiety disorder, 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 one aspect, the present document provides a method for treating depression in a subject in need thereof, which comprises the following steps:

(i) administering to a subject once daily a therapeutically effective amount of a Compound having the formula:

about two weeks; and also

(ii) repeated administration once daily to the subject of a therapeutically effective amount of Compound 1 for about two weeks in response to a recurrence of depressive symptoms, provided that there is an interval of at least six weeks between the administration of Compound 1 to the subject and the repeated administration of Compound 1 to the subject.

It is understood that the six-week interval, as described above, represents the duration between the last dose of Compound 1 administered to the subject and the first dose of re-administration of Compound 1 to the subject.

In some embodiments, Compound 1 is administered to the subject for 2 weeks. In some embodiments, Compound 1 is re-administered to the subject for 2 weeks. In some embodiments, the interval between administration of Compound 1 to the subject and re-administration of Compound 1 to the subject is 6 weeks. In some embodiments, the interval between administration of Compound 1 to the subject and re-administration of Compound 1 to the subject is 7 weeks. In some embodiments, the interval between administration of Compound 1 to the subject and re-administration of Compound 1 to the subject is 8 weeks.

In some embodiments, the depression is major depressive disorder (MDD). In some embodiments, MDD is moderate major depressive disorder. In some embodiments, 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 woman diagnosed with severe postpartum depression. In some embodiments, the subject has been experiencing a major depressive episode for about a 1-year period. In some embodiments, the subject is between about 18 and about 75 years of age. In some embodiments, the subject is between about 18 and about 65 years of age.

In some embodiments, the subject is administered about 10 mg of Compound 1. In some embodiments, the subject is administered about 20 mg of Compound 1. In some embodiments, the subject is administered about 30 mg of Compound 1. In some embodiments, the subject is administered about 40 mg of Compound 1. In some embodiments, the subject is administered about 10 mg of Compound 1 once per day. In some embodiments, the subject is administered about 20 mg of Compound 1 once per day. In some embodiments, the subject is administered about 30 mg of Compound 1 once per day. In some embodiments, the subject is administered about 40 mg of Compound 1 once per day. In some embodiments, the amount of Compound 1 administered to the subject is reduced when a serious side effect occurs. In some embodiments, Compound 1 is administered in the evening. In some embodiments, Compound 1 is administered with food. In some embodiments, Compound 1 is in a capsule. In some embodiments, the method further comprises administering a second therapeutic agent.

In one aspect, the present document provides a method for treating major depressive disorder in a subject in need thereof, wherein the method comprises the following steps:

(i) primary administration of a therapeutically effective amount of Compound of formula (I) once daily to a subject for 14 days:

and also

(ii) repeat administration of a therapeutically effective amount of Compound 1 to the subject once daily in response to a recurrence of symptoms of major depressive disorder,

provided that there is at least a six-week interval between the last dose of the primary administration of Compound 1 to the subject and the first dose of the booster administration of Compound 1 to the subject.

In one aspect, the present document provides a method for treating postpartum depression in a subject in need thereof, which comprises the following steps:

(i) primary administration of a therapeutically effective amount of Compound of formula (I) once daily to a subject for 14 days:

and also

(ii) repeat administration of a therapeutically effective amount of Compound 1 to the subject once daily upon recurrence of symptoms of major depressive disorder,

provided that there is at least a six-week interval between the last dose of the primary administration of Compound 1 to the subject and the first dose of the re-administration of Compound 1 to the subject.

In one aspect, the present document provides a method for treating generalized anxiety disorder in a subject in need thereof, comprising the following steps:

(i) primary administration of a therapeutically effective amount of Compound of formula (I) once daily to a subject for 14 days:

and also

(ii) repeat administration of a therapeutically effective amount of Compound 1 to the subject once daily in response to a recurrence of symptoms of major depressive disorder,

provided that there is at least a six-week interval between the last dose of the primary administration of Compound 1 to the subject and the first dose of the re-administration of Compound 1 to the subject.

In one aspect, the present document provides a method for treating bipolar depression in a subject in need thereof, the method comprising the following steps:

(i) primary administration of a therapeutically effective amount of Compound of formula (I) once daily to a subject for 14 days:

and also

(ii) repeat administration of a therapeutically effective amount of Compound 1 to the subject once daily in response to a recurrence of symptoms of major depressive disorder,

provided that there is at least a six-week interval between the last dose of the primary administration of Compound 1 to the subject and the first dose of the re-administration of Compound 1 to the subject. In some aspects, provided herein are kits, wherein the kit includes a list of instructions describing a method for treating major depressive disorder, bipolar depression, anxiety disorder, or postpartum depression by administering Compound 1, wherein the method comprises 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 to the subject once a day for several 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 to the subject once a day for several weeks. In a preferred embodiment, the episodic dosing regimen is from about 2 weeks to about 6 weeks. In a more preferred embodiment, the episodic dosing regimen is from about 2 weeks to about 4 weeks. In an even more preferred embodiment, the episodic dosing regimen is about 2 weeks or about 14 days. In another embodiment, the episodic dosing regimen is 2 weeks.

The present document also provides methods for 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, the present document provides a method for 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 between the ages of 18 and 64, inclusive. 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 in three capsules.

In some embodiments, the anxiety is generalized anxiety disorder. Generalized anxiety disorder (GAD) is characterized by persistent and excessive worry about various things. People with GAD are prone to catastrophic events and may be overly preoccupied with money, health, family, work, or other issues. People with GAD have difficulty controlling their worry. They may worry about real-life events more than seems reasonable or may expect the worst, even when there is no obvious reason to worry.

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 recurring unwanted thoughts (obsessions) and/or repetitive behaviors (compulsions). Repetitive actions, such as hand washing, counting, checking, or cleaning, are often performed in the hopes of preventing or making the obsessive thoughts go away. However, performing these so-called "rituals" provides only temporary relief, and failure to perform them significantly increases anxiety. Panic disorder is an anxiety disorder characterized by unexpected and recurring episodes of intense fear, accompanied by physical symptoms that may include chest pain, rapid heartbeat, shortness of breath, dizziness, or abdominal discomfort. Post-traumatic stress disorder (PTSD) is an anxiety disorder that can develop after exposure to a terrifying event or experience that results in harm or the threat of serious physical harm. Traumatic events that can trigger PTSD include violent assaults, natural or man-made disasters, accidents, or military action. Social phobia, or social anxiety disorder, is an anxiety disorder characterized by overwhelming worry and excessive self-consciousness in everyday social situations. Social phobia can be limited to only one type of situation—for example, a fear of speaking in formal or informal situations, eating or drinking in front of others—or, in its most severe form, can be so broad that the person experiences symptoms almost always when around other people.

Disclosed are methods for treating major depressive disorder, bipolar depression, anxiety disorder, or postpartum depression using an episodic dosing regimen, comprising dosing Compound 1 to a subject in need thereof. In some embodiments, the method improves cognitive function in a subject after completion of the episodic dosing regimen. In some aspects, the method improves cognitive function in a subject after completion of the episodic dosing regimen, wherein the episodic dosing regimen has a duration of from about 2 to about 8 weeks. In additional aspects, the method improves cognitive function in a subject after completion of the episodic dosing regimen, wherein the episodic dosing regimen has a duration of from about 2 to about 6 weeks. In other embodiments, the method improves cognitive function in a subject after completion of the episodic dosing regimen, wherein the episodic dosing regimen has a duration of from about 2 to about 4 weeks. In further embodiments, the method improves cognitive function in a subject after completion of the episodic dosing regimen, wherein the episodic dosing regimen has a duration of about 2 weeks or 14 days. In other aspects, the method improves cognitive functions in a subject after completion of an episodic dosing regimen, wherein the episodic dosing regimen has a duration of 2 weeks.

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

In certain other aspects described herein, kits are provided comprising a plurality of individual dosage units of a pharmaceutical composition comprising Compound 1 and a list of instructions as described herein. In some embodiments, the list of instructions describes a method for administering said pharmaceutical composition to a patient, wherein said method includes an episodic dosing regimen. In another embodiment, the present invention provides a kit comprising:

1. A plurality of individual dosage units of a pharmaceutical composition comprising Compound 1; and

2. A list of instructions for administering the indicated dosage units to a patient requiring it using an episodic dosing regimen.

In some embodiments, the list of instructions is printed on a suitable material, such as paper. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form includes prefilled ampoules or syringes with premeasured liquid compositions, or pills, tablets, capsules, or the like for solid compositions. In some embodiments, the unit dosage is a size 1 capsule. In other embodiments, the capsules are size 000, 00, 0, 1, 2, 3, or 4, as is common in the art.

Examples

Example 1: Compound 1 and postpartum depression

Compound 1 was studied for use in patients with depression. The study enrolled women (18-65 years) diagnosed with major postpartum depression (PDD) with a HAM-D total score greater than or equal to 26 at screening on Day 1. Subjects were administered capsules containing 30 mg of Compound 1 once daily. The dose could be adjusted to capsules containing 20 mg of Compound 1 if the 30 mg dose was not tolerated. Subjects who did not receive Compound 1 were given placebo. Seventy-eight subjects were treated with Compound 1 at a dose of 30 mg, and 73 subjects were given placebo.

Statistical results

Assuming a two-sided test at an alpha level of 0.05, a sample size of approximately 65 evaluable subjects per treatment group provided 90% power to detect a placebo-corrected treatment difference of approximately 4 points in the primary endpoint, a difference from baseline in the HAM-D total score at day 15 with a standard deviation (SD) of 7 points. The change from baseline in the HAM-D total score was analyzed using a mixed-effects model for repeated measures (MMRM). The model included the change from baseline at each visit as the dependent variable. Outcomes (least mean squares [LSMEAN] difference) were compared between the Compound 1 capsule and placebo groups at day 15.

For model-based point estimates (i.e., LSMEAN, 95% confidence intervals, and p-values), an unstructured covariance structure was used to model between-subject errors. If a convergence issue occurred with the unstructured covariance model, a Toeplitz matrix, composite symmetry, or autoregressive(1) (AR[1]) covariance structure was used, following this sequence until convergence was achieved. If the model still did not converge with an AR(1) structure, the results were discarded. In cases where the covariance structure was not UN, a sandwich estimator for the variance-covariance matrix was calculated using the EMPIRICAL option in the PROC MIXED statement in SAS.

