Use of neurostimulant steroids for the treatment of sexual dysfunction.

Abstract

The present invention relates to a method of treating sexual dysfunction and / or maintaining sexual function in a patient by administering a neurostimulatory steroid to the patient. The present invention relates to a method of treating sexual dysfunction in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of a formula selected from the group consisting of compound (1) and compound (2), or a pharma- ceutically acceptable salt thereof. Sexual dysfunction (SD) is a problem that can occur during any stage of the sexual response cycle.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 142,840, filed January 28, 2021, and U.S. Provisional Patent Application No. 63 / 142,833, filed January 28, 2021. The entire contents of the aforementioned applications are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present invention relates to a method of treating sexual dysfunction, such as treatment-induced sexual dysfunction, and / or maintaining sexual function in a patient by administering compound (1) or compound (2) described herein. [Background technology]

[0003] background Sexual dysfunction (SD) is a problem that can occur during any phase of the sexual response cycle. SD prevents an individual from experiencing satisfaction from sexual activity. The sexual response cycle traditionally includes an excitement phase, a plateau phase, an orgasmic phase, and a withdrawal phase. Both desire and arousal are part of the excitement phase of the sexual response. Sexual dysfunction can occur at any age. Physical and / or medical conditions as well as psychological disorders can cause problems with sexual function. Side effects of some medications, including antidepressants, can also affect sexual function.

[0004] Treatment-induced sexual dysfunction is an adverse effect associated with the administration of various antidepressants. Tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) are all associated with impairment of the stages of the sexual response cycle (interest, arousal, and orgasm) and effects on sexual frequency and pleasure. Studies have shown that citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, venlafaxine, imipramine, and phenelzine are associated with significantly higher rates of SD compared to placebo.

[0005] SD can be addressed by treating the underlying physical, medical, and / or psychological problems. Other methods of treating SD include medications (e.g., sildenafil (Viagra®), tadalafil (Cialis®), vardenafil (Levitra®, Staxyn®), avanafil (Stendra®), flibanserin (Addyi®), and bremelanotide (Vyleesi®)), the use of mechanical aids (e.g., vacuum aids, penile implants), sexual therapy, behavioral treatments, psychotherapy, and education and communication. Current methods used to treat or alleviate treatment-induced SD include waiting for spontaneous remission or tolerance, reducing doses, drug holidays, non-pharmacological interventions (e.g., exercise, psychotherapy), switching to a different antidepressant, and / or adding medications to treat sexual adverse effects.

[0006] There is a need for new and improved methods of treating SD, including treatment-induced SD. There is also a need for agents that prevent and treat CNS-related diseases without reducing or eliminating the side effects typically associated with antidepressants, particularly sexual dysfunction. The agents and methods of using said agents described herein are for this purpose. Summary of the Invention [Means for solving the problem]

[0007] The present invention provides a method of treating sexual dysfunction in a patient in need thereof, the method comprising administering a therapeutically effective amount of a compound of the formula selected from the group consisting of: [ka] to the patient.

[0008] Another aspect of the present invention provides a method of treating sexual dysfunction in a patient in need thereof, the method comprising administering a therapeutically effective amount of a compound of the formula selected from the group consisting of: [ka] to the patient.

[0009] In some embodiments, the compound administered is a compound of the formula: [ka] It is.

[0010] In some embodiments, the pharma- ceutically acceptable salt administered is a compound of the formula: [ka] is a pharma- ceutically acceptable salt of

[0011] In some embodiments, the compound administered is a compound of the formula: [ka] It is.

[0012] In some embodiments, the pharma- ceutically acceptable salt administered is a compound of the formula: [ka] is a pharma- ceutically acceptable salt of

[0013] In some embodiments, the patient has (or suffers from) a CNS-related disorder. In some embodiments, the CNS-related disorder is selected from the group consisting of sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognition disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome, tinnitus, and status epilepticus. In some embodiments, the CNS-related disorder is a mood disorder. In some embodiments, the mood disorder is major depressive disorder.

[0014] In some aspects, the compound is administered at a dose of about 20 mg to about 60 mg once a day. In some embodiments, the compound is administered at a dose of about 50 mg once a day for about 14 days. In some embodiments, the compound is administered at a dose of about 60 mg once a day for about 14 days.

[0015] In some aspects, the pharma- ceutically acceptable salt of the compound is administered once a day at a dose equivalent to about 20 mg to 60 mg of the free base compound.In some embodiments, the pharma- ceutically acceptable salt of the compound is administered once a day at a dose equivalent to about 50 mg of the free base compound for about 14 days.In some embodiments, the pharma- ceutically acceptable salt of the compound is administered once a day at a dose equivalent to about 60 mg of the free base compound for about 14 days.

[0016] In some aspects, sexual dysfunction is assessed by Sexual Functioning Questionnaire-14. In some embodiments, the Sexual Functioning Questionnaire-14 score at day 42 is about equal to or less than the baseline Sexual Functioning Questionnaire-14 score. In some embodiments, the patient is a female with a Sexual Functioning Questionnaire-14 score of not more than 41 at day 15, day 28, or day 42 after administration. In some embodiments, the patient is a male with a Sexual Functioning Questionnaire-14 score of not more than 47 at day 15, day 28, or day 42 after administration.

[0017] In some embodiments, sexual dysfunction comprises a decrease or loss of one or more of sexual pleasure, sexual desire, sexual frequency, sexual interest, sexual stimulation, sexual arousal, and orgasm.

[0018] Another aspect of the present invention provides a method of treating sexual dysfunction in a patient with major depressive disorder, the method comprising administering a therapeutically effective amount of a compound of the formula selected from the group consisting of: [ka] The method includes administering

[0019] Another aspect of the present invention provides a method of treating sexual dysfunction in a patient with major depressive disorder, the method comprising administering a therapeutically effective amount of a compound of the formula selected from the group consisting of: [ka] This includes administering a pharma- ceutically acceptable salt of

[0020] In some aspects, the compound administered is a compound of the formula: [ka] It is.

[0021] In some aspects, the pharma- ceutically acceptable salt administered is a compound of the formula: [ka] is a pharma- ceutically acceptable salt of

[0022] In some aspects, the compound administered is a compound of the formula: [ka] It is.

[0023] In some aspects, the pharma- ceutically acceptable salt administered is a compound of the formula: [ka] is a pharma- ceutically acceptable salt of

[0024] In some aspects, the compound is administered at a dose of about 20 mg to 60 mg once a day. In some embodiments, the compound is administered at a dose of about 50 mg once a day for about 14 days. In some embodiments, the compound is administered at a dose of about 60 mg once a day for about 14 days.

[0025] In some aspects, the pharma- ceutically acceptable salt of the compound is administered once a day at a dose equivalent to about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of the compound is administered once a day at a dose equivalent to about 50 mg of the free base compound for about 14 days. In some embodiments, the pharma- ceutically acceptable salt of the compound is administered once a day at a dose equivalent to about 60 mg of the free base compound for about 14 days.

[0026] In some aspects, sexual dysfunction is assessed by Sexual Functioning Questionnaire-14. In some embodiments, the Sexual Functioning Questionnaire-14 score at day 42 is about equal to or less than the baseline Sexual Functioning Questionnaire-14 score. In some embodiments, the patient is a female with a Sexual Functioning Questionnaire-14 score of not more than 41 at day 15, day 28, or day 42 after administration. In some embodiments, the patient is a male with a Sexual Functioning Questionnaire-14 score of not more than 47 at day 15, day 28, or day 42 after administration.

[0027] Another aspect of the invention provides a method of maintaining sexual function in a patient with a mood disorder, the method comprising administering a therapeutically effective amount of a compound of the formula selected from the group consisting of: [ka] to the patient.

[0028] Another aspect of the invention provides a method of maintaining sexual function in a patient with a mood disorder, the method comprising administering a therapeutically effective amount of a compound of the formula selected from the group consisting of: [ka] to the patient.