Similarly, MMRM was used to analyze the following variables: changes from baseline in the MADRS total score and the HAM-A total score, as well as subscale and item scores. For each model, the comparison of results between Compound 1 capsules and the corresponding placebo at the Day 15 time point was of interest. Model-based point estimates (i.e., LS means), 95% confidence intervals, and p-values are presented.

Results

Results show that the primary endpoint was met. The mean decrease from baseline in HAM-D total score was -18.0 (8.36) for subjects receiving Compound 1 (30 mg), compared with a mean baseline of 28.4 (2.09), and -13.6 (8.31) for subjects receiving placebo, compared with a mean baseline of 28.8 (2.32) on day 15. The difference, according to the model, in treatment groups on day 15 and the corresponding 95% internal confidence intervals (CI) was -4.2 (-6.9, -1.5) in favor of Compound 1, p-value = 0.0029. FIG. 1 shows the mean LS change from baseline in the Hamilton Rating Scale for Depression (HAM-D) total score over time by treatment group. FIG. 2 shows a forest plot of the subgroup analysis for the primary endpoint at day 15. FIG. 3 shows a histogram of Hamilton Rating Scale for Depression (HAM-D) remission by time point and treatment group. FIG. 4 shows a histogram of Hamilton Rating Scale for Depression (HAM-D) remission by time point and treatment group.

The HAM-D response and remission rates were significantly higher in subjects receiving Compound 1 compared with patients receiving placebo:

The HAM-D response rate was 53/74 (71.6%) for subjects receiving Compound 1 (30 mg) compared with 35/73 (47.9%) for subjects receiving placebo. The model-based odds ratio and corresponding (95% CI, confidence interval) was 2.63 (1.34, 5.16), p value = 0.0050.

Remission: 33/74 (44.6%) for subjects receiving Compound 1 (30 mg) versus 17/73 (23.3%) for subjects receiving placebo. The model-based odds ratio and corresponding odds ratio (95% CI) were 2.50 (1.22, 5.11), p value=0.0122.

Change in MADRS total score at day 15 and all other time points compared to baseline:

The mean reduction from baseline in MADRS total score was -22.0 (11.64) for subjects receiving Compound 1 (30 mg) compared to a baseline of 34.9 (4.41) and -17.7 (11.72) for subjects receiving placebo compared to a baseline of 36.3 (4.68) at Day 15. The model-estimated difference between treatment groups and the corresponding 95% confidence interval (CI) was -4.6 (-8.3, -0.8) in favor of Compound 1, p value=0.0182. The study results are shown in FIG. 5.

Change in HAM-A total score at day 15 and all other time points compared to baseline:

The mean reduction from baseline in HAMA total score was -16.5 (9.51) for subjects treated with Compound 1 (30 mg) from a mean baseline of 26.1 (5.88) and -12.9 (8.57) for subjects treated with placebo from a baseline of 27.2 (5.45) on Day 15. The model-estimated difference between treatment groups and the corresponding 95% confidence interval (CI) was -3.90 (-6.7, -1.1) in favor of Compound 1, p value=0.0063. The study results are shown in FIG. 6.

CGI-I response on day 15:

53/74 (71.6%) for subjects receiving Compound 1 (30 mg) compared with 38/73 (52.1%) for subjects receiving placebo. The odds ratio based on the model and corresponding confidence intervals (95% CI) was 2.15 (1.09, 4.27) in favor of Compound 1, p-value=0.0280. The results of the study described here are shown in FIG. 7.

The study demonstrated that Compound 1, administered at a dose of 30 mg once daily for 15 days (in a typical episodic dosing regimen), was effective in the treatment of postpartum depression compared to placebo.

Example 2: Phase 3, open-label, one-year study 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 (side) effect

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, Fifth Edition

ECG Electrocardiogram

eCRF Electronic Case Registration Form

EOT End of Treatment

ET Early Termination

FSH Follicle-stimulating hormone FSH

GABA (γ-aminobutyric acid)

HAM-D Hamilton Depression Rating Scale

HCV Hepatitis C virus

HIV Human immunodeficiency virus (HIV)

ICF Informed Consent Form

IRB Institutional Review Board

IRT Interactive Response Technology

ISI Insomnia Severity Index

MADRS Montgomery-Osberg Depression Rating Scale (MADRS)

MDD Major depressive disorder

MDE Major depressive episode

NCS has no clinical significance

PHQ-9 9-Item Patient Health Questionnaire

PK Pharmacokinetics

PSQ Patient Status Questionnaire

QTcF QT corrected according to Fridericia's formula

SAE Serious adverse effect

SAP Statistical Analysis Plan

SCID-5-CT Structured Clinical Interview for Diagnostic and Clinical Trials version of DSM-5

SD Standard Deviation

SDS Sheehan Disability Scale

SUSAR Suspected unexpected serious adverse reactions

TEAE Treatment-emergent adverse event

WHO (World Health Organization)

General research plan

Compound 1 was studied in an open-label, long-term, longitudinal study in adult subjects with MDD currently experiencing a major depressive episode (MDE). FIG. 8 shows a schematic representation of the study design.

The diagnosis of MDD was established using the Structured Clinical Interview for the DSM-5 Clinical Trial (SCID-5-CT) administered by a qualified health care professional. Subjects were assessed during a prescreening procedure during the screening visit to determine eligibility, including assessments on the MADRS and CGI-S.

The primary objective of the study was to determine the safety and tolerability of initial treatment and retreatment with Compound 1 in adults with MDD currently experiencing a major depressive episode (MDE) over a 1-year period.

The secondary objectives of the study were to evaluate the need for re-treatment with Compound 1 after initial treatment in adults with MDD currently experiencing MDE over a 1-year period, and to evaluate the response to initial treatment and re-treatment with Compound 1 after an initial 2-week treatment period (typical episodic dosing regimen) in adults with MDD currently experiencing MDE over a 1-year period.

The scientific objectives of the study were to develop a digital phenotype of adults with MDD currently experiencing MDE and evaluate potential correlations with clinical endpoints; evaluate the effect of Compound 1 on sleep; and evaluate patient-reported treatment outcome measures as they relate to the impact of depression on subjects' functioning, depression severity, functional capacity, subject symptom awareness, and subject satisfaction with Compound 1 treatment.

The primary endpoint of the study was the safety and tolerability of initial treatment with Compound 1 and retreatment with Compound 1, as assessed by parameters including: the incidence and severity of AEs/SAEs; changes from baseline in clinical laboratory parameters, vital signs, and electrocardiogram (ECG) results; and suicidal ideation and behavior assessed using the Columbia Suicide Risk Rating Scale (C-SSRS).

The secondary endpoints of this study were the need for retreatment with Compound 1, assessed by: time to first retreatment (Kaplan-Meier curves); the number of subjects eligible for retreatment; and the number of retreatment cycles for each subject. The following were taken into account: response to initial treatment and/or retreatment, assessed by the change in the 17-item HAM-D total score from baseline at the end of each 14-day treatment period (initial and/or retreatment); HAM-D response at the end of each 14-day treatment (initial and/or retreatment); recurrence, defined as a decrease in HAM-D score of ≥50% from baseline; HAM-D remission at the end of each 14-day treatment period (initial and/or retreatment), defined as a HAM-D total score ≤7; CGI-I response, defined as “much improved” or “much improved,” at the end of each 14-day treatment period (initial and/or retreatment); and change from baseline in the Clinical Global Impression - Severity (CGI-S) score at the end of each 14-day treatment period (initial and/or retreatment) (also referred to as typical episodic dosing regimens).

The exploratory endpoints of this study were: a digital phenotype developed by passively collecting baseline behavioral data such as GPS, text/phone use, and motor activity/sleep patterns in subjects who consented to use mobile phone-enabled software; the effect of Compound 1 on sleep as assessed by the Insomnia Severity Index (ISI); time to first use of a new ADT (Kaplan-Meier curves) and number of new ADTs used; patient-reported depressive symptoms as assessed by the 9-item questionnaire (PHQ-9); patient-reported functionality as assessed by the Sheehan Disability Scale (SDS); and patient-reported impact of depression on functioning, as well as patient perspective on symptoms and treatment satisfaction as assessed by the Patient Status Questionnaire (PSQ).

Subjects were enrolled for approximately 56 weeks: a screening period (28 days), an initial treatment period (14 days or typical episodic dosing regimen), a follow-up period (14 days), and an observation period (48 weeks). Additional 14-day retreatment periods (or repeat episodic dosing regimen) with Compound 1 could occur during the 48-week observation period.

All subjects received a daily oral dose of Compound 1 from days 1 to 14 of the first treatment cycle. Based on the recurrence, relapse, or reappearance of depressive symptoms, Compound 1 was administered in subsequent 14-day treatment periods (repeat administration or further episodic dosing).

Subjects who responded to Compound 1 were followed for 48 weeks.

Beginning on day 1, qualified subjects self-administered 30 mg of Compound 1 orally once daily in the evening for 14 days. A follow-up visit was conducted 14 days (±1 day) after completion of the 14-day treatment period.

If a subject did not demonstrate a response to Compound 1 by Day 15 of initial treatment, defined as a decrease in HAM-D score of ≥50% from baseline, the subject was withdrawn from the study at the completion of the 14-day observation period.

After the initial treatment period, subjects were followed naturally for 48 weeks. Subjects returned to the center every 8 weeks (beginning with the first observation period) for clinical evaluation during the 48-week observation period.

Compound 1 Treatment Cycles

Each 14-day Compound 1 treatment period and the corresponding 14-day follow-up period were considered a cycle (Day 28). The initial treatment was Cycle 1, and retreatments were numbered sequentially. Each cycle began 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 permitted; no new retreatment cycle was administered after 48 weeks. Subjects starting a new Compound 1 treatment cycle between weeks 45 and 48 were followed until the end of the treatment cycle (Day 28, the end of the post-treatment cycle follow-up period).