[0029] In some aspects, the compound administered is a compound of the formula: [ka] It is.

[0030] In some aspects, the pharma- ceutically acceptable salt administered is a compound of the formula: [ka] is a pharma- ceutically acceptable salt of

[0031] In some aspects, the compound administered is a compound of the formula: [ka] It is.

[0032] In some aspects, the pharma- ceutically acceptable salt administered is a compound of the formula: [ka] is a pharma- ceutically acceptable salt of

[0033] In some aspects, the mood disorder is major depressive disorder.

[0034] In some aspects, the compound is administered at a dose of about 20 mg to about 60 mg once a day. In some embodiments, the compound is administered at a dose of about 50 mg once a day for about 14 days. In some embodiments, the compound is administered at a dose of about 60 mg once a day for about 14 days.

[0035] In some aspects, the pharma- ceutically acceptable salt of the compound is administered once a day at a dose equivalent to about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of the compound is administered once a day at a dose equivalent to about 50 mg of the free base compound for about 14 days. In some embodiments, the pharma- ceutically acceptable salt of the compound is administered once a day at a dose equivalent to about 60 mg of the free base compound for about 14 days.

[0036] In some aspects, sexual dysfunction is assessed by Sexual Functioning Questionnaire-14. In some embodiments, the Sexual Functioning Questionnaire-14 score at day 42 is about equal to or less than the baseline Sexual Functioning Questionnaire-14 score. In some embodiments, the patient is a female with a Sexual Functioning Questionnaire-14 score of not more than 41 at day 15, day 28, or day 42 after administration. In some embodiments, the patient is a male with a Sexual Functioning Questionnaire-14 score of not more than 47 at day 15, day 28, or day 42 after administration.

[0037] Another aspect of the present invention provides a method of treating treatment-induced sexual dysfunction in a patient who is currently undergoing or has undergone a course of chemical psychotherapy, the method comprising administering a therapeutically effective amount of a compound of the formula selected from the group consisting of: [ka] to the patient.

[0038] Another aspect of the present invention provides a method of treating treatment-induced sexual dysfunction in a patient who is currently undergoing or has undergone a course of chemical psychotherapy, the method comprising administering a therapeutically effective amount of a compound of the formula selected from the group consisting of: [ka] to the patient.

[0039] In some aspects, the compound administered is a compound of the formula: [ka] It is.

[0040] In some aspects, the pharma- ceutically acceptable salt administered is a compound of the formula: [ka] is a pharma- ceutically acceptable salt of

[0041] In some aspects, the compound administered is a compound of the formula: [ka] It is.

[0042] In some aspects, the pharma- ceutically acceptable salt administered is a compound of the formula: [ka] is a pharma- ceutically acceptable salt of

[0043] In some embodiments, the chemical psychotherapy is an antidepressant. In some embodiments, the antidepressant is selected from a selective serotonin reuptake inhibitor, a selective norepinephrine reuptake inhibitor, a tricyclic, a monoamine oxidase inhibitor, or an atypical antidepressant.

[0044] In some embodiments, the patient has (or suffers from) a CNS-related disorder. In some embodiments, the CNS-related disorder is selected from the group consisting of sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognition disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome, tinnitus, and status epilepticus. In some embodiments, the CNS-related disorder is a mood disorder. In some embodiments, the mood disorder is major depressive disorder.

[0045] In some aspects, the compound is administered at a dose of about 20 mg to about 60 mg once a day. In some embodiments, the compound is administered at a dose of about 50 mg once a day for about 14 days. In some embodiments, the compound is administered at a dose of about 60 mg once a day for about 14 days.

[0046] In some aspects, the pharma- ceutically acceptable salt of the compound is administered once a day at a dose equivalent to about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of the compound is administered once a day at a dose equivalent to about 50 mg of the free base compound for about 14 days. In some embodiments, the pharma- ceutically acceptable salt of the compound is administered once a day at a dose equivalent to about 60 mg of the free base compound for about 14 days.

[0047] In some aspects, sexual dysfunction is assessed by Sexual Functioning Questionnaire-14. In some embodiments, the Sexual Functioning Questionnaire-14 score at day 42 is about equal to or less than the baseline Sexual Functioning Questionnaire-14 score. In some embodiments, the patient is a female with a Sexual Functioning Questionnaire-14 score of not more than 41 at day 15, day 28, or day 42 after administration. In some embodiments, the patient is a male with a Sexual Functioning Questionnaire-14 score of not more than 47 at day 15, day 28, or day 42 after administration. [Brief description of the drawings]

[0048] [Figure 1] FIG. 1 is a schematic diagram showing the MOUNTAIN study design according to Example 1.

[0049] [Diagram 2] FIG. 2 is a graph showing the mean change from baseline (± standard error) in Changes in Sexual Functioning Questionaire-14 (CSFQ-14) total score at baseline and days 15, 28, and 42 in patients administered 30 mg of Compound (1) or placebo according to Example 1.

[0050] [Diagram 3] FIG. 3 is a graph showing the percentage of patients with sexual dysfunction at baseline and at days 15, 28, and 42 across treatment arms (Compound (1) vs. placebo) according to Example 1.

[0051] [Figure 4] FIG. 4 is a graph showing odds ratios for females on various CSFQ-14 subscales at days 15, 28, and 42 across treatment arms (Compound (1) vs. placebo) according to Example 1.

[0052] [Diagram 5] FIG. 5 is a graph showing odds ratios for males on various CSFQ-14 subscales at days 15, 28, and 42 across treatment arms (Compound (1) vs. placebo) according to Example 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] Detailed Description The present invention generally relates to a method of treating sexual dysfunction and treatment-induced sexual dysfunction in a patient in need thereof, the method comprising administering to the patient a compound of the formula selected from the group consisting of: [ka] By administering.

[0054] The present invention also relates to a method of treating sexual dysfunction and treatment-induced sexual dysfunction in a patient in need thereof, the method comprising administering to said patient a compound of the formula selected from the group consisting of: [ka] by administering a pharma- ceutically acceptable salt of the formula:

[0055] The present invention also relates to a method of treating major depressive disorder in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound selected from the group consisting of Compound (1) and Compound (2) of the formula: [ka] to the patient, where the patient maintains sexual function during treatment.

[0056] The present invention also relates to a method of treating major depressive disorder in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound selected from the group consisting of Compound (1) and Compound (2) of the formula: [ka] to the patient, where the patient maintains sexual function during treatment.

[0057] I. Definition

[0058] As used herein, “compound (1)” refers to a compound having the following formula (or structure): [ka] Refers to...

[0059] Compound (1) is also known as zuranolone, 3α-hydroxy-3β-methyl-21-(4-cyanopyrazol-1-yl)-5β-19-norpregnan-20-one, and its IUPAC name: 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (CAS Registry Number 1632051-40-1). The chemical synthesis method of compound (1) was described in U.S. Pat. No. 9,512,165 and PCT Application WO 2014 / 169833, each of which is incorporated herein by reference in its entirety. Several crystalline forms of Compound (1) and methods for preparing the aforementioned forms have been described in U.S. Patent Application Publication No. 2019 / 0177359 and PCT Application International Publication No. WO2018 / 039378, each of which is incorporated by reference in its entirety.

[0060] As used herein, “compound (2)” refers to a compound having the following formula (or structure): [ka] Refers to...

[0061] Compound (2) is also known as 3alpha-hydroxy-3beta-methoxymethyl-21-(5-methyl-2H-tetrazol-2-yl)-19-nor-5alpha-pregnan-20-one, and its IUPAC name: 1-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethan-1-one (CAS Registry Number 1832596-09-4). The chemical synthesis method of compound (2) was described in PCT Application WO 2015 / 180679, the entirety of which is incorporated herein by reference.

[0062] Compound (1) and compound (2) are GABA A Synaptic Receptors and GABA A Targeting extrasynaptic receptors, GABA A It is a neuroactive steroid that has been shown to be a positive allosteric modulator of the GABA receptor. A As positive allosteric modulators of the receptor, compound (1) and compound (2) are useful as therapeutic agents for treating CNS-related disorders (e.g., depression, postpartum depression, and major depressive disorder) and for treating neurological conditions (e.g., essential tremor, epilepsy, and Parkinson's disease).

[0063] As used herein, the term "modulation" refers to the A Refers to the inhibition or enhancement of receptor function. "Modulators" (e.g., GABA A The compound that modulates the receptor function or a pharma- ceutically acceptable salt thereof is, for example, GABA A It can be an agonist, partial agonist, antagonist, or partial antagonist of the receptor.

[0064] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is suffering from a particular disease, disorder, or condition to reduce the severity of the disease, disorder, or condition (or any symptoms thereof) or to retard or slow the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate prophylactic actions taken before a subject begins to suffer from a particular disease, disorder, or condition.

[0065] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0066] As used herein, the "effective amount" of a compound (or its pharma- ceutically acceptable salt) refers to an amount sufficient to induce a desired biological response, for example, an amount sufficient to treat sexual dysfunction (e.g., treat treatment-induced sexual dysfunction).As will be understood by those skilled in the art, the effective amount of the compound of the present invention (or its pharma- ceutically acceptable salt) can vary depending on factors such as the desired biological goal, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health, and condition of the subject.An effective amount includes therapeutic and prophylactic treatments.

[0067] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound (or a pharma- ceutically acceptable salt thereof) is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound (or a pharma- ceutically acceptable salt thereof) means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, an amount that reduces or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic efficacy of another therapeutic agent.

[0068] In an alternative embodiment, the present invention contemplates administration of the compound of the present invention or a pharma- ceutically acceptable salt or pharma- ceutically acceptable composition thereof as a prophylactic agent before a subject begins to suffer from a particular disease, disorder, or condition.As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent its recurrence.A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease, disorder, or condition.The term "prophylactically effective amount" can include an amount that improves overall prophylaxis or an amount that enhances the prophylactic efficacy of another prophylactic agent.

[0069] A "patient" is a human (eg, male or female of any age group, eg, a juvenile subject (eg, infant, child, adolescent) or an adult subject (eg, young adult, middle-aged adult, or elderly adult)).

[0070] As used herein, the term "about," when referring to a numerical value or numerical range, allows for some variation of the stated value or range (e.g., within 10%, or within 5% of the stated value or limit of the stated range).

[0071] As used herein, the term "equivalent dose" refers to a biologically equivalent dose. For example, the equivalent dose of a 25 mg dose of a pharma- ceutically acceptable salt of Compound (1) or Compound (2) is the amount (by weight) of a pharma- ceutically acceptable salt required to provide a biologically equivalent dose of the free base of Compound (1) or Compound (2) to a 25 mg dose of Compound (1) or Compound (2).

[0072] As used herein, the term "unit dosage form" is defined to refer to the form in which Compound (1) or Compound (2) is administered to a patient. In particular, the unit dosage form may be, for example, a pill, a capsule, or a tablet. In some embodiments, the unit dosage form is a capsule. In some embodiments, the unit dosage form is a tablet.

[0073] As used herein, "solid dosage form" means a pharmaceutical dose in a solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalants, and chewables.

[0074] "Pharmaceutically acceptable" means approved or approvable by a regulatory authority of a federal or state government, or a corresponding authority in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more specifically, in humans.

[0075] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharma- ceutically acceptable and that possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic or organic acid addition salts and inorganic or organic base addition salts. Specifically, such salts include: (1) salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts formed with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, and the like. or (2) salts formed when an acidic proton present in the parent compound is replaced with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and, where the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmacologically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.See, e.g., Berge et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0076] "Sexual dysfunction" (or "SD") can include, but is not limited to, decreased or lost sexual pleasure, sexual desire, sexual frequency, sexual interest, sexual stimulation, sexual arousal, and orgasm, erectile dysfunction, priapism, orgasmic pain, anorgasmia, dyspareunia, spontaneous orgasm, ejaculatory disorders (delayed ejaculation, inhibition of ejaculation, retrograde ejaculation, spontaneous ejaculation, decreased ejaculate volume), sexual disinhibition, and sexual satisfaction.

[0077] "Sexual function" includes, but is not limited to, sexual pleasure, sexual desire, sexual frequency, sexual interest, sexual stimulation, sexual arousal, and orgasm.

[0078] Sexual dysfunction is a problem that can occur during any phase of the sexual response cycle. SD prevents an individual from experiencing satisfaction from sexual activity. The sexual response cycle traditionally includes an excitement phase, a plateau phase, an orgasmic phase, and a resolution phase. Both desire and arousal are part of the excitement phase of the sexual response.

[0079] Sexual dysfunction is a common symptom of major depressive disorder (MDD) treatment and antidepressant treatment, with symptoms typically appearing about 1 to about 3 weeks after treatment begins. Estimated prevalence ranges from about 4% to about 73%, depending on the type of antidepressant administered. II. Treatment Method

[0080] Described herein are methods of treating sexual dysfunction and / or maintaining sexual function in a patient in need of such treatment, and / or methods of treating major depressive disorder in a patient in need of such treatment, while maintaining sexual function during treatment, the methods comprising administering to the patient a compound selected from the group consisting of Compound (1) and Compound (2); or a pharmaceutically acceptable salt thereof.

[0081] In one aspect, the present invention provides a method of treating sexual dysfunction in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of Compound (1) and Compound (2).

[0082] In one aspect, the present invention provides a method of treating sexual dysfunction in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a pharma- ceutically acceptable salt of a compound selected from the group consisting of Compound (1) and Compound (2).

[0083] In one aspect, the present invention provides a method for treating sexual dysfunction in a patient with a mood disorder, the method comprising administering a therapeutically effective amount of a compound selected from the group consisting of Compound (1) and Compound (2).

[0084] In another aspect, the present invention provides a method for treating sexual dysfunction in a patient having a mood disorder, the method comprising administering a therapeutically effective amount of a pharma- ceutically acceptable salt of a compound selected from the group consisting of Compound (1) and Compound (2).

[0085] In some embodiments, the mood disorder is major depressive disorder.

[0086] In one aspect, the present invention provides a method for treating sexual dysfunction in a patient with major depressive disorder, the method comprising administering a therapeutically effective amount of a compound selected from the group consisting of Compound (1) and Compound (2).

[0087] In another aspect, the present invention provides a method for treating sexual dysfunction in a patient with major depressive disorder, the method comprising administering a therapeutically effective amount of a pharma- ceutically acceptable salt of a compound selected from the group consisting of Compound (1) and Compound (2).

[0088] In one aspect, the present invention provides a method of treating major depressive disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of Compound (1) and Compound (2), wherein the patient maintains sexual function during treatment.

[0089] In another aspect, the present invention provides a method of treating major depressive disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharma- ceutically acceptable salt of a compound selected from the group consisting of Compound (1) and Compound (2), wherein the patient maintains sexual function during treatment.

[0090] In one aspect, the present invention provides a method for maintaining sexual function in a patient having a mood disorder, the method comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of Compound (1) and Compound (2).

[0091] In another aspect, the present invention provides a method for maintaining sexual function in a patient having a mood disorder, the method comprising administering to the patient a therapeutically effective amount of a pharma- ceutically acceptable salt of a compound selected from the group consisting of Compound (1) and Compound (2).

[0092] In some embodiments, the mood disorder is major depressive disorder.

[0093] In some embodiments, the compound administered is Compound (1).

[0094] In some embodiments, the pharma- ceutically acceptable salt administered is a pharma- ceutically acceptable salt of Compound (1).

[0095] In some embodiments, the compound administered is Compound (2).

[0096] In some embodiments, the pharma- ceutically acceptable salt administered is a pharma- ceutically acceptable salt of compound (2).