The need for retreatment was assessed every 14 days via remote assessment during the 48-week follow-up period based on self-reported PHQ-9 scores; if the PHQ-9 score was ≥10, the subject returned on-site for a clinician-assigned HAM-D assessment. New cycles of Compound 1 treatment were initiated for subjects with a HAM-D score ≥20, determined approximately 1 week later by a PHQ-9 score ≥10.

A minimum period or interval of 8 weeks (56 days) was required between treatment cycles with Compound 1. This was based on the 8-week period required to establish "complete remission" of a major depressive episode (American Psychiatric Association, 2013) and was consistent with the treatment period required for any available antidepressant (ADT) to demonstrate maximum efficacy.

Because this was the first study to examine longitudinal re-treatment with Compound 1, based on known withdrawal symptoms associated with other GABAergic drugs and non-clinical data from a 9-month study of Compound 1 in dogs, the possibility of withdrawal-related events, including seizures, were also monitored.

Packaging and labeling of investigational drugs

Compound 1 was provided to the clinic pharmacist and/or designated site personnel responsible for dispensing the study medication in appropriately labeled, individual kits containing sealed unit doses. Each unit dose consisted of one capsule.

Administration of the study drug

Compound 1 was administered orally once daily in the evening with food. Practical options included taking Compound 1 within 1 hour after lunch or taking Compound 1 in the evening with a solid meal. If a subject forgot to take a dose, they simply skipped that dose (i.e., they were not supposed to take the morning dose) and took the next scheduled dose the following evening.

Because this was the first study to examine longitudinal re-treatment with Compound 1, based on the known withdrawal symptoms of other GABAergic drugs and non-clinical data from a 9-month study of Compound 1 in dogs (Investigator's Brochure), the possibility of drug-related withdrawal events (upon discontinuation of study drug or dose reduction), including seizures, was anticipated and monitored.

If a subject exhibited suicidality at any time, he or she was referred for assessment by the Investigator as soon as possible.

The assessments for the screening period and the treatment and follow-up periods are summarized in Table 1; the assessments for the observation period and any unscheduled visits are presented in Table 2.

Table 1

Screening period ^{a, b} Cycle ^c Open treatment period (initial and retreatment) Observation period Days Days D-28 to D-1 D1 D8
(+1d) D15
(±1d)/ EOT ^d D28 (±1d)
and/or ET Research procedure Informed consent X Subject re-examination X Inclusion/Exclusion X X Demography X Medical History/Family History X SCID-5 X ICD-10 X MGH ATRQ X Serum FSH test ^f X Physical examination ^g X X Body weight/height X X (weight only) Clinical laboratory tests ^h X X X X Drug and alcohol screening ⁱ X X X X Pregnancy test ^j X X X ^k Screening for hepatitis and HIV X Blood sample for research ^l O O O Genetic testing for ^m research O Vital signs ⁿ X X X X X 12-lead ECG ^o X X X C-SSRS ^p X X X X X MADRS X X HAM-Dq ^r X X X X ^s CGI-S X X X X X CGI-I X X X PHQ-9 X X X X SDS X X X PSQ X X ISI X X X X Dispensation of investigational medicinal products X X Administration of the investigational drug X (Day 1 - Day 14) Reporting/return of investigational medicinal products X X Digital phenotyping (mobile app) ^b,t O Side effects/SAE ^s,u X Previous/concomitant medications ^v X

CGI-I = Clinical Global Impression - Improved;

CGI-S = Clinical Global Impression - Severity;

C-SSRS = Columbia Suicide Severity Rating Scale;

D = (D) day;

ET = early termination;

ECG = electrocardiogram;

EOT = end of treatment;

FSH = follicle-stimulating hormone;

HAM-D = Hamilton Depression Rating Scale, 17 items;

HIV = human immunodeficiency virus;

ICD-10 = International Statistical Classification of Diseases and Related Health Problems, version 10;

ISI = Insomnia Severity Index;

MADRS = Montgomery-Åsberg Depression Rating Scale;

MGH ATRQ = Massachusetts General Hospital Antidepressant Treatment Response Questionnaire;

O = Optional;

SCID-5 = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition;

PHQ-9 = 9-item patient health questionnaire;

PSQ = Patient Status Questionnaire;

SAE = serious adverse event;

SDS = Sheehan Disability Scale;

wt = weight

^a Screening procedures should only be performed before the initial treatment period (cycle 1).

^b A minimum of 14 days of screening is required for subjects who have consented to use mobile phone-supported software for digital phenotyping.

^Each cycle is 28 days (±1 day) and consists of a 14-day treatment period and a 14-day observation period. The initial treatment is considered Cycle 1, and repeat treatments are numbered sequentially. Each repeat treatment cycle will begin on Day 1 (e.g., the first day of the first repeat treatment will be Day 1 of Cycle 2).

^Subjects who discontinue treatment prematurely must return to the treatment facility for end-of-treatment (EOT) as soon as possible, preferably on the day following treatment discontinuation. Follow-up visits should occur 14 days after the last dose of treatment. If at any time after the EOT visit, a subject decides to discontinue the study, the early discontinuer (ET) must return for follow-up (ET visit). EOT and ET visits may be on the same day if the subject discontinues the study drug and discontinues the study on the same day during a clinic visit; in this case, all activities scheduled for the EOT visit will be carried out.

^e Subjects will be asked to sign permission to enter their unique identifiers into the study registry (www.subjectregistry.com) for the purpose of identifying subjects who meet exclusion criteria for participation in another clinical trial.

^f Serum FSH assay will be performed at screening for women who are not surgically sterile to confirm whether a female subject with spontaneous amenorrhea for ≥12 months meets protocol-defined criteria for postmenopausal status.

A ^full physical examination will be performed during screening, and an abbreviated physical examination will be performed during the post-screening examination. The full physical examination includes an assessment of body systems (e.g., head, eyes, ears, nose, and throat; heart; lungs; abdomen; and extremities).

^h Laboratory tests for safety of use include hematology, serum chemistry, coagulation, and urinalysis.

ⁱ Urine toxicology tests for certain drugs of abuse (according to laboratory manual) and breath test for alcohol.

^j Serum pregnancy test at screening and URI pregnancy test during the study.

^k Female subjects who discontinue treatment prematurely will undergo a pregnancy test during their EOT visit.

^l Additional blood sample for hormone and biochemical testing for research subject to consent.

^m Optional genetic sample for biomarker testing with consent.

Vital ^signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (in the supine and standing positions). Pulse rate and blood pressure measurements in the supine position at all scheduled time points are taken after the subject has rested for 5 minutes and then transitioned to a standing position. Vital sign measurements may be repeated at the investigator's discretion as clinically indicated.

^o ECG is performed in three repetitions.

^The C-SSRS "Baseline/Screening" form is completed during screening. The C-SSRS "Since Last Visit" form is completed at any time of day and at all subsequent time points.

^q The HAM-D assessment should be done as early as possible during the visit.

^r The time frame for the HAM-D assessment is valid for the previous 7 days (1 week).

^s Subjects who do not demonstrate a response to Compound 1 by Day 15 of initial treatment, defined as a decrease in HAM-D score of ≥50% from baseline, are excluded from the study after completion of the follow-up visit.

^t Subjects who provide consent use mobile phone-enabled software from the screening visit throughout the study.

^u Data on adverse events are collected starting from the time informed consent is obtained and throughout the subject's participation in the study.

^v Previous medications will be collected at screening and concomitant medications will be collected at each subsequent visit.

Table 2

Observation period ^a (from Day 29 to Week 52) Remote Q2W assessment (±1 day) Visit Q8W/ET (± 3 days) Unscheduled visit (if necessary) ^b Research procedure PHQ-9 ^c X ^d X X Physical examination X Body weight X Clinical laboratory tests X Drug and alcohol screening X Pregnancy test X Vital signs X 12-lead ECG X C-SSRS X HAM-D ^e X X CGI-S X CGI-I X SDS X X ISI X X Concomitant medications ^f X X Digital Phenotyping (Mobile App) ^g O Side effects/SAE ^h X ECG=electrocardiogram; ET=early termination; HAM-D=Hamilton Depression Rating Scale 17-item; ISI=insomnia severity index; O=optional; PHQ-9=9-item patient health questionnaire; PSQ=patient status questionnaire; Q2W=every 2 weeks; Q8W=every 8 weeks; SDS=Sheehan Disability Scale; SAE=serious adverse event

^a The schedule of assessments during the follow-up period should be based on the last day of the previous treatment cycle (e.g., the first of the Q2W remote assessments will be on day 42 (±1 day), and the first of the Q8W visits will be on day 84 (±3 days)).

^b The subject should return for assessment outside the Q8W visit schedule if the PHQ-9 score is ≥10 and/or if any suicidal ideation or behavior occurs.

^c All PHQ-9 assessments are performed using mobile phone-enabled software.

^d The subject should complete the PHQ-9 every 14 days; if the PHQ-9 score is ≥10, the subject should return for a clinician-assigned HAM-D assessment visit approximately one week later. If the HAM-D score is <20, the subject should complete the PHQ-9 weekly: the subject should return for a HAM-D assessment every week as long as the PHQ-9 score remains ≥10; if the PHQ-9 score is <10, the subject should return for a PHQ-9 assessment every 2 weeks.

^e If the HAM-D score (obtained approximately one week after obtaining a PHQ-9 score ≥10) is ≥20 and remains so for at least 8 weeks from the last day of treatment of the previous Compound 1 treatment cycle (i.e., day 70 or later), the subject may begin a 14-day retreatment period with a 14-day observation period (see Table 1). If the HAM-D score is ≥20, but less than 8 weeks have passed since the last day of treatment of the previous Compound 1 treatment cycle (i.e., day 69 or earlier); the subject should be assessed on PHQ-9 weekly until the 8-week period has elapsed, after which the subject may begin the retreatment period with Compound 1 (see Table 1) or until a PHQ-9 score <10 is achieved.

^f Concomitant medications will be collected at each clinic visit.

^g Subjects who consent to digital phenotyping will use mobile phone-enabled software starting at the screening visit throughout the study.