[0097] In some embodiments, sexual function includes sexual pleasure, sexual desire, sexual frequency, sexual interest, sexual stimulation, sexual arousal, or orgasm.

[0098] In some embodiments, maintaining sexual function during treatment refers to patients who do not have sexual dysfunction during treatment. In some embodiments, maintaining sexual function during treatment refers to patients who do not have significant differences in sexual function during treatment. In some embodiments, maintaining sexual function during treatment refers to patients who do not have sexual dysfunction that is manifested by treatment. In some embodiments, patients maintain sexual function during treatment regardless of gender (e.g., female or male patients).

[0099] Evaluation of sexual dysfunction

[0100] Sexual dysfunction (SD) can be assessed by the 14-item Changes in Sexual Function Questionnaire (CSFQ-14). The CSFQ-14 provides scores on three scales that correspond to the stages of the sexual response cycle (e.g., desire, stimulation, and orgasm). The CSFQ-14 has five subscales that measure pleasure, desire / frequency, desire / interest, stimulation / excitement, and orgasm / completion. In some embodiments, the CSFQ-14 total score is assessed at baseline, 15 days, 28 days, and / or 42 days after administration of the study.

[0101] In some embodiments, a CSFQ-14 total score of 41 or less in a female patient is indicative of sexual dysfunction.

[0102] In some embodiments, a CSFQ-14 total score of 47 or less in a male patient is indicative of sexual dysfunction.

[0103] In certain embodiments, the CSFQ-14 total score at day 42 is about equal to or less than the baseline CSFQ-14 total score. In some embodiments, the patient is female and said patient has a CSFQ-14 total score not exceeding 41 at day 15 after administration. In some embodiments, the patient is female and said patient has a CSFQ-14 total score not exceeding 41 at day 28 after administration. In some embodiments, the patient is female and said patient has a CSFQ-14 total score not exceeding 41 at day 42 after administration. In some embodiments, the patient is female and said patient has a CSFQ-14 total score not exceeding 41 at day 15, day 28, or day 42 after administration. In some embodiments, the patient is male and said patient has a CSFQ-14 total score not exceeding 47 at day 15 after administration. In some embodiments, the patient is male and said patient has a CSFQ-14 total score not exceeding 47 at day 28 after administration. In some embodiments, the patient is male and said patient has a CSFQ-14 total score of no more than 47 at day 42 after administration. In some embodiments, the patient is male and said patient has a CSFQ-14 total score of no more than 47 at day 15, day 28, or day 42 after administration.

[0104] In some embodiments, the methods described herein measure the therapeutic effect by an increase in CSFQ-14 total score. In some embodiments, the therapeutic effect is an increase from baseline in CSFQ-14 total score after initiation of administration of Compound (1) or Compound (2). In some embodiments, the therapeutic effect is an increase from baseline in CSFQ-14 total score of about 2.5 to about 5.0, or about 3.0 to about 4.0, or about 3.0 to about 3.5 in female patients after administration of Compound (1) or Compound (2). In some embodiments, the therapeutic effect is an increase from baseline in CSFQ-14 total score of about 1.0 to about 5.0, or about 1.5 to about 3.5, or about 2.0 to about 3.5 in male patients after administration of Compound (1) or Compound (2).

[0105] In some embodiments, the methods described herein provide a therapeutic effect (e.g., as measured by an increase in CSFQ-14 total score) within about 42 days, about 28 days, or about 15 days. In some embodiments, the therapeutic effect is an increase in CSFQ-14 total score from baseline at the end of a treatment period (e.g., about 42 days, about 28 days, or about 15 days after initiation of administration of Compound (1) or Compound (2)). In some embodiments, the therapeutic effect is an increase in CSFQ-14 total score from baseline of about 2.5 to about 5.0, or about 3.0 to about 4.0, or about 3.0 to about 3.5 at the end of a treatment period (e.g., about 42 days, about 28 days, or about 15 days after initiation of administration of Compound (1) or Compound (2)) in a female patient. In some embodiments, the therapeutic effect is an increase from baseline in CSFQ-14 total score of about 1.0 to about 5.0, or about 1.5 to about 3.5, or about 2.0 to about 3.5 in a male patient at the end of a treatment period (e.g., about 42 days, about 28 days, or about 15 days after initiation of administration of Compound (1) or Compound (2)).

[0106] In some embodiments, the therapeutic effect is an increase from baseline in CSFQ-14 total score after initiation of administration of a pharma- ceutically acceptable salt of Compound (1) or Compound (2). In some embodiments, the therapeutic effect is an increase from baseline in CSFQ-14 total score of about 2.5 to about 5.0, or about 3.0 to about 4.0, or about 3.0 to about 3.5 in female patients after administration of a pharma- ceutically acceptable salt of Compound (1) or Compound (2). In some embodiments, the therapeutic effect is an increase from baseline in CSFQ-14 total score of about 1.0 to about 5.0, or about 1.5 to about 3.5, or about 2.0 to about 3.5 in male patients after administration of a pharma- ceutically acceptable salt of Compound (1) or Compound (2).

[0107] In some embodiments, the therapeutic effect is an increase from baseline in CSFQ-14 total score at the end of a treatment period (e.g., about 42 days, about 28 days, or about 15 days after initiation of administration of a pharma- ceutically acceptable salt of Compound (1) or Compound (2)). In some embodiments, the therapeutic effect is an increase from baseline in CSFQ-14 total score of about 2.5 to about 5.0, or about 3.0 to about 4.0, or about 3.0 to about 3.5 at the end of a treatment period (e.g., about 42 days, about 28 days, or about 15 days after initiation of administration of a pharma- ceutically acceptable salt of Compound (1) or Compound (2)) in a female patient. In some embodiments, the therapeutic effect is an increase from baseline in CSFQ-14 total score of about 1.0 to about 5.0, or about 1.5 to about 3.5, or about 2.0 to about 3.5 at the end of a treatment period in a male patient (e.g., about 42 days, about 28 days, or about 15 days after initiation of administration of Compound (1) or a pharma- ceutically acceptable salt of Compound (2)).

[0108] In some embodiments, the methods described herein provide a therapeutic or prophylactic effect as measured by CSFQ-14 total score, whereby patients treated with Compound (1) or Compound (2) have the same, similar, or not significantly different CSFQ-14 total score compared to patients not treated with Compound (1) or Compound (2). In some embodiments, the methods described herein provide a therapeutic or prophylactic effect as measured by CSFQ-14 total score, whereby patients treated with Compound (1) or a pharma- ceutically acceptable salt of Compound (2) have the same, similar (within about ±10%), or not significantly different (e.g., as measured by p-value) CSFQ-14 total score compared to patients not treated with Compound (1) or a pharma-ceutically acceptable salt of Compound (2).

[0109] CNS-Related Disorders

[0110] In some embodiments, the patient has (or is suffering from) a CNS-related disorder. Exemplary CNS conditions include sleep disorders (e.g., insomnia), mood disorders (e.g., depression (e.g., major depressive disorder (MDD) or postpartum depression (PPD)), dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., I and / or II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD))), schizophrenia spectrum disorders (e.g., schizophrenia, schizoaffective disorder), seizure disorders (e.g., epilepsy (e.g., status epilepticus (SE)), seizures), memory and / or cognition disorders (e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's dementia, Lewis body type dementia, dementia, vascular dementia), movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorders (ASD) (e.g., autism, monogenic causes of autism such as synaptophathy, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), vascular disease (e.g., stroke, ischemia, vascular malformations), substance abuse disorders and / or withdrawal syndromes (e.g., addiction to opiates, cocaine, and / or alcohol), and tinnitus.

[0111] In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is a mood disorder. In certain embodiments, the CNS-related disorder is a major depressive disorder. In certain embodiments, the major depressive disorder is a moderate major depressive disorder. In certain embodiments, the major depressive disorder is a severe major depressive disorder.

[0112] Mood disorders

[0113] Mood disorders are, for example, clinical depression, postpartum or puerperal depression, perinatal depression, atypical depression, melancholic depression, major psychotic depression, catatonic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression due to a chronic medical condition, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior.

[0114] Clinical depression, also known as major depression, major depressive disorder (MDD), major depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood, accompanied by low self-esteem and loss of interest or pleasure in activities that are usually found enjoyable. Some patients with clinical depression have difficulty sleeping, lose weight, and generally feel agitated and irritable. Clinical depression can affect how an individual feels, thinks, and behaves, and can cause a variety of emotional and physical problems. Individuals with clinical depression have problems performing daily activities, and can make an individual feel as if life is not worth living.

[0115] In certain embodiments, the patient has major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder.

[0116] Perinatal depression refers to depression during pregnancy. Symptoms may include irritability, crying, restlessness, sleep problems, exhaustion (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, inability to detach emotionally from the baby and / or fetus, and loss of interest in activities previously found enjoyable.

[0117] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a form of clinical depression that affects women after giving birth. Symptoms can include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying, anxiety, and irritability.

[0118] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and aggressiveness, marked weight gain or increased appetite, and patients with AD may also have significant social impairments as a result of excessive sleep or sleepiness (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived interpersonal rejection.

[0119] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), lack of responsiveness to pleasurable stimuli, a depressed mood that is more pronounced than grief or loss, extreme weight loss, or excessive feelings of guilt.

[0120] Psychotic major depression (PMD) or psychotic depression refers to major depressive episodes, particularly of a melancholic nature, when an individual experiences psychotic symptoms such as delusions and hallucinations.

[0121] Catatonic depression refers to major depression accompanied by the absence of motor behavior and other symptoms. Individuals may become mute and stuporous, unable to move, or exhibit purposeless or bizarre movements.

[0122] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that occur in the fall or winter.

[0123] Dysthymia refers to a condition related to unipolar depression in that the same physical and cognitive problems are manifested. These problems tend to be less severe but longer lasting (e.g., at least 2 years).

[0124] Dual depression refers to periods of major depression interspersed with periods of consistent depressed mood (dysthymia) lasting at least 2 years.

[0125] Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

[0126] Recurrent brief depression (RBD) refers to a condition in which an individual experiences depressive episodes approximately once per month, each lasting two weeks or less, typically less than two to three days.

[0127] Minor depressive disorder or minor depression refers to depression in which at least two symptoms are present for two weeks.

[0128] Bipolar or manic-depressive disorder causes extreme mood swings that include emotional elation (mania or hypomania) and depression (depression). During mania, an individual may feel or act unusually happy, energetic, or irritable. Individuals often make ill-considered decisions that downplay the consequences. There is usually a decreased need for sleep. During depression, individuals may exhibit crying spells, reduced eye contact with others, and a pessimistic outlook on life. The risk of suicide for those with the disorder is as high as more than 6% over a 20-year period, while self-harm occurs 30-40% of the time. Other mental health problems, such as anxiety disorders and substance use disorders, are commonly associated with bipolar disorder.

[0129] Depression due to a chronic condition refers to depression caused by a chronic condition such as cancer pain or chronic pain, chemotherapy, or chronic stress.

[0130] Treatment-resistant depression refers to a state in which an individual is treated for depression, but symptoms are not improved.For example, antidepressants or physchological counseling (psychotherapy) do not alleviate the symptoms of depression in individuals with treatment-resistant depression.In some cases, individuals with treatment-resistant depression improve symptoms, but then relapse.Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatments (including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and / or anxiolytics) and non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0131] Postoperative depression refers to feelings of depression following a surgical procedure (e.g., as a result of facing death). For example, an individual may feel persistent sadness or emptiness, loss of enjoyment or interest in normally enjoyed hobbies and activities, or continued lethargy or hopelessness.

[0132] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (eg, depression) that is associated with (eg, caused by) a women's health condition or disorder.

[0133] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation refers to thoughts about suicide or unusual preoccupations with suicide. The spectrum of suicidal ideation can vary widely, ranging from fleeting thoughts of suicide to constant thoughts, detailed planning, role-playing, and attempts. Symptoms can include talking about suicide, obtaining the means to kill oneself, withdrawing from social contact, preoccupation with death, feeling trapped or hopeless in a situation, increased alcohol or drug use, risky or self-destructive behavior, and saying goodbye as if they will never meet again.

[0134] Symptoms of depression include persistent anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, lack of energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, change in movement, loss of interest in enjoyable activities or hobbies, loss of concentration, loss of energy, low self-esteem, lack of positive thoughts or plans, oversleeping, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts.The presence, severity, frequency, and duration of symptoms may vary from case to case.Symptoms of depression and their relief may be confirmed by a doctor or psychologist (e.g., by mental status examination).

[0135] Depression and the behavioral patterns associated with depression may contribute to other disease processes, such as metabolic syndrome, which may exacerbate female sexual dysfunction. Sexual adverse effects in some women taking antidepressants can include problems with sexual desire and arousal.

[0136] Known depression scales, such as the Hamilton Rating Scale for Depression (HAM-D or HAMD-17), Clinical Global Impression (CGI), and Montgomery-Asberg Depression Rating Scale (MADRS), can be used to identify patients with major depressive disorder.

[0137] In some embodiments, the patient's HAM-D total score before treatment with Compound (1) or Compound (2) is at least 24. In some embodiments, the patient's HAM-D total score before treatment with Compound (1) or Compound (2) is at least 22. In some embodiments, the patient's HAM-D total score before treatment with Compound (1) or Compound (2) is at least 20. In some embodiments, the patient's HAM-D total score before treatment with Compound (1) or Compound (2) is between 14 and 18, inclusive. In some embodiments, the patient's MADRS total score before treatment with Compound (1) or Compound (2) is at least 32. In some embodiments, the patient's MADRS total score before treatment with Compound (1) or Compound (2) is at least 28.

[0138] Another aspect of the present invention provides a method of treating treatment-induced sexual dysfunction in a patient currently undergoing or having undergone a course of chemical psychotherapy, the method comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of Compound (1) and Compound (2).

[0139] In a separate aspect, the present invention provides a method of treating treatment-induced sexual dysfunction in a patient currently undergoing or having undergone a course of chemical psychotherapy, the method comprising administering to the patient a therapeutically effective amount of a pharma- ceutically acceptable salt of a compound selected from the group consisting of Compound (1) and Compound (2).

[0140] In some embodiments, the compound administered is Compound (1). In some embodiments, the pharma- ceutically acceptable salt administered is a pharma- ceutically acceptable salt of Compound (1).

[0141] In some embodiments, the compound administered is compound (2). In some embodiments, the pharma- ceutically acceptable salt administered is a pharma- ceutically acceptable salt of compound (2).

[0142] "Treatment-induced sexual dysfunction" or "treatment-emergent sexual dysfunction" refers to sexual dysfunction resulting from medication used to treat a CNS-related disorder. Tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) have all been associated with treatment-induced sexual dysfunction.

[0143] In some embodiments, the chemical psychotherapy is an antidepressant. In some embodiments, the antidepressant is selected from a selective serotonin reuptake inhibitor (SSRI), a selective norepinephrine reuptake inhibitor (NERI), a tricyclic, a monoamine oxidase inhibitor, or an atypical antidepressant.

[0144] SSRIs include antidepressants that increase serotonin levels in the brain.Exemplary SSRIs include, but are not limited to, citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft).

[0145] Exemplary NERIs include, but are not limited to, atomoxetine (Strattera), reboxetine (Edronax, Vestra), bupropion (Wellbutrin, Zyban), duloxetine, desipramine (Norpramin), amidaline (UK-3540-1), daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), tasulopram (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), and viloxazine (Vivaran).