^h Data on adverse (undesirable) effects should be collected starting from the moment informed consent is obtained and throughout the entire period of the subject's participation in the study.

Dose justification

The dose level in this study, 30 mg daily, was the same dose level that was effective and well-tolerated in the Phase 2 study in subjects with MDD. Dose adjustments up to 20 mg of Compound 1 were allowed; 20 mg of Compound 1 was expected to be well-tolerated, as this concentration is lower than the maximum tolerated dose. Due to the sedation/somnolence observed in previous clinical trials with morning administration and improved tolerability with evening administration, Compound 1 was administered in the evening in this study.

According to the DSM-5, a period of 8 weeks is required to consider a depressive episode "completely remitted" (American Psychiatric Association 2013). Furthermore, currently available antidepressants (ADTs) often require up to 8 weeks to achieve maximum effectiveness. Therefore, a minimum period of 8 weeks (56 days) was required between the end of a 14-day treatment period and the start of a new treatment cycle with Compound 1.

Dose adjustment criteria

If 30 mg of Compound 1 was not tolerated at any time, as assessed by the occurrence of a severe AE deemed related to study drug by the investigator, the dose was reduced to 20 mg as soon as possible and continued for the remainder of the treatment period. Dose adjustments related to moderate AEs were determined by the investigator. If the investigator deemed a dose change from 30 to 20 mg necessary, the subject returned to the site for administration of the adjusted dose. Any retreatment period began with a dose of 30 mg, regardless of whether a dose adjustment was required in the previous treatment period. Subjects intolerant of the 20 mg dose at any time were withdrawn from the study drug trials, and the subject was withdrawn from the study at the conclusion of the subsequent 14-day observation period.

Inclusion criteria for subjects

Subjects eligible for participation in the study met all of the following criteria:

1. The subject signed the ICF before performing any study-specific procedures.

2. The subject was a man or woman between the ages of 18 and 75 years, inclusive.

3. The subject was in good physical health and had no clinically significant abnormalities as determined by the investigator by physical examination, 12-lead ECG, or clinical laboratory testing.

4. The subject agreed to comply with the requirements of the study.

5. The subject had a diagnosis of MDD according to the SCID-5-CT, with symptoms present for at least a 4-week period.

6. Subject has a MADRS total score ≥28 at Screening and Day 1 (pre-dose).

7. Subjects taking antidepressants used to treat major depressive disorder must have taken these medications at the same dose for at least 60 days prior to Day 1.

8. The female subject agrees to use one of the following methods of contraception during study participation and for 30 days after the last dose of study drug, unless she is postmenopausal (defined as the absence of menses for 12 months without an alternative medical reason and confirmed by an FSH-follicle stimulating hormone [FSH] test > 40 mIU/mL), or is surgically sterile (hysterectomy or bilateral oophorectomy), or has not had sexual intercourse that carries a risk of pregnancy: combined hormonal contraceptives (containing an estrogen and a progestogen) associated with ovulation suppression, orally, intravaginally, or transdermally; oral, injectable, or implantable hormonal contraceptives containing only progestogens associated with ovulation suppression; intrauterine device; intrauterine hormone-releasing system; Bilateral tubal ligation/occlusion; partner has had a vasectomy; sexual abstinence (refusal from sexual intercourse).

9. The male subject agrees to use an acceptable method of effective contraception during the study and for 5 days after the last dose of study drug, unless the subject has not engaged in sexual activity that carries a risk of pregnancy. Acceptable methods of effective contraception for males include sexual abstinence, vasectomy, or the use of a condom with spermicide in combination with highly effective methods of contraception for females if the female partner(s) are of childbearing potential (see Inclusion Criteria #8 for information on acceptable methods of contraception).

10. The male subject agrees to refrain from donating sperm during the study period and for 5 days after receiving the last dose of study drug.

11. The subject agrees to abstain from drug and alcohol abuse during the study period.

Exclusion criteria for subjects

Subjects meeting any of the following criteria were excluded from participation in this study:

1. The subject attempted suicide in connection with the current episode of MDD.

2. The subject has a history of or has active clinically significant metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological, urogenital, neurological, or eye, ear, nose, and throat disease or any other acute or chronic condition that, in the opinion of the investigator, would limit the subject's ability to complete or participate in this clinical trial.

3. The subject had treatment-resistant depression, defined as the presence of persistent depressive symptoms despite treatment with adequate doses of antidepressants (excluding antipsychotics) from two different classes for at least 4 weeks of treatment during the current major depressive episode. The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire was used to meet this criterion.

4. The subject has received vagus nerve stimulation, electroconvulsive therapy, or ketamine during the current episode of major depression.

5. The subject was taking benzodiazepines, barbiturates, or GABA modulators (e.g., eszopiclone, zopiclone, zaleplon, and zolpidem) on day 28, or the subject was taking these agents daily or nearly daily (≥4 times/week) for a period longer than one year.

6. Subject received non-GABA anti-insomnia medications (e.g., melatonin, benadryl [antihistamines], trazodone, low-dose quetiapine, mirtazapine, etc.) and/or atypical antipsychotics (e.g., aripiprazole, quetiapine) on Day 14.

7. The subject had a documented allergy to Compound 1, allopregnanolone, or related compounds.

8. The subject had a positive pregnancy test at screening or on Day 1 prior to starting study drug administration for any treatment cycle.

9. A subject who was breastfeeding at Screening or on Day 1 (prior to study drug administration) did not agree to temporarily discontinue breastfeeding their child(ren) from immediately prior to study drug administration on Day 1 until 7 days after the last dose of study drug of each treatment cycle.

10. The subject had detectable hepatitis B surface antigen, hepatitis C virus (HCV), a positive HCV viral load, or human immunodeficiency virus (HIV) antibodies at screening.

11. The subject had a clinically significant abnormal 12-lead ECG during screening or baseline visits. NOTE: A mean QT interval calculated using the Fridericia method (QTcF) of >450 ms in men or >470 ms in women was grounds for exclusion from the study.

12. The researcher assessed the subject as experiencing active psychosis.

13. The subject has a documented history of seizures.

14. The subject has a documented history of bipolar disorder, schizophrenia, and/or schizoaffective disorder.

15. The subject had a history of mild, moderate, or severe substance use disorder (including benzodiazepines) diagnosed using DSM-5 criteria within 12 months prior to screening.

16. Subject was using psychostimulants (e.g., methylphenidate, amphetamine) or opioids regularly or as needed on Day -28.

17. The subject has received another investigational drug or system within 30 days prior to screening.

18. The subject has previously participated in a clinical trial of Compound 1 or brexanolone.

19. Use of any known strong cytochrome P450(CYP)3A4 inhibitors within 28 days or 5 half-lives (whichever is longer) or consumption of grapefruit juice, grapefruit, Seville oranges or products containing them within 14 days prior to receiving the first dose of study medicinal product for any treatment cycle with Compound 1.

20. Use of the following strong CYP3A4 inducers within 28 days prior to the first dose of study drug for any treatment cycle with Compound 1: rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, and St. John's wort.

21. The subject had a positive drug and/or alcohol screen at screening or on day 1 prior to dosing of the initial treatment cycle.

22. The subject is scheduled for elective surgery during the initial treatment and follow-up periods.

23. The subject has been diagnosed with and/or treated for any type of cancer (except basal cell carcinoma and melanoma in situ) within the last year prior to screening.

24. The subject exhibits sleep apnea syndrome.

25. The subject has undergone gastric bypass surgery, gastric band placement, or any procedure that interferes with gastrointestinal transit.

Subject criteria for discontinuation from the study.

Subjects could refuse to participate in investigational drug trials or discontinue participation in the study at any time for any reason. The investigator could withdraw a subject from the investigational drug trial or the study for any of the following reasons: the subject was unwilling or unable to adhere to the protocol; the subject experienced an intolerable AE; or other medical or safety reasons at the discretion of the investigator and/or medical monitor.

The investigator immediately notified the Sponsor and/or Medical Oversight if a subject refused to take the study drug or discontinued participation in the study for any reason. The reason was recorded in the subject's electronic case report form (eCRF).

If a subject consistently violated the protocol, the Investigator discussed possible termination of the study with the Sponsor. Any reasons for unwillingness or inability to adhere to the protocol were recorded in the subject's electronic eCRF, including: missed visits, interruptions in study drug administration, and use of unapproved medications.

Subjects who discontinued the study due to an AE, regardless of causality determined by the investigator, were followed until the effect ended, stabilized, or until the investigator determined that the effect was no longer clinically significant.

Subjects who discontinued study medication prematurely during the treatment period were referred for an end-of-treatment (EOT) visit as soon as possible, preferably on the day after discontinuation. A follow-up telephone call and remote assessment were conducted 14 days after the last dose of treatment. Thereafter, the subject continued the observation period as scheduled (Table 2).

If at any time during the follow-up or observation period a subject decided to discontinue the study, the subject contacted site management and completed their remote assessments through an early treatment discontinuation (ET) visit. The ET visit occurred on the same day as the EOT visit if the subject discontinued the study drug and discontinued the study on the same day during the treatment period; in this case, all activities scheduled for the EOT visit were carried out.

A subject was considered lost to follow-up after attempts to contact the subject were unsuccessful.

Individual subject criteria for termination

This was the first study to examine the effect of longitudinal repeated treatment with Compound 1.

Based on information on known withdrawal symptoms with other GABAergic drugs and non-clinical data from the 9-month study of Compound 1 in dogs (Investigator's Brochure), there was a potential for discontinuation-related events, including seizures. The following recommendations for discontinuation of study drug or dose reduction were provided to ensure subject safety: (1) any subject reporting a confirmed or suspected seizure at any time was discontinued from treatment and was not eligible for another treatment cycle but continued to be observed during the study; (2) after the first treatment period, the investigator monitored for the development of CNS-related signs and symptoms suggestive of seizures that were not associated with concomitant psychiatric or medical conditions. Examples of reported serious or severe events that may reflect an impending and/or increased risk of seizures/convulsions included transient confusion, tremor, involuntary muscle fasciculations, twitching of the arms or legs, or paresthesia. If such symptoms occurred, the investigator, in consultation with Sage Medical Monitor, considered reducing the study drug dose to 20 mg, discontinuing treatment to assess the effect on the symptom(s) (e.g., resolution, improvement, etc.), or discontinuing treatment. Subjects discontinuing treatment remained in the study, where they were monitored and assessed according to the protocol until the end of the study.