[0146] Exemplary tricyclic antidepressants include amitriptyline (Elavil, Endep), amitriptyline oxide (Amioxid, Ambivalon, Equilibrin), clomipramine (Anafranil), desipramine (Norpramin, Pertofrane), dibenzepin (Noveril, Victoril), dimethacrine (Istonil), dosulepin (Prothiaden), doxepin (Adapin, Sinequan), imipramine (Tofranil), Rofestin (Rofestin), serotonin (Serotonin ... These include, but are not limited to, pramine (Lomont, Gamanil), melitracen (Dixeran, Melixeran, Trausabun), nitroxazepine (Sintamil), nortriptyline (Pamelor, Aventyl), noxiptiline (Agedal, Elronon, Nogedal), opipramol (Insidon), pipofezin (Azafen / Azaphen), protriptyline (Vivactil), and trimipramine (Surmontil).

[0147] Exemplary monoamine oxidase inhibitors include, but are not limited to, isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), selegiline (Eldepryl, Zelapar, Emsam), metralindole (Inkazan), moclobemide (Aurorix, Manerix), pirlindole (Pirazidol), toloxatone (Humoryl), and bifemelane (Alnert, Celeport).

[0148] Dosage

[0149] In some embodiments, compound (1) or compound (2) is administered at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) or compound (2) is administered at a dose of about 15 mg to about 75 mg. In some embodiments, compound (1) or compound (2) is administered at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) or compound (2) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50 mg. In some embodiments, compound (1) or compound (2) is administered at a dose of about 60 mg.

[0150] In some embodiments, compound (1) is administered at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) is administered at a dose of about 15 mg to about 75 mg. In some embodiments, compound (1) is administered at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg. In some embodiments, compound (1) is administered at a dose of about 50 mg. In some embodiments, compound (1) is administered at a dose of about 60 mg.

[0151] In some embodiments, compound (2) is administered at a dose of about 10 mg to about 100 mg. In some embodiments, compound (2) is administered at a dose of about 15 mg to about 75 mg. In some embodiments, compound (2) is administered at a dose of about 20 mg to about 60 mg. In some embodiments, compound (2) is administered at a dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg. In some embodiments, compound (2) is administered at a dose of about 50 mg. In some embodiments, compound (2) is administered at a dose of about 60 mg.

[0152] In some embodiments, compound (1) is administered at a dose of about 50 mg.

[0153] In some embodiments, compound (2) is administered at a dose of about 60 mg.

[0154] In some embodiments, compound (1) or compound (2) is administered once a day at a dose of about 10 mg to about 100 mg. In some embodiments, compound (1) or compound (2) is administered once a day at a dose of about 20 mg to about 60 mg. In some embodiments, compound (1) or compound (2) is administered once a day at a dose of about 50 mg. In some embodiments, compound (1) or compound (2) is administered once a day at a dose of about 60 mg. For example, compound (1) is administered once a day at a dose of about 10 mg to about 100 mg. In other examples, compound (1) is administered once a day at a dose of about 20 mg to about 60 mg. In some examples, compound (1) is administered once a day at a dose of about 50 mg. And in other examples, compound (1) is administered once a day at a dose of about 60 mg. In yet another embodiment, compound (2) is administered once a day at a dose of about 10 mg to about 100 mg. In another embodiment, compound (2) is administered once a day at a dose of about 20 mg to about 60 mg. In some embodiments, compound (2) is administered once a day at a dose of about 50 mg. And in other embodiments, compound (2) is administered once a day at a dose of about 60 mg.

[0155] In some embodiments, compound (1) or compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for less than two weeks. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for one day. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for two days. In some embodiments, compound (1) is administered at a dose of about 50 mg once a day for about 14 days. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for about 28 days. In some embodiments, compound (1) or compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for about 42 days. In some embodiments, Compound (1) or Compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for at least 6 months. In some embodiments, Compound (1) or Compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for at least 1 year. In some embodiments, Compound (1) or Compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for the rest of one's life.

[0156] In some embodiments, compound (1) is administered at a dose of about 50 mg or about 60 mg once a day for less than 2 weeks. In some embodiments, compound (1) is administered at a dose of about 50 mg or about 60 mg once a day for 1 day. In some embodiments, compound (1) is administered at a dose of about 50 mg or about 60 mg once a day for 2 days. In some embodiments, compound (1) is administered at a dose of about 50 mg once a day for about 14 days. In some embodiments, compound (1) is administered at a dose of about 50 mg or about 60 mg once a day for about 28 days. In some embodiments, compound (1) is administered at a dose of about 50 mg or about 60 mg once a day for about 42 days. In some embodiments, compound (1) is administered at a dose of about 50 mg or about 60 mg once a day for at least 6 months. In some embodiments, compound (1) is administered at a dose of about 50 mg or about 60 mg once a day for at least one year. In some embodiments, compound (1) is administered at a dose of about 50 mg or about 60 mg once a day for the rest of one's life.

[0157] In some embodiments, compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for less than 2 weeks. In some embodiments, compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for 1 day. In some embodiments, compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for 2 days. In some embodiments, compound (2) is administered at a dose of about 50 mg once a day for about 14 days. In some embodiments, compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for about 28 days. In some embodiments, compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for about 42 days. In some embodiments, compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for at least 6 months. In some embodiments, compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for at least one year. In some embodiments, compound (2) is administered at a dose of about 50 mg or about 60 mg once a day for the rest of one's life.

[0158] In some embodiments, the patient is administered Compound (1) or Compound (2) at night. In some embodiments, the patient is administered Compound (1) or Compound (2) within 1 hour before the patient goes to bed. In some embodiments, the patient is administered Compound (1) or Compound (2) within 15 minutes before the patient goes to bed. In some embodiments, Compound (1) or Compound (2) is administered chronically.

[0159] In some embodiments, the patient is administered Compound (1) at night. In some embodiments, the patient is administered Compound (1) within 1 hour before the patient goes to bed. In some embodiments, the patient is administered Compound (1) within 15 minutes before the patient goes to bed. In some embodiments, Compound (1) is administered chronically.

[0160] In some embodiments, the patient is administered Compound (2) at night. In some embodiments, the patient is administered Compound (2) within 1 hour before the patient goes to bed. In some embodiments, the patient is administered Compound (2) within 15 minutes before the patient goes to bed. In some embodiments, Compound (2) is administered chronically.

[0161] In other embodiments, the pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 15 mg to about 75 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 50 mg of the free base compound. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at a dose equivalent to about 60 mg of the free base compound.

[0162] In some embodiments, a pharma- ceutically acceptable salt of Compound (1) is administered at a dose equivalent to about 50 mg of the free base compound.

[0163] In some embodiments, a pharma- ceutically acceptable salt of compound (2) is administered at a dose equivalent to about 60 mg of the free base compound.

[0164] In some embodiments, the pharma- ceutically acceptable salt of compound (1) or compound (2) is administered once a day at an equivalent dose of about 10 mg to about 100 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) or compound (2) is administered once a day at an equivalent dose of about 20 mg to about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) or compound (2) is administered once a day at an equivalent dose of about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, or about 60 mg of the free base compound. In some embodiments, the pharma- ceutically acceptable salt of compound (1) or compound (2) is administered once a day at an equivalent dose of about 50 mg of the free base compound. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered once daily at the equivalent dose of about 60 mg of the free base compound.

[0165] In some embodiments, a pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 50 mg or about 60 mg of the free base compound once a day for less than two weeks. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 50 mg or about 60 mg of the free base compound once a day for one day. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 50 mg or about 60 mg of the free base compound once a day for two days. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 50 mg or about 60 mg of the free base compound once a day for about 14 days. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 50 mg or about 60 mg of the free base compound once a day for about 28 days. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 50 mg or about 60 mg of the free base compound once a day for about 42 days. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 50 mg or about 60 mg of the free base compound once a day for at least 6 months. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 50 mg or about 60 mg of the free base compound once a day for at least 1 year. In some embodiments, a pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at an equivalent dose of about 50 mg or about 60 mg of the free base compound once a day for the rest of one's life.

[0166] In some embodiments, the pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered at night. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered within 1 hour before the patient goes to bed. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered within 15 minutes before the patient goes to bed. In some embodiments, the pharma- ceutically acceptable salt of Compound (1) or Compound (2) is administered chronically.

[0167] III. Pharmaceutical Compositions

[0168] Another aspect of the disclosure provides a pharmaceutical composition comprising Compound (1) or Compound (2) (also referred to as "active ingredient(s)") and a pharma- ceutically acceptable excipient for use in treating sexual dysfunction and / or maintaining sexual function in a patient. In another aspect, the disclosure provides a pharmaceutical composition comprising a pharma- ceutically acceptable salt of the active ingredient and a pharma- ceutically acceptable excipient for use in treating sexual dysfunction and / or maintaining sexual function in a patient. In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient or a pharma- ceutically acceptable salt of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient or a pharma- ceutically acceptable salt of the active ingredient.

[0169] The pharmaceutical compositions provided herein may be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal. In some embodiments, the pharmaceutical composition is administered orally.

[0170] The pharmaceutical composition of the present invention can also be delivered using various dosing methods. For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, for the purpose of raising the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic level of the active ingredient desired throughout the body, for example, an intramuscular or subcutaneous bolus dose allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (for example, by IV infusion) allows for a faster delivery, which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by IV infusion, to provide the maintenance of a steady-state concentration of the active ingredient in the subject's body. Furthermore, in still other embodiments, the pharmaceutical composition can be administered as a bolus dose initially, followed by a continuous infusion.

[0171] Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect together with suitable pharmaceutical excipients. Typical unit dosage forms include premeasured, prefilled ampoules or syringes of liquid compositions, or pills, tablets, capsules, and the like in the case of solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that serve to form the desired dosage form.

[0172] The ingredients described above for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0173] The compositions of the invention can be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0174] Compound (1) or compound (2), or a pharmaceutically acceptable salt thereof, can be administered as a single active agent or can be administered in combination with other active agents. In one aspect, the present invention provides a combination of compound (1) or compound (2), or a pharmaceutically acceptable salt thereof, and another pharmacologically active agent. The administration of the combination can proceed by any technique that is apparent to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0175] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to any type of animal. Modifications of pharmaceutical compositions suitable for administration to humans to make such compositions suitable for administration to various animals are well understood, and veterinary pharmacologists of ordinary skill can design and / or implement such modifications using routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005. EXAMPLES

[0176] IV. Working Examples

[0177] In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate the crystalline solid forms provided herein and are not to be construed as limiting the scope of the invention in any way.

[0178] Example 1. Resolution of Treatment-Related Impairment in a Phase 3, Randomized, Double-Blind, Placebo-Controlled MOUNTAIN Study of Compound (1) in Patients with Major Depressive Disorder

[0179] Introduction

[0180] Sexual dysfunction is a common symptom of major depressive disorder (MDD), with symptoms typically emerging 1-3 weeks after treatment initiation. Estimated prevalence ranges from 4% to 73%, depending on the type of antidepressant administered (Jacobsen, et al. CNS Spectr. 2020;25(1):50-63; and Lorenz T, et al. Mayo Clin Proc. 2016;91(9):1280-1286). Dysregulation of gamma-aminobutyric acid (GABA) signaling may contribute to the development of depression by disrupting adaptive signaling in key neural networks, such as those controlling mood, stimulation, behavior, and cognition (Luscher B,et al.F1000Research.2019;8:751;Maguire J.Front Cell Neurosci.2019;13:83;Fogaca MV,et al.Front Cell Neurosci.2019;13:87;Fischer AS,et al.Biol Psychiatry Cogn Neurosci Neuroimaging.2016;1(3):262-270;and Brown RE,et al.Front Neurol.2015;6:135). Binding of neuroactive steroids to GABAA receptors enhances both synaptic and extrasynaptic GABAA receptor populations and increases surface expression of GABAA receptors. Extrasynaptic GABAA receptors containing delta subunits are insensitive to benzodiazepines (Althaus AL, et al. Neuropharmacology. 2020;181:108333; and Martinez Botella G, et al. J Med Chem. 2017;60(18):7810-7819).

[0181] Compound (1) is an investigational neuroactive steroid and GABA receptor positive allosteric modulator under evaluation for the treatment of MDD as an oral, once-daily, 2-week treatment (Althaus AL, et al. Neuropharmacology. 2020;181:108333; Martinez Botella G, et al. J Med Chem. 2017;60(18):7810-7819; Hoffmann E, et al. Clin Pharmacokinet. 2020;59(1):111-120; Sage Therapeutics, Inc. Data on file. MLIB-2982; and Clayton, AHP presented at SOBP 2020 Virtual Meeting).

[0182] Results from the multicenter, double-blind, randomized, placebo-controlled Phase 3 MOUNTAIN trial (NCT03672175), which evaluated the efficacy, safety, and tolerability of 14 days of treatment with 20 mg or 30 mg of compound (1) compared to placebo (PBO), have been previously presented (Clayton, AHP presented at SOBP 2020 Virtual Meeting).

[0183] This analysis evaluated the effect of treatment with 30 mg of Compound (1) compared to PBO on sexual function as measured by the Change in Sexual Function Questionnaire-14 (CSFQ-14) in the MOUNTAIN trial.

[0184] method

[0185] Adult outpatients (18-65 years; n=581) with MDD (HAMD-17 total score ≥22 and MADRS total score ≥32) were randomized 1:1:1 to receive Compound (1) 20 mg (data not shown), Compound (1) 30 mg, or PBO, once nightly for 2 weeks and followed through day 42 (see Figure 1 for study design). Standard of care antidepressants at the same dose for ≥60 days prior to study day 1 were allowed. Exclusion criteria included a current depressive episode, a suicide attempt secondary to treatment-resistant depression, and a history of bipolar disorder, schizophrenia, and / or schizoaffective disorder.

[0186] Exploratory post-hoc analyses included assessment of sexual function at baseline, days 15, 28, and 42 using the 14-item self-report CSFQ-14.

[0187] Sexual function in men and women was assessed as an exploratory endpoint using the validated 14-item patient self-report CSFQ-14 scores at baseline, days 15, 28, and 42. The CSFQ-14 has five subscales measuring pleasure, desire / frequency, desire / interest, stimulation / arousal, and orgasm / completion, which were also assessed. Sexual dysfunction was defined as a CSFQ-14 score of 41 or less for women and 47 or less for men. TS A mixed model of repeated measures and generalized estimating equations was used for analysis of patients with a baseline HAMD-17 total score of 24 or greater (n=323).

[0188] result

[0189] For example, 227 women and 96 men with a baseline HAMD-17 total score of 24 or greater were included in this analysis. At baseline, the mean baseline CSFQ-14 score for Compound (1) 30 mg and PBO for female patients was TSThe mean age-related mortality rates for women with puberty were 31.7 (n = 121) and 33.7 (n = 105), respectively, and for men they were 42.1 (n = 45) and 40.9 (n = 51). All groups met baseline evidence of sexual dysfunction.

[0190] No impairment in sexual function was observed during the study compared with placebo, and baseline CSFQ-14 scores at days 15 (+4.0 [0.83] and +2.7 [0.74]), 28 (+3.3 [0.80] and +3.1 [0.82]), and 42 (+3.6 [0.87] and +2.9 [0.88]) in women were significantly higher than those at day 15 (+4.0 [0.83] and +2.7 [0.74]), 28 (+3.3 [0.80] and +3.1 [0.82]), and 42 (+3.6 [0.87] and +2.9 [0.88]). TS Least squares means (standard error) of change from improvement were not significantly different between Compound (1) 30 mg and PBO-treated patients. In men, there were no statistically significant differences between treatment arms at Day 15 (+1.3 [1.28] and +1.7 [1.23]), Day 28 (+1.7 [1.31] and +2.0 [1.30]), and Day 42 (+2.2 [1.33] and +3.5 [1.54]), respectively (see Figure 2).