Because this was an open-label study, any severe or serious events were assessed on an ongoing basis, including an assessment of the benefit/risk profile of Compound 1 in the context of the ongoing study. Based on these data, the sponsor modified or terminated the study.

Previous and concomitant medications and/or supplements

The start and end dates, routes of administration, dose/units, frequency of administration, and indications for all medications and/or supplements taken by the subject within 30 days prior to screening and throughout the study were recorded. Antidepressant therapy use in the three years prior to screening was also recorded.

Any medications and/or supplements necessary for the subject's well-being were given to the subject at the investigator's discretion at any time during the study.

Antidepressants that had been taken at the same dose for at least 60 days prior to Day 1 were allowed if the subject intended to continue using a stable dose of such during the initial treatment and follow-up period (up to Day 28 of Cycle 1).

See Table 3 for the permitted concomitant psychotropic medications during each study period.

Use of medications for worsening depressive symptoms after a course of treatment with Compound 1

Of the subjects who achieved remission or treatment response at Day 15 (78.6%), 6.1% had a HAM-D ≥22 at Day 42; another 18.2% had a HAM-D score of 16 to 21 at Day 42. This result means that most subjects for whom a new MDE is possible are likely to experience this new MDE episode after they enter the minimum required period (8 weeks or 56 days) before a new Compound 1 treatment cycle. For this reason, most subjects met the criteria (i.e., PHQ-9 ≥10 and HAM-D ≥20, confirmed for 2 weeks) for a Compound 1 treatment cycle, if deemed necessary; a 2-week period was required for the diagnosis of a new MDE (according to DSM-5).

For subjects who experienced a worsening of depressive symptoms after day 28 and did not yet meet criteria for a new treatment cycle with Compound 1, 2 intervention options were designed: as-needed medication (limited to a maximum of 4 days per week) and/or either the introduction of a new antidepressant (ADT) or an increase in the dose of the current ADT ( Table 3 ). Antidepressant (ADT) use conditions: to maintain clinical equivalence, all ADT use cases (e.g., new Compound 1, new ADT, or an increase in the dose of the current ADT) required a PHQ-9 ≥10 and HAM-D ≥20, confirmed for 2 weeks. If a subject on a stable ADT experienced a worsening of depressive symptoms (PHQ-9 ≥10), only as-needed medication use was recommended, provided the HAM-D score was <20; If the HAM-D score was ≥20, the current dose was increased or a new ADT was introduced. Additionally, physicians considered an individual subject's initial experience with Compound 1 when initiating any new ADT, as this could significantly reduce the likelihood that a new cycle of Compound 1 treatment would be approved when the time was right (i.e., the HAM-D could be <20). There were no PHQ-9 or HAM-D score requirements for "as-needed" medication use.

Approved "as needed" medications for symptom management include benzodiazepines, GABA modulators for insomnia (eg, eszopiclone, zopiclone, zaleplon, and zolpidem), and non-GABA medications used for insomnia; use of such treatments should be limited to a maximum of 4 days per week.

If medications and/or a new ADT were administered as needed, or the dose of the current ADT was increased, and the subject continued to exhibit HAM-D ≥20, a new cycle of Compound 1 treatment could be initiated on or after day 70. After completion of the new cycle of Compound 1 treatment, continuation of any interventions used during the previous observation period was at the discretion of the investigator.

Any use of benzodiazepines and/or GABA-modulating medications during the observation period was discontinued 7 days prior to any new Compound 1 treatment cycle. If necessary, use of non-GABA-modulating medication was discontinued 1 day prior to the start of any new Compound 1 treatment cycle.

Medicines intended for contraception were approved for women.

Table 3

Period Time of the event * Approved psychotropic drugs Justification Compound 1
treatment
(eg, episodic dosing regimen) From Day 1 to Day 14 Compound 1
Stable ADT
Lack of necessary medications ^a
No new ADTs Rate the answer to Compound 1 Compound 1
Observation From Day 15 to Day 28 Stable ADT
Lack of necessary medications ^a
No new ADTs To assess the safety of Compound 1 during follow-up Observation Observation days from day 29 to 7 days before the next Conjunction 1
treatment cycle, if applicable Benzodiazepines (regularly or as needed)
GABA modulators for insomnia as needed Establish "complete remission"
Assess the progression of symptoms over time Observation days from day 29 to day 1 before the next Conjunction 1
treatment cycle, if applicable If necessary, treatment of insomnia with drugs that do not modulate GABA From Day 29 for the duration of the next Compound 1 treatment cycle, if applicable Stable ADT
New ADTs (except benzodiazepines) ^b

^a “As needed” medications (benzodiazepines, GABA modulators for insomnia [eg, eszopiclone, zopiclone, zaleplon, and zolpidem], and non-GABA medications for insomnia (eg, melatonin, benadryl [antihistamines], trazodone, mirtazapine, etc.]) should be limited to 4 days per week maximum.

^b If a patient on a stable ADT experiences a worsening of depressive symptoms (PHQ-9 ≥10), it is recommended to use medications only “as needed” if the HAM-D score <20; if the HAM-D score ≥20, the current ADT dose may be increased or a new ADT may be introduced.

* Time relative to the initial/previous cycle of Connection 1

ADT=antidepressant; Stable ADT=ADT started before the study and continued at baseline, or any new ADT started during the observation period and continued thereafter during a new Compound 1 cycle.

Example 3: A Phase 3, randomized, double-blind, placebo-controlled study of the efficacy and safety of Compound 1 with a fixed-dose, repeatable regimen in the prevention of relapse in adults with major depressive disorder ( MDD )

The phase was an open-label phase followed by a randomized, double-blind, placebo-controlled study to evaluate the effect of Compound 1 monotherapy compared with placebo in a fixed-dose, repeat-dose regimen for the prevention of relapse in adult patients with MDD (Montgomery-Åsberg Depression Rating Scale [MADRS] ≥32, HAM-D ≥22) not currently taking antidepressants. FIG. 9 provides a schematic representation of the study design.

The planned duration of subject participation was up to 52 weeks, including a screening period (up to 4 weeks), an open-label (OL) phase (8 weeks), and a double-blind (DB) phase (40 weeks).

The screening period (Table 4) began with the signing of the informed consent form (ICF); the ICF was signed before any screening. The diagnosis of MDD was made according to the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), Clinical Trial Version (SCID-5-CT), administered by a qualified health care professional. Subjects completed preliminary screening procedures during the screening visit to determine eligibility, including completion of the MADRS and CGI-S.

Beginning on day 1 of the OL phase, eligible subjects self-administered a single dose of study drug once daily in the evening with a meal in an outpatient setting for 14 consecutive days. Practical options included taking Compound 1 within 1 hour after lunch or taking Compound 1 in the evening with a solid meal. Subjects returned to the study center during the OL treatment and follow-up periods, as shown in Table 5 .

Subjects who completed the OL phase (up to day 56) without significant tolerability issues, as assessed by the investigator, and who demonstrated a HAM-D response, defined as a decrease of ≥50% from baseline in the HAM-D total score, at visits 4, 6, 7, and 8 (see Table 5 ), met the criteria for the DB phase. One deviation of <50% decrease from baseline in the HAM-D total score at visits 6, 7, or 8 was allowed to meet the criteria for the DB phase.

Beginning on day 1 of the DB phase, eligible subjects were randomized to receive 30 mg of Compound 1 or matching placebo in a 1:1 ratio. The 40-week DB phase consisted of five 14-day treatment periods separated by a 6-week follow-up period; the end of each follow-up period coincided with the first visit of the following treatment period. During the 14-day treatment period, subjects self-administered a single dose of study drug once daily in the evening with meals in an outpatient setting. Subjects returned to the study center during the DB treatment and follow-up periods, as indicated in Table 5 .

During subsequent periods of the DB phase, depressive symptoms were monitored every 7 days using the remote PHQ-9; if the PHQ-9 score was ≥10, the subject returned to the treatment facility as soon as possible for a clinician-assigned HAM-D assessment ( Table 6 ). If the HAM-D was ≥18 during this visit, the subject returned to the treatment facility 7–14 days later for a repeat HAM-D assessment ( Table 6 ); if the HAM-D remained ≥18, the subject was considered to have relapsed. A subject was considered to have relapsed if there was any worsening of depression requiring hospitalization, any investigator-ascertained suicide risk, and/or any other clinically significant event not requiring hospitalization. Subjects who relapsed during the DB phase as determined by the investigator were withdrawn from the study after completion of the early termination (ET) visit; If a subject relapsed during the treatment period, the subject was scheduled for an end-of-treatment (EOT) appointment as soon as possible, as well as an ET visit 7 days after the EOT visit. The final assessment of relapse was made by the Independent Relapse Review Committee (IRAC).

If 30 mg of Compound 1 was not tolerated during any period of the study, as assessed by the occurrence of a severe AE deemed related to the study drug by the investigator, the dose was reduced to 20 mg and continued at that dose for the remainder of the treatment period. Dose adjustments related to moderate AEs were at the investigator's discretion. Subsequent treatment periods began with a 30 mg dose, regardless of whether a dose adjustment was required in the previous treatment period. Subjects who could not tolerate the 20 mg dose at any time were withdrawn from the study after completing the EOT visit scheduled as soon as possible and the ET visit 7 days after the EOT.

The primary objective of this study was to evaluate the efficacy of Compound 1 in a fixed, repeated treatment regimen to prevent relapse in subjects with major depressive disorder (MDD) who demonstrated a response to treatment with Compound 1 in the OL phase.

The secondary objective of this study was to evaluate the long-term safety and tolerability of a fixed-dose, repeatable regimen of Compound 1 for up to 1 year.

Other objectives of this study were to evaluate the efficacy of Compound 1 in combination with a fixed, repeated treatment regimen compared with placebo on performance status, activity, and health-related quality of life in subjects with MDD, and to evaluate the pharmacokinetics (PK) of Compound 1 using a population PK approach.

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

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

Other endpoints of this study were: changes from baseline in vital signs and electrocardiogram (ECG) in clinical laboratory parameters, changes from baseline in suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale (C-SSRS); withdrawal syndrome assessment using the Physician's Withdrawal Checklist (PWC-20); PRO score of work and activity impairment assessed by the change from baseline of the Work Productivity and Activity Impairment Questionnaire (WPAI) Specific Health Problem V2.0 (absenteeism, presenteeism, total work impairment, and total activity impairment); PRO score of health-related quality of life assessed by the change from baseline of the EuroQol Group 5-dimension 5-level questionnaire (EQ-5D-5L); PK parameters (e.g., clearance) and exposure estimates (e.g., area under the curve over a dosing interval, maximum plasma concentration) estimated using population PK methods.

Inclusion criteria:

Qualified subjects met all of the following criteria:

1. The subject signed the ICF before performing any study-specific procedures.

2. The subject was a man or woman between the ages of 18 and 65 years, inclusive.

3. The subject was in good physical condition and had no clinically significant abnormalities as determined by the investigator on physical examination, 12-lead ECG, or clinical laboratory testing.

4. The subject agreed to comply with the requirements of the study.

5. The subject was diagnosed with MDD, as determined by the SCID-5-CT, with symptoms present for at least a 4-week period.

6. The subject had at least 1 previous major depressive episode (MDE) in the 5 years prior to screening (not including the current episode).

7. Subject had a MADRS total score ≥32 and HAM-D total score ≥22 at Screening and on Day 1 (pre-dose) of the open-label (OL) phase.

8. The subject agreed to defer initiation of treatment with antidepressants, anxiolytics, anti-insomnia medications, psychostimulants, or prescription opioids until completion of the study.

9. Subjects receiving psychotherapy were required to have received it on a regular schedule for at least 60 days prior to Day 1.

10. The female subject agreed to use one of the following highly effective contraceptive methods during study participation and for 30 days after the last dose of study drug, unless she was postmenopausal (defined as the absence of menses for 12 months without an alternative medical reason and confirmed by a follicle stimulating hormone [FSH] test > 40 mIU/mL), surgically sterile (hysterectomy or bilateral oophorectomy), or agreed not to engage in sexual intercourse that carries a risk of pregnancy:

Combined (containing estrogen and progestogen) oral, intravaginal or transdermal hormonal contraceptives associated with ovulation suppression;

Oral, injectable, or implantable hormonal contraceptives containing only progestogens associated with ovulation suppression;

Intrauterine device;

Intrauterine hormone release system;

Bilateral tubal ligation/occlusion;

Partner who has had a vasectomy.

11. The male subject agreed to use an acceptable method of effective contraception for the duration of the study and for 5 days after the last dose of study drug, or the subject agreed not to engage in sexual activity that carries a risk of pregnancy. Acceptable methods of effective contraception for men included vasectomy or the use of a condom with spermicide in combination with highly effective contraceptive methods for women if the female partner was of childbearing potential (see Inclusion Criteria #10 for information on acceptable methods of contraception).

12. The male subject agrees to refrain from donating sperm during the study period and for 5 days after receiving the last dose of study drug.

13. The subject agrees to abstain from drug and alcohol abuse during the study period.

Exclusion criteria:

Subjects meeting any of the following criteria were excluded from participation in this study:

1. The subject attempted suicide in connection with the current episode of MDD.

2. The subject had a recent history or active clinically significant manifestations of metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, musculoskeletal, dermatological, urogenital, neurological, or eye, ear, nose, and throat disease or any other acute disease or chronic condition that, in the opinion of the investigator, would limit the subject's ability to complete or participate in this clinical trial.

3. Subjects with a body mass index (BMI) ≤18 or ≥50 kg/m2 at screening were excluded; subjects with a BMI of 40 to 49 kg/m2 inclusive at screening underwent a detailed assessment of comorbidities (such as sleep apnea, COPD), concomitant medications, and past tolerance to sedatives.

4. The subject had treatment-resistant depression, defined as the presence of persistent depressive symptoms despite treatment with adequate doses of antidepressants of two different classes in the current major depressive episode (excluding antipsychotics) for at least 4 weeks of treatment. The Massachusetts General Hospital Antidepressant Treatment Response Questionnaire was used for this purpose.

5. The subject has received vagus nerve stimulation, electroconvulsive therapy, or ketamine during the current episode of major depression.

6. Subject had been taking antidepressants for 60 days prior to Day 1.

7. The subject was taking benzodiazepines, barbiturates, or GABA modulators (e.g., eszopiclone, zopiclone, zaleplon, and zolpidem) on Day -28, or the subject had been taking these agents daily or nearly daily (≥4 times/week) for a period longer than one year on Day -28.

8. The subject received a benzodiazepine or GABA modulator with a half-life ≥48 hours (e.g., diazepam) within 60 days prior to Day 1.

9. Subject was taking non-GABA-related anti-insomnia medications (e.g., melatonin, Benadryl [antihistamines], trazodone) or first- or second-generation (typical/atypical) antipsychotics on Day 14.

10. Subject used psychostimulants (e.g., methylphenidate, amphetamine) or opioids, regularly or as needed, on Day -28.

11. The subject had a known allergy to Compound 1, allopregnanolone, or related compounds.

12. Subject had a positive pregnancy test at screening or on day 1 prior to dosing.

13. A subject who was breastfeeding at Screening or on Day 1 (prior to study drug administration) did not agree to temporarily discontinue breastfeeding from immediately prior to study drug administration on Day 1 until 7 days after the last dose of study drug in each treatment period.

14. The subject had detectable hepatitis B surface antigen, hepatitis C virus (HCV), a positive HCV viral load, or human immunodeficiency virus (HIV) antibodies at screening.

15. The subject had a clinically significant abnormal 12-lead ECG at screening or baseline visits. NOTE: A mean QT interval calculated using the Fridericia method (QTcF) of >450 ms in men or >470 ms in women was grounds for exclusion from the study.

16. The researcher assessed the subject as having active psychosis.

17. The subject has a history of seizures/convulsions.

18. The subject had a history of bipolar disorder, schizophrenia and/or schizoaffective disorder.

19. The subject had a history of mild, moderate, or severe substance use disorder (including benzodiazepines) diagnosed using DSM-5 criteria within 12 months prior to screening.

20. The subject has received another investigational drug or system within 30 days prior to screening.

21. The subject has previously participated in clinical trials of Compound 1 or brexanolone.

22. The subject has used any known strong cytochrome P450(CYP)3A4 inhibitors within 28 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study drug, or plans to use them during any treatment period, or has consumed grapefruit juice, grapefruit, or Seville oranges, or products containing them, within 14 days prior to receiving the first dose of study drug for any treatment period, or plans 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 study drug for any period of Compound 1 treatment: rifampin, carbamazepine, enzalutamide, mitotane, phenytoin, and St. John's wort.

24. Subject had a positive drug and/or alcohol screen at Screening or on Day 1 prior to open-label dosing.

25. The subject is scheduled for elective surgery or a procedure requiring general anesthesia at any time from the start of screening and throughout the study period. Procedures requiring conscious sedation and outpatient procedures performed under local anesthesia may be scheduled according to the following guidelines:

Procedures requiring conscious sedation (e.g., colonoscopy) are permitted no later than 7 days before the start of the first dose of each treatment period and no earlier than 7 days after the last dose of each treatment period from the start of screening and throughout the study.

Elective outpatient procedures performed under local anesthesia are permitted at any time during the study.

26. The subject has been diagnosed and/or treated for any type of cancer (except basal cell carcinoma and melanoma in situ) within the last year prior to screening.

27. The subject has undergone gastric bypass surgery with gastric band placement or any procedures that interfere with gastrointestinal transit.

28. The subject regularly participated in night shift work or was required to perform night shift work during any 14-day treatment period (intermittent night shift work was permitted during subsequent observation periods).

Dosage and administration

Compound 1 was available as hard gelatin capsules containing a white to off-white powder. In addition to the Compound 1 drug substance, Compound 1 capsules contained sodium croscarmellose, mannitol, silicified microcrystalline cellulose (SMCC), colloidal silicon dioxide, and sodium stearyl fumarate as fillers. Colloidal silicon dioxide was either a component of SMCC or the sole filler in the pharmaceutical composition. Compound 1 capsules were administered orally at doses of 30 or 20 mg.

Reference therapy, dosage and method of administration:

In the DB phase, placebo was given as hard gelatin capsules to be taken orally in the evening with food.

Duration of treatment:

All subjects received a daily dose of Compound 1 from days 1 to 14 in the OL phase. Subjects who demonstrated a HAM-D response to Compound 1 in the OL phase were randomized to receive either daily doses of Compound 1 or placebo during 14-day treatment periods separated by 6-week observation periods for 40 weeks in the DB phase (a total of six 14-day treatment periods during the 52-week study).

Table 4

Screening Period Research Day -28 to -1 Visit 1 Research Procedure Informed consent X Subject Double Check (US only) ^a X Inclusion/Exclusion X Demography X Medical/Family History X SCID-5 X ICD-10 ^b X MGH-ATRQ X Serum FSH test ^c X Complete medical examination ^d X Body weight/height X Clinical laboratory tests ^e X Screening for drugs and alcohol ^f X Serum pregnancy test X Screening for hepatitis and HIV X Preparation of the subject ^g X Measuring vital signs ^h X 12-lead ECG ⁱ X Baseline/Screening C-SSRS X HAM-D ^j X MADRS X CGI-S X Side effects /SAEs ^k X Current (previous) medications X CGI-S = Clinical Global Impression - Severity;
C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram;
FSH = follicle-stimulating hormone;
HAM-D = Hamilton Depression Rating Scale, 17 items;
HIV = human immunodeficiency virus;
ICD-10 = International Statistical Classification of Diseases and Related Health Problems, version 10;
MADRS = Montgomery-Åsberg Depression Rating Scale;
MGH ATRQ = Massachusetts General Hospital Antidepressant Treatment
Response Questionnaire (Response Questionnaire);
SCID-5 = Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition;
SAE = serious adverse event (side effect);
US = United States

^a Subjects at US hospitals will be asked to sign a release to have unique subject identifiers entered into a registry for the purpose of identifying subjects who may meet exclusion criteria for participation in another clinical trial.