[0191] CSFQ-14 TS The percentage of all patients with sexual dysfunction as assessed by threshold decreased from 82.4% (266 / 323) at baseline to 66.5% (181 / 272) at day 42 for Compound (1) 30 mg-treated patients and PBO-treated patients, respectively, with no significant difference in odds ratios for sexual dysfunction between treatment arms (see FIG. 3).

[0192] As shown in Table 1 below, there was no significant difference in the odds ratios for sexual dysfunction (e.g., a CSFQ total score of 41 or less for women and 47 or less for men indicates sexual dysfunction) between patients treated with Compound (1) 30 mg and patients treated with PBO.

[0193] The model used was a generalized estimating equation (GEE) binary response model with components for treatment (Compound (1) 30 mg or placebo), baseline CSFQ-14 total score, baseline antidepressant use (yes or no), assessment time point, and the interaction of treatment time point with an exchangeable covariance structure.

[0194] The odds ratio is an estimate of the odds of a subject treated with Compound (1) having CSFQ sexual dysfunction compared to the odds of a subject treated with a placebo.

[0195] [Table 1]

[0196] Additionally, there were no significant differences between Compound (1) 30 mg and PBO in the percentage of patients with sexual dysfunction as assessed by individual CSFQ-14 subscales.

[0197] As shown in Figure 4, there were no significant differences between Compound (1) 30 mg and PBO in the percentage of female patients with sexual dysfunction across the individual CSFQ-14 subscales, with the exception of desire / frequency on day 15 and orgasm / completion on day 28.

[0198] As shown in FIG. 5, there were no significant differences between Compound (1) 30 mg and PBO in the percentage of male patients with sexual dysfunction across the individual CSFQ-14 subscales, with the exception of stimulation / arousal on Day 42.

[0199] conclusion

[0200] This CSFQ-14 TS A post-hoc analysis demonstrated that there were no differences in sexual function between female or male patients receiving Compound (1) 30 mg or PBO in the MOUNTAIN study, and analysis of individual CSFQ-14 subscale scores showed similar trends of no consistent differences between patients receiving Compound (1) 30 mg or PBO, regardless of gender.

[0201] These data suggest that treatment with 30 mg of compound (1) is not associated with treatment-emergent sexual dysfunction, a side effect associated with antidepressants. These findings support further development of compound (1) for use as an oral, once-daily, as-needed, two-week treatment of MDD. Equivalence and Scope

[0202] In the claims, articles (e.g., "a," "an," and "the") can mean one or more, unless indicated to the contrary or otherwise clear from the context. Unless indicated to the contrary or otherwise clear from the context, a claim or description including "or" between one or more members of a group is deemed to satisfy that one, more than one, or all group members are present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one or all group members are present in, used in, or otherwise relevant to a given product or process.

[0203] Moreover, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element may be removed from the group. In general, when the invention or an aspect of the invention is referred to as comprising certain elements and / or features, it should be understood that certain embodiments of the invention or an aspect of the invention consist of or consist essentially of such elements and / or features. For purposes of simplicity, those embodiments have not been expressly set forth herein in these exact words. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow for the inclusion of additional elements or steps. Where ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can assume any specific value or subrange within the range set forth in various embodiments of the invention to the tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0204] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any incorporated reference and this specification, this specification shall control. Furthermore, any particular embodiment of the present invention that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Since such embodiments are deemed known to those skilled in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art. Other embodiments

[0205] 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 embodiments described herein is not intended to be limited to the above description, but is as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description can be made without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. A composition for treating sexual dysfunction in a patient with postpartum depression or major depressive disorder, comprising: 【Chemistry 31】 A composition comprising a compound of a formula selected from the group consisting of:

2. A composition for treating sexual dysfunction in a patient with postpartum depression or major depressive disorder, comprising: 【Chemical 34】 A composition comprising a pharma- ceutically acceptable salt of a compound of a formula selected from the group consisting of:

3. A composition for maintaining sexual function in a patient with postpartum depression or major depressive disorder, comprising: 【Chemistry 43】 A composition comprising a compound of a formula selected from the group consisting of:

4. A composition for maintaining sexual function in a patient with postpartum depression or major depressive disorder, comprising: 【Chemistry 46】 A composition comprising a pharma- ceutically acceptable salt of a compound of a formula selected from the group consisting of:

5. 1. A composition for treating treatment-induced sexual dysfunction in a patient currently undergoing or having undergone a course of chemical psychotherapy, said composition comprising: 【Chemistry 49】 wherein said patient has postpartum depression or major depressive disorder.

6. 1. A composition for treating treatment-induced sexual dysfunction in a patient currently undergoing or having undergone a course of chemical psychotherapy, said composition comprising: 【Chemistry 52】 wherein said patient has postpartum depression or major depressive disorder.

7. The compound of claim 1, 【Chemistry 101】 6. The composition of claim 1, 3, or 5, wherein 8. The compound of claim 1, 【Chemistry 102】 6. The composition of claim 1, 3, or 5, wherein

9. The pharma- ceutically acceptable salt is 【Chemistry 53】 7. The composition of claim 2, 4, or 6, which is a pharma- ceutically acceptable salt of the compound of formula (I).

10. The pharma- ceutically acceptable salt is 【Chemical 54】 7. The composition of claim 2, 4, or 6, which is a pharma- ceutically acceptable salt of the compound of formula (I).

11. The composition of claim 5, wherein the chemical psychotherapy is an antidepressant.

12. 12. The composition of claim 11, wherein the antidepressant is selected from a selective serotonin reuptake inhibitor, a selective norepinephrine reuptake inhibitor, a tricyclic, a monoamine oxidase inhibitor, or an atypical antidepressant.

13. The composition of claim 6, wherein the chemical psychotherapy is an antidepressant.

14. The composition of claim 13, wherein the antidepressant is selected from a selective serotonin reuptake inhibitor, a selective norepinephrine reuptake inhibitor, a tricyclic, a monoamine oxidase inhibitor, or an atypical antidepressant.

15. 6. The composition of any one of claims 1, 3, or 5, wherein the compound is administered once daily at a dose of about 20 mg to about 60 mg.

16. 6. The composition of claim 1, 3, or 5, wherein the compound is administered at a dose of about 50 mg once a day for about 14 days.

17. 6. The composition of claim 1, 3, or 5, wherein the compound is administered at a dose of about 60 mg once a day for about 14 days.

18. 7. The composition of any one of claims 2, 4, or 6, wherein the pharma- ceutically acceptable salt of the compound is administered once daily in a dose equivalent to about 20 mg to about 60 mg of the free base compound.

19. 7. The composition of claim 2, 4, or 6, wherein the pharma- ceutically acceptable salt of the compound is administered once daily for about 14 days in a dose equivalent to about 50 mg of the free base compound.

20. 7. The composition of claim 2, 4, or 6, wherein the pharma- ceutically acceptable salt of the compound is administered once daily for about 14 days in a dose equivalent to about 60 mg of the free base compound.

21. 6. The composition of any one of claims 1, 3, or 5, wherein the sexual dysfunction comprises a decrease or loss of one or more of sexual pleasure, sexual desire, sexual frequency, sexual interest, sexual stimulation, sexual arousal, and orgasm.

22. The composition described in any one of claims 2, 4, or 6, wherein the sexual dysfunction includes a reduction or loss of one or more of sexual pleasure, sexual desire, sexual frequency, sexual interest, sexual stimulation, sexual arousal, and orgasm.

23. The composition described in any one of claims 1, 3, or 5, wherein the patient has postpartum depression.

24. The composition of any one of claims 1, 3, or 5, wherein the patient has major depressive disorder.

25. The composition described in any one of claims 2, 4, or 6, wherein the patient has postpartum depression.

26. The composition described in any one of claims 2, 4, or 6, wherein the patient has major depressive disorder.

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