^b ICD-10 codes should be collected if available.

^c Serum FSH testing will be performed at screening for female subjects who are not surgically sterile to determine whether a female subject with spontaneous amenorrhea for ≥12 months meets protocol-established criteria for postmenopausal status.

^d A complete physical examination will be performed, including assessment of body systems (eg, head, eyes, ears, nose, and throat; heart; lungs; abdomen; and extremities).

^e Clinical laboratory tests include hematology, serum chemistry, blood coagulation, and urinalysis.

^f Urine toxicology for certain drugs of abuse (according to laboratory manual) and breath test for alcohol.

^g Subjects will be trained in the use of software applications and devices necessary to conduct the study by facility staff.

^h Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (in the supine and standing positions). Pulse and blood pressure measurements are taken in the supine position at all scheduled time points after the subject has rested for 5 minutes, and then after approximately 3 minutes in the standing position. Vital sign readings may be repeated at the investigator's discretion, as clinically indicated.

ⁱ ECGs will be collected in triplicate.

The ^HAM -D must be completed as early as possible during the visit. HAM-D assessments will be completed within the last 7 days (1 week).

^k Data on adverse events (side effects) will be collected starting from the time informed consent is obtained and throughout the subject's participation in the study.

Table 5

Open phase Double-blind period 1 Double-blind period 2 Double-blind period 3 Double-blind period 4 Double-blind period 5 EOS Day
research 1 8 (+1) 15 (+1) 21 (±1) 28
(±1) 42
(±1) 56
(±1) 63
(+1) 70
(+1) 76
(±3) 111
(+3) 118
(+1) 125 (+1) 131 (±3) 166 (+3) 173 (+1) 180 (+1) 186 (±3) 221 (+3) 228 (+1) 235 (+1) 241 (±3) 276 (+3) 283 (+1) 290 (+1) 296 (±3) 331 (±3) Visiting 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day of the treatment period 1 8 15/ EOT ^a 21 28 42 56/
1 ^b 8 15/ EOT ^a 21 56/
1 8 15/ EOT ^a 21 56/
1 8 15/ EOT ^a 21 56/
1 8 15/ EOT ^a 21 56/
1 8 15/ EOT ^a 21 56/
ET ^a Research procedure Turning on/
Exception X MADRS X Subject orientation X Randomization X Abbreviated physical
examination X X X X X X X X X X X X X Body weight X X X X X X X X X X X X X Clinical laboratory tests X X X X X X X X X X X Drug and alcohol screening X X X X X X Pregnancy test, urine X X X X X X X X X X X X X Vital signs X X X X X X X X X X X X X X X X X X X X X X X X X X X Open phase Double-blind period 1 Double-blind period 2 Double-blind period 3 Double-blind period 4 Double-blind period 5 EOS Day
research 1 8 (+1) 15 (+1) 21 (±1) 28
(±1) 42
(±1) 56
(±1) 63
(+1) 70
(+1) 76
(±3) 111
(+3) 118
(+1) 125 (+1) 131 (±3) 166 (+3) 173 (+1) 180 (+1) 186 (±3) 221 (+3) 228 (+1) 235 (+1) 241 (±3) 276 (+3) 283 (+1) 290 (+1) 296 (±3) 331 (±3) Visit 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day of the treatment period 1 8 15/ EOT ^a 21 28 42 56/
1 ^b 8 15/ EOT ^a 21 56/
1 8 15/ EOT ^a 21 56/
1 8 15/ EOT ^a 21 56/
1 8 15/ EOT ^a 21 56/
1 8 15/ EOT ^a 21 56/
ET ^a ECG with 12 leads X X X X X X X X X X X C-SSRS ^h X X X X X X X X X X X X X X X X X X X X X X X X X X X NAM-D ⁱ X X X X X X X X X X X X X X X X X X X X X CGI-S X X X X X X X X X X X X X X X X X X X X X CGI-I X X X X X X X X X X X X X X X X X X X X WPAI X X X X X X X X X X X X X X (ET only) EQ-5D-5L X X X X X X X X X X X X X X X X X X PWC-20 X X X X X X X X X X X X X PK in ^blood plasma X X X X X X X X X X X X X (ET only) Dispensation of the study drug X X X X X X X X X X X X Introduction to the study of the pre-para-ta X (QD for 14 days) X (QD for 14 days) X (QD for 14 days) X (QD for 14 days) X (QD for 14 days) X (QD for 14 days) Monitoring the use of pre-para-ta/return X X X X X X X X X X X X PHQ-9 ^k X(QW) Open phase Double-blind period 1 Double-blind period 2 Double-blind period 3 Double-blind period 4 Double-blind period 5 EOS Day
research 1 8 (+1) 15 (+1) 21 (±1) 28
(±1) 42
(±1) 56
(±1) 63
(+1) 70
(+1) 76
(±3) 111
(+3) 118
(+1) 125 (+1) 131 (±3) 166 (+3) 173 (+1) 180 (+1) 186 (±3) 221 (+3) 228 (+1) 235 (+1) 241 (±3) 276 (+3) 283 (+1) 290 (+1) 296 (±3) 331 (±3) Visit 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Day of the treatment period 1 8 15/ EOT ^a 21 28 42 56/
1 ^b 8 15/ EOT ^a 21 56/
1 8 15/ EOT ^a 21 56/
1 8 15/ EOT ^a 21 56/
1 8 15/ EOT ^a 21 56/
1 8 15/ EOT ^a 21 56/
ET ^a Side Effects/SAEs ¹ X Concomitant medications X CGI-I = Clinical Global Impression - Improved;
CGI-S - Clinical Global Impression - Severity;
C-SSRS = Columbia Suicide Severity Rating Scale;
ECG = electrocardiogram;
EOT=end of treatment;
EQ-5D-5L = EuroQol Group 5-dimensional, 5-level questionnaire;
EOS = end of study;
ET = early termination;
NAM-D = Hamilton Rating Scale for Depression, 17 items;
QD = once daily;
QW = once a week;
PHQ = 9-item Patient Health Questionnaire;
PWC-20 = 20-item Health Care Refusal Checklist;
SAE = serious adverse event;
WPAI = Work Performance Impairment Inventory

^Subjects who discontinue treatment early should return to the treatment facility as soon as possible for end-of-treatment (EOT), preferably on the day of discontinuation. Follow-up visits should occur as scheduled relative to the last day of treatment. If at any time after the EOT visit, the subject decides to discontinue participation in the study, the subject should return for an early termination (ET) visit. EOT and ET visits may occur on the same day if the subject discontinues the study drug and discontinues their participation in the study on the same day during a clinical visit. In this case, all activities scheduled for the EOT visit will be carried out.

^b The end of the open-label phase coincides with the first day of the double-blind phase (study day 56, visit 7). Subjects who do not respond to SAGE-217 during the open-label phase (Open-Label Phase) (see Criteria above) are excluded from the study on this day.

^c Subjects will be trained in the software applications and devices required to conduct the study by healthcare facility staff.

^d Clinical laboratory tests include hematology, serum chemistry, coagulation, and urinalysis.

^e Urine toxicology for certain drugs of abuse (according to laboratory manual) and breath test for alcohol.

^f Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (in the supine and standing positions). Pulse and blood pressure measurements are taken in the supine position at all scheduled time points after the subject has rested for 5 minutes, and then after approximately 3 minutes in the standing position. Vital sign readings may be repeated at the investigator's discretion as clinically indicated.

^g A three-lead ECG is performed. If ECG and PK samples are collected on the same day, a 12-lead ECG should be performed before PK sample collection.

^h Form C-SSRS is completed from the time of the last visit.

^The NAM-D should be completed as early as possible during the visit. The assessment timeframe for the NAM-D will be the last 7 days (1 week) on Day 56/1 of the Double-Blind Phase and "since the last visit" for Day 1 of the Open-Access Phase and all other visits.

^Plasma samples for PK analysis will be collected at any time during the clinic visit. The date and time of sample collection, as well as the date and time of the last dose, should be recorded. If ECG and PK samples are collected on the same day, a 12-lead ECG should be performed before PK sample collection.

^All PHQ-9 assessments are completed using mobile phone-enabled software. Subjects are required to complete the PHQ-9 every 7 days; if the PHQ-9 score is >10, the subject should return to the healthcare facility as soon as possible for a NAM-D assessment under the guidance of a clinician. If the NAM-D score is ≥18 during this visit, the subject should return to the healthcare facility in 7-14 days for a repeat NAM-D assessment. See Table 3 for assessments to be completed during these visits.

^l Data on adverse events should be collected from the time informed consent is obtained and throughout the subject's participation in the study.

Table 6

Research procedure Abbreviated physical examination X Clinical laboratory tests ^a X Pregnancy test, urine X Vital signs ^b X C-SSRS ^c X HAM-D ^d X CGI-S X CGI-I X WPAI X EQ-5D-5L X Side effects/SAE ^se X Concomitant medications X CGI-I = Clinical Global Impression - Improved;
CGI-S = Clinical Global Impression - Severity;
C-SSRS = Columbia Suicide Severity Rating Scale;
ECG = electrocardiogram;
EQ-5D-5L = 5-dimensional, 5-level questionnaire of the EuroQol Group;
HAM-D = Hamilton Depression Rating Scale, 17 items;
SAE = serious adverse event (side effect);
WPAI = Work Productivity and Impairment Inventory

^a Clinical laboratory tests include hematology, serum chemistry, coagulation, and urinalysis.

^b Vital signs include oral temperature (°C), respiratory rate, heart rate, and blood pressure (in the supine and standing positions). Pulse and blood pressure measurements are taken in the supine position at all scheduled time points after the subject has rested for 5 minutes, and then after approximately 3 minutes in the standing position. Vital sign readings may be repeated at the investigator's discretion as clinically indicated.

^c Form C-SSRS "Since Last Visit" must be completed.

^The HAM-D should be completed as early as possible during the visit. HAM-D scale assessments will be timed "since last visit."

^e Data on adverse events (side effects) are collected starting from the moment informed consent is obtained and throughout the entire period of the subject's participation in the study.

Example 4

Cognitive deficits can occur in individuals with depression and anxiety disorders, such as those diagnosed with major depressive disorder (MDD). Subjects receiving Compound 1 will be assessed using several cognitive tests or the Cogstate assessment to determine whether any changes in cognitive function are present.

Cogstate tests can be designed to measure specific cognitive domains and can be grouped together to form customized test sets that meet the unique requirements of a study design and subject population. Examples of Cogstate tests include:

The Behavioral Pattern Separation Object Test tests recognition memory using photographs of objects. Participants are given a series of photographs of common objects and must decide whether each object is used indoors or outdoors. They are then presented with a photograph of the object and must recall whether the object is the same, similar, or different from those in previously shown photographs.

The Continuous Paired Associate Learning test tests visual memory using a paired-associative learning paradigm. In this test, participants must learn and remember pictures located in different locations on a screen. In the first stage of the test, on-screen instructions ask, "Where are these pictures located?" A picture is presented in the center of the screen. The participant touches the peripheral location of the picture with the cursor and must memorize its location. In the second stage of the test, the same pictures are displayed in the center of the screen, but the peripheral location of each picture is hidden. The participant must click the peripheral location where the picture previously appeared.

The detection test measures processing speed using a simple reaction time paradigm. On-screen instructions ask, "Is the card upside down?" A playing card is presented face down in the center of the screen. The card is flipped face up. As soon as the card is flipped, the participant is asked to press "Yes." The participant is encouraged to work as quickly and accurately as possible.

The Face Name Associative Memory Test measures associative memory using photographs of real faces. Participants are given a series of photographs of faces and names, each associated with a name. Participants must memorize the face-name pair.

The Go-No-Go test is an inhibitory response test that uses a well-established recognition reaction time paradigm with playing card stimuli. In this test, all playing cards are either 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 "Go" key when the joker card is black and not respond when it is red.

The Groton Maze Learning Test measures executive function using a maze learning paradigm. Participants are presented with a 10x10 tile grid on the screen. Hidden between these tiles is a 28-step path. A blue tile marks the start, and a tile with red circles marks the finish. Participants must move one step at a time from the start to the finish by touching the tile next to their current location with their cursor. A green checkmark appears if the move is correct, and a red cross appears if the move is incorrect. After completing the task, participants return to the starting position to repeat the test and must attempt to recall the path they just took.

The identification test measures attention using a choice reaction time paradigm. On-screen instructions ask, "Is the card red?" A playing card is presented face down in the center of the screen. The card is flipped face up. Once it is flipped, the participant must decide whether the card is red or not. If it is red, the participant should press "Yes," and if it is not red, the participant should press "No." The participant is encouraged to work as quickly and accurately as possible.

The International Shopping List Test measures verbal learning using a word list learning paradigm. Participants are read a shopping list and are asked to memorize and recall as many items from it as possible.

The One-Back test tests working memory using the "n-back" paradigm. On-screen instructions ask, "Is the previous card the same?" A playing card is displayed face-up in the center of the screen. The participant must decide whether this card matches the previous one. If the card is the same, the participant should press "Yes," and if it is different, the participant should press "No." The participant is encouraged to work as quickly and accurately as possible.

The One Card Learning test tests visual memory using a pattern separation paradigm. On-screen instructions ask, "Have you seen this card before in this test?" A playing card is displayed face-up in the center of the screen, and the participant must decide whether they have seen this card before in this test. Participants are encouraged to work as quickly and accurately as possible.

The set shift test uses a set-shifting paradigm to measure executive function. On-screen instructions ask, "Is this the target card?" A playing card is displayed face up in the center of the screen with the word "Number" or "Color" written above it. If the word "Color" is written, the participant must say whether the target card is black or red. If the word "Number" is written, the participant must say whether the current number displayed on the card is correct. At the beginning of the test, the participant simply has to guess whether the current card is the target card. If they think the card is the target card, they must press "Yes." If they think the card is not the target card, they must press "No." When the participant makes their guesses, feedback is provided, and the next card is not shown until the correct answer is made. After the participant has progressed through the set of cards, the hidden rule is changed (e.g., from one color to another [intradimensional shift] or from color to number [extradimensional shift]). The participant is not informed when these set changes occur, and they must learn the new target rule to continue the test. The participant is encouraged to work as quickly and accurately as possible.

The Social-Emotional Cognition Test tests emotional recognition using the "odd-man out" paradigm. On-screen instructions ask, "Discard the odd one out." Four images are presented. One of these images will be different from the others, and the participant must decide which image is different and click on it. Participants are encouraged to work as quickly and accurately as possible.

The Two-Back test tests working memory using the n-back paradigm. On-screen instructions ask, "Is this the same card shown two cards ago?" A playing card is displayed face-up in the center of the screen. The participant must decide whether the card matches the card shown two cards ago. If the card is the same, the participant should press "Yes," and if it is different, the participant should press "No." The participant is encouraged to work as quickly and accurately as possible.

To assess cognitive decline, deficit, or improvement in subjects receiving Compound 1, a battery of tests, such as the battery of tests presented in Table 7, may be used to assess cognitive function.

Table 7: Details of the computerized cognitive tests in the Cogstate test series

Cogstate test Test requirements Theoretical cognitive model The main cognitive domain tested References confirming validity RECOMMENDED TESTS Detection test How to respond quickly to changes in visual stimuli Simple reaction time Psychomotor function ^1-3 Identification test How quickly can one determine the physical characteristics of a visual stimulus? Choice reaction time Visual attention ^1-3 International Shopping List Test with Delayed Playback Learn and recall a set of 12 words in three attempts, then recall the list after a delay Verbal list learning and delayed recall Verbal episodic memory ^2.4-6 Groton Maze Learning Test Find and remember the path hidden under a 10×10 matrix of identical tiles Hidden Path, Exploring the Labyrinth Executive function ^2.4-6

Subjects may be assessed using a series of Cogstate tests before Compound 1 administration, during Compound 1 administration, and after Compound 1 administration.

Links listed 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. Gálvez V, Li A, Huggins C, et al. Repeated intranasal ketamine for treatment- resistant depression - the way to go? Results from a piloted randomized 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.

Equivalents and scope of application

In the claims, articles such as "a," "an," and "the" may refer to one or more items unless otherwise stated or otherwise obvious from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the members of the group are present, used, or otherwise related to the given product or process, unless otherwise stated or otherwise obvious from the context. The invention includes embodiments in which exactly one member of the group is present, used, or otherwise related to the given product or process. The invention includes embodiments in which more than one or all of the members of the group are present, used, or otherwise related to the given product or process.

Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more listed claims are introduced into another claim. For example, any claim dependent on another claim may be amended to include one or more limitations found in any other claim that depends on the same base claim. When the elements are presented in list form, such as in a Markush group format, each subgroup of elements is also disclosed, and any element(s) may be deleted from the group. It should be understood that, in general, when the invention or aspects of the invention are referred to as comprising certain elements and/or features, certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and/or features. For simplicity, these embodiments have not been specifically set forth in haec verba herein. It should also be noted that the terms "comprising" and "including" are intended to be open-ended and allow for the inclusion of additional elements or steps. When ranges are specified, the endpoints are included within the ranges. Furthermore, unless otherwise stated or otherwise obvious from the context and understood by one of skill in the art, values that are expressed as ranges may take any specific value or sub-range value within the stated ranges in various embodiments of the invention, up to a tenth of the value of the lower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patent applications, journal articles, 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, the specification takes precedence. Furthermore, any specific embodiment of the present invention related to the prior art may be expressly excluded from any one or more claims. Since such embodiments would be known to one skilled in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any specific embodiment of the invention may be excluded from any claim for any reason, regardless of whether it is related to the existence of prior art or not.

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

Claims (24)

1. A method for treating postpartum depression in a subject in need thereof, comprising administering a therapeutically effective amount of Compound 1: subject once a day for two weeks. 2. The method of claim 1, wherein the subject has a total score on the Hamilton Depression Rating Scale (HAM-D) greater than or equal to 26 compared to baseline. 3. A method for treating postpartum depression in a subject in need thereof, comprising administering a therapeutically effective amount of Compound 1: subject once a day for two weeks; in which the subject has a Hamilton Depression Rating Scale (HAM-D) total score greater than or equal to 26 compared to baseline; and in which the subject demonstrates a response consisting of a decrease in the HAM-D score from baseline of greater than or equal to 50%. 4. The method according to any one of claims 1-3, wherein the method does not cause significant changes in cognitive functions in the subject. 5. The method according to any one of claims 1-3, wherein the method does not cause significant changes in cognitive functions in the subject after completion of two weeks of administration of Compound 1. 6. A method for treating postpartum depression in a subject in need thereof, comprising administering a therapeutically effective amount of Compound 1: subject, once a day for two weeks; where the method does not cause significant changes in the cognitive functions of the subject. 7. The method of claim 6, wherein the subject has a total Hamilton Depression Rating Scale (HAM-D) score greater than or equal to 26 compared to baseline. 8. The method of claim 6 or 7, wherein the subject exhibits a response comprising a decrease in the HAM-D score from the baseline level greater than or equal to 50%. 9. The method according to any one of claims 1 to 8, wherein the subject is a woman diagnosed with severe postpartum depression. 10. The method according to any one of paragraphs 1-9, wherein the subject is between 18 and 65 years of age. 11. The method according to any one of claims 1-10, wherein the subject is administered from 10 mg to 50 mg of Compound 1. 12. The method according to any one of claims 1 to 11, wherein the amount of Compound 1 administered to the subject is reduced upon the occurrence of a serious side effect. 13. The method according to any one of claims 1 to 12, wherein Compound 1 is administered in the evening. 14. The method according to any one of claims 1 to 13, wherein Compound 1 is administered with food. 15. The method according to any one of claims 1 to 14, wherein Compound 1 is in a capsule.